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pmc-8677995-1

An eighty year-old female presented with bleeding from the prolapsed uterus. The patient was admitted to the department of Gynaecology/Obstetrics and Gynaecological Oncology of Hospital in Dębica, Poland. In an obstetric history, she reported 3 vaginal births, the last one at the age of 30. Last menstruation was at the age of 52. She did not complain of any past diseases or current chronic diseases, she did not report any addictions and remained in 1 relationship. On admission, a large part of the vagina containing the cervix and a part of the uterine body was found below the vaginal introits (International Continence Society grade 3). Examination revealed an exophytic infiltrating lesions covering entire surface of hypertrophic cervix spreading to the vaginal fornices (Fig. ). Bimanual vaginal examination revealed a small myoma of 2 cm in diameter in the uterine body, adnexa impalpable. Per rectal examination showed a tumour in the anal canal. Moreover, the parametria were uninvolved in this examination. In the diagnostic procedure, the lesion in the cervix was sampled parallelly with curettage of the cervical canal and the uterine cavity. Then, rectoscopy was performed with sampling of the anal canal lesion for histopathology. The rectoscopic image is shown in Figure and the microscopic images of the cervical and anal canal samples in Figure . A polypoid lesion in the rectoscopy measuring 2.5 cm in diameter just behind the external sphincter and an infiltrating lesion occupying the posterior wall of the rectum, 4 cm away from the anal rim were found (Fig. ). Histological images of the cervical and anal canal lesions are shown in Figure . Microscopic examination revealed, in the cervical specimen, moderately differentiated invasive squamous cell carcinoma (SCC) (Fig. A), featuring a strong and diffuse immunohistochemical p16 reaction in the neoplastic cells (Fig. B). In the search of HPV high risk, the polymerase chain reaction (PCR) reaction was performed, which confirmed the presence of high risk HPV (HPV 16 and additional one from the group of High Risk HPV 31,33,35,39,51,52,56,58,59,66,68) in the cervical SCC. The microscopic examination of the biopsy specimen from the anal canal lesion revealed moderately differentiated adenocarcinoma (Fig. C) with patchy p16 immunohistochemical stain in the cancer cells (Fig. D), while the polypectomy specimen showed the conventional serrated adenoma with low grade dysplasia. The low grade dysplasia was also found at the diathermied margin. The PCR reaction excluded the presence of high risk HPV in the anal canal adenocarcinoma, followed by the negative result for low risk HPV PCR test. In addition real-time PCR was carried out for anal canal adenocarcinoma confirming NRAS mutation and excluding KRAS and BRAF mutation. Physical, endoscopic and histological examinations were supplemented with magnetic resonance imaging (MRI). Examination revealed prolapsed cervix of irregular morphology with the disrupted cervical stroma ring (long arrow). Multiple low T2 signal round myometrial lesions was suggestive of uterine fibroids (short arrows; hollow arrows). MRI also revealed irregular mass-like thickening of the distal part of the rectum and anal canal, superiorly to the anal sphincters. Both internal and external sphincters seemed uninvolved. The lesion was confined to the intestine wall and did not infiltrate ischioanal fat nor adjacent pelvic structures (Fig. ). The next lesion measuring 40 × 20 × 25 mm was identified in the cervix. It demonstrated a low signal on the T2-weighted sequence and a high signal in LAVA after contrast administration. No evidence of vaginal mucosa, bladder and rectal invasion was found. Superficial parametral invasion on the left was suspected (Fig. ). Diffusion-weighted magnetic resonance sequences suggested the malignant character of the thickening (A) of the rectal and anal canal wall. High signal on B-value diffusion-weighted MRI (B) with corresponding low signal on apparent diffusion coefficient (ADC) map (C) confirmed water diffusion restriction – a sign of malignancy (hollow arrows; Fig. ). T stage corresponded to the size of the primary tumour assessed by measuring in its longest diameter on T2-weighted MR images. In our case, the maximum tumour diameter was 23 mm. Based on the above data, cervical G2 squamous cell carcinoma FIGO II A 2 was diagnosed in the prolapsed cervix with the coexisting G2 anal canal adenocarcinoma pT1N0M0. Due to the predominance of symptoms related to CC and prolapse, the patient was offered a treatment consisting of, at the first stage, radical vaginal hysterectomy with extensive colpectomy preceded by laparoscopic pelvic and paraaortic lymphadenectomy, followed by the removal of the anus in the second stage. The patient agreed to some of the proposed treatment, however, she did not consent to the anal extirpation. Therefore, only laparoscopic pelvic and paraaortic lymphadenectomy with radical vaginal hysterectomy were performed. The key step of vaginal radical hysterectomy with the isolation of the right ureter is shown in Figure . The dissected ureteric angulation, known as knee of the ureter, allowed excision of the parametria. The postoperative course was uneventful. The patient was discharged on day 5. Microscopic examination of postoperative specimens revealed the cervix containing partially exophytic tumor measuring 2.5 × 3.5 × 7.5 cm, which appeared to be G2 HPV-associated squamous cell carcinoma, focally invading beyond the cervix into surrounding adipose tissue, sparing the parametria (pT2a2), with clear peripheral margins. The perineural and vascular space involvement was identified. Out of 13 regional lymph nodes examined, 2 showed metastasis (2/13). Due to the refusal of both anal extirpation and adjuvant chemotherapy, after a multidisciplinary consultation, the patient was qualified for radiotherapy (RT). She was transferred to the Radiotherapy Department at the Regional Hospital in Tarnow. The RT was dedicated as definitive treatment for ACC and adjuvant therapy for CC. RT was delivered via a two-step 3D conformal technique. The lymph nodes affected by SCACC and regional lymph nodes of anal cancer were included in step 1 and the dose of 50.4 Gy in 28 fractions was delivered. In step 2, boost of 3.6 Gy in 2 fractions to the primary anal canal was added. As the patient did not want to undergo resection of the anus, we planned brachytherapy in the third stage, as a way of dose escalation. The prescribed dose was defined as 98% of the planning target volume that should receive 98% of the dose. organ and risks were contoured, including the peritoneal space (bowel bag), bladder and bilateral femoral head. All constrains of tolerance doses for organ and risks were maintained. The treatment was tolerated well, however, Common Terminology Criteria for Adverse Events (v4.0), including grade 2 diarrhoea and anal canal colitis, were demonstrated. RT was completed without discontinuation through treatment. MRI performed on 45 postoperative days after radical vaginal hysterectomy and RT demonstrated a complete response. No sign of previous-seen mass-like thickening of the rectal wall on T2-weighted images (Fig. ). Diffusion-weighted imaging (Fig. ) confirmed no evidence of suspected regions of water diffusion restriction. The duration of follow-up was 6 months. Informed written consent was obtained from the patient for publication of this case report and accompanying images.

pmc-8678009-1

A 43-year-old woman, who presented with a 6-month history of hoarseness, was diagnosed with bilateral vocal cord polyps after laryngoscopy. Preoperative evaluation using chest computed tomography (CT) showed an intact tracheal wall with no abnormalities. Hence, vocal cord polyp resection via TLM was performed. Before the operation, a skilled anesthetist performed routine nasotracheal intubation with a video laryngoscope. The endotracheal tube cuff was filled with 10 mL water to replace air to make inadvertent laser damage to the endotracheal tube cuff more noticeable. During the operation, a saline-soaked absorbent cotton was placed at the subglottis to protect the trachea. There was no evidence of intraoperative damage to the tracheal wall. Fifteen hours after the operation, the patient experienced sudden dull pain in the anterior neck but no dyspnea. Repeat direct rigid laryngoscopy showed no abnormalities. This patient is considered to be a common throat in TML and discharged from the hospital. At 23 h after initial surgery, she returned to emergency room presenting subcutaneous emphysema and cough. Re-evaluation with a head, neck, and chest CT was done, which showed mediastinal emphysema and extensive subcutaneous emphysema from the base of the skull to the chest. A suspected tear on the membranous trachea located 4.5 cm under the glottis, extending to ∼8.5 cm under the glottis was noted (Fig. A–D). Bronchoscopy confirmed the tracheal rupture. The patient underwent emergency surgical chest exploration, which revealed a 4-cm long and narrow tracheal tear on the membranous trachea (Fig. ). The tracheal tear was sutured, and the surgeon ensured that there were no other injuries. The patient was discharged on the 11th postoperative day. During follow up after 1 month, no tracheal stenosis or respiratory dysfunction was noted.

pmc-8678014-1

The proband (III-3) (32 year-old, male) visited the Department of Neurology of our hospital for “unsteady steps for more than 7 months” More than 7 months prior to admission, the patient gradually had unsteady steps with no obvious predisposing causes, manifested as walking with a rolling gait. The patient's condition gradually worsened and manifested with increased step distance and drunk walking from side to side at admission. The patient complained of recent difficulties in eye opening, involuntary tremor of both upper limbs, and catatonia, which were aggravated after activities. Neurological examination: Conscious mind, dysarthria, normal memory, calculation and orientation power, normal visual acuity and field of both eyes, free movement of both eyes in all directions, horizontal nystagmus when both eyes look to the left, ptosis of both eyes, unstable and inaccurate bilateral finger-nose test, clumsy bilateral alternating bilateral movements, bilateral heel-knee-shin test, and no bilateral pathological reflex. Auxiliary examinations: Head magnetic resonance imaging (MRI) of the proband (III-3) showed cerebellar atrophy with no clear abnormal signals. Cervical MRI suggested no atrophy or thinning of the cervical cord (Fig. ). Family surveys: Figure shows the family history of the proband (III-3). The mother (II-3) developed similar symptoms in her 30s, was paralyzed in bed in the following days and died in her 40s. The elderly maternal uncle (II-2) and his children (III-1, III-2) have no clear clinical manifestations. The younger maternal uncle (II-5) began to suffer from illness in his 20s and died from disease in his 30s. The daughter of the younger maternal uncle (III-5) (25-year-old now) gradually had unsteady steps and unclear speech with no obvious incentive at around 20 years old, manifested as a slightly wide step base, unstraight walking, influent speech, and appearance of choking cough in drinking water in the past year (Table ). Neurological examination: conscious mind, dysarthria, horizontal nystagmus when both eyes look to the left and right, active tendon reflex of limbs, unstable and inaccurate bilateral finger-nose test, clumsy bilateral alternating movements, and bilateral heel-knee-shin test. Auxiliary examination: Head magnetic resonance imaging suggested cerebellar atrophy (Fig. ). After obtaining informed consent from patients and their families, serum samples of the proband (III-3) and his cousin (III-5) were collected to identify genes involved in the pathogenesis of SCA. The blood samples were sent to the Beijing High Trust Diagnostic for Whole Exome Sequencing. Sanger sequencing of the patients (III-3 and III-5) revealed a c.1852A > G missense mutation in the exon region of the AFG3L2 gene, resulting in a lysine-glutamate amino acid substitution (p.K618E) (Figs. and ). Sanger sequencing of the other family members (II-1, III-1) revealed no AFG3L2 mutations. We checked the human gene mutation database and found that the gene mutations reported here had not been reported before. According to ACGS recommended guidelines, we thought this mutation considered pathogenic. SCA28 is the one uniquely caused by a pathogenic variation in the mitochondrial protein AFG3L2. Combined with the clinical manifestations, auxiliary examinations and sequencing results of the patients (III-3 and III-5), the diagnosis of SCA28 was suspected. The patients did not receive any drug treatment and the proband receive rehabilitation treatment. The symptoms of ataxia were still progressively aggravated.

pmc-8678019-1

A 35-year-old man was admitted to our hospital with a 1-month history of epigastric pain, nausea, and vomiting. On admission, his vital signs were normal. He denied any previous medical history, including gastrointestinal disease, abdominal surgery, or significant medical illness. In addition, he was not taking any medications, including NSAIDs. Physical examination revealed asymptomatic brownish variable-sized round macules with scales on both palms and soles that had been present for several months (Fig. ). Skin lesions were consistent with secondary syphilis. No oropharyngeal or genital lesions were observed. Mild abdominal tenderness was elicited in the epigastrium. He reported sexual intercourse with multiple sexual partners several months prior to admission. Laboratory evaluation revealed normal hemoglobin, hematocrit, white blood cell count, and hepatic and renal function. The C-reactive protein level was elevated at 2.96 (normal, 0–0.3) mg/dL. The serum venereal disease research laboratory test was positive, with a titer of 1:8, and the fluorescent treponemal antibody absorption (FTA-ABS) test was reactive. Serum human immunodeficiency virus (HIV) antibodies were negative. Esophagogastroduodenoscopy (EGD) revealed multiple geographic ulcers with easy touch bleeding and whitish exudates in the antrum (Fig. ). The esophagus, body and fundus of the stomach, and duodenum were normal. Endoscopic biopsies taken from the antrum showed a dense mononuclear cell infiltrate with prominent plasma cells on hematoxylin–eosin staining (Fig. A). Helicobacter pylori was not detected by Giemsa staining. Because syphilis was suspected based on the results of skin lesions and serologic tests, Warthin–Starry silver staining was subsequently performed, and numerous spirochetes were identified in the lamina propria, confirming gastric syphilis (Fig. B). He was treated with an intramuscular injection of 2.4 million units of benzathine penicillin once a week for 3 weeks. His clinical symptoms resolved within 5 days of treatment initiation. Follow-up EGD after 2 months showed complete resolution of multiple geographic ulcers. Biopsies of the gastric mucosa were negative for spirochetes, and the lymphocytic infiltrate resolved. Informed consent was obtained from the patient for the purpose of publication.

pmc-8678019-2

A 33-year-old man presented at the outpatient clinic with a 1-month history of epigastric pain. Physical examination revealed mild abdominal tenderness in the epigastrium. Laboratory evaluation revealed normal hemoglobin, hematocrit, white blood cell count, and hepatic and renal function. The serum treponema pallidum hemagglutination test was positive, with a titer of 1:1280, and the FTA-ABS test was reactive. Serum HIV antibodies were negative. EGD showed multiple variable-sized whitish discolored flat elevated lesion with focal erosion and ulceration on the body (Fig. A) and large geographic ulcers with regular edges and even whitish exudates on the lesser curvature side of the lower body (Fig. B). Warthin–Starry silver staining of endoscopic biopsy specimens confirmed gastric syphilis. He was treated with an intramuscular injection of 2.4 million units of benzathine penicillin once a week for 3 weeks. The patient's clinical symptoms and gastric lesions were completely resolved. Informed consent was obtained from the patient for the purpose of publication.

pmc-8678022-1

A 27-year-old male patient was admitted to the emergency room of this hospital with shortness of breath that started a week before admission. A chest x-ray performed at emergency room showed a left-sided pneumothorax (Fig. A), and the patient was referred to the department of thoracic surgery. The left lung of the patient was totally collapsed, and there was a high possibility of REPE upon chest tube insertion with the symptom onset of a week. Accordingly, after explaining this situation to the patient and his caregivers, a 12 French trocar tube was inserted into the left thoracic cavity of the patient. In order to allow the lungs to expand slowly, natural drainage was performed without suction, and the rubber tube connecting the chest tube and the water seal bottle was partial clamped. On the day after chest tube insertion, there was an finding of air leakage through the chest tube, but the lungs were not found to expand much as a result of chest x-ray (Fig. B), thus the partial clamped rubber tube was de-clamped. However, about an hour after de-clamping, the patient suddenly complained of severe respiratory distress, cough with foamy sputum, and vomiting. Immediately the chest tube was clamped to stop drainage. With oxygen saturation measured 75%, oxygen was administered to the patient via an oxygen mask, but no improvement was observed. In turn, a chest x-ray was followed during additional high flow nasal prong (HFNP) therapy, exhibiting REPE findings such as newly developed ill-defined consolidation in the left lung (Fig. ). Oxygen saturation did not improve even after HFNP therapy, and further, persistent cough with foamy sputum, shortness of breath, and a drop in blood pressure occurred. With the need for intensive care recognized, the patient was immediately transferred to the intensive care unit and then was sedated and intubated to perform mechanical ventilation. After supportive care including mechanical ventilation, the condition of the patient was improved and then extubation was performed two days later. On the third day, chest computed tomography (CT) (Fig. ) was performed, and the patient was transferred to a general ward. From the 6th day, a chest x-ray showed no more edema (Fig. ). There was no finding of air leakage through the chest tube and a chest x-ray showed full lung expansion, in turn, the chest tube was removed on the 9th day of hospitalization. However, a chest x-ray showed recurrence of pneumothorax the day after removal of the chest tube, and the chest tube was inserted again. Both the patient and his caregivers wanted operation, so the video assisted thoracoscopic surgery (VATS) wedge resection was performed. Following operation, the patient recovered without any complications. For the follow-up at 6 months after operation, no adverse symptoms were found and the imaging findings were also found to be normal. This case report was approved by the Institutional Review Board of Soonchunhyang University Hospital (SCHCA 2021–09-007). The Patient has provided informed consent for publication of this case.

pmc-8678023-1

A 6-month-old male child was referred to our hospital with a mass on the anterior alveolar ridge of the mandible. The patient's parents noticed this mass at the age of 4 months, which rapidly increased in size thereafter. At his first visit to our hospital, his face was symmetrical, but the lower lip was protruded. A relatively well-defined spherical mass (30 × 20 × 20 mm) was located on the mandibular alveolar ridge extending from the right mandibular deciduous canine to the left mandibular first deciduous molar (Fig. ). The mass had normal mucosal color, was elastic hard and non-fluctuant with the left mandibular deciduous central incisor attached to the surface of the tumor. Computed tomography (CT) showed a relatively uniform multicentric osteolytic lesion extending from the right mandibular deciduous central incisor to the left mandibular deciduous canine with expansion of the surrounding bone and numerous displaced tooth germs. The density of the lesion mass was lower than that of the muscle, and the boundary with cancellous bone was irregular (Fig. ). Histopathological findings of the biopsy specimen showed that the biphasic tumor cells consisted of large melanin-containing epithelioid cells and small neuroblast-like cells forming a solid alveolar pattern (Fig. A) and a gland-like pattern (Fig. B). The large tumor cells had a slightly eosinophilic cytoplasm and an oval bright nucleus with small but distinct nucleoli. These were occasionally positive for melanin pigment, which was visualized in the form of black granules on Fontana-Masson staining (Fig. C) and were bleached with potassium permanganate–oxalic acid (Fig. D). The small tumor cells had a scanty cytoplasm and a slightly deeply stained round nucleus, often showing detached clusters. A small number of mitotic figures, and a low degree of cellular polymorphism were observed. Immunohistochemistry revealed that the large and small tumor cells were positive for neuron-specific enolase (Fig. A & B). The large tumor cells stained positive for cytokeratin (AE1/AE3), human melanin black-45, and vimentin (Fig. C–E). The small tumor cells stained positive for CD56 and synaptophysin (Fig. F & G). The tumor cells were negative for S-100 (Fig. H) and chromogranin A. The MIB-1 proliferation index was >50% (Fig. I). Based on these findings, the tumor was finally diagnosed as MNTI. The tumor continued to grow rapidly, and marginal mandibulectomy was performed under general anesthesia 28 days after the first visit to our hospital. The extent of resection was determined by referring to the mandibular 3D model which was created based on the CT data obtained before the surgery. Marginal mandibulectomy, approximately 5 mm lateral to the tumor, was successful in preserving the inferior margin of the mandible (Fig. ). The mental foramen on the left side was included in the resection, and the foramen on the right side was preserved. All deciduous tooth germs were included in the excision, except for the right deciduous second molar. After rounding the sharp edges of the bone with a file, the raw surface of the mandible was completely closed by the surrounding soft tissue with help of polydioxanone monofilament synthetic absorbable suture. The postoperative course was uneventful, and oral intake of milk was started 3 days after the operation. On the 7th day after the surgery, the patient was discharged from the hospital with good general condition. At the time of discharge, he had no abnormal facial swelling or infection in the surgical wound. Similar to biopsy specimens, histopathological findings of the excised mass showed that the tumor consisted of 2 types of cells: large polyhedral cells sometimes containing melanin granules and smaller round cells with hyperchromatic nuclei and scanty cytoplasm resembling lymphocytes. No nuclear atypia or mitosis was observed. Tumor cells were seen invading the surrounding tooth germs and bone. The patient is being closely followed up, and no evidence of recurrence or metastasis was observed on CT images taken 1 year after surgery (Fig. ). In this case, stomatognathic functions such as eating, swallowing, and pronunciation were normal post-surgery, but occlusal reconstruction and recovery of masticatory function following removal of the mandibular dentition will be important therapeutic goals in the future.

pmc-8678027-1

A 25-year-old man was diagnosed with temporal lobe epilepsy 12 years ago, which was treated with carbamazepine and zonisamide. Subsequently, valproate and lacosamide were added 5 and 3 years ago, respectively, due to poor seizure control. During a regular visit, a neurologist noticed that the patient's serum creatinine level increased from 0.98 to 1.29 mg/dL over 6 months. As his serum creatinine level continued to increase to 1.74 mg/dL, he was referred to the nephrology department. He presented no symptoms, and physical examination revealed no abnormal findings. Laboratory analyses showed renal dysfunction, mildly elevated C-reactive protein levels, and increased levels of urinary markers for tubular injury (see Table ). Renal biopsy was performed. Although the glomeruli were intact, there was marked interstitial lymphocytic and eosinophilic infiltration (Fig. A, B), suggestive of AIN. No immunoglobulin or complement deposition was observed. Since he had no other organ involvement (including uveitis) and no laboratory findings suggestive of autoimmune disorders such as sarcoidosis and Sjögren's syndrome, the AIN was ascribed to drug allergy. Based on a positive result of lymphocyte stimulation test (LST), zonisamide was discontinued and daily oral prednisolone (40 mg, 0.8 mg/kg) was started. Serum creatinine levels decreased to 1.35 mg/dl and prednisolone dose was tapered monthly. However, 10 months later, serum creatinine levels increased again to 2.07 mg/dL (Fig. ). 67Ga scintigraphy revealed significant radioactive tracer uptake in both kidneys (Fig. C), suggestive of AIN recurrence. Oral prednisolone (40 mg/d) was restarted, and valproate and lacosamide were discontinued based on a neurologist's recommendation. Renal function immediately improved, although minor epilepsy occurrence increased. Oral prednisolone was gradually tapered to 10 mg/d, after which serum creatinine levels increased again to 1.99 mg/dL. Repeat renal biopsy revealed similar findings of tubulitis with both lymphocytic and eosinophilic infiltrations. Prednisolone dose was increased to 60 mg (1.0 mg/kg) daily; nevertheless, it was difficult to discontinue carbamazepine due to the need for major epilepsy prevention. Since the patient had multiple AIN recurrence and was corticosteroid dependent, 1500 mg daily of oral mycophenolate mofetil (MMF) was added to the corticosteroid therapy. This treatment was well tolerated and enable successful prednisolone dose tapering to 5 mg daily, with serum creatinine level stabilization (Fig. ). He experienced no AIN recurrence with MMF treatment for over 20 months.

pmc-8679662-1

A 36-year-old male patient presented with anorexia, easy fatigability, and melena for 3 months. His clinical examination was largely unremarkable. We found melena on a digital rectal examination. An upper GI endoscopy revealed a large mass projecting into the gastric lumen ( ), arising from the posterior gastric wall. The lesion was closer to the lesser gastric curvature than the greater curvature. At the summit, the mass suffered from a bleeding mucosal ulcer, the cause of his melena. Several endoscopic biopsies were inconclusive, consisting of only gastric mucosal tissue within the biopsy specimens. An endoscopic ultrasound-guided needle aspiration revealed stromal cells on cytology. An abdominal CT demonstrated a well-defined, intramural mass arising close to the lesser gastric curvature with a small mucosal defect at the superolateral aspect of the lesion ( ). The soft-tissue fat planes were intact and there were no enlarged or abnormally enhancing lymph nodes. The patient's severe anemia was corrected with several preoperative transfusions. Operative steps : Under general anesthesia, the patient was positioned supine with his legs split. Laparoscopic ports were inserted as shown in . The initial diagnostic laparoscopy did not reveal any peritoneal involvement. The lesser sac was accessed by dividing the gastrocolic and posterior gastric attachments. The tumor mass was large, making gastric retraction difficult. The tumor base at the posterior gastric wall exhibited increased vascularity ( ) without any evidence of invasion into adjacent tissues. After replacing the stomach in its natural position, a liberal, longitudinal anterior gastrotomy was created at the summit of the tumor using ultrasonic shears. Manipulation of the tumor mass had caused brisk bleeding from the ulcer, which could not be controlled with bipolar energy. The tumor was delivered through the gastrotomy ( ) and pivoted over the shaft of a grasper placed parallel to the splenic axis. This caused the gastric wall adjacent to the tumor base to tent ( ), allowing us to apply several linear staplers across it ( ). All sequential stapler fires were applied in close apposition to the tumor, with the intention to save as much of the uninvolved posterior gastric wall. The use of staplers not only allowed us to resect the lesion, which halted bleeding, but also simultaneously reconstructed the posterior gastric wall. The staple line was oversewn on its luminal aspect with 2–0 polydiaxonone suture in a continuous manner after the resected lesion was placed in an endobag and parked adjacent to the right hepatic lobe. The anterior gastrotomy was closed using 2–0 delayed-absorbable barbed suture in two layers. The patient was placed in a steep Trendelenburg position, and saline was instilled into the upper abdomen. Intraoperative gastroscopy with intraluminal CO2 insufflation helped objectively confirm the integrity of the gastrotomy closures. The saline was suctioned out and a drain was placed adjacent to the stomach through the flank port. The specimen was retrieved through a Pfannenstiel incision. The resected specimen measured 9.5 × 8.5 × 7.5 cm ( ). The operative time was 195 minutes, and the estimated blood loss was 175 mL (see video, supplemental digital content 1, which demonstrates the clinical course of the patient and operative steps). The patient commenced oral fluids on the second postoperative day and a blenderized soft diet on day 4. His abdominal drain was pulled on day 4, and he was discharged from the hospital on day 5. He suffered a superficial surgical site infection (SSI) at the extraction site, which responded well to oral antibiotics. The histopathology report confirmed a GIST with negative margins, with 10to 12 mitosis per 10 high powered fields, indicating a high potential for malignancy. The tumor stained positively for CD34 and DOG-1, was weakly positive for c-kit, and negative for S100 and desmin on immunohistochemistry. After a consultation with the medical oncologist, adjuvant imatinib therapy was commenced.

pmc-8679997-1

A 76-year-old Asian man with a 55-year history of type 2 diabetes mellitus was referred to our hospital for right intermittent claudication of 3 years. He had diabetic retinopathy and had been treated with insulin for 3 years. Vascular examination revealed right femoral bruit and diminished right popliteal pulse, suggesting the presence of a right femoral lesion. However, the right ABI measured by a volume plethysmograph (Form PWV/ABI; Omron Health Care Co., Kyoto, Japan) was 1.28, within the normal range (1.00–1.40) (Fig. ). On the other hand, the left ABI was elevated to 1.55 (> 1.40), suggesting that the infrapopliteal arteries at the left ankle were incompressible. Upstroke time, the transit time from the nadir to the peak of the pulse volume waveform recording, of the right ankle was prolonged to 201 milliseconds (≥ 180 milliseconds), whereas upstroke time of the left ankle was within the normal range (130 milliseconds) (Fig. ). These findings suggest that the right ABI was falsely normalized due to incompressible infrapopliteal arteries at the right ankle despite the presence of PAD in the right extremity. Indeed, intra-arterial angiography revealed the presence of a severe stenotic lesion at the origin of the right superficial femoral artery (SFA) (Fig. A), whereas there was no occlusive arterial disease in the left extremity. Fluoroscopic images showed severe calcification of infrapopliteal arteries at the right ankle (Fig. B). Computed tomography also revealed severe calcification of the bilateral infrapopliteal arteries (Fig. ). Revascularization was not performed, and supervised exercise training was initiated. After completion of the 6-month supervised exercise training program, he continued to spend 2 hours a day walking. Five years from the initial assessment, the right ABI had decreased to 0.83, with upstroke time at the right ankle of 242 milliseconds, indicating the progression of the right lower extremity PAD (Fig. ). However, there was no deterioration in his symptoms, and he had no difficulty in performing daily activities.

pmc-8679997-2

A 66-year-old Asian man with a 28-year history of type 2 diabetes mellitus was referred to our hospital for bilateral intermittent claudication of 6 months and exertional dyspnea. He had diabetic retinopathy and was being treated with insulin. He was an ex-smoker with a history of 40 pack-years. Vascular examination revealed right femoral bruit, diminished right popliteal pulse, and absent right and left dorsalis pedis pulses, suggesting the presence of right femoral and bilateral infrapopliteal lesions. However, both the right ABI (1.11) and left ABI (1.03) were within the normal range (Fig. ). However, upstroke times were prolonged to 206 and 203 milliseconds (≥ 180 milliseconds) in the right and left ankles, respectively (Fig. ), suggesting the presence of bilateral lower-extremity PAD. The right ABI decreased from 1.11 to 0.48 and the left ABI decreased from 1.03 to 0.67 after exercise. Computed tomography angiography revealed the presence of right SFA stenotic lesions, bilateral infrapopliteal occlusive lesions, and spotty calcification in bilateral infrapopliteal arteries (Fig. ). Intra-arterial angiography revealed the presence of right SFA stenotic lesions and bilateral infrapopliteal occlusive lesions (Fig. A–C). Coronary angiography revealed severe stenotic lesions in the right coronary artery and the left anterior descending coronary artery (LAD). After percutaneous coronary intervention for the LAD stenosis, supervised exercise training was initiated.

pmc-8680031-1

A 37-year-old Hispanic male was hospitalized after being involved in a motorcycle crash. The patient suffered blunt chest and abdominal trauma as well as concussion without loss of consciousness. Upon arrival, the patient had a Glasgow Coma scale score of 15 and was hemodynamically stable. His abdomen was soft, nondistended, and nontender to palpation with no guarding. Labs were significant for hemoglobin count of 14.2 g/dL (normal 13.5–17.5 g/dL), white blood count of 11.8 1000/μL (normal 4.5–11 1000/μL), and lactate of 1.7 mmol/L (normal 0.7–2.1 mmol/L), which remained stable throughout his hospital course. Initial intravenous contrast-enhanced CT scan of the abdomen/pelvis was performed 10 minutes after patient presentation. The CT scan was interpreted by a radiology resident 15 minutes later and final interpretation by a board-certified emergency radiologist was completed in an additional 1 hour and 25 minutes. The initial CT interpretation indicated nonspecific wall thickening of the proximal jejunum, and occult small bowel injury could not be excluded. Given these findings, a repeat CT of the abdomen/pelvis with intravenous and oral contrast was ordered by the trauma service as per our institution’s standard protocol for evaluation of possible occult bowel injury in blunt abdominal trauma. The follow up CT performed after midnight, 8 hours after the initial CT, demonstrated trace pneumoperitoneum, possibly originating from the splenic flexure of the colon without evidence of extravasation of oral contrast (Fig. ). The time from repeat CT scan completion to initial interpretation by a radiology resident was 30 minutes. The resident made the surgery team aware of these findings immediately. A board-certified emergency radiologist reviewed and provided another preliminary interpretation for the study 10 minutes later, confirming the presence of pneumoperitoneum. Based on the presence of pneumoperitoneum in a patient with blunt abdominal trauma, the patient was taken to the operating room as per standard protocol at our institution. Six hours after the follow up CT was performed, an academic board-certified abdominal radiologist provided a final interpretation. On laparoscopy, cyst-like structures projecting from the wall of the distal transverse colon and splenic flexure were noted. Due to the patient’s body habitus, the surgery team did not feel that they could adequately explore the area and the decision was made to convert to exploratory laparotomy. No evidence of bowel perforation was found. A segmental section of the diseased portion of the colon was taken and sent to pathology. Pathology results showed multiple enlarged cystic nodules ranging from 0.5 to 3 cm in the bowel wall (Fig. ). Subsequently, the radiologic studies were reviewed by a panel of abdominal radiologists. The panel concluded that the proximity of the pneumoperitoneum to the pneumatosis cystoides intestinalis suggested that the pneumoperitoneum may have been caused by incidental atraumatic or traumatic rupture of the cysts. However, they could not rule out bowel perforation based on imaging alone. The patient had an uncomplicated postoperative course and was transferred to an acute care facility of equal acuity for further medical management as per the patient’s health insurance request.

pmc-8680034-1

A 76-year-old woman (para [P] 1) referred to our hospital with a chief complaint of abdominal distension and postmenopausal bleeding for 4 months consulted a gynecologist and was found to have a bulky uterus with a 132-mm subendometrial mass on vaginal ultrasonography. Adenosarcoma was suspected on the basis of findings from biopsy by hysteroscopy. She had no significant past medical history. Serum cancer antigen (CA) 125 and CA 19–9 were 283 U/ml (normal range 0–35 U/ml) and 11.5 U/ml (normal range 0–35 U/ml) respectively. Magnetic resonance imaging (MRI) was performed at 1.5 Tesra for further examination. Sagittal T2-weighted imaging (WI) (repetition time [TR]/echo time [TE], 4650/120 ms) showed a large, heterogeneous high-intensity mass, approximately 241 × 114 × 88 mm3 in size, without myometrial invasion expanding the uterine cavity and extending into the cervical canal (Fig. a). The enlarged uterine size was 250 × 126 × 99 mm3. The mass showed low intensity with areas of slightly high signal intensity on fat-suppressed T1WI (TR/TE, 600/10 ms) (Fig. b). The mass showed inhomogeneous contrast enhancement with cystic changes of variable sizes and necrotic foci, high intensity on diffusion-weighted imaging (DWI) (b = 1000 s/mm2, TR/TE, 7000/100 ms) (Fig. c) and low intensity (1.26 × 10−3 mm2/s) on apparent diffusion coefficient (ADC) maps. Uterine carcinosarcoma or adenosarcoma was suspected as the preoperative diagnosis. Total abdominal hysterectomy and bilateral adnexectomy with pelvic lymphadenectomy were subsequently performed. Benign glandular epithelial components surrounded by atypical stromal cells with a high mitotic rate (20/10 high power field [HPF]) were identified on pathological examination. High-intensity areas observed on T1WI corresponded to hemorrhage, and SO was present. The tumor was diagnosed as adenosarcoma with SO without myometrial invasion (T1aN0M0). A follow-up CT scan performed 6 months after surgery revealed peritoneal sarcomatosis. Although her gynecologist recommended adjuvant chemotherapy, she did not wish to receive the treatment and died of the disease 1.5 months after recurrence.

pmc-8680034-2

A 57-year-old woman (P 3) with complaint of low abdominal pain and abnormal uterine bleeding for 3 months consulted a gynecologist. Menstrual cycle length ranged from 30 to 40 days. She had no significant past medical history. Endometrial biopsy indicated atypical endometrial hyperplasia. Vaginal ultrasonography showed an enlarged uterus measuring 150 mm accompanied by a 73-mm tumor in the anterior wall, and both ovaries were not visualized. CA 125 and CA 19–9 were 40.3 U/ml (normal range 0–35 U/ml) and 1.1 U/ml (normal range 0–35 U/ml), respectively. Serum estradiol (E2) was within the normal limit (130.0 pg/mL). MRI showed a intrauterine mass, approximately 96 × 74 × 57 mm3 in size, protruding into the cervical canal with clearly defined inhomogeneous high intensity on T2WI (TR/TE, 6130/100 ms) (Fig. a) and low intensity with a slight high signal intensity area on fat-suppressed T1WI (TR/TE, 575/13 ms). The enlarged uterine size was 129 × 82 × 76 mm3.The mass showed inhomogeneous contrast enhancement with cystic changes of variable sizes and necrotic foci (Fig. b), high intensity on DWI (b = 1000 s/mm2, TR/TE, 4317/70 ms) (Fig. c) and low intensity (0.88 × 10−3 mm2/s) on ADC maps (Fig. d). A 22-mm solid nodule accompanied by a tiny cyst was detected in the right ovary. T2WI showed homogenous iso signal intensity with the uterine tumor on T2WI (Fig. a) and low intensity on T1WI. The nodule had homogeneous contrast enhancement with a tiny cystic change (Fig. b), high intensity on DWI (Fig. c), and low intensity (0.66 × 10−3 mm2/s) on ADC maps (Fig. d). Whole-body 18F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) showed increased FDG uptake (maximum standardized uptake value: 8.2) in the uterine tumor and no abnormal FDG uptake in any other organs, including the right ovarian nodule (Fig. e). Uterine carcinosarcoma or adenosarcoma metastasizing to the right ovary was suspected as the preoperative diagnosis. The patient underwent abdominal modified radical hysterectomy with bilateral adnexectomy, pelvic and para-aortic lymphadenectomy, and omentectomy. Benign glandular epithelial components surrounded by atypical stromal cells with a high mitotic rate (15/10 HPF) with minimal myometrial invasion and SO were present in the uterine tumor on pathological examination, and thus the tumor was diagnosed as adenosarcoma with SO (T1bN0M0). The right ovarian nodule was diagnosed as an adult granulosa cell tumor (GCT). A follow-up CT scan revealed a left upper lung metastasis 3 months after surgery. Accordingly, the patient underwent thoracoscopic segmentectomy of the left upper lobe. As of the writing of this report, at 22 months after the surgery, she has showed no signs of recurrence.

pmc-8680036-1

A 9-year-old female patient arrived at the emergency room because of a 36-h history of intermittent right lower abdominal pain, anorexia, vomit, and quantified high-grade fever. She had no pathological personal or family history of interest. On examination, the right iliac fossa was tender to palpation and no frank peritoneal signs were observed. Initial laboratory evaluation showed leukocytosis, neutrophilia, and an elevated C-reactive protein. Ultrasonography of the abdomen was inconclusive. A heterogeneous lesion of 40 × 37 mm within the colon, no appendix and some swollen mesenteric nodes of at least 10 mm were reported. A complementary abdominal CT scan revealed findings suggestive of ileocolic intussusception with an invagination area of approximately 6.6 × 4.9 cm. After surgical consult, the patient underwent an exploratory laparoscopy that required laparotomy conversion. A well-defined, 5 cm mass at ileo cecal valve and multiple hard pericecal lymph nodes were observed. Preserved permeability between the ileum and colon, complete integrity of the cecum wall and lack of vermiform appendix were also reported. The possibility of an auto-digested appendix and a cecal tumor were discussed. At this time, surgeons decided to resect retrocecal and pericecal lymph nodes and send these samples to pathology before any further intervention. The patient was admitted to the inpatient floor where antibiotic therapy based on ampicillin sulbactam, and metronidazole was initiated. The oncologist department was consulted and complementary laboratory exams including liver and renal function tests, uric acid, electrolytes, lactic dehydrogenase, and quantiferon-TB tests were ordered. Only lactic dehydrogenase was altered. A chest x-ray ruled out mediastinal masses. No alarming findings were reported. However, the patient presented gastric distension, abdominal pain and fever by the second hospitalization day. The content inside the suprapubic JP drain changed from a serohematic aspect to a dense cloudy fluid. A culture and cytochemical analysis of peritoneal fluid was performed without significant results. CBC showed mild leukocytosis and neutrophilia. Reactive C-protein remained elevated. Two blood cultures and an urinalysis were negative. Due to the uncertainty of the etiology of her clinical picture, infectology decided to change antibiotic therapy to piperacillin/tazobactam and amikacin. An abdominal x-ray showed air fluid levels in the small bowel and a colonic distention projected at mesogastrium. Gastroenterology suggested initiating bowel rest and placing a central line for parenteral nutrition. After five more days, elevated inflammatory markers, abdominal distension and pain, and the unusual JP drain aspect persisted. A new ultrasound confirmed that the mass and surrounding area had the same aspect as days before. The histopathological description of paracecal-retrocecal lymph nodes and the sample of mesenteric omentum obtained during the first intervention failed to detect neoplastic cells. Macroscopically, three encapsulated lymph nodes from 0.8 to 2 cm were received. Their physiological architecture was preserved; secondary lymphoid follicles with hyperplastic germinal centers containing macrophages with cellular debris were reported. The interfollicular population was polymorphic and contained frequent large cells with prominent immunoblast-like nucleoli. Other areas showed sinusoidal histiocytosis with eosinophils and neutrophils. There was fibrosis with a predominantly neutrophilic mixed inflammatory infiltrate that spread to neighboring adipose tissue in the periphery of the nodes. The immunohistochemical study confirmed the presence of follicular dendritic cells and B lymphocytes in the germinal centers (CD23 + + +/+ + + and CD20 + + +/+ + + respectively), T lymphocytes in the mantle zone (CD3 + + +/+ ++), macrophages in germinal centers and sinusoidal area (CD68 +/+ ++). Frequent CD30 + + +/+ + + immunoblasts and actin + + +/+ + + myofibroblasts within areas of fibrosis were also observed. EBV study using EBER in situ hybridization was negative. Ziehl Neelsen and PAS did not show any pathogen. The 22 × 0.6 cm omentum sample showed fibrous thickening of the septa and the presence of a mainly lymphocytic infiltrate. Fibrino-leukocytic material was also seen in the serosa. Pathologists concluded the possibility of an unspecified acute versus chronic epiploitis, lymphadenitis and serositis. Nevertheless, due to her unfavorable clinical evolution and the elevated inflammatory markers, a second surgical intervention was decided. The patient underwent an omentectomy and resection of approximately 40 cm of terminal ileum, cecum and ascending colon. Pericolonic lymph nodes were resected as well. A sample of a collection observed near the cecum was taken for culture and cytochemical studies before aspiration and drainage. After surgery, the patient remained hemodynamically stable, without abdominal pain or distention. A nasogastric tube was placed and parenteral nutrition continued. The peritoneal fluid analysis was negative. Improvement in inflammatory markers lead to amikacin discontinuation. And by the fifth postoperative day, JP drain, and nasogastric tube were removed. Later, a regular diet was successfully initiated, and the patient was finally discharged. The histopathological final report described an 8 cm ileal segment, and a 14 cm ascending colon including the cecum with a diameter that ranged from 1 to 3 cm. The external surface was covered by a pinkish-gray serosa with fibrinopurulent material over the ileocecal area. A completely subserous dilated appendix was identified within the cecum wall. It contained a white-yellowish purulent material at the tip (Fig. ). A well-defined nodular lesion of approximately 1.5 cm was also identified (Fig. ). The mucosa of the cecum was pink while ileal mucosa had a granular appearance. Nine nodules, which measured between 0.3 and 3 cm, were isolated from the surrounding area. The 12 × 4.5 cm omentum sample had no palpable nodes. A second omentum sample showed multiple whitish irregular fragments of bland tissue that measured between 0.8 and 1.5 cm. Microscopically, the histological findings of the fourteen isolated lymph nodes were compatible with follicular hyperplasia. The subserosal cecal appendix showed transmural necrosis and perforation causing leakage of purulent material and an acute inflammatory reaction of the surrounding adipose tissue which extended up to the cecal and ileal serosa. All layers of the appendix were independent and unrelated to the cecum wall (Fig. ). The distal portion of the appendix showed the proliferation of cellular nests that were composed of round uniform nuclei with a “salt and pepper” appearance (Fig. ). No mitotic activity was evidenced. It seemed to infiltrate the muscular layer of the appendix and reach a diameter of 1.5 cm. No lymphovascular or perineural invasion was observed. Disease free margins were reported. Ileum dissection showed Peyer’s patches hyperplasia with wide germinal centers. Tumoral cells’ immunochemical studies showed a Ki67 proliferative index of 2%, a positive (+ + +/+ + +) cytoplasmic granular pan-cytokeratin, a positive (+ + +/+ + +) cytoplasmic chromogranin and a negative synaptophysin reaction (Fig. ). Pathologists concluded the presence of an incidental well differentiated neuroendocrine tumor grade I pT1 pN0 at the tip of the appendix in the middle of a clinical picture caused by an acute necrotizing appendicitis of a complete subserosal appendix. Due to the stage, no further intervention was required. She fully recovered in subsequent controls. Nevertheless, correct management of short bowel syndrome will become a key feature for the preservation of her future quality of life.

pmc-8680040-1

A 31-year-old man with UC was presented to a local hospital due to diarrhea and hematochezia. The young man was diagnosed with UC 3 years ago but didn’t receive regular treatment as prescribed. After the treatment of mesalazine, anti-infection medicines of amoxicillin, parenteral nutrition supplementation and protecting the intestinal mucosa, all the symptoms worsened, and the patient began to develop fever and facial erythema with blisters forming at the raised border of the erythema (Fig. a, b). For further treatment, the patient was referred to our hospital with the complaints of bloody purulent stool for 1 month, fever for 9 days, erythema and blisters on face for 7 days. The initial laboratory examination demonstrated an elevated white blood cell count (10.60 × 109/µL, normal range 3.5–9.5 × 109/µL), increased C-reactive protein (173.96 mg/L, normal range 0–10 mg/L), procalcitonin (1.93 ng/mL, normal range < 0.05 ng/mL) and Epstein-Barr virus (EBV) DNA (1720 copies/mL, normal range 0 copies/mL) levels, together with a low haemoglobin (90.00 g/L, normal range 130–175 g/L) level. The computed tomography with contrast medium exhibited extensive colonic wall thickening with a few perienteral exudative changes and multiple lymph nodes in the retroperitoneal and mesangial areas, consistent with the characteristics of UC. Computed Tomographic Enterography showed extensive colonic thickening wall with a few perienteric exudative inflammation, and multiple lymph nodes in retroperitoneal and mesangial areas, which were consistent with the characteristics of UC. Biopsies of cutaneous lesions were performed, revealing localized epidermal ulceration with neutrophil infiltration and dermal appendages with the infiltration of chronic inflammatory cells and neutrophils (Fig. c, d). We considered the clinical diagnosis of acute febrile neutrophilic dermatosis. After ruling out other infectious diseases and lymphoproliferative syndrome, we decided to initiate corticosteroid treatment though high levels of EBV DNA. After that, the patient no longer developed fever and the skin manifestations improved significantly (Fig. ). Colonoscopy revealed scatter polypoid hyperplasia from the ascending colon to the sigmoid colon (Fig. a, b). Histology of the resected polyp was characterized by crypt dilatation, branching, twisting with interstitial edema, local interstitial fibrosis, and muscle fiber penetration growth. And localised neutrophils infiltrated into the epithelium to form cryptonitis. These histological results were consistent with the characteristics of MPPs (Fig. c, d). No recurrence of SS occurred within 3 months.

pmc-8680048-1

A 39-year old woman with a history of irritative LUTS with macrohematuria and recurrent proven urinary infections (4–5 per year) over more than 10 years was directed to us by her attending urologist. During cystoscopy diffuse atypical flat black pigmented bladder tumors were seen throughout the bladder. An initial tentative diagnosis was melanosis of the bladder []. The patient received an extensive transurethral bladder resection (TUR-B), in which most (but not all) of the tumor formations were resected. In multiple locations, a thick layer of black pigmented cells was scraped away from a healthy underlying urothelial submucosa (Fig. ). Retrograde ureteropyelography showed no evidence of intraureteral lesions (Fig. ). Histologically, condyloma-like benign hyperkeratotic squamous cell deposits could be seen in all resection samples (Fig. ) and the diagnosis of intravesical ichthyosis was made. Urine cytology showed no signs of malignancy. The preoperative urine culture only showed natural skin flora (100 CFU/ml). A profound anamnesis revealed that there was a 2-time history of extravesical CA (cervical, 10 years ago and perineal, 3 years ago) with cystoscopically no intravesical lesions at that time. The patient’s partner had no history of condylomata and both were never vaccinated against HPV. The patients only comorbidities were hypothyroidism (treated with L-Thyroxin 75 µg daily) and a penicillin-allergy. She was in a good physical condition and had never smoked. HPV-Screening (urethral swab) was mildly positive for HPV42-DNA, a standard HPV-Vaccine (Gardasil-9®) followed. Colonoscopy showed no signs of intestinal condylomata; one small sigmoidal tubulovillous adenoma was resected. Postoperatively, the recurrent urinary infections with macrohematuria persisted. Two control-cystoscopies after 2 and 5 months postoperatively showed minimal persistence of ichthyosis and extensive scarring, with no signs of active growth. The next cystoscopy is planned in 3 months, with a re-TUR-B if lesions progress.

pmc-8680332-1

A 57-year-old man presented to the gastroenterology department of our hospital with refractory ascites for two years. He had no history of metabolic syndrome or alcohol consumption. He had a history of hypertension, hypothyroidism, and chronic nephritis, who was treated with nifedipine tablets and thyroxine tablets. He denied any fever, chest pain, rashes, oral ulcers, arthralgias and visual changes, and had no recent travel and no sick contacts. In the past two years, he has been treated in the gastroenterology department of many hospitals for ascites, and has undergone blood tests, ascites test, gastroscopy, colonoscopy, abdominal enhanced CT, etc. However, there was no clear diagnosis. The patients received oral or intravenous furosemide, oral spironolactone, and abdominal puncture drainage to resolve ascites in many hospitals, but the results were not satisfactory. The physical examination included a poor general condition, palpable lymph nodes in both sides of the neck and groin with a larger diameter of about 1 cm, abdominal distension, no tenderness and rebound pain, positive mobile dullness, mild edema of both lower limbs, enlarged spleen which lower edge is 3 fingers under the ribs. The blood routine showed that white blood cells were 4.44 × 109/L, hemoglobin was 111.0 g/L, and platelets were 93.0 × 109/L. Urine protein was weakly positive, urine pentaprotein test showed that microalbumin was 82.40 mg/L (reference value 0–30 mg/L), immunoglobulin IgG was 33.40 mg/L (reference value 0–8.5 mg/L), transferrin was 3.29 mg/L (reference value 0–2.2 mg/L), α1-microglobulin was 54.20 mg/L (reference value 0–12 mg/L), β2-microglobulin was 0.19 mg/L (reference value 0–0.22 mg/L). Other positive laboratory indicators included uric acid 520 μmol/L, albumin 36.6 g/L, and erythrocyte sedimentation rate (ESR) 26.0 mm/h. Serum thyroid stimulating hormone (TSH) was 5.5400 mIU/L, serum free thyroxine (FT4) was 14.81 pmol/L, serum free triiodothyronine (FT3) was 1.74pmol/L, which was a slight decrease. Stool routine, urea nitrogen, creatinine, C-reactive protein (CRP), liver function, serum vitamin B12, IgG4, folic acid, hepatitis virus (A, B, C, D, E), tumor markers (CA125, CA199, CEA, AFP, PSA), brain natriuretic peptide (BNP), and tuberculosis detection (PPD test, T-spot), as well as other autoimmunity makers containing antinuclear antibody (ANA), anti-neutrophil cytoplasmic antibodies (ANCA), and rheumatoid factors were all unremarkable. The patient’s HIV, EBV, CMV or Toxoplasma was negative. HHV8 and IL-6 were not detected. The gastroscope showed superficial gastritis, and the colonoscopy showed no obvious abnormalities. The echocardiogram showed a little pericardial effusion. The enhanced CT of the chest and abdomen depicted pneumonia, bilateral pleural effusion, and abdominal effusion. We performed abdominal paracentesis for this patient. The ascites was yellow and clear, the nucleated cell count was 40 × 106/L, the mononuclear cells accounted for 80.6%, and the multinucleated cells accounted for 19.4%. The Rivalta test was negative. The content of adenosine deaminase (ADA) in ascites was 2.6 U/L (reference value 0–25U/L), lactate dehydrogenase (LDH) was 74 IU/L (reference value 120–250 IU/L), albumin was 15.7 g/L, CA125 in ascites was 542 ng/mL (reference value 0–7 ng/mL), CEA, APF, and CA199 were normal. No malignant cells and tubercle bacilli were found in multiple tests of ascites. Serum ascitic albumin gradient (SAAG) was 20.9 g/L. The patient had ascites, which should be polyserositis to be precise, superficial lymphadenopathy, enlarged spleen, hypothyroidism. We made differential diagnosis based on available data. The causes of ascites may be the following: liver cirrhosis, tuberculosis, tumor, rheumatism, endocrine, cardiac insufficiency, and nephritis. SAAG remains the most sensitive and specific marker for the differentiation of ascites due to portal hypertension from ascites due to other causes. The SAAG of the patient was greater than 11 g/L, however, there were no history of hepatitis, no esophageal/gastric varices under gastroscope, and no typical CT images of liver cirrhosis. We did not perform HVPG measurement and liver stiffness measurement, nor did we perform liver biopsy to rule out other rare causes of portal hypertension. We comprehensively considered and ruled out liver cirrhosis, which should be reported to a certain extent as a limitation of case reporting. He had no history or exposure of tuberculosis infection, no fever, no night sweats, negative tuberculosis test (PPD, T-spot), normal ADA in ascites, and no tuberculosis bacilli have been detected in ascites. So tuberculosis infection was also ruled out. The patient had a small amount of urine protein, mild hypothyroidism, normal rheumatism indicators, and no manifestation of cardiac insufficiency, so it was necessary to focus on tumors or other rare causes. After communicating with the patient and obtaining his consent, we gave him an in-depth comprehensive examination including bone marrow testing, PET-CT, and lymph node biopsy. PET-CT reported that his bilateral neck, axillary, retroperitoneum and groin had enlarged lymph nodes with a slight increase in FDG metabolism. Combined with the medical history, it was considered to be consistent with the metabolic changes of indolent lymphoma by the medical technicians. Bone marrow cytology indicated that bone marrow cells proliferated actively, granulocyte proliferation was obviously active with nucleus shifted to the right, erythroid proliferation was active, platelets were aggregated and distributed, and primitive cells accounted for about 1.0% of nuclear cells. The immunophenotyping of bone marrow lymphoma showed that the proportion of myeloid blasts was not high, with normal phenotype, the proportion of lymphocytes was not high, there were no abnormal monoclonal cells and no abnormal plasma cells. Was this patient with lymphoma? We were in confusion. Fortunately, the right neck lymph node biopsy pathology gave us the answer. Pathological examination of the lymph nodes showed that the lymph follicles increased, the germinal center was atrophied, the inter-follicular and paracortical areas showed vascular hyperplasia, and the mantle area was obviously hyperplasia with onion-skin-like change (Fig. ). Onion-skin-like appearance was a typical pathological manifestation of CD. The immunohistochemical results were: CD3 (paracortical cells +), CD5 (paracortical cells +), CD20 (germinal center cells +), PAX5 (germinal center cells +), CD21 (follicular dendrites +), CD34 (Vascular +), Bcl-2 (mantle area +), SOX11 (−), Cyclin D1 (−), Ki-67 (+, about 10%). Finally, the patient was diagnosed with CD. We recommended him use CHOP chemotherapy, but he refused and chose oral thalidomide, the patient had poor compliance and refused to use steroid therapy. Three months later, his symptoms did not improve significantly. Due to economic reasons, he still refused chemotherapy and chose oral diuretics to relieve ascites.

pmc-8680372-1

A 45-year-old female of Han nationality presented to a cirneal clinic in August, 2017 with a history of pain, redness, and decreased vision in her right eye 1 week after being exposed to river water. Corneal scrapings and confocal microscopy in vivo were performed instantly. A mass of hyphae was found in the 10% KOH wet mount stained with lactophenol blue and examined via confocal microscopy. Fungal keratitis was identified, and right corneal keratectomy was performed. Empirical antifungal and antibacterial therapy was initiated including topical and systemic fluconazole, levofloxacin, and cefminox sodium. After treatment of 2 weeks, the ulcer and symptoms did not improve and the patient was admitted to our hospital. Conjunctival congestion persisted, and a central corneal ulcer with a diameter of around 6 mm that reaches deep into the stromal layer can be seen (Fig. A, B). Subepithelial and superficial stromal opacities with dot-like and tentacle-like infiltrates accompanied this. Intracameral fluconazole injection was used to conduct a lamellar keratoplasty. Amphotericin B was administered immediately after the surgery. The first day post-surgery, hyperemia and a thin exudation membrane in the anterior chamber were discernible (Fig. C, D). Four days after the keratoplasty, full-thickness large central infiltrate with hypopyon was observed in the right eye (Fig. E, F). Given the increasing infiltrate with hypopyon and ineffectiveness of antifungal therapy, the right eye was enucleated. Microbial culture for corneal tissue revealed fungus-like organism showing long sparsely septate hyaline hyphae (Fig. G, H). The organism was further identified as P. insidiosum by ribosomal RNA (rRNA) gene sequencing with panfungal primers (ITS1/ITS4), which matched 99.23% with the P. insidiosum strain (GU137348.1). Then, the patient was adjusted with combined antibacterial treatment consisting of linezolid and azithromycin, and no recurrence of infection was observed on follow-up.

pmc-8680372-2

A 51-year-old female of Han nationality was referred to our hospital in September 2018 with complications of pain, redness, and hyperemia in her right eye after entry of some cigarette ash 1 week ago. Corneal scraping was performed, and Gram staining, KOH preparation, and cultures were negative. Antifungal and antibacterial treatment was initiated including levofloxacin eye drops, cefminox sodium, and voriconazole. After 2 weeks of outpatient treatment, the patient was hospitalized. A grayish-white ulcer was observed in the central of bitamporal cornea measuring 4 × 6 mm. Inflammatory infiltrates with feathered margins and hypopyon with a depth of 2 mm were seen, suggestive of a fungal infection. The cornea showed dense central stromal opacity surrounded by a reticular pattern of subepithelial and superficial stromal infiltration (Fig. ). Then penetrating keratoplasty was performed. Exudation was observed in anterior chamber on 2 days following surgery, and intracameral fluconazole injection was performed. However, the infiltrates extended progressively, and were unresponsive to any treatment. Therefore, by day 28 post-exposure, an enucleation was performed to remove infected tissue and relieve pain. One week later, a small amount of mycelial growth was observed within the corneal fragment on the potato dextrose agar (PDA) plate. Subculture in brain–heart infusion resulted in the rapid growth of a large mycelium at 35 °C. We have attempted to identify this mycelium by matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF-MS) but failed. There was no reference spectrum in the Bruker Filamentous Fungi databases despite the high quality of the protein spectrum. The mycelium was sent for internal transcribed spacer (ITS) rRNA gene sequencing analysis and unambiguously identified as P. insidiosum.. Three obvious protein peaks of the strain were found by MALDI-TOF-MS, which are 2094.01, 4834.62, and 9682.51 (× 103 m/z), respectively (Fig. ). Then, the reference spectrum of P. insidiosum was added to the in-house database according to Bruker MALDI-TOF-MS standard process to create a library. Therefore, the identification of P. insidiosum could be facilitated using MALDI-TOF-MS.

pmc-8680372-3

A 55-year-old male of Han nationality presented with irritation, pain, and hyposia in the left eye for 3 days after facial washing with contaminated river water. He went to a local ophthalmic clinic and was diagnosed with viral keratitis. After 4 days of antiviral therapy, the symptoms were not improved, so the patient was admitted to our hospital. Slit-lamp examination showed conjunctival hypertrophy and infiltrated growth into cornea about 2 mm from the nasal limbus. In the left eye, microvascular tissue hypertrophy of about 2.5 mm was seen across the corneal limbus, and hyperemia grayish-white infiltrate of cornea with a diameter of about 5 mm was observed (Fig. ). Direct microscopy of corneal scrapings stained with Gram and KOH preparation was negative for organisms. The patient was prescribed empiric fortified topical and systemic antibiotics, including ornidazole, tobramycin, vancomycin, natamycin, and fluconazole. On the third day after hospitalization, symptom improvement was not noted. Excision of pterygium and therapeutic penetrating keratoplasty were performed in the left eye. Cultures of his corneal tissue for bacteria, fungus, and Acanthamoeba were negative. Because there was evidence of increased keratoneuritis, antiamebic therapy (chlorhexidine) was initiated and voriconazole was added. Twelve days after the surgery, corneal opacity was rescraped and infiltration extended deeply into the anterior chamber. A second penetrating keratoplasty, virtually limbus to limbus, and intracameral amphotericin B injection were performed sequentially. However, 10 days after the second operation, the infection still spread to the adjacent sclera and progressed to endophthalmitis. Enucleation eventually had to be done. Subsequently, the corneal cultures growing on PDA plate were identified as P. insidiosum by MALDI-TOF-MS, confirming the diagnosis of pythiosis.

pmc-8683699-1

A 54-year-old medically free Saudi gentleman presented to our clinic complaining of a gradual painless decrease in vision of his left eye over one year. He also reported mild pain, photophobia, and redness from time to time. The patient underwent uneventful cataract surgery of both eyes 13 years prior to his presentation. The best-corrected visual acuity (BCVA) using a Snellen chart was 20/28 in the right eye (OD) and 20/400 in the left eye (OS). Slit-lamp biomicroscopic examination of the OD was unremarkable (Figure ). Upon examining the OS, there were 1+ (i.e., 6-15 cells per field) mixed anterior chamber cells. CCC was relatively small (measured 4.7 mm). In addition, a thick turbid greenish fluid was noted behind the IOL, limiting visualization of the posterior capsule (Figure ). B scan was performed due to poor visualization of the fundus, which revealed moderately dense vitreous opacities suggestive of vitritis. There was no associated choroidal thickening. Ultrasound biomicroscopy (UBM) showed a hyperechoic collection of turbid fluid behind the IOL with a distended capsular bag, confirming the presumed diagnosis of CBDS (Figure ). Late-onset CBDS with a high possibility of associated P. acnes was assumed, and surgical intervention was considered. After explaining the surgical procedure and obtaining written informed consent from the patient, a pars plana vitrectomy (PPV) with a posterior capsulotomy was performed. Initially, 23 gauge three PPV trocars were placed 3.5 mm away from the limbus. Then, through the superonasal sclerotomy site, a 27-gauge needle was inserted to pierce the posterior capsule and gently aspirate the liquified material. After aspirating and clearing the visual axis, a vitreous cutter was introduced through the same superonasal port to create posterior capsulotomy followed by core vitrectomy. Intravitreal vancomycin (1 mg/0.1 mL) was injected at the end of the procedure due to the high possibility of associated P. acnes endophthalmitis. After the procedure, the aspirated material was sent to histopathology for gram stains and cultures. After 72 hours, Thioglycolate broth was positive for the growth of P. acnes confirming the presumed diagnosis. The post-operative period was uneventful, and no signs of intraocular inflammation were detected. At six months, the patient had 20/25 BCVA and did fine without any complaints (Figure ).

pmc-8683972-1

A 40-year-old woman was admitted for evaluation of critical limb ischemia of the right leg. Medical history is significant for human immune deficiency virus (HIV) infection with undetected viral load, coronary artery disease, peripheral vascular disease, and polysubstance abuse. Vascular surgery performed bilateral lower extremity angiogram, femoral artery angioplasty, and a femoral artery stent. The postoperative course was uneventful. Apixaban 2.5 mg twice daily was added to her medication regimen of clopidogrel, Darunavir/cobicistat (Prezcobix), abacavir/dolutegravir/ lamivudine (Triumeq), atorvastatin, isosorbide dinitrate, and hydralazine. The patient returned one-week post-discharge with low back pain and a computed tomography (CT) scan demonstrated a large retroperitoneal hematoma (Figures -). Her hemoglobin level on admission was 9.2 g/dl, down from a discharge level of 11.9 g/dl. Her serum creatinine was stable at 0.8 mg/dl. On arrival to ED, blood pressure was 130/69 mm of Hg, the heart rate was 87 beats per minute, respiratory rate was 18 breaths per minute, and the temperature was 37.4 °C. The patient was managed conservatively, and both her hemoglobin and vital signs remained stable throughout her admission. She was discharged on apixaban and clopidogrel as recommended by the vascular team. The patient was readmitted four weeks later with urosepsis. A follow-up CT abdomen revealed a resolving retroperitoneal hematoma. The patient reported that during her outpatient management she had only been compliant with her antiretroviral therapy (ART) and not with her antiplatelet or anticoagulant medication (clopidogrel and apixaban). Her anticoagulant regimen was changed to enoxaparin out of concern with potential drug-drug interaction with apixaban and cobicistat, and the team continued clopidogrel. This warning was identified by the electronic medical records.

pmc-8684064-1

A 40-year-old gravida 1 para 0 Caucasian woman presented at 39 + 6 weeks gestational age with a 3-day history of new onset pain in an otherwise uncomplicated pregnancy. At 39 + 1 weeks gestation she had started outpatient cervical ripening with dinoprostone (Cervidil) because of her advanced maternal age. She described the pain along her right torso as severe, shooting, and sharp, but at times pleuritic in nature. It rapidly progressed from her right trapezius to encompass the entirety of her right torso, from her upper abdominal quadrant and epigastrium, radiating to her back, chest, shoulder, and neck. Her pain was initially attributed to possible radiculopathy, as she had a previous history of the same. Her vital signs at initial presentation were normal, with no hypertension noted, and there were no concerns regarding the fetal status. No further investigations were ordered and a full neurological examination was not documented. She represented less than 24 hours later at 40 + 0 weeks gestational age, and was found to be hypertensive at 157/101 and 164/112 mmHg. Oxygen saturation was 98% on room air. She had sinus tachycardia on arrival, ranging from 110 to 140 bpm and persisting throughout the peripartum period. She was tender in the right upper quadrant, however there were no peritoneal signs, and no hepatomegaly was appreciated in the presence of the gravid uterus. She was tender from the right side of her neck through to her right lower back. Her reflexes were 3 + bilaterally with no clonus. The fetal heart rate was normal. Her blood investigations revealed a hemoglobin of 105 g/L, platelets 156,000 g/L, alanine aminotransferase (ALT) 193 μ/L, aspartate aminotransferase (AST) 111 μ/L, and uric acid 429 μmol/L. White blood cell count, creatinine, lactate dehydrogenase (LDH), and coagulation profile were within the normal range. An electrocardiogram (ECG) showed sinus rhythm with no abnormal features, apart from the previously noted tachycardia. After diagnosing preeclampsia, induction of labor was started, as was an infusion of magnesium sulfate. Due to the unusual but significant pain that she was experiencing, a range of differential diagnoses were considered by the obstetrical and anesthesia team. Preeclampsia with HELLP syndrome was the working diagnosis, however differential diagnoses included fatty liver, radiculopathy, cholecystitis, pancreatitis, and pyelonephritis. The patient requested labor analgesia be initiated and a combined spinal epidural was placed when the patient’s cervix was 2 cm dilated. Analgesia was maintained via programmed intermittent epidural bolus with patient-controlled epidural analgesia as needed, in keeping with our institutional practice. The patient reported satisfactory analgesia with regard to her labor pain, but still complained of severe pain in her right torso that was unresponsive to acetaminophen and opioids. Blood investigations monitored every 4 hours remained stable with hemoglobin of 103–102 g/L, platelets 158,000–165,000 g/L, ALT 176–169 μ/L, AST 100–97 μ/L, and uric acid 400–420 μmol/L. The LDH, creatinine, and coagulation profile remained normal. Labor progressed to full dilation with oxytocin augmentation, but as a result of torso pain she was unable to exert adequate effort with pushing. Ultimately, the obstetrical team consented the patient for a trial of forceps and possible cesarean delivery. In the operating room, the obstetrics team performed an examination under anesthesia, which revealed the fetus to be in an occiput-transverse position at station zero, and the decision was made to proceed to cesarean delivery as the station was too high to perform a trial of forceps. A nonvigorous male infant was delivered with Apgar scores of 3 and 8 at 1 and 5 minutes, respectively. Placental delivery was uneventful. Atonic postpartum hemorrhage was treated with a bolus of 2 units IV oxytocin and carboprost 250 mcg intramuscular (IM), in addition to an oxytocin infusion. As per our institutional practice, a bolus of oxytocin is only used when the patient has multiple risk factors for intraoperative hemorrhage or is experiencing uterine atony. This low dose was chosen to prevent potential side effects (nausea, vomiting, chest pain) and complications (hypotension, hypertension, ST segment changes, myocardial ischemia, bronchospasm) that can be associated with higher dose boluses when given at the time of cesarean section [, ]. Prior to fascial closure, the obstetrics team manually explored the abdomen to the extent possible through the Pfannenstiel incision. No gross abnormalities were identified. The patient’s right torso pain persisted throughout her time in the operating room, with only a slight improvement after surgical anesthesia obtained via the epidural. After delivery, 2.5 mg of epidural morphine was given for postoperative analgesia. The patient was hemodynamically stable throughout the operation, although remained tachycardic. Estimated blood loss was approximately 900 mL. Postoperatively, the patient was sent for a computed tomography (CT) scan of her chest, abdomen, and pelvis, including contrast for a pulmonary embolism protocol to investigate the abdominal pain and persistent tachycardia. No pulmonary embolus was found and a small right pleural effusion with subsegmental atelectasis was noted. However, the most impressive feature on the scan was a large but intact subcapsular liver hematoma that measured approximately 16 × 7 × 14 cm (Fig. ). Portal hypertension was suggested by the presence of portosystemic varices. The general surgery team was consulted and recommended conservative management with strict blood pressure control requiring oral labetalol, frequent complete blood count (CBC) monitoring, and 48 hours of bedrest. If, however, the SCH had been diagnosed antepartum, labor would have been avoided and delivery would have been expedited via immediate cesarean section. The SCH is at risk of rupture with active pushing, convulsions, or abdominal trauma, including vigorous palpation of the right upper quadrant []. In this case, prophylactic antibiotics were not used as there were no signs of infection and the underlying etiology was noninfectious. Interventional radiology was on standby to perform hepatic artery embolization if the SCH significantly increased in size or there was concern about imminent rupture. Serial monitoring of blood work revealed a hemoglobin of 70 g/L and 56 g/L on postoperative days 1 and 2, respectively, prompting transfusion of two units of packed red blood cells on day 2. The patient was discharged on postoperative day 5 with her hemoglobin stable at 85 g/L. An early postoperative follow-up visit was arranged 15 days postpartum and at that visit the patient was noted to be pale, tachypneic, and upon questioning she stated increasing shortness of breath and a persistence of her pleuritic chest pain. She was sent back to the IWK Health Centre where her vital signs were as follows: heart rate 110–130 bpm, blood pressure 112/66 mmHg, oxygen saturation 97% on room air, respiratory rate 40–48, temperature 37.9 °C. Blood investigations revealed a white cell count of 6, hemoglobin 97 g/L, platelets 650,000 g/L, ALT 75 μ/L, AST 88 μ/L, LDH 1310 μ/L, and coagulation profile remained normal. A repeat abdominal CT scan reported an increase in the size of the liver hematoma to 14 × 8.5 × 18.3 cm (Fig. ). Although there was no evidence of active intralesional bleeding or rupture, the liver capsule was difficult to visualize in the superior aspect, and could suggest significant thinning and imminent rupture. The CT scan of the chest reported a large right pleural effusion with mediastinal shift (Fig. ). The patient was urgently transferred from the stand-alone maternity hospital to a nearby hospital under the care of the thoracic surgery team, with the general surgery team on standby. A chest tube was placed, but ultimately the patient required video-assisted thoracoscopic surgery (VATS), with right partial decortication of an infected, loculated pleural effusion prior to her discharge home. The pleural effusion aspirate showed no growth. The right pleural effusion was felt to be exudative in nature and secondary to the adjacent large SCH. Throughout the admission she remained normotensive and her hepatic hematoma remained stable with no signs of active bleeding. She was discharged home on day 2 following the VATS procedure, coinciding with day 21 following her cesarean section. At discharge, her hemoglobin was 74 g/L and her platelets were 884,000 g/L. She continued to receive follow-up with general surgery and obstetrics as an outpatient. A CT performed 4 weeks postpartum showed the hepatic hematoma had decreased in size to 12.6 × 6.4 × 15.1 cm and at 6 months postpartum had decreased to 3.8 × 2.2 × 3.1 cm and did not require any further follow-up.

pmc-8684096-1

Patient: a 55-year-old Japanese female. None of the factors contributing to lateral compartment knee disease, such as obesity, complications, or psychiatric disorders, were present in the patient. During hyaluronic acid (HA) treatment, although we prescribed strength training to the patient, she did not perform it frequently enough because of severe pain. As the knee pain was caused by tripping while playing tennis, the possibility of trauma cannot be ruled out. In 2013, due to pain in both knees, she visited our hospital and was diagnosed with OA of the knee. In December 2017, while playing tennis, the right knee developed a knee collapse. She was examined at the hospital, and an MRI of the right knee was performed. Horizontal dissection of the lateral meniscus and cartilage defect on the lateral condyle of the femur were observed. Since 2018, injections of hyaluronic acid have been administered every 2 weeks, but joint edema and pain recurrence have been remitted. The patient had already undergone HA treatment and received multiple steroid joint injections; however, these interventions were not very effective. Moreover, the patient was unwilling to undergo these treatments. The patient was aware that our hospital would start providing regenerative medicine treatments and had been waiting for a year before the start of the treatment. During that period, the patient received HA treatment, which proved ineffective. Therefore, the patient requested ASC treatment in April 2018. In April 2018, MRI of the right knee was performed. A cartilage defect was found in the external condyle of the femur, and the patient desired ASC transplantation. The range of motion of the right knee is 0–145. Anteroposterior (AP) and lateral radiograph of the right knee are shown in Fig. . On 28 April 2018, 20 mL ASCs were collected from the abdomen. On 11 June 2018, the first ASC transplantation was performed on the right knee. On 2 July 2018, although the effect was experienced after 1 week of treatment, the pain recurred when the subject moved violently. On 6 August 2018, the patient was in a good condition. When the Timed Up and Go Test was conducted, it showed improvement from 10 seconds to 7 seconds. On 10 September 2018, the patient was in a good condition. She resumed playing tennis and was living almost without pain. On 10 December 2018, an MRI was performed. There was no pain even when the subject jumped on one leg and a repaired cartilage defect was observed. On 22 April 2019, the second ASC transplant was performed on the right knee and the first ASC transplant was performed on the left knee. On 22 June 2019, there was a slight fever on the day of the procedure. On 5 August 2019, the patient was in a good condition. It became possible to assume a sitting position.

pmc-8684121-1

An obese 32-year-old Middle Eastern man with a body mass index (BMI) of 33 presented to the emergency department (ED) with a 6-day history of severe, worsening, generalized abdominal pain and vomiting. He had undergone LSG 13 days prior to the current admission at a private hospital. He was prescribed a protein pump inhibitor and enoxaparin 40 mg daily, which he had taken regularly. On examination, the patient looked unwell, dehydrated, and in pain. His Glasgow Coma Scale score was 15, and he had a heart rate of 135 beats per minute, blood pressure 132/82 mmHg, respiratory rate 20 breaths per minute, and body temperature 36.5 °C. On examination, his abdomen was distended with generalized tenderness, but his laparoscopic wounds had healed. Initial laboratory investigations revealed a white blood cell count (WBC) of 27,300/μL (4000–11,000 μL), hemoglobin 17.3 g/dL (10–15 g/dL), and serum lactate 7.6 mmol/L (0.5–1.9 mmol/L). Computed tomography (CT) of the abdomen and pelvis with intravenous contrast revealed extensive acute on chronic portosplenic and superior mesenteric vein thrombosis, with consequent small bowel ischemia (Fig. ). He was admitted under the care of the acute surgical team and resuscitated, and underwent laparoscopic exploration, which confirmed the CT findings. After conversion to midline laparotomy, 255 cm of small bowel was resected (Fig. ) and the abdomen was left open with a vacuum-assisted closure device dressing (Fig. ). The patient was transferred to the intensive care unit. A second look was carried out 24 hours later, and both the small and large intestines appeared healthy, so primary anastomosis and abdominal closure were performed. A solid diet was introduced gradually, and the patient was discharged home on day 12 postoperation on warfarin. A thrombophilia screen was negative. The patient was seen multiple times for follow-up; he was tolerating oral intake and had reduced his BMI to 19 with no clinical manifestations of short bowel syndrome.

pmc-8684161-1

A 63-year-old woman visited a clinic for a palpable right axillary mass. US showed a 2.5-cm irregular hypoechoic mass in the right axilla, which was considered to be a malignant lymph node such as metastasis (Fig. ). Similar to physical examination and mammography, US revealed no remarkable findings in both the breasts and the left axillary region. A 14-gauge core-needle biopsy revealed the right axillary lymph node as a metastatic carcinoma, possibly from the breast, with positive estrogen receptor (ER) status. Breast MRI was performed to determine the presence of occult breast malignancy. No lesions were detected in the right breast, whereas a 0.6-cm irregular enhancing mass was observed in the left upper inner breast, assessed as breast imaging reporting and data system (BI-RADS) category 4C (Fig. A). To exclude primary malignancies other than breast cancer as the origin of the metastasis, chest computed tomography (CT) and whole-body positron emission tomography-computed tomography (PET-CT) were performed. They revealed no specific findings, except the known right axillary metastasis. Second-look US showed a 0.6-cm irregular, indistinct, isoechoic mass in the left upper inner breast, corresponding to the mass observed on breast MRI (Fig. B). US-guided 14-gauge core-needle biopsy confirmed the mass as an invasive carcinoma of no special type. The ER status of the cancer was positive, same as that of right axillary metastasis. Therefore, the right axillary metastasis was suspected to originate from the left breast cancer, and surgery was planned for its management and to confirm the diagnosis. Right axillary lymph node dissection and left breast conserving surgery with sentinel lymph node biopsy were performed. The invasive carcinoma in the left breast was 6 mm in size, with cells positive for ER and progesterone receptor (PR) and negative for human epidermal growth factor receptor 2 (HER2). It was a low-grade invasive cancer with low Ki-67 expression (5%), histologic grade 1, and without lymphovascular invasion. Sentinel lymph node biopsy confirmed no left axillary involvement. In the right axilla, three macrometastatic lymph nodes were discovered, including the known palpable metastatic lymph node. Histologic findings of cancer cells in all three lymph nodes were fairly different from those of cancer cells in the left breast (Fig. ). Examination of the right axillary metastasis showed high-grade carcinoma with poorly formed glands and nests of atypical cells, while examination of the left breast mass showed low-grade cancer with well-differentiated glands and fairly uniform nuclei. These findings clearly indicated that the metastasis to the right axillary lymph node did not originate from the left breast cancer, although both of them showed ER positivity. Metastatic cancer cells in the right axilla were also positive for gross cystic disease fluid protein-15 (GCDFP-15) and GATA binding protein 3 (GATA3), suggesting that the metastasis was derived from the breast (Fig. ). Finally, the case was diagnosed as bilateral breast cancer consisting of occult right breast cancer with axillary metastasis (TxN1M0) and early-stage left breast cancer (T1bN0M0). Four cycles of doxorubicin and cyclophosphamide followed by four cycles of taxane (AC-T) chemotherapy, radiation therapy for each breast, and hormone therapy were administered after surgery. No recurrence or metastasis was observed 14 months postoperatively.

pmc-8684169-1

A 77-year-old Japanese woman, para 7, who went through menopause at age 48, suffered sudden onset of left lower abdominal pain and visited a primary care doctor. Computed tomography (CT) revealed torsion of a left ovarian cyst, and she was transferred to our hospital for surgery. She had a history of left-side breast cancer and underwent total left mastectomy at the age of 67, with no recurrence thereafter. Although she was a carrier of hepatitis C, her liver function and coagulation remained normal, and she was being followed-up without medication. Furthermore, she was taking nifedipine and candesartan cilexetil for hypertension. Meanwhile, her family history and psychosocial history were unremarkable. She also had no history of trauma. CT showed a 7.5-cm long elliptical mass in the left adnexal region that was continuous with the uterus (Fig. ). The ovary was atrophic because of the patient’s age, and difficult to identify; the appearance of blood and the continuity with the surrounding pelvic peritoneum were suggestive of retroperitoneal hematoma. Physical findings at admission were as follows: height, 144.5 cm; weight, 57.2 kg; body mass index (BMI), 27.4 kg/m2; blood pressure, 112/50 mm Hg; pulse, 72 bpm; and body temperature, 37.1 °C. Physical examination detected no significant findings. On external (body surface) and internal examinations, no palpable masses or tenderness were noted in the left pelvic area. Transvaginal ultrasound revealed an atrophied uterus; however, the bilateral adnexa could not be identified due to atrophy. The hematoma in the left pelvis could be identified. These findings were identical to those obtained by CT. Blood test results were a hemoglobin value of 9.5 g/dL, a hematocrit value of 28.4%, a white blood cell count of 7970/μL, and a C-reactive protein level of 0.05 mg/dL. Urinalysis revealed mild occult blood. After admission, the hematoma did not enlarge, and the hemoglobin and hematocrit levels did not decrease. After 11 days of bed rest, with no exacerbation of the inflammatory response, lower abdominal pain was relieved, and she was discharged. After discharge, we planned to investigate the cause of her bleeding on an outpatient basis, but 6 days after discharge, she was readmitted to our hospital after relapse of symptoms caused by retroperitoneal bleeding from the same site. The hematoma had grown to a size of 11.7 cm, and magnetic resonance imaging showed an abnormal vascular network extending from the left side of the uterus to the left adnexal area. Three-dimensional CT (3D-CT) similarly showed an abnormal vascular network on the left side of the uterus, and we suspected a possible arteriovenous malformation (AVM) or arteriovenous fistula (AVF) from the uterine artery to the left ovarian vein (LOV; Fig. ). We decided that urgent treatment was needed for her repeated bleeding and performed vascular embolization therapy simultaneously with angiography. However, angiography of the internal iliac artery, including the left uterine artery, and the left external iliac artery, did not show AVM or AVF into the LOV. Angiography of the left renal artery confirmed that the contrast medium discharged from the left kidney did not flow into the inferior vena cava (IVC) but flowed back into the LOV (Fig. a). Subsequent venography also confirmed that the blood from the LRV did not flow into the IVC but regurgitated into the LOV and the lumbar vein (Fig. b). Left ovarian venography showed retrograde blood flow into a dilated and tortuous aneurysm in the pelvis and into the right internal iliac vein via a vein around the uterus (Fig. c). The cause of retroperitoneal bleeding was rupture of the LOV, the distension of which was caused by reflux. We performed embolization of LOV with N-butyl-2-cyanoacrylate and placed a coil centrally to prevent recanalization. Postembolization LRV imaging showed blood flow to the upper left lumbar vein and vertebral plexus (Fig. d). CT on the second day after the procedure confirmed good embolization of LOV and reduction of the retroperitoneal hematoma to a size of 6.4 cm (Fig. ). The patient then underwent regular outpatient follow-up, and the retroperitoneal hematoma gradually shrank and disappeared. At her final visit 2 years later, the hematoma had not recurred. In this case, angiography confirmed the continuity of LRV and IVC but demonstrated no antegrade blood flow to the IVC. Therefore, we attributed LOV regurgitation to extravascular physical compression of LRV. After close examination of the CT images, we determined that LOV rupture was caused by NCS because the LRV was severely stenotic between the abdominal aorta and the SMA (Fig. ).

pmc-8684173-1

A 48-year-old G3/P2 woman presented to the Department of Gynecology with a physical examination. Ultrasonography (Fig. A) and enhanced computed tomography (ECT) (Fig. B) revealed pelvic masses. She was recommend to undergo laparoscopic ovarian cystectomy for a borderline ovarian tumor eight years before. During the eight years, she did not have regular medical examinations because there were no symptoms of diseases. She chose to undergo surgical treatment for pelvic masses. Finally, she underwent a hysterectomy and pelvic lymph node dissection for a recurrent mucinous borderline ovarian tumor (Fig. C). Postoperative routine examination showed endometrial lymphoma, and the other lymph nodes were not involved. Testing for immunoglobulin heavy chain (IGH) gene rearrangement showed a positive result (Table ). Uterine lymphoma was derived from the primary female genital system and was diagnosed as non-Hodgkin's lymphoma, consistent with diffuse large B-cell non-Hodgkin's lymphoma. Hematoxylin–eosin (HE) staining and immunohistochemistry were carried out to analyze the case specimen (Fig. ). The patients underwent bone marrow biopsy and PET-CT to observe whether there were other lymph node abnormalities. However, there was no evidence of bone marrow involvement by microscopic examination, and there was no abnormality in the whole body scan by PET-CT. Currently, the patient has received four postoperative courses of CHOP chemotherapy in the Department of Hematology. To date, no abnormality has been found in the follow-up.

pmc-8684194-1

Our patient was a 13-year-old Caucasian female with a history of anxiety, depression, and anorexia nervosa. She was admitted twice to our hospital. The first admission was in September 2019, when her parents brought her for losing 16 kg over 3–4 months. She was weighing 40 kg (BMI 16.0 kg/m2, 8.7%ile, z = − 1.4) and had sinus bradycardia (HR 30–40 BPM). Table and Fig. show changes in her lab values during her two admissions. The patient reported sadness, loneliness, anhedonia, and hopelessness and admitted to restrictive eating behaviors to lose weight. There was no history of purging, bingeing or laxative use. Although emaciated, she minimized the severity of her nutritional status or her preoccupation with her weight and body image. She denied suicidal ideation but desired death rather than pursuing an eating disorder treatment. The patient had compulsive tendencies for academic work and extracurricular pursuits and was highly driven. She had several moves during childhood and reported increased anxiety after a recent move to live with her father following parental divorce. She was starting a new school, as well. We placed her on 1:1 for safety concerns. The patient started restricting around the age of ten after having a growth spurt at puberty. Following her diagnosis of AN, she received eating disorder treatment at different levels of care, including inpatient, residential, partial hospitalization or Day Program, and intensive outpatient programs in four states. She would become physically aggressive towards staff and family to sabotage her recovery. In one incident, she bit a chunk off the nape of her sister’s neck during a family visit in her residential stay, leading her to be discharged. She admitted to becoming jealous of the sister as she was to go home after the visit while the patient was to remain confined to the unit. She had no remorse about the incident. There was a report where she left the gas stove on to burn the house and kill her mom and her siblings when she was angry. She again had no regrets about her actions. She had history of hurting the family cat. This history of repeated aggression over several years toward other people and animals indicated a possible CD diagnosis. Family history was pertinent for anxiety and mood disorders and AN. During admission, she hid meals, avoided cardiopulmonary monitoring, and refused nasogastric tube. She would engage in isometric exercises and avoid lying down. She did not take medication for anxiety. As she failed weight restoration in the medical hospital, we referred her to an out-of-state inpatient eating disorder unit for further treatment. Right before the transfer, she jeopardized the transfer by stabbing her pediatrician with a pair of scissors that she hid from the Child Life Services supplies in her room. She intended to hurt the physician for transferring her to the inpatient unit. A room search discovered multiple sharp objects under her mattress, including plastic knives, forks, and medical supplies. For ongoing aggression, she necessitated physical restraints and emergency use of Lorazepam. The patient was formally diagnosed with CD after this incident. The inpatient eating disorder facility refused to accept the patient after the violence, which led our interdisciplinary team to plan her weight restoration by implementing behavioral expectations and positive reinforcement techniques for meeting daily nutritional needs. Some of the privileges were using the phone, watching TV, or playing video games. We initiated and titrated chlorpromazine 50 mg twice daily for aggression. She gained 2.7 kg in about 6 weeks and her bradycardia resolved (see Fig. ). Her T3 and prealbumin normalized (see Table ). After 24 days in the hospital, she was discharged with a plan to start an eating disorder partial hospitalization program. Following discharge, she participated in the partial hospitalization program for 5 days. On the morning of the sixth day, she entered her father’s bedroom and stabbed him three times with a butcher’s knife. She had purchased the knife the day before to kill her father, blaming him for the eating disorder treatment. She was arrested and remanded to Juvenile Justice Center (JJC), where she started refusing to eat or to take chlorpromazine. She rapidly lost weight and was readmitted for her second admission to our pediatric hospital. On readmission, she weighed 36.5 kg (BMI 14.6 kg/m2, z = − 2.3, 1.0%ile) and was bradycardic and mildly hypothermic with a reduction in T3 and prealbumin. An echocardiogram demonstrated a trace posterior pericardial effusion with normal cardiac function. She was handcuffed and ankle-cuffed to her bed throughout her stay. We switched chlorpromazine to olanzapine (3.5 mg in divided doses), and added fluoxetine (10 mg daily) to address anxiety. She used Lorazepam for anxiety during feedings via NG tube initially. After gaining about 8 kg in about 6 weeks (see Fig. ), she was discharged back to the JJC, where she continued receiving eating disorder treatment. We suspected that some of the weight gain was related to rehydration. Her pericardial effusion resolved ultimately. We observed a shift in her statements during weight restoration. For example, “I don’t see how a boy could like me now that I have gained weight” changed to “it does bother me to gain weight, but I try and focus on getting my period back, which makes it easier.” The JJC’s focus on positive reinforcement and reward systems seemingly motivated her to earn additional privileges for desired behaviors. She proudly shared when gaining access to the commissary at JJC, an upgrade in her shoes, a later bedtime, and her ability to spend time with peers in the gym under supervision to prevent over-exercise. JJC staff, many of whom chaperoned her during hospitalization, learned positive reinforcement and practical techniques taught to parents in family-based treatment (FBT) programs and implemented those strategies while she remained incarcerated. Her desire of “never to be hospitalized again” served as a motivation to completing her meals. She had regular follow up with our adolescent medicine team to monitor her progress. As she continued to gain weight, and her anxiety and aggressive impulses decreased. After one visit with our psychiatry team 4 weeks after her discharge, JJC’s psychiatrist took over her psychiatric care and titrated olanzapine to 7.5 mg twice daily and fluoxetine 20 mg daily. Her olanzapine was subsequently decreased to 5 mg twice daily for mild elevation in transaminases that later resolved. Six months after discharge from the hospital, she was still in custody at the JJC, and her nutritional status remained stable. Her menses returned. After complaining of weight gain as an adverse effect of psychotropics, she discontinued olanzapine and later on fluoxetine. However, she maintained her body weight after stopping the medications (see Fig. ). She has remained in outpatient treatment; and we anticipate that this will be needed long-term given the severity of her symptoms of CD and AN.

pmc-8684204-1

A 41-year-old Ukrainian male [body mass index (BMI) 37.4] presented with complaints of numbness and cramping in the lower extremities, periodic numbness of fingers I–III of both hands, headache, and general weakness that gradually increased over 8 years. Over the past 2 years, the patient noted complete hair loss in the legs, thinning and increased vulnerability of the skin of the lower limbs, and the appearance of limited areas of severe hyperkeratosis on the feet. A callosity on the first toe of the left foot had led to the formation of a long-term, non-healing infected wound that was complicated by gangrene of the terminal phalanx and had led to its amputation. During examination, the skin of both feet was observed to be thinning with pigmentation, lamellar desquamation, and hyperkeratosis on the plantar surfaces (Fig. a–d). There were multiple epithelized and unhealed infected wounds on the feet that had developed as a result of microtrauma. The patient also suffered from class II alimentary–constitutional obesity [, ]. A neurological examination revealed impaired exteroception with symmetrical hyperesthesia of the metacarpophalangeal joints, hypoesthesia, anesthesia, and thermal hypesthesia to the level of the middle one-third of the legs by polyneuritic type (Fig. e). Vibrational sensitivity was reduced to 5 seconds by polyneuritic type. Positional sense was reduced in the distal joints. Tendon reflexes of the lower extremities were weakened. Using the Medical Research Council (MRC) scale, muscle strength in the flexors of the lower legs was reduced by 4 grades, by 5 grades in the extensors, and 5 grades in the distal sections. Before the start of treatment in September 2017, hand dynamometry measured 38 kg and 36 kg on the left and right sides, respectively, which increased to 46 kg and 45 kg following treatment in February 2018. Moderate atrophy and muscle pain in the lower legs and short foot muscles were also found. Sensitive ataxia was noted as well. Autonomic trophic disturbance of the lower extremities was characterized by hyperkeratosis, anhidrosis, and livedo reticularis (Fig. a). Despite the absence of complaints from the patient and his relatives, a decrease in cognition was uncovered using the Montreal Cognitive Assessment (MoCa) scale with a score of 18 out of 30, the Mini-Mental State Exam (MMSE) with a score of 23 out of 30, and the Frontal Assessment Battery (FAB) with a score of 13 out of 18. In addition, tests evaluating spatial orientation (the clock drawing task and drawing complex or three-dimensional figures), attention, delayed recall, and phonetic speech activity were found to cause the most difficulties (Fig. g–k). To identify the causes of polyneuritis syndrome, we excluded endocrine diseases [normal indicators of insulin, proinsulin, glycated HbA1c, adrenocorticotropic hormone, thyroid-stimulating hormone (TSH), triiodothyronine (T3), and thyroxine (T4)], infections (cytomegalovirus, Epstein–Barr virus, herpes, and borreliosis), and dysmetabolic origins (vitamin levels for B1, B6, B12, and homocysteine were normal; and amyloid deposition in the subcutaneous fat was absent). Electrophoresis of serum proteins allowed us to exclude the presence of paraprotein with a slight increase in the β1 fraction and hypergammaglobulinemia. Among the possible autoimmune causes, tests for antineutrophil cytoplasmic antibodies (ANCA), antinuclear factor, and extractable nuclear antigen antibodies were negative. An immunoblot of antibodies to gangliosides and onconeural antigens was negative as well. However, recombinant tissue transglutaminase 2 (TG2) IgA antibodies were found to be five times the normal level (90.3 IU/ml, which is normally less than 20 IU/ml). Anti-DGP IgG antibody values were normal (22.8 IU/ml). Among all the classes of antibodies, only the IgE level was increased at 122 IU/ml. As an additional source of confirmation for celiac disease, the HLA-DQ2 and HLA-DQ8 alleles were found to be present. No pathologies or abnormalities were detected following an electrocardiogram, echocardiography, thyroid, abdominal and pelvis ultrasounds, head magnetic resonance imaging (MRI), and chest computed tomography (CT). However, during a nerve conduction study (NCS), signs of gross axonal damage to the motor and sensory fibers of the lower extremities was uncovered, with a complete block at the distal stimulation points of the left tibial and peroneal nerves and signs of secondary demyelination. In the upper limbs, there were signs of moderate axonopathy of the ulnar nerve (Table ). To assess the involvement of the gastrointestinal pathological process, a fibroesophagogastroscopy was performed, during which an erythematous gastroduodenopathy was revealed. Biopsies of the gastric and duodenal mucosa were sent for morphological study (Fig. ). Morphological analysis of the duodenal mucosa biopsy (Table , Fig. ) identified changes (subatrophy of villi in combination with crypt hyperplasia) that correspond to celiac disease according to the Marsh IIIB classification. Figure shows duodenal mucosa relief, atrophy of the villi, and deepening of the crypts. In Fig. a, inflammatory infiltration, reactive changes in epithelial cells are presented. In Fig. b and c, pronounced diffuse lymphoplasmacytic infiltration, an increase of intraepithelial lymphocytes, and a decrease of goblet cells in the surface sections can be seen. Figure d and e shows pronounced diffuse lymphoplasmacytic infiltration, with a sharp increase in intraepithelial lymphocytes. In Fig. f, there are reactive changes in epithelial cells with nucleo- and nucleolomegaly, perinuclear vacuolization, nuclear hyperchromia, and increased mitotic activity. From Fig. a to f, the plates were stained with hematoxylin and eosin. Examination using direct immunofluorescence (DIF) reaction using antisera (Fig. g) uncovered C1q deposition (2+) in the papillary dermis, and linear IgA deposition (1+) along the basement membrane of the epidermis (Fig. h). Examination of the skin biopsy by DIF using antisera uncovered C1q deposits in the papillary layer of the dermis in the lower one-third of the shin, minor IgA deposits at the intercellular contacts of the epidermis, and linear deposits along the basement membrane of the epidermis. The pattern was similar to linear IgA dermatosis. Multidisciplinary therapy was initiated that included two cycles of five operations of medium-volume membrane plasma exchange, with an exfusion volume of 25–30% of the circulating plasma volume in combination with 1 g of intravenous pulse methylprednisolone. Metabolic therapy included the administration of α-lipoic acid (1200 mg/day); vitamins B6 (50 mg/day), B12 (1000 mg/day), and E (400 units/day); ipidacrine (60 mg/day); sulodexide (500 IU/day); and l-carnitine (3000 mg/day), as well as the initiation of gluten-free diet (GFD). Eight months following the start of treatment, regression of the clinical symptoms of axonal polyneuropathy and cognitive deficiency was observed (Fig. f). During the next neurological examination, polyneuritic hypoesthesia was observed at the level of the lower third of the legs with full normalization of thermoception and vibrational sensation. In the upper limbs, hyperesthesia (to the level of the wrist joints) in the distal phalanges occurred, and signs of hyperpathy appeared. The trophic status of the cutaneous lower extremities returned to normal, and previously nonhealing wounds epithelized. Cognitive function was normalized (MMSE score of 28; FAB score of 18; and a MoCA score of 28). The level of recombinant TG2 IgA antibodies decreased to 13.0 IU/ml.

pmc-8684250-1

A 70-year-old male, diagnosed with CTEPH, was hospitalized for PEA. He had post-exercise exhaustion and shortness of breath for almost 2 years, and experienced a sudden dizziness with visual rotation and syncope. Despite the medical therapy, the clinical symptoms gradually worsened. Echocardiogram showed a dilated and poorly functioning right ventricle, as well as a small left heart with normal systolic and diastolic function (Fig. -A1, A2)(Tricuspid annular plane systolic excusion (TAPSE) 9.6 mm, left ventricular ejection fraction (LVEF) 64%, average E/E′11.94, lateral E′12.1 cm/s,tricuspid regurgitation (TR) velocity 2.5 m/s). Ventilation/perfusion scan and computed tomography angiogram confirmed the presence of CTEPH at the sub-segmental levels. After the patient was induced, the initial pulmonary arterial pressure (PAP) was 93/46(63) mmHg, and preoperative right radial artery blood pressure (ABP) was 120/88 mmHg. Near infrared spectroscopy (NIRS) monitoring presented the basic cerebral regional oxygen saturation (rSO2) range from 60 to 65%. After median sternotomy, the ascending aorta and both vena cava were cannulated regularly, and CPB was initiated. After the initiation of CPB, the mean PAP (mPAP) decreased to the range from17 to 31 mmHg. Aortic cross-clamping and blood cardioplegia were administered during pulmonary arteries dissociation. Then, the removal of thickened arterial intima and old organized thrombi was completed under deep hypothermic (22 °C) low flow (DHLF) and deep hypothermic circulatory arrest (DHCA). NIRS fluctuates from 55 to 60% during DHLF and DHCA. After the surgical procedures, full flow was restored, heart rebeated, and the patient was gradually rewarmed to normal. Norepinephrine (0.05μg/kg.min), epinephrine (0.02μg/kg.min), and isoproterenol (0.02μg/kg.min) were used to maintain stable hemodynamics. Transesophageal echocardiogram (TEE) showed good systolic and diastolic heart function. However, during the first attempt to discontinue CPB, the PAP increased rapidly to 63/35(43) mmHg, with unstable hemodynamic (ABP 70/40 mmHg), and TEE suggested right heart insufficiency, accompanied with normal left ventricular function. Then, CPB was resumed immediately. After assisting for another 45 min and increasing the dosage of vasoactive drugs (norepinephrine 0.06μg/kg.min, epinephrine 0.05μg/kg.min, isoproterenol 0.05μg/kg.min), the separation failed again, just the same as the first time. Considering that severe residual PH combined with right heart dysfunction are the main reasons for the failure of CPB weaning, ECMO was adopted. Consequently, 19F arterial cannula and 22F venous cannula were inserted into the right femoral vessels, and femoral VA-ECMO was initiated with a flow of 3.0 ~ 3.5 L/min. On arrival at the intensive care unit, ECMO flow rate was 3.5 L/min, and severe PH (PAP 56/25 mmHg) persisted with low ABP (70/55 mmHg). Echocardiography revealed significant decrease of biventricular function (Fig. B)(TAPES4mm, LVEF28%, average E/E′15, lateral E′6.7 cm/s, TR velocity 4.1 m/s) on postoperative day (POD) 1, indicating the patient developed severe secondary left ventricular dysfunction on the basis of right ventricular dysfunction, during ECMO support. The postoperative troponin-T(C-TNT) increased gradually (Fig. ), which suggested the myocardial injuries occurred. Hence, comprehensive measures were adapted: ECMO flow rate was reduced from 3.5 L/min to 2.5 L/min to decrease left ventricular afterload while maintaining systemic perfusion, norepinephrine (0.1μg/kg.min), epinephrine (0.06μg/kg.min) and isoproterenol (0.06μg/kg.min) were increased to ensure coronary perfusion, inhaled nitric oxide and treprostinil were administered to relieve PH. Besides, tidal volume was reduced to 6 ml/kg, and PEEP (5 cmH2O) was initiated to achieve lung protective ventilation. Oxygen flow rate was increased from 2 L/min to 6 L/min, with oxygen concentration raised to 47% for myocardial oxygen supply improvement. Moreover, atrial septostomy was carried out to decompress the right ventricle, so as to reduce the PAP. Consequently, mPAP decreased to 10 mmHg gradually, and the cardiac function improved slowly. On POD 7, echocardiography revealed a normal sized heart with acceptable ventricular function (Fig. C). In this condition, ECMO was discontinued successfully, with satisfactory BP (90 ~ 120/50 ~ 80 mmHg), and normal PAP (mPAP 10-12 mmHg). The postoperative echocardiography data is shown in Table . The postoperative course was complicated by unexpected brain ischemia and luminal infarction, which required tracheostomy on POD 13. Finally, the patient’s family decided to transfer to local hospital for treatment On POD 16.

pmc-8684262-1

A three-month-old male infant presented with stridor and failure to thrive. He was delivered vaginally at full-term (birth weight 3.5 kg) and had an uncomplicated neonatal course. His parents reported that he had noisy and difficult breathing a few days after birth, which worsened over time and was associated with episodes of cyanosis and poor bottle feeding. A general pediatrician saw him at one month of age for stridor and poor weight gain, assumed a diagnosis of laryngomalacia, and advised the parents to increase the frequency of his feed. After that, his parents sought medical advice several times, including emergency department visits for significant respiratory distress, increasing stridor, and failure to thrive. He was then referred to our neurology clinic to assess hypotonia. No workup was performed, and he was not hospitalized before the referral. Physical examination revealed inspiratory stridor, suprasternal and subcostal retractions, tachypnea, and bilaterally reduced air entry. His oxygen saturation, which was 93% in room air, and improved slightly after oxygen supplementation. His weight at presentation was 4.2 kg, falling below the 3rd percentile of the WHO growth chart. No dysmorphic features were present. Chest X-ray and regular laboratory test findings were normal, including serum electrolytes, complete blood counts, renal and liver functions, thyroid hormone levels, and blood gas analysis. The patient was taken to the operating room for an airway assessment based on the above findings. The patient underwent flexible laryngoscopy, which revealed a cystic mass measuring approximately 2 x 3 cm in size, arising from the lingual surface of the epiglottis and significantly occluding the laryngeal inlet (Figure ). Direct laryngoscopy and bronchoscopy under general anesthesia were promptly performed to evaluate the extent of the cystic lesion. The vocal cords, subglottic area, and trachea were observed to be normal. A thyroglossal cyst and retention cyst were initially considered as the differential diagnoses. However, based on clinical, endoscopic, and later histological findings, a vallecular cyst was established as the final diagnosis. Microlaryngoscopic marsupialization was performed by the ENT surgeon to remove the cyst, which drained serous fluid. A biopsy of the cyst wall revealed the presence of connective tissue covered with non-keratinizing squamous epithelium with vascular congestion and chronic inflammation, suggestive of a vallecular cyst. Postoperatively, the patient was feeding well and showed a complete resolution of his symptoms. He remained asymptomatic at the follow-up visits at four and seven months. He quickly gained weight within a few months, reaching 5.5 kg at four months and 8.4 kg at seven months of age, indicating that the child’s weight had increased from below the 3rd percentile to the 50th percentile.

pmc-8684306-1

A 56-year-old hypertensive gentleman presented with worsening right eye pain, redness, and lid swelling associated with double vision for six weeks (Figure ). He was initially treated as conjunctivitis at a primary care center with topical antibiotics, but then later referred to the ophthalmologist for persistent right lid eye swelling, redness, chemosis, and visual impairment. The patient recalled a past history of a motor vehicle accident in which he sustained a mild head injury with scalp laceration about 20 years ago. He had bilateral visual acuity of 6/9. His right eye was proptosed with the presence of grade 1 relative afferent pupillary defect (RAPD). It was swollen, tender with palpable thrill, and an audible bruit was present. Slit-lamp examination revealed generalized episcleral congestion with corkscrew vessels (Figure ) and raised intraocular pressure (IOP) of 28 mmHg. Both optic discs and posterior poles were normal. An urgent computed tomography angiography (CTA) demonstrated an engorged right superior ophthalmic vein (SOV) (Figure ) and bulky right CS. The left SOV was prominent with a similar contrast enhancement to the internal carotid artery. He then underwent a digital subtraction angiography (DSA) which confirmed the presence of the right direct CCF. After an urgent successful embolization, his ocular symptoms resolved fully with normalized IOP and optic nerve functions.

pmc-8684306-2

A 65-year-old diabetic, hypertensive lady with hyperlipidemia presented with right eye blurring of vision associated with redness, lid swelling, and double vision for one month (Figure ). She was first treated for conjunctivitis by a private practitioner with topical antibiotics, who then referred to us for worsening ocular symptoms. Further history taking revealed a mild head trauma and facial injury in a motor vehicle accident about two months ago. A brain computed tomography (CT) scan was done and reported as normal. Her vision was 6/9 in both eyes, ocular examination showed the presence of grade one RAPD, proptosis, ophthalmoplegia, and audible bruit. Slit-lamp examination showed the presence of conjunctival chemosis and corkscrew vessels (Figure ) with IOP measured at 29 mmHg on the right eye. Both posterior segments of the eyes were normal. The patient underwent an urgent CTA, which showed enlarged and early filling of the right SOV (Figure ) with the early arterial enhancement of the right CS. The diagnosis of right direct CCF was confirmed with DSA and embolization was successfully performed to resolve the ocular sequelae.

pmc-8684306-3

A 49-year-old woman with underlying hypertension, was initially treated for right eye infective conjunctivitis. She was then referred for persistent and worsening eye redness for three weeks (Figure ). She denied any blurring of vision, lid swelling, or trauma. Her vision was 6/9 in both eyes with normal IOP. The dilated right episcleral vessels were blanched with topical phenylephrine 2.5%, hence she was treated for episcleritis with topical steroids. Her ocular condition improved after two weeks except for right eye IOP, which was raised to 24 mmHg. A topical IOP lowering agent was initiated for the working diagnosis of steroid responder. On subsequent review a week later, she was noted to have proptosis, orbital bruit, corkscrew vessels (Figure ) with controlled IOP and normal optic nerve functions. B-scan ultrasonography showed dilated SOV (Figure ) in the right eye. The patient underwent an urgent CTA that demonstrated the dilated right SOV (Figure ). Her DSA further confirmed the diagnosis of right indirect CCF. All the ocular features resolved following a successful embolization.

pmc-8684330-1

We present the case of a 74-year-old man who presented with a sudden onset of painless horizontal diplopia worse with a left-directed gaze. The double vision was aborted by occluding either eye. With eye-straining, he developed a dull bitemporal headache. He denied any vision loss, dysarthria, dysphagia, chewing difficulty, neck weakness, or breathing difficulty. A visit to the ophthalmologist confirmed a normal ocular funduscopic examination and left sixth nerve palsy. His condition remained static until he presented to the neurology clinic one month later. Past medical history was significant for bilateral below-knee amputations due to peripheral vascular disease secondary to smoking, which he quit many years ago. Otherwise, he was in relatively good health. He denied the use of any medications including antiplatelet therapy, cilostazol, statins, or anti-hypertensives. He also denied any constitutional symptoms such as fatigue, myalgias, muscle wasting, fevers, or joint pains. On examination, the patient appeared alert, oriented, well-nourished, and in no apparent distress. Blood pressure was recorded at 134/80 mmHg, a pulse at 64 beats per minute, and respiratory rate at 12 per minute. The patient refused to be weighed. His speech was of normal tone, volume, and prosody without any hint of dysarthria or fatigability. Cranial nerve examination revealed no facial weakness with symmetric smile, intact whistling, and no difficulty blowing his cheeks. There was an obvious left lateral rectus paresis upon assuming left gaze (Figure ). Vertical gaze was unaffected, and the pupils were spared. Masseter, genioglossus, and pterygoid function were preserved with intact jaw closure, deviation, and opening. The gag reflex was brisk. Neck flexion and extension showed adequate movement against resistance. Power in the arms was graded at 5/5 in all muscle groups with the medical research council (MRC) grading scale. Bilateral below-knee-amputation was noted, with preservation of bilateral hip flexion, adduction, and abduction. Deep tendon reflexes in the upper extremities were preserved with normal finger-to-nose coordination. A magnetic resonance imaging (MRI) of the brain with and without gadolinium enhancement revealed no lesion of the brainstem or cavernous sinus, and magnetic resonance angiography (MRA) revealed no cavernous sinus aneurysm. An MG panel for AChR modulating, binding, and blocking antibodies was negative. Striational antibodies were negative. A MuSK-antibody titer was high at 1.6 units per milliliter (mL); positive is 1.0 or higher. A sedimentation rate was normal. Based upon the negative MRI and MRA of the brain findings, the ocular manifestations, positive MuSK serology, a diagnosis of MuSK-ocular MG was made. A repetitive nerve stimulation (RNS) test and single-fiber electromyography (SFEMG) test were not scheduled. A trial of pyridostigmine at a dose of 60 milligrams (mg) three times daily was ineffective. The patient opted against therapy with prednisone and/or rituximab, and he preferred wearing an occlusive eye patch. The patient was advised about the potential for bulbar weakness and myasthenic crisis.

pmc-8684331-1

Chief complaint Our patient is a 65-year-old male who reported severe and progressive abdominal pain of three days’ duration. History of present illness The patient was admitted for stomach pain and lack of bowel movements for three days. The patient’s abdominal pain became progressively worse over the two days prior to admission. The patient reported that the pain is sharp, localized to the left side of his abdomen, and worse with movement. The patient also reports nausea but no vomiting. The patient denied any associated chest pain, shortness of breath, or fever/chills. Abdominal X-rays revealed small bowel dilation; CT scan conducted hours later revealed SBO. The patient also reported a long history of tenderness and a mass at the side of his past hernia repair. Past medical history The patient’s past medical history is significant for an open ventral hernia repair with mesh approximately four years prior to this encounter (2017), as well as multiple instances of SBO since the most recent of which resolved non-operatively some 10 months prior (October 2020) to this encounter. Examination On examination, the patient was found to have abdominal tenderness to palpation on the left side with rebound, severe tenderness at the umbilicus with a palpable mass, and the patient was unable to tolerate nasogastric tube (NGT) placement. The examination was otherwise unremarkable. Investigations Both abdominal X-rays and CT were obtained. The X-rays showed small bowel dilation and adynamic air-fluid levels, with suspicion of either ileus or partial SBO (Figure ). CT showed decompressed distal and terminal ileum consistent with SBO, as well as soft tissue thickening within the central abdomen deep to the umbilicus in a region of dilated and decompressed ileum, which could possibly be the cause of obstruction and perhaps due to adhesions or mass (Figure ). No recurrence of hernia was noted. Preoperative diagnosis Based on the patient’s history and associated investigations/imaging, the preoperative diagnosis was SBO. Treatment The patient underwent exploratory laparotomy, release of SBO with removal of abdominal wall mesh and Jackson-Pratt (JP) drain placement. An incision was made directly over the site of the previous mesh that was around the site of the umbilicus. Dissection was taken down to the deep subcutaneous tissue. The peritoneum was then opened superior to the mesh. The mesh was then dissected out anteriorly and circumferentially, and then the incision was taken down inferiorly as well. There was small bowel tightly adherent to this mesh, the evident source of the obstruction, and this was freed from the mesh (Figure ). The mesh was then completely removed; the small bowel could now be clearly identified, and the site of obstruction was clearly released when it was freed from the mesh. The adhesions were carefully lysed. The small bowel was carefully examined to confirm that the site of obstruction was clearly released. The mesh did not erode into the bowel, and at this time a resection was not indicated. A JP drain was left in the abdomen and the incision was closed. A photograph of the mesh removed from the patient was taken after the conclusion of the procedure. Postoperative diagnosis The postoperative diagnosis was SBO due to adhesions with abdominal wall and ventral hernia mesh. Outcome/progress After recovering from anesthesia, the patient was followed in an inpatient setting for four additional days, the course of which was uneventful. The patient was discharged home on the fourth postoperative day and followed in an outpatient setting.

pmc-8684351-1

This is an otherwise healthy 35-year-old male who was brought to our emergency department by ambulance after being crushed underneath a car; while performing some repairs on the undercarriage the jacks failed and the vehicle fell directly onto his head. Emergency personnel at the scene reported he was alert and coherent, but had obviously sustained significant facial trauma and he was intubated for airway protection. On arrival to our institution, head, spine, chest, abdomen, and pelvis computed tomography (CT) scans were obtained in accordance with standard trauma protocols. Multiple, comminuted facial and basilar skull fractures, with a large volume of pneumocephalus, though without any evidence of intracranial hemorrhage, were found (Figure ). Spinal column imaging revealed intradural air spanning C1-C4 and L3-S1 levels (Figure and 1C). There was no imaging evidence of direct spinal trauma, nor any evidence of pneumothorax or pneumoperitoneum. Neurologic examination revealed an intubated young male with a Glasgow Coma Scale (GCS) of 8T, given that he opened his eyes briefly when stimulated, and displayed purposeful and localizing movements in all extremities but did not follow commands. He had no apparent focal neurologic deficits. He had multiple facial ecchymoses and lacerations as well as dried blood at the nares and in both ears, though without obvious rhinorrhea or otorrhea. In accordance with institutional policy, head-injured patients with depressed GCS are admitted to the trauma intensive care unit (ICU) and head imaging is repeated after 6 hours. In this case, a second head CT was unchanged from the first. His GCS improved rapidly and he was extubated 9 hours after admission. Repeat neurologic examination revealed delayed development of a right facial nerve paresis for which he was prescribed a two-week course of dexamethasone without significant improvement noted by the time of discharge. He otherwise remained without strength or sensation deficits in his extremities. He was discharged home in good condition on post-injury day 3.

pmc-8684351-2

This is an otherwise healthy 25-year-old male who was brought to our emergency department by ambulance after a fall of 8-10 meters; while leaning against the railing of a third-story balcony he lost balance and fell backward over the rail to the ground below. Emergency personnel at the scene found him comatose and pulseless. After several rounds of cardiopulmonary resuscitation (CPR) and rapid sequence intubation, he was stabilized for transport to our hospital. On arrival to the emergency department, he had developed refractory hypotension and lost a carotid pulse for which he again required a round of CPR before return of spontaneous circulation. Once resuscitated and stabilized, head, spine, chest, abdomen, and pelvis CT scans were obtained. He was found to have bilateral temporal bone fractures as well as a transverse clival fracture, as well as diffuse but predominantly right-sided traumatic subarachnoid hemorrhages with scattered locules of pneumocephalus (Figure ). Spinal imaging revealed intradural air at the L3-L4 levels (Figure ). There was no imaging evidence of direct spinal trauma, nor any evidence of pneumothorax or pneumoperitoneum. Neurological examination on arrival revealed an intubated young male with a GCS of 6T: he did not open his eyes nor display any localizing movements but was able to withdraw all of his extremities from painful stimuli. He had dried blood in both ears but was otherwise without otorrhea or rhinorrhea. He was admitted to our trauma ICU and an intracranial pressure monitor was placed and monitoring was noted as normal. A follow-up head CT was unchanged. His GCS improved rapidly and he was extubated 11 hours after admission, and his intracranial monitor was removed. Repeat neurological examination noted that he was coherent and oriented, but amnestic to his injury. He had developed a left facial nerve paresis and was prescribed a two-week course of prednisone without significant improvement noted by the time of discharge. He remained without strength or sensation deficits of his extremities. Pelvic injuries necessitated operative fixation on hospital day 2. He was discharged to rehabilitation in good condition on post-injury day 8.

pmc-8684352-1

A 54-year-old male with a history of alcohol abuse presented to the emergency with acute-onset, diffuse, cramping abdominal pain, worst in the epigastrium and lasting one day. He denied fever, vomiting, loss of appetite or weight loss, diarrhea, constipation, or rectal bleeding, or any prior similar episodes. He had no prior abdominal surgeries. On examination, he was in distress and had moderate guarding and generalized tenderness with hypoactive bowel sounds. He was afebrile. Laboratory evaluation showed microcytic anemia and thrombocytopenia on complete blood count, hypokalemia on basic metabolic profile, and a normal lipase level (Table ). Abdominal X-ray showed an evolving small bowel obstruction (Figure ), which was confirmed by a CT scan of the abdomen and pelvis with contrast (Figure ). On the same CT scan series, a urachal remnant with a superimposed mass lesion was depicted (Figures , ). A decision was made to go forward with an emergent surgery to release the small bowel obstruction. After receiving a platelet transfusion, the patient underwent an exploratory laparotomy. He was found to have a high-grade small bowel obstruction due to an extensive mass concerning for a malignancy. A frozen section was intraoperatively sent and read as adenocarcinoma (Figure ). An incisional biopsy of the urachal mass was also sent. The final pathology specimen was reported as a moderately differentiated urachal adenocarcinoma (Figure ) with positivity for CK20, CDX2, and CK7 (focal) stains (Figure ). The patient was staged at Stage IIID (Sheldon staging) due to the spread to local viscera other than the bladder. The tumor was deemed unresectable due to the involvement of multiple loops of the small bowel and the mesentery of the small and large bowels. Systemic chemotherapy with 5-fluorouracil (5-FU), folinic acid, and oxaliplatin (modified FOLFOX-6) was initiated. The patient has received six cycles of chemotherapy so far. He has tolerated chemotherapy well enough and is still awaiting additional imaging to evaluate the response to therapy.

pmc-8684359-1

The patient is an 81-year-old male with medical comorbidities of hypertension, coronary artery disease, and non-melanoma skin cancer who presented with a new cutaneous manifestation. He reported a two-week history of a progressively enlarging asymptomatic lesion on his left chest. Five months prior he had a CABG procedure with internal thoracic artery harvesting without the use of fluoroscopy. Physical examination revealed a well-demarcated erythematous, indurated plaque overlying the previous harvest site of his left internal thoracic artery (Figure ). A punch biopsy was performed to further classify this new development; histopathologic evaluation revealed an uninvolved epidermis with diffuse dermal sclerosis and underlying panniculitis (Figure , Figure , Figure ). In the absence of any prior history of scleroderma (cutaneous or systemic), these localized sclerodermatous changes were attributed to recent arterectomy. Given the asymptomatic nature of the plaque, the management options were discussed with the patient, and he opted for observation during his bi-annual skin examinations.

pmc-8684360-1

The patient is a 28-year-old male with prior history of a grade 3 astrocytoma, who presented to our emergency department (ED) after having a general tonic-clonic seizure (GTC). Initially, his disease was appreciated four years prior when he presented with a GTC and was found to have a grade 3 astrocytoma of the left occipital lobe (Figure ). He underwent maximal safe resection followed by adjuvant EBRT to 45 Gy in 25 fractions at an outside institution. Due to reasons outside the patient’s control, he received only two cycles of adjuvant temozolomide following EBRT. He developed disease recurrence, presenting as a GTC six months prior to this ED presentation, where imaging demonstrated tumor progression with increased extension into the parietal lobe (Figure ). He subsequently underwent a second maximal safe resection later that month. Final pathology returned as GB. Follow-up imaging four months afterward demonstrated disease progression and he was started on bevacizumab as well as a tumor treatment field (TTF) device. He unfortunately only tolerated TTFs for one month, ending one month prior to the ED presentation. Upon admission to our hospital from the ED, MRI demonstrated progression of disease in the left occipital-parietal lobes with extension into the splenium and anterior-inferior extension into the left thalamus and basal ganglia (Figure ). His physical exam was notable for mild right-hand weakness, but he was otherwise neurologically intact. Despite changes to his antiepileptic medication, he had seizure recurrence a few weeks following admission. Presuming that the area of tumor recurrence received a definitive dose in the past, the consensus decision was to proceed with repeat maximal safe resection with GammaTile placement. A dose of 60 Gy was prescribed to a 5 mm depth using a total of eight tiles, each containing four Cesium-131 3.5U seeds, to line the post-operative cavity volume of 17.6 cc. A significant portion of the occipital-parietal disease was debulked, with final pathology again demonstrating a grade 4 astrocytoma with molecular studies indicating an IDH-mutated, ATRX mutated, and MGMT promoter methylated phenotype with hypermutation. Postoperatively he was noted to have right upper and lower extremity weakness/spasticity with right foot drop and mild right face weakness. He required a cane to assist with ambulation and reported word-finding difficulties and decreased short-term memory. He was planning to start adjuvant temozolomide; however, he developed a severe GTC with increased muscle weakness and altered mental status two months later. MRI following this episode demonstrated mildly increased enhancement to the tissue surrounding the surgical bed with the progression of disease in the splenium and left thalamus/basal ganglia (Figure ). Given this symptomatic disease progression, a treatment plan was made to take the progressive regions of disease outside the irradiated GammaTile volume to 35 Gy in 10 fractions. As shown in Figure , an initial planning target volume (PTV) was delineated consisting of the T1 post-contrast-enhancing disease with a 5 mm margin. The volume that received greater than 35 Gy from the GammaTile treatment was excluded from the PTV. The PTV was then separated into two portions by subdividing the remaining volume between tissue that received less than 17.5 Gy (PTV1), and that which received 17.5-35 Gy (PTV2). Using a volumetric modulated arc therapy plan with five arcs, one non-co-planar, a homogeneous dose of 35 Gy in 10 fractions was delivered to PTV1. This dose was calculated to have a biologically equivalent dose in 2 Gy fractions (EQD2) of 45 Gy. Dose painting gradually decreased the dose from 35 Gy to as low a dose as achievable approaching the resection bed border of PTV2 (Figure ). A composite of the GammaTile dose volume (Figure ) with a dose delivered from PTV1 and PTV2 resulted in a homogeneous dose of approximately 50 Gy EQD2 to the residual disease extending into the splenium and the left thalamus/basal ganglia (Figure ). Digital imaging and communications in medicine (DICOM)-RT data from the initial 45 Gy delivered from the outside institution were obtained, and cumulative dose to critical organs at risk (OARs), including the brainstem, ocular structures, and cochlea, were within established constraints. Due to the hypermutation phenotype of his tumor, the patient was started on CCNU (100 mg/m2) and completed his EBRT with no issue or progression of his current neurological symptoms. He was last seen in follow-up by our team three months after his most recent EBRT, at which point he reported significant improvement in the right leg tremors/spasms and improved headache. He demonstrated decreased right foot drop but continued to have word-finding difficulties and short-term memory deficits. He has not developed any new areas of muscle weakness or paresthesia, visual loss, or other forms of altered sensoria. The current plan is to complete six cycles of CCNU with alternative systemic therapy thereafter upon disease progression. While temozolomide could be used to this effect, the high mutational burden found in his most recently resected disease would permit entry into currently available trials of immunotherapy.

pmc-8684363-1

A 60-year-old female was referred from the emergency department with a foreign body sensation in the throat, dysphagia, and odynophagia. The symptoms developed while the patient was having her lunch. She had no other related gastrointestinal complaints (i.e., hematemesis, drooling, or vomiting) or airway-related complaints (i.e., choking, cyanosis, cough, dyspnea, or hemoptysis). The patient’s medical and surgical histories were only significant for bronchial asthma, dyslipidemia, fibromyalgia, and hypertension. She was hemodynamically stable and saturating well on room air with no signs of respiratory distress. Physical examination was unremarkable except for mild tenderness over the anterior neck above the level of the thyroid cartilage. A lateral neck soft tissue X-ray confirmed the presence of a foreign body in the hypopharynx with a linear radiolucency in the retropharyngeal space representing free air (Figure ). A neck computed tomography (CT) scan demonstrated a linear hyperdense foreign body in the hypopharynx with free air along the retropharyngeal space representing a concealed perforation (Figure ). The patient was admitted for endoscopic examination under general anesthesia and foreign body removal. The patient was intubated using a flexible fiberoptic bronchoscope to avoid dislodging the foreign body. During fiberoptic intubation, a whitish plastic foreign body was found in the hypopharynx, which was removed using foreign body forceps under endoscopic guidance. Examination post foreign body removal showed a small wound in the posterior pharyngeal wall, which represents the site of the perforation (Figure ). The examination was completed using rigid esophagoscopy, which showed a normal intact esophagus. Following the procedure, the patient was treated conservatively with close observation, strict nasogastric tube (NGT) feeding, analgesics, and intravenous piperacillin/tazobactam 4.5g every 8 hours for seven days. An upper gastrointestinal series using Gastrografin (Bayer, Leverkusen, Germany) was performed after a week of the incident and showed a normal contrast passage through the hypopharynx and esophagus without any evidence of leakage. Flexible nasopharyngeal endoscopy was repeated and demonstrated intact nasopharynx, oropharynx, with a small and almost healed posterior pharyngeal wall perforation. The patient was allowed to resume oral feeding and was discharged home in a stable condition.

pmc-8684398-1

A 67-year-old male with a past medical history of coronary artery disease (CAD) with two stents in the first diagonal branch of the left anterior descending artery six years before admission, hypertension, hyperlipidemia, glaucoma, and previous anaphylaxis to nuts presented to the emergency department (ED) with anaphylaxis after eating a nut-containing bar. Shortly after ingestion, he called emergency medical services (EMS) for hives and difficulty breathing. He was tachypneic, diaphoretic, and nauseous on arrival to the ED, tripoding with a hot-potato voice, and had oropharyngeal angioedema. Vital signs showed a temperature of 98.5 (F), heart rate of 73 beats per minute, blood pressure of 140/89 mmHg, respiratory rate of 19 cycles per minute, and oxygen saturation of 95% while on 6 liters of oxygen via nasal cannula. After receiving epinephrine x3, methylprednisolone 125mg x2, and diphenhydramine the patient was still symptomatic. Epinephrine infusion was commenced at 1 microgram/minute for refractory anaphylaxis. ENT observed uvula edema without laryngeal edema on two separate fiberoptic exams. Given voice changes in the ED, the patient was admitted to the ventilator unit for monitoring of biphasic anaphylactic reaction. He was titrated off the epinephrine drip for lack of hemodynamic instability congruent with anaphylaxis. Initial laboratory investigations showed a troponin of 0.03ng/ml at 4.5 hours post-ingestion which increased to 2.98 and 3.08 at 18 and 23 hours post-ingestion, respectively. The patient initially denied chest pain; however, when informed of his cardiac enzyme elevation, he retrospectively endorsed intermittent, non-radiating, mid-sternal chest pressure that was 5/10 in intensity after receiving epinephrine, which decreased to 2/10 in intensity within 24 hours. Electrocardiogram (EKG) at 22 hours post-ingestion showed sinus rhythm, left anterior fascicular block, and no ST-segment changes (Figure ). He was started on aspirin, heparin infusion, and atorvastatin. An echocardiogram showed a normal left ventricular (LV) systolic function with an ejection fraction of 56-60%. Additionally, LV segmental wall motion abnormalities, hypokinesis in the mid inferolateral segment were also found. Chest X-ray did not show any abnormalities. Elective coronary angiogram (Figure ) was significant for single-vessel disease. The left main, left circumflex, and right coronary arteries were normal. Of note, a patent stent in the inferior branch of the diagonal artery with 30% in-stent restenosis and a jailed superior branch of the diagonal with 95% ostial lesion was also revealed. Serial troponin monitoring showed a downward trend of 2.78 and 2.0ng/ml, at 30 and 39 hours post-ingestion, respectively. The patient's chest pain resolved, and he was discharged to follow up with the outpatient cardiology clinic.

pmc-8684410-1

A 74-year-old male with a history of two transient ischemic attacks was brought into our facility for altered mental status after being found unconscious by a relative. His social history was significant for 55 pack-years of smoking. Due to his mentation on arrival, no further history was obtained. Vital signs were normal on admission. Physical examination on admission showed non-responsiveness to sternal rub, dry mucous membranes, decreased skin turgor, and thick white plaques around the corners of his mouth. Examination of the extremities showed 1+ bilateral lower leg edema, and pulmonary examination revealed right-sided wheezes and rales. On admission, the patient had an elevated blood glucose of 662 mg/dL (normal: 70-110 mg/dL), an anion gap of 15, ß-hydroxybutyrate of 1.86 mmol/L (normal: 0.02-0.27 mmol/L), point-of-care (POC) lactate of 3.3 mmol/L (normal: 0.5-2.0 mmol/L), serum potassium of 3.8 mEq/L, urine volume of 850 mL, and no ketones on urinalysis. The arterial blood gas (ABG) showed a pH of 7.48, HCO3 of 24.6, and PCO2 of 33 meq/L. The slightly elevated anion gap on admission is likely multifactorial. It could have been caused by the increase in the negative charge for albumin and enhanced production of lactate seen in metabolic alkalosis []. Conversely, it is also possible that scant ketones, which are produced in a hyperosmolar hyperglycemic state, as seen by mildly elevated β-hydroxybutyrate and the absence of ketones in the urine, could have contributed to the elevated anion gap []. Additionally, the patient had hypernatremia (sodium of 185 mEq/L corrected for hyperglycemia), acute kidney injury (blood urea nitrogen [BUN] of 49 mg/dL, creatinine [Cr] of 1.55 mg/dL, from a previous baseline Cr of 1.01 mg/dL), and hemoconcentration (hemoglobin [Hb] 17.1 g/dL, hematocrit [Hct] 51.6%). Chest X-ray indicated a potential right lower lung zone infiltrate. Computed tomography (CT) of the chest indicated right lower lobe mass or consolidation, with multiple mediastinal and hilar masses as well as enlarged left axillary nodes compatible with lymphadenopathy, suggestive of malignancy and metastatic disease (Figures , ). CT of the abdomen showed heterogeneous liver attenuation but could not differentiate between nonocclusive disease and metastatic disease. Adrenal nodules and kidney nodular densities were also present (Figure ). CT of the brain showed a suprasellar mass measuring 1.2 x 1.1 x 0.9 cm (Figure ). The patient was started on half normal saline and insulin, and the acute kidney injury significantly improved on day 3; however, no significant improvement in sodium level was noticed after correction for elevated glucose levels (Figure and Table ). Additional investigations for the refractory hypernatremia showed a urine osmolarity of 699 (normal: 50-1,400), serum osmolarity of 360 (normal: 280-301), urine sodium of 10 mEq/L (normal: 20 mEq/L), serum AM cortisol of 61.3 ug/dL (normal AM: 6.2-19.4 ug/dL), 1-mg dexamethasone suppression test cortisol of 6.06 ug/dL (normal: <1.8ug/dL) and ACTH of 228 pg/mL (normal: 7.2-63.3 pg/mL) (Table ). MRI of the brain revealed a 1.1 x 1.2 x 1.1 cm enhancing lesion of the optic chiasm without evidence of mass effect (Figure ) and small lymph nodes in deep portions of the bilateral parotid glands that were potential metastasis. Throughout the admission, the patient’s arterial blood gas (ABG) showed a primary respiratory alkalosis with secondary metabolic alkalosis (pH of 7.48, HCO3 of 24.6, PCO2 of 33 meq/L), which was persistent until discharge (pH of 7.48, HCO3 of 27.6 meq/L, PCO2 of 37 mmHg). Additional endocrine investigations demonstrated an follicle-stimulating hormone (FSH) of 0.3 miU/L (normal: 1.5-12.4 miU/L), luteinizing hormone (LH) < 0.3 miU/L (normal: 1.7-8.6 miU/L), testosterone of 27 ng/dL (normal: 264-916 ng/dL), thyroid-stimulating hormone (TSH) of 0.01 u/iU/L (normal: 0.34-5.60 u/iU/L), and prolactin of 9.7 ng/mL (normal: 4.0-15.2 ng/mL). The plan was to obtain a lung biopsy to determine whether the mass was cancerous or not and to conduct a high dexamethasone suppression test for ectopic ACTH production. However, the patient declined further workup or treatment, opting for hospice instead. Despite initial fluid resuscitation with half normal saline followed by dextrose water, the hypernatremia did not correct. The hypernatremia later resolved after the patient was started on desmopressin on day 7 of admission. The patient was sent home on hospice and was advised to increase his water intake.

pmc-8684438-1

A 45-year-old transgender male with a history of Guillain Barre Syndrome and heterozygous Factor V Leiden underwent gender reassignment surgery, including phalloplasty, mastectomy, and vaginal eversion. The phalloplasty was complicated by postoperative penile artery thrombosis, recurrent episodes of extended-spectrum beta-lactamase (ESBL) Klebsiella urinary tract infection (UTI) from a chronic suprapubic catheterization, and colovesical fistula. The patient presented with lethargy, shortness of breath, 15 lb weight gain, and lower extremity edema for the past three months. Physical exam revealed tachycardia, holosystolic murmur at the apex, faint bibasilar crackles, and right lower extremity edema. Laboratory work showed leukocytosis (WBC 11.6 K/uL), creatinine 0.7 mg/dL, hemoglobin 8.8 g/dL, B-type natriuretic peptide of 610 pg/mL, and D-dimer of 3469 ng/mL. CT chest revealed cardiomegaly, pulmonary edema, bilateral lower lobe consolidations, and pleural effusions, a large pericardial effusion, and a 5x10 cm perisplenic abscess found to be secondary to septic emboli. Echocardiogram showed a 2.1 cm mobile vegetation on the anterior leaflet of the mitral valve (Figure ), moderate-severe mitral valve insufficiency (Figure ), ejection fraction of 65%, markedly dilated left atrium, elevated peak pulmonary artery pressure at 57 mmHg, and large pericardial effusion without evidence of tamponade. Broad-spectrum IV antibiotics were started for infective endocarditis and diuresis for new-onset heart failure. Splenic fluid and blood cultures grew Enterococcus faecalis. He underwent subsequent cardiothoracic surgery with an On-X mechanical mitral valve (On-X Life Technologies Inc., Austin, TX). Unfortunately, the postoperative course was complicated by mediastinal thrombus formation and hemothorax requiring surgical exploration. Once stabilized, the patient was discharged and upon discharge was placed in IV penicillin G and ceftriaxone to complete six weeks of antibiotic therapy.

pmc-8684444-1

Chief complaint A 50-year-old male presented to the clinic with ongoing RLQ abdominal pain of one-month duration, associated with mild fever. History of present illness The patient was referred to the surgery clinic by his primary care physician (PCP) after experiencing ongoing RLQ pain and showing evidence of lymph node enlargement on CT imaging. At presentation, the patient reported a history of mild fever associated with RLQ pain. Two months prior to our encounter, the patient was started on an antibiotic regimen of levofloxacin with mild improvement in RLQ pain. Some mild pain symptoms continued. The patient also experienced pain while urinating and testicular pain approximately one month prior to the encounter. The patient denied any associated chest pain, shortness of breath, nausea/vomiting, or chills. The patient's heart rate and blood pressure were noted to be within normal limits. Past medical history The patient’s past medical history includes hypertension being treated with lisinopril, and diabetes mellitus being managed with metformin. Patient encounter records confirm that at some time between two and three months prior to presentation, the patient began taking levofloxacin daily. An occurence of painful rectal bleeding in 2015 prompted a colonoscopy, which revealed a colonic polyp and grade two hemorrhoids. The patient also suffered a left hand crush injury of the third and fourth digits in 2015. Examination At the time of the encounter, physical examination revealed RLQ tenderness, but was otherwise unremarkable. The patient’s heart rate, blood pressure, and other vital signs were within normal limits, and the patient was afebrile at the time of examination. Investigations The patient’s PCP ordered CT imaging, which showed an appendiceal diameter on axial image of 8mm, and a cluster of prominent lymph nodes adjacent to the appendix, the largest of which was also 8mm (Figures , ). Radiologic interpretation suggested these findings could be indicative of acute or chronic inflammation that may be an unusual presentation of chronic appendicitis. A dilated right extrarenal pelvis and proximal ureter with minimal right calyceal dilation were also seen (Figures , ). In addition, a small non-obstructing stone in the right renal pelvis was seen, suggesting a chronic ureteropelvic junction stricture. Preoperative laboratory results showed a white blood cell count of 10.4x10^3 cells/µL. Pre-operative diagnosis Based on the patient’s history of present illness and associated investigations the preoperative diagnosis was chronic appendicitis. Treatment Laparoscopic appendectomy was performed on the patient. The appendix was identified and found to be chronically scarred and chronically inflamed in appearance. The mesoappendix was taken down with Sonicision, the base transected with Endo-GIA, and delivered from the peritoneal cavity in an Endobag and sent to pathology. Post-operative diagnosis The post-operative diagnosis was chronic appendicitis. Outcome/progress After recovering from anesthesia, the patient was discharged home on the same day as his procedure with no complaints and is currently being followed in an outpatient setting. The patient continues to report complete resolution of his symptoms. Postoperative histopathology report on the specimen taken from the patient (Figure ) showed chronic lymphoplasmacytic inflammation with associated histiocytes and granulation tissue, further supporting the diagnosis of chronic appendicitis.

pmc-8684528-1

A 38-year-old woman presented with a 16-year history of ulcerative colitis being treated with mesalazine and infliximab. She had been undergoing routine colonoscopy examinations. Multiple random biopsies performed from the transverse colon to the rectum during colonoscopy suggested rectal cancer, for which she was referred to our hospital for surgery. A follow-up colonoscopy revealed the absence of the haustra between the transverse colon and rectum, without any obvious tumors. Histopathological examination of multiple random biopsy specimens obtained from the transverse colon to the rectum showed dysplasia with p53 overexpression in the rectum, which suggested cancer. We performed laparoscopic proctocolectomy and D2 lymphadenectomy concomitantly with TaTME. The procedure involved two surgical teams. We inserted five abdominal ports, and the colon was mobilized from the ileocecal region to the rectum along with laparoscopy-guided dissection of blood vessels. The rectum was mobilized in the TME plane, and the left and right neurovascular bundles were incised. Transanal surgery was performed simultaneously using the laparoscopic procedure. We used the Lone Star Retractor System (Cooper Surgical, Trumbull, CT, USA), GelPOINT path transanal access platform (Applied Medical, Rancho Santa Margarita, CA, USA), and AirSeal system (ConMed, Utica, NY, USA) to ensure active smoke evacuation to aid in the visualization of the operative field. Circumferential mucosectomy was performed with preservation of the anal sphincter muscle. We used a purse-string suture and closed the rectal lumen to prevent mucus leakage and cancer cell dissemination. Mucosectomy was performed starting from the dentate line and extending into the anal canal. The circular and longitudinal muscles were incised, and the abdominal cavity was opened (Figure ). The specimen was extracted after a slight extension of the umbilical port site. We created an ileal pouch (J-pouch) and performed an ileal pouch-anal anastomosis. Finally, we performed a diverting-loop ileostomy. The operation time was 286 minutes, and the estimated blood loss was 52 mL. Histopathological examination of the resected specimen revealed low-grade rectal dysplasia without any evidence of malignancy. It took some time to adjust to the ostomy pouch, and the patient was discharged 21 days postoperatively without any complications. The patient underwent loop ileostomy closure four months postoperatively and recovered without significant loss of the anal sphincter function. The anal sphincter function remained at four months after the second surgery. At four months after the second surgery, the patient is doing well.

pmc-8684541-1

A 77-year-old male, with a history of chronic obstructive pulmonary disease (COPD), diagnosed with left shoulder melanoma in 2015, treated by wide excision along with radiation therapy, had a relapse locally at the original site with lung metastasis (stage IIA; pT4, N0, M1b) and was BRAF negative in 2017. He was started on pembrolizumab in August 2017 with a cycle of every three weeks for treatment. Two years later, in 2019, he presented with generalized weakness, productive cough that was clear, acute on chronic worsening dyspnea, and diarrhea for the past week, with his last dose of pembrolizumab three weeks back. He denied any fever, orthopnea, or lower extremity swelling. He admitted to paroxysmal nocturnal dyspnea. He uses 3 L of home oxygen presently requiring high-flow oxygen. On exam, he had audible crackles on the right side along with diminished lung sounds throughout the right lung. His chest X-ray (CXR) showed right middle and lower lobe infiltrates along with interstitial changes. The white blood cell count was normal. His chest computerized tomography (CT), as seen in Figure , showed severe bullous changes in bilateral lungs, a small right pleural effusion, a spiculated nodule in the left lower lobe measuring 1.1 cm by 2.2 cm, thickening of the interlobular area, and interval interstitial infiltrate in the posterior segment of the right upper lobe, right middle lobe, and right lower lobe. At this time, his pembrolizumab was discontinued, and he was started on broad-spectrum antibiotics including atypical coverage. Methylprednisolone was also started. He underwent bronchoscopy with bronchoalveolar lavage to rule out infection, which showed mucosa inflammation of the right lower lobe, right middle lobe, and the anterior segment of the right upper lobe with dark yellow mucus plug seen. Bronchoalveolar lavage (BAL) cultures, viral panel, and Pneumocystis carinii smear were negative. He was discharged home in October 2019 on prednisone 40 mg b.i.d. with a plan to taper down over the next six weeks in the outpatient setting. He developed two consecutive episodes of secondary spontaneous pneumothorax in which he required chest tube placement and missed at least one week of his steroids, which lead to a flare-up of his pneumonitis and getting readmitted to the hospital in November 2019. He was restarted on steroids and followed up with an outpatient pulmonologist where his steroids were weaned in the next eight weeks. Repeat chest CT, as seen in Figure , done three months later showed near resolution of the interstitial infiltrate in the right upper, middle, and lower lobes and unchanged left lower lobe spiculated nodule. In June 2021, he was tapered down to prednisone 2.5 mg daily. His respiratory status was stable, with chest CT showing resolution of pneumonitis. In September 2021, he expired in his sleep.

pmc-8684541-2

A 64-year-old female undergoing chemotherapy and radiation for malignant mucosal lentiginous melanoma of the left gingiva (stage III; pT3, N1, M0) presented in February 2020 with fatigue and worsening shortness of breath for the last two months. She had a left modified radical neck dissection with resection of the left oral cavity. She then underwent 30 treatments of external beam radiation. After radiation was completed, she was started on nivolumab 240 mg IV every two weeks in August 2019. In January 2020, her nivolumab was held due to worsening transaminitis and thyroiditis, which presented as hypothyroidism and then hyperthyroidism after starting levothyroxine. CT abdomen was done at that time, which showed increased heterogeneous attenuation of the liver. She was started on prednisone 40 mg daily. With her history of being a current smoker of 1 ppd for the last 30 years, she admitted to a productive cough that was clear in nature, chest tightness, and orthopnea but denied paroxysmal dyspnea and fever. Chest CT without contrast, done in February 2020, as seen in Figure , showed multiple pulmonary nodules with some interstitial/ground-glass changes in the upper lobes bilaterally, right middle lobe, and right lower lobe, which were worse than her previous chest CT two weeks prior, as seen in Figure . She was diagnosed with nivolumab-induced pneumonitis. Her lab work showed a very low thyroid-stimulating hormone (TSH) level of < 0.07 along with her free triiodothyronine (T3) being normal, free thyroxine (T4) of 4.6, and negative thyroid peroxidase antibody (TPO) antibody. Levothyroxine was then stopped. She still had transaminitis. She was started on ceftriaxone and azithromycin for possible pneumonia. A higher intravenous dose of steroids was initiated. She underwent bronchoscopy with BAL with findings of erythematous bronchial mucosa of the right lower lobe. BAL results were negative, including a viral panel, Gram stain and culture, and fungal stain and culture. After increasing the steroids, she felt better, and her breathing improved. She was discharged on prednisone 60 mg daily and was recommended to follow up on an outpatient basis with oncology and pulmonology. Unfortunately, she did not follow up with either oncology or pulmonology and was lost to follow-up.

pmc-8684541-3

A 65-year-old female diagnosed with non-small cell adenocarcinoma of the right middle lobe, as seen on chest CT (stage IIA, pT2B, pN0, M0) in 2017, underwent right middle lobectomy and mediastinal node dissection three months later. The pathology report showed moderately differentiated adenocarcinoma with visceral pleural invasion and transcription termination factor 1 positive. She completed carboplatin/Alimta in 2018. In January 2019, her repeat chest CT (Figure ) showed multiple nodular masses in the right lower lobe where her original lung cancer was. A positron emission tomography (PET)/CT scan was done, which showed subpleural nodules with moderate fluorodeoxyglucose (FDG) activity, indicating relapse. At that time, she had declined a biopsy. She was started on palliative chemotherapy of carboplatin, taxol, and pembrolizumab in March 2019 and finished the regimen in May 2019. A repeat chest CT done in May 2019 showed a decreased size of her right lower lobe pulmonary nodules without evidence of progression or new distant lesions. She started pembrolizumab for maintenance therapy in June 2019. Then, her chest CT in October 2019 (Figure ) showed complete resolution of the pulmonary nodules with no evidence of progression or new lesions. However, in March 2020, her creatinine (Cr) level started to increase to 3.07 even though she was asymptomatic with no lower extremities edema. Her baseline Cr level was around 1.0-1.2. Her Cr level had increased to 5.53 in April 2020 and further workup was initiated. Her protein: Cr ratio was 1315, no monoclonal protein was identified, and antinuclear antibodies (ANA) and vasculitis profile were negative. Complement levels were normal. She subsequently underwent a kidney biopsy with pathology (Figure ) showing acute and chronic interstitial nephritis grade 3 and tubulitis. Further workup with the kidney was unremarkable. Her pembrolizumab was held toward the end of March, and she was started on a prednisone 40 mg taper. Her Cr did improve to 1.19, close to her baseline, in May 2020. She completed the steroid taper in July 2020. With the improvement of her Cr, she resumed pembrolizumab in July 2020; however, her Cr level started to increase up to 2.09. She was restarted on prednisone 20 mg daily, and after discussion with oncology, a decision was made to stop pembrolizumab indefinitely. In September 2020, she was tapered down to 10 mg daily. She eventually expired a few months later.

pmc-8684541-4

A 53-year-old female was diagnosed with metastatic melanoma (cTx, pN1b, M1) in February 2019. She originally presented with left inguinal swelling of four months duration in October 2018. Her ultrasound at that time had only shown a prominent left inguinal lymph node for which core biopsy was done in February 2019, confirming it to be melanoma. Her abdomen pelvis CT also showed bilateral inguinal lymph nodes with a lesion at the splenic lower pole. Follow-up chest CT had shown a neoplastic solid mass in the spleen. She had a left inguinal node dissection in March 2019, which was positive for melanoma with 1/22 nodes positive, the largest one being 5 cm. The PET/CT scan seen in Figure in March 2019 was positive for multiple discrete hypermetabolic foci within the spleen without abnormal foci of increased fluorodeoxyglucose (FDG) in either the liver or lungs. She underwent splenectomy in April 2019 with pathology reporting multiple foci of metastatic melanoma. She was started on pembrolizumab in April 2019. However, in January 2020, she presented to outpatient oncology with progressive generalized weakness, extreme fatigue, lethargy, myalgia, poor appetite, weight loss, and mood changes over a period of 6-8 weeks. Labs in February 2020 showed low free cortisol of 0.2 ug/dL and low adrenocorticotropic hormone (ACTH) of < 1.1 pg/mL. Her luteinizing hormone, follicle-stimulating hormone, and prolactin were normal. She was diagnosed with pembrolizumab-induced hypophysitis, and the decision was to hold her pembrolizumab. She was started on prednisone 1 mg/kg/day with gradual tapering to the maintenance dose of 10 mg daily. Repeat cortisol level done in March 2020 was within the normal range of 3.0 ug/dL. Her cortisol response to adrenocorticotropic hormone (ACTH) was also normal at 3.2 ug/dL. She then resumed pembrolizumab in March 2020. Her repeat chest CT in May 2020 was negative for any recurrent cancer. She is currently tolerating pembrolizumab, reporting good energy levels without any fatigue, myalgia, or mood changes while still on prednisone 7.5 mg daily. She finished her treatment course of pembrolizumab in April 2021. With her latest follow-up in August 2021, she did not have any recurrent disease and is in remission, remaining on prednisone 7.5 mg daily.

pmc-8684581-1

A 71-year-old lady initially presented with gradual onset of painless lower limb weakness for one week “off legs”, lower limb paresthesias and increased urinary frequency. Patient denied any recent symptoms of infective etiology. There was no recent or past history of trauma or accidents. Patient’s past medical history was unremarkable and also had no family history of significant concern. Patient was a non-smoker and teetotaler and there was no exposure to environmental factors such as industrial chemicals, radiation, heavy metals or any toxin exposures reported. Patient led an active life as a housewife (Eastern Cooperative Oncology Group [ECOG] performance status 1 before admission) and used to live with her partner. On examination she had symmetrical lower limb motor weakness in an upper motor neuron pattern with Medical Research Council (MRC) muscle power 4/5 both proximally and distally on admission. There were reduced sensations in lower limbs symmetrically to fine touch, pinprick, temperature and proprioception, initially mild but progressed to significant sensory loss over next couple of weeks with sensory level slightly below umbilicus at T11. There was relative sparing of saddle area and anal tone was patulous. There was no spinal tenderness. Her deep tendon reflexes in lower limbs were exaggerated with extensor plantar responses. Rest of the general and systemic examination was unremarkable. Her blood tests including full blood count, inflammatory markers, B12, folate, thyroid functions, calcium, liver function test and myeloma screen came back normal. Cerebrospinal fluid (CSF) analysis done on second day after admission was unyielding and non-specific with normal protein, glucose and cytology etc. She was evaluated with non-contrast MRI spine which showed focal myelopathic cord signal at the conus and at the level of T10 and T11 vertebrae (radiological differential diagnosis on MRI were B12 deficiency/inflammatory/infection) (Figure ). While being evaluated for same, she underwent a chest x-ray which was suggestive of suspicious nodules in the right lower and mid zone. This triggered further computed tomography (CT) scans with contrast which showed disseminated malignancy with metastatic lesions to anterior chest wall, liver, lungs, and a necrotic 3.5 cm nodal mass in the left gastric region. There was no obvious primary identified on the CT scan. Tumor markers cancer antigen (CA)-125, CA 19-9, carcinoembryonic antigen (CEA) and CA 15-3 were all negative. A repeat MRI spine with contrast was done afterward with suspicion of spinal metastasis which has led to lower limb weakness. MRI contrast showed a 20*10*19 mm enhancing soft tissue metastatic mass lesion seen within conus in comparison with plain MRI done one week earlier (Figure ). There was no obvious primary identified on the CT. This was discussed in upper GI MDT (Gastrointestinal multidisciplinary team) and was thought to be a disseminated malignancy arising from a gastric primary. An endoscopic ultrasound (EUS) showed a deep, malignant-looking gastric ulcer on the high anterior greater curve of stomach. This was seen with EUS as a hypoechoic mass extending into the serosal margin. Biopsy from the stomach lesion surprisingly showed a metastatic malignant melanoma. Histopathology showed scanty strips of benign columnar epithelium with most of the tissue representing tumour, focally necrotic (Figure ). Immunohistochemical assays for focal Melan-A, human melanoma black-45 and SOX10 confirmed the diagnosis of malignant melanoma. Real-time polymerase chain reaction (PCR) analysis of the BRAF gene was done which revealed the presence of a mutation within codon 600. This case was discussed again in dermatology-oncology MDT after biopsy results and was decided that the best course of action would be palliative treatment, considering the advanced stage of the disease and poor performance status. Management options and prognosis were discussed with patient who agreed to palliative management. After discharge patient contracted coronavirus disease 2019 (COVID-19) pneumonia for which she was again hospitalized and treated with oral dexamethasone 6mg (milligrams) once a day and oxygen inhalation via nasal cannula between 2-4lit/min for 10 days. She further had developed bilateral segmental pulmonary emboli and was started on anticoagulation with apixaban. Her neurological symptoms worsened and progressed to paraplegia, urinary and fecal incontinence over a period of three to four weeks since initial presentation. Patient passed away three months after diagnosis of metastatic melanoma under community palliative care.

pmc-8684629-1

The patient was a 79-year-old Caucasian male with a 7-year history of myelodysplastic syndrome (MDS) and a complaint of abdominal pain. The pain started in the evening of the day before and was accompanied by fever, oral intolerance, nausea, and vomiting. He did not complain of bowel habit changes, although he had a history of chronic constipation. Past medical and surgical history was positive for MDS and cholecystectomy. MDS was controlled with daily thalidomide, deferasirox, dimethicone, pantoprazole, gabapentin, vitamin B12, and folic acid. He also took erythropoietin and rivaroxaban three times a week and filgrastim every fifth day. The family history and habitual history of the patient were unremarkable. The patient was awake and oriented on admission, yet he was ill, dehydrated, and mildly agitated. He had blood pressure 95/60 mmHg, pulse rate 105/min, respiratory rate 17/min, Temperature 37.9 °C, and O2 Saturation 90% on ambient air. Tenderness of the epigastrium and right upper quadrant of the abdomen was noted, without abdominal distension, rebound tenderness, or guarding. Laboratory results were as mentioned in Table . The patient’s electrocardiogram was unremarkable. Plain thoracic and abdominopelvic radiographs were normal. In abdominopelvic ultrasonography, mild fluid in subhepatic and inflamed echogenic fat in the upper abdomen and around the pancreas was found, along with duodenal wall thickening. With the impression of pancreatitis, intravenous Ciprofloxacin, Metronidazole, Ondansetron, normal saline, and one unit of packed red blood cells were administered. As the patient did not have a proper urinary output (200ml since urinary catheterization), the computed tomography (CT) scan was performed without intravenous contrast. The abdominopelvic CT scan demonstrated edematous wall thickening of the entire duodenum with water halo and significant adjacent fat stranding and swelling of the pancreas. Pancreatitis was a potential etiology of secondary duodenal wall thickening []. However, observing the bulk of the pathologic changes at the duodenum and severe duodenal wall edema also raised the possibility of primary duodenal pathology. Accordingly, a sign of ischemia was suggested, and a contrast-enhanced CT scan was advised to evaluate the related vessels further. The patient remained hypotensive and oliguric regardless of intravenous fluid resuscitation. Nine hours after admission, norepinephrine was initiated. However, blood pressure remained low and fluctuated during the next five hours, with the minimum being 60/40 mmHg. Despite supportive treatment, the patient’s condition deteriorated to the extent of severe electrolyte imbalance, gasping, severe acidosis (arterial pH = 6.8), and GCS 4/15. Due to the mentioned deterioration, another abdominopelvic CT scan with intravenous contrast was requested at the fourteenth hour of admission. The second CT scan demonstrated a marked decrease in the enhancement of the edematous duodenum and target sign. Since the related visible vessels were patent, microvascular ischemia or necrosis of the duodenum was highly suggested (Fig. ). The patient was immediately transferred to the operating room in a critical condition. With a midline laparotomy incision, 400 mL serous fluid was drained. Kocher’s maneuver was performed to explore the duodenum and the retroperitoneal structures. Duodenum (D2–D3–D4) was grossly ischemic, the stomach was dilated, and the small bowel distal to the Treitz ligament appeared normal (Fig. ). The Pancreas was normal in view, without any saponification, inflammation, or edema in favor of pancreatitis. Exploration of the superior mesenteric artery and vein did not reveal any pathologic findings. Whipple’s procedure was planned initially. However, the patient’s cardiac arrest during the operation directed the plan to a damage control surgery. The overall operation time was approximately one hour and a half. To do the pyloric exclusion in the shortest time, the pylorus was isolated, and a polyester surgical tape was passed behind that. Tight ligation of the tape around the pylorus temporarily excluded the ischemic duodenum. To achieve a damage control surgery, decompression of the stomach was done by a red (18 French) nasogastric tube (Fig. ). Lastly, an open (corrugated sheet) drain was placed near the duodenum, and the patient was then transferred to the intensive care unit. Despite two hours of supportive therapy, blood pressure remained 40 mmHg/pulse, leading to a cardiac arrest with asystole rhythm and patient expiration. According to the refusal of next of kin to consent, an autopsy was not performed.

pmc-8684637-1

A 72-year-old man presented to emergency room with 8-h fatigue and 4-h mild exertional dyspnea, palpitation, and blurred vision. He was a nonsmoker and denied previous history of cardiovascular disease. Physical examination showed sinus tachycardia (117 bpm) and normal blood pressure (120/70 mmHg). The position and range of apical impulse were normal. There were no heart murmurs, no crackles or wheezes on chest auscultation. In ECG, the ST-segment was elevated by 2–3 mm in leads II, III, and aVF, with Q-waves (Fig. A). Cardiac troponin T was 3.33 ng/mL (normal range 0–0.04). A diagnosis of acute inferior myocardial infarction was established. Dual anti-platelet therapy (loading doses: aspirin 300 mg and clopidogrel 300 mg) was initiated to prepare for primary PCI. Coronary angiography (CAG) showed multi-vessel lesions, including a total occlusion of the distal portion of a dominant right coronary artery (RCA), 90% stenosis of the proximal portion of the left anterior descending artery (LAD), and diffuse stenosis (50–60%) of the left circumflex artery (LCX) (Fig. A–C). The culprit lesion was in the distal portion of the RCA. The patient received a loading dose of glycoprotein IIb/IIIa inhibitor (tirofiban) after the angiography. Percutaneous balloon angioplasty was then conducted; one BuMATM 2.5 × 20 mm sirolimus-eluting stent was placed to restore blood flow in RCA (TIMI grade 3) (Fig. D). ST-segment elevation and depths of the Q-waves were attenuated after the primary PCI (Fig. B). Secondary PCI was planned for LAD lesions 5 days later. Immediately prior to transfer to the cardiac intensive care unit (CCU), the patient developed severe dyspnea. Heart rate (HR) was 120 bpm, and blood pressure (BP) decreased to 90/60 mmHg. Auscultation revealed a loud harsh holosystolic murmur along the left sternal border and crackles throughout both lungs. NYHA functional class of heart failure was IV. A mechanical complication was suspected, but not investigated immediately. We immediately placed an IABP (1:1 augmentation ratio) from femoral access, and the patient received 3-mg morphine, 20-mg furosemide, and 0.1-mg recombinant human brain natriuretic peptide (rhBNP). Once the IABP was inserted, symptoms became alleviated. The BP stabilized at 110/70 mmHg and the augmentation pressure was 120 mmHg. Then the patient was transferred to CCU safely. Transthoracic echocardiography (TTE) was performed the next day and revealed a left-to-right shunt in the posterior portion of the interventricular septum with a size of 11.4 mm (Fig. ). The left ventricle end-diastolic diameter (LVED) was 50 mm, and the diameter of the right ventricle was 20 mm. We also detected regional wall-motion akinesia of the left ventricle in the inferior and posterior sections. Left ventricular ejection fraction (LVEF) was 59%. The estimated pulmonary arterial pressure and right ventricular systolic pressure were 48 mmHg. A calculated Qp/Qs was 2.905. There was no regurgitation of the mitral valve or pericardial effusion. An updated diagnosis of ventricular septal rupture was made. We decided to continue IABP to support cardiac function. Medications included aspirin (100 mg orally once a day), clopidogrel (75 mg orally once a day), atorvastatin (20 mg orally once a day), furosemide, spironolactone, and nitrates, as well as an intravenous infusion of rhBNP. The patient received a subcutaneous injection of 40-mg enoxaparin every 12 h to prevent deep vein thrombosis. Omeprazole (40 mg per day) was used to prevent gastrointestinal mucosal injury. An attempt to wean IABP was made on day 12 on the ground of stable hemodynamics and disappearance of all symptoms. Five minutes after reducing the augmentation ratio from 1:1 to 1:2, the patient felt dyspnea, and the BP decreased from 116/68 mmHg to 71/50 mmHg. The augmentation ratio was increased back to 1:1. Dyspnea gradually dissipated, and the BP normalized. We realized the shunt was in a large amount according to the Qp/Qs. IABP can decrease the shunt, so we decided to implement a prolonged use of IABP, which continued at 1:1 ratio for another 16 days. During the use of IABP, we enhanced the medical and nursing concern including checking the circulatory status of the lower limb of the puncture with Doppler ultrasound every day, limiting its movement to avoid dislocation of the balloon catheter and bleeding, and continuous administration of anticoagulation by subcutaneous injection of enoxaparin to prevent deep vein thrombosis. The aspirin, clopidogrel, atorvastatin, spironolactone, and rhBNP were administered during the month when IABP was used. An antibiotic (cefamandole 2000 mg intravenously every 12 h) was given for prophylaxis for bacteremia during invasive IABP insertion from day 21 to 27. Psychological therapy was adopted to enable the patient to cooperate on prolonged use of IABP. Surgical repair was offered to the patient on day 27 since the friable tissue in the ischemic myocardium should be sufficiently mature at this time to allow repair. However, the surgeons considered that it was too risky to perform the surgical repair due to the limitation of technique at that time. Firstly, the VSR located at the posterior muscular part of the ventricular septum was lower and deeper than a perimembranous ventricular septal defect approached through a right atriotomy and the tricuspid valve, so the surgical repair was more difficult and beyond the techniques of the surgeons, when they only had experience in the treatment of perimembranous ventricular septal defects at that time. Secondly, the EuroSCORE [] of this case they calculated was 16, and the predicted mortality was 59.07%, which was too high for them to operate safely. Meanwhile, we also consulted the anesthesiologist to evaluate the patients for general anesthetization, and the anesthesiologists deemed there would probably be high risk in the process of a general anesthesia for the open surgery and especially under extracorporeal circulation support. Surgery was also declined by the patient and his family due to the high risk of open surgery and under general anesthesia and extracorporeal circulation support. Instead, the patient opted to receive percutaneous closure of the VSR. So we decided to choose percutaneous VSR closure for this specific high-risk senior patient. On day 28 (4 weeks after VSR), the patient didn’t feel dyspnea or any other discomfort with stable vital signs (HR 90 bpm, BP 98/67 mmHg, augmentation pressure 112 mmHg). We believed the waiting period for the infarcted myocardium to recover was enough according to the documented experiences [, ]. Left ventriculography confirmed an 11-mm left-to-right shunt (Fig. A). Transcatheter closure was conducted via the femoral artery and subclavian vein. Upon establishment of the transseptal wire loop as a rail, the patient developed ventricular fibrillation, and he lost consciousness followed by. A 200-J electrical shock was delivered immediately and restored sinus rhythm. Then the patient regained consciousness. After the wire loop through the rupture was established, the HR suddenly decreased to 30 bpm. A temporary pacemaker was placed, and we proceeded to implant a 24-mm double-umbrella AGA AMPLATZERTM occluder to close the VSR (Fig. B). The vital signs were stable (HR 78 bpm, BP 110/72 mmHg). Echocardiography after the procedure revealed no residual shunt, and no interference of valve functions by the occluder. The estimated Qp/Qs was 1.086. The temporary pacemaker was removed after the closure operation. Two days later, the augmentation ratio was decreased to 1:2 and then to 1:3. IABP was weaned off on day 31. Secondary PCI was conducted on day 35 for LAD lesions (Fig. ). The patient was discharged on day 41. At the last follow-up 6 years later, CAG and TTE revealed no in-stent restenosis, no left-to-right shunt, no mitral regurgitation, and 51% LVEF. He kept taking aspirin, atorvastatin, and metoprolol regularly as the medication therapy. All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient.

pmc-8684643-1

In 2017, an 83-year-old Japanese woman presented to our department with a chief complaint of a mass in her right maxillary premolar region. She had initially noticed a painless mass in her right maxillary premolar region in 2002. After she had first noticed of the mass, it grew gradually in size, but she sought no treatment for it. She was referred to us for examination and treatment because it was difficult to perform tracheal intubation for surgery of sigmoid colon cancer at another hospital. Her history included sigmoid colon cancer, subarachnoid hemorrhaging, bronchitic asthma, and cardiac insufficiency. Regarding the intra- and extra-oral findings, a massive pedunculated mass in the right maxillary premolar region measuring 83 × 58 × 35 mm was palpable (Fig. ). Furthermore, it covered the front of the right palate, and it protruded to the extra-oral region from the right maxillary premolar alveolar region. Its surface was almost entirely smooth, and some erosions and ulcerations were seen. It was elastic and hard and showed no tenderness on palpation. There was no palpable regional lymphadenopathy, and a laboratory examination revealed no abnormal values. Panoramic X-ray revealed the shadow of the mass in the right maxillary premolar region, which included some hard tissue (Fig. ). Computed tomography (CT) showed scattering calcified images in the mass (Fig. ). Magnetic resonance imaging was not performed because she had vertebral artery clips and screws in her forehead. Given the above findings, we suspected benign gingival tumor in the right maxillary premolar region and performed a biopsy under local anesthesia (Fig. a, b). Histologically, proliferation of dysplastic squamous epithelia was observed (Fig. ). We noted subepithelial mild dysplastic spindle-shaped cells and collagenous fibers, and scattered calcification and ossification were also observed (Fig. ). Immunohistochemically, the spindle cells were negative for pan-cytokeratin (AE1/AE3), and nuclear translocation of β-catenin was not observed in the spindle cells (data not shown). Therefore, we excluded a diagnosis of carcinosarcoma and fibromatosis. However, we were unable to diagnose absolutely whether the dysplastic squamous epithelia were pseudocarcinomatous hyperplasia of the gingiva or well-differentiated squamous cell carcinoma. In addition, positron emission tomography with computed tomography (PET/CT) revealed that the maximum standard unit value (SUVmax) of the sigmoid colon and the oral lesion were 15.27 and 14.99, respectively, and there were no other obvious metastases (Fig. ). Therefore, we performed tumorectomy under general anesthesia. The pedicle of the tumor was located at the right maxillary premolar area, and the tumor—including the tissue surrounding the lesion—was resected as one mass together with the periosteum (Fig. a–d). At that time, partial destruction of the maxillary bone was seen. The exposed bone surface was slightly curetted. After resection, the wounded area was covered with artificial dermis (TERDERMIS). Finally, tie-over dressing by gauze with ointment was performed. The microscopic findings of the surgically removed tumor were similar to those of the biopsy specimen. The body of the tumor was composed of spindle-shaped cells that were proliferating with collagenous fiber, and scattered bone formation was also observed (Fig. ). The destruction of the basement membrane by atypical squamous epithelia was observed in the surgically removed specimen, suggesting stromal invasion. In addition, immunohistochemical analysis revealed that the dysplastic squamous epithelia were positive for Ki67 and CK17, suggesting that they were squamous cell carcinoma, not pseudocarcinomatous hyperplasia. Furthermore, some spindle cells were positive for smooth muscle action (SMA), indicating myofibroblastic differentiation. Therefore, the epithelial component of the tumor was considered to be well-differentiated squamous cell carcinoma. Because most of the tumor was occupied by spindle-shaped cells and marked ossification histopathologically, we diagnosed the tumor as POF with squamous cell carcinoma (pT1N0M0). One week after surgery, we removed the gauze and covered the wound with an oral appliance for protection (Fig. a, b). There have been no signs of local recurrence or metastasis during follow-up as of 2 years after surgery.

pmc-8684656-1

A 19-years-old female was first found with occupation about 6.2 cm × 5.7 cm in the right adrenal five years ago based on CT scan at a regular physical examination, accompanied with fever and headache with high blood pressure. Tumor resection was performed, and pathological diagnosis was right pheochromocytoma. The patient was regularly subjected to follow-up. During this hospitalization, CT scan found multiple tumor occupation in left adrenal and paraganglion region zones with round nodular shadows. Meanwhile, she had fever and headache with high blood pressure. Based on medical history and examination, she was diagnosed as left pheochromocytoma. Meanwhile, the occupying lesions in right lung and pancreas were found, located in extrabasal segment of inferior lobar and head respectively. The case characteristics were summarized: 1. A 12y female; 2. Tumor occupation was first found in right adrenal; 3. Tumor resection was performed and the pathological diagnosis was pheochromocytoma; 4. Multiple round nodular shadows were found in left adrenal and paraganglion region zones after five years; 6. The symptoms were fever and headache with high blood pressure; 7. The diagnosis was pheochromocytoma (PCC) and paraganglioma (PGL) (Combined PPGLs); 8. The occupying lesions located in right lung and pancreas were scanned and diagnosed with masses.

pmc-8684675-1

A 57-year-old Caucasian woman was recently diagnosed with advanced stage ovarian cancer. Otherwise healthy, she had initially consulted her general practitioner simply for abdominal distension. Further investigations [abdominal computed tomography (CT), serum CA125determination and laparoscopy] revealed a peritoneal carcinomatosis. The diagnosis of stage III (FIGO classification) ovarian cancer was established and the patient received a carboplatin-paclitaxel based chemotherapy regimen in a neoadjuvant setting. The indication of a debulking surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) was retained by our institutional tumor board. A CVL was inserted via the right jugular vein into the superior vena cava in prevision of surgery and the appropriate positioning of the catheter was verified by chest x-ray. An implantable central venous catheter (Port-a-Cath) was already in place (Fig. ). The first 48 postoperative hours were marked by difficult pain management, hypotension, and transient hyperlactatemia responding to fluid replacement and norepinephrine. On postoperative day 3, she presented acute onset dyspnea when transferred from the bed to a chair, and a major drop in pulse oxygen saturation (from SpO2 96% to 83%) justified the administration of oxygen (5 L/min) via a nasal cannula. On physical examination, her body temperature was 37.4 °C, blood pressure 135/81 mmHg, heart rate 122 beats/min, respiratory rate 20/min. No chest pain was reported. Pulmonary examination revealed a bilateral reduction of basal breath sounds with dullness at percussion. Chest x-ray examination (Fig. ) showed bilateral pleural effusions that could largely explain patient’s dyspnea and oxygen desaturation. After switching from a nasal cannula to a nonrebreather mask (FiO2 0.40), the patient’s condition seemed to stabilize in supine position. A measurement of the arteriovenous oxygen difference was obtained via sampling through the arterial and central venous line after the patient was again lying in supine position (Table ). A sampling error or a wrong positioning of the recent CVL was suspected, but a sample taken from the Port-a-Cath confirmed the venous value. A transthoracic echocardiography (TTE) with bubble test failed to show a right-to-left shunt, atrial septum was intact. No pulmonary hypertension was detected and right ventricle was not dilated. A CT pulmonary angiography (Fig. ) showed large bilateral pleural effusions with atelectasis of both lower lobes, acute pulmonary embolism in the right middle and upper lobe pulmonary arteries, and ultimately an anatomical variant of the left upper pulmonary vein draining into the left innominate vein. Following bilateral chest drainage, the patient was treated with low molecular weight heparin twice daily. There was no evidence for deep venous thrombosis. This was followed by a significant clinical improvement, a disappearance of the platypnea–orthodeoxia complaints and a reduction of oxygen requirement over the following days. At 1-year follow-up, TTE showed no right ventricular dilation and absence of pulmonary hypertension. From an oncological perspective, stability was also observed during her niraparib maintenance therapy, with absence of new lesions at a 1-year follow-up abdominal CT.

pmc-8684807-1

A 31-year-old man categorized as New York Heart Association Class IV was admitted to the hospital after suffering from anorexia for 2 weeks and dyspnoea for 1 week in August 2001. He had previously undergone surgery for appendicitis and had on other past medical history. He exhibited mild intellectual disability, and electrocardiography (ECG) depicted a short PR interval with pre-excitation and negative T waves (). Echocardiography revealed a hypertrophic dilated left ventricle with poor systolic function [left ventricular ejection fraction (LVEF) 24%] and signs suggestive of non-compaction myocardium (). Doppler parameters indicated reduced e′ velocity at the mitral valve annulus and increased tricuspid regurgitation velocity. A restrictive filling pattern was evident via pulse Doppler of the mitral valve. According to the American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines and references, his left ventricular diastolic dysfunction was in Grade 3. There was severe mitral and tricuspid regurgitation. Abnormal laboratory parameters included elevated total bilirubin (85.3 µmol/L), indirect bilirubin (55.4 µmol/L), and aspartate aminotransferase (284 IU/L). He experienced sudden cardiac death at the age of 33 years.

pmc-8684816-1

A 62-year-old Caucasian man was admitted to our department in June 2020. He was diagnosed with follicular lymphoma in 2010 and treated with an R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) for six cycles, achieving complete response; in 2017, because of a disease recurrence, he was treated with six chemotherapy cycles with R-bendamustine, followed by maintenance therapy only with rituximab for 2 years. The last administration was in February 2020. Clinical and radiological follow-up was negative; during the maintenance therapy, the patient had urinary tract recurring infections, gingivitis, and herpes zoster cutaneous reactivation. He sought medical attention because of progressive vision loss. His pharmacological therapy included atorvastatin, amlodipine, and pantoprazole. He was afebrile; his vital signs were in range. General and neurological physical examination was negative, except for right homonymous hemianopia. Brain computed tomography (CT) showed an uneven cortical and subcortical hypodense lesion in the left posterior temporal and occipital areas, with no contrast enhancement. Magnetic resonance imaging (MRI) confirmed the left parenchymal lesion, composed of two parts: a periventricular one showing inhomogeneous signal (decrease in T1-weighted, increase in T2-weighted sequences); and a more uniform one, involving white matter and characterized by strong T2-weighted and fluid-attenuated inversion recovery (FLAIR) hyperintensity and T1 hypointensity. Restricted diffusion was noted in both components, especially in the white matter, but no gadolinium enhancement was observed. Magnetic resonance (MR) spectroscopy pointed out a reduction of N-acetyl aspartate peak, an elevated choline peak, and a double peak of lactic acid. Total body contrast CT did not document hematological disease activity and confirmed the two previously known lymph nodes, a left axillary and a right mediastinal para-esophageal one, stable in dimensions (16 × 10 and 11 × 6 mm, respectively). Neurological findings were interpreted as a consequence of intracranial relapsed lymphoma. So, after a multidisciplinary assessment, brain biopsy was planned. Histological samples showed a large number of macrophages (CD68+, CD14+) overshadowing any other cell, except for isolated reactive astrocytes and mild perivascular T-lymphocyte infiltrates. No neoplastic cell was clearly individuated. No microbiological test was performed on brain tissue. The patient, discharged after brain biopsy, returned to the hospital because of worsening eyesight, mental confusion, and psychomotor slowing. Laboratory investigation on blood was not significant: peripheral blood cell count was normal with 4.61 × 109 white blood cells and mild reduction in hemoglobin level (13.9 g/dL); C-reactive protein was < 5 mg/L. Electrolyte levels, renal function, liver enzyme levels, and coagulation examinations were in range. Brain MR was repeated (Figs. , ) and showed, especially on FLAIR/T2-weighted images, the hyperintense left temporal–parietal–occipital and peritrigonal lesion notably increased in dimension and extended from the left to the right hemisphere through the corpus callous. It was also characterized by vasogenic edema with a slight mass effect on cortex gyri. There was no significant contrast enhancement; diffusion-weighted imaging (DWI) showed restricted diffusion around lesion edges. Despite the rapid progression of clinical and imaging findings, the absence of significant contrast enhancement and, above all, the inconclusive response of previous histological report excluded the hypothesis of an expanding neoplastic lesion; MR features were instead considered suggestive for inflammatory demyelinating process, and progressive multifocal leukoencephalopathy was finally suspected. Therefore, a diagnostic lumbar puncture was performed. Cerebrospinal fluid appeared clear and colorless. Chemical–physical analysis showed presence of 10 leukocytes/μL (0.00–5.00) and mild elevation in protein level (albumin 0.350 g/L); glucose level was normal (cerebrospinal-fluid-to-serum ratio 82%). There was an immunoglobulin G (IgG) level of 0.025 g/L and an IgG index (Link index) of 0.66 (< 0.7). Oligoclonal bands were negative. Bacterioscopic and microscopic examination for Cryptococcus neoformans was negative; cultural examinations for mycobacteria, Listeria monocytogenes, Borrelia burgdorferi, and Toxoplasma were negative; galactomannan antigen was absent; polymerase chain reaction for Epstein–Barr virus (EBV), cytomegalovirus (CMV), herpes simplex 1 and 2, HHV6, HHV7, HHV8, varicella–zoster, measles, BK virus, adenovirus, enterovirus, Toscana virus, and rubella was negative; virus JC quantitative real-time PCR was positive with detection of numerous viral genomes (9,548,473 units/μL). CSF serology for aforementioned infectious agents was negative. CFS immunophenotype, despite the low amount of cells after centrifugation, was characterized by 18.0% of lymphocyte, predominantly T, without any B population. Blood serology for HIV Ag/Ab was negative. Coronavirus disease 2019 (COVID-19) swab test was negative. He was treated supportively with trazodone and mirtazapine. The outcome was poor: neurological findings continued to worsen, and he progressively became blind, confused, and disorientated. He was finally transferred to a hospice for palliative care (Table ).

pmc-8685210-1

In December 2017, a 19-year-old female was referred to our hospital with a recent diagnosis of histiocytic sarcoma. The patient had presented as pharyngeal pain and left neck mass with fever for 2 months. She had received tracheotomy because of airway obstruction resulting from the large mass arising from the left parapharyngeal space at local clinic. PET/CT scan showed a large solid mass located in the left parapharyngeal space with compression of pharyngeal cavity and multiple enlarged lymph nodes in the left neck (). The histopathological review confirmed diagnosis of HS. Histologically, HS is composed of large polygonal cells with epithelioid-to-pleomorphic morphology, abundant eosinophilic to vacuolated or foamy cytoplasm, ovoid to irregularly shaped nuclei, and variably prominent nucleoli (). For immunohistochemical markers, most HS express CD68 and CD163 and partially express S100 (). Chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOEP)) was initially started on December 8, 2017 with the aim of stabilization of the fulminate disease course; however, the lesions did not shrink and pain and dysphagia were heavier caused by the compression of the pharynx (). In order to relieve the compression, irradiation to the lesions of pharyngeal and neck was started on day 11 of chemotherapy. After irradiation of 20 Gy/10 F, the size of lesions became a little bit smaller (pharyngeal mass: from 6.0 cm × 4.4 cm to 5.6 cm × 4.0 cm; neck mass: from 3.5 cm × 2.8 cm to 2.9 cm × 2.6 cm). Meantime, next-generation sequencing (NGS) of tumor tissue was performed using a panel of 93 genes (Gene+ OncoLym). This analysis revealed the presence of oncogenic mutation c.2888-1G>T in the MET gene, exon 14 (allele frequency, 5.58%), as well as an activated mutation c.361T>A (C121S) in the MAP2K1 gene, exon 3 (allele frequency, 17.23%). MEK inhibitor trametinib has been reported to be effective in HS patients with MAP2K1 mutation (); however, trametinib was not available in China at that time. It has been reported that patients with MET exon 14 skipping mutation-positive nonsmall cell lung cancer are sensitive to MET inhibitor crizotinib (); therefore, this histiocytic sarcoma patient began to take crizotinib (250 mg, twice daily) after irradiation of 20 Gy/10 F. Partial response (PR) was observed after radiotherapy of a total dose of 60 Gy/30 F and 1-month treatment of crizotinib, with sum of the product of the longest perpendicular dimensions (SPD) decreased by 57% (). The lesions kept shrinking () after radiotherapy, and crizotinib was still taken daily for 1 month more. However, 2-month treatment of crizotinib cost her family RMB 100,000 Yuan. The patient could no longer afford such an expensive drug. In order to search for new targetable therapeutic drugs, NGS was done again with a panel of 1,021 genes (Gene+ Onco-C1021T). The most frequently mutated genes were mutation c.410G>A (G137D) in the DUSP2 gene, exon 2 (allele frequency, 18.9%), mutation c.290G>A (C97Y) in the HIST1H3B gene, exon 1 (allele frequency, 15.9%), and mutation c.3646A>T (S1216C) in the GRIN2A gene, exon 13 (allele frequency, 15.7%). Both DUSP2 and GRIN2A are in the RET signaling pathway. Imatinib is a tyrosine kinase inhibitor (TKI) that inhibits RET, PDGFR, and KIT. It has been reported to be effective in some HS cases (). The patient was subsequently treated with imatinib (400 mg daily) and thalidomide (100 mg daily) since March 2018. The cost of imatinib and thalidomide was RMB 2,600 Yuan/month. Two months after the treatment, excellent PR was observed () compared with tumor size in March 2018. Four months later the re-evaluation by CT scans showed a nearly complete remission (CR) (). The patient took maintenance of imatinib and thalidomide for 2 years and stopped the treatment in March 2020. To date (September 2021), 45 months after HS diagnosis, she is still alive without tumor recurrence. To explore the possible underlying mechanism of imatinib plus thalidomide in this HS patient, experiments in vitro were performed in a canine HS cell line DH82. Results of cell counting kit-8 (CCK8) assays showed that the proliferation activity of DH82 was significantly inhibited by imatinib but not thalidomide (). Combined thalidomide and imatinib treatment did not improve the inhibitory effects of imatinib to DH82 (). We speculated that no synergistic effect existed between imatinib and thalidomide, but each of them might have its own specific antitumor activity. As mentioned above, mutations of DUSP2 and GRIN2A are involved in the RET signaling pathway. RET signaling leads to the activation of the RAS/MAPK and the PI3K/AKT pathways and has key roles in cell growth, differentiation, and survival (). Further KEGG pathway enrichment analysis of NGS results from patient’s tissue also revealed that PI3K/AKT and MAPK pathways were activated in this HS patient (). Immunohistochemistry staining on the patient’s tissue was performed to detect phosphorylated ERK (p-ERK) and phosphorylated JNK (p-JNK) of MAPK pathway and phosphorylated AKT (p-AKT) of PI3K/AKT pathway. Results showed that p-AKT and p-ERK were strongly positive, while p-JNK was almost negative (), indicating the patient actually harbored the activation of MAPK and PI3K/AKT pathways. Treatment of DH82 with imatinib demonstrated that p-ERK and p-AKT were substantially inhibited with imatinib while p-JNK was slightly elevated in a dose-dependent manner, which confirmed the inhibitory effects of imatinib on DH82 by targeting activation of MAPK and PI3K/AKT pathways ().

pmc-8685408-1

A 43-year-old primipara presented with severe hypertensive disorder of pregnancy and fetal growth restriction (FGR) at 19 gestational weeks. At 23 6/7 gestational weeks, an emergency cesarean section was conducted due to worsened hypertensive disorders of pregnancy (HDP) and a non-reassuring fetal status. “En caul” delivery could not be achieved because of the thick uterine wall. The caul refers to the amniotic membrane. To be born in a caul (en caul) means to be born with the head covered by the amnion (or be born within an intact unruptured amnion). A male infant with a birthweight of 293 g was born without any apparent trauma. Endotracheal intubation and surfactant replacement were performed immediately after birth in the delivery room. The umbilical venous catheter (UVC) and the peripheral arterial catheter were successfully placed, while umbilical arterial catheter (UAC) insertion was unsuccessful. Initial examination revealed anemia (hemoglobin level: 10.8 g/dl), disseminated intravascular coagulation (DIC), and the presence of slight ascites on ultrasonography, suggesting intra-abdominal bleeding. Intensive treatment, including HFOV, inotropes, steroids, and massive blood and plasma transfusion for the progressive anemia and DIC, was started. However, liver and adrenal bleeding gradually became evident on ultrasonography () and he continued to suffer from refractory hypotension and further progressive anemia. Throughout the course, his parents hoped to switch to palliative care, seeing his irreversible worsening clinical condition. He died of hemorrhagic shock at 3 DOL.

pmc-8685408-2

A 40-year-old primipara woman was diagnosed with FGR at 19 gestational weeks. She was transferred to our hospital at 22 gestational weeks due to severe HDP. A female infant was born at 22+6/7 gestational weeks with a birthweight of 279 g after an emergency en caul cesarean section due to maternal HDP. Endotracheal intubation and surfactant administration were performed in the delivery room. The UAC and the PICC were successfully placed, while UVC insertion was unsuccessful. Prophylactic indomethacin was administered once, causing PDA closure at 1 DOL. The circulatory status of the patient was successfully stabilized within 72 h of life without IVH. Mean fluid intake during the first weeks of life was 143.0 ml/kg/day. Enteral feeding with breast milk was started at 3 DOL. The breast milk secretion was insufficient; therefore, we increased enteral feeding slowly and started to use hydrolyzed formula milk at 23 DOL. She did not develop NEC throughout her clinical course. Although HFOV, five-time repeated surfactant replacement, and systemic hydrocortisone were required to manage the severe bronchopulmonary dysplasia, she was successfully extubated at 73 DOL. Oral feeding was started at 101 DOL and the patient was discharged at 146 DOL with home oxygen therapy, without tube feeding. She did not develop IVH or PVL. Although ophthalmologists diagnosed her ROP (right; stage II, left; stage III), no therapy was required. She is now 8 months of corrected age and stays healthy in the outpatient clinic without signs of developmental delay; she already sits, rolls over, and pulls up to standing.

pmc-8685493-1

A 53-year-old female participant in the BCG-DENMARK-COVID trial was included in early June 2020 and randomized to BCG, which was applied intradermally in the right deltoid region. A rather strong local skin reaction to the vaccine followed, with clear, yellowish serous secretion from the injection site lasting 4 to 5 months. Additionally, swollen and sore lymph nodes in the axil on the vaccinated side were noted. The lymph node symptoms led to her being examined for breast cancer in January 2021. The participant had been BCG-vaccinated as a child at school entry, and a scar from the childhood vaccination was noted on her right shoulder at the trial inclusion procedure. According to her mother, she had also reacted strongly to the childhood BCG vaccination. As far as she (and her mother) knows, she has never been exposed to TB. The participant is healthy and takes no medication. By the end of January 2021, she received the first Moderna Covid-19 vaccination in the left arm. She received no other vaccines during follow-up. The participant reacted to the Covid-19 vaccine with fever, muscle pain, and a large local reaction (the area being red and inflamed) which subsided within a few days. One to two days after vaccination, the trial BCG vaccination site scar began to itch and she experienced renewed secretion from the site, and the lymph nodes felt sorer. The itching and the secretion lasted for a week. Three weeks later, she received the second Moderna vaccination, after which she felt ill again. Also, this time the BCG site began to itch during the following day. There were no other symptoms, and the secretion from the BCG scar did not reappear. The itching lasted for 2 weeks. No treatment was needed or provided. Again, she did not notice symptoms from the childhood BCG scar.

pmc-8685493-2

A 49-year-old female participant was enrolled and randomized to BCG in June 2020. The vaccine was applied intradermally in the right deltoid region. She was not aware of having received a BCG vaccination as a child. However, when she was included in the trial, a BCG scar was noted on the right arm. In October 2020, she received an influenza vaccination (Vaxigriptetra®). No reaction at the trial BCG scar was noted. The participant takes omeprazole daily as a treatment for her gastroesophageal reflux disease and levocetirizin (Xyzal®) for her chronic urticaria. Late December 2020, she received the Pfizer-BioNTech Covid-19 vaccine in the left arm with no subsequent reaction at any of the BCG scar sites. After her second dose of Pfizer-BioNTech vaccine late January 2021, also in the left arm, she noted itching, clear yellowish secretion, and some bleeding from the BCG scar site on the right arm. She did not experience swollen lymph nodes. The symptoms lasted for 2 weeks and resolved without treatment. There was no reaction at the site of the childhood BCG scar. She had no other symptoms after the Pfizer-BioNTech vaccine.

pmc-8685498-1

We hereby report the case of a 16-year-old Caucasian female who has been followed at our Allergy Unit of Meyer Children's University Hospital in Florence for allergic asthma since the age of 6. At the physical examination, she presented a history of respiratory clinical manifestations such as cough and shortness of breath. During her asthma history, she also reported two hospitalizations: the first one during a wheezing episode triggered by an airway infection and the second one during an asthmatic attack without an infection. She required treatment with short-acting β2-agonist and systemic corticosteroids during her asthma exacerbations. The patient presented positive skin prick tests to house dust mites and cat fur from the first clinical evaluation and a positive skin prick test to pollen (grass, mugwort, hazel, birch, and poplar) during the follow-up. She also suffered from food allergy, i.e., to nuts, with sensitization to lipid transfer protein and profilin. At the age of 2, the patient had anaphylaxis after eating cashew and adrenaline autoinjectors were prescribed. She had skin prick tests, prick by prick tests, and blood tests for nuts, and they resulted positive not only for cashew but also for peanut, almond, hazelnut, walnut, pine nut, and pistachio, which were all excluded from the diet. Moreover, with carrots and fennels, she presented itch in her throat and dyspnea. For this reason, following the positive skin prick tests, the patient also excluded these foods from the diet. At 16 years old, the patient presented anaphylaxis twice after eating a pear and shrimps, which were then excluded from her diet. Apart from asthma and food allergy, she did not suffer from other illnesses. The patient reported a parental history of atopic disease: her mother suffered from nickel contact allergy and her father from rhinoconjunctivitis with grass and Parietaria pollen sensitization. We have evaluated all the possible differential diagnoses with asthma or additional factors, which were eventually ruled out. For example, no clinical features of chronic bronchitis, cystic fibrosis, or gastroesophageal reflux were detected. The patient also underwent an electrocardiogram, which did not reveal any rhythm abnormalities. After the diagnosis of asthma, she attended periodic follow-up visits at our Allergy Unit, where spirometry was performed each time as well. Afterwards, at 16 years old, her asthma clinical manifestations worsened progressively, becoming severe despite treatment with high-dose inhaled corticosteroid, long-acting β2-agonist, and anti-leukotriene (fluticasone/salmeterol and montelukast) (). Indeed, she had frequent asthma exacerbations, especially in the evenings, about once every month, and dyspnea for minimal physical efforts while under these treatments. In addition, the patient presented a spirometry with a reversible lung obstruction. Indeed, the patient presented a basal FEV1 of 79% with a positive bronchodilatation test equal to 290 ml (+12%). Thus, treatment with subcutaneous injections of the anti-IgE antibody omalizumab, 600 mg every 2 weeks, was started at the age of 16 years, although it was used as off-label due to her high total IgE serum concentration (2,003 kU/L). The patient's clinical condition benefitted from the treatment with omalizumab (, ), with clinical improvements after the first injection and with an improvement of the spirometry (FEV1 = 94%, with a negative bronchodilatation test) performed after the seventh injection. During the SARS-CoV-2 pandemic, the patient did not change her habits, including going to school, and on October 20, 2020, one of her classmates resulted positive for SARS-CoV-2 from real-time polymerase chain reaction (RT-PCR) on a nasopharyngeal swab. Therefore, she was sent home for quarantine. Indeed, she did not suffer from clinical manifestations typical of COVID-19, nor her asthmatic signs or symptoms did worsen at the time. However, after 7 days, she performed RT-PCR on a nasopharyngeal swab, which resulted positive for SARS-CoV-2. The patient was still without clinical manifestations at the time, but after 2 days she developed diarrhea, asthenia, myalgia, epistaxis, and maximum body temperature 37.5°C treated successfully with paracetamol. At that time, the patient had been undergoing therapy with subcutaneous omalizumab every 2 weeks for about 3 months, as well as fluticasone/salmeterol and montelukast daily (). Moreover, during quarantine, omalizumab treatment was easily continued at home, and it was switched to self-administration through telephonic support and digital material available online (), such as educational videos and the Asthma Control Test. It is worth mentioning that the patient remained free of asthma clinical manifestations the whole time she was positive of SARS-CoV-2, without significant differences in asthma management during this period (). Furthermore, no drug adverse events have been recorded. Finally, she reported good self-confidence with the administration of omalizumab at home.

pmc-8685724-1

Our case concerns a 48-year-old male with a history of syphilis and heterozygous AS sickle cell trait. Mantle cell lymphoma with multiple lymphomatous polyposis had been diagnosed based on a bone marrow biopsy. The patient received three cycles of R-Maxi CHOP and three cycles of R-High Dose-Ara-C (Nordic protocol ) with complete response on the CT scan. His peripheral blood stem cells (PBSC) were mobilized and harvested on his last cycle of R-High Dose Ara-C with granulocyte-colony stimulating factor (G-CSF) and plerixafor. Seven months after his diagnosis and two months after his last chemoimmunotherapy, he underwent the BeEAM protocol for an autologous HCT, which consists of bendamustine 200 mg/m2 intravenously given on days –8 and –7, cytarabine 200 mg/m2 intravenously twice a day on days –6 to –3, etoposide 100 mg/m2 intravenously twice a day on days –6 to –3, and melphalan 140 mg/m2 intravenously on day –2. He was only taking vitamin D supplements at the time. Baseline laboratory workup was unremarkable, as shown in . On day –8, he began the BeEAM protocol and received his first dose of intravenous bendamustine 440 mg (200 mg/m2). He also received intravenous fluids as part of the BeEAM protocol. From day –6, his urine output, serum sodium and serum creatinine started to increase (). His urine output markedly increased from 3725 mL on day –8 to 7425 mL on day –3 and the serum creatinine increased from 75 µmol/L on day –7 to 155 µmol/L on day –3. His serum sodium also increased to a peak of 155 mmol/L on day –2. During this time, the patient only complained of mild nausea. Vital signs were stable. Forced diuresis with furosemide was suspended and oral hydration was optimized. On day –1, the patient started complaining of polyuria, nocturia and thirst. However, he could not drink, since he had severe mucositis and odynophagia due to his chemotherapy, which led him to be put on total parenteral nutrition a few days after. A nephrology consultation request was made. Laboratory studies revealed the following values: random urine sodium 56 mmol/L; random urine osmolality 307 mOsm/kg and specific urine gravity from urinalysis 1.006. Despite the normal range of urine osmolality, the nephrologist team suspected a nephrogenic diabetes insipidus (NDI) along with concomitant dehydration in absence of other identified causes of polyuria. However, no water deprivation test or desmopressin challenge was done since the patient had developed an acute kidney injury (AKI), and required fluids for his hypernatremia and his upcoming HCT. After the HCT, the patient’s infusion was first switched to 0.45% sodium chloride and subsequently to dextrose 5%. Serum sodium levels showed little improvement while fluid balance improved but remained negative. On day 5, desmopressin 1 mcg was administered subcutaneously with no effect on diuresis. The following day, a desmopressin (4 mcg) challenge was administered intravenously and showed a 33% increase from baseline urine osmolality of 204 mOsm/kg to an average of 277 mOsm/kg with a decrease in diuresis. These values were compatible with a diagnosis of diabetes insipidus. The patient remained polyuric and highly dependent on fluids due to his hypernatremia. Since he was partially responsive to the desmopressin challenge, intranasal desmopressin was started on day 8. The dose was increased until it reached desmopressin 40 mcg twice daily intranasally on day 11 (). A brain magnetic resonance imaging (MRI) was then performed on day 12 to rule out central lymphomatous infiltrates, which came back negative and therefore reinforced a diagnosis of partial NDI. On day 13, his natremia returned to normal range along with diuresis decreased to 600-800 cc/8 h, intravenous dextrose 5% was stopped. Desmopressin was weaned off and then stopped on day 15. By then, the patient’s nocturia had markedly improved and NDI was considered resolved. On day 18, the patient was discharged from the hospital. To this day, he remains in remission of his lymphoma.

pmc-8685794-1

A 38-year-old woman, 32+ 2 weeks pregnant, previous smoker with a past history of one miscarriage and livedo reticularis was admitted to the emergency department (ED) of her local hospital due to a sudden onset of pain, cold and functional impotence of the lower limbs. During the obstetric evaluation, fetal death was observed. Given the suspicion of lower limb ischemia, low weight molecular heparin was started, and the patient was transferred to our hospital, which has vascular surgery. On admission in our ED, she was alert and oriented, hemodynamically stable and presented with tachypnea. Absence of pulses, cold and pallor of the lower limbs, with minimal neurosensory deficit and muscle weakness were observed. Laboratory workup showed hypocapnia, thrombocytopenia, elevation of liver and pancreatic enzymes, elevated total creatinine kinase (CK) and lactate dehydrogenase (LDH). Table resumes clinical and laboratory evolution during hospitalization. The Computed Tomography angiography (Angio CT) showed bilateral (central and lobar) pulmonary embolism (PE), deep venous thrombosis of the inferior vena cava and left iliac axis, areas of splenic and right kidney infarction and multiple arterial and venous thrombosis. Juxta-renal aortic thrombosis (Fig. ) was also observed as well as thrombosis of the left renal artery (with hypocaptation of the left kidney), right common iliac artery, left hypogastric artery, left common femoral artery, right deep femoral artery and right tibioperoneal trunk (Fig. ). As lower limb ischemia was tolerated (acute limb ischemia - grade IIA), surgery was postponed. The patient was admitted to the intensive care unit (ICU) where presumptive CAPS diagnosis was made and anticoagulation with unfractioned heparin infusion was started. Despite anticoagulation, the patient presented worsening of neurosensory deficit and muscle weakness (acute limb ischemia - grade IIB), with the need of urgent revascularization surgery. Under general anesthesia, a cesarean section was performed to extract the dead fetus, and intrauterine balloon tamponade was placed for control of postpartum hemorrhage, followed by bilateral thromboembolectomy of the lower limbs and axillary-bifemoral bypass with synthetic prosthesis. Surgery was uneventful. Fetus had no anatomical abnormalities and weighed 1540 g. The patient recovered both lower limb perfusion as well as bilateral femoral, popliteal and distal pulses and was extubated the next day. During her stay in the ICU, the patient maintained therapeutic anticoagulation, underwent a total of six sessions of plasmapheresis and the first dose of rituximab (1000 mg) was administered. Under this treatment, an evident improvement was observed: the platelet count, hepatic enzymes and serum creatinine normalized. On the sixth day of hospitalization, she was transferred to an intermediate care unit at the hospital of her residence area where she continued TPE until the 14th day, when the second dose of rituximab was administered. After those treatments, the patient was discharged with a vitamin K antagonist. Regarding the initial laboratory workup, before plasmapheresis or rituximab infusions, antiphospholipid antibodies were negative (LA, aCL and β2GPI) as well as screening for thrombophilia (including protein C and protein S deficiency, antithrombin III deficiency, Leiden Factor V mutation and prothrombin mutations), and other autoimmune diseases. Histological examination of the placenta showed areas of small vessel infarction. Six months after discharge, the patient has resumed her day-to-day life activities. She remains under warfarin therapy and the bypass is functional, with distal pulses maintained and without intermittent claudication. Additional workup was repeated and continued to be negative for aPL (even with the patient taking warfarin, which could cause a false positive lupus anticoagulant) and other autoimmune diseases (including SLE, vasculitis and sarcoidosis), with normal complement counts (C3, C4 and CH50) as well as negative for thrombophilia, cryoglobulinemia, cold agglutinin disease, autoimmune hemolytic anemia, paroxysmal nocturnal hemoglobinuria and infectious diseases (negative for hepatitis B virus, hepatitis C virus, cytomegalovirus, Epstein Barr and toxoplasmosis). CD19 positive cells are still depleted (0,1%; normal 7–23%), due to previous rituximab infusions. Other extra-criteria antibodies testing was not available in the laboratory and was not performed [Table ].

pmc-8685809-1

A 24-year-old man was admitted to our hospital 48 h after developing an acute retrosternal chest pain that was radiated to the upper back, associated with multiple episodes of vomit (food content), and progressive dyspnea. Additionally, he describes intermittent difficulty swallowing solid food. His medical history is significant for well-controlled asthma using salbutamol as needed. Initial evaluation revealed a temperature of 38.4 degrees; blood pressure, 100/60 mmHg; heart rate, 118/min; respiratory rate, 26/min, and SpO2, 94% on room air. Additionally, the physical examination showed subcutaneous emphysema in the cervical and thoracic regions, shallow breathing, dullness to percussion in both lung bases. His investigation results on admission revealed white blood cell count of 21,000/μL (91% Neutrophils), C-reactive protein (CRP) and procalcitonin were 39.2 mg/dL and 9 ng/mL respectively. Liver and renal function were normal. The patient was admitted with sepsis of unclear etiology, although there was a suspicious for esophageal perforation predisposing mediastinitis and sepsis. A contrast-enhanced thoracic computed tomography (CT), showed a pneumomediastinum, cervical emphysema, bilateral pleural effusion, as well as extraluminal oral contrast surrounding the distal portion of the gastro-esophageal junction region and fluid-air level indicating a collection in the posterior mediastinum (Fig. a–d). Initial management included intravenous fluid, nothing per oral (NPO), broad spectrum antibiotics, and analgesia. Due to the clinical condition of the patient, time of the rupture and inaccessibility to an intensive care unit due to the Covid 19 pandemic situation, the thoracic surgery and gastroenterology teams decided a nonoperative approach based on endoscopic therapy. The patient underwent endoscopy that showed a distal esophageal lineal tear just above Z line of approximately 4 cm with irregular edges. Irrigation and drainage of food debris of the cavity was performed before a distal auto-expandable esophageal prosthesis SX-ELLA (ELLA-CS) of 25 mm × 18 mm × 15 cm with antimigration technology and anti-reflux valve was placed (Fig. ). The thoracic surgeon decided to put a bilateral pleural tube oriented toward the perforation preventing future complications. Biopsies of the esophageal mucosa were obtained confirming the clinical suspicion of eosinophilic esophagitis (Fig. a). Five days after admission, a new endoscopic procedure was performed, showing migration of the esophageal stent into the stomach, a persistent perforation defect in the lower third of the esophagus with granulation tissue and two small cavities suggesting a fistulous tract. A fistulogram was performed confirming the fistulous tract between the esophagus and the pleura (Fig. a, b). Based on these findings and previous case reports found in the literature it was decided to place an endoluminal vacuum-assisted closure with sponge in the area of perforation with the fistula (Fig. c–e) to control both complications. The sponge was cutted to 7 cm, adjusted and grasped with a tripod equipped endoscope and introduced in the cavity under direct visualization. After placement of the sponge, a vacuum device was connected and set to a continuous 125 mmHg sub-atmospheric, moderate intensity pressure. In the second intervention for dressing change of the sponge, two OVESCO clips (OTSC®) were placed as a strategy to reduce the size of the tear and closure of the fistula, reducing up to 30% of the longitudinal size. The patient required four additional dressing changes of endoscopic vacuum-assisted closure with sponge, each one performed every 72 h, until the fistulogram showed resolution of the esophago-pleural fistulous tract (Fig. a–c). Despite good progress of the esophago-pleural fistula, the patient condition got worse due Clostridium difficile colitis. Despite appropriate antibiotic treatment, and resucitacion with fluids the patient developed shock with severe acute respiratory distress syndrome requiring vasopressor support and mechanical ventilation with neuromuscular blockade. The gastroenterology team decided to place a new esophageal prothesis in order to avoid dressing changes of the sponge and worsening of the clinical condition. Considering Clostridium difficile infection, a recto-sigmoidoscopy was performed which reported ischemic colitis and pseudomembranes. Due to lack of improvement despite treatment due to uncontrolled foci of infectious (colon), an emergency left hemicolectomy and a Hartmann’s procedure were performed. Over the next 7 days, the patient condition improved, allowing to perform an endoscopy with fistulogram that showed a recurrent fistulous esophago-pleural tract (Fig. a). The esophageal prothesis was removed and a new vacuum-assisted closure with sponge was placed. Three dressing changes of endoscopic vacuum-assisted closure with sponge were performed before esophago-pleural fistula resolution was evident (Fig. b, c). The sponge and the OTSC® was retired due to a complete fistula resolution. A follow-up endoscopy performed 3 days after the last vacuum-assisted closure with sponge was removed, that showed epithelized esophageal mucosa with granulation tissue (Fig. d). After 46 days the patient was discharged with outpatient follow-up. Two months later, the patient was asymptomatic, tolerating solids in the diet. A prednisone base therapy and food elimination diet were initiated as a measure of control of his eosinophilic esophagitis.

pmc-8686213-1

A 50 years old male long-distance truck driver presented to our Hospital in Addis Ababa, Ethiopia with severe constant retrosternal chest pain, diaphoresis and vomiting of ingested matter for the previous two days. The patient had a history of hypertension and elevated blood cholesterol levels. He was brought to the emergency department after he experienced an acute loss of consciousness of short duration. He reported that, after an episode of severe chest pain, he was not aware of his surroundings and lost control over his truck for a few seconds. The truck went off the road but fortunately no one was injured. The patient had no previous history of heart disease, and no cough or pleuritic pain. There was no history of alcohol or cigarette use. Physical examination was normal except for hypertension (blood pressure 160/100 mm Hg) and low-grade fever with axillary temperature of 37.5 °C. He was admitted to hospital. Initially he was investigated for an acute coronary syndrome. Echocardiogram findings and serum troponin levels were normal. On the second days of his admission, he experienced one episode of bloody vomiting. On further questioning, his physicians learned that the patient had pain on swallowing. They also discovered that he was taking ceftriaxone injections and Doxycycline 100 mg capsules twice per day for four days. The medications were prescribed in another health facility for a febrile illness. The patient had no prior history of esophageal disease. A gastroenterologist was consulted and esophagogastroduodenoscopy (EGD) was performed. There were multiple mucosal ulcerations in the proximal and middle esophagus (Figs. and ) as well as at the lower esophageal sphincter. In addition, hyperemia and erosions were seen in both stomach and duodenum. Mild bleeding was noted. Laboratory tests were normal except for a mild transient elevation of liver transaminases and a triglyceride level of 243 mg per deciliter. Serum albumin and bilirubin were normal. Hepatitis B surface antigen and Weil flex test were positive. Ultrasound of the abdomen showed increased echogenicity of the liver consistent with liver steatosis and fatty liver. There were no features of cirrhosis or portal hypertension. Chest X-ray, Complete blood count, blood film, and fasting blood sugar were all normal. H.Pylori stool antigen test, Hepatitis C. Virus and HIV antibody tests were negative. Diagnosis of Doxycycline-induced esophageal ulcerations was made, and doxycycline was discontinued. The patient was treated with ceftriaxone one gram intravenous twice daily to complete the course of treatment for the acute febrile illness and omeprazole 40 mg intravenous twice daily. He was also given antacid suspension orally. Parenteral analgesics were added as required. The pain and fever subsided gradually and the patient was discharged improved after 6 days, on omeprazole 20 mg orally twice daily for four weeks. He was advised to swallow pills in upright position and with water to prevent recurrence of similar problems. After 3 weeks, the patient returned for follow-up. He was asymptomatic. Liver transaminases were normal. Hepatitis B. Viral DNA level was 99 international unit per milliliter. Hepatitis e antigen was negative. Antiviral treatment was not indicated and the patient was linked to care for his hypertension and chronic hepatitis B infection.

pmc-8686214-1

A 55-year-old man presented with sudden onset of dizziness, diplopia, difficulty of closing eyes, and trouble of chewing after lifting heavy goods 3 days prior to admission. He had a history of mild hypertension for 1 year with treatment of amlodipine 2.5 mg/d and poorly-controlled asthma. On examination, he showed completed bilateral horizontal gaze palsy which was uncorrected by vestibuloocular reflex. Gazed-evoked upbeat nystagmus (UBN) was observed on attempted upward gaze but not on straight-ahead gaze position. In addition, he had bilateral peripheral facial paralysis with predominance on the left. Examination on other cranial nerves, including facial sensation, taste, hearing, and pharyngeal reflex, were normal. Mild ataxia was noticed on the left upper extremity when performing finger-to-nose test. His muscle strength was 5 on four limbs and he had normal pinprick sensation and brisk tendon reflexes. Brain MRI revealed hyperintensity in right middle cerebellar peduncle and bilateral dorsal pontine tegmentum on diffusion-weighted image, indicating new infarction (Fig. a). No periventricular white matter lesions were observed. CT angiography of vertebrobasilar artery showed no evidence of significant stenosis (Fig. b). CSF examination showed normal protein level and CSF analysis for oligoclonal band, myelin oligodendrocyte glycoprotein antibody, and aquaporin-4 antibody were negative. Contrast-enhanced transcranial doppler showed > 50 microbubbles during the Valsava maneuver, suggesting potential cardiac right-to-left shunt. Further transoesophageal echocardiography revealed patent foramen ovale (PFO; Fig. c) with a tunnel length of 12.6 mm. Transthoracic echocardiography revealed left atrial diameter of 32 mm and left ventricular ejection fraction of 70.4%. No left ventricle hypertrophy or atrial septal aneurysm was observed. Holter monitor examination in hospital did not capture remarkable arrhythmias, i.e. atrial flutter or atrial fibrillation. Rrivaroxaban 15 mg/d was prescribed at discharge and closure of PFO was then administrated. His symptoms relieved and follow-up MRI at 6 month showed an old infarction of the same region on T1 weighted image (Fig. d) without other evidence of demyelination.

pmc-8686221-1

A 69-year-old Han man complained of chest distress and shortness of breath after stress for four months. He was diagnosed with hypertension for four months, and he felt that these symptoms were accompanied by high blood pressure. The maximum blood pressure measured was 200/110 mmHg. Benidipine hydrochloride (4 mg twice daily), metoprolol succinate (47.5 mg Qd), furosemide (20 mg Qd) and spironolactone (20 mg Qd) were applied to control blood pressure. In addition, he had a dull pain in his left waist for four months. Abdominal enhanced computerised tomography (CT) demonstrated a suspected left renal infarction. His past medical history included 10 years of diabetes mellitus and hyperlipidemia. During this hospitalization, he was diagnosed with resistant hypertension with chronic renal disease and renal dysfunction (creatinine 122 µmol/L, eGFR = 51.80 mL/min × 1.73 m2). Abdominal enhanced CT was reperformed and showed that his left renal artery was nearly occluded, his right renal artery had mild to moderate stenosis and his left kidney had atrophied. An invasive angiography with angiographic catheter JR 4.0 further demonstrated a 95% stenosis of the proximal segment of the left renal artery, and the middle segment was blurred with multi-channel-like blood flow (Fig. , Additional file ). An RDC guiding catheter was used and run through across the lesion. The proximal lesion was pre-dilated by a 4.0 mm × 15 mm balloon at 10 atm. A commercially available IVUS system (iLAB, Boston Scientific Corporation, Marlborough, Massachusetts) was used to acquire IVUS images. A 40 MHz, 2.6 F imaging catheter (Atlantis SR Pro or Pro 2, Boston Scientific) was advanced distal to the lesion, and an automated pullback was performed at a speed of 0.5 mm/s. Multiple lumens and HLS were demonstrated by IVUS, and the cavity was surrounded by fibrous tissue (Fig. , Additional file ). A lesion of the middle segment of the left renal artery was sequentially dilated by a 1.5 × 15 mm balloon, 2.5 × 10 mm balloon and 4.0 × 15 mm balloon at 8–12 atm, and an express SD 5.0 × 19 mm stent was implanted at 12 atm successfully, overlapping with the proximal segment of the left renal artery (Fig. , Additional file ). The final angiogram showed restored flow to the distal renal artery. The patient recovered well and was discharged with atorvastatin (20 mg Qd), ezetimibe (10 mg Qd), aspirin (100 mg Qd), clopidogrel (75 mg Qd), Sacubitril Valsartan Sodium (25 mg Bid) and metoprolol succinate (47.5 mg Qd). Over three months of follow-up, the patient achieved complete remission of chest distress, shortness of breath and waist pain. Blood pressure was well controlled around 130/75 mmHg and renal function was recovered (creatinine 96 µmol/L, eGFR 69.21 mL/ (min × 1.73 m2).

pmc-8686233-1

A 14-month-old Congolese male child with oculocutaneous albinism visited the Mbujimayi pediatric clinic with fever and fatigue. He was originally from Kasai Oriental, a region of the Democratic Republic of the Congo. He was the youngest in a family of five children, three of whom had oculocutaneous albinism. He himself has sickle cell disease and the rest of the siblings have a sickle cell trait (Fig. ). He was born at term with a birth weight of 3000 g, and presented with spontaneously resolutive neonatal jaundice. The other significant history was episodes of fever with a monthly frequency of two episodes. No vaso-occlusive crisis was clearly diagnosed, in particular no dactylitis episode was reported. The vaccination schedule according to the expanded program of immunization in the DRC was respected with Bacille Calmette et Guérin (BCG) vaccine against tuberculosis; diphtheria, tetanus and pertussis (DTP) vaccine; oral polio vaccine (OPV) against polio; hepatitis B and haemophilus influenzae vaccine (HepB-HiB1); rotavirus vaccine (Rotasiil1); pneumococcal vaccine (Prevenar); measles vaccine (VAR); and yellow fever vaccine (AAV). The patient has never been hospitalized and has always been treated on an outpatient basis in health centers during febrile episodes such as malaria or typhoid fever. The siblings reported no particular clinical history. His parents are not albinos and have no specific medical history; they never benefited from a prenuptial test. They reported their fear of the judgment of others because they have albino children when they are not affected. The patient was wide awake with good contact and interaction. Generalized pallor was noted with subicteric conjunctivae, and the irises were bluish gray and translucent, thus appearing red with nystagmus (Fig. ). The patient’s skin was pinkish white, depigmented, without any particular lesions or bruises. On physical examination, weight and height were at the third and tenth percentile for age, respectively. There was no fever (temperature 36.5 °C), the respiratory rate was high (53 cycles/minute), as well as the heart rate (176 beats/minute), but the latter was regular with the presence of a 1/6 systolic murmur at the mitral focus. The oxygen saturation was 94%. The oral examination was normal. The lymph nodes were free, without lymphadenopathy. The lung examination was normal. The abdomen was supple and painless. There was stage III splenomegaly according to the Hackett classification. Laboratory tests showed a hemoglobin level of 48 g/L and white blood cells at 13,200/μl (complete blood count performed with the Sysmex poch-100i; Sysmex, Norderstedt, Germany). The diagnosis of SCD has been suggested on the basis of pallor, jaundice, and severe anemia. It was confirmed first by a positive rapid test (BioMedomics, Inc, Morrisville, USA) and then by hemoglobin electrophoresis. The diagnosis of albinism was proven by molecular genetics on a blood sample and identification of the mutation involved, that is homozygosity for the 2.7 kb deletion of OCA2 (laboratory “Centro Nacional de Biotecnologia CNB-CSIC Campus de Cantoblanco, Darwin 3, 28049 Madrid, Spain). A family investigation was then performed (see Fig. ). Given the very low hemoglobin level, the patient’s age, and SCD, a blood transfusion was indicated. Antibiotic treatment (ceftriaxone and amikacin) was started in the hospital. The evolution was favorable. On discharge from hospital, routine prophylaxis with folic acid and oral penicillin was initiated, and advice on crisis prevention and medical monitoring was given to the parents. A dedicated patient monitoring program has been set up for sickle cell anemia and albinism with hygiene advice and sun protection measures. The patient received a hat, sunglasses, and sun protection cream. Ophthalmologic follow-up has also been set up. The evolution remains dermatologically stable, no skin lesion was observed. For SCD, the patient received treatment with hydroxyurea since early 2020. It is still too early to objectify the benefit of this therapy but he had only one infectious episode, one vaso-occlusive crisis, and did not require blood transfusion for over a year.

pmc-8686241-1

A girl presented with asymptomatic proteinuria, which was revealed by a urinary screening test performed in Japan when she was 3 years old. She had no family history of renal or neurological disorders. The urine protein to creatinine ratio (UPCR) was 1.0–1.5 g/gCr (reference range < 0.2 g/gCr) at that time. Ultrasonography revealed normal echogenicity in both kidneys. She developed nephrotic syndrome, without systemic edema, at the age of 8 years. Polyuria and polydipsia with a urine output of 3L in a day were also documented. UPCR was 11.5 g/gCr, and the serum albumin level was 2.1 g/dL (reference range 3.7–5.5 g/dL). The serum creatinine level was 0.97 mg/dL (eGFR was 46.8 mL/min/1.73m2). The urine specific gravity was 1.008, and urinary beta 2-microglobulin increased to 9,269 µg/L (reference range ≤ 150 μg/L). A kidney biopsy revealed that 13 (52%) of 25 glomeruli showed segmental or global sclerosis. Furthermore, two glomeruli showed cellular lesions, which were characterized by swollen, vacuolated, and proliferative glomerular epithelial cells, throughout Bowman’s space. The underlying glomerular capillaries were partially collapsed and occluded by swollen endothelial cells and karyorrhexis, which was consistent with a pathological diagnosis of FSGS (Fig. A) []. No glomeruli with collapse and overlying podocyte hypertrophy and hyperplasia were not observed. Cystic dilatations of the tubules and interstitial fibrosis were also observed (Fig. B). The patient presented with no neurological manifestations, such as seizures or developmental delays. Brain magnetic resonance imaging (MRI) and electroencephalogram detected no abnormalities. She could hold her head up at 4 months old, sit at 8 months old, pull up to stand at 9 moths and speak single words at 1 year and 6 months old. She did not need special support to attend school. Her renal function continued to deteriorate, and she eventually developed ESRD, despite the administration of angiotensin receptor blockers. At 9 years of age, pre-emptive kidney transplantation was performed, with a kidney donated by her mother. No recurrence of proteinuria has been observed for 1 year and 9 months after transplantation. We performed whole-exome analysis using a previously described method [], focusing on variants in the genes that are currently known to cause FSGS or nephronophthisis (Tables S and S), and identified a de novo novel heterozygous C to A transition (c.1461C > A) in the last exon of TRIM8, resulting in a premature stop codon (p.Tyr487*). The alternative and reference allele counts were 68 (46%) and 80 (54%), respectively. Sanger sequencing showed that the individual had the variant but that her parents did not. This variant was absent in population databases including the Exome Aggregation Consortium database (ExAC, ), Genome Aggregation Database (gnomAD, ), 1000 Genomes (1000G, ), ESP6500 (). No additional pathogenic variants in the genes that are currently known to cause FSGS or nephronophthisis were identified (Tables S and S). This variant was classified as pathogenic (PVS1, PM1, PM2, PM6, and PP4) based on the criteria developed by the American College of Medical Genetics and Genomics []. The sequence analysis of mRNA was performed as previouly reported methods []. RNA was extracted from peripheral blood mononuclear cells with the RNeasy Mini Kit (QIAGEN), according to the manufacturer’s instructions. The RNA was treated with DNase (QIAGEN) to avoid genomic DNA contamination, and 200 ng of total RNA was reverse transcribed, using the SuperScript VILO cDNA Synthesis Kit (Thermo Fisher Scientific) for the mRNA analysis. The following primers were used to amplify and sequence exon 6 of TRIM8 from cDNA: 5’-GAGTGTCCCCCTGTACCCTT -3’ (forward) and 5’-CTACAGGGTGTATGGGCAGC-3’ (reverse). Polymerase chain reaction experiments were performed, using Invitrogen Platinum II Taq Hot-Start DNA Polymerase (Thermo Fisher Scientific) and T100TM Thermal Cycler (Bio-Rad Laboratories) identifing mRNA sequences transcribed from the TRIM8 mutant allele (Fig. ), which confirmed the escape from nonsense-mediated mRNA decay (NMD) []. Immunohistochemical analysis were performed using the formalin-fixed paraffin-embedded kidney biopsy specimens obtained from the present patient and nine control individuals consisting of three living kidney transplantation donors who served as normal controls, five patients with primary FSGS and one patient with nephronophthisis who served as disease controls. We performed autoclave-based antigen retrieval, for 15 min at 105 °C, in Bond Epitope Retrieval Solution 2 (Leica Biosystems Newcastle, Ltd., Newcastle Upon Tyne, UK). Specimens were incubated with goat polyclonal antibody against an epitope corresponding to amino acids 540–551, at the C-terminus of human TRIM8 (Abcam, Cambridge, MA, USA; catalog no. ab4302), overnight, at a dilution of 1:500 []. Immunofluorescence staining, using the anti-TRIM8 antibody in normal control specimens, is shown in Fig. (Fig. A–E). TRIM8 expression was observed in the nuclei of all glomerular cells (Fig. A–C). Double immunostaining with mouse anti-human podocalyxin monoclonal antibody (PHM5, Merck Millipore, Darmstadt, Germany), at a dilution of 1:100 which was used as a podocyte marker (Fig. B) [] and mouse anti-human cluster of differentiation 34 (CD34) monoclonal antibody (QBEND/10, Leica Microsystems, Wetzlar, Germany), at a dilution of 1:40 which was used as an endothelial cell marker (Fig. C) [] showed that TRIM8 was expressed in the nuclei of podocytes and endothelial cells, respectively. Proximal tubular cells that were identified by mouse anti-human cluster of differentiation 10 (CD10) monoclonal antibody (56C6, Leica Microsystems, Wetzlar, Germany) without dilution [] and distal tubular cells that were identified by mouse anti-human epithelial membrane antigen (EMA) monoclonal antibody (Clone E29, Dako, Santa Clara, California, USA) without dilution [] also showed the nuclear expression of TRIM8 protein (Fig. D and ). Similar findings were observed in specimens from disease controls (Fig. S). In contrast, the present patient showed a lack of TRIM8 protein expression in any cells in the glomeruli and tubules (Fig. F–J). The tubules showing cystic dilatation were positive for EMA, but negative for CD10, indicating that cystic dilatation was evident in the distal tubules (Fg. I and ). IHC staining, using anti-SOCS1 goat polyclonal antibody (Abcam, catalog no. ab9870), at a dilution of 1:500 [] of the kidney biopsy specimens derived from the present patient showed stronger cytoplasmic SOCS1 expression in glomerular and tubular cells than observed in control samples (Fig. S).

pmc-8686261-1

A 71-year-old male was admitted to the hospital due to productive cough along with low grade fever, chest pain and shortness of breath. His past medical history included hypertension and glaucoma, and he took irbesartan regularly (150 mg per day). The patient did not smoke cigarettes, drink alcohol or use recreational drugs. No relevant travel history or contact history were detected. The patient had no food or drug allergies. Three weeks before admission, the patient began to have productive cough, with chest tightness and a temperature of 38 °C. After 2 weeks of progressive symptoms, the patient visited the local hospital. He reported pleuritic chest pain of visual analogue scale score 2. His vital signs and other physical examination results were reported as normal. Initial blood test showed elevated white blood cell (WBC) count (14.8 × 109/L) and C-reactive protein (CRP) level (86 mg/L) as well as liver enzyme elevation. Other laboratory test results were normal. Chest computed tomography (CT) revealed patchy opacities in both lower lobes and a small amount of right-sided pleural effusion. He was then admitted to the local hospital and received intravenous sulperazon (cefperazone–sulbactam) 2.0 g once every 8 h, but symptomatic improvement was not noted. Repeated chest CT scan revealed increased pleural effusion in the right. Subsequently, the patient was transferred to our hospital for treatment. On the admission, his temperature was 37.8 °C, pulse rate 109 beats/min, respiratory rate 18 breaths/min, blood pressure 145/87 mmHg, and oxygen saturation 98% on room air. The patient reported no night sweats, weight loss, joint pains, or myalgias. Pulmonary auscultation found decreased breath sounds on both lower fields. No icterus or lymphadenopathy was detected. Thoracocentesis was performed immediately and a chest tube was introduced. Purulent and hemorrhagic fluid was aspirated (Fig. A), and laboratory tests of the pleural effusion revealed an exudate (fluid protein 25.70 g/L, serum protein 28.70 g/L [normal: 35.0–55.0 g/L], fluid lactate dehydrogenase 621 U/L, serum lactate dehydrogenase 355 U/L [normal < 243 U/L]). Other pleural fluid analysis showed: WBC 5000/µL with 88% neutrophils, red blood cells 21,000/µL, fluid glucose 7.31 mmol/L, and fluid adenosine deaminase 18 U/L. Pleural fluid smear, gram stain, bacterial culture, acid-fast bacilli culture and smear, and cytology were all negative. Blood culture was also negative. He was diagnosed as empyema and intravenous tazocin (piperacillin-tazobactam) 4.5 g once every 8 h was initiated. During the treatment, repeated blood and fluid cultures were all negative, so the pleural effusion was sent for NGS. Deoxyribonucleic acid (DNA) was extracted directly from the pleural fluid. The extracted DNA was amplified, purified, and sonicated to a size of 200–300 bp. Fragmented DNA was end repaired to construct DNA libraries, and supplemented with adapter overnight followed by polymerase chain reaction (PCR) amplification. Qualified DNA libraries were sequenced using the BGISEQ-100 platform. We generated high-quality sequencing data by removing low-quality reads, low-complexity reads, and reads shorter than 35 bp. Human data were mapped to a human reference (hg19) and excluded. The remaining sequencing data were aligned to the bacterial, virus, and fungal databases. All pathogen sequence reference databases were from National Center for Biotechnology Information (NCBI) (). NGS identified 14 out of 19317 reads uniquely corresponding to S. constellatus. Although the number of the reads was small, S. constellatus was the only pathogen detected. Tazocin was used continuously for 12 days, then followed by moxifoxacin 400 mg per day for a total of 14 days. Meanwhile, the pleural effusion was drained continuously through the chest tube. The patient claimed gradually resolved symptoms under antibiotic treatment and effusion drainage, and subsequent CT scanning confirmed the improvement (Fig. B, C).

pmc-8686295-1

A 13-year-old male patient had a history of progressive subungual melanosis in the hallux of the right foot for over 4 years, but no pseudo-Hutchinson signs (Fig. A). After resection, the tumor was pathologically diagnosed as a subungual melanocytic nevus. The defect of the nail matrix was repaired with a lateral toe pulp island flap based on the plantar digital artery (Fig. B and C). The patient was monitored for 16 months and made a full recovery after surgery (Fig. D–F).

pmc-8686295-2

A 5-year-old female patient had a history of progressive subungual melanosis for more than 2 years and intermittent pain in the fifth toe of her right foot for more than half a year (Fig. A). After resection, the tumor (total nail matrix) was pathologically diagnosed as a subungual melanocytic nevus of the fifth toe. The defect of the total nail matrix was repaired with a lateral toe pulp island flap based on the plantar digital artery (Fig. B and C). The patient was monitored for five months and had a satisfactory outcome (Fig. D and E).

pmc-8686295-3

A 1-year-old boy was pathologically diagnosed with a subungual melanocytic nevus on his right index finger (Fig. A). The patient had been suffering from progressive subungual melanosis for over half a year. After removing the nail plate, split-thickness excision of the pigmented nail bed lesions was performed under a microscope (Fig. B and C). Furthermore, the residual nail bed was flattened under a microscope (Fig. D). The patient was monitored for 20 months and had a satisfactory outcome (Fig. E).

pmc-8686371-1

This boy, born at 30+ 1 weeks of gestation to a 32-year-old mother, was the first child of non-consanguineous Caucasian parents. The mother was overweight before pregnancy, with a BMI of 30. Elevated maternal serum biochemical markers in the first trimester of pregnancy prompted a prenatal noninvasive test for trisomy 21, which was negative. The mother consulted at her local hospital, a type 2 perinatal centre, for headaches that had worsened over 48 h. The examination found arterial hypertension (145/95 mmHg) with no other sign of preeclampsia. Foetal heart rate monitoring was non-reassuring, with reduced variability and decelerations. Ultrasound and Doppler assessment showed decreased active foetal movements, absent diastolic flow in the umbilical artery, and cerebral vasodilation (resistance index = 0.5). Intramuscular betamethasone (12 mg) was administered to the mother, and caesarean delivery was decided on 1 h later in a context of more pronounced decelerations. Apgar scores were 4/7/10 at 1, 5 and 10 min, respectively; arterial cord blood pH was 6.97 and cord lactate was 16 mmol/L. Birthweight was 930 g (<3rd centile, according to Olsen curves []), and head circumference was 25.5 cm (3rd-10th centile). Pathological examination of the placenta found four foci of infarction, with size varying between 7 and 12 mm in the major axis, representing < 10% of placental volume. Examination outside these areas was considered normal. The neonate was bagged with 30% oxygen for a few minutes and then supported with nasal continuous positive airway pressure (CPAP). Peripheral venous catheterization was performed to provide standard hydration, vitamin K (1 mg), and a bolus dose of caffeine (20 mg/kg). The newborn was then transferred to a type 3 NICU. On admission, 3 h after birth, the fraction of inspired oxygen (FiO2) required to maintain adequate oxygenation had increased to 70%, prompting surfactant administration (200 mg/kg of poractant alfa), according to the less invasive surfactant administration procedure with propofol (1 mg/kg) for premedication, as stated in our service protocol []. Soon after, the FiO2 required to maintain adequate oxygenation decreased to 25% and capillary blood gases showed improved pH (7.28) and lactate (6.8 mmol/L) compared to cord blood values. An epicutaneocaval catheter was inserted into the left basilica vein at the 7th postnatal hour to perfuse PN with a separate glucose-amino acid solution (2.7 ml/h of Pediaven NN2, Fresenius Kabi, Sèvres, France), an additional solute of amino acids (0.3 ml/h of Primène 10%, Baxter, Maurepas, France), and ILE (0.2 ml/h of Medialipide 20%, B. Braun Medical, Boulogne, France), the whole providing 7 g/kg/day of carbohydrates, 2 g/kg/day of proteins, and 1 g/kg/day of lipids, with carnitine (8 mg/kg), multivitamins (Cernevit, Baxter, Maurepas, France) and trace elements (Nutryelt, Aguettant, Lyon, France). Enteral feeding was initiated, with 16 ml per day of donor human milk administered continuously through a gastric tube. Thrombocytopenia (33,000/mm3, see reference ranges for newborns and infants used by our laboratory in the Table (Table )) and impaired coagulation tests (prolonged prothrombin time – with a decrease in all vitamin K-dependent factors – and partial thromboplastin time, fibrinogen < 0.35 g/L) prompted the administration of 20 ml/kg of fresh frozen plasma. Twenty-four hours after birth, the respiratory state was stabilized with CPAP + 6 cm H2O and FiO2 24%; haemodynamics was adequate with heart rate: 152 bpm, mean arterial blood pressure: 35 mmHg, and diuresis: 5.2 ml/kg/h over the first 24 h. Five episodes of hypoglycaemia, ranging between 1.4 mmol/L and 2.5 mmol/L and occurring after PN initiation, had required 10% glucose intravenous boluses. The PN prescription was changed to (i) a preparation in the department of a mixture of glucose, proteins and electrolytes corresponding to respective glucose and protein intakes of 10 g/kg/day and 3 g/kg/day, infused at a rate of 4.1 ml/h, and (ii) continuation of the same ILE at a rate 7 ml/day, i.e. 0.3 ml/h, corresponding to lipid intake of 1.5 g/kg/day. The exact wording for the parenteral nutrition over the next 24 h was: (i) Preparation (with details on the different solutes of the mixture): total 98 ml, at a flow rate of 4.1 ml/h, and (ii) Medialipide 20%: 7 ml, given separately from the main mixture. The prescription, however, was misinterpreted by the nurse, who administered ILE at a rate of 7 ml/h. The error was identified 4 h later by the physician who visited the infant for an increase in oxygen requirements. The infant was found to have tachypnoea, with a respiratory rate of 60–70 breaths per minute compared to 40–50 in the preceding hours. Other vital signs were normal, lungs were clear to auscultation, there was no cardiac murmur, and neurologic examination was normal. ILE was immediately stopped, but it was estimated that the infant had received 5.6 g of this emulsion, i.e. 25 mg/kg/min of lipids over 4 h, before cessation. The infant’s condition rapidly deteriorated. Four hours after stopping ILE, the infant was still tachypnoeic, and the FiO2 required to maintain adequate oxygenation had increased to 50%. The infant’s alertness, muscle tone and motor skills were preserved. Values for systolic, diastolic, and mean blood pressure (respectively 49, 27, and 35 mmHg) were comparable to those observed in the previous hours. Capillary blood gases showed pH: 6.98, PCO2: 56 mmHg, PO2: 45 mmHg, bicarbonate: 13 mmol/L, and lactate: 11.4 mmol/L. Echocardiography found markers of pulmonary hypertension (PH), with peak tricuspid regurgitant jet velocity reaching 3 m/s – for an estimated systolic pulmonary artery pressure of 35–40 mmHg − and a predominant right-to-left shunt in the ductus arteriosus. Nitric oxide (20 ppm) was administered on the inspiratory branch of the CPAP circuit, and transcutaneous blood gas monitoring was implemented. After a transient improvement lasting a few hours, with FiO2 reduced to 35%, acute respiratory distress syndrome developed (Fig. ). This required intubation and high-frequency oscillatory ventilation 10 h after the lipid overdose. Chest X-ray following intubation showed reticular infiltrates with a positive air bronchogram and reduced lung volume (Fig. ), prompting the administration of a second dose of surfactant. Shock occurred in the following hours, with collapsed blood pressure and anuria, refractory to continuous alkalization with 4.2% bicarbonate, albumin, norepinephrine, and an attempt to restart diuresis with furosemide (Fig. ). Successive echocardiographs while the infant was still being treated with inhaled nitric oxide showed persistent PH, as previously described, normal left ventricular function (fractional shortening 30–35%), adequate cardiac output (estimated at 200–250 ml/kg/min), and absence of cardiac thrombus or pericardial effusion. Bleeding in the gastric and tracheal tubes and at the entry of the epicutaneocaval catheter, associated with profound thrombocytopenia (< 10,000/mm3), prompted the transfusion of platelets, red blood cells, and fresh frozen plasma. Seventeen hours after the end of lipid overload, biological assays revealed a very high serum triglyceride level, 51.4 g/L, moderate cytolysis (alanine aminotransferase: 91 IU/L, aspartate aminotransferase: 151 IU/L, creatine kinase: 1002 IU/L, lactate dehydrogenase: 1936 IU/L), renal failure (creatinine: 122 μmol/L), haemodilution (protein: 20 g/L, albumin: 11 g/L, sodium: 130 mmol/L), hyperglycaemia (26 mmol/L), hypophosphataemia (0.86 mmol/L), normal calcium (2.36 mmol/L), and increased lactate (12.2 mmol/L). Persistent thrombocytopaenia was associated with decreased neutrophil count (340/mm3). Coagulation tests could not be performed at this time point because of extreme lipaemia. The first exchange transfusion (ET) was started 5 h later, i.e. 22 h after stopping ILE, a delay required for the placement of a double lumen umbilical venous catheter and the reception of blood products. After the exchange of 210 ml, i.e. approximately a 3-volume exchange transfusion, this technique reduced the triglyceride level to 13.72 g/L. The same technique with the same exchanged volume was repeated a few hours later, and the last analysis 43 h after the lipid overload showed a reduction in the triglyceride peak by 14- to 15-fold (Fig. ). The infant’s condition nevertheless remained critical, with persistent bleeding and shock despite repeated transfusions of platelets and fresh frozen plasma, catecholamines, the vasopressin analogue terlipressin and broad-spectrum antibiotics (cefotaxime, amoxicillin and amikacin). Glycaemia was constantly > 25 mmol/L despite continuous insulin infusion (0.1 IU/kg/h). A peritoneal catheter was placed, but the renal replacement therapy was ineffective in producing significant ultrafiltration and reversing oedema and acidosis. Two blood cultures and a peritoneal fluid culture did not identify any pathogens. Hypofibrinogenaemia (0.5 g/L), with prolonged coagulation times beyond the measured thresholds, was observed. Factors II, V, VII and X ranged from 11 to 19%. The infant died 96 h after birth, i.e. 69 h after lipid overload, in a context of refractory lactic acidosis (Fig. ). A few blood tests could be carried out a posteriori on samples preceding the lipid overload kept in the biochemistry laboratory. The acylcarnitine profile found increased free carnitine (235 μmol/L) and increases in short- and medium-chain acylcarnitines, which could be attributed to supplementation. We observed no increase in long-chain acylcarnitines, potentially suggestive of carnitine palmitoyl transferase 1 deficiency, but classically observed with carnitine supplementation. Amino acid chromatography showed an increase in alanine and proline, as frequently observed in relation with lactic acidosis and birth asphyxia. In addition, a decreased ratio of branched-chain amino acids/(phenylalanine + tyrosine) was suggestive of hepatic dysfunction. Parents were immediately informed of this serious adverse event associated with care. They did not want an autopsy to be carried out, but they gave their consent for whole-exome sequencing for themselves and their infant to search for abnormalities, particularly metabolic diseases, which might have favoured such a severe clinical expression of lipid overload. Whole-exome sequencing did not identify a pathogenic variant that could be related to the infant’s symptoms. The event was reported to the quality and risk management department of our institution, to the regional pharmacovigilance center and to the regional health agency. It was entered in the national pharmacovigilance database, for transmission to the European and global pharmacovigilance databases (EudraVigilance and VigiBase).

pmc-8686532-1

A 25-year-old woman, without previous medical history, presented for infertility lasting for more than one year. Clinical examination was normal but abdominal and pelvic computed tomodensitometry (CT) revealed a cyst of the left ovary associated with abundant peritoneal ascites that could correspond to mucinous material. Pelvic magnetic resonance imaging (MRI) confirmed ascites and showed a heterogeneous mass of the left ovary measuring 8.4 × 6.8 cm with adipose, solid and cystic regions that were suggestive of a dermoid cyst. The right ovary and uterus seemed normal. No other lesion was seen in the rest of the body, notably in the digestive system. In this context, surgery by left oophorectomy with appendicectomy and omentectomy was performed 3 months after the first consultation, without resorting to additional hyperthermic intraperitoneal chemotherapy (HIPEC). Intra-operative examination revealed mucinous material inside the peritoneal cavity and a normal digestive tract with a normal appendix. There was no complication of the surgery. The 5-month follow-up based on clinical and imaging surveillance revealed no complaints. Without relapse, the patient was able to pursue her plan to have a child. Macroscopically, the left ovary was cystic measuring 9.5 × 7 × 7 cm and weighing 305 g. It was ruptured on 4 cm. Its cut section revealed a heterogeneous and viscous mass with hair. The appendix, measuring 6 cm in length, and the omentum were macroscopically normal. Histologically, the ovarian cyst corresponded to a mature pluritissular teratoma with intermingled skin and pilosebaceous annexes, serous and mucinous glands, respiratory epithelium, adipose tissue and smooth muscle (Fig. ). The organoid areas with the aspect of a colon, representing about 20% of the ovarian cyst, were composed of colonic mucosa, muscularis mucosae, and submucosa from the surface to the depth. A thick muscularis propria was also observed. In the colonic mucosa, some glands were elongated and layered with moderate proliferating epithelial cells with minimal atypia, near to mucin pools stained with Alcian blue. The colonic epithelial cells were immunohistochemistry stained with CK20 and CDX2, and showed heterogeneous staining for CK7. These cells were negative for estrogen and progesterone receptors (Fig. ). The ovarian surface was covered with hyperplastic mesothelial cells and presented acellular mucinous pools, also found in the omentum. The left fallopian tube was normal. The appendix examined in totality was histologically normal besides mucin deposits on the surface of the serosa. It did not present any mucocele or LAMN/HAMN. All together, these data suggested a diagnosis of acellular PMP (according to Carr classification []) caused by a ruptured appendiceal-like mucocele associated with LAMN, in a left ovarian teratoma. Next generation sequencing of the LAMN of the teratomatous mucocele revealed an activating mutation of KRAS gene c.35G > A corresponding to the p.(Gly12Asp) substitution (Fig. ). Complementary molecular analysis by SNaPshot showed an associated mutation of GNAS c.602G > A resulting in p.(Arg201His). No mutation was found by these two techniques on the other tissues of the ovarian teratoma (squamous, respiratory, adipose or smooth muscle elements) or in the normal appendix and ovarian parenchyma (Fig. ).

pmc-8686539-1

A 45-year-old woman presented to pulmonary clinic for evaluation of worsening dyspnea, cough, and hypoxemia. Her medical history was significant for limited cutaneous systemic sclerosis (lcSSc), pulmonary arterial hypertension (PAH), and interstitial lung disease (ILD) (Fig. A). She had no history of atopy or food allergies and used an albuterol inhaler as needed. PAH had been diagnosed seven years prior to presentation when she had a reported pulmonary artery (PA) pressure of 80/39 mmHg, mean PA pressure of 56 mmHg, pulmonary capillary wedge pressure (PCWP) of 12 mmHg, and cardiac output by thermodilution of 3.17 L/min. Her pulmonary function tests (PFTs) at that time showed a forced vital capacity (FVC) of 3.06 L (75% predicted) and a diffusing capacity for carbon monoxide (DLCO) of 19.61 mL/min/mm Hg (66% predicted). Per her medical records and history, the patient had been treated with dual therapy (tadalafil and macitentan) for PAH and was subsequently able to wean from oxygen supplementation that she had previously required, indicating a therapeutic response. Her ILD was considered mild, and she did not require supplemental oxygen at rest or with exertion. She was treated with mycophenolate mofetil for a year after her initial diagnosis, but the patient discontinued this medication about 6 years prior to presentation due to fear of reactivating remote Lyme infection after she had read about chronic Lyme disease on the internet. The patient had been stable on her regimen of tadalafil and macitentan until 3 months prior to presentation when she began to experience rapidly progressive dyspnea and new onset hypoxemia. Right heart catheterization (RHC) revealed that her PAH had worsened with a mean PA pressure of 72 mmHg and a new drop in cardiac index (1.7 L/min/m2), requiring initiation of subcutaneous treprostinil. Additional history revealed she had taken oral helminth therapy as an alternative treatment for lcSSc. She ingested Necator americanus larvae on 3 separate occasions, 12 weeks apart, with an increasing number of helminths with each dose (3, 5, and 15 larvae). She experienced abdominal pain and diarrhea after the first ingestion. Her respiratory symptoms started 6 weeks after the third and largest dose of helminths. In the clinic, patient appeared to be in mild respiratory distress with a respiratory rate of 24 breaths per minute, and she required 6–8 L/min of oxygen via nasal cannula to maintain saturations above 90%. She was tachycardic (104 beats/min) with a loud second heart sound, jugular venous distension, and severe lower extremity pitting edema up to her thighs. Auscultation of the chest revealed bibasilar rales. Dermatologic exam was notable for scattered telangiectasias over her face, arms, and hands. Complete blood count showed leukocytosis (13.5 × 103/uL) with 10% eosinophils (absolute count of 0.98 × 103 cells/uL). Of note, prior blood counts from 2017 had shown normal eosinophil counts (291 × 103 cells/uL). Basic metabolic profile was significant for an elevated creatinine (1.31 mg/dL) but was otherwise normal. Serum brain natriuretic peptide level was elevated at 578 ng/L. IgE was also elevated at 1372.9 IU/mL, and IgG antibodies to Strongyloides were detected. Multiple stool analyses were negative for ova and parasites. PFTs at that time revealed an FVC of 2.03 L (49% predicted), a decline of over 1.0 L since her prior testing; complete testing was not possible due to her respiratory symptoms. High resolution computed tomography (HRCT) of the chest showed worsened subpleural reticulations, traction bronchiectasis, and diffuse ground glass opacities suggesting chronic pulmonary fibrosis in a pattern consistent with non-specific interstitial pneumonia. The patient’s CT scan revealed progressive ILD and showed new diffuse ground glass opacities compared imaging from four years prior (Fig. A–D). There were also signs of decompensated right heart failure, including markedly enlarged dilated right heart chambers, pericardial effusion, and flattening of the interventricular septum (Fig. E). Though some of the ground glass opacities could have been consistent with pulmonary edema or parenchymal inflammation, additional areas had tract-like abnormalities leading to pleural edge, atypical for either of those entities [] and not conforming to normal pulmonary vasculature (Fig. D). Immediately after her disclosure of the ingestion of parasites, the patient was treated with albendazole and corticosteroids for presumed Löffler’s syndrome with transient improvement in her dyspnea and hypoxemia. However, due to progressive hypoxemia and signs of decompensated right heart failure on her examination at her outpatient visit, she was admitted to the hospital. Transthoracic echocardiogram revealed preserved left ventricular function but severely dilated right sided chambers, with a right ventricular systolic pressure estimated at 90 mmHg. Repeat RHC revealed persistently elevated mean PA pressure of 73 mmHg, worsened PCWP of 17 mmHg, and elevated pulmonary vascular resistance of 11.5 Wood units. Due to rapid decompensation and severity of hypoxemia, bronchoscopy was not able to be performed. Respiratory failure progressed, with the development of refractory hypoxemia and right heart failure that did not respond to aggressive medical therapy in the intensive care unit, including intravenous diuresis and treprostinil as well as inhaled epoprostenol. She was emergently evaluated for lung transplantation but was not offered listing due to her comorbidities, which included severe esophageal dysmotility and renal dysfunction. Her respiratory status continued to deteriorate despite aggressive medical intervetion, and the patient decided to transition to comfort-focused care. She passed away shortly thereafter, and post-mortem examination was declined by her family.

pmc-8686560-1

A 36-year-old woman presented to a local hospital with a history of neck pain. Computed tomography (CT) and magnetic resonance imaging (MRI) demonstrated a tumor arising from the anterior elements of the C1 and C2 vertebrae. Cervical spine fusion and mass reduction surgery were performed. The resected specimen showed diffuse proliferation of plasma cells and was diagnosed as “plasmacytoma” at that time. Additional radiotherapy was performed, but the patient later dropped out from the treatment course. Sixteen years later, at the age of 52 years, the patient returned complaining of dysarthria. CT and MRI showed a similar but much larger mass at the same location, and recurrence of the tumor was diagnosed (Fig. ). The mass compressed the spinal cord and was thought to be responsible for the dysarthria. The patient was referred to our hospital for further examination and treatment. Quantitative serum Ig analysis showed an increased level of IgG (2096 mg/dl; reference range 870–1700 mg/dl) and normal levels of IgM (203 mg/dl; reference range 46–260 mg/dl) and IgA (293 mg/dl; reference range 110–410 mg/dl). A serum Ig-free light chain study revealed increased levels of both free kappa light chain (61.5 mg/l; reference range 2.42–18.92 mg/l) and free lambda light chain (88.1 mg/l; reference range 4.44–26.18 mg/l) (kappa/lambda: 0.70). Excisional biopsy of the tumor was performed. Flow cytometry analysis demonstrated a distinct population of abnormal plasma cells which were positive for CD56 (96%), CD38 (70%), CD45 (9%), and CD19 (1%). Approximately 96% of these tumor cells co-expressed cytoplasmic kappa and lambda light chain based on a CD38-positive gate strategy (Fig. ). Histologically, the specimen showed diffuse proliferation of plasmacytoid tumor cells with pale paranuclear area and dense chromatin, and immunohistochemistry showed that these tumor cells were strongly and diffusely positive for CD138 (Fig. a, b) and MUM1, and negative for CD3, CD20, and CD56. Immunohistochemistry for IgL demonstrated co-expression of kappa and lambda light chain (Fig. c, d). Additionally, we demonstrated in situ hybridization (ISH) targeting IgL mRNA using FFPE specimen, and ISH also revealed that tumor cells co-expressed kappa and lambda light chain (Fig. e, f). Bone marrow biopsy showed no evidence of plasmacytes showing dual expression or deviation of kappa and lambda light chain, and additional CT and MRI revealed no skeletal abnormality except for the primary lesion, and absence of end-organ damage attributable to a proliferative plasma cell disorder. We reviewed the previous specimen and performed additional IgL immunohistochemistry. The sample revealed a histological pattern similar to that of the later sample as well as co-expression of kappa and lambda light chain (Additional file : Fig. S1). Taking these findings together, the tumor was diagnosed as SPB with dual expression of the kappa and lambda light chains. After diagnosis, the patient underwent nine courses of VRD (bortezomib, lenalidomide, and dexamethasone) therapy, which reduced the size of the lesion. Two years after diagnosis, the lesions have not increased in size, and bone marrow examinations have shown no progression to PCM.

pmc-8686567-1

In May 2021, a 19-year-old caucasian male patient was referred to the university hospital of Brandenburg owing to a severe decline of excretory kidney function. The serum creatinine concentration was 649 µmol/l (normal range 62–106 µmol/l) at the time of admission (Fig. ). The patient suffered from mild dyspnea, lack of appetite, and moderate itchiness. The patient did not report any known diseases, nor did he take any medication on a regular basis. Approximately 10 weeks earlier, he had an upper respiratory tract infection that did not require antibiotics or other medications such as nonsteroidal anti-inflammatory drugs (NSAIDs). Since then, he did not recover completely but instead suffered from persistent fatigue. Also, he lost 8 kg of body weight until admission. He denied fever, nausea/vomiting, myalgia, arthralgia, skin abnormalities, photosensitivity, Raynaud symptoms, and hair loss. He did not report morning stiffness or lower back pain. Three weeks before admission, he noticed pain in his right eye, accompanied by redness and blurred vision. A prompt ophthalmological examination led to the diagnosis of anterior uveitis. The ocular inflammatory process was not treated in a systemic manner, particularly not with systemic steroids, antibiotics, or NSAIDs. He exclusively received steroid-containing eye-drops. One day before admission, he underwent outpatient control of several blood parameters to identify the etiology of ocular inflammation. Serum analysis showed severely deteriorated kidney function. At the time of admission, he presented an overall reduced physical condition. His height was 180 cm and body weight 93 kg (BMI: 28.7). His initial blood pressure was 144/114 mmHg and heart rate 124 beats per minute. Respiratory rate was 14 breaths per minute, and peripheral oxygen saturation was 99%. He had no increased body temperature. Examination of heart, lungs, and abdomen did not reveal any pathological findings, the same applied for both the central and peripheral nervous system. Abdominal skin was moderately affected by striae distensae. Besides impaired excretory kidney function, the patient showed moderately increased C-reactive protein (CRP) (45.7 mg/l; normal range < 5 mg/l) and elevated haptoglobin (2.6 g/l; normal range 0.3–2.0 g/l). Also, parathormone (PTH) was mildly elevated (72.8 pg/ml; normal range 15–65 pg/ml). Immune diagnostics revealed the following positive findings: anti-nuclear antibodies (ANA) titer (1:160; normal range < 1:160) and anti-La (56.6; normal range < 46). Both cytoplasmic and perinuclear Anti-Neutrophil Cytoplasmic Antibodies (c- and pANCA) were negative, anti-proteinase 3 was 2.3 U/mL (normal range < 10 U/mL). Light chain (LC) diagnostics showed increases of both, kappa- and lambda-LC (121 mg/l; normal range 3.3–19.4 mg/l, and 60.1 mg/l; normal range 5.71–26.3 mg/l), and the ratio differed from the normal range as well (2.01; normal range 0.26–1.65). Total serum immunoglobulin-G (IgG) was mildly elevated (22.1 g/L; normal range 5.49–15.8 g/L). Chlamydia pneumoniae-IgG (21 RE/ml; normal range < 16 RE/ml) was positive, as was serological testing for Epstein–Barr virus (EBV) [virus-capsid antigen (VCA) EBV-IgG-antikoerper (Ak) (enzyme-linked immunosorbent assay) 137 RE/mL (normal range < 16 RE/mL), Epstein-Barr Nuclear Antigen 1 (EBNA 1)-IgG-Ak 1.02 (normal range < 80)]. Differential blood cell count showed an eosinophil percentage of 3.6% (normal range 0.5–7%). Other non-aberrant findings were monocytes, platelet count, and serum and urine calcium. Semiquantitative urine analysis showed a proteinuria of 0.25 g/l and few erythrocytes (25/µl; normal: negative). The daily proteinuria was determined to be 0.77 g (normal range < 0.15 g). Urinary eosinophils were negative. Transthoracic echocardiography showed a mildly reduced left ventricular ejection fraction (50%; normal range > 60%). Diastolic function was impaired, although mild as well. The inferior part of the left ventricle was akinetic. Visually, the right ventricular function was slightly reduced. Computed tomography of thorax and abdomen revealed diffuse intraabdominal lymph node expansion. The initial ophthalmological investigation confirmed the diagnosis of unilateral anterior uveitis of the right eye. Specifically, the right conjunctiva showed perilimbical hyperemia, and the cornea was unaffected. The anterior chamber was not flattened and did not contain relevant cell numbers. Retinal investigation did not reveal any signs of inflammation. Due to AKI of unknown origin, we performed kidney biopsy (6 days after admission). Two samples were obtained from the left kidney. Initial ultrasound analysis showed normal organ dimensions and no signs of obstruction. The pathological investigation by an experienced renal pathologist showed interstitial inflammatory infiltrates around the tubuli mainly composed of lymphocytes (Fig. ). The findings led to the diagnosis of acute interstitial nephritis []. Signs of glomerular inflammation were absent. The diagnosis was tubulointerstitial nephritis with anterior uveitis (TINU) syndrome of no specific or suspected origin. Immediately after admission, the patient received intravenous glucocorticoids (prednisolone 250 mg daily) on three consecutive days, followed by oral prednisolone (1 mg/kg daily for 7 days, dose reduction of 10 mg daily every 7 days thereafter) since we initially suspected an ANCA-associated autoinflammatory disease. Also, we started the patient on renal replacement therapy (RR, hemodialysis) after central vein catheter insertion into the right femoral vein. Volume depletion during individual dialysis session was not mandatory since urine production was not affected. One week after admission, the patient suffered from fever and general weakness. He received intravenous antibiotics (piperacillin and tazobactam) and was transferred to the local intensive care unit (ICU). The central vein catheter was removed since the patient showed localized pain around the insertion area, that is, signs of catheter-related blood infection. RRT was continued after establishing a new central vein catheter at the ICU. Two days after the initial fever attack, the patient developed generalized rash including moderate itchiness. The antibiotics therapy was adapted to meropenem. During the ICU stay, oral prednisolone therapy was continued as initiated. Discharge from the ICU was initiated after 3 days. The last dialysis treatment session was performed 1 week before discharge from the hospital (Fig. ). Kidney excretory function continuously improved, with a last serum creatinine concentration of 214 µmol/l. Also, the ocular manifestation resolved almost completely after local corticosteroid eye drop treatment for 7 days. The in-hospital stay lasted for nearly 3 weeks, and the further management was planned in the outpatient area.

pmc-8686569-1

A 58-year-old Japanese woman with a 3-year history of genital ulcers and oral aphthae was admitted to our hospital. She had a history of uterine fibroids and thrombocytopenia during pregnancy. Her family history included hypertension and diabetes in her mother and MDS in her offspring. A year ago on admission, she developed abdominal pain and persistent diarrhea. Colonoscopy revealed multiple colonic ulcers, and she was referred to our hospital. On physical examination, we found erythema nodosum without uveitis on the left forearm. Laboratory tests revealed macrocytic anemia (red blood cell count, 251 × 104/μl; hemoglobin level, 9.3 g/dl). White blood cell and platelet counts were 4800/μl and 14.3 × 104/μl, respectively. Serum C reactive protein levels were 0.35 mg/dl and anti-nuclear antibody was negative. Human leukocyte antigen analysis was positive for B51 and A26. Colonoscopy showed multiple, round, punched-out ulcers from the terminal ileum to the descending colon (Fig. a, ). Intestinal Behçet’s disease (BD) was diagnosed, and she received 3600 mg of mesalazine, 0.5 mg of colchicine, and 30 mg of oral prednisolone per day. Adalimumab, a TNF inhibitor was also added for maintenance therapy. However, during steroid tapering, her abdominal symptoms relapsed. Persistent anemia was observed and bone marrow examination was performed. The results revealed the presence of trisomy 8, trisomy 9, and X chromosome abnormalities (48, + 8, + 9, X, i(X) (q10) in 12 out of the 20 cells examined; Fig. ). The patient’s bone marrow was hypoplastic with the appearance of micromegakaryocytes and < 1% of atypical cells, resulting in the diagnosis of low-risk MDS (refractory anemia). At the age of 60, Infliximab (5 mg/kg) against refractory intestinal BD was initiated instead of Adalimumab. Infliximab was temporary effective for abdominal symptoms, however, she developed pneumonia with fever at the age of 61. Chest X-ray and lung computed tomography (CT) showed diffuse ground-glass opacities in both lungs (Fig. a, ). High-resolution chest CT and histopathology via transbronchial lung biopsy revealed the presence of pulmonary alveolar proteinosis (Fig. ). Her serum GM-CSF concentration was 4.3 pg/ml (normal range, < 5 pg/ml) and an anti-GM-CSF antibody was negative. Based on findings with the underlying disease, a diagnosis of SPAP was established. She was treated with infliximab (5 mg/kg) for active intestinal BD for every 4 weeks and received whole lung lavage to improve respiratory symptoms with SPAP. She is now preparing to receive bone marrow transplantation as a curative treatment.

pmc-8686580-1

A 36-year old woman was referred to a tertiary unit at 29+5 weeks of gestation due to fetal cardiomegaly and mild ascites (Fig. a, b), which was detected on a scan undertaken for suspected small for gestational age. The woman was nulliparous with a low-risk first trimester combined screening test and unremarkable anomaly scan. She was rhesus B negative and underwent non-invasive prenatal testing that determined the rhesus genotype of the fetus to be rhesus B negative. Otherwise, no red blood cell antibodies were reported. Of note, the maternal grandmother was known to have sideroblastic anaemia that was diagnosed at 17 years of age. The mother of the unborn fetus and her brother had undergone testing as children but were told that no further follow-up was needed. Unfortunately, additional information regarding and genetic testing for this family history was not available. The woman had mild macrocytic anaemia with haemoglobin of 10.4 g/dl and a mean corpuscular volume of 104 fl. The woman had not received any preconceptional or genetic counselling. Upon arrival, the first scan in our department demonstrated a middle cerebral arterial (MCA) peak systolic velocity (PSV) value above 1.5 Multiples of the Median (MoM). Fetal biometry was normal, as was the amniotic fluid index and umbilical artery doppler. Dexamethasone for fetal lung maturation was administered, and an uncomplicated in utero fetal blood transfusion (IUT) was performed at 30+3 weeks of gestation. The pre-transfusion fetal haemoglobin was 4.4 g/dl, which was increased to 14.1 g/dl following 120 mL of blood transfusion through the intrahepatic portion of the umbilical vein (Fig. ). Investigations to determine the underlying cause of fetal anaemia included microarray comparative genomic hybridization, serology to exclude congenital infection, a peripheral blood film and fetal bilirubin to detect haemolysis. These preliminary investigations were normal. A fetal MRI brain was performed, which showed no abnormalities. In the subsequent weeks, the MCA-PSV improved, as did the cardiomegaly. At 35+3 weeks of gestation, the MCA-PSV increased to above 1.5 MoM. The options of delivery and ex-utero transfusion versus IUT were discussed with the multidisciplinary team and with parents. As it was considered that an IUT would allow pregnancy to proceed to term, it was decided to proceed with IUT. A second IUT took place with a pre-and post-transfusion fetal haemoglobin of 9.7 and 15 g/dl, respectively. The MCA-PSV remained stable until 37 weeks and three days when a caesarean section for breech presentation was planned. Fetal biometry was consistent with previous measurements, and the amniotic fluid index and umbilical artery doppler were normal. The woman was counselled regarding the need for delivery and likely need for exchange transfusion in the neonatal period. Delivery of a female infant via caesarean section due to breech presentation was performed at 37 + 4 weeks. The birth weight was 3150 g, and apgar scores were 8 and 10 at 1 and 5 minutes, respectively. Subsequently, the infant again became anaemic, requiring regular 3–4 monthly blood transfusions but she is making good developmental progress. Her anaemia was unresponsive to pyridoxine. Iron levels should be closely monitored to detect the need for chelation therapy in future care plans, since iron toxicity is a major cause of morbidity and mortality in XLSA []. Fetal and maternal blood was collected for DNA extraction, at the time of the first IUT. DNA was sequenced by next-generation sequencing for 11 genes associated with sideroblastic anaemia. Analysis was performed using Agilent SureSelect XT custom enrichment technology and Illumina DNA sequencing. Significant maternal cell contamination of the fetal blood sample was excluded using the ABI AMPFLSTR Identifiler PCR Amplification Kit. A heterozygous variant in the ALAS2 (NM_000032.4) gene was identified in both the mother and the fetus. The c.488G > A; p.(Arg163His) variant identified affects a conserved amino acid and is absent from the gnomAD controls database []. The variant was therefore classified as pathogenic according to the American College of Medical Genetics (ACMG) variant interpretation guidelines []. The findings for both the mother and the fetus were confirmed by Sanger sequencing. These results were available two days following delivery and verified a heterozygous ALAS2 c.488G > A; p.(Arg163His) and SLC4A1 c.876 + 5G > A mutations in both the baby (Fig. a) and the mother (Fig. b). X-inactivation studies [, ] were undertaken. There was no significantly skewed X-inactivation in the sample provided from the baby. The level of X-inactivation in the mother could not be determined, as she was uninformative for the AR locus [].

pmc-8686586-1

We report a 31-year-old Saudi male patient who presented initially to the neurology clinic at King Faisal Specialist Hospital and Research Centre, Jeddah, to evaluate reversible recurrent rhabdomyolysis. The patient was healthy and had no medical background prior to this presentation. He denied the use of any medications or herbal agents. His family history was negative for any neurological illnesses, and his parents were not related. The patient was unemployed at the time of the first presentation. He habitually smoked one pack of cigarettes per day for 10 years, however, he had no history of alcohol intake or illicit drug use.

pmc-8686601-1

An 80-year-old Japanese woman presented with a history of TTS complicated by ischemic enteritis (Fig. ). She was previously admitted to our hospital, where she presented with bloody stools due to ischemic enteritis, and was treated with hydration of 1500–2500 mL/day and dobutamine. The patient was subsequently discharged without cardioprotective drugs. She was married and had one daughter. She had no family history of cardiovascular disease. She used to cook at a nursing home but she retired. She had smoking history and a drinking habit. She presented to our hospital with upper abdominal pain and bloody stools, 4 months after her first hospital admission for TTS. At the examination, her general condition was good, she was conscious alert, with a temperature of 36.6 °C. Her height and weight were 148 cm and 42 kg (body mass index 19), respectively. Her blood pressure was 114/80 mmHg, heart rate was 90 bpm, and arterial oxygen saturation on room air was 97%. Her abdominal pain improved upon admission. Her abdomen was flat, soft, tender, and had good gurgling,however, digital rectal examination showed blood on the examining finger, indicating a possible relapse of ischemic enteritis. Physical examination showed a regular cardiac rhythm with normal S1 and S2, no detectable murmurs, and clear lungs. Although the patient did not experience chest pain, her electrocardiogram revealed negative T waves in many leads (I, II, III, aVL, aVF, V2, V3, V4, V5, V6). Blood examination showed that her brain natriuretic peptide (BNP) and troponin I levels had risen to 1578 pg/mL (healthy upper limit 18.4 pg/mL) and 357.2 pg/mL (healthy upper limit 15.6 pg/mL), respectively. Her blood urea nitrogen (BUN) and creatinine levels had risen to 26.1 mg/dL (healthy upper limit 20.0 mg/dL) and 0.87 mg/dL (healthy upper limit 0.79 mg/dL), respectively. There were no findings of liver dysfunction. Echocardiography showed wall motion abnormality centered on the left central ventricle, with ballooning of the apical portion. We suspected the recurrence of TTS. We believe that the abdominal pain and dehydration due to ischemic enteritis may have contributed to the development of TTS. As a treatment, we gave the patient a small amount of oxygen (2 L/min). She also received 10,000 units/day of continuous intravenous heparin for 2 days to prevent left ventricular thrombosis, and fluid replacement of 1500 mL/day to treat TTS (Fig. ). Although her body weight increased temporarily, the urine volume was normal, oxygenation was stable, and exacerbation of heart failure was not observed. The BNP level also showed a downward trend; hence, diuretics were not administered and hydration was continued. The BNP level and myocardial wall motion were normalized on the fourth day after admission (Fig. ). For differentiation of ischemic heart disease, a coronary angiography and an acetylcholine provocation test were conducted on the 22nd day after admission. Although no significant stenosis was found in the coronary artery, the acetylcholine provocation test revealed a considerable multivessel coronary spasm in the left coronary artery, suggesting coronary vasospastic angina pectoris associated with TTS, which was treated using β-blockers, calcium channel blockers, and nicorandil. She was discharged on the 22nd day. The negative T-wave on the electrocardiogram normalized on the 60th day after discharge. (Fig. ). She was also treated in gastroenterology and psychiatry, and was prescribed probiotics and anxiolytics. Her ischemic enteritis remained stable without abdominal pain. Subsequent follow-up showed no recurrence of TTS over 3 years.

pmc-8686604-1

A 63-year-old female patient was admitted to our hospital with intermittent epigastric abdominal pain for the past three months. Results of the physical examination on admission indicated no icteric sclera. The abdomen was soft with no palpable abdominal mass. The patient had experienced a weight loss of about five kg in the past two months and had no history of hepatitis B or C. She had been exposed to dogs and sheep and denied any history of exposure to infected cases from the epidemic area. After admission, CA19-9 was measured and was 796.20 U/mL. No serological examination for echinococcosis was performed because of the limited conditions of our hospital. Test results from pelvic ultrasound indicated menopausal uterus and uterine fibroids. Test results from gastroscopy showed chronic non atrophic gastritis. Colonoscopy revealed multiple polyps in the large intestine (basically removed); intestinal histopathology (cecum, biopsy) showed severe chronic inflammation of the mucosa and adenomatous hyperplasia of the individual glands. Contrast-enhanced computed tomography of the upper abdomen (Fig. A) revealed a more homogeneous thickening of the gastric wall in the antrum. Round unenhanced low-density foci with a diameter of 4.6 cm was seen in the S7 segment of the liver. Nodular calcifications were also observed. No significant dilatation was noted in the intrahepatic and extrahepatic bile ducts. The size and shape of the gallbladder were normal, the wall was not thick, and no significant abnormal density was observed in the cavity. The pancreas, spleen, and adrenal glands showed no significant abnormalities. Test results from computed tomography indicated liver cyst and intrahepatic calcifications. Contrast-enhanced magnetic resonance imaging of the liver and gallbladder (Fig. B, ) revealed a normal size and shape of the liver and proportion of each lobe, and the intrahepatic and extrahepatic bile ducts and flow vessels ran naturally. A long T1 and long T2 cystic signal with a diameter of about 4.7 cm was observed in the right lobe of the liver, with liquid level, short T1 high signal intensity in the lower layer, high signal intensity on diffusion-weighted imaging sequence, and enhancement of the cyst wall on the enhanced scan. Test results from magnetic resonance imaging showed that the space-occupying lesion of the right lobe of the liver had been considered to be more likely a hepatic hydatid cyst. Preoperatively, three-dimensional reconstruction demonstrated the location of the tumor and its relationship with the surrounding vessels (Fig. A). The patient underwent laparoscopic S7 segmentectomy. Intraoperative findings showed that the tumor was located at the S7 segment of the liver and was about 5 × 4 cm in size and partially protruding from the surface of the liver, with an intact capsule and clear boundary with normal liver tissue. The tumor compressed the right hepatic vein and its tributaries and densely adhered to the right hepatic vein (Fig. B). On postoperative pathology, a mass was observed immediately adjacent to the liver capsule, with a volume of 5 × 5 × 4.5 cm. The section surface showed a brown turbid fluid, a smooth inner wall, and greyish red, greyish yellow, and soft section surfaces of other liver tissues. The pathological section showed a low-grade mucinous cystic neoplasm (volume 5 × 5 × 4.5 cm) in the S7 segment of the liver, with steatosis in the surrounding hepatic tissue area, chronic inflammatory cell infiltration in the portal area, and no tumor cell involvement in the margin of the liver resection. Immunohistochemistry demonstrated tumour cells CK7 (+), CK19 (+), and CEA (−); stromal cells ER (+), PR (+), α-inhibin (a small amount +), vimentin (+), desmin (+), and actin (+) (Fig. A–C). This study was approved by the Ethics Committee of Yantai Affiliated Hospital of Binzhou Medical University.

pmc-8686613-1

In 2009, a 29-year-old Peruvian male presented with a 3-month history of a chronic cough productive of yellow/green coloured sputum with occasional haemoptysis, associated with significant fatigue, diminished appetite, weight loss (7 kg in two months), night sweats and back pain. A chest X-ray demonstrated right-sided apical cavitation with prominent bilateral hilar lymphadenopathy. A sputum specimen was positive for acid fast bacilli. Microscopic Observed Drug Susceptibility (MODS) testing did not indicate drug resistance. The patient was treated with a 4-drug (rifampicin, isoniazid, pyrazinamide and ethambutol) anti-TB antibiotic regimen for a course of two months. Rifampicin and isoniazid was continued for a further four months. Sputum smears became negative after one month of treatment suggestive of a favourable disease progression and six subsequent sputum smear samples were negative. A repeat chest radiograph demonstrated right-sided apical fibrous reticular infiltrates consistent with treated inactive TB. The patient was considered to be in remission and remained asymptomatic thereafter. The patient was born in the Callao region of Peru (population size 800,000). The patient shared one bedroom with his wife, son and parents in law. The patient’s locality is known for a pig farm that employs many of the region’s residents. Our patient’s bother worked on this pig fam and had regular contact with our patient. 1-month prior to our patient’s presentation the patient’s brother was successfully treated for TB, the causative MTBC agent was not identified. The patient did not report any other contacts with domestic or wild animals and denies ingesting unpasteurised dairy products. There was no further household transmission of TB between our patient and the other members of his household. The patient’s sputum sample was processed on both liquid (MODS) and solid Ogawa medium. An aliquot was sub-cultured and underwent Spoligotyping after DNA extraction at the Universidad Peruana Cayetano Heredia (Lime, Peru) [, , ]. The isolate was identified as M. caprae and was further genotyped using a 15-loci MIRU-VNTR analysis at the Kobe Institute (Kobe, Japan) following established protocols []. Subsequent whole genome sequencing identified the sample as M. caprae.

pmc-8686613-2

In 2008, a 64-year-old Peruvian male presented with a 3-month history of a productive cough with haemoptysis and shortness of breath. A sputum smear was positive for acid fast bacilli. MODS testing did not indicate drug resistance. A chest radiograph demonstrated apical cavitation of the left upper and middle lung lobe with blunting of the left costo-diaphagmatic angle. The patient was treated with the standard 4-drug regimen for a total course of 6 months. Sputum smears became negative after one month of treatment suggested favourable disease progression and five subsequent sputum smears were negative. However, 1 month after the patient stopped treatment he deteriorated clinically and had three positive smears. He was treated with a second line anti-TB regimen of ethambutol, pyrazinamide, ethionamide, ciprofloxacin, cycloserine, kanamycin and para-aminosalicylic acid for a total duration of 18 months. Despite initial improvements in symptoms, the patient relapsed again on 2nd line therapy and died of respiratory failure in 2012. The patient lived alone in the region of Lima South (population size 1,200,000). Prior to his initial hospitalisation the patient had spent two months visiting family in the city of Huánuco in central Peru. This region has the greatest density of cattle farms and grazing cows in the country. While the consumption of unpasteurised milk in Huánuco is commonplace, our patient denies consuming unpasteurised dairy products. The patient’s sputum sample was processed on both liquid (MODS) and solid Ogawa medium. An aliquot was sub-cultured and underwent Spoligotyping after DNA extraction at the Universidad Peruana Cayetano Heredia (Lime, Peru) [, , ]. The isolate was identified as M. bovis and was further genotyped using a 15-loci MIRU-VNTR analysis at the Kobe Institute (Kobe, Japan) following established protocols []. Subsequent whole genome sequencing identified the sample as M. bovis.

pmc-8686832-1

The proband, a 2-year-old Russian girl at the time of the last clinical evaluation, was admittedto the neurological department with repeated, prolonged myoclonic, and generalized seizures responsive only to intravenous injection of diazepam. She was the fourth child of healthy parents from a non-consanguineous marriage. The proband has three healthy siblings (). During the pregnancy, a risk of miscarriage was observed at 12 weeks of gestation. Delivery and neonatal period were unremarkable. At the age of 4 months, during obstructive bronchitis, she developed an absence seizure with apnea 3–5 s long that repeated daily afterward. At the age of 5 months, during hot water bathing, the proband had a prolonged generalized myoclonic seizure for 40 min that was responsive only to diazepam injection. Similar episodes repeated every 7–10 days without any provoking factors. On brain magnetic resonance imaging (MRI), periventricular leukomalacia was noted and was considered as a result of ischemic brain injury with no relevance to the epileptic phenotype of the patient. Routine electroencephalography (EEG) did not show any epileptiform activity in the interictal period. Antiepileptic therapy included carbamazepine (300 mg/day), topiramate (87.5 mg/day), and clonazepam (0.75 mg/day), which had no effect on seizure frequency and duration. In the evaluation, the proband had prolonged myoclonic, tonic-clonic, and atonic seizures once a week. Early motor milestones were normal, but language development was delayed. Neurological examination at the age of 2 revealed moderate hypotonia with brisk tendon reflexes and mild gait ataxia. Based on the clinical picture, the proband was diagnosed with DS.

pmc-8687813-1

The patient is a 7-year-old boy born and raised in the Central-West region of Brazil (Cuiabá) from nonconsanguineous parents. He exhibited odontogenic abscesses associated with unexplained sinusitis at age 4 with resolution of the condition after standard treatment. At the age of 5 years, a low-impact trauma in the right elbow, evolved to a local disproportional inflammation within a few hours, was treated with immobilization with plaster splint. Over the following two weeks, the patient developed fever and persistent, painful edema diagnosed as pyoarthritis in the right elbow. At that time, laboratory analysis revealed mild anemia (hemoglobin (Hb) = 10.0 g/dL), hematocrit (Ht) = 30.5%), high levels of acute reactant markers (erythrocyte sedimentation rate (ESR) = 21 mm, and C-reactive protein (CRP) = 15.3 mg/dL (reference value (RV) < 1 mg/dL)). Also, a computed tomography (CT) of the right elbow revealed the presence of diffuse periosteal reactions affecting the proximal metaphyseal regions of the radius and ulna, as well as of the distal metaphyseal region of the humerus plus voluminous joint effusion and diffuse soft tissue elbow enlargement, especially in the medial aspect. With the diagnostic impression of probable sepsis of the elbow, the patient underwent arthrotomy with surgical drainage of a large amount of purulent fluid with lumps, and broad-spectrum antibiotic therapy was initiated. After 72 hours of antibiotic therapy and arthrotomy, the patient maintained the marked painful edema in his right elbow and culture of the synovial fluid came out negative. The patient remained hospitalized until the 53rd postoperative day when he presented with sudden and pronounced edema and pain in the left knee after trauma caused by falling from his own height while playing in the corridor of the ward. He underwent to another arthrotomy of the left knee with discharge of abundant purulent liquid. Due to persistent painful edema, the patient underwent another arthrotomy of the left knee for drainage of a joint effusion that was repeatedly purulent, all with negative cultures. Of note, a magnetic resonance imaging of the left knee () showed significant inflammatory arthropathy, with joint effusion associated with diffuse synovitis; extension of the inflammatory process into the periarticular soft parts affecting the popliteus and quadriceps muscle; extrusion of the medial meniscus; and small foci of inflammatory edema affecting the subcortical bone marrow of the trochlear sulcus and the medial femoral condyle, which may have corresponded, according to the radiological report, to the focus of incipient osteomyelitis. After 60th day of hospitalization, the patient was discharged, but two weeks after, there was another need for hospitalization due to another arthritis. At that time, laboratory analysis demonstrated high levels of acute reactants markers, and he never evaluated to sepsis. Another arthrotomy was necessary again with pus drainage. Because of the recalcitrant situation and the suspicion of an inborn error o immunity, a target gene panel (Invitae panel, 407 genes, Jeffrey Modell Foundation Partnership Program) was requested, and an already reported mutation in the PSTPIP1 (c.688 G > A (p. Ala230Thr)) gene was found in the patient and in the mother. Curiously, just after genetic founding, the mother discovered similar cases in the family and reported of herself having a prolonged episode of arthritis in the right knee, which began after trauma during a soccer game at the beginning of her adult life. During the reported occasion, she fully recovered, and other members of the family have not yet been genetically investigated. She also reported of having had cystic acne throughout adolescence and young adulthood, with nowadays facial skin marked by scar depression. Finally, genetic sequencing was not just essential for the diagnosis but also for genetic counseling and clarification of the underlying condition. During 2 years of follow-up, no episodes of pyoderma gangrenosum were noted, neither in the mother nor in the index patient. After being discharged from his last hospital stay, the patient presented at the age of 8 with two more subsequently episodes of left knee arthritis triggered by low-impact local trauma and a new episode of arthritis, this one in the right ankle, due to trauma secondary to the use of inadequate footwear (). In these episodes, the response to treatment with prednisone 1 mg/kg over 3 weeks was satisfactory, followed by gradual withdrawal. However, no specific measure could be accessed to infer the impact of the nonpreventive treatment with anti-IL1, as suggested in the literature. Unfortunately, anti-IL1 blockers are not available, in both public and private systems in Brazil, and that is the reason the patient did not receive it.

pmc-8687820-1

A 45-year-old Caucasian male visited his gastroenterologist for follow-up on Crohn's disease, which was limited to the terminal ileum. Three months prior to the present episode, treatment with 6-mercaptopurine was discontinued due to elicited leukopenia. There were no clinical signs of activity of Crohn's disease, but he reported an acute worsening of chronic lower back pain for three weeks, which was accompanied by chills for two days. Due to the absence of fever, he was discharged after blood cultures were drawn. After 48 hours, a Gram-positive coccus (Granulicatella adiacens) was detected, and he was requested to come to our emergency department. He reported no recent history of dental treatment, signs of respiratory infection, or gastrointestinal complaints. On physical examination, he did not appear acutely ill. The blood pressure was 130/93 mmHg, his pulse 120 beats per minute, and his auricular temperature 37.5°C. Except for a holosystolic heart murmur in the apical region, no abnormalities were found on examination. Specifically, no spinal percussion tenderness or focal neurological deficit was detected. His hemoglobin level was 11.0 g/dL (ref. 14–18 g/dL), and his white blood cell count was within the normal range. The erythrocyte sedimentation rate (46 mm/h; ref. 0–10 mm/h) and C-reactive protein (45 mg/L; ref <8 mg/L) were elevated. He received penicillin 12 ∗ 106 U/24 h and gentamicin 3 mg/kg/24 h intravenously for possible endocarditis. Both transthoracic and transesophageal echocardiograms were performed, which showed mitral valve insufficiency based on a prolapse, but no vegetation or other echocardiographic signs of infectious endocarditis. Therefore, the Dukes criteria were not met, and endocarditis was ruled out with reasonable certainty. Gentamicin was discontinued, and the dose of penicillin lowered to 6 ∗ 106 U/24 h. Lumbar MRI showed vertebral osteomyelitis at discus L2 and L3 (white arrow, ). In total, our patient was treated with intravenous penicillin for Granulicatella adiacens osteomyelitis for three weeks, followed by two weeks of oral clindamycin (600 mg three times daily). Clindamycin was chosen for its high bone tissue penetration. Six weeks after cessation of antibiotic treatment, the patient had fully recovered. In addition, this was supported by low inflammation markers and negative follow-up blood cultures.

pmc-8687828-1

A 72-year-old female presented to the emergency room after injuring her left eye during a syncopal episode. A computed tomography scan performed in the emergency department revealed disorganization of the left globe with blood in the vitreous humor. Her medical history included hypertension, systemic lupus erythematosus, and coronary artery disease. Her vital signs were within normal limits with the exception of mild systolic hypertension. She underwent immediate globe rupture repair under general anesthesia with successful reapproximation of a large 20 mm scleral laceration. In the immediate postoperative period, rather than performing subtenon injection due to the possibility of a more posterior rupture, the surgeon chose to perform a retrobulbar block using 5 mL of bupivacaine 0.5% for postoperative pain management and akinesis (to prevent extrusion of additional intraocular contents). This was done using a 31 mm 25-gauge blunt needle. No blood was aspirated back into the syringe, and the needle advanced without incident. Prior to injection, the patient was breathing spontaneously via the anesthesia machine circuit and had not received any additional narcotics/muscle relaxants for 2.5 hours. There was full recovery of neuromuscular blocking agent after reversal, as demonstrated by the use of a nerve stimulator. Over a duration of 7 minutes, however, the anesthesiologist noted a steady increase in end-tidal CO2, resulting in apnea. She remained intubated and was transported to the postanesthesia care unit for an additional 1.5 hours, after which she was successfully extubated. She was admitted to medicine and monitored for an additional time of 48 hours. No new neurologic or cardiac deficits were found, and she was discharged without event.

pmc-8687841-1

An 11-year-old female soccer player presented to the office with left knee pain that she first noticed 5 years ago after falling off a bike. Since that time she had a low level of pain in the knee, which was now significantly worse over the last month as soccer activities increased, the pain was worse with stairs, running, squatting, and kneeling; it was located in the anterior medial aspect of her knee. She denied radiation of the pain, numbness, tingling, popping, or locking. She had infrequent effusions and was using ice and NSAIDS as needed for pain. She had also tried a course of physical therapy with no improvement. An X-ray showed an osteochondritis dissecans (OCD) lesion of the lateral trochlear groove (), and an MRI was obtained to stage the lesion. The MRI showed a stable OCD lesion of the trochlea (). Given the stability of the lesion and patient age, the decision was made to proceed nonoperatively with weight bearing in a locked knee brace for 8 weeks for activities of daily living and restriction from athletics/sports. At her 8th week follow-up, she still had occasional pain with mild flexion and the X-ray showed bone formation of the trochlear groove without any subchondral collapse or loose bodies (). She was continued in the locked knee brace for another 4 weeks. At her 12th week follow-up, she was pain free and was taken out of the knee brace. Physical therapy was started to strengthen her left lower extremity which had undergone atrophy in the brace, and by 16 weeks, she had regained her strength and was participating in soccer drills. She was transitioned from formal therapy to a home exercise program, and at 20 weeks, she was cleared to return to all activity, doing so without complication.

pmc-8687844-1

The patient was a previously healthy 6-year-old girl of northern European descent whose only concerns had been enlarged tonsils, chronic constipation, and slow growth. She had no other health problems. There was no family history of endocrine or immunologic diseases. While watching television, she developed a grand mal seizure and became apneic. She was emergently transported to Children's Mercy Hospital. Initial physical examination was unremarkable except for short stature, with weight 20 kg (37.7 percentile) and height 104.6 cm (less than the 1st percentile). Family history revealed that the patient's mother is 162.6 cm tall and father is 177.8 cm tall; midparental height is 167.7 cm (50th percentile). She was found to have a critically low total calcium of 1.1 mmol/L (normal range 2.2–2.5 mmol/L) and a blood glucose of 3.6 mmol/L (normal range 3.6–6.1 mmol/L). Her phosphorus was elevated at 3.6 mmol/L (1–1.9 mmol/L), and magnesium was low at 0.49 mmol/L (0.66–0.94 mmol/L). Initial iPTH level was low at 7 ng/L (10–89 ng/L), and subsequent iPTH levels remained low. She was diagnosed with primary hypoparathyroidism. She received intravenous calcium chloride and magnesium sulfate. Computed tomography of the head was normal. An extensive endocrine workup revealed that she had Howell-Jolly bodies consistent with autoimmune hyposplenism, a condition frequently seen in APS1 []. No other autoimmune deficiencies were noted at that time. Karyotype was 46, XX. Evaluation of 22 q 11 variants was normal. A growth hormone (GH) stimulation test was performed during initial admission. Her peak GH level was 12.8 ng/mL (normal >10 ng/mL). With the documentation of two unusual autoimmune findings, genetic testing for AIRE gene was performed. The patient was found to be a compound heterozygote for 2 known disease-causing variants. The first was a nucleotide change of C > T in exon 6 of the AIRE gene resulting in the substitution of the normal arginine codon with a stop codon at position 257. This mutation is denoted R257X or Arg257Term. The second mutation was a 13 base-pair deletion in exon 8, beginning in codon leucine 323 and resulting in a change from leucine to serine, followed by a frameshift and premature stop codon 50 residues downstream (denoted c.967 979del13 and p.Leu323SerfsX50). Thus, she was heterozygous for R257X and c.967 979del13. Both are common, independently recurring mutations in APS1 []. The 13-base deletion has been published with various nomenclature (c.965 977del13 or p.Cys322fsX5l). After testing positive for AIRE gene variants, additional serologic testing revealed seropositivity for 21-hydroxylase antibodies (a marker for adrenal autoimmunity) and positivity for intrinsic factor autoantibodies (a marker for atrophic gastritis). shows her positive serology over time, along with her immunosuppressive medications. Antibody testing for thyroid disease, type 1 diabetes mellitus, and celiac disease yielded negative results at that time. At the age of 6 and a half years, a low-dose ACTH stimulation test showed a borderline peak cortisol of 433 nmol/L (normal >500 nmol/L). ACTH stimulation testing was repeated a year later, at which time, she demonstrated a peak cortisol level of 334 nmol/L, in addition to an elevated renin level. Subsequently, hydrocortisone and fludrocortisone replacement therapy were initiated. shows the number of autoimmune conditions over time along with her immunosuppressive medications. Because of persistent short stature, she underwent repeat GH stimulation testing around age 9. Her peak GH level was 11.8 ng/mL, demonstrating GH sufficiency again. However, as her height was below the 3rd percentile, growth hormone therapy was initiated with excellent response. She ultimately achieved an adult height of 161.5 cm, within the range of her midparental height. Her liver enzymes were modestly elevated at this time. Serologic testing revealed positive smooth muscle antibodies, which are associated with autoimmune hepatitis. At age 10, she developed hypertension and nephrocalcinosis and was placed on thiazide diuretics. At the age of 11 years, serologic testing revealed positive glutamic acid dehydrogenase (GAD), antinuclear antibodies (ANA), and Sjögren syndrome antibodies (SSA). Her thyroid antibodies have remained negative throughout her course. Over time, her smooth muscle antibodies and SSA antibody levels have gradually normalized (). At age 12 years, she began to develop patches of alopecia on her scalp, which was distressing to her. We referred her to rheumatology for aggressive management of her APS1. She was begun on rituximab, monoclonal antibody therapy directed at CD20, a B cell epitope. Unfortunately, soon after she received 2 doses of rituximab, her hair loss progressed rapidly to alopecia totalis and then progressed to alopecia universalis. The patient was referred to pediatric dermatology, who began with intralesional triamcinolone injections but soon added oral methotrexate. She was begun on 20 mg weekly, but this was increased to 25 mg weekly at age 16, which she continues to date. She was empirically placed on 1 mg folic acid daily and vitamin B12 with the methotrexate therapy. Complete hair regrowth was achieved within a year. denotes progressive hair loss ( and ) followed by hair regrowth (). The patient has tolerated the methotrexate well. At the age of 15, she was referred to gynecology for fertility discussion. Periods had been regular throughout, and gonadotropins were normal. Ovarian antibodies, known to be nonspecific, were measured at that time and were positive. Midcycle LH was 25 IU/L, and FSH was 7.1 IU/L. Anti-Müllerian hormone (AMH) level was 21.3 pmol/L (normal range for AMH 7.5–91.8 pmol/L). Six months later, the AMH level was noted to be 6.9 pmol/L, suggestive of low ovarian reserve [, ]. She then underwent fertility preservation. The procedure was highly successful, with 21 eggs harvested and stored. Surprisingly, five months after the retrieval, AMH levels were found to have normalized at 152.4 pmol/L. Her LH and FSH normalized. Her most recent LH is 0.5 IU/L, and her LH is 1.9 IUL. Cycles have remained regular throughout. At age 18, a bone mineral density study noted focal areas of severely decreased bone mineral density in the distal femurs. Plain films showed ill-defined lucencies with adjacent sclerosis in the distal femurs, which we attribute to metaphyseal dysplasia, a rare bone condition previously described in 2003 in 2 unrelated patients with APS1 []. Six months later, she suddenly developed profound hypokalemia, which was thought to relate to apparent mineralocorticoid excess that has been described in APS1 []. This was managed with spironolactone and a reduction in fludrocortisone. A few weeks later, she experienced sudden mental status changes. She was seen emergently and was thought to be in septic shock. Testing for active COVID-infection was negative, but she had IgG antibodies to COVID-and met the diagnostic criteria for multisystem inflammatory syndrome in children (MIS-C). She required fluids and intensive care support. She recovered uneventfully from MIS-C, although she remains with elevated brain natriuretic peptide. She is currently doing well as a college student at a major university and undergoes frequent laboratory monitoring.

pmc-8570624-1

A 3-year-old boy was admitted with severe respiratory distress and tachypnea after upper respiratory tract infection. He had dyspnea, cough, orthopnea, respiratory rate about 43 /min, and mild plethora of the face. He was the only child of family, and his parents were not relatives. He was born through normal vaginal delivery, and his Apgar score was 10 at birth and 5 minutes after birth. He had no developmental delay, but his weight and height were under 3 percentiles of growth, which was also evident on physical examination. We did not find significant data in his past medical history. On physical examination, we found a 5 x 4 cm mass on the left supraclavicular area and neck. The mass was firm and non-tender. Blood pressure was normal. Skin examination revealed multiple café-au-lait spots (). Laboratory data showed hemoglobin (Hb) 10.9 g/dL, WBC 13300 /µL, neutrophil 29%, eosinophil 7%, monocyte 8%, lymphocyte 56%, platelet count 262000/µL, urea 21mg/dL, creatinine 0.6 mg/dL, uric acid 3.9 mg/dL, and lactate dehydrogenase (LDH) 754 U/L. Beta-HCG was 0.66 m IU/ml and alpha fetoprotein was 1.01 IU/ml. Chest radiograph was obtained, which showed a large mediastinal mass (), and chest CT scan revealed a heterogenous mass on the left mediastinum () with extension from thoracic inlet to the neck (). The mass compressed the neck vessels and airway. Corticosteroids were started because of respiratory distress and superior vena cava syndrome. After three days, the patient became stable, and incisional biopsy was taken from the neck mass, indicating proliferation of spindle cells within wire-like collagen fibrils in loose background, in favor of neurofibromatosis ().

pmc-8570626-1

The patient was a 7-year old boy from Miandoab, a city in the south of West Azarbaijan province, Iran. He exhibited no history of prenatal and postnatal diseases and had a normal growth. His healthy parents were cousins. He had successfully passed the first grade of the primary school. The patient suddenly experienced febrile serial generalized tonic-clonic seizures and the hospitalized in Shahid Abbasi teaching Hospital in Miandoab. After controlling his seizures using the bolus doses of phenobarbital and phenytoin, his consciousness level decreased, thereby necessitating endotracheal intubation and assisted ventilation. Then the patient was transferred to our tertiary subspecialty ward in Urmia’s Motahari Hospital. When we visited the patient for the first time, he was suffering from a deep coma; however, his vital signs were normal. On physical examinations, his pupils were dilated with inadequate response to light, the liver was palpable about 4cm below the costal margin; his muscular tone severely diminished, and deep tendon reflexes were undetectable. His examination was otherwise normal. Routine laboratory tests revealed a nonketotic hypoglycemia () and elevated liver enzymes (). According to the endocrinology consultation, a blood and urine sample was obtained to further evaluation into the exact cause of hypoglycemia. The obtained results ruled out ethiologies such as lipid malabsorbtion (TG=92 mg/dl¸ cholesterol 73 mg/dl¸ LDL=37 mg/dl; disorder of respiratory chain (lactate =13 ng/dl)¸ adrenal insufficiency ( cortisol=62.4µg/dl)¸ hypopituitarism (ACTH=411 pg/ml), and hyper insulinemia (insulin= 0.7µIU/ml)[Figure 3] Laboratory tests suggested by our pediatric gastroenterologist to detect the viral or immune cause of hepatitis revealed nothing, and the urine toxicology screening test was negative. Since his older male sibling died five years ago with the similar symptoms, the inherited inborn errors of metabolism were highly likely; thus, we delivered dried blood spot samples to a lab in Germany for tandem mass spectrometry. The brain computerized tomography revealed no edema. Unfortunately, the patient died two days after admission due to multiple organ system failures. The acylcarnitine analysis showed significantly elevated levels of medium-chain acylcarnitines (hexanoylcarnitine(c6)1.3µmol/lit (0- 0.15) and octanoylcarnitine(c8)0.73 µmol/lit (0- 0.23), which is compatible with medium-chain acyl-coA dehydrogenase deficiency (). The filter paper screening also revealed no indication of congenital hypothyroidism ¸ adrenal hyperplasia¸ galactosemia ¸biotinidase deficiency¸ amino acid metabolism disorders and tyrosinemia typ1. Molecular genetics verification was impossible due to the patient's death.

pmc-8570629-1

A 10-year-old girl was referred to our center due to a lack of balance and urinary incontinence from three weeks ago. The patient was the third child of consanguineous parents. Nervous development of the patient was normal before the onset of disease. The disequilibrium had progressed gradually and was consistent with the symptoms of cerebellar involvement and urinary incontinence. Due to prior low-grade fever, the patient had been treated with the suspicion of viral cerebellitis in the previous center and then referred to us owing to the worsening of symptoms. During the physical examination, the patient was unable to sit and walk independently, and cerebellar tests, including finger to nose and tandem gait, were abnormal, deep tendon reflexes were diminished, and Babinski sign was detected bilaterally Brain and cervico-thoraco-lumbar magnetic resonance imaging was performed for further investigation. These tests were normal. Lumbar puncture was also normal (glucose=50 mg/dl, protein= 30 mg/dl white blood cell = 3, and red blood cell = 0). High concentration of lactate dehydrogenase (LDH=4775) and anemia (Hb=8.8 gr/dl, mean corpuscular volume=104 fL, Red blood cell= 2540000, platelet = 163000) were detected in biochemical tests. Thus, the possibility of malignancy was raised. Organomegaly and lymphadenopathy were not seen in abdominal sonography, and hypercellular marrow with megaloblastic changes was observed in bone marrow examination. In addition to these data, elevated mean corpuscular volume (MCV=104 fL) with hyper segmented neutrophil in peripheral blood smear was noted, and the diagnosis of megaloblastic anemia was established. Consequently, vitamin B12 and folate levels were assessed. The serum level of vitamin B12 was found to be 70.41 pg/ml., which was significantly lower than the normal range (160-970 pg/ml). The range of folate was also normal. Regarding the low prevalence of vitamin B12 deficiency in healthy persons, extensive studies have been performed to find out the cause. In order to rule out atrophic gastritis, gastric and duodenal endoscopy and biopsy were performed. The data from the stomach and upper gastrointestinal tract were normal. There was no evidence for celiac disease in duodenal biopsy, and serum anti-tissue transglutaminase (TTG) was within the normal range. Gastrointestinal transit evaluation showed no defect in the mucous membranes of jejunum and ileum. Thus, gastrointestinal disorders were rejected. In urinalysis, 2+ proteinuria was observed with no leukocyturia and hematuria. Further nephrological evaluations, including renal sonography and other specific tests, demonstrated proteinuria (random urine protein/creatine ratio was 1) with an unknown etiology. To rule out the metabolic disorders that can interfere with the metabolism of vitamin B12, chromatography of blood amino acids, urine organic acids assessment, and tandem mass spectrometry were carried out, but no abnormality was detected. Finally, based on the investigations and hematologic and nephrological findings, the diagnosis of Imerslund-Gräsbeck syndrome was established. The patient was treated with a high dose of vitamin B12 daily injection (1000 microgram intramuscular) for one week, followed by 1000 microgram weekly, leading to improved balance. In one-month follow-up, she was able to walk, her cerebellar symptoms had greatly disappeared, and the patient had no incontinency; however, proteinuria persisted.