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pmc-6005284-1

In July 2015, an 8-month-old female of Staffordshire Bull Terrier, housed in Milan province (northern Italy) and purchased from an Italian dog breeder, was taken to a veterinary clinic on account of her frequent and violent sneezing that lasts for two days. During anamnestic data collection, the owner reported that sneezing occurred after the dog had been taken for a walk in a rural area close to his house. At clinical examination the bitch also presented stertorous and reversal sneezing. Anamnesis, dog breed, and symptoms made clinicians suspect a nasal foreign body and/or a brachycephalic airway obstructive syndrome (BAOS). No antimicrobial or anti-inflammatory therapies were being administered to the dog. The bitch was then anesthetized for laryngoscopy, tracheoscopy, and anterior and posterior rhinoscopy. Laryngeal inspection revealed everted laryngeal saccules, whereas tracheoscopy did not show any remarkable alteration. Posterior rhinoscopy evidenced few small mucosal erosions (diameter < 2 mm) surrounded by mildly thickened and oedematous mucosae in the rhinopharynx; a small quantity of mucus-like material was also present. The anterior rhinoscopy highlighted two and three whitish fusiform organisms in the right and in the left nasal cavities, respectively; all the observed organisms appeared to be vital, presenting high mobility on the nasal mucosal surface. Attempts to catch them using endoscopic forceps failed and only after nasal lavage was one of them isolated and collected. Noticeably, following nasal lavage, the acute and violent sneezing improved considerably which might be due to removal of most of the observed organisms. The collected organism resembled a larva of Diptera and while waiting for further investigations after rhinoscopy the dog was also treated for three times every 7 days (days 0, 7, and 14) with subcutaneous administration of 300 μg/kg of ivermectin. After treatment, sneezing disappeared completely, and only moderate reversal sneezing, probably due to everted laryngeal saccules, remained present. The larva was sent to the Department of Veterinary Medicine of Milan for identification; it was studied under the light microscope and identified according to morphological keys [–]. The specimen was identified as a first instar larval stage (L1) of O. ovis L. (Diptera: Oestridae). The fusiform and dorsoventrally flattened L1, about 1.18 mm long and 0.44 mm wide, was divided into 11 segments (). On its surface, these segments presented trichoid cuticular sensilla (). Such structures are thermosensitive; they allow L1 to both locate and, in association with its quick mobility, rapidly reach the nasal cavities to find a suitable niche for its development. Ventral and lateral clusters of spines were also evident on the larva surface. They measured about 20 μm and 30 μm in length, respectively, and their distribution resembled the typical pattern described in Oestrus larvae. In subfamily Oestrinae, lateral and ventral spines can help a larva attach to and move on the host's mucosal surface without being expelled by its sneezing. The larva under investigation showed a distinctive cluster of spines on the terminal abdominal segment, though its bilobated shape was not perfectly preserved. Cranially, a pair of prominent, dark brown oral hooks, connected to the internal cephalopharyngeal skeleton, as well as defined antennal lobes, measuring about 18 × 22 μm could be noticed. Broad tracheal trunks, about 20 μm wide, ended between the tenth and eleventh body segments ().

pmc-6005285-1

An approximately 3-year-old, intact female, 260 g red corn snake (Pantherophis guttatus) was evaluated by the Zoological Medicine Service, University of Florida, for a midbody swelling and a three-week history of anorexia. The snake was purchased from a breeder 2.5 years priorly and did not have any previous health concerns. The reptile was kept in a tank with aspen bedding, in a room kept at 25°C throughout the year. During winter, supplemental heating was offered in one end of the tank using a heat lamp. Temperature and humidity in the enclosure were not monitored. The snake was fed a frozen-thawed adult mouse once weekly. During the feedings, the snake was transferred to a different container without any bedding, where it was left with the food item until consumed. The owner reported that the snake normally defecated regularly, but that for the past three to four weeks the stools had been dryer, smaller, and less frequent. The snake remained active at home and displayed a normal behaviour. The owner also had a wild caught, apparently healthy grey ratsnake (Pantherophis spiloides) kept in a separate tank. During physical examination, the red corn snake was quiet, alert, and responsive, and appeared in good body condition. A soft, ventral, intracoelomic swelling (6 × 4 cm) was palpable approximately at midbody and elicited discomfort to the patient when manipulated. Ultrasonography (Philips iU22 ultrasound machine, Philips Medical Systems, Bothell, WA 98021, USA), through multifrequency linear transducers, revealed a cylindrical structure lateral to the caudal liver, coursing caudally and medially to reside in proximity to the stomach. At this location, the segment thought to represent the stomach was markedly and focally fluid dilated. Caudally, from this region of dilation, an additional cylindrical segment surrounded those described previously, resulting in a concentric ring appearance (). The central component of the concentric ring demonstrated blood flow, using color Doppler. Based on these findings, a gastrointestinal intussusception was suspected and surgery was recommended. The snake was sedated with 0.1 mg/kg of body weight (BW) of hydromorphone (West-Ward, Eatontown, NJ 07724, USA) administered intramuscularly. Intubation with a 14 G catheter was possible following the sedation and the animal was maintained on 1-2% isoflurane (Piramal Healthcare Limited, Andhra Pradesh 502321, India) in a mixture of oxygen and nitrous oxide (1 L/min of each). The patient received positive intermittent manual ventilation at a rate of four breaths per minute. The patient was placed in left lateral recumbency, and the surgical site was prepped aseptically. A 10 cm incision was made two scale rows dorsal to the ventral scales. The incision followed along the edges of the scales, forming a scalloped pattern. The underlying muscle layers were incised at the end of the ribs. A Lonestar retractor (Jorgensen Labs Inc., Loveland, CO 80538, USA) was used to improve visualization of the coelomic cavity. After manipulation of the tissues, a gastrotomy was made laterally and spanned most of the length of the stomach and into the duodenum approximately 2 cm. The esophagus was observed to be intussuscepted into the stomach (), and then this combination was further invaginated into the duodenum () forming a second intussusception. A diagnosis of double compounded esophagogastric and gastroduodenal intussusception was made. The stomach was extracted from the duodenum and then the esophagus was extracted from the stomach. There were adhesions formed between the esophagus and stomach that were bluntly dissected in order to extract the esophagus from the stomach (). Grossly, the gastric longitudinal rugae appeared hypertrophied. Samples of gastric mucosa were placed into 10% buffered neutral formalin for histopathologic evaluation. The stomach was closed in two layers with 3-0 PDS (Ethicon LLC, Cincinnati, OH 45242, USA) with a Lembert pattern in the mucosa/submucosa layer, followed by a simple continuous pattern for the serosal muscularis layer. Due to the nature of the intussusception, the incision in the duodenum had a transverse as well as a longitudinal component. The transverse incision in the duodenum was closed with four simple interrupted sutures using 4-0 PDS (Ethicon LLC, Cincinnati, OH 45242, USA). The longitudinal component was closed with a simple continuous pattern using 4-0 PDS. A gastropexy via interrupted circumcostal sutures was performed with 3-0 PDS to prevent recurrence of the intussusceptions. The body wall was closed routinely. The muscle layer was closed with 3-0 PDS in a simple continuous manner. The integument was closed with nine horizontal mattress and one simple interrupted sutures to cause an eversion of the scales using 3-0 PDS. The patient was discharged the following day. Treatments included famotidine (Mylan Institutional LLC, Rockford, IL 661103, USA) at 0.026 mg/kg BW SC q48h, ceftazidime (Hospira Worldwide Inc., Lake Forest, IL 60045, USA) at 22 mg/kg BW SC q72h, and meloxicam (Putney Inc., Portland, ME 04101, USA) at 0.1 mg/kg BW SC q48h. The snake was not fed for two weeks before reexamination. The owner provided a supplemental heat lamp in the tank to have a warm basking spot and a cooler temperate area. All bedding was removed from the enclosure and only clean newspaper or paper towels were used as a substrate. In histologic sections of the stomach, epithelium on the gastric surface and in gastric glands was hyperplastic (). Dilation of the mucosal glands and fibrosis of the lamina propria were also evident. Myriad protozoa that were 2 μm in diameter, eosinophilic to basophilic, and periodic-acid-Schiff- (PAS-) positive and that had variably distinct 0.5–2 μm basophilic nuclei were closely associated with the apical epithelial surfaces as well as being free within the lumen (). Small numbers of heterophils, lymphocytes, and plasma cells were in the lamina propria. A diagnosis of chronic proliferative gastritis due to Cryptosporidium sp. was made based on these findings. Two weeks postoperatively, the snake was recovering well. The surgical site was clean, well apposed, and free of any discharge. The ventral surface associated with the incision was mildly distended and the scales appeared slightly dull. The owner had no concerns at that time, and the snake maintained BW. All medications were discontinued and the snake was tube-fed 2.5 mL of carnivore care (Oxbow Animal Health, Murdoch, NE 68407, USA) slurry to help encourage normal gastrointestinal movements and to administer a small first meal. The owner was allowed to start refeeding the snake smaller prey items such as pinkies every five days for 1 month, and then increasing to one hopper every 5 days for another month, followed by adult mice once weekly as the preoperative husbandry practices. At four weeks after surgery, the skin sutures were removed. A brief ultrasound exam was performed and did not show any obvious abnormalities around the stomach. The owner reported one abnormal bowel movement, described as diarrhea, that occurred four to five days after feeding the first pinkie mouse. The owner also reported that the snake had a normal shed two weeks priorly without any complications. The animal had lost 30 g (approximately 12% of BW) since initial presentation, but this was expected due to the current feeding schedule. A gastric wash was performed and submitted for polymerase chain reaction (PCR) to speciate the Cryptosporidium present in the stomach. However, there were no organisms in the sample, and the PCR came back negative. Unfortunately, at 15 months after surgery, the snake was found deceased in its enclosure. The owner reports that the snake would have intermittent episodes of regurgitation when it was fed adult mice but seemed to tolerate eating smaller food items without difficulties. The snake behaved normally, remained with a good appetite, and did not have other clinical signs until the day it was found dead. The cause of the regurgitations is unknown, but worsening of the chronic Cryptosporidium sp.-associated gastritis is suspected. The snake was not submitted for postmortem examination.

pmc-6005287-1

An eleven-year-old female spayed Labrador Retriever was presented for evaluation of multinodular subcutaneous masses in the dorsal cervical area (). Three nonadjuvant vaccinations, DA2PP-Lepto, Rabies, and Bordetella, had been injected into this same area during a wellness examination three weeks earlier. The dog's previous vaccination history included routine boosters at standard intervals administered at variable sites since puppyhood. Fine needle aspiration cytology of the masses revealed a mesenchymal spindle cell proliferation with a high level of atypia and minimal numbers of inflammatory cells. A wide surgical excision of the entire site with 3 cm margins was performed the following week. The excised tissue contained a regionally extensive, expansile, and infiltrative spindle cell neoplasm surrounded by a pseudocapsule and mild to moderate chronic inflammation with multifocal lymphonodular aggregates. The center of the neoplasm had undergone extensive necrosis, and the myxomatous matrix was admixed with grey-brown globular material. The neoplastic cells were fusiform to spindloid, formed interlacing bundles, and had moderate amounts of darkly eosinophilic cytoplasm. The nuclei were ovoid and had a stippled chromatin pattern with numerous, variably sized prominent nucleoli. There was marked anisokaryosis and anisocytosis. Binucleated and multinucleated cells as well as karyomegaly were multifocally observed. The mitotic count was 20 in 10 high powered fields (HPF, FN22), and there were occasional bizarre mitotic figures (). A grade 3 soft tissue sarcoma was diagnosed based on the degree of necrosis, cellular atypia, and the high mitotic count. The neoplasm had narrow but completely excised surgical margins. The surgical wound healed without any complications; however, multiple subcutaneous nodules were identified at the excision site ten weeks later. Repeat fine needle aspiration cytology confirmed a recurrence of the sarcoma. Hematology, serum biochemistry, and urinalysis were unremarkable, and three-view thoracic radiographs did not identify metastatic disease to the lungs. A second, broad excision of the injection site with 3 cm margins was performed. The neoplasm appeared histologically similar to the previously excised grade 3 soft tissue sarcoma with an increased mitotic count of 30/10 HPF. The sarcoma had focally infiltrated the skeletal muscle. Excision was reported to be complete with narrow margins. Neoplastic cells were immunohistochemically positive for Vascular Endothelial Growth Factor receptor (VEGFr) (), Platelet Derived Growth Factor receptor (PDGRr) (), Stem Cell Factor (SCF), and Epithelial Growth Factor Receptor (EGFR) and negative for VEGF, PDGR, KIT, and p-53. Based on the expression of VEGFr and PDGFr, a response to targeted tyrosine kinase inhibitor therapy with toceranib, a small molecule inhibitor of VEGFr2 and PDGFrβ, was hypothesized. Toceranib was initially administered orally at a dose of 2.1 mg/kg and then increased to 2.8 mg/kg on a Monday-Wednesday-Friday schedule. No adverse effects were noted at these doses and no hypertension or proteinuria was detected. Repeat CBC and serum biochemistry profiles were normal throughout the course of therapy and thoracic radiographs did not show any evidence of metastatic disease. A small cluster of subcutaneous nodules was identified at the excision site fifty weeks after the first surgery and a third complete excision with 3 cm margins was performed. Histology confirmed a recurrence of the grade 3 soft tissue sarcoma and the toceranib was continued. At the time of submission of this manuscript, the dog remains in remission ninety-three weeks after initial diagnosis.

pmc-6005288-1

An adult captive male bateleur eagle (Terathopius ecaudatus) estimated to be 32 years old and weighing 2.4 kg was presented for evaluation of left hindlimb lameness. The animal had been transferred from another institution 4 weeks prior to presentation with a history of osteoarthritis at the left intertarsal joint and an asymptomatic systolic heart murmur. Laxity and varus deviation of the distal left hindlimb at the intertarsal joint were first observed 2 years prior to presentation at the animal's previous institution. It had also been treated for several previous episodes of bilateral pododermatitis. Several days after transfer into a new enclosure, the animal began to exhibit intermittent non-weight-bearing left hindlimb lameness and was prescribed tramadol (5.5 mg/kg bodyweight (BW) orally twice daily) for pain management. The animal failed to sufficiently respond to this treatment over the course of 1 month and began spending increased time in a sternal position or on the ground of the enclosure. Under general anesthesia with isoflurane gas and oxygen, a physical examination with radiographs, complete blood count, and plasma biochemistry was performed to evaluate the lameness. Physical examination revealed firm periarticular enlargement, reduced range of motion, subluxation, and dynamic varus deviation at the left intertarsal joint (). No evidence of pododermatitis was observed at either foot. Orthogonal view radiographs of the pelvic limbs revealed muscle atrophy of the left hindlimb, moderate soft-tissue expansion around the left intertarsal joint with an uneven joint space that was widened at its lateral and narrowed at its medial aspects on the dorsoplantar radiographic view, and evidence of degenerative joint disease at this joint (). A complete blood count and plasma biochemistry were considered unremarkable when compared to species reference values []. The chronic degenerative joint disease and instability likely associated with previous joint ligament or tendon rupture was thought to be the underlying cause of the lameness. The animal was prescribed meloxicam (0.5 mg/kg BW orally once daily) and continued on tramadol. A visual evaluation performed 2 weeks later revealed continued intermittent lameness of the left hindlimb with reduced weight-bearing and frequent placement of the limb in an abnormal extended position. Gabapentin (3 mg/kg BW orally once daily) was prescribed for additional pain management; however, progressive lameness of the left hindlimb persisted despite these conservative management efforts. Reevaluation was performed 10 weeks later when the animal was observed to be non-weight-bearing on the left hindlimb after several traumatic collisions within its enclosure. The patient was anesthetized as previously described. Physical examination findings were consistent with the animal's exam performed 10 weeks earlier, although bruising was present at the left ventral pelvic region, likely due to the recent observed collisions. Stress radiographs of the distal limbs were performed, confirming subluxation at the left intertarsal joint (). Repeated complete blood count and plasma biochemistry revealed elevated creatine kinase (1175 U/L; Species 360 database reference values 133–795) consistent with muscle damage from soft-tissue trauma or capture and handling []. A support bandage was applied to the left intertarsal joint region, and the animal's prescriptions of tramadol, meloxicam, and gabapentin were continued. Based on physical examination findings, diagnostics, and the patient's failure to respond adequately to conservative management alone, surgical stabilization of the left intertarsal joint was scheduled for the following week. The animal was induced under general anesthesia as previously described, intubated, and maintained on isoflurane gas and oxygen throughout the surgical procedure. The left intertarsal joint was aseptically prepared, and sterile adhesive drape (Ioban™, 3M, St. Paul, USA) was applied to the limb. A 2 cm incision was made over the lateral aspect of the left intertarsal joint, and the soft-tissues were bluntly dissected from the distal tibiotarsus and proximal tarsometatarsus. A 30 ga. needle was placed into the intertarsal joint space to confirm its location, and a 2 mm drill bit was used to make an intraosseous tunnel through both cortices of the distal tibiotarsus extending proximomedially from the distolateral aspect of the metaphysis (). A second intraosseous tunnel was produced at the proximal tarsometatarsus extending distomedially from the lateral aspect of the bone. Incisions were made over the medial aspects of the tibiotarsus and tarsometatarsus at both exit points of the intraosseous tunnels, and soft-tissues were bluntly dissected away from the underlying bone to allow application of the stabilization implants. A flexible suture passer was used to shuttle a single strand of braided suture material (#2 Arthrex FiberWire®, Arthrex, Inc., Naples, USA) from the lateral entry points of both intraosseous tunnels to the medial exit points at both bones (). Each end of the suture material was threaded through both holes of a 2-hole titanium suture button (Arthrex, Inc., Naples, FL, USA) and back through its respective intraosseous tunnel to exit at the lateral aspect of the intertarsal joint. The buttons were positioned against the bones while the braided suture material was tied with the joint in a neutral position. Range of motion and varus/valgus stability of the intertarsal joint were assessed prior to tying of the suture to ensure appropriate joint stability and range of motion. Closure of the soft-tissues and skin was performed using 3-0 polydioxanone suture in a simple interrupted pattern. Postoperative radiographs revealed that the titanium button at the tarsometatarsus was positioned craniolaterally to what was considered ideal; however, the joint appeared stable during manipulation. The animal received perioperative butorphanol (2 mg/kg BW intramuscularly), meloxicam (0.5 mg/kg BW intramuscularly), clindamycin (20 mg/kg BW intravenously), enrofloxacin (15 mg/kg BW subcutaneously diluted 1 : 10 in lactated ringer's solution), and intraoperative lactated ringer's solution (10 ml/kg/hr BW intravenously). The patient continued tramadol, meloxicam, and gabapentin and was also prescribed prophylactic clindamycin (20 mg/kg BW orally once daily) and enrofloxacin (20 mg/kg BW orally once daily) for 7 days. Initial observations made during the first 3 weeks of postoperative recovery revealed gradual initial improvement in weight-bearing with significant persistent lameness. At 5 weeks after surgery, the animal was observed spending the majority of its time in sternal recumbency with reluctance to stand, and a reevaluation with the consulting veterinary surgical specialist was scheduled for the following week. The animal was induced, intubated, and maintained under general anesthesia as previously described. Radiographs confirmed suboptimal positioning of the previously placed joint stabilization implants, and persistent subluxation of the left intertarsal joint was demonstrated in stress radiographic views (). The previous surgical stabilization was considered unsuccessful, and a second joint stabilization surgery was elected. The patient was aseptically prepared, consistent with the initial surgical procedure. Incisions were made at the medial and lateral aspects of the left intertarsal joint, and evaluation of the previously placed stabilization implants revealed that the distal titanium suture button had become unsecured from the intraosseous tunnel at the medial tarsometatarsus, leading to surgical stabilization failure and subsequent postoperative laxity at the joint. The previously placed implants were removed, and the surgical stabilization procedure was repeated similarly to what was described for the first surgical procedure. The intraosseous tunnel at the distal tibiotarsus was re-used, and the intraosseous tunnel at the proximal tarsometatarsus was evaluated, was determined to have widened, and was revised. A 1.143 mm diameter K-wire was passed from proximolateral to distomedial across the proximal tarsometatarsus. Suture material (#5 Arthrex FiberWire, Arthrex, Inc., Naples, USA) was threaded through the intraosseous bone tunnels and titanium buttons as described for the first surgery. The suture was tightened with the aid of a suture tensioner (Arthrex, Inc., Naples, FL., USA) to 5 kg, and the joint was cycled to ensure stability and range of motion. The tensioner was then removed and the suture was tied. A two-layer closure of the soft-tissues and skin was performed using 4-0 poliglecaprone suture in cruciate and simple continuous patterns. Lidocaine (1 mg/kg BW) was administered as an incisional block, postoperatively. The animal received perioperative butorphanol (0.5 mg/kg BW intramuscularly), meloxicam (0.5 mg/kg BW intramuscularly), and enrofloxacin (10 mg/kg BW subcutaneously) administered in lactated ringer's solution (40 ml/kg BW subcutaneously). Postoperative examination revealed only mild medial subluxation of the left intertarsal joint during flexion that was comparable to that observed at the contralateral limb. No significant medial subluxation was elicited with the joint in extension. Postoperative radiographs indicated appropriate positioning of the stabilization implants (). Prophylactic enrofloxacin (15 mg/kg BW orally once daily) and clindamycin (20 mg/kg BW orally once daily) were prescribed for 28 days. Meloxicam, tramadol, and gabapentin were continued as previously prescribed, and activity restriction with lowered perches was implemented for 6 weeks. Postsurgical visual and physical evaluations were performed periodically over the next 6 months. At 3 weeks after the second surgery, the bird was noticed spending less time in sternal recumbency than following the initial surgery, although the animal continued to have noticeable lameness at the left hindlimb. A postsurgical reevaluation performed under general anesthesia at 7 weeks revealed improved medial-lateral stability at the left intertarsal joint, although the animal continued to exhibit lameness at the left hindlimb. At 14 weeks following the second surgery, the animal was observed perching normally with good weight-bearing on both hindlimbs. Only slight intermittent favouring of the left hindlimb was observed during ambulation. Due to clinical improvement, the animal was weaned from gabapentin at 20 weeks without any increase in lameness or time spent in sternal recumbency but was maintained on tramadol and meloxicam for management of chronic pain related to the animal's underlying degenerative joint disease. At 6 months following the second surgery, the animal was using the limb well during perching and ambulation with only mild occasional favouring of the limb observed. Periodic examinations, observations, and reports from animal caretakers indicated overall improvement in the animal's mobility and use of the limb for several years following the second surgical stabilization and ongoing treatment with pain medications. Only mild occasional lameness of the left hindlimb was observed during this time. Three years after the second surgical stabilization was performed, the animal developed a more pronounced lameness. Evaluation of the animal at this time revealed radiographic progression of degenerative joint disease at the left intertarsal joint, although no change in joint stability was noted. A complete blood count and plasma biochemistry were considered unremarkable when compared to species reference values []. The animal's medications were adjusted with meloxicam administered at 1 mg/kg BW orally twice daily and tramadol at 10 mg/kg BW orally twice daily. The animal responded positively to this change and was maintained on these medications to better manage the chronic pain associated with the condition.

pmc-6005289-1

An eight-year-old, female intact Golden Retriever, weighing 27 kg, was referred for investigation of urinary and faecal incontinence, which acutely appeared following two months of chronic vaginal discharge. The latter partially responded to antibiotic treatment. After neurological consultation, the animal was scheduled for magnetic resonance imaging (MRI) of the lumbar-sacral region under general anesthesia. On preanesthetic examination the dog appeared slightly nervous but in good physical condition (ASA II). The heart rate was 90 beats per minute (bpm), respiratory rate was 15 breaths per minute (brpm), pulse quality was good, mucous membranes were pink, and capillary refill time was less than 2 seconds. Thoracic and cardiac auscultation were unremarkable, as were the results of hematological and biochemical blood tests. After a mild sedation was achieved administering methadone intramuscularly (0.2 mg kg−1; Synastone, Auden Mckenzie Ltd., UK), anesthesia was induced intravenously 30 minutes later with fentanyl (3 μg kg−1; Sublimaze, Janssen-Cilag Ltd., UK) and propofol (2.5 mg kg−1; Rapinovet, Schering-plough Animal Health UK). The trachea was intubated with a cuffed tube; the cuff was inflated; intubation was unremarkable. Anesthesia was maintained with isoflurane (IsoFlo, Abbott Laboratoires, UK) in 100% oxygen, delivered through a circle system. Monitoring consisted of capnography, measurement of inspired and expired anesthetic gases and oxygen, measurement of noninvasive arterial blood pressure (Datex AS3, Helsinki, Finland), and esophageal stethoscope. Shortly after commencement of isoflurane administration, a gasping breathing pattern was noted, with a respiratory rate of 40–50 brpm and jerk movements of the mouth and all four limbs. Heart rate was 140 bpm. Inadequate depth of anesthesia was considered the cause of the observed movements; thus ventilation was assisted manually (15 brpm) and the vaporizer setting was increased from 2% to 3% (oxygen 3 L min−1) in order to deepen the anesthetic plane. Further, a bolus of fentanyl (1 μg kg−1) was administered intravenously. At that time, end-expiratory carbon dioxide tension (PE′CO2) was 22 mmHg. Because the respiratory pattern did not change during the following 10 minutes, and suspecting an underlying pulmonary disease, MRI was cancelled while thoracic radiographs and an arterial blood gases analysis were performed. Radiographs were unremarkable and alkalemia due to primary respiratory alkalosis was apparent in the arterial blood gases analysis results (). The dog was allowed to recover from general anesthesia. Once the vaporizer was turned off and the breathing system flushed with oxygen, the dog's breathing pattern improved and became normal. The recovery from general anesthesia was uneventful. MRI was rescheduled for the following day. On day 2, preanesthetic assessment was unremarkable and similar to that obtained the previous day. Dexmedetomidine (1.25 µg kg−1 Dexdomitor, Orion Pharma, Finland) and methadone (0.25 mg kg−1) were administered slowly intravenously. The resulting sedative effect was good with the animal relaxed in lateral recumbency. Anesthesia was induced with propofol (1.5 mg kg−1) and, after intubation of the trachea with a cuffed tube, maintained with isoflurane (vaporizer setting was 3%) in 100% oxygen at the flow of 3 L min−1, delivered through a circle system. Also in this occasion tracheal intubation was unremarkable. As on day 1, the animal started gasping and jerking continuously as soon it was connected to the breathing system. At that point, isoflurane was immediately turned off and the breathing system flushed with pure oxygen. Anesthesia was then maintained with a constant rate infusion (CRI) of propofol (0.3 mg kg−1 min−1), after slow administration of a loading dose (0.5 mg kg−1). As the animal's breathing pattern did not improve, atracurium (0.2 mg kg−1, Tracrium Injection, GlaxoSmithKline, UK) was administered intravenously and intermittent positive pressure ventilation (Penlon Nuffield 200 ventilator) was started to maintain eucapnia (PE′CO2 35–45 mmHg). Respiratory rate was set to 15 breathes per minute, tidal volume was 300 mL, and peak inspiratory pressure was 12 cmH2O. The rest of the anesthetic time was uneventful, but it was necessary to top up atracurium every 15–20 minutes, because hiccups restarted as soon as neuromuscular function started returning. An extensive invasive sacrococcygeal neoplasia was found on MRI. The owner decided to euthanize the dog but declined postmortem examination.

pmc-6005290-1

A 45-day-old male Saanen kid was presented to the Veterinary Teaching Hospital, College of Veterinary Medicine, Sudan University of Science and Technology, with a history of an increasing swelling over prescrotal region. On physical examination, the kid was found to be alert. The temperature, pulse, and respiratory rates were found within the normal range. A fluid-filled pocket (Figures and ) ventral to the penile urethra was seen and the urine was observed dripping from the prepuce and urethral process. Manual compression of the diverticulum showed subcutaneous urine leakage. Only a small amount of urine could be voided from the external urethral opening. Needle centesis of the pocket revealed a presence of a fluid which was confirmed as urine on physical and chemical examination. Ultrasonographic examination was done on the right flank of the kid to visualize the kidneys. A real-time ultrasound scanner (Pie Medical Esaote, Aquila, Netherlands) equipped with switchable frequency (3.5–5) MHz curvilinear probe was used. Both kidneys were normal. The urinary bladder was also assessed and it was full of urine. Blood sample was taken for a complete blood count which revealed normal values. Urinalysis was also done and it was within the reference range. No other congenital anomalies, such as cryptorchidism or hermaphrodism, were identified. The kid was referred to surgery. The animal was sedated using xylazine (Xylovet 20 mg/mL-Cp-Pharma) at a dose rate of 0.15 mg/kg. The site of operation was aseptically prepared with iodine (yamidine-povidone-iodine 10% USP). The site was locally infiltrated by lidocaine (Lignox 2%-Indoco) and finally draped for surgery. Urethral diverticulectomy was performed by elliptical skin incision around the dorsal border of the diverticulum after complete evacuation of urine using a 10 cc syringe. After incising the subcutaneous tissue, two hypospadiac urethral fistulae were identified. A small one () was found in the cranial part of the penis 1 cm ventrocaudal to the urethral process. The other large one () was found 5 cm caudal to the small one and cranial to the scrotum. Urethral catheterization was performed before closing the 1st urethral opening. The other opening could not be corrected due to catheterization failure. Incision on the urethral mucosa was extended through the opening and then sutured together to close the opening through simple interrupted sutures using polyglycolic acid, size 2/0; Huai'an Pingan Medical Instrument Co. Ltd., China. Subcutaneous tissues were sutured through simple continuous suture using absorbable surgical suture, Truglyde USP (size, 1, suture India PVT, Ltd). Finally, the skin was sutured by horizontal mattress using Ethilon polyamide, size 1, Ethicon Ltd. UK. After finishing operation, antibiotic injections were given to the animal (Penicillin-Penivet) for five days. The wound was dressed daily till the stitches were removed after 10 days. No mention was given to the large opening because of catheterization failure.

pmc-6005293-1

A 5-year-old female Cownose (Rhinoptera bonasus) was managed in Oceanarium, the large scale exhibition area of Aquaria in Kuala Lumpur (KLCC) with over 40 species of elasmobranchs and teleost fish. She is fed with marine chopped fish twice a day and Mazuri supplement (vitamins and minerals). Cownose's caretaker noticed her left eye ball is protruding out from the orbit. He suspected she had crushed into the artificial coral when the male rays chased her for mating, and the period correlates with the mating season. The case was presented to University Veterinary Hospital (UVH), Universiti Putra Malaysia, on the same day that he complained of the eye trauma during field visit to Aquaria KLCC. Physical examination was carried out. The Cownose was alert and responsive as she was actively swimming in the holding area. She was weighing 8 kg and had a Body Condition Score of 3 out of 5 and less than 5% dehydration. Temperature and pulse rate were not obtained, while the respiratory rate was 65 breaths per minutes. The left eye globe with hyphema was protruded from the orbital space and attached to the optic nerve (). The pupillary reflex could not be assessed due to hyphema. The left orbital space was exposed and periocular tissue tear was present around the left orbit (). Besides, multiple abrasions were observed at the cranial margin of the both pectoral fins, which was more severe on left fin. Immersion anaesthesia was opted. Seventeen ppm of isoeugenol (brand name: Aqui-s) was used as anaesthetic agent for both induction and maintenance of surgical plane. The anaesthetic bath was prepared by filling a tank with 475 L of artificial sea water from the holding area and added with 14.8 mL of Aqui-s. Ventilation rate was the only parameter that was used to monitor the anaesthesia depth of the Cownose. The normal ventilation rate was taken at rest before induction, which will be used as the baseline to monitor ventilation throughout the anaesthesia []. Ventilation rate of Cownose was taken by observing movement of spiracular flap and recorded every 5 minutes. The Cownose was left in the anaesthetic bath for 10 minutes until its ventilation rate ceased to 40 breaths per minute and dropped in pectoral fin stroke activity (). Later she was transferred by using canvas hammock to surgical tank with wet towel at the bottom and covered with another wet towel on her dorsum to maintain skin moisture [] (). The maintenance of surgical plane and establishment of rebreathing system was done by flushing water with anaesthetics agent through the gills via right spiracle (respiratory opening caudal to eye) with a 20 mL syringe. The Cownose was presented in ventral recumbency and assistants aided in restraining by gently exerting force at the dorsum as a part of tonic immobilization. Routine skin preparation around the left eye was done by using diluted chlorhexidine gluconate (dilution ratio 1 : 30) and diluted povidone iodine (dilution ratio 1 : 30) []. A ring block was done around the left eye by using 5 mL 20 mg/mL Lidocaine as local anaesthesia to reversibly desensitize the skin as well as analgesia (). Diluted gentamycin (5 mL, 100 mg/mL gentamycin + 5 mL sterile water) was prepared to flush the left orbital space and globe to minimize secondary infection since sterile surgical field is impossible to be established in the field setting (). The optic nerve was clamped by using 2 Rochester Pean forceps (). A surgeon knot was placed proximal to the first forceps with 2.0 PDS to ligate the blood vessel for haemostasis. Then the optic nerve was transected between the 2 forceps by using scalpel blade #20 (). The globe, the remaining conjunctivae fat, and extraocular muscle tissue were removed. The pedicle was checked for presence of bleeding before releasing it into the orbital space. The inner and outer muscular attachments were sutured with 2.0 PDS using interrupted suture pattern to close the orbital space (). Periorbital skin closure was done with 2.0 PDS in interrupted suture pattern (). The enucleation procedure took 15 minutes to be completed. Fresh sea water without an anaesthetic agent was used to flush through the spiracle to perfuse the gills and accelerate recovery from anaesthesia. The recovery from anaesthesia was indicated by increasing ventilation rate to preinduction rate, which was 66 bpm in Cownose and when she started struggling actively by flapping pectoral fins at 25th minutes. Postoperatively, 5 mg/kg enrofloxacin was administered intramuscularly at the dorsolateral musculature close to the spine and terramycin ointment (active component: oxytetracycline hydrochloride) was applied twice a day topically on the suture site to prevent secondary infection of the suture site, orbital space, and optic sulcus []. Besides, the caretaker was instructed to apply povidone iodine (brand name: Betadine) on the abrasions of the pectoral fins twice a day until wound healed to prevent the proliferation of Fusarium sp., an environment saprophytic fungi [–]. Client education consisted of isolating the Cownose from the school in holding area until surgical wound healed before releasing it to the large exhibition area, for ease of monitoring and for the prevention of possible infection at suture site as well as for administering daily treatment []. Besides, daily monitoring of suture site for break and possible signs of secondary infection such as discolouration of skin, fungal growth on the wound, inappetence, and loss of body condition is recommended by Mylniczenko and Penfold []. Next, putting of the mating pairs into separate tanks during mating season is necessary and a good practice. The mating process of rays is always aggressive as female rays always are being bitten and injured by the male rays, in which death can occur in severe case []. Others include reducing risk of crushing into decorations; isolation also reduces the stress of mating animals by avoiding being attacked by other fish during and after mating. At day 7 after operation, we had a revisit trip to Aquaria KLCC for the follow-up. She was responding well to the treatment with good appetite and no clinical abnormalities were observed, and suture materials were still intact (). The last follow-up was on day 24 after operation and was done by phone; Cownose was having good appetite and the scars were returning to normal skin colour.

pmc-6005294-1

A 9-year-old, 18.1 kg, spayed female, Blue Heeler-Cross dog was presented to the University of Wisconsin Veterinary Care (UWVC) for a draining cutaneous lesion on the right flank, intermittent fever, spinal pain, pelvic limb paresis, and muscle wasting, progressive over 12 months. A year prior to presentation the draining cutaneous tract was biopsied and cultured by the primary care veterinarian. Histopathology showed pyogranulomatous inflammation with severe vasculitis, and aerobic and anaerobic bacterial cultures were negative. Thoracic radiographs showed normal pulmonary parenchyma with no evidence of fungal granulomas. Urine was submitted for Blastomyces quantitative sandwich enzyme immunoassay (EIA; Miravista Diagnostics) and was negative. Pentoxifylline [22 mg/kg orally every 8 hr (Mylan Pharmaceuticals Inc., Morgantown, West Virginia, USA)] had been administered for 30 days to treat vasculitis, with minimal improvement in the draining tract. Anti-inflammatory prednisone [1 mg/kg orally every 24 hr (Roxane Laboratories Inc., Columbus, Ohio, USA)] resulted in substantial improvement in the fever and lesion drainage. As the prednisone dosage was tapered to 0.25 mg/kg orally every 48 hours, the fever returned and the draining tract worsened. Travel history included west Texas and northern California, but the dog had resided in Iowa and Wisconsin for the preceding four years. On physical examination at UWVC, the dog was quiet, alert, responsive, and hydrated, with pink mucous membrane, a normal capillary refill time, and normal heart and respiratory rates. The rectal temperature was elevated at 104.1°F. The dog was paraparetic and was in pain upon thoracolumbar spinal palpation. An alopecic lesion with thickened dermis and a draining tract producing serosanguinous and mucopurulent fluid was present in the right flank. A fluctuant subcutaneous mass was palpable between ribs 12 and 13 in the left hypaxial area. There was no evidence of retinal abnormalities, mucocutaneous lesions, or long bone pain, and the dog was neurologically appropriate. The remainder of the physical examination was within normal limits. Given the history and clinical presentation, a primary differential diagnosis for the thoracolumbar pain, fever, draining tract, and fluctuant subcutaneous mass was a migrating foreign body with possible secondary bacterial infection. Cytological examination of fluid from the left hypaxial fluctuant mass showed mixed inflammation, with nondegenerate neutrophils predominating and no microorganisms seen. An aerobic bacterial culture of fluid from the draining tract grew Staphylococcus pseudintermedius and Streptococcus dysgalactiae. A complete blood (cell) count (CBC) revealed mild normocytic normochromic anemia (hematocrit: 0.35 L/L; reference interval: 0.39 to 0.57 L/L), with a mild leukocytosis consisting of mature neutrophilia (neutrophils: 12.2 × 109/L, reference interval: 2.6 to 10.0 × 109/L). The serum biochemical panel was normal except for elevated globulins (49 g/L; reference interval: 22 to 35 g/L), consistent with an inflammatory response. A CT scan of the chest and abdomen was performed under general anesthesia and revealed pulmonary nodules with mildly enlarged sternal and cranial mediastinal lymph nodes. There was mild permeative to moth-eaten lysis of the cranioventral aspect of the vertebral body of T13, consistent with osteomyelitis. Multiple fluid pockets were present in the subcutaneous tissues, with the largest within the left hypaxial muscles at the level of T13 and in the subcutaneous tissues immediately lateral to the right pelvic inlet. The dog was treated with amoxicillin/clavulanic acid [25 mg/kg PO q8 hr (Augmentin; GlaxoSmithKline, Philadelphia, Pennsylvania, USA)] to treat a bacterial infection suspected to be secondary to a migrating cutaneous foreign body that could no longer be detected. The owners were instructed to treat the dog for a total of 2 months and to monitor lameness, body temperature, and draining tracts. The dog continued to have febrile episodes, trembling, and cutaneous drainage despite treatment with amoxicillin/clavulanic acid. The dog also developed right hind limb lameness and a new soft tissue swelling at the level of the right tarsus. The dog represented to UWVC for reevaluation 6 months after initial presentation. Physical exam findings were similar to initial presentation with the addition of a right tarsal swelling. A repeat CT scan of the chest and abdomen showed static pulmonary nodules and the development of pleural effusion. The vertebral bodies of T13 and L1 had progressive lysis consistent with progressive osteomyelitis. The previously noted fluid pocket within the left hypaxial muscle at the level of T13 had enlarged in size, but the caudal right fluid pockets had decreased in size. An undetected persistent foreign body was suspected, and the left caudal thorax and abdomen were explored surgically. An elliptical incision was made around the fluctuant subcutaneous swelling over the cranial left flank near the 13th rib, and the surrounding subcutaneous tissue was dissected to isolate the abnormal tissue, which was excised and submitted for histopathology. Below the swollen tissue, multiple draining tracts were identified and followed communication with the thoracic cavity was documented, but no foreign body could be identified. The peritoneum, abdominal musculature, and subcutaneous tissue were closed and a Jackson-Pratt drain was placed at in the cranial left flank. The skin was closed using staples. Histopathology of the abnormal tissue showed marked locally extensive pyogranulomatous and lymphoplasmacytic dermatitis and cellulitis with draining tracts and intralesional fungal conidia. The fungal conidia were round structures approximately 30–40 micrometers in diameter with 2 micrometers of thick pale basophilic cell walls and heterogeneous amorphous pale amphophilic central material, consistent with immature Coccidioides immitis spherules (). These findings were consistent with a diagnosis of disseminated coccidioidomycosis with cutaneous, vertebral, and pulmonary involvement. To enable future clinical monitoring, serum was submitted for detection of Coccidioides antibodies by agar gel immunodiffusion (IDEXX Laboratories), and the serum antibody titer was 1 : 32. Treatment with fluconazole (Harris, Fort Myers, Florida, USA), 7.7 mg/kg PO, and q12 h was started along with terbinafine (Camber, Piscataway, New Jersey, USA), 27 mg/kg, PO, and q24 h. Anecdotally, terbinafine has been proposed to have synergistic effects when added to fluconazole in the treatment of Coccidioides []. Over the next 4 weeks, the previous dosage of prednisone was tapered and discontinued. The patient's response to antifungal therapy was evaluated at the initiation of and throughout treatment using a modified Mycosis Study Group (MSG) score that is used in human patients (). The original MSG score takes into account clinical signs, radiographic imaging, and antibody titer and generates a composite score [–]. A modified MSG score that omits the radiographic component was used in this dog as has been described previously [, ], since the dog's lesions were best documented using a CT scan and repeated CT scans under anesthesia to monitor treatment response were not considered in the dog's best interest. Thoracic radiographs were considered to be an inaccurate substitution for a CT scan in this case, since the pulmonary nodules seen on CT were below the limit of detection on the baseline radiographs performed by the primary care veterinarian. During treatment with fluconazole and terbinafine, the dog developed inappetence, which resolved when terbinafine was discontinued after 4 weeks of treatment. After 3 months of fluconazole treatment, the dog's energy level had improved and the cutaneous lesion was no longer draining, although there was a fluctuant subcutaneous swelling at the site of the previous tract. The dog continued to have febrile episodes with trembling, but they were less frequent. The Coccidioides antibody test showed a rising titer (1 : 64) despite fluconazole treatment. Recheck chemistry panel was normal except for persistently elevated globulins (50 g/L; reference interval: 22 to 35 g/L) and mildly elevated serum alkaline phosphatase (270 U/L; reference interval: 20 to 157 U/L). As a result of the persistent fever, rising antibody titer, and a MSG score that was classified as unresponsive, rescue therapy with liposomal amphotericin B infusions and voriconazole was offered to the owner. The owner declined hospitalization for amphotericin B but elected to start voriconazole (Glenmark, Mahwah, New Jersey, USA), at 2.7 mg/kg, PO, q12 h, on an empty stomach. One week after starting voriconazole, a serum trough concentration was measured at 1.7 mcg/mL, which is within the therapeutic range targeted in humans with systemic mycoses (reference interval: 1.0–6.0 mcg/mL; the University of Wisconsin Health and Clinics Clinical Laboratories in Madison, Wisconsin) [, ]. After 3 months of voriconazole treatment, the dog was consistently afebrile with no draining tracts, resolved paraparesis, and a normal energy level and appetite. The remaining clinical signs were pain upon thoracolumbar spinal palpation and a fluctuant swelling on the right flank cranial to the location of the draining tract. Repeat Coccidioides antibody titer at 6 months after diagnosis and 3 months after starting voriconazole was at 1 : 32. Chest radiographs showed normal pulmonary parenchyma with no nodules and the absence of pleural effusion. Recheck voriconazole serum trough concentration was submitted to the Fungus Testing Laboratory at the University of Texas Health Science Center in San Antonio, Texas, and was considered therapeutic at 2.01 mcg/mL (reference interval: 1.0 to 6.0 mcg/mL). A serum biochemical panel showed new hypoalbuminemia (16 g/L; reference interval: 27 to 39 g/L) and continued but stable hyperglobulinemia (46 g/L; reference interval: 24 to 40 g/L). Alkaline phosphatase had improved (191 U/L; reference interval: 5 to 160 U/L) from the previous biochemical panel. Because of the severity of the hypoalbuminemia, additional testing was performed; serum bile acids were within normal limits, (1.6 μmol/L preprandial; reference interval: 0 to 6.9 μmol/L; 6.2 μmol/L postprandial; reference interval: 0 to 14.9 μmol/L), urine was negative for proteinuria, and a baseline cortisol was only modestly decreased at 38.6 nmol/L (reference interval: 55.1 to 165.54 nmol/L). An ACTH stimulation test was not performed because the negative predictive value for hypoadrenocorticism remains high at the cut-point of a baseline cortisol ≥40 nmol/L, [] and azoles are known to suppress endogenous cortisol concentrations []. The dog was not clinically treated for hypoalbuminemia and FAST scan of the thorax and abdomen was negative for free fluid. Overall, the patient's modified MSG score was improved based on the amelioration of clinical signs and decreased Coccidioides antibody titer. After 6 months of voriconazole treatment, the fluctuant right flank swelling was enlarged and was turgid upon palpation. The voriconazole serum concentration was below therapeutic range (0.60 mcg/mL; reference interval: 1.0 to 6.0 mcg/mL). The voriconazole dosage was increased from 2.7 mg/kg to 4.1 mg/kg twice daily. Recheck serum voriconazole concentrations after one week of this higher dose were within the therapeutic range (1.25 mcg/mL; reference interval: 1.0 to 6.0 mcg/mL). Repeat Coccidioides antibody titer was stable at 1 : 32. Serum biochemical panel showed static to mildly improved albumin (19 g/L; reference interval: 27 to 39 g/L) and stable hyperglobulinemia (46 g/L; reference interval: 24 to 40 g/L). The ALP was mildly increased to twice the upper limit of the normal range (336 U/L; reference interval: 5 to 160 U/L), which was suggestive of cholestasis secondary to azole therapy. The bilirubin and ALT remained within normal limits. The patient's modified MSG score after increasing the voriconazole dose was stable based on continued resolution of the fever, resolved skin drainage, improved muscle mass, and stable Coccidioides antibody titer. At the time of writing, 13 months after diagnosis of disseminated coccidioidomycosis and 7 months into voriconazole therapy, the dog continues to feel well and remains free of fever or draining tracts, with normal energy and pelvic limb strength, with the exception of residual thoracolumbar pain and subcutaneous swelling in the right flank.

pmc-6005304-1

A 12-year-old, 12 kg, spayed, female terrier mix was noted by her owner to have excess tearing and a collection of blood in her left eye. The primary care veterinarian diagnosed anterior uveitis and hyphema (OS). Serum chemistry revealed a mildly elevated AST of 73 (15-66) and CPK of 1267 (59-895). Complete Blood Count (CBC) revealed 6 nucleated RBCs/100 WBCs, and T4 was normal. Her primary care veterinarian attributed the hyphema to trauma and prescribed oral carprofen tablets (25 mg BID) and NeoPolyDex (neomycin, polymyxin B, and dexamethasone 0.1%) ophthalmic suspension (TID). After several weeks without improvement, the owner sought consultation with a veterinary ophthalmologist. Examination revealed continued anterior uveitis and development of iris bombe in OS, as well as early immature cataract in the right eye (OD). The OS showed a fixed pupil with absent light reflexes due to posterior synechiation. There was a normal palpebral reflex but absent menace response and very diminished, but present dazzle reflex. The present hyphema in OS prevented visualization of the posterior segment. The OD showed trace flare consistent with anterior uveitis. OD also showed normal pupillary light reflexes as well as normal palpebral reflex, menace response, and dazzle reflex. Tonometry revealed 14 mmHg in both eyes. The presence of bilateral uveitis was indicative of a systemic condition. Doppler oscillometry during the first visit revealed a systemic blood pressure of 85 mmHg which ruled out hypertensive retinopathy. An infectious disease panel was obtained and submitted. Dorzolamide 2% ophthalmic solution (OS TID) and atropine 1% ophthalmic ointment (OD for 3 days) were added to the treatment regimen. Follow-up evaluation showed the hyphema in OS to be resolved as was the uveitis in OD with the above treatment. In addition, the intraocular pressures were 9 mmHg OD and 15 mmHg OS. The left eye continued to show iris bombe; therefore, an ocular ultrasound was performed which revealed a retinal detachment and a preretinal hyperechogenicity suspected to be vitreous hemorrhage, but no evidence of an intraocular tumor. Infectious disease fungal serology was negative for histoplasma, blastomyces, aspergillus, cryptococcus, and coccidiomycosis. Urine blastomyces antigen was negative. Ehrlichia canis titer was negative; Rocky Mountain spotted fever titer was 1 : 64 (normal < 1 : 64) which was suspected to be secondary to prior exposure as opposed to active infection. Toxoplasmosis ELISA IgM titer was negative but IgG titer was 1 : 256. CBC and chemistries were normal at this time with normal AST and CPK and no nucleated red blood cells. Clindamycin (150 mg po BID; 25 mg/kg/day) was prescribed for 30 days on an empirical basis to treat presumptive toxoplasmosis. A decision was eventually made to enucleate the OS as the eye was no longer visual (previously only demonstrating light perception), and the intraocular pressure had increased to 36 mmHg. Uveitis in the OD also became progressively worse necessitating topical treatment with NeoPolyDex ophthalmic suspension (TID), several topical nonsteroidal anti-inflammatories (diclofenac 0.1% ophthalmic solution, then flurbiprofen 0.03% ophthalmic solution, both TID), and atropine 1.0% ophthalmic ointment once weekly. The OS was submitted for histopathologic evaluation and revealed the following findings: (1) mesenchymal malignant neoplasia suggestive of metastatic hemangiosarcoma, (2) severe hyphema and hemorrhage in the posterior chamber and vitreous, (3) iatrogenic lens capsule rupture, and (4) chronic glaucoma. The presence of atypical fusiform cells, carpeting the posterior aspect of the iris and ciliary body surface, dissecting the hemorrhage in the posterior chamber, and forming vascular channels, was deemed to be suggestive of metastatic hemangiosarcoma to the eye (). Pleomorphism was moderate with a few karyomegalic cells and mitotic figures. There was no significant inflammatory component that would be consistent with infectious uveitis. This diagnosis prompted a search for the primary neoplasm and further diagnostic work-up including thoracic radiographs and abdominal ultrasound. The ultrasound demonstrated an ill-defined, heterogeneous, partially cavitated mass measuring 3.4 cm in the spleen, distorting the normal contour. Thoracic radiographs were unremarkable. The patient underwent splenectomy and liver biopsy which showed a mass in the spleen measuring about 5 cm in diameter, still contained within the capsule. Intraoperative evaluation/inspection of the liver did not reveal gross abnormalities. There was no evidence of gross metastasis in the omentum or mesentery. The pathology report noted part of the splenic parenchyma to be effaced by a nonencapsulated, invasive, neoplastic growth with extensive tumoral necrosis and hemorrhage. The growth comprised erratic streams of neoplastic, endothelial-like, fusiform cells forming the linings of tortuous blood-filled channels and cavities supported by fibrous stroma (). There was mild anisocytosis, mild anisokaryosis, and a low mitotic count (1 mitotic figure per 10 consecutive high power fields, 400x). To further confirm the diagnosis of splenic hemangiosarcoma, immunohistochemical analysis using a monoclonal mouse anti-human CD 31 antibody (DakoCytomation, Denmark) was conducted on the splenic tumor tissue using an automated slide staining system (IntelliPATH, Biocare Medical, Pacheco, CA). Presence of CD 31 (platelet and endothelial cell adhesion molecule) staining confirmed the tumor to be of vascular origin. As can be seen in , the neoplastic cells were immunoreactive for CD31 antibody. The remaining splenic parenchyma was congested with extramedullary hematopoiesis. The liver biopsy showed hepatocellular hydropic degeneration. A decision was taken by the owner to use conventional adjuvant chemotherapy with doxorubicin monotherapy. Following the first cycle at a dose of 28 mg/m2, the dog experienced several episodes of vomiting. No further cycles of intravenous chemotherapy were administered. After consultation with several schools of veterinary medicine and a veterinary oncologist, the owner decided on a regimen of I'm-Yunity (polysaccharopeptide from the Coriolus versicolor mushroom, dose of 100 mg/kg/day po), metronomic chlorambucil 1.0 mg po QD (2.0 mg/m2), high doses (900 mg) po QD of omega-3 fatty acids, and Yunnan Baiyao 250 mg po BID for two weeks on, one week off. Initially, firocoxib 57 mg po QD was used in combination with chlorambucil but was discontinued after two weeks due to gastrointestinal toxicity. Over the next 24 months, the patient maintained a stable weight, demonstrating high energy level and excellent quality of life. There were no adverse effects of the treatment regimen and the patient was on this combination continuously for two years. Her vision continued to deteriorate in the right eye due to progressive cataract formation and continued uveitis despite the use of flurbiprofen, tacrolimus, and NeoPolyDex TID. Serial thoracic radiographs and abdominal ultrasound obtained every 3-4 months over 24 months showed no evidence of visible pulmonary, hepatic, or right atrial metastases. Over the two-year time frame, the patient developed polyuria and polydipsia, mild anemia of chronic disease (Hgb/Hct = 13/34 decreased from 16/50), progressive increase in alkaline phosphatase (from 221 to 727, normal range 20–150), and rising BUN/creatinine (from 20/0.8 to 47/1.5 mg/dl) (IRIS stage 2 renal disease). Otherwise, her laboratory parameters were normal. Several days after achieving 24-month survival, the patient developed new onset tonic seizures. Phenobarbital was started at a dose of 16 mg po BID, increasing to 32 mg po BID. However, seizure frequency continued to increase with one to two episodes daily over the course of the next 10 days. Therefore, a decision was made to euthanize the patient given that the most likely cause of the seizures was a brain tumor.

pmc-6005396-1

A 60-year-old man who presented with a recent history of impaired vision of right eye for about 3 months due to brain lesions. He was diagnosed with liver cancer and underwent surgery three months ago. The pathological result is hepatocellular carcinoma. His right eye showed impaired vision and the proton MRI revealed brain metastasis located in the right orbital part (Figure ). The patient was not suitable for the surgical excision due to his poor physical conditions after liver tumor resection. CyberKnife radiosurgery was delivered at a dose of 22.5 Gy in three fractions (Figure -). Both sodium and proton MRI (Siemens Magnetom 7T, Erlangen, Germany) were performed periodically at 7T by the time schedule of pre-treatment, 48 hours after SRS, with one week follow up and one month follow up. The scan parameters are listed in Table . The sodium signal in the tumor is obviously higher than the opposite normal brain tissue within one month after SRS (E-H). However, the T2 magnetic resonance imaging reveals no obvious changes (A-D) (Figure ). The quantified sodium signal intensity in MRI was shown in Table . The time course of sodium signal intensity in the tumor showed a dramatic increase in the treated brain tumor compared to the pretreatment and SRS within 48 hours. And the signal intensity decreased at one week after SRS compared to 48 hours after SRS. However, the increased signal intensity was observed at one month. The TSC ratio of tumor to cerebrospinal fluid (CSF) is much more intuitive (Figure ).

pmc-6005402-1

An 11-year-old boy reported to the department of oral and maxillofacial surgery, Bhimavaram, Andhra Pradesh, India, with a chief complaint of swelling over the left cheek since three months. The swelling was asymptomatic and gradually progressing. A detailed history from the attending parent revealed no significant medical history and no previous history of trauma in the concerned area. On an extraoral examination, there was a gross facial asymmetry on the left side of the face due to the presence of a swelling that extended superiorly from the infraorbital margin to the upper lip inferiorly, obliterating the nasolabial fold. No secondary changes were noticed over the skin. There was no sensory deficit in relation to the facial structures. On a thorough intraoral examination, dentition was mixed, with mild caries affecting the deciduous teeth, none involving the pulp, and revealed a bicortical swelling on the left side extending from the labial frenum medially till the distal aspect of the deciduous second molar, obliterating the labial and buccal vestibule (Figure ) An orthopantomogram (OPG) revealed a well-defined unilocular radiolucent lesion circumscribing the permanent teeth buds of the central, lateral incisor and canine in the second quadrant (Figure ). It measured around 3 cm in its greatest dimension. The paranasal sinus (PNS) view revealed radiolucency extending superiorly till the infraorbital margin with the canine involved (Figure ). The canine was in Nolla’s stage 7 and the central and lateral incisors were in stage 8. Aspiration of the cystic contents revealed a straw-colored fluid. Based on the clinical and radiographic findings, a provisional diagnosis of a dentigerous cyst was made (Figure ). A differential diagnosis of unicystic ameloblastoma and a cyst involving the maxillary antrum were considered. Based on the above diagnosis, the patient was planned for decompression of the lesion under general anesthesia. After obtaining a procedural and general anesthesia consent from the parents, a thorough pre-anesthetic evaluation was carried out and the obtained routine blood investigation parameters were within normal limits. Under general anesthesia, the extraction of the deciduous central, lateral incisors and canine was done and an opening was created in the anterior wall of the cyst through which part of the lining was removed and sent for histopathological examination. To maintain the patency of the opening, a marsupialization catheter device customized from the tip of a suction catheter (Figure ) was inserted through the opening and was secured to the margins using 3-0 silk sutures (Figure ). Parents were instructed to irrigate the cystic cavity using normal saline twice a day for a period of one month, through the opening. The histopathological report obtained confirmed the diagnosis of a dentigerous cyst. The patient was regularly recalled every week and was assessed for the maintenance of patency through the device. Radiographs were taken at regular intervals to aid in assessing the eruption of the impacted permanent teeth. Device removal was performed after three months (Figure ). After a period of three months, the radiographic examination revealed a gradual resolution of the radiolucency of the lesion and a spontaneous eruption of the central and lateral incisors, indicating osteogenesis (Figure ). So, during a subsequent visit, the patient was referred to the department of orthodontics for the assistive eruption of permanent teeth into the dental arch through traction. Initially, brackets were bonded on the central and lateral incisors and the canine and the flap was closed. Strap-up was done with 0.016 Niti wire. Later, leveling and alignment was done for about six months with 0.0018 Niti 17x25 Niti, 19x25 Niti, 19x25 SS (Figure and Figure ). After reaching 21x25 SS, wire traction was applied using ligature wire. After the eruption of the central and lateral incisors, an open coil spring was placed for the alignment of the canine after gaining space (Figure ). The canine was brought into occlusion and finishing and detailing were done. The entire treatment spanned five years for all the three impacted teeth to get aligned in the dental arch (Figure and Figure ).

pmc-6005769-1

A 63-year-old man with a deep vein thrombosis diagnosed 5 days prior, presented with fever, tachycardia, and nausea/vomiting. The patient had a past medical history of cerebrovascular accident 9 years prior with residual left-sided weakness, epilepsy, hypertension, and hyperlipidemia. The patient denied smoking, alcohol, or drug use. The patient was transferred from an acute rehab center where a left lower extremity deep vein thrombosis had been found on ultrasound 5 days prior, and anticoagulation started. He was bridged from enoxaparin to oral warfarin. Initial laboratories were as follows: white blood cell count 12,600/mL 3 , hemoglobin 14.0 g/dL, platelet 302,000/mL 3 , total bilirubin 2.1 mg/dL, aspartate aminotransferase 68 IU/L, alanine aminotransferase 56 IU/L, prothrombin time 20.3 seconds, international normalized ratio (INR) 1.95, albumin 3.1, fibrin degradation products > 10 and < 40, blood urea nitrogen 14, and serum creatinine 0.83. Initial physical exam showed left lower lobe decreased breath sounds, and an unremarkable abdominal exam. At that time, the patient denied any pain, current nausea/vomiting, shortness of breath, constipation, or diarrhea. Chest X-ray suggested consolidation in the left lower lobe. The decision was made to admit the patient as he met the criteria for systemic inflammatory response syndrome, possibly due to a left lower lobe pneumonia versus pulmonary embolism. For further evaluation, a chest computed tomography (CT) scan was ordered. While the CT scan showed no evidence of pulmonary embolism or pneumonia, it did incidentally reveal a distended appearance to the gallbladder ( ). Ultrasound showed distended gallbladder with a heterogeneous mixture of intermediate and low echogenic material with no evidence of stones, which was concerning for possible pus or hemorrhage. Liver was of normal size and echogenicity. Patient was started on ceftazidime, clindamycin, and vancomycin empirically for systemic inflammatory response syndrome/sepsis. The patient was initially ruled out as a surgical candidate due to his elevated INR, and given his extensive deep vein thrombosis, it was felt that the risk of stopping anticoagulation outweighed the benefits and he was recommended for interventional radiology (IR)-guided cholecystostomy. Repeat physical exam on hospital day #2 revealed a firm, tender right upper quadrant of the abdomen, with all other quadrants being soft and nontender. The patient's INR spiked to 6.28 on hospital day #2 and his hemoglobin dropped to 9.8 g/dL. This elevation of his INR was attributed to his continued anticoagulation, which was subsequently discontinued. INR on hospital day #3 was 4.53, and 4.94 on hospital day #4, at which point vitamin K and fresh frozen plasma were administered. INR improved to 1.69 on hospital day #5. IR-guided cholecystostomy was attempted on hospital day #4. The decision to proceed with an IR-guided approach had been made earlier as it was felt he was at high risk for surgery and septic. However, there was an organized clot with no drainable material and subsequently no drain left in place. An inferior vena cava filter was placed on hospital day #8. The family and patient had also up to this point refused surgery due to his history of stroke, do not resuscitate/do not intubate status, and their perceived risk of surgery. However, they eventually agreed to have surgery. On hospital day #11, laparoscopic cholecystectomy was performed, and revealed dense adhesions surrounding the gallbladder including the omentum and bowel. These adhesions were taken down to reveal a very large distended gallbladder with areas of necrosis and perforation. The contents of the gallbladder contained approximately 1,000 cubic centimeters of old clot which had perforated near the infundibulum with clot extending out into Morison's pouch and the right upper quadrant causing dense adhesions to the liver. The gallbladder was freed from these adhesions and the clot was removed. The gallbladder was dissected and freed from surrounding adhesions. The cystic duct was secured with a “PDS Endoloop” made by Ethicon. During the course of the operation, patient experienced significant bleeding and required four units of packed red blood cells. The operation was converted to an open cholecystectomy to obtain hemostasis, and a Jackson-Pratt drain was left in place. Pathology of the gallbladder specimen showed extensive hemorrhage, acute inflammation, and necrosis. Pathology of a liver specimen showed moderate fibrosis, which was suggestive of cirrhosis. However, hepatitis serology was all negative, and ultrasound of the liver showed a liver of normal size and echogenicity. No other investigation showed signs of chronic liver disease. Patient had one episode of bleeding from his drain which required transfusion, but the remainder of his hospital course was otherwise uneventful. The patient was considered too high risk for further anticoagulation and was discharged with an inferior vena cava filter in place.

pmc-6005892-1

A 38-year-old man with schizophrenia presented after his second suicide attempt through an overdose with 48 tablets of burotizolam, 42 tablets of haloxazolam and 14 tablets of levomepromazine. The patient's childhood and adolescent development was normal. He was a good student and an active soccer player in high school. His social skills were standard, and he had no family history of mental illness. When he was 23 years old and a fourth year university student, he became convinced that he was being observed and he withdrew from social activities. His parents brought him to a psychiatric hospital, and he was diagnosed with schizophrenia according to DSM-IV-TR (). The prescribed medication worked well and he was able to graduate from university at 27 years old. After graduating, he worked part time in a convenience store or at a nursery for several years. He then started to work at a distribution business under a handicapped employment program. His father committed suicide 3 years before he first presented at our hospital and a friend also died from a sickness. Because his auditory hallucinations repeatedly told him that he was responsible for their deaths, he could not stop blaming himself for their passing, in spite of his mother and brother telling him that he was not responsible. He was pessimistic about his future partly because he was able to earn only a meager income. In order to increase his income, he started a second part-time job at a supermarket in addition to his distribution job. He slept less and felt the accumulation of fatigue. He started to stockpile sleeping medications and he eventually took 76 tablets of brotizolam and 30 tablets of eszopiclone. The next morning his mother found him unconscious and called an ambulance. His mother brought his empty medicine containers to the hospital. At his first presentation, his physical examinations and vital signs were normal. He appeared to be very sleepy, but he managed to speak. The emergency department doctor ordered a blood test, a chest x-ray, an electrocardiogram test, a urine toxicology test, and a computed tomography brain scan. All results were within normal range, except a positive result for benzodiazepine in his urine and a slightly elevated white blood cell count (10.92 × 103/μL). The emergency doctor enlisted a psychiatric doctor to evaluate his mental state. The patient claimed that his auditory hallucinations sounded like someone was booing in addition to radio sounds from a distance. He also claimed he was being tracked by the police. He admitted suicidal ideation and reported that he was sad because he could not die. Because his depressive symptoms occurred 4 weeks prior to his first admission, the authors carefully excluded the possibility of schizoaffective disorder and depressive disorders or bipolar disorder. However, the patient did not show manic symptom or markedly diminished interest, and his depressive thoughts seemed to ease shortly after his admission. Obviously, his mood episodes have been present for a minority of the total duration of the active and residual phases of illness; however, his memory changing delusion and auditory hallucination remains continuously. Furthermore, he showed negative symptom that he had withdrew from social activity except working. The authors diagnosed schizophrenia according to DSM 5 (). His decreased ability to discriminate between his thought and true memories as mentioned previously suggests the presence of disturbance of the self which also supports this diagnosis (). The authors prescribed risperidone 6 mg, brotizolam 0.25 mg, and eszopiclone 2 mg. Soon after the treatment started, he became calm and claimed his suicidal ideation disappeared. However, during the patient's second hospitalization, 6 months later, he admitted that he had lied. He wanted to go home quickly so he pretended to be healthy. He subsequently obtained a distribution job contract for the coming season by himself and he was supposed to be followed by a nearby clinic as a condition of his hospital discharge. He started his distribution job but he could not work regularly. Again, he wanted to earn more money so he started attending lectures to get a healthcare worker license. Consequently, his sleep time was reduced and he started to feel life was troublesome once again. He subsequently overdosed as mentioned previously. The next morning, his mother brought him to the emergency department again. She had no idea when he attempted to commit suicide but she last saw him the previous night at 10 p.m. His mother brought his empty medicine containers. His vital signs were normal, and he managed to speak. The emergency doctor conducted a blood test, a chest x-ray and a computed tomography brain scan. All the results were normal, except an elevated white blood cell count (12.16 × 103/μL), creatine kinase (429 U/L), and chloride (109 mmol/L). His mother brought with her more than 100 risperidone tablets. It became obvious that he had not taken his pills regularly. The authors thought his adherence worsened during his psychotic period and started a long acting injectable antipsychotic (LAI). Because the patient worked regularly, the authors choose an injection given once in a 4-week period. Furthermore, because several studies showed it made significant improvements in the quality of life (), the authors chose aripiprazole LAI at 400 mg. The authors also prescribed 20 mg of suvorexant per day and gradually discontinued brotizolam 0.25 mg and flunitrazepam 2 mg because the authors were concerned about a possible third suicide attempt while using benzodiazepine. Because both of the patient's admissions were associated with poor sleep, the authors examined the patient by polysomnography (PSG) and a multiple sleep latency test (MSLT) to exclude comorbid diseases such as sleep apnea syndrome or restless legs syndrome. As shown in Figure , he woke frequently during his sleep (25.6 times per hour on average as shown in Figure ) and he lived with excessive daytime sleepiness (he fell asleep within 2 min; on four out of five trials during the MSLT, as shown in Figure ). His Apnea-Hypopnea Index (AHI) was slightly elevated (5.1 times/hour), and respiratory events were not associated with significant desaturations (the minimum SpO2 was 95%). His BMI was 19.8. Malocclusion or tonsil swelling was not observed. Figure shows the patient's sleep log. The patient did not show sleep phase advance or delay. The patient's Pittsburgh Sleep Quality Index (PSQI) score was 13, while over 5 points on the PSQI represents insomnia (). Two months after his second admission, he was discharged while being prescribed suvorexant 20 mg, and chlorpromazine 25 mg per day in addition to aripiprazole LAI 400 mg per month. His Brief Psychiatric Rating Scale (BPRS) () dropped form 48 at admission to 42 at discharge. Six months after his second admission, the authors and the patient started CBT-i according to the CBT-i therapeutic manual (). The authors also referred to the four causes cited by Chiu et al. (): (a) beliefs that sleep problems cannot be changed; (b) trauma and adversity; (c) lifestyle choices and lack of motivation; (d) medication side effects and the 12 problems cited by Waite et al. (): (a) Poor sleep environment; (b) Lack of daytime activity; (c) Lack of evening activity; (d) Disrupted circadian rhythm; (e) Sleep as an escape from distressing experiences; (f) Fear of bed; (g) Nightmares; (h) Night-time awakenings; (i) Sleep disrupted by voices/paranoia; (j) Worry; (k) Neuroleptic medication side effects; and (l) Reducing hypnotics. Our CBT-i consisted of eight sessions with each session ranging from 30 to 45 min. The first two sessions were educational sessions that attempted to find disturbances such as a misunderstanding of sleep hygiene or an inadequate sleep environment. In the other six sessions the authors and the patient tried to find other targets to tackle. For instance, the patient tried eating a carbohydrate (banana) before sleep, stopped checking his watch, warmed his body before going to bed, turned off small lights in his room, changed his routine of taking a bath before eating dinner to prevent him from taking a nap after dinner, bought a blackout curtain and an air conditioner. He also tried to wake up early in order to exercise in the morning instead of doing in the middle of the night because he believed he can fall asleep soon after the exercise. The whole course of sleep and psychological tendencies are shown in Figure . The patient's BPRS dropped to 24 and his PSQI dropped to 8. His sleep time increased steadily however, at his sixth session, he claimed that he could not sleep at night and he felt a strong sense of sleepiness during the day. His mental health care team consisted of two physician groups; with one group treating his psychiatric symptoms and the other group (the authors) treating his sleep abnormality. The first physician group increased the patient's chlorpromazine from 25 to 37.5 mg. The authors, as the second physician group treating the patient's sleep abnormality, discussed reducing the patient's chlorpromazine with the first physician group because the authors believed that his sleep troubles were not caused by a difficulty in falling asleep but by the dosage of chlorpromazine being too high for the patient's current ability to fall asleep which was gradually being strengthened by CBT-i. At the seventh session, the authors encountered another misunderstanding of the patient in which the authors believed the patient's headaches were being caused by a lack of sleep, while the patient used chlorpromazine as a painkiller. The authors prescribed acetaminophen 400 mg as a painkiller, and stopped the administration of chlorpromazine. At the eighth session, the patient claimed that he had almost no trouble sleeping except when he forgets to take suvorexant.

pmc-6005974-1

In 2016, a 25-yr-old woman complained of fever and abdominal pain. She was living in a small village in Mianeh, East Azerbaijan Province, Iran (). The latitude for Mianeh is: 37.426434 and the longitude is 47.724111. The patient declared a regular picking and eating local watercress in the rural area. She was admitted to a local hospital and was treated symptomatically. Despite treatment, fever, jaundice, right upper quadrant abdominal pain and loss of appetite continued for 6 months. Informed consent was taken from the patient. Initial laboratory findings were as follows: white blood cells 4.3×103 μL, platelets 245 ×103 μL, hemoglobin 12.3 g/dL, hematocrit 37.9%. Peripheral blood smear revealed eosinophilia as high as 36% of the white blood cells. Stool examination was negative for ova/cysts. Liver function tests showed elevated liver enzymes (aspartate transaminase 37 [normal < 31] U/L, alanine transaminase 63 [normal < 32] U/L, alkaline phosphatase 458 [normal 98–279] U/L and a normal total bilirubin. Abdominal ultrasonography showed splenomegaly (140 mm). A magnetic resonance cholangiopancreatography (MRCP) revealed an ill-defined lesion of 96×53 mm at 4th and 8th segments of liver with dilation of intrahepatic bile ducts inside the lesion and splenomegaly was seen. The initial pre-treatment CT imaging revealed a hepatosplenomegaly with regional lymphadenopathy and several subcapsular lesions in both liver lobes. In the search for a potential malignancy, liver biopsy was performed. Section from liver tissue showed focal lobular necrosis with peripheral palisading spindle-shape epithelioid cells; surrounded by moderate inflammatory cells mainly eosinophils and plasma cells beside a few lymphocytes. Other parts of liver tissue showed mild infiltration of a few eosinophils, lymphocytes and few plasma cells without piecemeal necrosis or bile duct damage, which led to the suspicion of a parasitic infection (toxocariasis, capillariasis or strongyloidiasis). On May 24, 2016, the patient was referred to the Department of Medical Parasitology and Mycology of Tehran University of Medical Sciences, Tehran, Iran. After reviewing the clinical / para-clinical findings and interviewing, fascioliasis was suspected. ELISA test was performed as previously described (). Antibodies specific to Fasciola ES antigens were detected in the serum sample. Furthermore, the formalin ether concentration technique showed the presence of F. gigantica eggs (135 μm-80 μm) in feces (). Egaten treatment was started at the dose of 10 mg/kg. The drug was given as a single oral dose. Three months after treatment, the patient was examined again, fecal examination was negative for F. gigantica eggs, and IgG titers decreased but remained positive during 9 subsequent months. Blood examinations revealed an improvement in the liver function tests with a decrease in blood eosinophil counts (5%) In order to provide genetic diagnosis, the stool sample was washed twice with phosphate buffered saline (PBS) to remove the ethanol. The egg walls were mechanically disrupted using glass beads (0.45–0.52 mm diameter) and by freezing and heating (−70 °C for 5 min and 90 °C for 5 min). Total genomic DNA was extracted, using a commercial kit (QIAamp DNA Stool Mini Kit; Qiagen GmbH, Hilden, Germany) according to the manufacturer’s instructions. ITS-1 fragment (about 700 bp) was amplified by PCR using a set of 5’- ACCGGTGCTGAGAAGACG -3’ and 5’- CGACGTACGTGCAGTCCA -3’ as forward and reverse primers, respectively, following the protocol previously described (). The negative control was a reaction mixture of distilled, without the DNA template. . The PCR products were separated in 1.5% agarose gel using Simply Safe (Eurx, Cat. No. E4600-01). A phylogenetic tree was constructed, based on the ITS-1 gene sequences to show the relationships between the available sequences of F. hepatica, F. gigantica in the GenBank, and sequence of our sample (700 bp), using the MEGA 6 software () ().

pmc-6005995-1

A 61-year-old man underwent resection of a part of his tongue due to tongue cancer and was admitted to our hospital for hepatocellular carcinoma with about 5 cm diameter of tumor at the liver segment IV. Computed tomography (CT) showed that the tumor was enhanced during the arterial phase and washed out during the portal phase, and the tumor pressed the right anterior branch to the main branch of Glisson and the middle hepatic vein; hence, the diagnosis of hepatocellular carcinoma was made (Fig. ). The indocyanine green retention rate at 15 min was 21.8%. Child-Pugh score was A. The patient tested negative for hepatitis B surface antigen and hepatitis C virus antibody. He had a history of excessive consumption of alcohol, and alcoholic liver damage was considered as a possibility. Partial hepatectomy with segments IV + V and cholecystectomy with cystic duct-tube drainage were performed. Intraoperative findings indicated that the anterior branch of bile duct was exposed at the resected area, and some small bile ducts were ligated. On POD 1 following hepatectomy, bile leakage developed from the drain placed in the foramen of Winslow. CT showed fluid collection in the cavity between the liver and fistula to drain. Cholangiography via the endoscopic bile duct enhancement showed no communication between the common bile duct and abdominal cavity. Drip infusion cholangiography (DIC)-CT revealed the bile duct of the peripheral side. We maintained simple drainage to reduce the cavity. On POD 19, this patient had fever and CT revealed that the fluid collection has increased (Fig. ). Percutaneous drainage to the cavity near the liver cut surface was performed. Cholangiography via the c-tube did not show the anterior branch of the bile duct. Fistulogram from the drainage tube at the abdominal cavity showed the bile duct at segments V and VIII (Fig. ). We diagnosed the bile leakage from the isolated bile duct of segments V and VIII. Further management was needed to control the persistent biliary leak of 200–250 mL/day. Liver function was evaluated again. The indocyanine green retention rate at 15 min was 27.7%. LHL15 was 0.575. Liver volume of segments V and VIII was 260 mL, and remnant liver volume was 1272 mL, which were calculated using the 3D image analysis system (SYNAPSE VINCENT; Fuji Photo Film Co., Ltd.). Functional remnant liver volume (FRLV) was calculated based on the liver volume using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced MRI for 20 min []. FRLV after liver resection of segments V and VIII was 2176 mL. Even if the function becomes extinct by PTPE to segment V and VIII, remnant liver volume was sufficient. We considered that bile leakage could not be cured with either PTPE or bile duct ablation alone, because of the large volume of bile leakage more than 200 mL per day. The therapeutic strategy involved combination therapy of PTPE and bile duct ablation. First, percutaneous transhepatic cholangiography drainage (PTCD) tube was inserted to the bile duct of segment V. PTPE with coil embolization was performed to the part of the portal vein of segments V and VIII by puncturing the part of the portal vein of segment V. The liver volume of segments V and VIII was decreased from 260 to 123 mL after PTPE. After the PTPE, bile leakage decreased to about 50 mL/day. We confirmed that cholangiography via the PTCD tube showed the bile duct at segments V and VIII. For bile duct ablation, 1.2 mL pure ethanol was injected from the PTCD tube. Over 1.2 mL of ethanol leaked into the abdominal cavity. After ethanol injection, the PTCD tubes were clamped for 5 min. Then, another bile duct ablation with 2.0 mL of pure ethanol was performed 1 week after of the first procedure. After bile duct ablation, bile leakage has decreased from 50 to 10 mL/day gradually. The patient left the hospital, and he was rehospitalized and reinjected with 2.0 mL of pure ethanol for three times. The drainage tube and bile duct tube were removed on POD 139 (Fig. ). The clinical course is summarized in figure. Complications with combination treatment of PTPE and bile duct ablation were not noted.

pmc-6006004-1

A previously healthy 48-year-old male was found to have multiple hepatic tumors and a giant tumor (67 × 53 mm) superior to the inferior vena cave by abdominal ultrasonography during a routine medical examination. He consulted a general physician for further evaluations and had been referred to us because plain CT confirmed multiple tumors, including a giant tumor, in the liver. A laboratory workup on admission showed that total bilirubin (0.6 mg/dL) and albumin (4.2 g/dL) concentrations were within their normal ranges, whereas aspartate aminotransferase (37 IU/L), alanine aminotransferase (70 IU/L), alkaline phosphatase (176 U/L), and gamma-glutamyl transpeptidase (170 IU/L) concentrations were mildly increased. Tumor markers, including alpha-fetoprotein (2.9 ng/ml), protein induced by vitamin K absence or antagonist-II (11 mAU/ml), and carcinoembryonic antigens 19-9 (4.0 IU/L), were within normal limits. Abdominal ultrasonography (US) revealed well-defined, hypo echoic masses in segment 1 (S1) (67 × 53 mm in diameter), S6 (13 mm), and S2 (9 mm) in the liver (Fig. –). Abdominal dynamic CT revealed a low-density 65-mm diameter mass with an irregular margin in plain, peripheral early ring enhancement in the arterial phase, and internal heterogeneous enhancement in the delayed phase (Fig. –). Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic response imaging (EOB-MRI) demonstrated a low-signal intensity mass on T1-weighted images. This mass contained several high-signal intensity areas on T2-weighted images. EOB-MRI also revealed a hypointense mass in the hepatobiliary phase (Fig. –). Furthermore, it showed higher intensity compared with the normal liver parenchyma on DWI with a high b value of 1000 (Fig. ). Its ADC value was 2.11 × 10−3 mm2/s (peripheral area) and 2.45 × 10−3 mm2/s (central area), and the ADC mean was 2.33 × 10−3 mm2/s. It was described as a high-intensity mass on the ADC map (Fig. ). There was no accumulation of [18F]-FDG on FDG-PET (Fig. ). Hepatic arteriography revealed hypervascular masses in S1 (65 mm in diameter), S6 (16 mm), and S2 (9 mm) of the liver, with no pooling (Fig. , ). In addition, gastroscopy and colonoscopy showed normal findings. On the basis of these imaging findings, a preoperative diagnosis of multiple scirrhous hepatocellular carcinomas characterized by abundant fibrous stroma was made, and caudate lobectomy of the liver and partial hepatectomy of S2 and S6 were performed. The resected specimen contained a 55 × 56 mm yellowish white solid mass. The cut surfaces of the tumor were elastic and soft with smooth margins (Fig. ). Histopathological examination showed that the tumors were composed of various sized irregularly dilated vessels with some blood thrombi, inflammatory cell infiltration, fibrous and hyalinized sclerotic or myxomatous stroma (Fig. , ). On immunohistochemistry staining, these vascular endothelial cells were positive for CD34, suggesting sclerosing hemangioma (Fig. ). The patient tolerated the procedure well and was discharged on postoperative day14. The patient gave consent for publication of details of his case. Hemangiomas are the commonest benign hepatic tumors, being found in up to 7% of autopsies in one series []. Hemangiomas have a predilection for women in a ratio of 5:1. They are characteristically discovered incidentally during abdominal imaging in individuals aged 40 to 50 years []. Hepatic sclerosing hemangioma, first reported by Shepherd et al. in 1983 [], is a rare type of hepatic hemangioma composed of abundant acellular hyalinized tissue in which small vessels are occasionally seen. Another study reported finding them in only two of 1000 autopsies []. Hepatic sclerosing hemangiomas are caused by degenerative changes such as thrombus formation, necrosis, and scar formation in hepatic cavernous hemangiomas; however, the mechanism(s) for these degenerative changes has not yet been determined []. Makhlouf and Ishak compared the findings in sclerosed hemangioma and sclerosing hemangioma []. They asserted that recent hemorrhages and hemosiderin deposits rich in mast cells are present in sclerosing hemangiomas, whereas fibrosis, increased elastic fibers, and dystrophic or psammomatous calcifications with decreased numbers of mast cells are characteristic of sclerosed hemangiomas []. These pathological changes can result in the radiological features on CT and MRI being atypical of hemangioma; thus, these lesions can be diagnosed as malignant tumors such as intrahepatic cholangiocarcinoma, metastatic liver cancer, and hepatocellular carcinoma. We searched for “hepatic sclerosing hemangioma” in PubMed and ICHUSHI, a bibliographic database established in 1903 and being updated by the Japan Medical Abstracts Society, and identified 41 patients, including our patient, the characteristics of which we here summarize. Concerning imaging studies, Miyamoto et al. [] summarized the imaging findings in 41 hepatic sclerosing hemangiomas. Their average diameter was 41.8 mm, ranging from 10 to 145 mm. Abdominal US showed hyperechoic masses in 10 patients and hypoechoic masses in 14. Plain CT generally showed a low-density mass, whereas dynamic CT showed ring enhancement, resembling metastatic liver cancer or intrahepatic cholangiocarcinoma, in 31 of 40 (78%) reported cases. MRI showed low-intensity signals in 28 of 30 (93%) reported cases on T1-weighted images and high-intensity signals in 25 of 30 (83%) reported cases on T2-weighted images. FDG-PET showed no accumulation of [18F]-FDG in six patients who underwent this procedure []. The radiological features revealed by dynamic CT and MRI resembled those of hepatic malignancies. Thus, there were indeterminate imaging features, some imaging findings pointing to intrahepatic cholangiocarcinoma, metastatic liver cancer, or scirrhous hepatocellular carcinoma (ring enhancement, hyperintensity on T2 with hypointensity on T1 imaging). Generally, imaging findings of ring enhancement on dynamic CT is less typical of classical hepatocellular carcinoma than of metastatic liver cancer or intrahepatic cholangiocarcinoma. In recent years, there have been a small number of reports in which DWI and DWI-based ADC were successfully used to differentiate sclerosing hemangioma from liver malignancies. The ADC values for hepatic hemangiomas are reported to be higher than those of malignant liver tumors due to restricted water diffusion from high cellular density [, ]. In our case, the ADC mean was 2.33 × 10−3 mm2/s, and the mass showed higher than the normal liver parenchyma with a high b value of 1000 on DWI. It was described as a high intensity mass on an ADC map, indicating that possibility of the sclerosing hemangioma, used as a diagnostic aid to detect. FDG-PET showed no accumulation of [18F]-FDG, it suggested the possible benign character of this sclerosing hemangioma. However, it should be noticed that negative predictive value of FDG-PET for primary hepatocellular carcinoma is less than 50% with sensitivity over 80% []. Therefore, we selected hepatic resection as a first-line strategy for the management of tumors with unknown potential. Histopathologically, the cut surfaces of our patient’s resected tumors corresponded with cross-sectional CT images; the dynamic enhancement pattern is related to the vascular spaces component and the central areas of low density on the arterial and delayed phase to the sclerotic component, which on examination were yellowish-white with many hyalinized areas with poor vessels and fibrous changes [, ]. Additionally, our patient’s serum tumor markers, including AFP and PIVKA-2, were within normal limits. If these multiple tumors had been hepatocellular carcinomas, concentrations of these markers may have been high. Thus, it also suggests that the multiple tumors were not hepatocellular carcinomas. Confirmation of our provisional diagnosis would have required obtaining a liver biopsy. Although a fine needle biopsy can differentiate a sclerosing hemangioma from hepatocellular carcinoma, this procedure can potentially lead to rupture or seeding of hepatocellular carcinoma. Fine needle biopsies should only be performed to confirm inoperable hepatocellular carcinoma because seeding of tumor in the needle tract has been reported in 1–3% of cases []. We suspected that our patient’s lesions were scirrhous hepatocellular carcinomas because of the imaging features. In addition, it was considered that the lesion protruding into the intraperitoneal cavity rupture was at risk of rupture. The likelihood of malignancy and risk of rupture resulted in our decision to perform hepatic resection on our patient.

pmc-6006242-1

A 52 year-old Chinese man presented with gross hematuria and had a left nephrectomy done in January 2014. Pathology revealed clear cell RCC of Furhman 2 grading, with invasion of the renal vein and peri-renal fat. There were synchronous solitary right lung and right hilar lymph node metastases. Having declined high-dose interleukin-2, he was started on pazopanib in March 2014, achieving partial response. In January 2015, pazopanib was stopped and surgery was attempted for the oligometastatic disease, but the right hilar node was found to be stuck down intra-operatively. External beam radiotherapy was administered post-operatively in February 2015 to the hilar node (55 Gy in 20 fractions). In May 2015, after 4 months off anti-angiogenic therapy, there was global progression of disease with the right hilar node enlarging and new metastases appearing in multiple sites (lungs, muscle, bones). Sunitinib was started (May to September 2015), and the patient went on to receive further lines of drug treatment with everolimus (October 2015 to February 2016) and axitinib (March to October 2016). He also had palliative surgery to the right radius (curettage and fixation in October 2015) and right proximal femur (curettage and bipolar hemiarthroplasty in November 2015). In November 2015, radiotherapy was also given to the right radius and femur post-operatively, to an enlarging and symptomatic scalp metastasis at the vertex, and to 4 brain metastases by gamma knife technique. Further courses of radiotherapy were given to a large lytic sacral metastasis (February to March 2016), several skin and subcutaneous tumors (May to June 2016), and the left knee (July to August 2016). In addition, subcutaneous denosumab was given as adjunctive treatment for bone metastases from October 2015 to September 2016. In October 2016, computed tomography (CT) scan showed widespread metastases with interval progression in the skeletal muscles, liver, spleen, right kidney, right adrenal, pancreas, peritoneum, lungs and right hilar nodal mass. Apart from 3 new small cutaneous metastases, the patient did not have symptoms related to any specific organ site. He required the use of a walking aid after his previous hip surgery. Performance status was 2 by Eastern Cooperative Oncology Group score (ECOG). There were multiple enlarging metastases within the single right kidney, but renal function was appropriate for a post-nephrectomy setting. For example, an upper pole lesion now measured 6.5 × 4.3 cm compared to 2.5 × 2.4 cm in the scan 5 months prior. In view of the florid radiologic progression and previous multiple lines of anti-angiogenic treatment, he was offered immunotherapy. Axitinib was stopped and a single dose of nivolumab at 100 mg was given within the same day. The patient developed acute renal failure 2 weeks later with oliguria, rising creatinine and hyperkalemia. Serum creatinine rose progressively from a pre-nivolumab level of 117 μmol/L to a high of 247 μmol/L in the following 5 weeks (Fig. ). Urine sediment was not active (1 white cell and 1 red cell per high power field each, and no casts). Serum phosphate and serum creatine kinase were normal. Other blood indices showed anemia, mild hypercalcemia (2.81 mmol/L), raised alkaline phosphatase (ALP) and lactate dehydrogenase (LDH). Ultrasound (US) of the remaining kidney showed infiltrative renal tumors. There was no hydronephrosis and renal perfusion was good. Except for renal parenchymal tumor infiltration and inflammatory edema, no other plausible causes of acute renal failure were identified. Renal biopsy was not performed as this was a single kidney. There was clinical deterioration with development of dyspnea, back pain, edema and drop in performance status to ECOG 3. At 4 weeks from nivolumab, the subject of hemodialysis was broached but the patient declined. He also expressed his preference not to have aggressive resuscitation or intensive care unit management, and was referred to the home hospice service. Although the recent 3 new skin metastases had resolved, a non-contrasted CT at 5 weeks post-nivolumab documented worsening tumor in multiple sites: skeletal muscles, liver, spleen, pancreas, peritoneal nodules, lungs, right hilar nodal mass and other soft tissue areas. The right kidney was larger, consistent with increasing intrarenal tumor or inflammation. He was at home on expectant management for the next 4 weeks. Several visits were made by the home hospice team. Palliative medications included oral tramadol and gabapentin, and he was prepared for death. At week 10, the patient unexpectedly walked into the clinic, having felt better a week prior. There was clinical improvement in his general condition and he reported an increase in urine output. Serum creatinine had improved to 131 μmol/L (Fig. ), ALP was normal, and serum calcium had normalized without any anti-resorptive agent. There was severe anemia (hemoglobin 4.4 g/dL) and the LDH was raised at 1019 units/L (range 250–580). Chest radiography showed improvement in the right hilar and lung shadows. Red cell transfusion was administered. At week 11, non-contrasted CT scan showed improvement in tumor status in most of the involved sites including a decreased size of the right kidney. Blood and bone marrow investigations for the anemia were consistent with immune-mediated hemolysis and oral prednisolone was started at week 13. The patient continued to improve and a contrast CT at week 20 showed dramatic improvement in tumor status. In some sites, including the kidney, essentially complete remission was seen. Serum creatinine returned close to baseline (Fig. ). Prednisolone was tapered off to complete a 3 month course with hemoglobin stabilizing at 11.3 g/dL. At 6 months post-nivolumab, the patient was doing well without further immunotherapy. Serial CT and US images of the right kidney were analyzed (Fig. ). CT imaging showed marginal increase in kidney size from baseline to the 5 week post-nivolumab scan, and subsequent decrease at the 11 week scan when the renal function had recovered. There was no pre-nivolumab US scan, but the US scans done at 2 and 5 weeks post-nivolumab showed worsening of the renal tumor load (Fig. ). Onset of diffuse renal cortical swelling was also noted in the US at 5 weeks post-nivolumab, as demonstrated by the progressive compression and obscuration of renal medulla and sinus fat. The US changes are commensurate with the progressive worsening of renal function at these time points. A lower pole metastasis shown in the US at 2 weeks post-nivolumab was significantly larger than the corresponding lesion on the baseline contrast CT, despite the differences in imaging modality. A contrast CT at 4 months as well as an US at 6 months post-nivolumab showed decreased renal size and near complete resolution of the renal metastases.

pmc-6006564-1

A 30-year old woman presented with two weeks of left lower quadrant discomfort during her second month of pregnancy. Ultrasound revealed a mixed cystic and solid left adnexal mass measuring 8.6 × 6.7 × 8.3 cm. Left salpingo-oophorectomy was performed early in the second trimester. Grossly, the left ovary demonstrated an intact 7.5 cm complex cystic-solid mass, with nearly half involved by a friable, tan-yellow tumor with papillary excrescences, some of which were freely floating within the cyst cavity. Histologic sections demonstrated a struma ovarii with over 50% characterized by the classic features of a well-differentiated papillary thyroid carcinoma (Fig. ). The periphery of the tumor impinged on the ovarian capsule and vascular structures; however, no definitive evidence of invasion was seen on the histologic sections reviewed (Fig. -). Typical histology for an ovarian mature cystic teratoma (such as areas of squamous differentiation) were present in other areas of the tumor (Fig. ). The tumor expressed positive immunohistochemical staining for thyroglobulin (Tg) and thyroid transcription factor 1 (TTF1, Fig. ), but was negative for BRAF V600E. Serum Tg was 83.5 ng/mL (reference range for euthyroid status in nonpregnant adults 0–35 ng/mL) seven days after surgical resection of the ovarian mass. The elevated Tg level is reasonably expected given the proximity to surgery and Tg half-life of 65 h [] and the known increase in Tg levels during pregnancy [, ]. Thyroid function tests (TSH 1.66 mU/L) and thyroid ultrasound were normal. Levothyroxine (L-T4) was started to suppress thyroid stimulating hormone (TSH) to 0.1–0.5 mU/L although TSH ranged 0.86–1.41 mU/L during pregnancy. After delivery, Tg was 2.9 ng/mL (TSH 0.57 mU/L). With thyroglobulin levels in a reasonable range as above, the risk of additional studies during pregnancy in terms of radiation or hypothyroid exposure, unknown risk of metastatic disease, and unknown incremental benefit of intervention during pregnancy, the decision was made to delay further testing and therapy until after delivery. Two months after delivery, the patient underwent total thyroidectomy to permit evaluation for metastatic disease and monitoring for recurrence by Tg levels. The thyroid pathology was benign. Several months after delivery and cessation of lactation, the patient underwent L-T4 withdrawal and her Tg unexpectedly rose from 0.8 ng/mL (TSH 5.8 mU/L) to 113.7 ng/mL (TSH 46 mU/L). A concurrent diagnostic I-131 scan (1 mCi) with planar and SPECT/CT imaging revealed focal central neck activity consistent with thyroid remnant and the presence of iodine-avid skeletal metastatic disease involving the left ninth rib, bilateral proximal femurs, and sacrum (Fig. -). Following 320 mCi I-131 therapy based on blood dosimetry calculations, post-therapy scan revealed the additional finding of miliary pulmonary metastases (Fig. ). Due to high-quality SPECT/CT images, separate dedicated CT and bone scan were not necessary. She was subsequently treated with TSH suppression resulting in an undetectable Tg < 0.1 ng/mL (TSH 0.02 mU/L). In order to assess the interval response to I-131 treatment, follow-up evaluation after L-T4 withdrawal protocol was obtained nine months later, demonstrating a stimulated Tg of 0.2 ng/mL (TSH 36.4 mU/L) and negative diagnostic I-131 scan without focal abnormal radioiodine uptake in the neck or skeleton. As she was planning for a second pregnancy and her pulmonary disease was not visible on the prior diagnostic I-131 scan but became apparent only on the post-therapy scan, a 100 mCi I-131 therapeutic challenge was performed to eliminate any microscopic residual disease and more accurately ascertain the treatment response. The post-therapy I-131 scan demonstrated complete resolution of pulmonary metastatic disease; however, faint residual foci of activity were demonstrated in the left ninth rib, sacrum, and left proximal femur, consistent with a partial therapeutic response in the skeleton (Fig. ). Eight months later, Tg was < 0.1 ng/mL (TSH 0.02 mU/L). The patient continues to do well, being conservatively managed with active clinical and biochemical monitoring during L-T4 suppression therapy.

pmc-6006666-1

A 79-year-old woman was referred for evaluation of abnormal murmur. She presented with a 3-months history of worsening shortness of breath and orthopnea. Physical examination revealed a soft continuous murmur at the left upper chest with basal crackles in both lungs. Chest radiography showed mild cardiomegaly with mild pulmonary congestion. The ECG showed regular sinus rhythm without evidence of ischemia or prior myocardial infarction. Transthoracic echocardiography demonstrated a mildly dilated LV with markedly dilated left atrium. The LV ejection fraction was 60% with no wall motion abnormality. There was an unusual, tubular-like structure inside the interventricular septum with a turbulent, predominantly diastolic flow on color Doppler (Fig. , arrows; Additional file ). Transesophageal echocardiography revealed a markedly dilated RCA arising from the right aortic sinus (Fig. , arrow; Additional file ), while the origin of the left coronary artery (LCA) could not be demonstrated. There was a tortuous, abnormal vessel located adjacent to the main pulmonary artery (MPA) emptying into the posteromedial aspect of the MPA. There was an accelerated, continuous flow across the stenotic ostium (asterisk, Fig. , Additional file ). Moreover, there was severe MR from a restricted posterior leaflet of the mitral valve (MV) associated with ventricular remodeling in combination with mitral annular dilatation (Fig. , Additional file ). Coronary angiography with a single RCA injection revealed a markedly dilated RCA (Fig. ) providing multiple intercoronary collaterals of various sizes communicating with the left coronary system (Fig. ). The LCA later opacified the MPA through a stenotic ostium (Fig. , asterisk; Additional file ), establishing the diagnostic hallmark of ALCAPA syndrome. The calculated ratio of pulmonary-systemic blood flow was 1.4, confirming a significant left-to-right shunt. Coronary computed tomography angiography clearly identified the ALCAPA with a retropulmonary ostium (Fig. and , asterisks). Volume-rendered image depicted the course of the anomalous coronary arteries and its inter-coronary collateral pathways along the epicardial surface and where the LCA connected to the MPA (Fig. and , open arrow; Additional file ). Stress cardiovascular magnetic resonance perfusion imaging demonstrated no myocardial ischemia, suggesting adequate collateral circulation to the LV.

pmc-6006706-1

Herein, we describe the case of a 73 year-old man in good health, who developed widely disseminated sebaceous carcinoma including metastases to brain, visceral organs, lymph nodes, and bone. He initially presented in late October 2016 for removal of a rapidly growing nodule in the anterior abdominal wall. Two days later he developed confusion, urinary incontinence and progressive aphasia. Emergent magnetic resonance imaging (MRI) of the brain showed 4 enhancing gray-white matter junctional lesions, the two largest measured 3.8 × 3.3 cm in the right frontal lobe and 2.3 × 2.5 cm in the left frontal lobe. Two smaller enhancing lesions in the right parietal lobe measured 8 mm and 4 mm in diameter. In November 2016, he underwent craniotomy and resection of bilateral frontal lobe tumors, and he made a full neurologic recovery and went on to receive post-operative gamma knife radiosurgery to the resection cavities and the small parietal brain lesions (Fig. ). His case was reviewed in melanoma tumor boards at the Masonic Cancer Clinic, University of Minnesota. Sections of tumor revealed sheets of epithelial cells with moderate eosinophilic cytoplasm and areas of tumor infiltrating lymphocytes (Fig. ). Cells exhibited nuclear pleomorphism and increased mitotic activity (Fig. ), desmoplastic stromal reaction and necrosis (Fig. ). Immunohistochemical staining was positive for cytokeratin AE1/AE3 and cytokeratin 7, and negative for S100, HMB45, Melan-A, CD45, calretinin, ERG, p40, TTF1, CDX2, and GATA3. The immunoprofile ruled out melanoma, mesothelioma, lymphoma, sarcoma with epithelioid features, and most visceral carcinomas. Microscopic examination revealed intracytoplasmic lipid vesicles (Fig. ), confirmed by diffuse membranous reactivity for adipophilin [, ] (Fig. and ). The findings supported a histopathologic diagnosis of sebaceous carcinoma. Importantly, additional tumor testing confirmed high expression of PD-L1 in 100% of tumor cells (Fig. ). Commercial genomic testing using next-generation sequencing (Foundation Medicine, Massachusetts, USA) confirmed the tumor was microsatellite stable and carried a mutational burden of 17 mutations/Mb. Table also shows various somatic mutations in genes for regulatory transcription factors, DNA repair proteins, growth factor receptors, and targetable MAPK signaling proteins. Several of the affected genes have also been described in cases of sebaceous carcinoma reported in the COSMIC () database []. Initial staging positron emission tomography-computed tomography (PET/CT) revealed evidence of widely disseminated disease involving lung and liver, muscle, bone, and multi-compartment bulky lymphadenopathy in chest and abdomen (Fig. ). Standard chemotherapy approaches using platinum-based chemotherapy were reviewed. However, the patient and family strongly favored a less toxic therapy, considering advanced age and quality of life concerns. Given the strong rationale for use of checkpoint inhibitors in several other tumor types, moderately high tumor mutational burden (17 muts/Mb), and strong PD-L1 expression the patient opted for anti-PD1 immunotherapy. He initiated off-label treatment with pembrolizumab (2 mg/kg, every 3 weeks) in December 2016. Follow up PET/ CT scan 3 months after the initiation of anti-PD1 therapy revealed remarkable improvement in lymph nodes, lung, and soft tissue, however, there were multiple new and enlarging hepatic and osseous metastases initially worrisome for progression(Fig. ). After multidisciplinary review, the findings were felt consistent with pseudo-progression and immunotherapy was continued. Restaging PET/ CT obtained after 6 months of treatment showed further significant improvements in all previously noted lesions (Fig. ), with residual FDG activity seen in small mediastinal and abdominal lymph nodes. To further characterize the patient’s innate and adaptive immune status at the time of his near complete response, a flow cytometry study of peripheral blood was performed. Lymphocyte subset analysis showed evidence of circulating CD45RA-CD27+ central memory (CM) and effector memory (EM) T cells, and a population of mature CD16 + CD57+ NK cells (Fig. ). He continued on pembrolizumab, however, after 10 months of therapy he developed severe fatigue and orthostatic hypotension requiring hospitalization. Laboratory testing showed him to have secondary adrenal insufficiency with low (< 0.7 mcg/dL) serum cortisol and low (< 11 pg/mL) ACTH levels. He began 1 mg/kg prednisone with a prolonged steroid taper, and during high dose steroid therapy pembrolizumab dosing was interrupted. In December 2017, with 12 months of follow-up, restaging PET/CT was obtained and showed new FDG avid mediastinal and abdominal lymph nodes and a new hepatic and small bowel lesion (Fig. ). Biopsy of the liver lesion in January 2018 confirmed recurrent metastatic sebaceous carcinoma, and repeat immunohistochemical staining showed tumor cells continued to express high levels of PD-L1 (not shown). After discussion, the patient elected to restart immunotherapy, and he was continued on maintenance adrenal replacement therapy with hydrocortisone (10 mg/5 mg). Recent restaging studies demonstrate growth of the mediastinal metastases and a reduction in the size of the hepatic and small bowel metastases, suggestive of pseudoprogression and a durable ongoing response to pembrolizumab (Additional file ).

pmc-6006709-1

A 70 years-old man with a dilated ischemic cardiomyopathy, triple coronary artery bypass grafting (CABG) in 1990 and chronic renal failure (baseline GFR: 45 ml/min/1.73 m2) underwent a coronary angiography for a Non-ST segment elevation myocardial infarction (NSTEMI). Baseline values of Hs-Troponin T and CK-MB were 497 ng/l and 211 U/l respectively. Native coronary circulation was completely occluded at the proximal segments. Grafts angiography showed a tandem calcified lesions of SVG on distal right coronary artery (RCA) (Fig. ) and an ostial stenosis of the SVG on first obtuse marginal branch (OM1). Left internal mammary artery on the mid left anterior descending artery was patent. Ad Hoc PCI of SVG on RCA was attempted. The proximal calcified stenosis has been crossed with a 1.5 x 12 mm balloon only with the support of Guidezilla™ guide extension catheter (5-in-6 Fr), however the non compliant (NC) balloon 2.5 x 15mm was unable to break the hard and calcified plaque (Fig. ). After several attempts, the procedure was interrupted with a suboptimal result (Fig. and ). An elective PCI of SVG on RCA with rotational atherectomy was performed (left radial approach, 6 French). Two runs with 1.25 mm burr (Fig. ) and 2 runs with 1.5 mm burr (Fig. ) were carried out. Then, the use of distal anchoring balloon warranted support and tracking, made as centring rail for the advance of the tip of the “mother-and-child” catheter into the SVG. During slow deflation of the balloon, the Guidezilla™ catheter (5-in-6 Fr) was advanced distal to the proximal stenosis to be stented, thus allowing a first drug eluting stent (DES) 3.5 × 48 mm to be placed on the mid-distal segment of the graft according to a LSD technique. The same technique was applied to deploy a second DES proximally to the first one (3.5 × 28 mm on proximal segment). During both rotational atherectomy and PCI, as well as at the final angiographic control, we did not observe any sign of embolization and the procedure was successfully completed with a final TIMI III flow without complications. A slight elevations of the cardiac biomarkers the day after the procedure (Hs-Troponin T 564 ng/l and CK-MB 308 U/l) was followed by a gradual reduction of the latters in the next 4 days and the patient was discharged in stable conditions.

pmc-6006723-1

A 9-month-old female presented with a 2-month history of abdominal distension and weight loss. The patient underwent an uncomplicated birth following an unremarkable pregnancy at 39-weeks gestational age via elective caesarean section. The toddler attained normal developmental milestones aside from the inability to roll prone from supine. Initially at the 70th percentile at birth for weight, she presented at the 30th percentile with stable height and head circumference (50th percentile). The patient did not exhibit any clinical features of Beckwith Wiedemann Syndrome including omphalocele, macroglossia and macrosomia. There is no consanguinity, no family history of recurrent malignancies, haematological or renal conditions. Initial limited ultrasonographic study of the abdomen demonstrated massively enlarged kidneys with loss of corticomedullary differentiation. The right kidney measured 13.1 cm and the left measured 15 cm (normal approximately 6 cm) []. Multiple ill-defined hypoechoic areas were seen randomly interspersed within the renal parenchyma bilaterally suggesting presence of nephrogenic rests and therefore nephroblastomatosis. It was not possible to rule out the presence of Wilms tumour within the nephrogenic rests on ultrasound. No evidence of hydronephrosis, hydroureter or free fluid was seen. Computed tomography (CT) of the abdomen and pelvis with IV and oral contrast demonstrated homogenous, diffuse, renal enlargement and loss of normal architecture with renal parenchyma replaced by homogenous low attenuating peripheral masses bilaterally (Fig. ). There were two ill-defined hypodense areas in the medial aspect of the left kidney concerning for malignancy. Residual normal renal parenchyma was present as areas of striate enhancement, hyperdense in comparison to the thick rind of peripheral nodules. Based on clinical presentation and CT findings, the patient was diagnosed with bilateral DHPLNB. Gadolinium enhanced magnetic resonance imaging (MRI) of the abdomen performed after 6 weeks of chemotherapy demonstrated hypointense peripheral masses on T1/T2 images with thick septations suggestive of bilateral DHPLNB. A small heterogeneously enhancing lesion with multiple small linear and round cysts in the medial left kidney was characterized on T1 imaging, suspicious for a superimposed Wilms tumor (Fig. ). Diffusion weighted imaging was not conducted. No metastases were seen on CT chest with contrast. Pathology after left partial nephrectomy confirmed Wilms tumor. Cytogenetic analysis was conducted revealing a normal female karyotype (46XX). No other tumour markers or genetic testing was performed. Bilateral DHPLNB complicated by a left renal mass (likely Wilms Tumour) Renal lymphoma (uncommon in infants and young children). The patient was treated with COG protocol AREN 0534 EE-4A chemotherapy, including vincristine and dactinomycin for 20 weeks. Due to the presence of the superimposed left renal mass, a left partial nephrectomy and perihilar lymph node dissection was performed. Following the surgery, she also received left flank radiotherapy to a dose of 1080 cGy in 6 fractions. Pathology was consistent with DHPLNB and resection of a Wilms tumor. Resection margins were positive. Nodal dissection was negative. Following surgical resection and chemotherapy, the patient was followed with MRI every 3 months for a year. Thereafter, the patient was followed with MRI every 6 months for 2 years. Currently, the patient is now on surveillance with ultrasounds every 3–4 months.

pmc-6006740-1

The patient was a 7-year-old Turkish girl born to non-consanguineous parents. She was being followed up since 3 years of age because of bilateral glaucoma and was prescribed medicines [50 mL of Sholl solution and anti-acidosis capsule (three times a day)] and eye drops (β-blocker and carbonic anhydrase inhibitor). Her mother had oligohydramnios; the patient had intrauterine growth retardation and was born prematurely. There was no family history of any inherited diseases, cataract or pRTA. Both her weight and height were below the 3rd percentile, and she demonstrated intellectual disability. However, the other physical examinations, including neurological signs, were unremarkable. The laboratory tests were as follows: Na, 139 mmol/L; K, 3.1 mmol/L; Cl, 110 mmol/L; blood urea nitrogen, 12 mg/dL and creatinine, 0.9 mg/dL. Blood gas analysis revealed a pH of 7.22, HCO3− concentration of 11 mmol/L and PCO2 of 29 mmHg. In addition, urinalysis revealed a pH of 5, no protein and no glucose. The urinary excretion of amino acids was normal, and the urinary β2-microglobulin level was 110 μg/L (normal: < 240 μg/L). These investigations revealed that the patient had pRTA without Fanconi syndrome – generalized dysfunction of proximal tubule. Considering her short stature, the levels of thyroid hormones, IGF-I and IGFBP3 were normal. Furthermore, whereas the renal ultrasound revealed a 9-mm diameter parenchymal stone in the right kidney, brain MR imaging revealed no intracranial calcification. Neither of the parent showed these symptoms. At the age of 9, our patient presented with micrognathia, fish-mouth, epicanthal folds, ptosis, low-set ears, a short neck with a low hairline, a broad shield-like chest, wide-spaced nipples, hypoplastic areolae, cubitus valgus and short fourth metacarpals, with other symptoms due to NBCe1A absence such as dental abnormalities, suggesting the coincidence of Turner’s syndrome. In addition, her weight and height were still below the 3rd percentile. Hormonal investigation data were as follows: FSH, 69.3 mIU/mL (normal: 4.5–20.0 mIU/mL); LH, 15.9 mIU/mL (3.5–14.0 mIU/mL) and oestradiol, < 5.0 pg/mL, suggesting hypergonadotropic hypogonadism. Her karyotype was 45, XO which confirmed the diagnosis of Turner’s syndrome. From 200 μL of peripheral blood samples obtained from the patient and her parents, we extracted DNA using the QIAamp DNA Blood Mini Kit (Qiagen Inc.) according to the manufacturer’s instructions. Similarly, we extracted RNA from 1 to 2 mL of the peripheral blood sample using the Isogen (Nippon Gene) or the QIAamp RNA Blood Mini Kit (Qiagen Inc.) according to the manufacturer’s instructions. Then, the complementary DNA (cDNA) of the patient was synthesised from the polyA(+) RNA of the peripheral white blood cells using the cDNA Synthesis Kit (Takara) as previously described [] or the RevertAid First Strand cDNA Synthesis Kit (Thermo Scientific) according to the manufacturer’s instructions. The polymerase chain reaction (PCR) condition used was as follows: denaturation for 9 min at 95 °C, followed by 35 cycles of 95 °C for 1 min, 60 °C for 1 min and 72 °C for 1 min, with a final extension at 72 °C for 7 min. PCRs were performed using a thermal cycler PerkinElmer GeneAmp PCR System 2400 (PerkinElmer Japan, Applied Biosystems Division, Tokyo, Japan). The DNA sequence of each PCR product was determined using the Sanger sequencing method, with the primers shown in Table , in an ABI3100 sequence analyser (Life Technologies, Carlsbad, CA). In addition, AmpliTaq™ (Roche) and attached buffers were used for PCR. The primers in Table were used for the analyses of exons and splicing site sequences of SLC4A4. The sequences of primers used for the detection of β-actin and fragments of SLC4A4 coding sequences were as follows: hACTB748F, 5’-ATTGGCAATGAGCGGTTC-3′, and hACTB979R, 5’-TCTTCATTGTGCTGGGTGC-3′; exon2-3bridgeF, 5’-GTTGGTGGAGATGATTGTTGAC-3′, and exon6-7bridgeR, 5’-GTCATGGAACACCTCATCAGAC-3′; exon5-6bridgeF, 5’-TGCCCACAAGGTTCTTGTTC-3′, and exon8-9bridgeR, 5’-ACCACAGAACCGTCCAGTTC-3′. The quantitative RT-PCR (qRT-PCR) was performed according to its instructional manual, with TaqMan Gene Expression Master Mix (Applied Biosystems, Foster City, CA, USA), TaqMan Gene Expression Assays (Hs00186798_m1 for SLC4A4, Hs01060665_g1 for β-actin; all from Applied Biosystems) and sequence detection system (7500 Fast Real-time PCR System; Applied Biosystems). The expression level was quantified relative to the abundance of β-actin cDNA. The sequencing analysis of the SLC4A4 gene (OMIM 603345, ENST00000340595.3, NM_003759.3) across each exon, including the adjacent intronic sequences of approximately 100 base pairs of the proband, revealed two heterozygous mutations as follows: (a) c.1076 + 3A > C, three bases after the end of exon 7 (Fig. and ) c.1772 − 2A > T, two bases before the beginning of exon 12 (Fig. ). In addition, we analysed the SLC4A4 genes of her parents and confirmed that her mother and father had heterozygous mutations c.1076 + 3A > and c.1772 − 2A > T, respectively. No other mutations in the SLC4A4 gene were detected in the genomes of the patient or her parents. Of note, both mutations are absent from the ExAC database (/). Owing to the locations of both mutations on the splice sites, we performed in silico assays to elucidate whether the splicing sites were altered in the proband. We used the webtools ‘Splice Site Score Calculation’ () [, ], ‘NetGene2 Server’ (), ‘Human Splicing Finder Version 3.1’ () and ‘Berkeley Drosophila Genome Project Splice Site Prediction by Neural Network’ () for the in silico evaluation of these mutations. The ‘Splice Site Score Calculation’ demonstrated that the scores of the original sequences were 9.2 and 9.8, whereas the scores of the aberrant sequences were 2.5 and − 1.2, respectively (in order of c.1076 + 3A > C, c.1772 − 2A > T). Because the mean score of the 3′ splice site in constitutive exons was 7.9 and that of the 5′ splice site in constitutive exons was 8.1, the proband’s data suggested that the mutations could cause aberrant splicing (data not shown). In contrast, ‘NetGene 2 Server’ suggested that there may be no splice donor site for the c.1076 + 3A > C mutation and that there may be an aberrant acceptor splice site in c.1772 − 2A > T (data not shown), whereas The ‘Human Splicing Finder Version 3.1’ suggested that in c.1772 − 2A > T the acceptor splice site is broken (data not shown). The ‘Berkeley Drosophila Genome Project Splice Site Prediction by Neural Network’ [] suggested that c.1076 + 3A > C mutation abolishes the original splice donor site and provides an alternative splice donor site (c.1076 + 197_198GT). It also suggested that c.1772 − 2A > T abolishes the original acceptor site and provides alternative acceptor sites (c.1772 − 29_ − 28AG, c.1772 − 37_ − 36AG, c.1772 − 168_ − 167AG). Furthermore, the estimated models of aberrant transcription according to previous literature [, ] suggested the appearance of nonsense codons in each allele of the patient’s genome (Fig. and ). We tried to assess the sequence of the SLC4A4 cDNA because we obtained the cDNA of the proband from her mRNA. However, we did not detect the expression of SLC4A4 (Fig. ). Then, owing to the detection of the expression of β-actin in the proband’s cDNA (Fig. ), the absence of the SLC4A4 cDNA sequence suggested that SLC4A4 was either not expressed or expressed at extremely low levels in the proband. We further tried to confirm the expression amount of the SLC4A4 compared to β-actin in the patient by the qRT-PCR. The relative expression ratio of SLC4A4 to β-actin in the proband was extremely low compared to that of the healthy human control (P < 0.01), mother (P < 0.05) and father (P < 0.1) (Fig. ).

pmc-6006788-1

The patient was a 57-year-old woman who lives in Chiang Klang District, Nan Province, northern Thailand. She is a gardener and has never been abroad, only travelling to Phitsanulok and Phijit, provinces near Nan in Thailand. The patient presented in May 2014 at Chiang Klang Hospital with a single skin nodule on her left cheek (1.0 × 1.5 cm), and also with crusting at the left angle of the mouth (Fig. ). No skin nodules in other sites of the body were observed. Two pieces of formalin-fixed skin biopsy from the cheek nodule (0.6 × 0.5 × 0.4 cm3 and 0.5 × 0.5 × 0.2 cm3) were sent to the Department of Pathology, Faculty of Medicine, Chiang Mai University for histopathological investigation. Histopathological analyses revealed epidermal ulceration with a heavy, chronic inflammation of the dermis (Fig. ) and numerous intracellular small round or oval-shaped bodies, with the appearance of amastigotes (1–2 μm in width and 2–4 μm in length) of Leishmania spp. (Fig. ). A week later, a fresh skin biopsy from the nodule (0.4 × 0.5 × 0.3 cm3) was collected and sent to Department of Parasitology, Faculty of Medicine, Chiang Mai University for confirmation of diagnosis by parasite culture and species identification. The skin biopsy sample was cultured in Schneider’s insect medium supplemented with 20% foetal bovine serum (FBS) and 50 International Units penicillin/ml, 50 μg/ml streptomycin at 25°C. Motile promastigotes were first observed on day 3 of the culture. Therefore, the patient was confirmed as diagnosed with cutaneous leishmaniasis. She was treated with oral amphotericin B at 1 mg/kg/day for 1 day and fluconazole at 200 mg/day for 45 days. The skin lesion had disappeared completely by six months after treatment (Fig. ). Pre-treatment laboratory investigation showed only mild anaemia with a haemoglobin concentration of 10.9 g/dl, white blood count of 7700 cells/mm3, and platelet count of 483,000/mm3. There was no hepatosplenomegaly or palpable lymph nodes. Liver function was not investigated, renal function was within normal limits and HIV serology was negative. The patient declined a bone marrow biopsy for evaluation of visceral leishmaniasis. She did not report any other underlying disease, routine drug use, or any other symptoms, and in general was in a good state of health.

pmc-6006841-1

An 85-year-old Japanese man with a history of malignant melanoma of the nasal cavity presented to our department with severe thyrotoxicosis and poor blood glucose control. He had been treated for hypothyroidism secondary to Hashimoto’s disease and type 2 diabetes mellitus with insulin self-injection therapy before undergoing treatment of malignant melanoma. A surgical operation of his nasal cavity was done at first, followed by one of four planned cycles of nivolumab therapy. Subsequently, two courses of ipilimumab were given as standard therapy after nivolumab therapy. Two weeks later after receiving a dual course of ipilimumab as a third treatment, he presented with a fatigue, nausea, and sweating, which progressed to clinical and biochemical thyrotoxicosis. On admission to our hospital, he was febrile with a temperature of 38.0 °C, tachycardic, agitated, and acutely anxious but still conscious (restlessness). His Glasgow Coma Scale score was 14/15. His blood pressure had decreased to 70/50 mmHg. His physical examination revealed a diffuse goiter without exophthalmoses. His abdomen was soft and non-tender and his skin was warm and wet. He was also diaphoretic with jugular venous distension and peripheral edema, and his chest was clinically clear. His medical history included hypothyroidism due to Hashimoto’s disease, diagnosed at 62 years of age and treated with thyroid hormone replacement, as well as type 2 diabetes mellitus treated by self-injection of insulin with a good glycemic control. He had both family histories of thyroid diseases and diabetes. An electrocardiogram showed marked tachycardia with atrial fibrillation, but a chest radiograph was normal. The laboratory data are shown in Table . Laboratory investigation revealed the following thyroid function results: thyroid-stimulating hormone (TSH) below sensitivity, free triiodothyronine (FT3) 31.7 pg/ml, and free thyroxine (FT4) 3.43 ng/dl. Remarkably, his thyroglobulin was elevated to 48,000 IU/ml. TSH receptor antibody was negative, and a 99mTc-labeled thyroid scan revealed a markedly decreased uptake (Tc retention index-uptake ratio 0.0%; normal range 0.4–3.0). His blood glucose was markedly elevated; in which case, we needed to increase the amount of insulin to control his blood glucose. Further immunological investigation revealed normal serum levels of anti-glutamic acid decarboxylase (GAD) antibody, anti-insulinoma antigen 2 (IA-2) antibody, and insulin autoantibody (IAA). According to the diagnostic criteria of the Japan Thyroid Association for thyroid storm [], he was diagnosed as having thyroid storm 1 (TS1), definite thyroid storm, since he had thyrotoxicosis, a central nervous system symptom (restlessness), fever (38 °C), GI symptoms (nausea, vomiting), and tachycardia (135 beats per minute) in atrial fibrillation. Based on the diagnostic criteria of Burch and Wartofsky for thyroid storm, he scored 60; a score higher than 45 is suggestive of thyroid storm []. Graves’ disease was less likely as thyroid-stimulating immunoglobulin was within the normal range, and 99mTc-scintigraphy revealed a quite low uptake. These results indicated that his diagnosis of thyroid storm was due to destructive thyroiditis. His clinical course is shown in Fig. . He was treated with an intravenously administered insulin infusion and intravenously administered fluid therapy. At first, the thyroid storm was treated with orally administered potassium iodide (50 mg every 6 hours) and a short-acting beta-adrenoreceptor blocker, landiolol hydrochloride, was used at 4–10 μg/kg per minute to control his heart rate. The potassium iodide was aborted when he was diagnosed as having distractive thyroiditis. Prednisolone was given at 0.5–0.7 mg/kg per day as a treatment for irAE and thyroid storm. Although previous reports suggested the optimum dosage of prednisolone to be 1–2 mg/kg per day [, ], we used a lower dose due to the coexisting and uncontrolled diabetes mellitus. By day 5, his tachycardia had resolved, and the landiolol hydrochloride was discontinued. On day 11, his thyroid function was found to have improved, and the amount of total insulin used to control his blood glucose was decreased. On day 25, he was found to have hypothyroidism, and so we restarted the replacement of thyroid hormone. He was discharged from our hospital on day 35 on daily maintenance insulin injection and levothyroxine sodium hydrate.

pmc-6006860-1

A 20-year-old female patient presented to our hospital with a history of severe and dull substernal chest pain and breathlessness after being hit by a baseball to her chest 2 h ago. Immediately after being hit, she had an episode of syncope briefly without convulsion. The symptoms lasted for half-an-hour and resolved spontaneously. Her vital signs showed blood pressure of 95/64 mmHg and pulse of 70 beats/minute. There was no sign of chest wall penetrating injury. Electrocardiogram (ECG) revealed sinus rhythm with QS complexes in leads V2 to V3, ST segment elevation and T-wave inversion in leads V2 to V5 (Fig. ). Laboratory tests showed cardiac Troponin I level of 19.03 ng/ml (normal range < 0.01 ng/ml). Chest computer tomography (CT) revealed no traumatic injury but demonstrated coronary artery calcifications (Fig. ). Her parents recalled a history of high fever lasting for several days at the age of 5-year-old. The patient was admitted to our hospital diagnosed of acute traumatic MI. Serum Troponin I was peaked to 20.3 ng/ml, creatine phosphokinase(CK) to 1237 U/L and CK-MB to 101 U/L 12 h after admission. Serum BNP level was normal at 85.9 pg/ml on admission. During hospitalization, serial ECG changes were consistent with an evolving MI. She had frequent ventricular premature beats on the Holter monitor. Trans-thoracic echocardiography revealed normal left ventricular size and mild anterior hypokinesis. Notably, multiple giant left anterior descending (LAD) aneurysms with diameters from 7.5 to 8.5 mm (Fig. ) and slow flow velocity were detected. To further assess CAA, we performed contrast enhanced coronary artery computer tomography angiography (CTA)with three-dimensional (3-D)reconstruction of coronary arteries. A ringed calcification in the proximal portion of LAD artery with multiple aneurysms, thrombi and occlusions were visualized (Fig. ). CTA also demonstrated multiple aneurysms with beads-on-string appearance in the LAD artery (Fig. ). Antinuclear antibody (ANA) was minimally positive (1:10) with unknown significance. Serum levels of C3 (0.864 g/L), C4 (0.912 g/L), CRP (< 1.0 mg/L), ASO (< 25 IU/ml), ESR (15 mm/h), Rheumatoid Factor (< 25 IU/ml) and ANCA were within normal ranges. Those results did not seem to support active vasculitis, rheumatic or immunologic diseases. Based on the typical images and her childhood fever history, we recognized that the patient’s underlying coronary structural abnormality was most likely originated from KD. Considering stable hemodynamic parameters and multiple giant aneurismal dilatations of LAD artery, we managed this young patient with a conservative strategy including dual anti-platelet treatment with aspirin and clopidogrel for at least 1 year, and titrations of captopril and metoprolol to prevent ventricular remodeling. At the 2-month follow-up, the patient remained asymptomatic. ECG showed QS complex only in V2 and V3 leads and other abnormalities were resolved (Fig. ). Echocardiography revealed left ventricular diastolic dimension of 48 mm, normal LAD artery velocity, and no ventricular dilatation or akinesis. She remained asymptomatic two year later.

pmc-6006918-1

We present the case of a 33-year-old female who was an unrestrained driver in a MVC with major front-end damage where airbags were deployed. She arrived to Advocate Christ Medical Center (a high volume, academic, level 1 trauma center) unresponsive with a Glasgow Coma Scale (GCS) of 5 and was intubated for airway protection. Breath sounds were noted to be present bilaterally. She was tachycardic and hypotensive with a heart rate of 143 and blood pressure of 71/46. A focused assessment with sonography for trauma (FAST) demonstrated no evidence of intra-abdominal or pericardial fluid. A left sided hemothorax was present on chest x-ray, and a chest tube was placed with 1200 mL of bloody output initially (See Fig. ). At this point, the decision was made to take patient emergently to the operating room (OR) for exploration. A left anterolateral thoracotomy incision was made with the patient in a supine position. There was a significant amount of blood upon entry into the chest cavity, and there was no cardiac tamponade. Despite cross clamping the pulmonary hilum, the bleeding continued. While being resuscitated with the massive transfusion protocol, there was no end tidal CO2 noted. The pericardium was opened, heart delivered, and cardiac massage was started. A separate defect in the superior, right side of the pericardium was found as well as a 3 cm defect in the anterior right atrium (See Fig. ). Despite measures to control hemorrhage and resuscitate the patient, the patient did not survive. The blood loss was greater than 6 l.

pmc-6006918-2

The second case is a 58-year-old male who was involved in a high-speed MVC. The patient had a prolonged extrication from his vehicle and was intubated after being found unresponsive. On arrival his GCS was 3 T. He was hypotensive with FAST negative for intra-abdominal blood, but a large left hemothorax was identified on the left upper quadrant view. A chest tube was placed with initially 900 mL of blood out followed by 200 mL per hour for 2 h. Based on the output and ongoing resuscitation requirements, the decision was made to take the patient to the OR. A left anterolateral thoracotomy incision was made with the patient in supine position. There was approximately 1 L of clotted blood within the chest cavity coming from an anterior pericardial laceration, about 15 cm in length. Through the defect there was brisk bleeding coming from a 1 cm laceration on the left atrial appendage (See Fig. ). The injury was debrided and repaired using a running 3–0 polypropylene suture over a Satinsky clamp. The pericardial defect was closed to prevent cardiac herniation. The patient recovered well and was eventually discharged home.

pmc-6006941-1

A 42-year-old female was seen by a primary care physician, whose examination of the oral cavity revealed smooth bilaterally enlarged tonsils, with the right tonsil being slightly larger than the left. No surface abnormality was evident. She was prescribed two courses of amoxicillin but did not improve. She was then referred to our otorhinolaryngology department. Her medical history was unremarkable. We found no unexplained cervical lymphadenopathy, no significant systemic symptom, no malignancy, and no immunocompromise. All laboratory parameters were within normal limits. Magnetic resonance (MR) images of the palatine tonsils did not reveal any obvious mass lesion. Axial noncontrast T1 (600/8/2 [TR/TE/NEX]) and coronal STIR MR (5700/80/1) images of the palatine tonsils showed that the right tonsil was larger than the left. No mass or abnormal T2 prolongation (suggestive of a tumor) was evident. An axial T2-weighted image (4400/100/2) and a postgadolinium T1-weighted image with fat saturation (550/8/1) also failed to reveal any mass in the right tonsil, but on postcontrast MRI, the left tonsil showed mucosal crypts with linear enhancement, while on the right side the crypts were partly obliterated by a large mass and did not display enhancement (Fig. ). The patient underwent complete surgical resection of the right tonsil because of a possible malignancy. Histological examination of the specimen revealed diffuse sheets of monomorphous plasmacytoid cells with abundant, eosinophilic finely granular cytoplasm, and eccentric nuclei. Occasional binucleated and pleomorphic cells with giant nuclei and prominent nucleoli were also observed, as were mitotic figures. No amyloid deposition was apparent. Immunohistochemically, the plasma cells were diffusely immunoreactive for the λ light chain (DAKO, Glostrup, Denmark), IgG (DAKO), and CD43 (DAKO); partially positive for epithelial membrane antigen (DAKO); but negative for the κ light chain (DAKO), IgA (DAKO), IgM (DAKO), and CD20 (DAKO). Additional immunohistochemical staining showed that the cells were positive for the plasma cell markers CD138, MUM-1, and CD56. Thus, we diagnosed a plasmacytoma (Fig. ). A metastatic workup was performed to search for multiple myeloma/light chain disease. Laboratory testing revealed the absence of anemia, and the serum calcium, albumin, total protein, and creatinine levels were normal. The urine lacked Bence-Jones protein. The bone survey was negative. Bone marrow biopsy revealed < 5% plasma cells, ruling out plasmacytoma of the bone. No monoclonal gammopathy was evident, precluding an immunofixation disorder. The kappa-to-lambda ratio was normal. No adjuvant treatment was indicated, and the patient remains clinically free of disease after 6 months of follow-up.

pmc-6007005-1

A 29-year-old male, with a known surgical history of LRYGB 9 years ago, presented to the emergency department complaining of sharp, severe abdominal pain in the right upper quadrant (RUQ). The pain began two months ago in an intermittent fashion that would occasionally radiate to his right shoulder and progressively became worse with time. The patient did not report any constipation, distension, or vomiting despite feeling nauseated during these attacks. The pain was not related to any movement or meals and it was moderately relieved by over the counter analgesia. Ten years ago, the patient was diagnosed with obstructive sleep apnea (OSA), through a sleep study, due to morbid obesity. He then was advised to undergo LRYGB as a treatment. He does have any other medical problems. Family history is notable for diabetes mellitus and hypertension but no history of hyperlipidemia or obesity. His body mass index (BMI) prior to the surgery was 49.3 Kg/m2. He underwent a successful LRYGB with no complications or readmissions. After the surgery for a year and a half, he followed up with his primary surgeon. During that time, he lost 75 Kg, reaching a BMI of 26.9 Kg/m2. He then was able to maintain his weight following the operation, but failed to continue to follow up for the past 2 years. In those 2 years, he gained weight, raising his BMI to 29.9 Kg/m2, after which he modified his diet to reduce his BMI to 23.9 Kg/m2. This weight reduction was achieved prior to his presentation. On physical examination, the patient was afebrile with normal vital signs. Examination of his abdomen revealed moderate tenderness over the epigastrium, central abdomen, and right hypochondrium with a positive Murphy’s sign. His laboratory investigations, including complete blood count, urine analysis, liver and renal function tests, were all within normal limits. An ultrasound examination revealed two gallstones and upper borderline diameter of common bile duct, raising the suspicion of biliary obstruction. Correlating his investigation results with his symptoms, he was admitted and scheduled for a cholecystectomy. Formal laparoscopic cholecystectomy was carried out the next morning. During exploration, twisting of the common channel was observed, indicating an internal hernia, although the patient’s complaint did not suggest internal hernia in the differential diagnosis. The internal hernia was identified but reduction was not feasible through laparoscopy. Mini midline laparotomy was subsequently done for reduction of the hernia and more detailed exploration. The hernia was through the mesenteric defect between the alimentary limb and the biliopancreatic limbs. Both limbs of the anastomosis were identified and complete reduction of the internal hernia was done, in addition to suturing of the defect found in the mesentery. No other defects were found. The small intestine’s mesentery showed prominent whitish colored vessels. Whitish thick fluid was noticed, accumulating in the right paracolic gutter and in Morison’s pouch. All of the fluid was then aspirated, measuring a total of 752 mL. Analysis of the fluid showed a triglyceride level of 534 mg/dL and a Lactate Dehydrogenase (LDH) level of 512 U/L. A classic Blake drain 24 F was inserted into the pelvis. The patient passed an uneventful post-operative period. On Postoperative Day (POD) one, fluid collected from the drain was 440 ml, chylous in appearance, while on POD 2–4 the drainage was serous in appearance. The drain was removed on POD 4. The patient was discharged on POD 4 after being able to ambulate independently on his own and eat and drink with no complications. The patient did not return back for his follow-up visits and when he was called by the team, he confirmed that he has no complains up to this day.

pmc-6007058-1

A 34-year-old man with a 15-year history of Crohn’s Disease (CD) was admitted to our hospital due to abdominal pain, non-bloody diarrhea and weight loss. Physical examination demonstrated moderate abdominal tenderness with an abdominal mass in the right lower quadrant. Laboratory findings revealed a significantly elevated C-reactive protein (CRP 7.5 mg/dl). Colonoscopy with ulcerations localized at the Bauhin’s valve and histological examination of obtained mucosal biopsies were suggestive for active CD. As endoscopic intubation of the terminal ileum was not possible, MR enteroclysis was performed and indicative of a predominant inflammatory, short-segment stenosis of the terminal ileum. Given the acute disease flare and the stricturing phenotype, medical treatment was switched from prednisolone and azathioprine to the anti-tumor-necrosis-factor (TNF)-alpha antibody adalimumab. Twelve weeks after induction of adalimumab therapy, clinical remission was achieved and CRP level returned to normal. Another four months later, clinical remission was still maintained and laboratory inflammation markers remained low, but the patient presented in the clinic for Cranio-Maxillo Surgery due to severe pain in the mandibular area. Examination of the oral cavity detected ulcerative lesions of the buccal-side mucosa of the right mandible (Fig. ). To rule out malignancy, a biopsy of the oral lesions was obtained and revealed ulcerative stomatitis with noncaseating granulomas consistent with oral CD (Fig. ). Intensification of immunosuppressive therapy was initiated by shortening the adalimumab administration interval to weekly administration. A follow-up examination after 10 weeks confirmed complete healing of the oral CD lesion (Fig. ). During a follow-up period of 12 months, no signs of active CD became evident under continued therapy.

pmc-6007063-1

An 11-year, 7-month-old girl visited the Kyungpook National Children’s Hospital because of a short stature. The patient had been born via vaginal delivery at a gestational age of 38 weeks; she weighed 2.6 kg at birth, and there were no perinatal problems. However, she had an incomplete cleft palate and craniosynostosis at birth. Hearing loss in both ears was detected at the age of 1 month by brainstem-evoked response audiometry during an initial screening test. An ‘inborn errors of metabolism’ workup performed after birth revealed congenital hypothyroidism, for which the patient received levothyroxine at the local hospital until she was 3 years old; normal thyroid function was confirmed after discontinuing the medication. When she was 1 year old, she was transferred to our hospital because of a developmental delay and for a repair of her incomplete cleft palate and craniosynostosis. Brain computed tomography revealed an auditory defect, and she began wearing hearing aids, as prescribed by an otolaryngologist. The patient underwent skull reconstruction and incomplete cleft palate repair at the Departments of Plastic Surgery and Neurosurgery, respectively. She was scheduled for follow-up at the Department of Pediatric Neurology due to her developmental language delay, but she was lost to follow-up. When the patient re-visited our hospital at the age of 11 years and 7 months, she had a height of 124.8 cm (standard deviation score [SDS]: − 3.6), weight of 46 kg (SDS: 0.65 kg), and body mass index (BMI) of 29.53 kg/m2 (Z score: 1.89). She had distinctive facial features, including abnormally long openings between the eyelids, arch-shaped eyebrows, a thin upper lip, and large ears (Fig. ). Moreover, she showed postnatal growth retardation and skeletal anomalies, including an incomplete cleft palate, craniosynostosis, and brachydactyly (Fig. ). These dysmorphic features and her developmental delay were considered suggestive of Kabuki syndrome. Her karyotype was 46,XX. Her bone age was 8 years and 10 months, which was considered delayed according to the Greulich and Pyle atlas []. Based on these characteristic clinical features, mutational analyses for the KMT2D and KDM6A genes were performed. The CARE guidelines were followed in reporting this case, and the molecular analyses were approved by the Institutional Review Board of the Kyungpook National University Chilgok Hospital after obtaining informed consent from the patient’s parents. Genomic DNA was extracted from peripheral blood, and library preparations were performed with the TruSight One Sequencing Panel (Illumina, Inc., San Diego, CA, USA), which enriches a 12 Mb region spanning 4813 genes of clinical relevance. Large-scale parallel sequencing was performed with the Illumina NextSeq platform. Sequence reads were aligned with the hg19 reference sequence using the Burrow-Wheeler Aligner (version 0.7.12, MEM algorithm). Duplicate reads were removed using Picard Tools (version 1.96). Local realignment and base quality recalibration were performed with the Genome Analysis Toolkit (GATK, version 3.5), and variant calling was performed using the GATK HaplotypeCaller. Variants were annotated with the Variant Effect Predictor and AnnoVar. Common variants with minor allele frequencies (≥1%) were filtered out using public databases (1000 Genomes Project, Exome Variant Server, and Exome Aggregation Consortium). Population-specific common variants were further filtered using the Korean Reference Genome Database []. The patient had the nonsense mutation of c.8200C > T, p(Arg2734*) in exon 32 in the KMT2D gene. As neither parent had this mutation, as determined by Sanger sequencing, the patient had a de novo heterozygous mutation in the KMT2D gene (Additional file : Figure S1). We then performed additional examinations to detect other anomalies associated with Kabuki syndrome. Two-dimensional echocardiography, abdominal ultrasonography, and brain magnetic resonance imaging that had been performed at 1 year of age, showed no abnormalities. Ophthalmological findings were also normal. The patient exhibited several endocrine problems (transiently congenital hypothyroidism, CDP, obesity and GH deficiency); additional endocrine tests were performed upon admission to our hospital (at the age of 11 years and 7 months). The patient had transiently congenital hypothyroidism. When she was 7 days old, her free thyroxine (T4) was 1.09 ng/dL (reference range [RR], 0.8–2.0 ng/dL), triiodothyronine (T3) was 1.3 ng/mL (RR, 0.2–2.0 ng/mL), and thyroid-stimulating hormone (TSH) was 22.8 mIU/L (RR, 0.7–13.1 mIU/L). She received levothyroxine until she was 3 years old, and normal thyroid function was confirmed after discontinuing the medication. Upon admission to our hospital, she was 11 years and 7 month old her free T4 was 1.6 ng/dL (RR, 0.8–1.8 ng/dL), T3 was 0.8 ng/mL (RR, 0.6–1.9 ng/mL), and TSH was 3.5 mIU/L (RR, 0.3–4.0 mIU/L), indicating normal thyroid function. Regarding puberty, the patient showed Tanner stage I–II of breast development; her basal luteinizing hormone level was < 0.07 mIU/mL (RR, 5–20 mIU/mL), basal follicle-stimulating hormone level was 6.19 mIU/mL (RR, 0.3–10 mIU/mL), and estradiol level was < 11.8 pg/mL (RR, 0–16 pg/mL), suggesting a CDP. She was obese and had a buffalo hump. Her cortisol levels while awake at 8 AM, 5 PM, and midnight were 6.93 μg/dL (RR, 3–22 μg/dL), 12.46 μg/dL (RR, 3–22 μg/dL), and 14.87 μg/dL (RR, < 7.5 μg/dL), respectively. Her corresponding adrenocorticotropic hormone levels were 34.2 pg/mL, 40 pg/mL, and 42.8 pg/mL, respectively (RR for all, 0–60 pg/mL). Her urine-free cortisol was 28.9 μg/dL (RR, 4.3–176 μg/dL). Even though the midnight cortisol level was elevated, a low-dose dexamethasone suppression test showed a cortisol level of 0.68 μg/dL (RR, < 1.8 μg/dL). A lipid profile showed a total cholesterol level of 150 mg/dL (RR, 125–200 mg/dL), triglyceride level of 66 mg/dL (RR, < 200 mg/dL), and LDL-cholesterol level of 53 mg/dL (RR, < 130 mg/dL). Her aspartate aminotransferase and alanine aminotransferase levels were 24 U/L (RR, < 97 U/L) and 17 U/L (RR, < 41 U/L), respectively. A GH stimulation test (spanning 2 days) was performed because of her short stature and delayed bone age. On the first day, the patient was administered levodopa (500 mg); the samples for the GH assessment were acquired at 0, 30, 60, 90, and 120 min. On the next day, the patient fasted for 8 h in the morning and was intravenously administered 0.1 U/kg of rapid-acting insulin diluted in 5 mL of normal saline for over 1 min, after which the samples for GH assessment were acquired at 0, 15, 30, 60, 90, and 120 min. The maximum GH concentrations in both tests were below 5 μg/L (RR, > 7 μg/L); therefore, the patient was diagnosed with GH deficiency. Her insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 3 (IGFBP-3) levels were 130.5 ng/mL (RR, 99–537 ng/mL, SDS: − 1.67) and 3760 ng/mL (RR, 2400–8400 ng/mL, SDS: 0.91), respectively. The patient started GH replacement therapy (Eutropin 0.03 mg/kg/day) when she was 11 years and 7 months old and is currently scheduled for regular follow-ups for growth and puberty changes.

pmc-6007364-1

A 43-year-old man with a history of hypertension, hyperuricemia, android obesity and bilateral carpal tunnel, presented at his general practitioner with intermittent pain in right lumbar region. On abdominal examination we palpates an epigastric mass, the rest of the physical examination was normal. A abdominal CT scan was realized and demonstrates the presence of a voluminous mass of 24 × 15 × 13 cm3, partially cystic, located in the epigastric region, between the left lobe of the liver, the stomach, the pancreas and the transverse colon. The differential diagnoses are: cystic lymphangioma, cystic mesothelioma, non-communicating GD and cystic GIST. A biology carried out at the same time an increased CEA level of 281 µg/L, and CA 19-9 being within normal limits. MRI gave a diagnosis of a non-communicating GD (Fig. ). The PETCT showed a moderately hypermetabolic uptake in the posterior wall of the mass, which could not differentiate a benign or malignant origin. Gastric endoscopy showed an extrinsic compression of the gastric body, with a normal mucosa. A decision for laparotomy surgery was made in view of the possible neoplastic degeneration and the difficulties caused by the volume of the mass. During the surgery, a GD of 30 cm of major axis, located along the entirety of the small curvature and under tension was highlighted (Fig. ). The incision of the cyst allowed 2 L of mucus to be evacueted. The lumen of the cyst did not communicate with that of the stomach. We performed a total gastrectomy with a roux-en-y loop oesophago-jejunostomy and a lymphadenectomy. The histological examination described a normal stomach with a GDC without communication and adjacent to the little curvate. The size of the empty GDC was 21 cm × 10 × 9.5 cm (Fig. ). The sample of the GDC showed a mucus-secreting epithelium with some zones of ulceration. The wall was thick and had a fibrous and muscular aspect. No evidence of dysplasia or metaplasia was found in the stomach and neither in the GDC. The immune marking of pancytokeratine was normal and the KI67 proliferation was little elevated. The PAS coloration showed mucus but there was no signet ring cell. Overall, 18 sampled lymph nodes were free of malignancy. The diagnosis was a total GDC with no malignant transformation. The postoperative course was uneventful and, the patient was discharged on the 10-day postoperatively. At 6 months postoperatively the patient is currently well. The CEA is currently at 3,06 mg/L.

pmc-6007444-1

A 24-year-old Caucasian male presented to our outpatient clinic with fever and pain in the right upper abdominal quadrant. He had a history of a recent upper respiratory tract infection, which was treated with oral amoxicillin. The patient also had a history of left adrenal gland resection, distal pancreatectomy, and splenectomy due to a large pheochromocytoma two years earlier. His past medical history was otherwise unremarkable. A clinical examination revealed a tenderness in the epigastric abdomen and a cervical lymphadenopathy. An ultrasound examination revealed a thickened gallbladder wall as a sign of acute cholecystitis without evidence of gallstones or sludge, as shown in Figure . Due to increasing leukocytosis, abdominal pain, and the history of a huge pheochromocytoma, computed tomography (CT) was performed. This confirmed an acalculous cholecystitis and showed a generalized lymphadenopathy. Laboratory values were significant for: white blood cell (WBC) count 23.940/µl (range: 4.500-9.500/µl), thrombocytes 426.000/µl (150.000-400.000), lactate dehydrogenase (LDH) 438 U/l (135-225), aspartate aminotransferase (AST) 116 U/l (10-50), alanine aminotransferase (ALT) 185 U/l (10-50), gamma-glutamyltransferase (GGT) 258 U/l (10-71), alkaline phosphatase (AP) 437 U/l (40-129), c reactive protein (CRP) 10.2 mg/l (< 5mg/l). Table summarizes the laboratory values throughout the hospital stay. Figure presents the course of the patients' liver enzymes. The mononucleosis enzyme-linked immunosorbent assay (ELISA) showed elevated virus capsid antigen (VCA) immunoglobulin G (IgG) levels (39 U/l; range < 0 U/l) and normal VCA immunoglobulin M (IgM) levels. The heterophile antibody test for mononucleosis IgM antibodies was positive. We performed a cytomegalovirus (CMV) ELISA, which showed normal values for IgG and IgM. Epstein-Barr virus (EBV)-specific nuclear antigen (EBNA) antibodies were negative. A VCA IgM control test two weeks later showed elevated VCA IgM antibodies. The peripheral blood smear confirmed atypical lymphocytosis. Under symptomatic therapy, the patient’s state improved rapidly and he was discharged on the 17th day after admission in good general condition.

pmc-6007447-1

A 47-year-old woman presented to the emergency department with concerns of left upper abdominal pain for one day. She reported that the moderate to severe abdominal pain had a gradual onset, was crampy, constant, and located in the left upper part of her abdomen radiating to the lower chest and back. The pain was associated with diaphoresis, nausea, and several instances of vomiting non-bloody, non-bilious liquid. On admission, her vitals were stable. The results of her complete blood counts, comprehensive metabolic panels, and hepatic function tests were within reference ranges. Her coagulation profile was at a subtherapeutic level. Her past medical history includes nonischemic cardiomyopathy with left ventricular thrombus and four previous cerebrovascular accidents with residual right leg numbness. Her condition was being managed with warfarin. A physical examination showed fine crackles within the left lower lobe and significant tenderness in the left upper abdomen. The patient reported that she had stopped taking warfarin two days prior to admission. Cardiac magnetic resonance imaging (MRI) showed septal and apical predominantly transmural infarct. A transthoracic echocardiogram showed a mildly dilated left ventricle with moderate to severe left ventricular dysfunction, an ejection fraction of 30% to 35% with distal anterior, anteroseptal, and apical akinesis with mild mitral regurgitation. Cardiac catheterization findings were unremarkable. A computed tomography (CT) scan of her abdomen showed mild cardiomegaly with previous infarction on the anterior-inferior wall of the left ventricle. We noted a 37.47 mm calcified thrombus in the left ventricular apex with peripheral calcifications (Figure ). We also noted infarction in the spleen and right kidney with bilateral renal scarring (Figures -). The patient was initially started on a heparin drip and later bridged to warfarin on the third day. She was discharged with complete resolution of her abdominal pain after seven days, and medication compliance was reinforced before discharge.

pmc-6007448-1

A 27-year-old African American male with a past medical history of asthma and allergic rhinitis presented with a three-week history fever of unknown origin. Associated symptoms included drenching night sweats, weight loss, fatigue, nausea, and diarrhea. On physical examination, he was found to be hemodynamically stable and febrile at 102°F. He was also found to have extensive left sided, posterior, cervical lymphadenopathy. Laboratory studies indicated a mild anemia with negative hepatitis panel, anti-nuclear antibody (ANA), human immunodeficiency virus (HIV1/HIV2), Lyme antibody, and infectious mononucleosis (IM) serology, non-reactive rapid plasma reagin (RPR), and a negative Babesiosis smear. Computed tomography (CT scan) of the chest and abdomen were unremarkable. Ultrasound (U/S) and CT imaging of the neck demonstrated extensive adenopathy throughout the left posterior cervical carotid chain (Figure ). U/S guided lymph node biopsy showed polymorphous appearance with areas of zonal necrosis and a subpopulation of medium-large atypical lymphoid cells suggesting an atypical lymphoproliferative disorder. Excision biopsy was performed to rule out malignancy and Hodgkin disease. Pathology showed histiocytic necrotizing lymphadenitis (Figure ). The histologic, immunohistochemical and flow cytometric findings were consistent with histiocytic necrotizing lymphadenitis. Immunohistochemical stains were performed to include BCL2, CD2, CD3, CD5, CD7, CD15, CD20, CD30, CD34, CD68, CD117, CD138, Epstein–Barr virus (EBV), herpes simplex virus (HSV), PAX5, Alk1, cytomegalovirus (CMV), Ki67, pankeratin, S100. Proliferating histiocytes marked with CD68 were negative for the listed T cell and B cell markers. Phenotypic analysis by flow cytometry revealed a mixed population of mature T and B lymphocytes with normal T cell:B cell ratio for lymph node. Monoclonal T cell or B cell populations were not detected and there was no immunophenotypic evidence of an acute leukemic process. The patient was managed with ibuprofen and fully recovered in five months’ time.

pmc-6007497-1

We present a case of a 68-year-old Caucasian female known to have multiple comorbidities: seropositive rheumatoid arthritis, common variable immunodeficiency, hypertension, hypothyroidism, and osteoporosis. The patient was diagnosed with rheumatoid arthritis in 2013. She developed cutaneous vasculitis, confirmed by biopsy performed by her primary care physician in May, 2015. She was initially treated with mycophenolate, hydroxychloroquine, and prednisone with initial improvement. The prednisone was tapered off, but she then developed worsening of joint symptoms and synovitis. For this reason, she was switched to methotrexate. Six months later, leflunomide was substituted due to hair loss and inadequate disease control on methotrexate. It was several months later that her cutaneous lesions worsened again. The decision was made to start the patient on abatacept. Arrangements were made with required laboratory testing and screening prior to starting abatacept. On the following visit, the patient was given abatacept 10 mg/kg intravenous infusion with concurrent therapy of leflunomide, hydroxychloroquine, and prednisone. The patient was reevaluated after two weeks of infusion, with clearing of lesions several days after the first dose of abatacept. On her four-month follow-up visit, the patient continued to demonstrate a satisfactory response to this therapy. Prednisone was discontinued, and the patient was kept on abatacept, hydroxychloroquine, and leflunomide. The patient returned to office a month later without any recurrence of her cutaneous lesions.

pmc-6007498-1

The case of a 46-year-old male patient with a background of HHT and aortic valve replacement due to aortic insufficiency is presented. He denies having had psychiatrict treatment, consumed antipsychotic drugs, had recent molar extractions or a background of TMJ dislocation. On the fifth day after a lung transplant, in the intensive therapy unit, the patient begins to experience symptoms of mandibular pain, trismus and extrapyramidalism symptoms in the form of oromandibular dystonia. In physical exam he presented signs of bilateral jaw subluxation with reuptake inhibition of the articular condyle–disc complex, contraction at the masticatory muscles level, fascies dolorosa, dystonia of the facial third with articular blocking and incapacity for bucal closure or lateral excursion and slight dysphagia. As background of the hospitalization, he had received, an hour before said event, 2.5 mg of haloperidol and 0.25 mg of risperidone (two doses) due to hyperactive delirium. It was decided to take a computed tomography (CT) of the craniofacial complex and brain without IV contrast (Fig. ), where the following was seen: dislocation of both mandibular condyles with anterior position to the temporal’s glenoid cavity, without evidence of associated bone injuries. Analgesia and muscular relaxation of the patient was carried out. The Nelaton reduction maneuver and later placing of Barton bandaging was done following the technique, using an antiseptic. Posterior clinical and radiological reduction is verified through CT, evidencing a normal condylar position. The patient progresses without further subluxations during his hospitalization.

pmc-6007794-1

A 61-year-old male was referred to our burn center with burn injuries. The burn percentage was 20% Total Burn Surface Area (TBSA) and IIb-III degree, involving thorax, abdomen, and right arm. Patient was treated with split-thickness skin graft. We discharged the patient after successful management with healed graft and nearly healed donor wounds. 8 months later, the patient was referred to us from his primary care physician for management of infected open wounds in donor sites. Physical examination revealed infected area with hypergranulated tissue in donor sites, left upper limb and left lower limb (Figure 1 ). Wound cultures showed Staphylococcus aureus, Escherichia coli and Staphylococcus epidermidis (Methicillin-resistent, MRSE) bacteria. Patient was a heavy smoker and suffered from multiple sclerosis. Up to our knowledge, neglect and inadequate wound care were responsible for the opening and secondary infection of donor sites. One day after admission we performed a surgical debridement and removed the hypertrophic granulation tissue. After the operation we started daily wound dressing with a non-adherent antimicrobial alginate dressing (Silvercell®) and irradiation with water-filtered infrared-A (wIRA). Water-filtered infrared-A (wIRA) protocols used at our department were radiations all wound areas three times daily with a 60 cm distance for 30 minutes with a “Hydrosun 505®” model (Hydrosun Medizintechnik, Müllheim, Germany). The patient tolerated this application well without any complaints. After 5 weeks the patient was discharged with healed donor sites left thigh and left lower leg and nearly totally healed sites left forearm and left upper arm (Figure 2 ).

pmc-6008297-1

An 80-year-old man with known cervical canal stenosis due to ossification of the cervical posterior longitudinal ligament was transferred to an emergency room soon after a falling accident. The patient was alert and had complete tetraplegia, sensory deficits below the C4 cervical sensory level, and progressive restrictive respiratory failure that required assisted ventilation, and, eventually, a tracheostomy. Cervical spine magnetic resonance imaging showed cervical cord compression that was worse at the C3–C4 intervertebral level, and an intramedullary high signal at C3 and C4 vertebral levels, and the patient was managed conservatively. During the conventional weaning process of trials of intermittent spontaneous breathing in the ICU, an unexpected cardiac arrest made both the patient and medical staff reluctant to proceed with further weaning. Fifty-eight days after cervical cord injury, the patient was transferred to our hospital for further rehabilitation. He was fully conscious and received pressure-support mechanical ventilation with back-up rates of 16 breaths. He had total tetraplegia below shoulder girdle muscles with a preserved sensation from C2 to C3 on both sides, and a urinary obstruction. The limbs and trunk were stiff with contracture, and muscle stretch reflexes of the limbs were abolished. Neurological level of injury was C3 according to the ISNCSCI, with a total sensory score of four. There was no sensory sacral sparing, while the deep anal pressure was preserved, and the American Spinal Injury Association scale graded B. Chest roentgenogram and computerized tomography showed bilateral, widespread atelectasis. The patient occasionally showed signs of pulmonary infection. Intensive pulmonary care and rehabilitation, including physical support for expectoration, mechanically assisted removal of tracheal secretions (CoughAssist E70®, Philips Japan, Tokyo), ventilator muscle training, and management of the spasticity of the abdominal wall, resulted in the improvement of the roentgenological findings. His expiratory tidal volume (VT) measured 150 mL. Although the neurological status according to the ISNCSCI was unchanged, the patient was willing to be weaned from mechanical ventilation as his general condition improved. After informed consent was given, we attempted automated weaning from mechanical ventilation using IntelliVent®-ASV on and after 131 days of injury. IntelliVent®-ASV (Hamilton Medical AG, Switzerland) is a closed-loop ventilation mode that adjusts the pressure support in terms of the percentage of the ideal minute volume (%MV). The ideal MV (100%MV) is calculated from the patient’s height and gender. Based on Otis’ equation [], adaptive support ventilation will select the best VT–respiratory rate (RR) coupling for the optimal work of breathing. IntelliVent®-ASV has interrelated functions: an auto-adjustment for carbon dioxide (CO2) elimination, an auto-adjustment for oxygenation, an auto-weaning tool named Quick Wean (QW), and a spontaneous breathing trial (SBT). The setting of the target %MV is automated based on either the monitored end-tidal CO2 or monitored spontaneous breathing rate. The auto adjustment of fraction of inspiratory oxygen or positive end-expiratory pressure is based on the monitored oxygen saturation fraction of hemoglobin with a pulse oximeter (SpO2) []. The QW mode is an optional automated weaning, and progressively reduces the pressure support, monitors for readiness-to-wean criteria, and provides the option to automatically conduct a fully controlled SBT. In the QW mode, when the spontaneous rate is less than the upper limit of the predicted target range, %MV is automatically decreased gradually to the selected level. To facilitate the recovery of VT by means of the loading work on respiratory muscles, we set the level of support to 70%MV for the QW mode. When spontaneous breathing satisfied the pre-determined conditions of oxygenation and ventilation for 1 min, the SBT mode was used. We operated the SBT mode during the day from 9:00 a.m. to 6:00 p.m. In the QW mode, the duration of 70%MV and SBT time (25%MV) increased gradually (Figs. and ). Twenty-two days after the introduction of the QW and SBT modes in association with intensive pulmonary rehabilitation, SBT was running almost fully during the daytime. At this time, the expiratory VT was increased to 350 mL from 150 mL upon admission to our hospital. Thereafter, we withdrew the pressure support ventilation during the nighttime 39 days after the introduction of the auto-weaning mode, and the patient’s weaning process was completed.

pmc-6008505-1

A fifty-six-year-old hypertensive male came in for consult due to an inability to abduct the right eye. History of the present illness started about thirty-four years prior when he first noted a limited abduction of the right eye. During the interim, he noted a gradually progressive limitation in all movements of the right eye, and a limitation in adduction of the left eye, associated with occasional diplopia. No consults were sought until a month prior when he noticed a sudden-onset right-sided facial weakness and dysarthria, with no hemiparesis or hemiplegia. The patient came into the clinic with good visual acuity, good color vision, and no relative afferent pupillary defect, but with a right horizontal conjugate gaze palsy, a limitation of adduction of the right eye with associated nystagmus of the left eye on abduction, and a right peripheral facial nerve palsy demonstrated by a four-millimeter lagophthalmos, a shallow nasolabial fold, and an inability to wrinkle the forehead. The rest of the neurologic examination was unremarkable. Slit lamp examination was also essentially unremarkable except for immature cataracts. Indirect ophthalmoscopy showed evidence of hypertensive retinopathy on both eyes. Figure 1 shows the patient’s extraocular muscle movements in a composite diagram. There is a right horizontal gaze palsy and a limited adduction of the right eye. The sole extraocular muscle movement remaining is an abduction of the left eye. Figure 2 highlights the peripheral facial nerve palsy. The patient has a shallow nasolabial fold on the right, a four-millimeter lagophthalmos on the right, and weakness of the occipitofrontalis, corrugator supercilli and procerus muscles. On magnetic resonance imaging, there is a hemorrhage with a complete hemosiderin ring at the level of the pons/ponto-medullary junction, associated with a well-defined lesion with a “popcorn ball” appearance resembling that of a cavernoma (Figure 3 , Figure 4 , and Figure 5 ). The patient was co-managed with neurosurgery and neurology services for possible resection.

pmc-6008506-1

A 21-year-old female presented with complaints of seeing a black spot in front of the right eye associated with distortion of the central vision of one week duration. There was no history of trauma. Best-corrected visual acuity (BCVA) in both eyes was 20/20. Anterior segment examination was essentially normal in both eyes. Fundus examination of the right eye revealed a yellowish-gray subretinal lesion with subretinal fluid supero-temporal to the fovea and pigment epithelial detachment (Figure 1 ). The lesion spared the fovea. Optic disc and retinal vasculature appeared normal and no vitreous cells were noted. Fundus examination of the left eye was normal. The patient was a diagnosed case of factor VIII deficiency about a month back. Her coagulation profile and hemogram were normal. However, factor VIII – C level was 37.5% (Normal range 50–150%). Fundus fluorescein angiography (FFA) revealed a classic extrafoveal choroidal neovascular membrane (CNVM) (Figure 1 ). Focal laser photocoagulation to the CNVM was done after discussing the treatment options with the patient. The patient reported after 6 weeks with visual acuity in the right eye 20/30, N6. Clinical examination revealed a regressing extrafoveal neovascular component and an active juxtafoveal neovascular component. Clinical findings were confirmed on FFA and optical coherence tomography (OCT) (Figure 2 ). The patient was treated with photodynamic therapy (PDT) followed by intravitreal triamcinolone acetonide (IVTA) injection (4 mg/0.1 ml) 2 days later. After 6 weeks, visual acuity in the right eye was 20/30 and the intraocular pressure (IOP) was 32 mmHg. Topical Timolol maleate 0.5% twice a day was started. Since there was persistent hyperfluorescence related to the extrafoveal CNVM, thermal laser photocoagulation was done. With treatment, IOP came down to 12 mmHg in 2 weeks and the same treatment was continued. On the next visit eight weeks later, visual acuity was 20/60, N10. Clinical examination revealed recurrence of the juxtafoveal choroidal neovascular membrane, which was confirmed on FFA and OCT. The patient was treated with four intravitreal injections of bevacizumab (1.25 mg/0.05 ml) at an interval of 4–6 weeks. The IOP was found to have normalized and hence topical antiglaucoma treatment was stopped. Six weeks after the fourth injection, visual acuity in the right eye improved to 20/30, N6. CNVM appeared scarred (Figure 3 ). However, there was persistent leakage on FFA. The patient was treated with a combination of PDT and intravitreal bevacizumab. After 7 weeks, visual acuity improved to 20/20. Clinically, CNVM appeared scarred. The patient was followed up at intervals of 2 weeks. Fourteen weeks later, the patient reported with an increase in distortion in the right eye. BCVA was 20/20 in the right eye. OCT showed subretinal fluid and FFA showed recurrent extrafoveal CNVM. The patient was treated with intravitreal bevacizumab (1.25 mg/0.05 ml). The patient was seen six weeks later when she reported resolution of symptoms; her visual acuity was 20/20. Clinical findings were confirmed on OCT and FFA (Figure 4 ). When seen last (i.e. 10 years post bevacizumab injection), BCVA was maintained at 20/20 and the fundus remained stable.

pmc-6008534-1

A 54-year-old woman with all limbs intact received BPA in advance of right thumb carpometacarpal arthroplasty with ligament reconstruction. Immediately after BPA onset, she felt her right forearm and hand resting across her chest when it was hanging over the side of the gurney. After surgery, her right hand felt “heavy” with the fingers stacked vertically on top of each other, as shown in Figure . She began experiencing right thumb pain 14–16 h after the operation had been completed. However, the sensation of immobility of her 2nd through 5th digits in the stacked position lasted for ~3.5 days after surgery and 69 h after the anesthesia wore off. During this time, although the patient described the phantom sensations as being uncomfortable, she experienced no pain in the fingers. No nerve conduction studies were performed. This study was carried out in accordance with the recommendations of the University of Tennessee Health Science Center. The procedure discussed in this report was not part of a research study but rather routine clinical care. The subject gave written informed consent for publication of her clinical details in accordance with the Declaration of Helsinki.

pmc-6008614-1

A 70-year-old man presented to the emergency department (ED) after falling twice at home. While standing after eating a light meal, he had two separate episodes of brief loss of consciousness. On the second fall, the patient had hit his right shoulder, cheek, and foot, prompting the visit. The patient had received a colonoscopy earlier in the day for routine cancer screening. He had followed proper protocol regarding his bowel prep and had not had any immediate complications related to the procedure or anesthesia. Since the colonoscopy, he had continuous bouts of cramping abdominal pain. He had also felt dizzy throughout this period but attributed it to dehydration related to his bowel prep. The patient denied striking his head, chest pain, shortness of breath, nausea, vomiting, or blood in his stools. His past medical history was significant for coronary artery disease, hyperlipidemia, and hypertension. The patient took his benazepril, aspirin, and atorvastatin on the day prior to colonoscopy. On physical exam, the patient was afebrile with a heart rate of 87 and blood pressure of 130/78. The patient's head, neck, chest, and neurological exams were entirely normal. His abdominal exam was remarkable for tenderness in the right and left lower quadrant with some voluntary guarding, but no masses or rebound was appreciated. His orthopedic exam demonstrated tenderness to his right acromioclavicular joint and ecchymosis of his right 5th metatarsal with no deformity and normal range of motion at all joints. On laboratory evaluation, the patient's hemoglobin was 12.4 g/dL, with normal platelets and chemistry studies. Head computed tomography (CT) and shoulder and chest radiography were normal. Foot radiography demonstrated a nondisplaced 5th metatarsal fracture. CT of the abdomen and pelvis demonstrated moderate hemoperitoneum with splenic laceration (Figures , , and ). The patient was admitted to the intensive care unit and underwent serial abdominal exams and every four-hour hemoglobin measurements. His hemoglobin fell to 8 g/dL at 48 hours after admission but subsequently stabilized. The patient was observed in the hospital and ultimately discharged home on hospital day 3 in good condition.

pmc-6008617-1

A 36-year-old woman (height, 147 cm; weight, 50 kg) with CIPA was scheduled for revision of left total hip arthroplasty. She was diagnosed as having CIPA because of recurrent episodes of unexplained fever, anhidrosis, burns, and bone fractures after birth. She had previously undergone 7 operations for spinal deformity and 1 operation of total hip arthroplasty in both the left and right sides. Although lack of general diaphoresis and thermal nociception were observed, the patient performed body surface cooling at her own discretion when she felt she was at a risk of hyperthermia, and her body temperature was kept approximately 36°C. No signs of mental retardation or orthostatic hypotension were observed. No abnormality was detected on chest radiographs and electrocardiograms. Blood biochemistry revealed no abnormality except mild anemia indicated by a hemoglobin level of 10.6 g/dl. No premedication was administered. After the patient was brought into the operating room, routine monitoring and measurement of the bispectral index (BIS) were started. Body temperature was measured at 3 different sites (urinary bladder, esophagus, and precordial skin) and controlled by a hot-air-type heater. Propofol was administered at an effect-site concentration of 4 μg/ml by target-controlled infusion. After muscle relaxation had been achieved by administration of 50 mg of rocuronium, the trachea was intubated. Immediately after endotracheal intubation, systolic blood pressure increased from 130 to 145 mmHg, and heart rate increased from 60 to 95 beats per minute (bpm). Two minutes later, systolic blood pressure had decreased to 125 mmHg. Propofol was continuously infused intravenously at a target concentration of 2 to 4 μg/ml () and BIS levels were maintained between 40 and 60. After an arterial catheter had been placed, her position was changed from the supine to right lateral position. Surgery was then started. Since no circulatory change associated with pain occurred during surgery, opioids were not administered. Regarding hemodynamics, when 600 ml of blood was rapidly lost within 20 minutes, blood pressure decreased from 113/66 to 93/55 mmHg and heart rate increased from 55 to 70 bpm ( a). Similarly, when 850 ml of blood was lost within 30 minutes, systolic blood pressure decreased from 108/65 to 95/60 mmHg and heart rate increased from 66 to 74 bpm ( b). Administration of 0.1 mg of phenylephrine increased blood pressure from 87/55 to 117/76 mmHg and decreased heart rate from 70 to 65 bpm ( c). The operative time was 6 hours and 49 minutes, and the duration of anesthesia was 8 hours and 41 minutes. The volume of blood loss was 3350 ml. Blood transfusion was performed with 1600 ml of preoperatively donated autologous blood, 900 ml of salvaged blood, and 720 ml of fresh frozen plasma. Intraoperative body temperature was controlled and kept between 36.0°C and 36.9°C at all 3 measurement points. After surgery had been completed, the patient was returned to the supine position and she was extubated. Since she did not complain of any pain after the surgery, no analgesic was administered. She was discharged at 6 weeks after the operation. Blood samples were collected 3 times: before anesthesia induction, after the start of surgery, and at the end of surgery. The levels of catecholamine fractions and cortisol were measured. Norepinephrine levels were below the normal range at all time points, and the levels of epinephrine and cortisol were within the normal ranges at all time points ().

pmc-6008645-1

The first patient, who was a man in his late seventies with an unremarkable previous medical history, presented with isovascular nodule accompanied by slow venous wash-out on abdominal dynamic CT in the left lobe of liver. The laboratory data, including the blood cell count, chemistry, and tumor marker levels, were within the normal limits, with the exception of mildly elevated CRP (0.39 mg/dL) and decreased hemoglobin (8.9 g/dL) levels. Neither infection of HBV nor infection of HCV was noted. Based on the clinical findings, the initial diagnosis by the clinicians was most likely HCC, and, thus, left partial hepatectomy was performed. On gross examination, the cut surface of hepatic nodule () showed a poorly demarcated peripheral nodule in lobulated margins, measuring 32 x 21 mm in diameter, which appeared clearly whitish in color. The background of this liver showed no remarkable change (). A microscopic examination of the tumor demonstrated an unencapsulated, ill-defined, and expansive nodule (). This cancerous nodule showed a solid proliferation of atypical epithelial cells, arranged predominantly in solid nests (), trabeculae, and/or ill-defined, fused tubule-like structures (). On a high-power view, these atypical cells were small-to-medium-sized and relatively uniform, having enlarged hyperchromatic nuclei and scant cytoplasm without any evidence of intracytoplasmic mucin (). Intriguingly, prominent fibrous stroma was not evident in this tumor. Immunohistochemistry revealed that the abovementioned carcinoma cells were specifically positive for not only CK7 (cholangiocytes marker) but also CK8/CK18 (markers for both hepatocytes and cholangiocytes) and CK19/CD56 (potential stem cells markers), whereas they were negative for Hepatocyte (hepatocytes marker) [, ]. Based on all of these features, the final diagnosis was primary CHC-INT. To date, this patient has been followed up for 1 year since surgery, and he remains well without any sign of recurrence.

pmc-6008645-2

The second patient, who was also a man in his early seventies with more than 25-year follow-up for HCV-positive chronic hepatitis and recurrent HCC, presented with mildly hypervascular and ring-enhanced nodule accompanied by venous wash-out on abdominal dynamic CT in the S5 of the remnant liver. The laboratory data were mostly within the normal limits, with the exception of mildly elevated AST (37 IU/L), total bilirubin (1.8 mg/dL), and CEA (5.55 ng/mL) levels. No infection of HBV was observed. Based on the clinical findings, the initial diagnosis by the clinicians was recurrent HCC, and, thus, partial S5 hepatectomy was performed. On gross examination, the cut surface of hepatic nodule () showed a poorly demarcated portal nodule in lobulated margins with central necrosis, measuring 35 x 26 mm in diameter, which appeared clearly whitish in color, accompanied by not only gross but also histopathological portal vein permeation (). A microscopic examination of the tumor showed an unencapsulated, ill-defined, and expansive/infiltrative nodule, displaying a solid proliferation of atypical epithelial cells, arranged predominantly in solid nests, trabeculae, and/or irregular and fused tubule-like structures, aggressively involving the portal vein with focal perineural invasion (). On a high-power view, these atypical cells were very similar to those of the abovementioned first case. Prominent fibrous stroma was not seen either. The background of this liver showed mild chronic hepatitis (F1/A1) and steatosis. Immunohistochemistry showed that those carcinoma cells were specifically positive for not only CK7 () but also CK18 () and c-kit (potential stem cells marker) [, ], whereas they were negative for CK8, Hepatocyte, and CD56. Based on all of these features, the final diagnosis was primary CHC-INT as well. The recurrence of CHC-INT in the remnant liver occurred 1 year and 3 months after this surgery, but he remains not worse with follow-up for the postoperative 2 years.

pmc-6008661-1

A 62-year-old male presented with refractory sacral coccygeal pain. The patient had past medical history of type 2 diabetes mellitus (treated with linagliptin/metformin), nontreated high blood pressure, right-sided hemiparesis following meningitis in childhood, nephrolithiasis, and smoking history. The pelvic computed tomography (CT) revealed a 9x7.5x9 cm bulky mass in the sacrum with locally increased soft tissue density, causing extensive lytic lesions of the sacred vertebrae and extending to the left iliac bone, suggestive of chordoma. The patient underwent total sacrectomy with partial excision and reconstruction of the left iliac bone. The anatomopathological examination revealed sacrococcygeal involvement by a thyroid carcinoma, as verified by immunohistochemical staining for thyroglobulin and TTF-1, predominantly papillary (follicular variant), however with foci of nondifferentiated (insular) carcinoma (Figures and ). Thyroid ultrasonography showed a solid nodule of 20 mm in the right lobe and two solid hypoechogenic nodules of 11 and 9 mm in the left lobe, the smallest with coarse calcifications. No lymphadenopathies were found. 18F-fluorodeoxyglucose positron-emission tomography (18F-FDG-PET) revealed a hypermetabolic focus in the left lobe of the thyroid, consistent with the suspected malignant neoplasia, and uptake of the radiopharmaceutical drug in the fifth lumbar vertebra and pelvic bones, consistent with secondary involvement (). Consequently, the patient underwent total thyroidectomy. Histological examination revealed only follicular and oxyphilic variants of multifocal papillary carcinoma (at least six foci) and none of insular carcinoma, with dimensions ranging from 2 to 15 mm, without signs of hematogenic, lymphatic, or perineural permeation, as well as no signs of invasion of the capsule or extrathyroidal extension, with resection margins uninvolved by tumour (pT1b[m]NxM1R0) (). Radioactive iodine therapy (RAI) was then performed. Posttherapy scintigraphy showed hyperfixation in the remnants of the sacrum and lower lumbar spine, bilateral iliac bone, and anterior cervical region (). TSH-stimulated thyroglobulin was 24490 ng/mL. Follow-up magnetic resonance imaging (MRI) revealed persistence and progression of the pelvic lesion. At this time the patient was unable to walk, had a chronic indwelling bladder catheter, suffered from fecal incontinence, and presented with uncontrolled refractory chronic pain.

pmc-6008661-2

A 64-year-old male presented with pain in the left iliac region for 6 months. His past medical history was significant for gastric peptic ulcer disease (submitted to partial gastrectomy and chronically treated with lansoprazole), nephrolithiasis, and hyperuricemia. At admission a poorly defined mass on the left posterior iliac crest was palpable. The patient underwent a pelvic CT, which revealed a 9 cm lytic lesion of left iliac bone with soft tissue involvement (). A biopsy was performed and the histological examination and immunohistochemical staining for thyroglobulin and TTF-1 showed iliac involvement of a well-differentiated thyroid carcinoma (Figures and ). Thyroid ultrasonography disclosed a poorly defined 8 mm nodule in the left inferior lobe, heterogeneous and partially calcified, and a 4 mm hypoechoic nodule in the right lobe, without associated lymphadenopathies. The patient was submitted to total thyroidectomy and anatomopathological examination revealed a 1.1 cm papillary carcinoma, of follicular variant, with capsular invasion and limited extrathyroidal extension (ETE). Consequently, RAI therapy was performed. Postablative 131 iodine scintigraphy and 18F-FDG-PET () did not reveal further lesions. TSH-stimulated thyroglobulin was 185051 ng/mL. The patient is currently waiting for a hemipelvectomy.

pmc-6008675-1

A 57-year-old Japanese man was admitted to our hospital with a chief complaint of back pain and fever for one month. A computed tomography (CT) scan showed an aneurysm of the infrarenal aorta, with a diameter of 34 mm, and inflammation of the surrounding adipose tissue, nodular lesions of the bilateral lungs, and left maxillary sinusitis (). He was referred to our hospital for further evaluation and treatment. At the time of admission, the patient was 168 cm tall and weighed 56.6 kg. His blood pressure was 98/69 mmHg, pulse was 84 beats per minute, and body temperature was 39.6°C. Serum creatinine was 0.66 mg/mL, and urinalysis showed 1+ occult blood; urinary sediment contained 20 red blood cells per high-power field. Serum analysis showed leukocytosis (10,000/μL) and an elevated C-reactive protein level (29.5 mg/dL). The anti-PR3-ANCA level was 187 IU/mL, and the anti-MPO-ANCA level was normal. The abdominal aortic aneurysm was suspected to be infected, and we began administering antibiotics. The patient's general medical condition failed to improve. The clinical findings of left maxillary sinusitis, multiple nodular lesions in the lungs, fever, and positive anti-PR3-ANCA were clinically suspicious for GPA. Video-associated thoracoscopic lung biopsy was performed. The biopsy specimens demonstrated granulation tissue with necrosis and multinucleated giant cells (). Most infiltrating cells were neutrophils. The ratio (%) of IgG4 to total IgG-positive cells was 33%, and there were 60 IgG4+ plasma cells per HPF in the lung. The patient was diagnosed with GPA. He was treated with an intravenous semipulse dose of methylprednisolone, followed by oral prednisolone 1 mg/kg (55 mg) per day and intravenous administration of cyclophosphamide (700 mg/body once per month). All of the patient's symptoms and CT findings rapidly improved (), and the PR3-ANCA level promptly decreased to the normal range. The diameter of the aneurysm changed from 34 mm to 21 mm after treatment. On tapering doses of steroids, the patient is currently in remission, and the inflammation and PR3-ANCA elevation have completely resolved. There has been no disease recurrence for 4 years after initiation of therapy.

pmc-6008686-1

A 55-year-old male presented to the emergency department 3 weeks after right frontal nodule resection of his multifocal glioblastoma multiforme. The tumor was also in the corpus callosum and the right pontine area. The patient was known to have high ICP (confirmed by magnetic resonance imaging) due to the mass effect of the tumor for which a debulking surgery was done. Recovery from surgery went well, and the patient had a residual left-sided weakness and was able to ambulate by using a walker at discharge. At presentation to the emergency department, the patient had 2 episodes of unprovoked syncope with nausea, somnolence, and worsening of his left-sided weakness. The patient's past medical history was insignificant except for controlled hypertension and epilepsy. The patient's home medications were dexamethasone, levetiracetam, hydromorphone, perindopril, amlodipine, and pantoprazole. While in the emergency room, the patient was noted to have a temporary pause on the cardiac monitor which was symptomatic. The patient's vital signs on admission were a Glasgow Coma Scale of 15, blood pressure of 132/86, heart rate of 61, and respiratory rate of 18 (regular), afebrile, and an oxygen saturation at 94% on 2 L/min of oxygen. When the oxygen was removed, the patient's respiratory rate decreased to 12, oxygen saturation dropped to 89%, and the patient became nonalert. An EKG was done which showed multiple intermittent sinus pauses of durations of 4–6 seconds. The blood work and urine analysis were all within the normal range. A diagnosis of SSS was made, and the patient was admitted to the CCU for pacemaker implantation. While admitted to the CCU, his EKG showed intermittent sinus pauses with the longest having a duration of around 3.6 seconds. A pacemaker was inserted. A 24-hour monitoring post procedure was uneventful, and the patient's telemetry showed a normal sinus rhythm in the 80s to 90s with no paced beats. The patient was then discharged home to be followed up at the pacemaker clinic. During the follow-up, the patient's hemiparesis did not recover and was still using the walker to ambulate. A computed tomography (CT) scan done later showed rapid progression of all lesions, except the one in the pons, with vasogenic edema. There was a significant mass effect with midline shift and uncal herniation.

pmc-6008689-1

A 66-year-old phototype 6 woman from North-Africa was admitted to our department due to an indolent ulcerovegetative mass that developed on the anterior face of the right thigh. The lesion spontaneously exhibited greyish discharge. The patient anamnesis revealed that she had sustained a hot-water burn to her leg at the age of 11 years. She stated no definitive treatment by skin grafting and had only been treated conservatively following injury. The burned right thigh healed progressively, leaving a large scar on the skin surface. There had been no particular issues concerning the lesion until 2 months previously, at which point the patient noticed a progressive mass in the scar area but had not taken any steps to have it cured. Upon physical examination, the mass was 4 x 2 cm and suggested at diagnosis of Marjolin's ulcer (Figures and ). Histopathologic features of the surgical specimen were characterized by predominant chondroid matrix with marked cellularity, high grade atypia, and high mitotic activity. Foci of bone and osteoid formation were also seen (Figures and ). A diagnosis of cutaneous extraosseous osteosarcoma was suggested after excluding an origin in bone or other primary tumor sites by computed tomography. Indeed, clinical examination and extensive total body radiologic workup revealed absence of bone lesions in any body site. Unfortunately, the patient rejected the therapeutic proposal of definitive large surgical excision and we failed to obtain any notice regarding her further evolution.

pmc-6008691-1

A 48-year-old woman, gravida 1, para 1, visited the internal medicine department at another hospital with a complaint of abdominal fullness and weight loss of 10kg during the last year. A huge abdominal mass was palpated, and she was referred to the gynecology department to search for a tumor of uterine origin. She was premenopausal and had no significant past medical history. Physical findings revealed a large elastic hard mass extending from the xiphoid to the pubic bone. The magnetic resonance imaging (MRI) examination revealed a huge tumor on the uterine corpus, and a number of dilated vessels were observed between the tumor and the myometrium. Therefore, the tumor was suspected to derive from the uterus. The tumor showed an uneven signal on T2-weighted sagittal section (), and the enhanced MRI study showed that the tumor edge but not the center was enhanced (). As such, necrosis was suspected to have occurred in the center of the tumor. Uterine sarcoma was primarily suspected due to the large size, degeneration, and necrosis on MRI imaging. Computed tomography (CT) examination showed no lymph node swelling or distant metastasis. Preoperative laboratory testing revealed anemia (hemoglobin level, 5.6g/dl). We transfused 18 units of RCC before surgery. CT examination and ultrasonography on lower extremities indicated an absence of thrombosis. Preoperative serum levels of CEA, CA 19-9, CA 125, and LDH were within normal limits. A biopsy of the endometrium was not collected as the sounding examination of the endometrium was unsuccessful due to a deviated uterine cervix. At this point, preoperatively, we suspected the tumor was a leiomyosarcoma or leiomyoma with degeneration. The patient underwent laparotomy, where we identified a huge tumor occupying a space from the pelvis to the diaphragm. The tumor surface was smooth and hard with many dilated veins (). A massive tumor with a diameter of 30 cm was observed arising from the posterior uterine wall with a smooth contour and invaded the retroperitoneal cavity under the mesentery. The tumor was firmly adhered to both the mesentery and right ovary. There were no findings of extra-uterine dissemination. The intraoperative frozen section report for the uterine tumor was of degenerated myoma with no findings indicating malignancy. A total abdominal hysterectomy (TAH) and right salpingo-oophorectomy (RSO) were performed. The operation duration and blood loss were approximately 216 minutes and 1000 ml, respectively. The excised specimen weighed 7600 g. Macroscopic findings of the tumor revealed a well-circumscribed tumor showing extensive continuity with the posterior wall of the uterus, measuring 28 × 23 cm (). On the sliced surface of the tumor, an obvious heterogeneous pattern was recognized within the mixture of a whitish homogeneous area, suggesting benign uterine fibroids, and a vulnerable area, due to bleeding and necrosis (). For the intraoperative frozen section, we examined three areas, namely, a white homogenous part, a necrotic part, and a cystic part, of which all were findings of a leiomyoma. In the permanent histological examination, 10 additional sections were collected from the tumor. The basic histological findings of all the sections were the same. The tumor was comprised of spindle-shaped cells, homologous to smooth muscle cells, which were arranged in bundles with areas of hyalinization, consistent with a degenerated leiomyoma. The tumor was mostly comprised of degenerated uterine leiomyoma. However, enlarged blood vessels were observed within an area of approximately 2 cm × several mm, and proliferation of atypical cells showing a fine meshwork microvascular structure was observed in the blood vessel cavity (). These atypical cells consisted of various contours, such as cubic, polygonal, and short spindle shape. The nucleus was circular with a high degree of vacuolar enlargement and pleomorphism. Abnormal mitotic figures were also interspersed (). A tumor derived from a blood vessel was thus considered, and malignancy was suggested by the presence of nuclear atypia and abnormal mitosis. Immunohistochemical analysis revealed the atypical tumor cells to be positive for ERG, CD31, and AE1/3 (Figures and ), partially positive for Factor VIII, and negative for α-SMA, desmin, H-caldesmon, EMA, CD34, and D2-40. From the above, the atypical tumor cells were of epithelial origin and the final diagnosis was epithelioid angiosarcoma arising in a degenerated uterine leiomyoma. The efficacy of postoperative adjuvant therapy for angiosarcoma has not been demonstrated and there is currently no established chemotherapy regimen. In this case, because the atypical tumor was observed in the blood vessel cavity, we thought it could have been spread hematogenously throughout the body. Hence, we selected adjuvant chemotherapy rather than adjuvant radiotherapy. Six courses of combination adjuvant chemotherapy with paclitaxel (150mg/m2), epirubicin (50mg/m2), and carboplatin (area under the curve = 4) were administered in the present case, following referral to previous reported cases. No recurrence has been observed 10 months after the primary surgery.

pmc-6008761-1

A 60-year-old woman came to our attention for abdominal pain, distension, and weight loss (about 6 kg in two months). Abdominal examination revealed a bulky mass occupying the right abdominal quadrants. She was submitted to laboratory routine tests without evidence of chronic liver disease and no alterations of serum tumor markers. Computed tomography (CT) scan confirmed the presence of an expansive mass (15 × 12 × 23 cm), poorly separable from the surrounding liver parenchyma, with heterogeneous contrast enhancement. The lesion was partially cystic with thickened walls and an intralesional solid component (). After multidisciplinary discussion with radiologist and oncologist, indication to surgery was given and the patient underwent laparotomy. At exploration, a well-defined, partially cystic tumor was found originating from the fifth and sixth hepatic segments and adherent to—but not infiltrating—the right colon and omentum. En bloc resection of the mass and a S5-S6 liver bisegmentectomy were performed. The postoperative period was uneventful, and the patient was discharged on sixth postoperative day. The surgical specimen consisted of a lobulated yellow-reddish neoplasm sized 33 × 19 × 11 cm, with gelatinous cystic and hemorrhagic areas on cut surface. A fibrous discontinuous pseudocapsule separated the tumor from the adjacent compressed liver parenchyma. Microscopically, the tumor was composed of stellate or spindle shaped cells with bizarre morphology and ill-defined outlines, loosely arranged in an abundant myxoid matrix (). Scattered tumor cells with marked nuclear abnormalities and hyperchromasia, as well as multinucleated giant cells, were present. Atypical mitotic figures were easily found. Characteristically, tumor cells showed multiple, different-sized, eosinophilic, PAS-positive globules in the cytoplasm. Immunostainings revealed CD10, CD68, and vimentin expression in tumor cells, with focal and weak expression of wide spectrum cytokeratins (AE1/AE3) (). These features were sufficient for the diagnosis of UESL. After the definitive histological diagnosis and multidisciplinary evaluation, the oncologist proposed an adjuvant therapy of six cycles with vincristine, actinomycin D, and cyclophosphamide, which was accepted by the patient. 30 months after surgery, she is alive without signs of recurrence.

pmc-6008769-1

A 14-year-old male with DMD has been on daily oral steroid since 9 years of age. He weighed 53 kg (47th percentile) and was 147 cm tall (less than 3rd percentile). He became nonambulatory at 12 years of age. Forced vital capacity (FVC) was 2.37 L or 80% predicted. A polysomnogram was completed and revealed moderate obstructive sleep apnea. His echocardiogram (ECHO) was normal with cardiac magnetic resonance imaging (MRI) demonstrating normal left ventricular ejection fraction (LVEF). He participated in many school activities including wheelchair soccer. He presented to the emergency department with confusion, tachycardia, tachypnea, and fever up to 39.2 degrees Celsius a few hours following soccer practice. During practice, he had been transferred from his wheelchair and his right leg had brushed the ground causing him to have to be placed on the ground until more help was obtained to put him back in his wheelchair. Brain computed tomography (CT) was negative for any acute intracranial process contributing to his current state. Chest computed tomography (CT) scan was negative for pulmonary embolism but showed patchy diffuse nodular airspace opacities seen scattered throughout both lung fields (). He had progressive acute hypoxic respiratory failure requiring mechanical ventilation. Shortly after intubation, he suffered cardiac arrest requiring 3 minutes of cardiopulmonary resuscitation (CPR) before return of spontaneous circulation. ECHOs were consistent with increased pulmonary vascular resistance including moderate right ventricle dysfunction and elevated pulmonary arterial pressure. Duplex ultrasound evaluation of lower extremities was without evidence of deep venous thrombosis bilaterally. X-rays of lower extremities revealed cortical step off at the proximal left femoral neck and nondisplaced fracture at the distal right tibial metaphysis and fibular metaphysis (). Ophthalmologic exam revealed Purtscher-like retinopathy. The patient was treated with 48 hours of antibiotics that were discontinued with negative blood, urine, and mini bronchoalveolar lavage (BAL) culture. The patient was treated with mechanical ventilation and right ventricular afterload reduction with milrinone and inhaled nitric oxide for pulmonary hypertension. These therapies were able to be weaned off, and the patient was able to be extubated on day five of admission. He was later transferred to the pediatric floor and later discharged home without any residual effects from the entire event.

pmc-6008769-2

An 11-year-old male with DMD has been on daily oral steroid since 9 years of age. He weighed 30 kg (5.6th percentile) and he was 120 cm tall (less than 3rd percentile). He is able to ambulate without assistance. FVC was 1.5 L or 96% predicted. His ECHO was normal with cardiac MRI demonstrating normal LVEF. He sustained a nondisplaced Salter-Harris type II fracture of the distal left femur () from a fall that required surgical fixation and was able to be discharged home on the day of operation. He presented to the emergency department two days after his operation with seizure, tachycardia, tachypnea, and fever up to 38.6 degrees Celsius. He had progressive acute hypoxic respiratory failure requiring mechanical ventilation. Shortly after intubation, he developed pulmonary hemorrhage and anemia remedied with fresh frozen plasma, ventilator adjustments, and blood transfusion. A fast spin MRI of his head was negative. CT scan of his chest demonstrated bilateral patchy infiltrates; no pulmonary embolism was identified (). ECHO revealed mildly elevated tricuspid regurgitation velocities representing increased right ventricular and pulmonary artery pressures. He was placed on broad spectrum antibiotics for 72 hours but blood, urine, and mini BAL remained negative. Mechanical ventilation was able to be weaned and the patient was extubated on day five of admission. He was later transferred to the pediatric floor and later discharged home without any residual effects from the entire event.

pmc-6008772-1

Twin 1, a three-year-old Caucasian boy, was initially referred by his family physician with photophobia and frequent blinking of the left eye to Royal North Shore Hospital. He had varicella-zoster virus (VZV) keratitis of the left eye with positive VZV on Polymerase Chain Reaction (PCR) and was treated with intravenous acyclovir and topical acyclovir. His symptoms and follow-up examinations showed resolution. One year from this presentation, best-corrected visual acuity (BCVA) in the right was 20/80 and could not be obtained in the left due to objection to occlusion. Examination under anaesthesia (EUA) revealed corneal neovascularization bilaterally (Figures -). There was blepharitis and conjunctivitis bilaterally, with a stromal infiltrate and overlying epithelial defect in the right eye. He was investigated for causes of interstitial keratitis and corneal neovascularization. Blood tests, and corneal and conjunctival swabs were unremarkable (). Given the results and EUA findings the diagnosis was staphylococcal hypersensitivity/chronic blepharokeratoconjunctivitis (BKC) secondary to meibomianitis, with corneal neovascularization and scarring [, ]. He was prescribed oral erythromycin (160mg, twice a day), chloramphenicol ointment (1%, three times a day) for both eyes, and topical fluorometholone (0.1%, twice a day) for the left eye. Review two weeks later showed progressive corneal neovascularization and infiltrate. Due to the progression despite conventional treatment and to aid compliance with the treatment, the decision was made for subconjunctival triamcinolone acetonide and bevacizumab, with regular EUA for treatment and monitoring of progress and side effects. Two weeks later, he received subconjunctival triamcinolone (4mg/0.1mL × 0.55mL) to the inferior conjunctiva and subconjunctival bevacizumab (2.5mg/0.1mL × 0.05mL) to the superior conjunctiva of the right eye. Extensive lid hygiene including 5% povidone-iodine lid scrubs and Meibomian gland expression was performed, and this was repeated at subsequent EUA. Intraocular pressures (IOP) by iCare® tonometer (iCare Finland) were 14mmHg in each eye. He continued on the same medication regimen and SteriLid (TheraTears®) two to three times per week. Six weeks after the injections, the mother of Twin 1 reported significant improvement in his symptoms. At EUA eight weeks after the injections, the right cornea looked markedly improved (Figures -). IOPs were 12mmHg in the right and 6mmHg in the left eye. Given that there had been dramatic improvement with no significant side effects observed, he was continued on the same regimen and the left eye was injected with the same dose of triamcinolone and bevacizumab. At EUA 11 weeks after the left eye injections, there was quiescent interstitial keratitis. Adjunctive diathermy was applied to the patent superior and inferior feeder vessels in the left eye. Further subconjunctival triamcinolone (4mg/0.1mL × 0.5mL) was injected inferiorly in each eye. Binocular BCVA (due to objection to occlusion) was 20/63. At EUA 5 months after the further bilateral triamcinolone injections, there was central corneal scarring and suppressed blood vessels bilaterally (Figures -). Diathermy was applied at the limbus to further feeder vessels of each eye. IOP was 16mmHg in the right and 19mmHg in the left eye. Binocular BCVA (due to objection to occlusion) 24 months after presentation was 20/63.

pmc-6008780-1

A 59-year-old man presented to the urgent care clinic at the School of Dentistry complaining of an upper lip mass for one-year duration. The mass started out as a small bump and had grown steadily since then. 3 months prior to his presentation, a draining parulis developed on the mass. The patient had no history of systemic symptoms such as fever, chills, weight loss, or fatigue. He was aware of a dark-colored “dead tooth” for several decades in the area of concern but denied any previous history of swelling in the area. The patient had recently moved to the United States from Nigeria and had previously been without access to adequate dental care. The patient said that a doctor in Nigeria told him that the lesion was likely cancerous. On exam, there was a large, painless, fibrous, exophytic mass in the anterior maxillary labial vestibule (Figures and ). The base of the mass approximated the apex of tooth #8. A yellow purulent material was observed draining from the parulis (). Tooth #8 was discolored and was confirmed to be nonvital on pulp testing. There was a significant gap between teeth #7 and 8. Tooth #8 was displaced medially and was extruded relative to the adjacent dentition. A periapical radiograph revealed a large unilocular radiolucency associated with the apex of tooth #8 (). Cone-beam computed tomography again demonstrated a large cystic-appearing defect in the anterior maxilla with perforation of the buccal and palatal cortices . The lesion extended to the nasal floor on the ipsilateral side. The patient was referred to the oral surgery department for excisional biopsy. After tooth #8 was removed, an incision was made around the base of the stalk that connected the mass to the labial and alveolar mucosa. Sharp dissection was used to free the mass, and the specimen was sent for histopathologic analysis. The mass communicated with a cystic lesion of the maxilla. The cyst was enucleated with a curette and also sent for pathology. Perforation of the cyst through the buccal and palatal cortices was noted during the procedure. Slight undermining of the wound margins allowed for closure with resorbable sutures. At the patient's one-week follow-up (), he was doing very well. He reported minimal pain, no neurosensory disturbances, and no systemic or local symptoms of infection. He and his family were very relieved to learn that the lesion was benign. He was happy with his appearance after having the mass removed.

pmc-6008794-1

A 15-year-old female with a past medical history of obesity presented to the emergency department with a marked 90-degree flexion at the thoracolumbar region. She was able to walk only by using a walker in an unusual manner; she placed her axillae on the hand grips. The patient described constant back pain almost daily for which she took ibuprofen with moderate relief. These symptoms began three years ago following a sexual assault and have progressed significantly. As per the patient's mother, the only time the patient's spine straightened out was during deep sleep. She had no neurologic complaints, specifically denying any sensory or motor deficits, fatigue, ptosis, or any complaints consistent with any form of endocrinopathy. Her family history included siblings with epilepsy, ADHD, and mood disorders. The patient denied any substance abuse, including use of alcohol or cigarettes, as well as being sexually active. She reported no history of mood or psychotic symptoms and no suicide attempts. Despite the pain, however, the patient was not concerned with her condition. The patient herself was not interested in physical therapy or additional diagnostic testing or counseling despite her mother's encouragement. She refused a gynecological examination due to anxiety following having been a victim of sexual assault; it was unclear the extent of counseling, if any, she received following the assault. The patient was a seventh grader at a local school where she participated in extracurricular activities. She reported being well accepted by her peers. She stated having a good social support network including friends and family. Her parents were separated and she lived with her mother and brother. Physical exam revealed an obese (BMI 39.2) Caucasian female, leaning forward with the spine nearly ninety degrees at the waist. Extremities showed normal strength, sensation, and range of motion. The patient was unwilling to attempt spinal extension. Tenderness to palpation of the paraspinal muscles was present. The rest of the physical examination was unremarkable. Upon Pediatric Neurology consultation, no evidence of neuromuscular disease was found. Plain radiography of the cervical, thoracic, and lumbar spine was limited due to her deformity, but no abnormalities were noted. Magnetic resonance imaging of the same was unrevealing. Psychiatric consultation was obtained; they concluded that the patient's symptoms were likely manifestations of Conversion Disorder, following exclusion of organic causes. While she is currently receiving social services support and physical therapy; she declines psychiatric outpatient care at this time.

pmc-6008800-1

A 28-year-old female with insignificant past medico surgical history presented with one day of acute onset pain in the periumbilical region that later migrated and confined to the RIF. She had associated intermittent fever, nausea, and loss of appetite. She did not have any urinary symptoms, bowel irregularities, or gynecological complaints. Abdominal examination was performed by two senior surgeons at two different occasions; the same day had findings of guarding and rebound tenderness at RIF. Hematological tests showed polymorphonuclear leukocytosis with left shift. Biochemical tests and urinalysis were normal. Urinary pregnancy test was negative. Abdominal radiographs were unremarkable. USG could not visualize appendix and was inconclusive except for probe tenderness in RIF. CT scan of the abdomen could not be done due to unavailability. A clinical diagnosis of acute appendicitis was made assigning an Alvarado score of 9/10. Laparotomy was performed using the Lanz incision in RIF. Intraoperatively appendix was found to be normal without evidence of inflammation or infection in RIF. In view of symptoms and signs, a possibility of other pathology was thought. Walking the bowel proximally up to 3 feet (1 m) did not show a Meckel's diverticulum or any other small bowel lesions. There were no obvious mesenteric lymph nodal enlargement and pelvic organs looked pristine. Approaching closure, just when the medial edge of the incision was retracted superomedially, a hemorrhagic lesion seemed to appear little deeper in the mid abdomen. Therefore, the incision was extended transversely from the medial edge to explore further. Entire bowel was explored and this revealed an ulcerated lesion measuring 7 × 5 cm arising from the antimesenteric border of the ileum 8 feet (2.5 m) from ICJ with localized interloop hemoperitoneum and inflammatory exudates as shown in . Resection of ileal segment containing the lesion was performed followed by restoration of bowel continuity and peritoneal toileting. The lesion was subsequently reported to be an ulcerated malignant ileal GIST. Histopathologically, gross examination confirmed the operative findings, and the cut section revealed a nodular lesion protruding out of the serosal surface measuring 7 × 5 cm along with 2 lymph nodes each measuring 2 × 1 cm. Microscopically, the growth from the ileum had villous lining epithelium with focal ulceration. The submucosal region had a circumscribed nodule with proliferation of loosely cohesive spindle cells; some of which were arranged in vague storiform pattern and others in long fascicles. There were areas with epitheloid cells forming small anastomosing nests and cords. The areas in between these showed skenoid fibers along with focal areas of hemorrhage, infarction, and congestion as shown in . The mitotic figures were seen (8/50 high-power field). The lymph nodes were microscopically identified to be reactive, and the resected margins of the ileum were free of tumor. Based on tumor size and mitotic activity, possibility of a malignant GIST was suggested along with immunohistochemical analysis (CD117 and CD34) for further confirmation. The patient had an uneventful recovery and was discharged on the 8th postoperative day. She was advised to review a week later at the outpatients but failed to report. All possible contacts were used to trace her, but she remained inaccessible and lost to follow-up.

pmc-6008806-1

A 54-year-old, obese, Caucasian female, a current smoker, presented to the clinic with complaints of intermittent vaginal bleeding for approximately one week and that she “felt something” in her vaginal area. Her past medical history includes diabetes mellitus, hypertension, and an abdominal hysterectomy 30 years ago due to heavy menstrual bleeding of benign etiology. Upon examination, a pedunculated mass was found on the vaginal wall at approximately 7 o'clock. The mass, measuring 2.0 × 1.5 × 1.3 cm, was subsequently excised. Histologic examination revealed a clear cell carcinoma. Immunohistochemical stains were positive for CD10, PAX-8, and carbonic anhydrase 9/IX (CA-IX) and negative for CK7. A diagnosis of metastatic CCRCC was made (). Radiological studies then revealed a left renal mass, bilateral adrenal masses, and enlarged retroperitoneal lymph nodes. A subsequent left radical nephrectomy and adrenalectomy was performed. On gross examination, a unifocal tumor that measured 14.7 cm in its greatest dimension was identified. Pathologic examination confirmed the renal origin of the vaginal carcinoma. The nephrectomy diagnosis was established as CCRCC with rhabdoid differentiation and multinucleated giant tumor cells. The World Health Organization (WHO)/International Society of Urologic Pathologists (ISUP) grade was 4. The tumor invaded into the perinephric fat tissue, renal sinus, and major branches of the renal vein. Tumor necrosis and lymphovascular invasion were identified. All margins, including Gerota's fascia, ureteral and vascular, were free of malignancy. The left adrenal gland was involved with metastatic CCRCC. The final pathological stage was pT3a pNx pM1. Multiple pulmonary nodules, measuring up to 4 mm, and a right adrenal nodule were observed on imaging. The patient is now receiving adjuvant targeted therapy (Sunitinib 50 mg). The lung nodules are no longer seen, and the right adrenal nodule had decreased more than 30% in size. Interestingly, her vaginal mass recurred, increased in size, and changed in shape since her last resection. She, thus, underwent a partial excision of the new lesion on the vaginal wall. The pathologic examination revealed a CCRCC, with extensive rhabdoid differentiation this time ().

pmc-6008810-1

A sixteen-year-old boy nonswimmer was hospitalized after drowning in cold river water. Based on data given by the passing eyewitness, the teenager jumped into the river to retrieve a sheep he was tending but immediately disappeared from the water surface. This youth of the same age promptly dived into the river, found the victim's body on the bottom at a depth of 2 metres, raised him, and swam to the shore, which was about 3 metres away. Based on the rescuer's statement, the drowning boy was unconscious, was not breathing, had blue lips and nail pates, and had very cold skin. Due to knowledge about First Aid acquired in high school, the rescuer started measures for basic life support (BLS (Basic Life Support)), freed the airway, performed several mouth to mouth breaths, and started chest compression. After 2-3 minutes the victim vomited, threw up water, coughed, and started breathing. In the next few minutes he regained consciousness. In the meantime, members of his family had been called and they brought the patient to our institution in a private vehicle. At arrival he was somnolent, oriented, anxious, and pale, with tachypnea (number of respirations 30/min), with hypothermic-body temperature 35.1°C, shivering (whole body), and with the subjective sensation of cold. He was admitted to the JIT and the following was monitored: ECG TA, pulse, body temperature, and pulse oximetry. A nasogastric tube and a urinary catheter were placed. Auscultation of both lungs revealed weakened breathing sounds, especially in the basal and middle parts, with many early and late inspirium cracklings and low tone whistling. Cardiac action was arrhythmic accompanied by tachycardia up to 120/min, BP (blood pressure) 100/55 mmHg. There were no signs of neurological deficit or lateralization, GCS (Glasgow Coma Scale) 13/15. Using transcutaneous pulse oximetry at admission we measured the following: O2 saturation, which was 80% (during the course of treatment it normalized); pH 7.32; O2 54.8 mm Hg; CO2 55 mm Hg; BE—1.60 mmol/L; C-reacting protein 96 mg/L; Er 5.11 × 1012/L; Hb 136 g/L; Le 14.3 × 109/L; glycemia 4.0 mmol/L. Chest radiography showed spotty shadows in the middle and inferior lobes with free costodiaphragmatic recess sinuses bilaterally. The ECG at arrival indicated an irregular rhythm, HR (heart rate) 120/min with short-term atrial fibrillation that later corrected spontaneously into normal sinus rhythm. Immediately upon admission we continued reanimation. The patient was warmed up with thermal blankets. Oxygen therapy was applied using an oxygen mask with reservoir without rebreathing, at a flow rate of 8 l/min, decreasing to 6 l/min in order to maintain SpO2 ≥ 94%. Parenteral antibiotic therapy (III generation cephalosporin, aminoglycosides, and metronidazole) and parenteral rehydration were administered. On the fifth day after admission the patient showed complete recovery, including withdrawal of the chest radiographic symptoms and no pathological signs were visible on physical examination of the lungs. However, during each attempt to get up, we registered atrial fibrillation or individual SVES (supraventricular extrasystole) and VES (ventricular extrasystole) triplets. On echocardiographic examination the structure of the left ventricular myocardium was hyperechogenic; echocardiography was performed with slightly restricted LVEF During halter ECG examination we registered multiple strings of VES triplets, frequency 150 per minute. An appropriate dose of Presolol was included in the therapy, with advice of strict inaction and avoidance of any kind of physical exertion. Two months later the control echocardiography revealed that heart function had improved further, FS 0.34%; EF > 45%.

pmc-6008859-1

A 27-year-old male was referred to our hospital by a secondary care center due to a sudden onset of visual loss in his right eye, which occurred while weight-lifting in sports gym 4 days previously. The clinic referred the patient with fundus photographs which were screened 4 days before () and after the Nd: YAG laser hyaloidotomy treatment. Snellen acuity was 10/10 in both eyes. There was no afferent papillary defect and anterior segment examination was normal. The intraocular pressures were measured as 14 mmHg in both eyes. Dilated fundus examinations revealed a normal macula in left eye. But there was a retinal pigment epithelium (RPE) alteration at the margin of the inferior temporal arterial vascular arcade in the right eye and resolved preretinal and subretinal hemorrhages were seen in the macula (). A diagnosis of Valsalva retinopathy was made based on the history and the treatment photographs of Nd:YAG laser hyaloidotomy (). The patient was also screened with fundus fluorescein angiography for any other vascular pathologies (). At 1st month of examination all hemorrhages were resolved but RPE alterations were still at the margin of the inferior temporal arterial vascular arcade in the right eye (). The patient was screened with (OCTA) (OCTA; Avanti, Optovue RTVue XR). The OCTA images revealed 2 lesions. On en face OCT angiogram of OCTA full thickness retinal hole formation and ellipsoid zone damage at the superior and inferior margin of the inferior temporal arterial vascular arcade were seen (). Superficial vascular plexus was also damaged at that region. The projection of the evacuation of blood from subhyaloid space and the full thickness retinal hole formation were same ().

pmc-6008866-1

A 5-year-old boy was hospitalized with a 3-month history of intermittent fevers, fatigue, migratory joint pain, and weight loss. Three months ago, the patient was diagnosed with group A Streptococcus pharyngitis and was prescribed a 10-day course of amoxicillin. Two weeks later, he started having pain in his knees, elbows, shoulders, and neck. The patient was diagnosed with influenza and completed a course of oseltamivir. His joint pain and intermittent fever persisted. He began to develop malaise, weakness, and difficulty waking and was noted to have cough. During the next month, the patient was evaluated twice in different emergency departments with the same complaints. Evaluation at the emergency department revealed a mildly elevated C-reactive protein and erythrocyte sedimentation rate. Chest X-ray findings were consistent with pneumonia, and he was prescribed amoxicillin/clavulanic acid. Blood and urine cultures were negative. Three weeks later, the patient presented to his pediatrician with complaints of bilateral ear pain. His fevers, joint pain, difficulty walking, and fatigue persisted. During physical examination, the pediatrician noted a new systolic murmur. It prompted his hospitalization for further evaluation and management. On examination, the patient appeared unwell, but nontoxic. His temperature was 96.8°F (36.0°C), heart rate was 123 beats/min, respiratory rate was 23/min, blood pressure was 109/65 mm Hg, and oxygen saturation was 98% on room air. His growth was plotted on the 25th percentile for weight and height. He had a V/VI holosystolic murmur with thrill at the mitral area with radiation to the axilla and interscapular area. The boy reported pain during active and passive motion of both knees and the neck. His left knee was slightly swollen. Examination of the skin revealed presence of small (1 centimeter in diameter) painless, firm nodules over extensor surfaces of ankles and elbows bilaterally, consistent with subcutaneous nodules. Further review of the patient's history of present illness reveled noncompliance with previously prescribed treatment. Parents reported that the boy refused to take antibiotics. Laboratory evaluation showed the white blood cell count of 9.9 × 103 μ/L (9.9 × 109/L), platelet count of 495 × 103/µL (495 × 109/L), hemoglobin level of 11.2 g/dL (112 g/L), C-reactive protein level of 84.3 mg/L (802 nmol/L), and erythrocyte sedimentation rate of 93 mm/hr. Antistreptolysin O titers were 4,133 IU/ml (reference range, <150 IU/ml). Results of urinalysis were normal. Electrocardiography showed normal sinus rhythm with signs of left ventricular hypertrophy with volume overload with increased R wave voltage above 98th percentile for age in leads V5 and V6 and Q wave in lead V6 above 98th percentile for age (). Echocardiographic findings included moderate left atrial enlargement, severe mitral valve regurgitation (), and aortic valve regurgitation. The PR interval was within a normal limit of 0.120 seconds for 5-6-year-old children. Based on the history of preceding group A Streptococcus infection, clinical symptoms, elevated acute phase reactants, and echocardiographic findings, the patient was diagnosed with acute rheumatic fever. This patient received intramuscular penicillin G benzathine and was started on glucocorticoids for severe carditis. He also was prescribed aspirin for symptomatic management of arthritis with an initial dose at 75 mg/kg per day in divided doses every 6 hours during two days of hospitalization. The dose of aspirin at discharge was decreased to 50 mg/kg per day in divided doses every 8 hours. The patient was discharged with recommendations to continue secondary prophylaxis with penicillin G benzathine every 4 weeks for the next 10 years.

pmc-6008880-1

An 81-year-old man presented with abdominal discomfort and distention. His medical history was remarkable for hypertension and type 2 diabetes mellitus. He and his family denied alcohol abuse. Physical examination revealed hepatomegaly without jaundice, ascites, or hepatic encephalopathy. Laboratory data included platelet count 101,000/mm3, total bilirubin 0.9 mg/dl, AST 33 IU/L, ALT IU/L, and PT-INR 1.15. The serum AFP and PIVKA-II levels were 1081.0 ng/ml and 43 mAU/ml. Serologic tests for hepatitis B and C virus were negative. The diagnosis of nonalcoholic steatohepatitis with Child-Pugh A liver cirrhosis was made and four HCC lesions were found in segments II, VI, and VIII on the imaging. The largest one was located near the liver capsule in segment II measuring 6.5 cm in diameter. The other three lesions were less than 2 cm with one in segment VI and two in segment VIII. Segmental TACE with epirubicin and iodized oil was performed and he was discharged uneventfully. He was doing well until he developed abdominal pain 15 days after TACE which was gradually getting worse emergency transport to the hospital. His temperature was 37.7°C, blood pressure 102/41 mmHg, and pulse rate 79/minute. On physical examination, the abdomen was distended and hard to palpation without rebound tenderness. His hemoglobin was 12.6 g/dl. A contrast enhanced computed tomography (CT) scan of the abdomen showed iodized oil and intraperitoneal free air with a rupture of the HCC in segment II into the peritoneal cavity adjacent to the gastric wall (). Extravasation of contrast medium was not seen. Emergent upper gastrointestinal endoscopy confirmed no gastric mucosal lesions or a site of perforation. Without evidence of septic shock or hemorrhage, surgical drainage and transcatheter arterial embolization (TAE) are considered less effective. He was treated nonoperatively with piperacillin and tazobactam. Although an abdominal abscess formed, he was discharged on hospital day 18 with continued antimicrobial therapy. Five weeks after undergoing TACE, he was readmitted with hematochezia and hemorrhagic shock. The hemoglobin level was dropped to 6.6 g/dl. A contrast enhanced CT scan demonstrated gastric extraluminal compression by an HCC lesion with extravasation of contrast medium into the stomach (). Emergent upper gastrointestinal endoscopy showed a submucosal tumor with central ulceration located on the anterior wall of the gastric body, corresponding to extraluminal compression by a HCC (). The hemorrhage from the ulcer was successfully controlled by hypertonic saline-epinephrine injection. Another submucosal tumor was found in the gastric fundus without ulcer formation (). The patient's condition stabilized and he was discharged for palliative care and died six weeks after undergoing TACE.

pmc-6008881-1

A previously healthy 16-year-old female visitor from Japan presented to an adult emergency room (ER) with altered mental status and emesis. She was found lying on a bathroom floor in her hotel. There was a history of polyuria and polydipsia for 2 weeks and 8 to 10 kg weight loss during the previous month. Her vital signs upon arrival to the pediatric intensive care unit (PICU) were temperature of 98.1° Fahrenheit, heart rate 110/min, respiratory rate 26/min, blood pressure 140/81 mm of Hg, and 100% oxygen saturations without supplemental oxygen. Her capillary refill time was 4-5 seconds. Her weight was 57 kg. Her Glasgow Coma Scale (GCS) was 13 in the ER, which improved to 15 upon arrival to PICU. Skin rash with infected lesions was noted in her groin. The rest of her physical examination was unremarkable. Workup in the ER showed hyperglycemia of 472 mg/dL, metabolic acidosis (pH 6.75, pCO2 18.4, pO2 149, HCO3 2.5, base deficit 32.6, anion gap 23.5), ketosis (beta-hydroxybutyrate 11.41), glucosuria, and ketonuria, which were consistent with diabetic ketoacidosis. Her white cell counts were 22.3 k/L, hemoglobin 15.8 g/dL, and hematocrit 47%. The rest of her workup was unremarkable. The patient received fluid resuscitation with 30 mL/kg of 0.9% normal saline (NS) and 50 mEq of sodium bicarbonate in the ER. Continuous insulin infusion was started at 0.1 unit/kg/hr. After that she was started on intravenous fluids containing 0.45% saline and 75 mEq/L of sodium bicarbonate. This was administered at 150 mL/hr, which was 1.25 times the usual daily maintenance requirement for her weight. A consultation with our PICU was obtained at this stage. No further bicarbonate boluses were given. Her fluids were changed to isotonic fluid with potassium phosphate and potassium chloride and without any bicarbonate. It was administered at the rate of 1.5 times maintenance of daily requirement for weight. She was transferred to the PICU at this stage, where she continued to exhibit severe metabolic acidosis with pH 6.97, pCO2 26.7, HCO3 6.1, and base deficit of 24.5. The DKA management was continued with close monitoring and serial laboratory evaluations. After few hours of her arrival in the PICU, the patient became disoriented and confused. She was given one time 5 ml/kg of 3% hypertonic saline (HS) due to concern for cerebral edema and she responded well. Four hours later she developed lethargy followed by apnea. She was given additional doses of 3% HS bolus (5 mL/kg) and 0.8 g/kg of 20% mannitol. The hyperosmolar therapy was effective but only transiently; the patient eventually required intubation and mechanical ventilation for recurrent apnea. CT head obtained at that time showed a thin, right parietal subdural hemorrhage without any evidence of edema or mass effect. Of note, CT scan was obtained after the initiation of hyperosmolar therapy. Hyperosmolar therapy was continued afterwards with 3% HS and 20% mannitol. It was guided with close monitoring of renal function including serum sodium and serum osmolarity. The doses and other parameters were maintained per standard of care [, ]. The patient's serum sodium was 135 upon arrival in the ER and 143 at around 11 hrs before the initiation of hyperosmolar therapy and reached to 160 at 71 hrs when hyperosmolar therapy was discontinued. It was normalized to 143 at 131 hrs of admission. Her osmolarity was 298, 305, 335, and 299 at those timings (sodium in mmol/L and osmolarity in msom/kg). The rate of glucose reduction was < 50 mg/dl/hr. MRI brain obtained at 60 hrs of admission showed mild edema of the cortex and sulci and diffuse edema of the pons and midbrain with restricted diffusion in the pons consistent with central pontine myelinolysis also known as osmotic demyelination syndrome. There was no significant change in the subdural hemorrhage (Figures –). MR angiogram showed no evidence of vessel abnormality. The patient required continued mechanical ventilation and further management in the PICU. She became more responsive on day 5, and her support was gradually weaned until extubation on day 7. At that time she exhibited only mild residual dysmetria, trivial ataxia, mild left sided weakness, and neglect. All deficits subsequently improved. Her course was complicated by an isolated focal seizure that responded to standard antiepileptic medication. She also developed bilateral upper extremity deep venous thromboses (DVT). Hematology workup showed no underlying hypercoagulability. Thus the DVT was considered as another complication of DKA [–]. Her overall hospital length of stay was 14 days, and by the date of discharge she was able to ambulate with a walker and speak and eat without difficulty.

pmc-6008890-1

A previously healthy 29-year-old female was being transferred to the “Sismanoglio” General Hospital of Athens, Greece, due to pulmonary embolism (PE) 24 hours following a caesarian section. She had already received a bolus of intravenous 5000 E Heparin. The patient was hemodynamically unstable (blood pressure= 90/40 mmHg, heart rate= 140 beats/min, saturation= 85%, and breathing rate= 30 breaths/min) and afebrile (37 C). During the transportation, she suddenly went into cardiopulmonary arrest with pulseless electrical activity. CPR was immediately instituted according to advanced life support guidelines. Manual chest compressions and artificial ventilation were performed. The CPR was effective and the patient was then transferred to the Intensive Care Unit (ICU). About 3 hours later, she continued being hemodynamically unstable, her hematocrit had dropped 10 points (from 33% at ICU admission to 23% at that point), and she had a distended abdomen. She was transfused with two blood units and an emergency Diagnostic Peritoneal Lavage (DPL) was positive for intra-abdominal bleeding. At that point she was urgently taken into the operating theatre. An exploratory laparotomy was decided upon. About two liters of blood was removed from the abdomen. The intraoperative finding was an approximately 5 cm liver laceration at the left lobe, near the attachment point of the left coronary ligament. Liver suturing was performed and the intra-abdominal bleeding was successfully controlled. Unfortunately the patient passed away 3 hours after the operation. Cause of death was the massive pulmonary embolism.

pmc-6008890-2

A previously healthy 62-year-old female was transferred with an ambulance to the emergency department due to drowning at the sea. CPR had been instituted in situ by an experienced lifeguard. At presentation the patient was hemodynamically unstable (blood pressure= 100/55 mmHg, heart rate= 135 beats/min, and breaths= 25 per min) and afebrile (36.7 C). Her laboratory investigation showed hematocrit (Hct)= 23% and hemoglobin (Hgb)= 7.3 g/dL. Fluid resuscitation was performed and she was also transfused with 2 blood units, but she continued being hemodynamically unstable. After the transfusion she had Hct= 19% and Hgb= 6.4 g/dL. The abdominal ultrasonography revealed free intra-abdominal fluid. Bedsides, chest X-ray was negative for tympanic abdomen or pneumoperitoneum. At that point an exploratory laparotomy was decided upon. The site of bleeding was found to be vessels originating from the lesser curvature of the stomach, which were successfully ligated. The patient had an uneventful recovery and was discharged on the 12th postoperative day. Eight years after the event, she continues her everyday activities, without any limitations.

pmc-6008935-1

A 49-year-old Japanese woman underwent an MRI examination in the referring hospital for an assessment of the orthopedic disease of her right hip joint, and the MRI revealed a tumor in her pelvis. She was referred to our hospital, where an MRI examination again showed tumor mobility (Fig. ), and a tumor derived from the intestinal tract was suspected. In the contrast CT image (Fig. ), a mass approx. 45 mm in size was found on the right side of the pelvic floor, and in the blood vessel construction image, the tumor was nourished by vessels from the splenic artery to the greater omentum. In 18F-fluoro-2-deoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT), no abnormal accumulation was observed (Fig. ). The results of complete blood cell counts and biochemical tests were all normal. Cancer antigen 19-9 (CA19-9) showed a mild elevation at 37.8 U/mL (normal range < 37.0 U/mL), and carcinogenic embryonic antigen (CEA) was normal at 0.8 ng/mL (normal range < 5.0 ng/mL). Based on all of these results, the preoperative diagnosis was a suspected omental primary tumor or accessory spleen. There was a danger of torsion irrespective of the presence or absence of malignancy, and the patient desires surgery to remove the tumor; the surgery was conducted concurrently with the diagnosis and treatment. The surgery was a single-incision laparoscopic-assisted greater omental tumor resection. A longitudinal incision was made approx. 4 cm around the umbilicus. A multichannel port (x-Gate®, Sumitomo Bakelite, Tokyo) was inserted in the wound. Observation of the abdominal cavity revealed a red and solid tumor mass of approx. 4 cm. Adhesion with the surrounding tissue was not observed. The greater omentum and the tumor were guided out of the body through the gate hole (Fig. ), and the tumor was excised together with the greater omentum. The tumor, a light brown tinged solid mass with a smooth border, was 5.2 × 3.8 × 3.5 cm in size with a well-defined border (Fig. ). Histopathologically, the tumor involved large and small blood vessels (Fig. ), and tumor cells with eosinophilic cytoplasm were increased in number, in sheet form (Fig. ). In immunohistochemical staining, the tumor cells were found to be positive for HMB45 (Fig. ), Melan-A (Fig. ), and α-SMA (Fig. ), but negative for CD34, Desmin, c-kit, and s-100. Based on the above results, the tumor was diagnosed as an omental PEComa. There has been no recurrence at 16 months after the surgery.

pmc-6008944-1

A 26-year-old primigravida at 39-week gestation by date of last menstrual period, presented to the Muhimbili National Referral Hospital, Tanzania, in active labor. She had no significant past medical history and an uncomplicated antenatal course. Shortly after midnight she had a precipitous vaginal delivery. After delivery, the woman began hemorrhaging profusely. Her uterus was vigorously massaged, ten international units (IU) of intravenous oxytocin were administered, and the placenta manually removed. Despite the interventions, the patient continued to bleed and lost consciousness. On pelvic examination, the uterus was well contracted, bleeding superior to her cervix was minimal, and second degree bilateral vaginal sulcal lacerations were identified. Fluid resuscitation was initiated, and the patient was emergently taken to the operating theatre by the in-house Obstetrician and Gynecology resident for examination under anesthesia and repair of her vaginal lacerations. Despite attempts at suture repair, hemorrhage from the laceration sites continued. The senior Obstetrician and Gynecology consultant was also unsuccessful in gaining control of the hemorrhage and therefore placed an ESM-UBT device into her vagina. The ESM-UBT device was inflated with 300 cc of water and secured with vaginal packing. Hemorrhage ceased and antibiotics, intravenous fluids, and blood products were administered. The ESM-UBT device was removed after 48 hours, no further repair was necessary, and bleeding did not recur. The woman was discharged home on postpartum day two and at her six-week postpartum visit had fully recovered.

pmc-6008944-2

A 22-year-old gravida two para one woman, six-week pregnant by dating from her last menstrual period, presented to a private maternal health facility for termination of her pregnancy via dilation and suction curettage. Upon attempted cervical dilation the woman began hemorrhaging profusely. She was referred by ambulance to the Mahatma Gandhi Institute for Medical Sciences where she presented extremely pale, weak, and in shock with vital signs including a blood pressure of 80/30 mm/Hg and heart rate of 145 bpm. Outside imaging that was brought with the patient, when reviewed at the referral facility, clearly identified a cervical pregnancy. The patient was emergently taken to the operating theatre where resuscitation was initiated, and a rapid pelvic exam was performed. Examination revealed severe bleeding and a swollen cervix ballooned with clots. An ESM-UBT device was intentionally placed into the cervix, inflated with 200 cc of water which formed a dumbbell, filling the cervix and ballooning into the lower uterine segment and vagina. Vaginal packing was used to secure the uterine balloon's position. The woman was transferred to the intensive care unit where she received isotonic fluids and two units of blood. The ESM-UBT device was removed after 24 hours without any resumption of bleeding. There were no complications on six-week follow-up.

pmc-6008944-3

A 27-year-old gravida three para two woman, 23-week pregnant by date from her last menstrual period, presented to the Government Medical College Nagpur National Hospital, India, with vaginal bleeding. She had no significant past medical history. On physical examination, her fundal height was consistent with a 32-week uterus, there was moderate vaginal bleeding, and her cervix was closed. An ultrasound examination was remarkable for absence of a fetus and a solid collection of echoes with numerous anechoic spaces consistent with a molar pregnancy. The patient was taken to the operating theatre for cervical dilation and evacuation under general anesthesia. Following evacuation, the uterus was atonic and hemorrhage ensued with an estimated blood loss of greater than two liters. Bimanual uterine massage was performed, the bladder was drained, fluid resuscitation was initiated, and oxytocin (20 IU) and ergometrine (0.4 mg) were administered intravenously. Despite these interventions, profuse bleeding continued, and her vital signs deteriorated to a blood pressure of 84/60 and heart rate of 120. An ESM-UBT device was inserted into the uterus, inflated with 300 cc of water, and hemorrhage was immediately arrested. Her condition stabilized, and she was transfused blood. The ESM-UBT device was removed after 24 hours with no bleeding recurrence and the woman was discharged home two days thereafter. Pathology results confirmed a complete molar pregnancy. There were no complications on subsequent two- and six-week follow-up visits and she remains within their system for clinical monitoring throughout the year.

pmc-6008945-1

A 67-year-old Caucasian female patient presented to the hospital with one day history of hematemesis and melena. She had two episodes of bright red emesis and four episodes of dark colored stools the day she presented, followed by a brief syncopal episode lasting for 10-15 seconds. She also complained of epigastric pain. She was diagnosed with polycystic liver disease and portal hypertension one year ago when she presented similarly with hematemesis and melena. At that time, she had an esophagogastroduodenoscopy (EGD) which showed esophageal varices and underwent banding. She denied any history of alcohol use, NSAID ingestion, or peptic ulcer disease. She was gravida 3, para 3, and had tubal ligation following her last pregnancy. She denied use of oral contraceptive pills or hormonal replacement therapy in the past. Her family history was significant for cystic liver disease and chronic liver failure in mother and maternal aunt. At the time of presentation, she was afebrile (temperature of 98.7°F), tachycardic (heart rate of 110 beats/min), tachypneic (respiratory rate of 18/min), and hypotensive (blood pressure of 97/60 mmHg). Cardiopulmonary examination was normal. Abdominal examination showed mildly distended abdomen with epigastric and right upper quadrant tenderness, and bowel sounds were normal. Extremities showed bilateral 1+ pitting edema. Initial laboratory work showed hemoglobin of 7.7 g/dl, hematocrit of 24%, white blood count of 10.8 cells/mm3, and platelet count of 162 cells/mm3. Metabolic panel showed nonanion gap metabolic acidosis with serum bicarbonate of 17 mEq/L, normal serum BUN, and creatinine of 23 mg/dl and 0.57 mg/dl, respectively. Liver panel showed total bilirubin of 2.2 mg/dl, direct bilirubin of 0.4 mg/dl, albumin of 2.5 g/dl, alkaline phosphatase of 51U/L, AST of 22 U/L, and ALT of 16 U/L. Gamma-glutamyltransferase was measured to be 27 U/L and prothrombin time (INR) was measured to be 1.46. She was aggressively resuscitated with fluids, pressors, and packed red blood cell (PRBC) transfusion. Octreotide and proton pump inhibitor infusions were started. Patient was electively intubated for hemodynamic instability and altered mental status. An EGD was done which showed four columns of large esophageal varices with red wale sign showing stigmata of high risk for bleeding and type 1 gastroesophageal varices (). Four bands were successfully applied starting from cardia up to midesophagus. A computed tomography (CT) of abdomen showed multiple cysts in the liver with evidence of portal hypertension in form of splenomegaly, ascites, and esophageal varices (). Liver surface was smooth and no thrombus was identified in hepatic veins and inferior vena cava. Bilateral kidneys were normal with no evidence of renal cysts (). Vital signs and hemoglobin were monitored closely. Patient was successfully extubated next day and pressors were weaned off. Patient did not have any further episode of hematemesis but continued to have melena. She slowly dropped her hemoglobin requiring transfusions with PRBC. An EGD was repeated which reveled 3 more columns of esophageal varices with intact bands from previous EGD. Four more bands were placed on remaining varices. Following repeat EGD patient's hemoglobin remained stable for rest of her hospital stay. During her hospital stay, she also underwent therapeutic paracentesis with removal of 330 ml of peritoneal fluid for worsening ascites (). Peritoneal fluid analysis showed serum ascites albumin gradient (SAAG) of more than 1.1 g/dl, normal white cell count, negative gram stain, and cultures. She was started on propranolol, furosemide, and spironolactone. She was discharged home with recommendations to follow up in outpatient clinic with a plan of repeat EGD in 3-4 weeks.

pmc-6008950-1

A 59-year-old Asian male presented to the gastroenterology office for a follow-up of a previously found duodenal lesion. He had an EGD at an outside facility 2 years earlier for evaluation of abdominal pain which showed a 1.2 cm duodenal polypoid lesion in the second portion of the duodenum. Pathology of the polyp revealed heterotopic gastric mucosa with benign lobules of gastric glands. He also was found to have chronically active H. pylori gastritis with numerous Helicobacter organisms and atrophic gastritis with patchy areas of intestinal metaplasia. At that time, he was instructed to follow up for a repeat endoscopy for surveillance in two years. As recommended, two years later he presented to our office for surveillance of his duodenal lesion. Due to his history of atrophic gastritis and a large duodenal lesion, we performed an upper endoscopy that showed atrophic gastritis, duodenitis, and a single 10 mm polyp in the second portion of the duodenum. The duodenal polyp was biopsied. Pathology revealed polypoid gastric metaplastic mucosa with focal epithelial atypia including nuclear enlargement, stratification, nucleoli, and few mitoses. The patient was referred for endoscopic ultrasound to further characterize the lesion and complete resection. Several weeks later he underwent an endoscopic ultrasound that revealed a 13-mm pedunculated and sessile polyp on the lateral wall opposite to the major papilla in the second portion of the duodenum (). The polyp was removed en bloc using a hot snare following a 4-mL saline lift. Two endoclips were placed for hemostasis. Pathology revealed a pyloric gland adenoma (Figures , , and ) with predominantly low grade dysplasia (Figures and ) and some small areas of focal high grade dysplasia. The slides were read by the in-house pathologist and were also reviewed by a GI expert pathologist at the University of Michigan. The patient was recommended to follow up for surveillance upper endoscopy in 6 months due to the areas of high grade dysplasia found on pathology. He was lost to follow-up for over one year. Fifteen months after the PGA was removed, the patient did follow-up for a surveillance upper endoscopy. A duodenal scar was found at the site of the PGA and a biopsy was taken from the site. There was no evidence of residual pyloric gland adenoma. The patient was then recommended to follow up for surveillance endoscopy in 5 years in accordance with the ASGE guidelines for surveillance of gastric adenomatous polyps.

pmc-6008951-1

The patient is a 56-year-old man with a past medical history significant for poorly controlled insulin-dependent type 2 diabetes mellitus, hypertension, hypothyroidism, and meatal stenosis with incomplete bladder emptying who presented the University Medical Center emergency room with a seven-day history of perineal pain and fever. One week prior to presentation, he was seen in the emergency room with the same symptoms and was placed on a 14-day course of ciprofloxacin for a suspected urinary tract infection. Also, the patient was admitted to the medical intensive care unit 10 months previously for severe sepsis secondary to Candida glabrata urinary tract infection with candidemia. The patient denied penile trauma, gross hematuria, and dysuria. Upon presentation, he was hemodynamically stable with a blood pressure of 145/77 mmHg, and he had mild tachycardia with a heart rate of 110 beats per minute and a fever of 101.4 F. On physical exam, the patient had mild tenderness to palpation at the penoscrotal junction with induration, no crepitus was palpated, and there were no skin changes. His laboratory values were significant for an elevated white blood cell count (WBC) of 20,000/μL, a creatinine level of 1.4 mg/dL, and a hemoglobin A1c level of 9.4%, and all other values were within normal limits. On computerized tomography (CT) scan, emphysematous changes were noted with in the ventral portion of the penile shaft with air at the bulb of the corpus spongiosum (Figures and ). The patient had a postvoid residual of 320 ml; thus, a transurethral Foley catheter was placed with withdrawal of 700 ml of clear yellow urine which was sent for culture. The patient was begun on intravenous (IV) meropenem, fluconazole, and daptomycin. Repeat CT scan on hospital day 1 was largely unchanged, and the patient remained febrile to 102.3 F. On hospital day 2, meropenem and daptomycin were discontinued, and the patient was switched to piperacillin/tazobactam based on recommendations from the Infectious Disease team. A pelvic magnetic resonance imaging (MRI) with and without gadolinium was obtained at this time which showed reduced blood flow to the corpus spongiosum compared to the corpus cavernosum on T1-weighted imaging with gadolinium (). The patient was then taken to the operating room on hospital day 3 due to worsening penile pain and induration, a persistently elevated white blood cell and continued fever. On cystourethroscopy, the urethral mucosa appeared dusky from the anterior to the membranous urethra. A longitudinal incision was made in the perineum, the urethra was palpated and noted to be indurated and firm, and thus the bulbospongiosus muscle was split and a longitudinal incision was made in Buck's fascia with expulsion of approximately 10 ml of purulent fluid which was sent for culture and gram stain. The remaining necrotic spongiosal tissue was debrided with blunt dissection, a penrose drain was placed within the defect, and the skin was closed loosely. On postoperative day 2, his white blood count decreased to 13,000/μL and he remained afebrile for 48 hours. The patient's intraoperative wound culture was found to be positive, and using automated Matrix Assisted Laser Desorption Ionization Time of Flight (MALDI-TOF) mass spectrometry, the organism Candida glabrata was identified by our microbiology laboratory. The wound culture result was identical to his urine culture. The patient was then switched to micafungin based on the Infectious Disease team's recommendations. He was subsequently discharged to home on postoperative day 14 on a 14-day course of oral voriconazole with the transurethral Foley in place.

pmc-6009011-1

The following case is of a 66-year-old man with a complicated cardiac history, who for some time has been experiencing limiting angina despite being on maximally titrated medical therapy of aspirin, prasugrel, carvedilol, ranolazine, isosorbidemononitrate (sustained release), atorvastatin, lisinopril, nitroglycerin patch, and as needed sublingual nitroglycerin. His cardiac history includes extensive coronary artery disease (CAD). Status post coronary artery bypass graft 15 years ago (CABG: reverse saphenous vein graft to first and second obtuse marginal arteries in a sequential fashion and reverse saphenous vein graft to posterior descending artery and posterolateral artery in a sequential fashion) Status post redo CABG 2 years ago (CABG: left internal mammary artery [LIMA] to the left anterior descending artery [LAD]) Status post multiple stents He also has a history of hypertension, diabetes (on metformin), dyslipidemia, and prior bilateral carotid endarterectomy. He was evaluated by cardiothoracic surgery 8 months prior, and they recommended against reoperation. About 4 months prior, he underwent another coronary angiography. This angiogram showed a relatively long 95% stenosis in the mid-LAD. The stenosis extended from the mid-LAD to a bit passed the LIMA anastomosis, with retrograde flow into the LIMA (). Some tenting of the LAD at the anastomotic site was also noted. Several predilations were performed at 8 and 10 atmospheres with no significant improvement to the stenosis. A 2.25 × 28 mm Synergy drug-eluting stent (Boston Scientific) was then deployed at 12 atmospheres and postdilated with 2.25 × 20 mm noncompliant balloon at 14 atmospheres. The stent was successfully deployed in the mid-LAD with no residual stenosis. A slight kink in the distal one-third of the stent at the LIMA insertion point was noted (). further demonstrates the movement of the intact stent during diastole and systole. The patient's symptoms temporarily improved. A short time after, he presented again with rest pain. His vital signs were stable. Physical examinations, including cardiac exams, were unimpressive. Electrocardiogram (EKG) showed normal sinus rhythm without significant ST/T changes. Two troponin levels drawn 12-hour apart were both normal. Repeat coronary angiography was performed. It revealed a mid-LAD stent fracture with 70% in-stent restenosis (fractional flow reserve of 0.78) (). Coronary intervention was performed and a Xience Alpine DES was deployed inside the fractured Synergy DES with TIMI III flow and no residual stenosis (). The patient tolerated the procedure and was discharged in stable condition.

pmc-6009022-1

A 26-year-old-woman, with history of labial herpes and asthmatic bronchitis, presented with bilateral retroocular pain, odynophagia, fever, vaginal discomfort and vulvar ulcers. The ulcers continued to progress despite treatment with nonsteroidal anti-inflammatory drugs and valacyclovir, prescribed at the primary healthcare site. Two days later, after initial consultation at our emergency room, she was admitted immediately at the Vulvar Clinic of our institution, with increasing vulvar pain, without other symptoms. Physical examination of the vulva showed extended vulvar oedema and kissing pattern ulcers on labia minora and majora, vagina and cervix (). Inguinal lymph nodes were also bilaterally swollen. The patient denied the use of other medications and sexual activity in more than 6 months. First blood tests only showed C-reactive protein 12.35 mg/dL (normal: <0.5 mg/dL). Serologies for herpes virus 1 and 2, Ebstein-Barr virus (EBV; IgG+), cytomegalovirus, mycoplasma pneumoniae, parvovirus B19, toxoplasmosis, rubella, hepatitis, human immunodeficiency virus, and syphilis (using the Venereal Disease Research Laboratory test) were negative. After this, a multidisciplinary approach was performed. When directly asked, she complained about mild eye dryness and she often felt a discomfort of dry mouth. There was no familial history of autoimmune diseases, but her father had some episodes of oral aphthosis. Immunological examination was positive for rheumatoid factor (RF – 22.3 UI; normal: <15 UI), anti-nuclear antibodies [ANA (speckled, titer 1:320)] and antibodies to SSA/Ro (SSA 3+/ Ro52KD 3+)—initial screening step of ANA by indirect immunofluorescence on HEp-2 cells (Euroimmun ®, Germany); autoantibodies confirmation assay by line immunoblot (ANA profile 3 - Euroimmun ®, Germany)—antibodies detected on strips were evaluated semiquantitatively (negative, 1+, 2++, and 3+++). Anti-SSB/La, anti-RNP, anti-Sm, anti-dsDNA, antineutrophil cytoplasmic, anticardiolipin, and anti-beta(2)-glycoprotein1 antibodies were negative. Serum C3 level was 1.79 g/L (normal: 0.9-1.8 g/L) and C4 level was 0.31 g/L (0.1-0.4 g/L). Immunoglobulins (IgG, IgM, IgA) were measured and a high IgG level was found (20.50 g /L; normal: 7-16 g/L). Erythrocyte sedimentation rate was also high (45 mm/h; normal: <16 mm/h). Lupus anticoagulant and HLA-B27 were both negative. Ophthalmological evaluation was refused by the patient. Labial salivary gland (LSG) biopsy revealed focal lymphocytic sialadenitis (FLS), with a focus score (FS) =1 (per 4 mm2) obtained by four LSGs (3-5 mm). No other histopathological features were reported. The patient was diagnosed as having pSS on the basis of dry eyes and dry mouth, positive anti-SSA/Ro antibody, and typical histopathologic abnormalities on LSG biopsy. Prednisolone 20 mg/day was prescribed and vulvar healing appeared within 2 weeks with partial loss of left labia ().

pmc-6009024-1

A 25-year-old gentleman presented to our clinic with a complaint of recurrent pain and swelling on his right cheek of three-month duration. He visited a general practitioner each time, and the condition was resolved with analgesic and antibiotics. However, his symptoms got worse and he attended our Oral Surgery Clinic for consultation. The patient is a fit and healthy young man with no relevant medical history and no known history of allergy. Past surgical history revealed that he had underwent bimaxillary orthognathic surgery one and half year earlier in a local hospital. Although the postoperative period was uneventful, the surgical team informed him that there was a dislodged orthodontic appliance in his right cheek that must have occurred during the operation. The team explained to the patient that this accident was realized later on the next day after the surgery when the molar tube from the right maxillary second molar was found missing, and its presence was confirmed high up in the right maxillary-zygomatic buttress area shown in the postoperative X-ray image taken on the next day following the surgery. A series of further postoperative radiographs confirmed its location, lying outside the right maxillary antrum. Due to the pronounced postoperative facial oedema at that time, no attempt was made to remove the appliance. The absence of sign and symptoms during further follow-up sessions confirmed the decision to leave it in-situ with continuous clinical observation. On examination, there was no extraoral swelling noted. The mandible and maxilla seemed firm indicating good healing following previous mandibular saggital split and maxillary Le Fort I osteotomy sites and a stable class I dental occlusion. Intraorally, there was a sinus with slight pus discharge on the upper right buccal sulcus region adjacent to the upper right first premolar. All teeth in that quadrant were firm and vital. Tenderness was elicited upon palpation on the upper right vestibular region. We suspected the sinus track may originate from the dislodged appliance embedded in the cheek soft tissue. A periapical view was then taken with gutta-percha inserted into the sinus for foreign body localization purpose. The radiograph revealed the gutta-percha pointed towards the site of titanium plate and screws placed used for rigid fixation, and with the molar orthodontic tube appliance in its vicinity (). A cone beam CT was performed to provide a 3D detailed location of the appliance (Figures and ) and confirmed it to be located outside the maxillary antrum. The presence of the molar orthodontic tube foreign body reaction was suspected as the most probable cause of the recurrent right cheek pain and swelling associated with an intraoral discharging sinus. Exploration of the site was performed through the sulcular incision under general anesthesia. The dislodged molar tube was identified lying on the zygomatic bone just beneath the raised flap. It was removed by dividing some surrounding fibrous tissue strands. Just below it, one titanium straight bone plate with four screws used for fixing the previous Le Fort I osteotomy site was inspected and found to be rigidly embedded in normal bone. However, a decision was made to remove them based on the fact that they are present in an infected area. (). The Le Fort I osteotomy site showed good healing with new bone formation. Patient had an uneventful recovery thereafter, and the orthognathic surgical team who attended him previously was informed of his progress.

pmc-6009035-1

A 9-year-old girl was admitted due to repeated loss of consciousness, concomitant with a pale face, palpitations, and convulsions, which had persisted for 2 years and had been aggravated during the previous 2 months. These symptoms occurred automatically. The patient denied experiencing any sweating, nausea, vomiting, trembling, or an obvious sense of hunger before meals. The patient was previously misdiagnosed with epilepsy in another hospital, but no abnormal findings were detected on a 24-h electroencephalogram at our hospital. Her abdominal perfusion CT showed a highly perfused nodule within the pancreatic tail; A magnetic resonance scan confirmed the location of this nodule and indicated that its size was 11.6 × 13.2 mm (Fig. -). Additionally, 68Ga-exendin 4 PET-CT showed a region in the pancreatic tail with abnormally high metabolism and overexpression of the glucagon-like peptide-1 receptor (Fig. -). Lab testing showed a low fasting blood glucose (BG) of 2.2 mmol/L (reference range: 3.9–6.1 mmol/L), a high proinsulin level of 4455.9 pg/mL (reference range: 30–180 ng/mL), a normal C-peptide level of 2.56 ng/mL (reference range: 0.8–4.2 ng/mL), a serum insulin level of 15.35 μIU/mL (reference range: 5.2–17.2 μIU/mL), and a gastrin level of 92.6 pg/mL (reference range: < 100 pg/mL). These results confirmed a diagnosis of insulinoma. Imaging examination showed no abnormalities indicative of parathyroid adenoma or malignancy in the pituitary or adrenal glands. Lab testing showed normal levels of parathyroid hormone (PTH), blood calcium, phosphate, follicle-stimulating hormone (FSH), growth hormone (GH), prolactin (PRL), adrenocorticotropic hormone (ACTH), 24-h urinary free cortisol (24 hUFC), and serum cortisol. Her luteinizing hormone (LH) level was 0.24 IU/L (reference range: 2.12–10 IU/L during the follicular phase), which was considered related to her age. Preoperative preparation: To avoid recurrent symptoms and to maintain her fasting BG at a tolerably low level, the patient was given regular snacks before bedtime. BG can be controlled at a level between 50 and 60 mg/dL preoperatively. Surgical procedure: The patient underwent minimally invasive insulinoma enucleation surgery under the Da Vinci robot-assisted system with intraoperative ultrasound (IOUS) connected. The patient was put in a head-low, feet-high and left-lateral position. The robotic system was positioned at the head of the patient, while the assistant surgeon stood between the patient’s legs. Abdominal exploration via laparoscopy was conducted, and no obvious abnormalities were found. The robotic lens and operating arms were docked. The gastrocolic ligament was dissected with an ultrasonically activated scalpel. The head of the pancreas was exposed by grasping the colon downward and lifting the stomach. Towards the tail of the pancreas, we separated and exposed the spleen. The surgeon then controlled the ultrasound probe, exploring the tumor from the pancreatic tail to the head and the uncinated process with the assistance of a prograsp clamp. A quasi-circular, hypoechoic lesion was found at the end of the pancreas with a diameter of approximately 10 mm and a clear boundary. We marked the normal pancreatic tissue around the lesion with an electrotome, and while dividing the pancreas sequentially, suction was used continually to visualize the tumor capsule. Precise positioning was achieved using IOUS, and the tumor was completely resected along the capsule (Fig. -). A peritoneal drainage tube was placed. The surgery went well, lasting 65 min (skin to skin), and the volume of intraoperative bleeding was 5 mL. Intraoperative BG is documented in Table . After surgery, the patient was given liquid diet on POD2. The drain was clean and was removed on POD4, and the patient gradually resumed her normal diet. She was discharged to home on POD6. During the following 1.5 years, the patient had no recurrence of the disease. No postoperative complication occurred, such as pancreatic fistula or pancreatic function deficiency. Pathological examination showed that the tumor was a pancreatic neuroendocrine tumor (Grade 2 with a Ki-67 index of 4%) (Fig. -). This tumor was positive for CgA, Syn, and AE1/AE3 (Fig. -). Insulin staining was partially positive (Fig. ), while gastrin, glucagon, and somatostatin staining were negative (Fig. -). Sanger-directed sequencing for the MEN1 gene mutation was performed on a peripheral blood sample, revealing a homozygous pathogenic mutation of c247_250delCTGT (p.Ile85Serfs*33) (Fig. ). This point mutation was also detected in the frozen tissue of the patient.

pmc-6009036-1

A 41-year-old woman presented to our hospital for further evaluation and management of persistent liver dysfunction, painless xanthochromia, and skin itching for 3 months. On admission, a physical examination showed severe icteric sclera and skin without abdominal tenderness or positive shifting dullness. Liver function showed severe hepatic injury and obstructive jaundice (Table ). US showed a 5.0 × 5.3 cm, well-circumscribed anechoic lesion with many separations, increased through-transmission of sound, and no evidence of mural nodularity. Epigastric enhanced CT showed a cystic mass with sharply defined margins and smooth, thin, non-reinforced walls in the left medial liver lobe, and obstruction of the biliary tract. The contents of the mass were homogeneous, with water-density lesions, suggesting that it was a cyst. MRI showed a homogeneously hypointense lesion on T1-weighted imaging and this was homogeneously hyperintense on T2-weighted imaging. US, CT, and magnetic resonance cholangiopancreatography (MRCP) showed a slightly ectatic right hepatic duct, a greatly ectatic left hepatic duct and common bile duct, an enlarged gallbladder, and a normal distal end of the choledochus (Fig. ). Possible reasons for biliary obstruction were bile duct tumor, common bile duct stones, or compression of the common bile duct by a hepatic cyst. Endoscopic retrograde cholangiography (ERC) was performed to define the cause of obstruction. This procedure showed that the right hepatic duct was ectatic, but the left hepatic duct and common bile duct were not observed. There were no stone, but a large lump was observed in the common bile duct, which suggested suspicious bile duct tumor. Endoscopic sphincterotomy, endoscopic retrograde biliary drainage(ERBD), and endoscopic nasobiliary draingage(ENBD) were successfully performed to drain bile for severe hepatic injury and jaundice, rather than laparotomy, because of coagulation disorders (Fig. ). After these procedures, the icteric sclera and skin gradually faded, liver function was obviously improved, and coagulation disorders were close to normal levels (Table ). Four weeks later, an open operation was performed for suspicion of bile duct tumor. In exploration of the common bile duct by a choledochoscope, a large pedunculated lump protruding into the common bile duct from the left hepatic duct was discovered. This lump was completely removed from the root of the lump by endoscopic needle-knife electrotomy without active hemorrhage (Fig. ). The morphology of the lump was similar to the gallbladder with a capsule wall and capsular space (Fig. ). The choledochoscope was inserted into the hepatic duct from the stump of the lump and there was no viscous liquid secreted by cystadenoma or cystadenocarcinoma. Postoperative pathology of the lump suggested a hepatic cyst wall without heterocysts or tumor cells (Fig. ). A T tube was retained in the common bile duct in order to prevent bile leakage and observe the recovery of the root incision of the lump and postoperative bleeding. Two months later, all of the liver function indices recovered to the normal range (Table ). Epigastric US and CT showed a normal hepatic duct and the hepatic cyst was the same size compared with preoperatively. A choledochoscopic examination was performed through a T-tube fistula. There was no evidence of bile duct tumor. The choledochoscope could enter into the cyst from the defect of the bile duct wall, and the mucosa around the incision recovered well, with no signs of stricture. Three years after the procedure, the patient was in a good general condition, without signs of cholestasis or bile duct stones. The cyst had barely changed (Fig. ).

pmc-6009975-1

Prior to this admission, a 27-year-old woman sought medical attention at a local hospital because of facial redness and edema caused by eating a mango. She was treated with dexamethasone (5 mg intravenously daily) for five days. The patient gradually developed a round face, acne, hirsutism, hypokalemia, and 5 kg of weight loss over the course of one month since receiving dexamethasone. Upon hospitalization, the patient presented with a one-month history of facial edema, weight loss, and acne. She had no family history of Cushing’s syndrome, pheochromocytoma, or multiple endocrine neoplasia type 2. A 5.5-cm mass located in the right posterior lobe of the liver was detected by ultrasound in a routine physical examination 16 months ago at a local hospital; however, the patient had no symptom and did not seek further medical attention at that time. The patient’s blood pressure was 120/75 mmHg in both arms in the supine position, with a regular pulse of 76 bpm. Her height was 164 cm and her weight was 48 kg (body mass index:17.8 kg/m2). The patient had “moon face” and severe facial edema, beard, central deposition of fat with slim extremities and atrophic muscles, and no pretibial edema. The skin was diffused with acne and both armpits had hyperpigmentaion. Laboratory tests revealed marked hypokalemia (2.1 mmol/L; normal range, 3.5–5.5 mmol/L), which could not be normalized with oral and intravenous potassium supplementation until spironolactone was added. A 75-g oral glucose tolerance test confirmed diabetes mellitus with a fasting blood glucose level of 9.19 mmol/l and a 2-h glucose level of 21.66 mmol/L, with a HbA1c level of 6.3%. She was started on insulin aspart30 (48 U daily). Endocrinological investigation identified severe hypercortisolism with loss of circadian rhythm. Plasma ACTH level was elevated to 1157 pg/mL, confirming ACTH-dependent Cushing’s syndrome. Except for testosterone, the catecholamine metabolites, growth hormone, calcitonin, and prolactin levels were all within the normal range (Table ). MRI and contrasted MRI revealed no pituitary adenoma and EAS was considered. Abdominal contrast-enhanced CT scanning revealed that the mass lesion was located in the right adrenal gland and not in the right hepatic posterior lobe. The mass was a heterogeneous solid tumor which was mildly enhanced with some patchy nonenhancing areas (Fig. ). PET/CT showed moderate fluorodeoxyglucose (FDG) uptake in the mass (Fig. ). Both contrasted CT and PET-CT revealed bilateral adrenal hyperplasia, but the neck, thorax, and pelvis were normal. We prepared to do inferior petrosal sinus sampling (IPSS) for ACTH assays, adrenal vein sampling for ACTH assays to make out the origin of ACTH. But the patient’s general condition rapidly deteriorated after admission, Adrenal tumorectomy was performed. During surgery, when the right adrenal mass was mobilized, no hypertensive crisis occurred. A 6.5-cm black mass was found arising from the medial branch of the right adrenal gland (Fig. ). Hematoxylin-eosin staining of the tumor revealed that most of the cells were chromaffin-like cells. In addition, there were multifocal oval eosinophilic cells under the tumor capsule (Fig. ). Immunohistochemical staining showed positive staining for chromogranin A (CgA) (Fig. ) and CD56 (Fig. ), with a Ki67 labeling index of approximately 16% (Fig. ) for chromaffin-like cells. No positive ACTH immunostaining was noticed (Fig. ). Positive immunostaining for CRH and Melan-A (Fig. and ) and negative immunostaining for CgA and CD56 were found in the eosinophilic cells, indicating that CRH production is indeed derived from the tumor’s peripheral cells. One day after surgery, ACTH levels had decreased from 715 to 14.3 pg/ml and serum cortisol level had decreased from more than 50 to 10.4 μg/dl. One week postoperatively, blood potassium and glucose levels normalized without the need for medication. The signs and symptoms of Cushing’s syndrome gradually disappeared within two months, and the hydrocortisone supplementation (initial dosage was 60 mg daily and tapered gradually) was discontinued seven weeks postoperatively. CT revealed that the left adrenal gland was almost reduced to the normal size three months later. The patient is currently under regular follow-up and remains well nine months after surgery.

pmc-6010360-1

A four-year-old girl with a history of asphyxiating thoracic dysplasia (Jeune syndrome) and end-stage renal disease, with a post-renal transplant, was on immunosuppressive therapy for chronic rejection. She was admitted to our tertiary care pediatric intensive care unit (PICU) with cardiorespiratory failure. The child was intubated and started on mechanical ventilation. The child was on daily peritoneal dialysis for renal failure and on dapsone for Pneumocystis prophylaxis for the last six months. During the hospital stay, she developed multiple complications, including sepsis, electrolyte imbalance, and thrombocytopenia. She was on various medications, including fentanyl, midazolam, mycophenolate, prednisolone, pantoprazole, cefepime, and dapsone. During the third week of hospital stay, the child had diarrhea and then developed metabolic acidosis. She was also noted to have cyanosis, low oxygen saturation (82% to 87%) by pulse oximetry (peripheral capillary oxygen saturation (SPO2)), despite the escalation of inspired oxygen to 100%. A blood gas analysis consistent with metabolic acidosis (ph 7.23, oxygen partial pressure (PaO2) 125 mmHg, partial pressure of carbon dioxide in arterial blood (PaCo2) 42 mmHg, HCo3 14.6, bases excess (BE) -9). With cyanosis, low oxygen saturation by pulse oximetry (SPO2) in the setting of normal oxygen partial pressure (PaO2) methemoglobinemia was suspected. Co-oximetry was ordered, which revealed a methemoglobin level of 21.5% (normal range 0 to 2%). Laboratory workup ruled out hemolysis. Since the child had end-stage renal disease, methylene blue was not considered as a treatment option, and she was started on daily ascorbic acid 500 mg via a gastrostomy tube. Dapsone was discontinued and pentamidine nebulization monthly started for Pneumocystis prophylaxis. Serial methemoglobin levels on co-oximetry showed an improving trend. Within 48 hours, the methemoglobinemia resolved and the level came down to 0.4 mg/dl. Ascorbic acid was continued for four more days and discontinued. Off ascorbic acid, the methemoglobin level remained less than 0.3 mg/dl. After a meticulous review of the medications and workup, we concluded that dapsone was the probable cause of methemoglobinemia in this child.

pmc-6010361-1

A 15-year-old girl presented to the emergency department with a history of progressive lower limbs weakness for 10 days, inability to pass urine and intermittent grade 6/10 lower abdominal pain for two days. She had no associated symptoms like fever, rash, headache, backache or blurring of vision. No antecedent respiratory tract infection or diarrheal illness. Past medical history was insignificant. About 24 days prior to these symptoms, she received neural tissue sheep brain anti-rabies vaccine following a dog bite. On physical examination, the patient was not in acute distress. She was afebrile and her vitals were: a) Blood pressure: 130/80 mm Hg; b) Respiratory rate: 18 breaths/minute; c) Heart rate: 102 bpm. Neurological examination revealed no facial asymmetry and intact cranial nerves. Motor system examination of the lower limbs revealed following: a) Power of the knee: grade ⅕ below the knees; b) Power of the hips: grade ⅕ of the hip flexors and extensors bilaterally; c) Tone and reflexes of the legs: hypotonia of legs bilaterally with loss of knee and ankle reflexes bilaterally; d) Joint position and vibration sense: reduced joint position and vibration was noticed, and there was hyperesthesia of the soles bilaterally. Upper limbs were normal on physical examination. The cardiorespiratory system was unremarkable on examination. On abdominal examination, urinary bladder was palpable above the symphysis pubis and was tender on palpation. Laboratory investigations revealed hemoglobin of 12.5 g/dl with the hematocrit of 44%; TLC was 6500/cmm and ESR at the first hour using Westergren method was 23 mm. Cerebrospinal fluid examination (CSF) revealed clear fluid, normal opening pressure, glucose 75 mg/dl (normal range: 45–100 mg/dl), proteins 2.5 g/l (normal range: 0.18–0.45 g/dl) and WBCs 2/cmm (albuminocytologic dissociation). Based on physical examination and CSF findings a provisional diagnosis of Guillain–Barre syndrome was made. Electrophysiological study (confirmatory test) revealed demyelinating polyneuropathy consistent with Guillain–Barre syndrome. Plasmapheresis and physical therapy sessions resulted in a nearly complete recovery in six to eight months.

pmc-6010465-1

A 68-year old gentleman presented with an isolated right axillary mass in October 2014. An axillary biopsy revealed poorly-differentiated (Grade 3, Ki67 85%) neuroendocrine carcinoma of unknown origin (positive for CD56, chromagranin and synaptophysin; negative for TTF1, CDX2 and Merkel Cell Polyomavirus). Positron emission technology/computed tomography demonstrated a right axillary mass and no other identifiable sites of disease. The patient received six cycles of carboplatin and etoposide chemotherapy between Oct 2014 and April 2015 with RECIST partial response after three cycles but with evidence of tumor growth after cycle 6. He was referred to the Experimental Cancer Medicine Team and consented to TARGET in June 2015. In parallel he was referred for surgical resection of the isolated axillary mass which achieved a complete resection and permitted access to fresh tissue for PDX and translational research in July 2015. Following a brief disease-free period, the patient relapsed with metastatic nodules within the retroperitoneum in December 2015. The patient was treated with capecitabine and temozolamide between March and October 2016 with best response of progressive disease. Treatment was switched to interferon and sandostatin and his disease has remained stable by RECIST 1.1 criteria on this combination at the time of writing.

pmc-6010516-1

A 40-year-old Caucasian male, with a prior diagnosis of PAN, presented in January 2016 with large volume hematemesis from esophageal varices related to portal hypertension. Throughout his childhood he had chronic arthralgia and swelling of his ankles diagnosed as juvenile idiopathic arthritis. By age 4, he manifested developmental delays, including difficulty with ambulation. At the age of 20, he developed recurrent ischemic strokes causing persistent dysarthria, ataxia, and weakness. During that time, he developed recurrent violaceous subcutaneous lesions that would ulcerate, but were responsive to glucocorticoids. He was diagnosed with PAN based on skin biopsies. He required a long-term maintenance dose of prednisone 7.5 mg daily, as reduction would led to recurrent skin lesions. In childhood, he developed poorly explained visual loss without evidence of inflammatory eye disease on physical exam. His visual acuity had been stable for the last couple years prior to presentation. His history was also remarkable for recurrent mouth and genital ulcers, which were also responsive to glucocorticoids. He had lymphopenia (absolute lymphocytes count 400/μl [1000-4800], CD3 422/μl [600-2990], CD4 370/μl [440-2160], CD8 49/μl [120-1320], CD19 11/μl [100-700]), yet normal lymphocyte proliferation studies to mitogens. Additionally, he had hypogammaglobulinemia (IgG 383 mg/dl [762-1488], IgA 46 [70-390], IgM <20 [38-328]), but had protective antibody levels to both tetanus and pneumococcus. There was no history of recurrent infections.

pmc-6010516-2

A 43-year-old Caucasian male, brother to Patient 1, had a similar presentation. At 5 years of age, he was diagnosed with juvenile idiopathic arthritis after presenting with polyarthritis. At the age of 8, he was diagnosed with stage IV Hodgkin’s lymphoma (records were not available). He was initially treated with radiation therapy alone, but later transitioned to chemotherapy [initially with MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) and later converted to ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine)] with remission achieved 1 year later. At age 24, he developed sudden onset left-sided persistent numbness followed by bilateral sensorineural hearing loss with near complete left-sided deafness. At age 26, he presented with bright red blood in his stool, which required resection of 6 inches of small intestines for reasons that were unclear. By age 29, he developed heart failure and pulmonary hypertension presumed secondary to ABVD treatment. His history was also significant for superior vena cava occlusion, presumed secondary to a port catheter, and esophageal varices. Immunologic evaluation revealed normal immunoglobulins, lymphocyte proliferation to mitogens, and lymphocyte subsets except for a slightly low CD8 count (83/μl). He had protective antibody levels to tetanus. Based on these presentations, there was a high suspicion for DADA2. Written informed consent was obtained for each patient, as well as their parents for genetic testing, and for the publication of this case report. ADA2 exon sequencing was performed on both patients and their unaffected parents as previously described (). Adenosine deaminase 2 levels were tested only in Patient 2 with comparisons made to DADA2 patients, adult carriers for ADA2 mutations and adult healthy controls.

pmc-6010554-1

A 35-year-old female was admitted to our hospital complaining of an intermittent headache for 5 years, menopause for more than 2 months, and blurred vision and lactation for more than 1 month. Five years prior, the patient began suffering from intermittent and gradually deteriorating occipital and frontal headaches. One month prior to admission, she had impaired vision and an absent right temporal view and simultaneous bilateral galactorrhea, without purulent or bloody secretions. Since the onset of symptoms, the patient experienced no nausea or vomiting, sleepiness, chills, hair loss, or fatigue. Computed tomography (CT) showed an irregular cystic solid mass in the suprasellar area. The size of the mass was 1.4*1 cm and could be markedly enhanced. The CT value of the solid part of the lesion on plain CT was 40 Hounsfield units (HU); in the enhancement, the value was 74 HU, and the cystic part showed no enhancement. The boundary of the lesion was less clear, the density was not uniform, and no obvious calcification was observed. The cavernous sinus was involved. There were no abnormalities in the ventricular system, sulcus, brain split and pool. Moreover, there was no shift in the midline structure, and no abnormalities were found in the skull structure. The sinuses exhibited no obvious abnormalities. Magnetic resonance imaging (MRI) of the brain and pituitary showed an irregular cystic solid mass in the suprasellar area, involving in the pituitary stalk, and the boundary between the lesion and pituitary was unclear. In addition, the mass pressed on the optic chiasm, and the solid part of the lesion was significantly enhanced, while the cystic part showed no enhancement. There was no abnormal signal in the brain or paranasal sinuses nor signs of calcification (Figure ). Auxiliary examinations revealed that the patient's urine volume and specific gravity were within the normal range (urine volume: 1,800 mL/day; urine specific gravity: 1.015). A pituitary function evaluation showed hyperprolactinemia (45.47 μg/L, normal range for female: 2.8–29.2 U/L) and intact growth hormone (GH) and gonadotropin function. The insulin-like growth factor 1 (IGF-1) level was 120 ng/ml (109–284 ng/ml). The pituitary-thyroid and pituitary-adrenal axis were intact (Tables –). The blood sedimentation and CRP level were normal, and indicators related to tuberculosis and other infections were negative. Because of the thickening of the pituitary stalk, CSF analysis was performed to identify the nature of the mass lesion before any invasive procedures were performed. The results of CSF analysis were normal except for a significantly increased human HCG (18.54 U/L, normal range: 0–5 U/L) level. However, the serum HCG and α-fetoprotein (AFP) levels were normal. A biopsy was recommended to clarify the diagnosis, but the patient declined. Considering the possibility of a germinoma, radiotherapy was recommended. No regression of the intracranial mass and no resolution of the headache were observed after 10 radiotherapy treatments (total 10 Gy). Therefore, the patient was admitted a second time. Apart from a deficiency in GH and hypogonadotropic hormones, the other axes were intact (Tables –). The IGF-1 level was 89 ng/ml (109–284 ng/ml). A repeated CSF analysis indicated there was no obvious decrease in the HCG level in the CSF (17.41 U/L, normal range: 0–5 U/L). An MRI showed no signs of shrinkage of the mass (Figure ). Due to the enlarged intracranial mass, the patient was transferred to the neurosurgical department for total resection of the mass. The pathological analysis was indicative of a craniopharyngioma (Figure ). Under a microscope, the lateral fissure was separated at the saddle area, and CSF was released. The brain tissue collapsed, and a portion of the temporal lobe was removed. The tumor was located in the suprasellar area. The tumor was removed from the second gap along the longitudinal axis of the pituitary stalk and was frozen for analysis. The tumor and hypothalamus were closely related. Hemostasis was achieved, and the gauze inventory was correct. The surgery was complete following strict closure of the dura mater, bone flap reduction and fixation, suturing of the temporalis muscle and scalp, and placement of an external dura mater drain. The tumor specimens were sent for pathological analysis. After surgery, the patient did well and had no complaints of headache, vomiting, polyuria, polydipsia, sleepiness, or anorexia. She did not receive any hormone replacement. One year later, she was admitted to our endocrinology department for re-evaluation. Her urine volume and specific gravity were within the normal range (urine volume: 1,500 mL/day; urine specific gravity: 1.017). The urine osmotic pressure was 752 mOsm/L (0–1,000 mOsm/L), the blood osmolality was 292 mOsm/L, and a pituitary stimulation test revealed normal frontal lobe function except for an impaired GH level (Tables , ). The IGF-1 level was 92 ng/ml. HCG levels in the serum and CSF were within normal limits (serum HCG: 0.1 U/L; CSF HCG: 0.31 U/L). The slightly increased prolactin detected preoperatively had decreased to within the normal range. Cranial and pituitary MRI showed no expansion of the sellar region, no signs of a local tumor, no abnormal enhancement, a clear boundary of the optic chiasm, and no signs of tumor recurrence (Figure ).

pmc-6010806-1

A 54-year-old male businessman presented to our clinic with progressive shortness of breath for the last three months. He also complained of intermittent cough with yellowish sputum and dyspnoea upon exertion for half a year. He had a history of well-controlled hypertension and smoking one pack of cigarettes per day. Family history was remarkable for adenocarcinoma of the lung. Travel history was remarkable for travel to Yunnan, China, in the past year. He first visited a pulmonologist in a local clinic a month prior to admission, where chest X-ray demonstrated increased infiltration over bilateral lung fields. Oral azithromycin was administered, but his dyspnoea progressed. He then visited our clinic for a second opinion. Upon examination, he denied fever, joint pain, dry eyes or mouth, muscle weakness, pitting oedema over lower legs, and skin rash. Physical examination was unremarkable, except chest auscultation demonstrating fine crackles over bilateral lung fields. Chest X-ray showed diffuse interstitial infiltration bilaterally (Fig. ). He was admitted for further workup and monitoring of his respiratory performance. During hospitalization, the patient had no fever, and respiratory pattern was smooth. Peripheral capillary oxygen saturation (SpO2) was 95% under ambient air. Serum white blood cell count showed no leucocytosis or left shift. Autoimmune markers, including rheumatoid factor, antinuclear antibody, anti-Smith antibody, anti-ribonucleoprotein antibody, anti-SSA, anti-SSB, and anti-Scl-70, were all negative. Polymerase chain reaction of Pneumocystis jiroveci from induced sputum was negative. One of three sets of sputum culture demonstrated non-tuberculous mycobacteria, which was later attributed to environmental contamination given his symptoms and image findings. Chest CT disclosed extensive patchy ground-glass opacities superimposed with thickened interlobular septa and intralobular lines over both lung fields, demonstrating a “crazy paving” pattern (Fig.). Pulmonary function test showed normal spirometry and moderately reduced diffusing capacity of the lungs for carbon monoxide (DLCO) on single breath diffusing capacity test (5.42 mmol/min/kPa, correlated with 57.7% of predicted value). Bronchoscopy indicated no endobronchial lesions. A radial probe endobronchial ultrasound (EBUS) showed a “blizzard sign”, suggesting ground-glass opacity over the superior segment of the right lower lobe (Fig.) . Brush cytology, bronchoalveolar lavage (BAL), and biopsy were performed. Brush cytology was negative for malignant cells. Macroscopically, the BAL specimen was clear in appearance. Microbiological workup of BAL was negative for presence of bacteria, tubercolosis (TB), non-tuberculous mycobacteria (NTM), fungus, and Pneumocystis jiroveci. We performed both a forceps biopsy and a cryobiopsy on the larger-sized lesions. Pathological report of the four 0.2 × 0.2 × 0.1 cm tissue fragments obtained by forceps biopsy indicated only chronic inflammation. On the other hand, the four 0.5 × 0.5 × 0.2 cm tissue fragments acquired by cryobiopsy revealed periodic acid-Schiff (PAS)-positive granular proteinaceous exudate with mild interstitial lymphocytic infiltration filling the alveolar spaces consistent with PAP (Fig.). We discussed the treatment options with the patient, and whole lung lavage was advised. The patient declined our suggested treatment and opted for close surveillance. He was discharged with outpatient follow up. Later, his shortness of breath spontaneously resolved, and serial chest X-rays showed resolution of the interstitial infiltration of the lungs.

pmc-6011099-1

A 5-year-old male initially came to the attention of the immunology service at 2 years of age with a history of recurrent sinopulmonary infections and a family history of XLP1 (nonsense mutation c. 191G>A in the SH2D1A gene). Of note, his uncle with XLP1 had a history of EBV-related central nervous system (CNS) lymphoma. SAP expression was found to be absent in NK and CD8 cells, confirming the diagnosis of XLP1. NKT cells were undetectable. Profound hypogammaglobulinemia was also noted. He was monitored and maintained on monthly intravenous immunoglobulin (IVIG) infusions with only minor breakthrough sinopulmonary infections. Adherence to IVIG was suboptimal due to social reasons. The family deferred stem cell transplantation. At the age of 5 years, he presented with acute behavioral changes, manifesting as uncontrolled aggression, requiring inpatient psychiatric treatment. Basic labs including complete blood count and comprehensive metabolic panel were normal. Specifically, no cytopenias, no transaminitis, and normal inflammatory markers including C-reactive protein (CRP) and platelet count were noted. MRI of the brain showed multiple small nonenhancing foci on T2 FLAIR sequence, mostly in the frontal lobes and scattered throughout the subcortical white matter (). The lesions remained unchanged on repeat MRI at 2 weeks and again at 4 months following presentation, suggesting that these lesions may be consistent with glial scars without acute inflammation of the brain. PCR revealed presence of EBV in the blood (2300 copies/ml). Cerebrospinal fluid (CSF) also demonstrated EBV (73 copies/ml). CSF was otherwise normal apart from only slightly elevated CSF WBC (8 cells/mm3), of which 79% were lymphocytes and 21% monocytes. Intravenous gamma globulin 1 g/kg and intravenous ganciclovir 10 mg/kg/day were started immediately. However, despite 14 days of ganciclovir treatment, EBV counts remained significantly elevated. Rituximab was administered on days 16 and 23 of admission. Prednisolone 1 mg/kg/day was given daily on days 16 through 23, and IVIG 1 g/kg was repeated on day 23. Valganciclovir 45 mg/kg/day was continued for 4 months after ganciclovir treatment. Prior to rituximab infusion, EBV counts had reached 2300 copies of EBV genome/mL of blood. Five days after the second rituximab infusion CD19+ and CD20+ lymphocytes and EBV PCR were found to be absent in the blood and remained absent for 5 months, at which time hematopoietic stem cell transplant (HSCT) was performed ( and ). IgM to EBV was undetectable at the time of presentation, and the patient never seroconverted.

pmc-6011100-1

A 12-year-old girl (height, 144 cm; weight, 40 kg) was presented to the hospital with an episode of seizure with impaired consciousness. Her BG at that time was 60 mg/dL (normal value of casual BG: 70–200 mg/dL). Glucose was administered and she recovered consciousness. She had no significant comorbidities prior to hospital admission. From her family history and further investigation, she was diagnosed as having insulinoma and hyperparathyroidism in MEN-1. Arterial phase images of computed tomography showed a vascularity-rich tumor of 20 mm in diameter located in the head of the pancreas. The feeding artery of the tumor was not clearly demonstrated by angiography and selective arterial calcium injection. We considered that extended surgical procedures such as pancreatoduodenectomy might be required depending on intraoperative findings; therefore, open abdominal surgery rather than laparoscopic surgery was scheduled. Her intact parathyroid hormone level was 66.0 pg/ml (normal value: 10–65 pg/mL) and her adjusted serum calcium level was 10.3 mg/dL (normal value: 8.7–9.9 mg/dL), although parathyroid ultrasound examination revealed no parathyroid tumor. Other tumors complicated with MEN-1 were not detected. The results of other preoperative examinations were unremarkable. On the day before surgery, an Enlite™ sensor of MiniMed™ 620G (Medtronic Diabetes, Northridge, CA, USA) SCGM system was inserted into her upper arm. Although MiniMed 620G was combined with an insulin pump, we did not use the pump. The SCGM system was calibrated as recommended by the manufacturer with capillary BG measured by OneTouch® UltraVue™ Blood Glucose Meter (Johnson & Johnson, New Brunswick, NJ, USA). No premedication was given and she walked into the operating room. Capillary BG was 80 mg/dL and the SCGM system was calibrated. Continuous glucose infusion was started at 4.6 g/hr, and general anesthesia was induced with 80 mg of propofol, 50 mcg of fentanyl, and 0.02 mcg/kg/min of remifentanil. Muscle relaxation was obtained by administration of 30 mg of rocuronium, and the trachea was intubated. After induction of general anesthesia, an epidural catheter was inserted at the eighth and ninth thoracic interspace. Anesthesia was maintained with 1.7% sevoflurane, 0.01–0.02 mcg/kg/min of remifentanil, and intermittent thoracic epidural administration of 0.25% levobupivacaine (3 ml). An arterial catheter was inserted, and arterial BG measured by an ABL800 Flex Blood Gas Analyzer (Radiometer, Brea, CA, USA) was 71 mg/dL, which was compatible with IG of 73 mg/dL. An additional 2 g of glucose was given intravenously before the start of surgery, and IG increased from 77 mg/dL to 101 mg/dL at 20 minutes (). After that, IG mildly decreased and returned to almost the same level after 1 hour. The surgeon informed us that the tumor would be removed by enucleation shortly. Just before tumor resection, arterial BG was 76 mg/dL and IG was 80 mg/dL. At 20 minutes after tumor resection, IG showed a rapid increase. We therefore decreased the continuous glucose infusion rate to the usual dose of 1 g/hr, and IG gradually decreased and was stabilized at about 140 mg/dL. During surgery, blood pressure was between 90/50 and 120/70 mmHg, and heart rate was between 60 and 90 bpm. She was extubated in the operating room and transferred to the general surgery ward. The operation time was 2 h and 24 min, and the anesthesia time was 3 h and 53 min. Postoperative pain was controlled well by continuous epidural analgesia (12 mcg of fentanyl and 0.2% levobupivacaine at 4 ml/hr) and administration of 600 mg of acetaminophen (every 6 hr). Her postoperative course was uneventful and she was discharged on POD 10.

pmc-6011104-1

An 83-year-old woman was referred to our department for further examination of a left renal tumor 20 mm in diameter in her horseshoe kidney. She had no remarkable medical history except for uterine cancer at 49 years of age. The laboratory data showed slight anemia and a low liver function (Hb 12.3 g/dL, AST 52 IU/L, ALT44IU/L, and LDH 201 IU/L). Contrast-enhanced computed tomography (CT) showed a renal tumor covered with a capsule and buried by nearly 30%. The tumor was supplied by four arteries toward the left kidney (). We set the laparoscopic ports as shown in . We first approached intraperitoneally and then cut the peritoneal and approached to the renal helium. We encountered a thin artery and cut it after confirming the supplied area by clamping. We then clamped the main artery and cut the tumor with a 1 mm surgical margin. No urinary tract leakage was observed. After coagulation using bipolar forceps, we sutured using 1-0 Vicryl (Ethicon, Cincinnati, OH, USA) then sprayed with Arista AH (BARD; Warwick, RI, USA). We then fixed the thread as shown in . After confirming the lack of active bleeding, we placed a drainage tube and closed the incision. The total operation time was 2 h 39 min, with 11 min of clamping. A histopathological examination revealed clear cell carcinoma (grade 2, INFα, v[−], pT1a). The patient was discharged 11 days after surgery and has been free from recurrence for 43 months.

pmc-6011110-1

A 50-year-old man underwent live laparoscopic donor nephrectomy (LLDN), through transperitoneal approach, on his left kidney as a donor for his sister. This procedure went uneventful and the patient was discharged 3 days after surgery. However, within one week after the procedure the patient experienced pain at the left side of the scrotum and left upper leg. During physical examination, a hypersensitive scrotum (allodynia) was noted whereas no other abnormalities were seen. The urologist was consulted but no urologic complications were found. The neuropathic pain area befitted the genitofemoral nerve (GFN). Conservative treatment was initiated with neuroleptic drugs and blocks of the L1/L2 dorsal roots with local anaesthetics and pulsed radiofrequency lesioning. These treatments did not result in significant pain relief and he could not work. Three years after the start of the neuropathic pain, operative treatment aiming at pain relief was initiated. In a multidisciplinary meeting it was concluded that a nerve entrapment of the GFN was suspected to be the most likely cause of the patient's neuropathic pain. Eventually, an exploratory transperitoneal laparoscopy was performed. After extensive adhesiolysis, a hemoclip used for closure of the ureter at the time of nephrectomy was identified in close relation to the GFN and removed. Due to the local scarring it could not be surgically assessed to which extent the GFN was actually damaged or a neuroma was formed. It seemed, however, highly likely that the pain originated from the GFN in this area. We therefore cut the GFN proximally in a normal looking segment (). Pathological analysis of the tissue confirmed this to contain nerve tissue. Within 2 weeks following surgery, the patient was completely pain-free and could return to his normal activities.

pmc-6011111-1

A 32-year-old Caucasian male with a known history of depression presented to the emergency department accompanied by police after a violent outburst following prolonged DFE abuse during a suicide attempt. On admission, he was emotionally labile and had contusions on his left shoulder and upper extremities due to a physical altercation with police. He was initially confused and verbally abusive, but within six hours he was oriented, cooperative, and able to provide a reliable history. The patient stated that he had huffed keyboard cleaner several days per week for the past year; however, the frequency had increased over the last month to several times daily. Other than depression, the patient had no other known medical problems. He denied any personal or family history of kidney disease. The patient denied drinking alcohol, and he reported smoking one-half pack of cigarettes per day for the previous two years. He denied any other substance abuse except for DFE. He reported no use of nonsteroidal anti-inflammatory (NSAID) medications. During this episode of difluoroethane abuse, he had no loss of consciousness, but experienced frightening visual and auditory hallucinations as well as anxiety that persisted even after returning to his self-reported baseline mental status. Initial labs revealed a WBC count of 21,000 with polymorphonuclear predominance of 81%, an elevated creatinine of 1.5mg/dL with no known baseline, BUN of 10mg/dL, GFR of 54 mL/min/1.73 m2, lactic acidosis, creatine kinase of 350 U/L, and a carboxyhemoglobin level of 3.1%. Urinalysis was significant for 3+ proteinuria, moderate blood, 14 RBCs, 3 WBCs, and 3 hyaline casts. He had a negative urine drug screen. The patient received single renally adjusted doses of Vancomycin and Piperacillin-Tazobactam, intravenous 0.9% saline, and oxygen by nasal cannula while in the emergency department prior to admission. Over the next 24 hours, he received intravenous fluids and oxygen with subsequent normalization of lactic acid, creatine kinase, and leukocyte count. His creatinine down trended to 1.3mg/dL. However, 36 hours into admission, his serum creatinine inexplicably rose to 2.3 with a rise in carboxyhemoglobin to 3.6%, while his urine output remained stable (). Repeat urinalysis showed a small amount of blood with RBC of 2, negative proteinuria, and no evidence of infection. His normal saline infusion was transitioned to bicarbonate with saline, but was discontinued after the patient developed pruritus. Ultimately, he was transitioned to normal saline at 75 ml/hour. A renal ultrasound showed increased echogenicity of both kidneys consistent with medical renal disease, without change in size, atrophy, or cystic lesions (). Thus, it is likely that the patient had some degree of chronic kidney disease (CKD) prior to admission. For the next three days, he continued to receive intravenous normal saline with subsequent improvement of creatinine and normalization of his urinalysis and was discharged with a creatinine of 1.6.

pmc-6011113-1

A 44-year-old female patient reported to the Department of Oral and Maxillofacial Surgery, and Periodontology at the Dental School of Ribeirao Preto, University of São Paulo for a placement of implants. During the initial examination, it was observed that the right upper central incisor had an unsatisfactory temporary Richmond type crown that was changed by a metal core, post, and new temporary crown. The new temporary crown was fitted to the removable partial denture that was used by the patient (). Surgical guides were made and the patient was referred for implant placement, in the region of teeth 12, 35, 36, 44, and 46. After approximately 8 months, it was verified that the implant located in the anterior region was positioned further apical and buccal () making it impossible to fabricate a successful implant crown from an esthetic point of view. The implant was gradually removed using the implant removal instrument (Implant Retrieval Tool; Nobel Biocare), with antirotational movement (). Following this surgical procedure, a new implant was installed (cone morse 3.5 × 11 mm, Conexão, Brazil), with a torque of 30 N, and positioned in the mesiodistal direction. Specifically, the implant was placed closer to tooth 14 in the buccal-palatine direction on the bone ridge (located around 1 mm for the palatal from an imaginary curvature passing through the buccal surfaces of the present teeth and 1 mm infraosseo in the coronoapical direction) (). After the surgery, the removable partial denture was removed. This was followed by the fabrication of a temporary fixed partial prosthesis with retention used during the osseointegration phase on teeth 11 and 14 (): this was only for esthetic purpose. This was in addition to the installation of prostheses on the implants in the regions of teeth 35, 36, 44, and 46. Immediately after the second stage surgery, the temporary fixed partial denture was performed using the healing cap as an abutment and a lateral incisor as a mesial cantilever. Following the rehabilitation procedures, this temporary fixed partial denture was changed to a provisional fixed prosthesis with the mesial cantilever screwed into the implant. During this phase, periodic acrylic resin implements were added to the temporary prosthesis to promote gingival conditioning (Figures and ) and black triangle closure (Figures and ) and also to improve gingival esthetics. At the end of two months, the implant prosthesis with a mesial cantilever was installed (). This case report was approved by the institution's Ethics Committee on Human Research and followed the ethical principles of the Declaration of Helsinki, in addition to complying with specific legislation.

pmc-6011114-1

A 26-year-old Yemeni male patient from Taiz Province was referred to the restorative dental clinics at King Saud University, Saudi Arabia. His chief complaint was an unpleasant smile caused by generalized tooth discoloration. His medical history was irrelevant. The fluoride level in the water around Taiz Province is >3.6 mg/l []. Clinical examination revealed generalized fluorosis with loss of the outermost enamel in irregular areas involving less than half of the entire surface, as well as changes in the morphology caused by merging pits and marked attrition (). In this case, based on the Thylstrup and Fejerskov index (TFI) for dental fluorosis classification, the dental fluorosis was classified as TFI = 7 []. After the clinical examination, radiographs, preoperative photographs, and upper and lower alginate impressions for diagnostic models were taken. The patient was presented with treatment options, which included ceramic or composite veneers, along with the advantages and disadvantages of each option. The patient agreed to smile enhancement using ceramic veneers for his upper teeth given that he desired an optimum aesthetic and a long-term result. The veneers would be placed on the patient's upper teeth, from his upper right 2nd premolar to upper left 2nd premolar. The patient decided to postpone veneering his lower teeth, given his limited financial capacity. Diagnostic models were analyzed to evaluate the occlusion, and a diagnostic wax-up was made of white-colored wax. The use of the wax-up allows the patient to preview the desired appearance of his teeth, and this wax-up is also essential for the fabrication of a clear matrix for temporary restorations. The desired shade was selected using the VITAPAN classical shade guide (VITA Zahnfabrik, Germany). The enamel of the eight maxillary teeth was prepared using a flat-end tapered diamond bur to a depth of 0.5–0.75 mm facial reduction with 1.5 mm incisal reduction (). A chamfer finish line was maintained at the level of the gingival margin. The proximal margin was extended into the facial and gingival embrasures. Following tooth preparation, gingival retraction was achieved using retraction cords (Ultrapak Cord #00, Ultradent Products Inc., South Jordan, UT, USA) soaked in a hemostatic agent. Impressions were taken with a polyvinylsiloxane material (Virtual, Ivoclar Vivadent, Amherst, NY). The impression material was manipulated according to the manufacturer's instructions. Temporization was performed by spot etching on the facial surface of each prepared tooth with 37% phosphoric acid (Total Etch, Ivoclar Vivadent, Schaan, Liechtenstein). Bonding agent (OptiBond Solo Plus, Kerr, Orange, CA, USA) was applied on the enamel-etched spots and light cured for 20 seconds using a high-intensity light-emitting diode (LED) curing light (Elipar S10, 3M ESPE, MN, USA). The clear matrix that was previously fabricated was loaded with a temporization material (Protemp Plus, 3M ESPE, MN, USA) and placed over the prepared teeth. Light curing was done for 10 seconds per tooth. Then, the matrix was gently teased away from the prepared teeth. A number 12 scalpel blade was used to remove the partially cured temporization material. Facial and lingual embrasures were refined with a thin diamond disk, the occlusion was adjusted, and the temporary restorations were polished using polishing discs and points (). Ceramic veneers were fabricated with a lithium disilicate-reinforced glass ceramic material (IPS e.max Press, Ivoclar Vivadent, Schaan, Liechtenstein). Temporary veneers were removed, and the teeth were cleaned using pumice. Ceramic veneers were tried-in using a transparent shade try-in paste (Variolink Veneer try-in paste, Ivoclar Vivadent, Schaan, Liechtenstein) to assess marginal adaptation and shade. Afterwards, veneers were prepared for bonding. Fitting surfaces of the veneers were etched with hydrofluoric acid (Porcelain Etchant 9.5%, Bisco Inc., Schaumburg, IL, USA) for 60 seconds, washed under running water for another 60 seconds, and dried with an air syringe. A layer of silane coupling agent (Monobond Plus, Ivoclar Vivadent, Schaan, Liechtenstein) was applied on the veneers' fitting surfaces and gently air-dried after one minute. Then, the prepared teeth were etched using 37% phosphoric acid for 30 seconds, rinsed, and dried. A clear mylar strip was placed interproximally to prevent inadvertent bonding to the adjacent tooth and to facilitate the subsequent removal of excess resin cement in the embrasures. A layer of bonding agent (Adhese Universal, Ivoclar Vivadent, Schaan, Liechtenstein) was applied on the prepared tooth surfaces and air-thinned. Then, Heliobond (Ivoclar Vivadent, Schaan, Liechtenstein) was placed on the prepared tooth surfaces. The inner surface of the veneers was covered with light-cured resin cement (Variolink Veneer, transparent shade, Ivoclar Vivadent, Schaan, Liechtenstein). Veneers were positioned appropriately on the teeth by applying gentle pressure, following which excess resin cement was carefully removed with an explorer before light curing. Light curing was first performed for 2 seconds, and the excess resin cement was removed with a microbrush. After that, each veneer was light-cured from the facial aspect for 40 seconds and from the lingual aspect for 40 seconds. The two veneers of the central incisors were first simultaneously cemented. This was followed by cementation of the veneers of the two lateral incisors. Then, the veneers of the two canines were cemented. Finally, veneers for the first and second premolars were cemented simultaneously on each side. Minimal gingival flash of the resin luting cement was removed with a number 12 scalpel blade. A flame-shaped fine diamond bur was used to finish the ceramic margins and to contour the embrasure surfaces. Occlusion was assessed and adjusted. Flossing was performed to ensure interproximal contact patency. Ceramic polishing was performed using a series of polishing cups and points (OptraFine polishing system, Ivoclar Vivadent, Schaan, Liechtenstein). Interproximal contacts were finished with finishing and polishing strips. Final surface lustre was achieved by using a diamond polishing paste with a rubber prophylaxis cup. The postoperative clinical photographs are shown in . The patient was satisfied with the final result ().

pmc-6011115-1

A 75-year-old male visited a urological practitioner because of nocturia. An elevated serum prostate specific antigen (PSA) level of 76.2 ng/mL was observed, and digital rectal examination showed diffuse induration of the prostate. Pelvic MRI demonstrated extensive high signal of the prostate in diffusion-weighted imaging (DWI) (). Fluorodeoxyglucose-positron emission tomography/CT revealed multiple spine and pelvic bone and para-aortic and pelvic lymph node metastases (Figures and ). Based on these findings, the patient was diagnosed with metastatic prostate cancer (cT3aN1M1b) and treated without prostate needle biopsy, with primary androgen deprivation therapy (ADT), including a GnRH antagonist (degarelix) and anti-androgen agent (bicalutamide). The PSA level immediately declined and reached nadir (0.23 ng/mL) after 8 months. However, 15 months after the start of ADT (PSA level, 2.33 ng/mL), the patient was diagnosed with CRPC and referred to our hospital. To evaluate the patient's current disease status, we performed CT, bone scan, and WB-MRI. We observed discrepancies between the WB-MRI, bone scan, and CT. CT showed multiple osteoblastic lesions in the spine and pelvic bone (Figures and ) and shrunken para-aortic lymph nodes. Bone scan similarly showed multiple accumulations at the same bone sites as the CT (). However, these osteoblastic lesions showed almost no high signal in DWI of WB-MRI, suggesting that the lesions did not have viable tumor cells (Figures –). In contrast, the primary lesion had a diffuse high signal remaining in DWI of WB-MRI (). We then performed histopathological examinations of both the prostate and the vertebra. The prostate needle biopsy demonstrated that 10 of 12 cores had viable prostate cancer cells (). Meanwhile, we performed the CT-guided needle biopsy from the osteoblastic lesion of the second lumbar vertebra, which was diagnosed with bone metastasis by CT and bone scintigraphy, to exclude vertebral bone metastasis of prostate cancer by an orthopedic unit of another hospital, which the patient visited owing to lumbago and bilateral lower limb paralysis. Histopathological examination of the osteoblastic lesion demonstrated no malignant cells (). Considering the results of the bone needle biopsy, we comprehensively reviewed the patient's image findings. A CT scan in the second lumbar vertebra revealed an osteoblastic change (885.4 Hounsfield unit), T1- and T2-weighted imaging of MRI revealed low signal intensity, and the ADC value was low (0.498 × 10−3 mm2/s); however, b = 0 and b = 1200 of DWI exhibited no high signal intensity, suggesting a benign osteoblastic change induced by the treatment effect (Figures –). With orthopedic conservative therapy in accordance with the diagnosis of lumbar hernia, the lumbago and bilateral lower limb paralysis completely resolved. Based on the findings of our WB-MRI and histopathological examinations, we reasoned that viable tumor cells inducing disease progression may primarily exist in the primary lesions and not in the metastatic lesions. Then, to control the overall disease, we changed the patient's medication from bicalutamide to enzalutamide for potentially existing micrometastases and added prostate RT (74 Gy). After this, his elevated PSA immediately declined and was controlled at a level of <0.2 ng/mL.

pmc-6011119-1

A 64-year-old-man with an eighty-pack-year smoking history presented with insidious onset of worsening shortness of breath over a period of 6 months. He had previously undergone ablation for atrial fibrillation, as well as surgery and radiation for prostate cancer. Six months before presenting to our institution, he had fallen and fractured 2 right-sided ribs and developed an upper respiratory tract infection one month later. Over the next 3 months, the patient continued to experience intermittent fevers, chills, cough, wheezing, and exertional dyspnea. The patient was initially treated with oral antibiotics for presumed community-acquired pneumonia; however, his symptoms persisted despite multiple courses of antibiotics and inhaled bronchodilators, and he was ultimately hospitalized. Serum serology for coccidioidomycosis was negative. Sputum cultures grew normal upper respiratory flora. His chest radiograph showed a left lower lobe (LLL) infiltrate. A computed tomogram (CT) of the chest showed a LLL consolidation, with evidence of narrowing of the LLL bronchus (). There was an abrupt cutoff in the LLL bronchus, but no endobronchial lesion was detected (). A bronchoscopy performed at the hospital showed a “rounded, nonulcerating, pink mass-like growth” obstructing the LLL bronchus. Brushings from the growth were negative for malignancy, but no biopsies were obtained. He was referred to our center for evaluation of this endobronchial lesion. Upon further examination, the patient recalled a significant decline in his exercise tolerance about 6 months prior to the current presentation. His pulmonary function tests showed severe airflow obstruction, with FEV1 of 1.53 L (42% predicted), which was a decline from his previous FEV1 of 2.2 L (63% predicted) 6 months earlier. The patient's physical examination revealed decreased breath sounds at the lower left lung base, with wheezing limited to the LLL. Although he had continued to smoke for the past 6 months, he had quit smoking 3 weeks prior to the current presentation. Based on his symptom complex, worsening airflow obstruction, and the mass seen on prior bronchoscopy, the likely differential diagnoses included primary lung cancer, lung carcinoid tumor, and foreign body aspiration. Although foreign body aspiration was unlikely, the development and progression of his symptoms over just 6 months would also be unusual for primary lung cancer or for lung carcinoid tumor. The patient underwent another bronchoscopy, which revealed a narrow LLL bronchus, with a fleshy endobronchial mass lesion (). Multiple fine needle aspirates were obtained using a Wang needle (CONMED, Utica, NY), but every pass was positive for dense acute inflammation on rapid onsite evaluation. Multiple endobronchial biopsies were then obtained, and 2 pearly white structures with a brown detached cover were revealed (). The object was extracted in its entirety using a Zero Tip Airway Retrieval Basket (Boston Scientific, Marlborough, MA) and biopsy forceps; the object was identified as an aspirated almond. An ultrathin bronchoscope was then used to examine the airways distal to the aspirated almond, and there was no evidence of any additional foreign material. A bronchoalveolar lavage was performed at the end of the case, and specimens were sent for culture. Pathology of the extracted foreign body was consistent with vegetable matter (), and bronchoalveolar lavage cultures were negative for bacterial or fungal organisms. A 10-day course of amoxicillin-clavulanate was prescribed due to the imaging evidence of aspiration pneumonia secondary to almond aspiration. On follow-up examination one month later, he reported drastically increased exercise tolerance and his cough and wheezing had disappeared; meanwhile, pulmonary function tests showed an increase in his FEV1 to 2.12 L (60% predicted), and a repeat flexible bronchoscopy revealed no bronchial stricture. The patient shared that while he was recovering from his rib fractures, his favorite snack (enjoyed in the supine position) was almonds. While foreign body aspiration for 6 months could lead to irreversible parenchymal changes, a follow-up CT scan at 3 months revealed complete resolution of parenchymal infiltrates in this case (). At the time of his 6-month follow-up, his exercise tolerance had returned to baseline and he had successfully quit smoking.

pmc-6011120-1

A healthy 11-year-old girl was presented to the National University of Malaysia (UKM) Paediatric Dental Clinic with a referral for further management of pulp necrosis of an immature lower right second premolar (tooth 45), secondary to the fractured tubercle of dens evaginatus. Two weeks earlier, she had treatment at a general dental clinic for pain related to tooth 45. Tooth 45 had spontaneous and lingering pain following cold and thermal stimuli. The tooth was diagnosed to have symptomatic irreversible pulpitis, and root canal therapy was initiated. The canal was accessed, and pulp extirpation performed before the placement of intracanal nonsetting calcium hydroxide by the general dental practitioner (GDP). At the time of current assessment, her tooth-related symptoms had completely resolved. General oral examination showed the presence of generalised mild gingivitis with a basic periodontal examination (BPE) score of 1 in all sextants. The patient's oral hygiene was fair with a plaque score of 30%. The patient is still in her mixed dentition with the presence of the primary maxillary canines. Her upper dental arch was well aligned, and mild crowding of anterior teeth was noted in the lower arch. Tooth 45 has an occlusal glass ionomer dressing of the access cavity made for the pulp extirpation earlier by the GDP (). Cold and electric pulp sensibility testings showed positive responses to all fully erupted premolars indicative of tooth vitality expect for tooth 45. Tooth 45 also has slight tenderness to percussion. Periapical radiograph of tooth 45 showed an immature root with convergent open apex and small periapical radiolucency. The pulp space of tooth 45 is of an even width from the coronal to the apical portion (). Based on the assessments, tooth 45 was diagnosed with pulp necrosis secondary to fractured dens evaginatus and symptomatic apical periodontitis. On the day of initial assessment, tooth 45 was isolated with rubber dam after infiltration of local anaesthetic solution (2% lidocaine with 1 : 80000 adrenaline). Pulp chamber was reentered through the previously prepared access cavity. The root canal was exposed and irrigated with saline. After that, the canal was dried with paper points and the tooth working length was estimated with a K-file No. 60. A working length, 2 mm short of the apical opening, was determined (17 mm). The canal was gently prepared with the K-file No. 60 and then irrigated with a copious volume of 1.5% sodium hypochlorite (NaOCI). After drying the wet canal with paper points, nonsetting calcium hydroxide was placed into the canal and the access cavity was double sealed with Cavit™ 3M, USA, and glass ionomer cement (GIC) (Riva Self Cure™ SDI, Australia). Two weeks later, the tooth was reassessed for any signs and symptoms of infection. The tooth was no longer tender to percussion, and there was no indication of infection-related signs and symptoms. After isolation with a rubber dam, the root canal of tooth 45 was reaccessed and irrigated with a copious volume 1.5% NaOCl to remove the nonsetting calcium hydroxide. Then, the canal was irrigated with sterile water and dried with paper points. Subsequently, the canal was irrigated with 17% EDTA (Pulpdent™, Watertown, Massachusetts) for a minute and dried with paper points. Finally, under the guidance of a dental operating microscope (Carl Zeiss Surgical GmbH, S100), the apical region was filled using the EndoSequence (BC RRM-Fast Set Putty, Brasseler, USA) material up to 4 mm thickness to create an apical seal (). The orifice of the root canal was double sealed with a cotton pellet, temporary filling material (Cavit 3M, USA), and GIC (Riva Self Cure SDI, Australia). Once again, the root canal was reaccessed two weeks later, irrigated with 1.5% NaOCl, and dried with paper points. Next, the dried canal was obturated with thermoplasticised gutta-perca using the Obtura III Max System (Obtura Spartan® Endodontics) (). After that, the access cavity was double sealed with GIC (Riva Self Cure SDI, Australia) and nanohybrid composite (AURA™ SDI, Australia), respectively. Following the obturation, tooth 45 was reviewed at three-month and six-month intervals. During both reviews, tooth 45 was asymptomatic. However, at the six-month review, a periapical radiograph of tooth 45 showed an unexpected finding. The apical root of tooth 45 continued to grow beyond the apexification level with a normal periodontal ligament space and lamina dura. No evidence of periapical radiolucency was noted (). However, regular annual monitoring of tooth 45 is essential to ensure that the coronal seal is intact and no apical complication further arises.

pmc-6011124-1

The patient is a 50-year-old African American female with a history of bilateral breast reduction twelve years ago, iron deficiency anemia, and obesity, who presented to the surgeon's office complaining of tenderness of her right breast. The patient reported that recently she had been developing keloids along the scar of the right breast with some areas having a blue hue; her left breast was unremarkable. She noticed that after wearing a sports bra there was increased pressure and abrasions to the keloid, leading to cellulitis and edema. She was previously treated with two courses of antibiotics for what was presumed to be an infected keloidal scar of her right breast but with minimal improvement. On exam, she had a large 10 cm diameter keloidal region on the inferior and lateral aspect of the right breast with edema and cellulitis. The keloidal area had no palpable fluctuance; she exhibited no nipple discharge or palpable adenopathy of the right axilla (). The patient had a benign-appearing mammogram 8 months prior, and all of her screening mammograms since her breast reduction have been without signs of malignancy. Another mammogram was ordered but was not performed due to patient discomfort. An ultrasound of the breast was preformed and suggested marked edema and skin thickening suggestive of infection but no definitive fluid collection or underlying suspicious mass was observed. The patient underwent a right breast partial mastectomy for cosmesis and resection of the infected keloidal area. Intraoperatively, the mass was highly vascular, firm, but not fixed to the chest wall. Postoperatively, the pathology revealed a high-grade primary angiosarcoma of the breast with negative margins. Patient underwent a computed tomography of the chest, abdomen, and pelvis, which did not show any evidence of gross metastatic disease. The patient then underwent completion mastectomy and scheduled for adjuvant chemotherapy with combination gemcitabine and Taxotere, followed by radiation.

pmc-6011125-1

The 41-year-old male patient F.C.F. showed no comorbidities and denied alcoholism, smoking, and taking regular medication. He started having fever, myalgia, anorexia, vomiting, jaundice, and colure on July 14, 2016. He took antiviral drugs with monohydrate dipyrone (750 mg/day) associated to chlorpheniramine maleate (6 mg/day) and paracetamol (>4 g/day) at his peril. He denied taking any other drugs on that occasion. Because his clinical condition had not improved, he went to the hospital, where he underwent medical tests such as complete blood count (CBC): hemoglobin 13.2 g/dL, hematocrit 39.6%, platelets 343,000/mm3, white blood cells (leucocytes 5200/mm3), liver function Aspartate transaminase (AST) 39.8 U/L, Alanine transaminase (ALT) 40.1 U/L, gamma-glutamyl transferase (GGT) 346 U/L, and alkaline phosphatase 98.5 U/L. In addition, the NS1 test for dengue was negative and the abdominal ultrasound showed the liver with diffuse increase in parenchymal echogenicity, indicating mild/moderate steatosis. The patient was diagnosed with hepatitis due to the clinical signs assessed, results of laboratory tests, and excessive intake of paracetamol. The patient was hospitalized, and after 4 days of intravenous hydration and clinical assessment, he was discharged from the hospital. Fifteen days after his discharge, the patient related that he had daily high fever, appetite loss, sweating, weight loss (8 kg), and progressive worsening. On August 6, 2016, the infectious disease specialist ordered new medical tests when examining the patient. The results revealed that blood count was hemoglobin 10.2 g/dL; hematocrit 30.7%; red blood cells 4.16 million/mm3; and platelets 200,000/mm3. It also revealed anisocytosis, microcytosis, and hypochromia; white blood cells were leucocytes 9700/mm3, banded neutrophils 6%, segmented neutrophils 76%, and lymphocytes 10%. Liver function tests indicated aspartate transaminase (AST) 64 U/L, alanine transaminase (ALT) 85 U/L, gamma-glutamyl transpeptidase (GGT) 560 U/L, and lactic dehydrogenase 248 U/L. C-reactive protein was 134.29 mg/L. Serologies were ordered for leptospirosis, rickettsialpox, hepatitis, syphilis, Zika virus, Chikungunya, Epstein-Barr virus, cytomegalovirus, toxoplasmosis, and human immunodeficiency virus (HIV). All of them had negative results. Furthermore, blood cultures were conventionally performed using the Bact/Alert 3D 120 automated microbial detection system. The initial incubation was performed with chocolate agar medium, in 5–10% CO2 at 35°C–37°C for 24 hours. Three blood samples were collected in the first 24 hours, at a minimum 15-minute interval between them, using venous puncture in different places. The colonies isolated on chocolate agar plates were identified by colonial morphology, gram stain, and oxidase reaction. Colonies appeared smooth, round, uniform, grey/brown, and 1 mm in diameter. The oxidase test and tributyrin agar test were positive. This result was positive for the presence of the microorganism M. osloensis in the three samples. Transesophageal echocardiography (TEE) was ordered, and it showed prolapsed mitral valve involving the posterior leaflet (P2 segment) with an echogenic structure adhered to the atrial face, with approximate dimensions of 0.47 × 0.85 cm, compatible with endocardial vegetation, determining failure of coaptation and a moderate degree of valvular insufficiency and eccentric jet. Intracavitary thrombi were absent, and systolic and diastolic functions of the left ventricle were normal. According to the criteria of Habib et al. [], the diagnosis of IE was confirmed, and the patient was hospitalized for intravenous antibiotic therapy. Antibiotic therapy was prescribed from August 8 to September 28 with the administration of vancomycin for four days, gentamicin for 10 days, and ampicillin for 6 days, and after the result of blood culture, ceftriaxone was introduced for 36 days. Remission of signs and symptoms was observed as of August 12. Laboratory tests results were better, and blood cultures were sterile. Theses exams were repeated on August 21 and on September 15. Their results showed no alteration. After completing the therapeutic treatment with specific antibiotics, the patient underwent serial laboratory tests and was hospitalized. Another TEE was carried (09/21), and it revealed chordal rupture and moderate mitral regurgitation. Surgical correction was performed. On September 26, the patient underwent implantation of a mitral valve prosthesis. Surgery was performed without any complications. However, neither the culture nor the pathological anatomy of the surgically removed valve was performed. On October 06, the patient was discharged from the hospital with a prescription for oral anticoagulant warfarin. Eighteen months after the endocarditis episode, the patient was asymptomatic, in good physical condition. He attends follow-up visits with a cardiologist at the same hospital.