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616bc5c68d16fb4ffb21ea45bb72e4a4

Neoadjuvant therapy with gemcitabine plus doxorubicin results in a high tumor response rate with moderate oral and hematologic toxicity .

A phase II study of neoadjuvant gemcitabine plus doxorubicin in stage IIIB breast cancer: a preliminary report. The purpose of this ongoing study is to determine the response and safety of a combination of gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) plus doxorubicin as neoadjuvant therapy for stage IIIB breast cancer. Thirty-nine chemotherapy-naive patients were enrolled in the study. The median age was 54 years (range, 32 to 74 years), and the median Karnofsky performance status was 100. gemcitabine 1,200 mg/m(2) was given on days 1 and 8, and doxorubicin 60 mg/m(2) on day 1, followed by surgery or radiotherapy. Ninety-seven of 117 cycles (83%) were administered at full dose. An overall response rate of 95% was obtained, with a complete response in 18% (seven patients) and a partial response in 77% (30 patients). Twenty-eight patients (72%) underwent breast surgery after a maximum of three cycles of neoadjuvant therapy. World Health Organization grade 3/4 toxicities included leukopenia in nine cycles (8%), neutropenia in 16 cycles (14%), febrile neutropenia in 11 cycles (9%), and anemia in two cycles (2%). The most important nonhematologic toxicity was grade 2/4 mucositis in 16 cycles (14%), and/or grade 2/3 diarrhea in 10 cycles (9%). Neoadjuvant therapy with gemcitabine plus doxorubicin results in a high tumor response rate with moderate oral and hematologic toxicity . Semin Oncol 28 (suppl 10):57-61.

https://pubmed.ncbi.nlm.nih.gov/11510035/

cc9932640d9be5ec55eb2675d707e52e

Treatment of invasive sphenoidal aspergillosis is surgical , followed by antifungal therapy , mostly amphotericin B. To optimize the adjuvant antifungal treatment , which is often limited by severe side effects , the new triazole antifungal agent voriconazole with broad coverage of fungal pathogens including Aspergillus was investigated in a study of 4 patients with clinical , radiological and histological signs of invasive sphenoidal aspergillosis .

Invasive sphenoidal aspergillosis: successful treatment with sphenoidotomy and voriconazole. Treatment of invasive sphenoidal aspergillosis is surgical , followed by antifungal therapy , mostly amphotericin B. To optimize the adjuvant antifungal treatment , which is often limited by severe side effects , the new triazole antifungal agent voriconazole with broad coverage of fungal pathogens including Aspergillus was investigated in a study of 4 patients with clinical , radiological and histological signs of invasive sphenoidal aspergillosis . They first underwent endoscopic sphenoidotomy with drainage and extraction of the fungal mass. Postoperatively, 2 patients were immediately treated with voriconazole. Two patients initially received amphotericin B; but this treatment had to be stopped because of acute renal toxicity. Finally, all patients were treated orally with 200 mg voriconazole twice a day for 12-14 weeks. After this combined treatment all patients were asymptomatic and there were no endoscopic or radiological signs of residual fungal disease. The only side effects were nausea in one and transient visual disturbances in 2 other patients. In the 4 patients presented and treated, voriconazole was shown to be effective and less toxic than amphotericin B in adjuvant treatment of invasive sphenoidal aspergillosis.

https://pubmed.ncbi.nlm.nih.gov/17159376/

af6d0095cfd9cc4170dc875f6c8ad4d1

At cross over the ORR was 0 % and 18 % on cross over to vinorelbine and docetaxel respectively with a median TTP of 17.3 weeks ( 95 % CI , 16.3 - 18.1 ) and 18.7 weeks ( 95 % CI , 13.9 - 23.4 ) for those receiving vinorebine and docetaxel at cross over respectively .

A randomized feasibility study of docetaxel versus vinorelbine in advanced breast cancer. docetaxel and vinorelbine have demonstrated efficacy in the treatment of metastatic breast cancer (MBC). This prospective feasibility study compared the efficacy of these two treatments in MBC. ### methods Patients with MBC progressing following anthracycline treatment were randomly assigned to either docetaxel (100 mg/m(2)day 1 q3W) or vinorelbine (25mg/m(2) day 1 q2W). Patients were eligible to cross over at progression. Objective response rates (ORR), time to progression (TTP) and overall survival (OS) were measured. ### results 37 patients were randomised. 2 patients were excluded due to protocol violations. Of 35 remaining patients 17 received docetaxel and 18 received vinorelbine per protocol. ORR was 12.5% and 6.0% respectively for docetaxel and vinorelbine. The median time to progression was 10.4 weeks (range 6-14 weeks) in docetaxel arm and 7.6 weeks (range 4-11 weeks) in vinorelbine arm (p = .82). The clinical benefit rate (defined as complete response, partial response plus stable disease) was 44% in the docetaxel arm and 12% in the vinorelbine arm. Based on intent to treat the median OS in the docetaxel arm was 34 weeks (95% CI, 20.7-48) and 21.2 weeks (95% CI, 17-25.4) in vinorelbine arm (p = .388). 16 patients crossed over, 5 from docetaxel to vinorelbine and 11 from vinorelbine to docetaxel. At cross over the ORR was 0 % and 18 % on cross over to vinorelbine and docetaxel respectively with a median TTP of 17.3 weeks ( 95 % CI , 16.3 - 18.1 ) and 18.7 weeks ( 95 % CI , 13.9 - 23.4 ) for those receiving vinorebine and docetaxel at cross over respectively . vinorelbine however was much better tolerated with fewer grade 3-4 toxicity events (n = 4) than docetaxel (n = 27). ### discussion While docetaxel resulted in a longer TTP and OS in this study it did not reach statistical significance. TTP duration for those patients who crossed over was similar, but overwhelmingly vinorelbine had fewer significant grade 3-4 toxicities than docetaxel. Only two previous randomized studies have compared the efficacy of single agent docetaxel and vinorelbine following prior anthracycline exposure, one in an unselected population [16], and the other, HERNATA, in HER2 positive disease with trastuzumab used in both arms [17]. The patients randomized in this study were relatively heavily pretreated with the majority having received 2-3 lines of prior treatment for their metastatic disease. The lower response rates with vinorelbine as compared to docetaxel in this study concur with results reported in other studies [16]. However, the numbers in both this study and the other unselected study [16] are small and need to be interpreted with caution. With regard to toxicity, in the present study, grade 3-4 hematological adverse events and infection were tenfold greater with docetaxel as compared with vinorelbine, consistent with results in HERNATA [17]. While others have reported a significantly higher number of overall grade 3-4 toxicities with vinorelbine [16], the fact that, as in HERNATA, discontinuations due to toxicities in that study [16] were significantly greater with docetaxel as compared to vinorelbine suggests either the toxicity data collected did not reflect the true toxicities on treatment or that docetaxel toxicities were in some way more severe or protracted leading to more numerous discontinuations [16]. Larger randomized studies are needed to determine (1) the efficacy of docetaxel versus vinorelbine in anthracycline pretreated disease and (2) the efficacy of vinorelbine after prior taxane exposure, and particularly how it may compares both with regard to efficacy and tolerability with other possible regimens that may utilized such as carboplatin-gemcitabine [20] or eribulin [21]. The longer as well as comparable TTP at cross over for both agents compared to that upfront suggests there may be enrichment at cross over of a group of patients who are not only fit for further treatment but are more likely to a derive continued benefit from additional treatment.

https://pubmed.ncbi.nlm.nih.gov/23002126/

8af357219cf885cb867e13a5fdf0022e

The drugs approved in Europe for the systemic treatment of herpes zoster are aciclovir , valaciclovir , famciclovir and brivudine .

[Update in the treatment of herpes zoster]. The systemic treatment of herpes zoster shortens the healing process, and prevents or alleviates pain and other acute or chronic complications, especially when it is administered in the first 72 hours after symptoms appear. This treatment is especially indicated in patients over the age of 50 and in those who, regardless of age, have head and neck involvement, especially in herpes zoster ophthalmicus. The drugs approved in Europe for the systemic treatment of herpes zoster are aciclovir , valaciclovir , famciclovir and brivudine . brivudine shows greater effectiveness against the varicella-zoster virus than aciclovir and its derivatives, and can be given just once a day for seven days, compared to multiple doses of the latter. As opposed to the others, brivudine is a non-nephrotoxic drug that should not be administered to immunodepressed patients or to those being treated with 5-fluorouracil. The treatment of herpes zoster to reduce pain should be combined with analgesics and neuroactive agents (amitriptyline, gabapentin, etc). While corticosteroids are of dubious efficacy in the treatment of post-herpes neuralgia, the intensity and duration of the pain can be reduced with some topical treatments (capsaicin, lidocaine patches, etc). Finally, this review discusses treatment guidelines for special locations (cranial nerves) and different subpopulations (children, pregnant women, immunodepressed patients, etc).

https://pubmed.ncbi.nlm.nih.gov/16595111/

e2fbcabdf6187dc1681261af1681670e

In this parallel group , randomized , double-blind study , 301 PD patients , the majority with motor fluctuations , received entacapone ( 200 mg ) or placebo with each daily dose of standard or controlled-release ( CR ) levodopa .

Efficacy and safety of entacapone in Parkinson's disease patients with suboptimal levodopa response: a 6-month randomized placebo-controlled double-blind study in Germany and Austria (Celomen study). To determine the efficacy and safety of the catechol-O-methyltransferase (COMT) inhibitor entacapone, used as an adjunct to levodopa, in Parkinson's disease (PD) patients. ### Patients And Methods In this parallel group , randomized , double-blind study , 301 PD patients , the majority with motor fluctuations , received entacapone ( 200 mg ) or placebo with each daily dose of standard or controlled-release ( CR ) levodopa . The 24-week treatment period was followed by 2 weeks of entacapone withdrawal. Efficacy was determined by home diaries ('on' and 'off' times), Unified Parkinson's Disease Rating Scale (UPDRS) and changes in levodopa dosage, and safety by adverse-event inquiry, vital signs, electro cardiography (ECG) and laboratory tests. ### results In the total population, the UPDRS activities of daily living and motor scores were significantly improved (P < 0.05) by entacapone vs placebo. In fluctuating patients, 'on' time increased (1.7 h) and 'off' time decreased (1.5 h) significantly more with entacapone than with placebo (0.5 and 0.6 h, respectively; P < 0.05), and the daily levodopa dose was reduced by 54 mg with entacapone and increased by 27 mg with placebo (P < 0.05). entacapone benefit was lost on withdrawal. entacapone efficacy was comparable between patients using CR and standard levodopa preparations. Increased dyskinesias (entacapone 34%, placebo 26%) and nausea (10 and 5%, respectively), mostly occurring shortly after treatment initiation, were generally managed by reducing the levodopa dose. Diarrhoea (entacapone 8%, placebo 4%) was seldom severe. There were no differences in vital signs, ECG or laboratory results. ### conclusion entacapone is an effective and safe levodopa extender and enhancer, improving the symptomatic efficacy of levodopa in PD and adding to the patients' benefit.

https://pubmed.ncbi.nlm.nih.gov/11939936/

7bd40e2672dafd76efef54ff7abc63aa

Importance of adding neomycin to metronidazole for bowel preparation .

Importance of adding neomycin to metronidazole for bowel preparation . A prospective randomized trial has investigated whether it is necessary to add oral neomycin to oral metronidazole as a means of preventing sepsis in elective colonic resection. Seventy-three patients completed the study; 41 received metronidazole and placebo neomycin and 32 received metronidazole and active neomycin. There was a significant reduction in the incidence of wound infection in patients receiving neomycin and metronidazole (22%) compared with metronidazole alone (51%, P<0.02). There was also a significant reduction in anaerobic infections in the group receiving metronidazole and neomycin compared with metronidazole alone (P<0.05). These results indicate that oral metronidazole alone is of no benefit for patients requiring elective colonic operations and that if oral metronidazole is advised it should always be given in combination with oral neomycin.

https://pubmed.ncbi.nlm.nih.gov/7017122/

ada8d4f1718084cd5e05de0a435a0497

The effects of metformin ( MET ) and curcumin ( CUR ) single treatments have been tested against breast cancer ; however , their combination has not been explored .

Combination of metformin and curcumin targets breast cancer in mice by angiogenesis inhibition, immune system modulation and induction of p53 independent apoptosis. The effects of metformin ( MET ) and curcumin ( CUR ) single treatments have been tested against breast cancer ; however , their combination has not been explored . Here, we evaluated the antitumor activity of MET and CUR combination against breast cancer in mice. ### Materials And Methods The antiproliferative activity of single and combined treatments against breast cancer cell lines was determined. Vascular endothelial growth factor (VEGF) and ### results The combination treatment exhibited the highest effects against tumor proliferation and growth. It significantly reduced VEGF expression, induced ### conclusion The combination can be a potential therapeutic option to treat breast cancer. However, further testing is needed to measure the exact serum levels of MET and CUR and to further explain the obtained results.

https://pubmed.ncbi.nlm.nih.gov/28491145/

feacfbaedd37f2a268494690707ec2ed

Warfarin was associated with a significantly higher risk of MB ( HR = 1.52 , 95 % CI = 1.14 - 2.04 ) , CRNM bleeding ( HR = 1.27 , 95 % CI = 1017.15 - 1.40 ) , and recurrent VTE ( HR = 1.50 , 95 % CI = 1.24 - 1.82 ) compared with apixaban .

Comparative Clinical and Economic Outcomes Associated with Warfarin Versus Apixaban in the Treatment of Patients with Venous Thromboembolism in a Large U.S. Commercial Claims Database. Venous thromboembolism (VTE), constituting deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common cause of vascular-related morbidity and mortality, resulting in a significant clinical and economic burden in the United States each year. Clinical guidelines recommend that patients with DVT and PE without cancer should be initiated on anticoagulation therapy with a direct oral anticoagulant over a vitamin K antagonist. Yet there is limited real-world evidence comparing the economic burden of warfarin and apixaban in treating VTE patients in a large commercially insured population. ### objective To compare safety and effectiveness of warfarin and apixaban and evaluate associated economic burden in treating VTE patients in a large U.S. commercial health care claims database. ### methods The PharMetrics Plus database was used to identify oral anticoagulant (OAC)-naive patients aged ≥ 18 years who initiated apixaban or warfarin within 30 days of a qualifying VTE encounter and had continuous health plan enrollment with medical and pharmacy benefits for 6 months before treatment initiation. apixaban initiators and warfarin initiators were matched using the propensity score matching (PSM) technique. Cox proportional hazard models were used to assess and compare the risk of major bleeding (MB), clinically relevant nonmajor (CRNM) bleeding, and recurrent VTE. Generalized linear models were used to assess and compare the all-cause health care costs. A 2-part model with bootstrapping was used to evaluate MB- and recurrent VTE-related medical costs. ### results Among 25,193 prematched patients, 13,421 (53.3%) were prescribed warfarin and 11,772 (46.7%) were prescribed apixaban. After 1:1 PSM, 8,858 matched warfarin-apixaban pairs were selected with a mean follow-up of 109 days and 103 days, respectively. Warfarin was associated with a significantly higher risk of MB ( HR = 1.52 , 95 % CI = 1.14 - 2.04 ) , CRNM bleeding ( HR = 1.27 , 95 % CI = 1017.15 - 1.40 ) , and recurrent VTE ( HR = 1.50 , 95 % CI = 1.24 - 1.82 ) compared with apixaban . warfarin patients had significantly higher all-cause medical costs per patient per month (PPPM; $2,333 vs. $1,992; ### conclusions warfarin use was associated with a higher risk of MB, CRNM bleeding, and recurrent VTE compared with apixaban. warfarin use was also associated with higher all-cause medical costs, MB-related medical costs, and recurrent VTE-related costs PPPM compared with apixaban.

https://pubmed.ncbi.nlm.nih.gov/32452277/

17cd6451aee625142a75f18fe3653670

A combination chemotherapy regimen containing mitomycin-C ( 10 mg/m2 , day 2 ) , vincristine ( 0.5 mg/m2 , days 1 and 4 ) , bleomycin ( 30 U QD , days 1 - -4 as a continuous intravenous infusion during courses one and two only ) , and cis-platinum ( 50 mg/m2 , days 1 and 22 ) was administered every 6 weeks to 14 evaluable patients with advanced ( i.e. , Stage IVB ) and/or recurrent squamous cell carcinoma of the cervix .

Mitomycin-C, bleomycin, vincristine, and cis-platinum in the treatment of advanced, recurrent squamous cell carcinoma of the cervix. A combination chemotherapy regimen containing mitomycin-C ( 10 mg/m2 , day 2 ) , vincristine ( 0.5 mg/m2 , days 1 and 4 ) , bleomycin ( 30 U QD , days 1 - -4 as a continuous intravenous infusion during courses one and two only ) , and cis-platinum ( 50 mg/m2 , days 1 and 22 ) was administered every 6 weeks to 14 evaluable patients with advanced ( i.e. , Stage IVB ) and/or recurrent squamous cell carcinoma of the cervix . Four patients (29%) achieved a complete response, lasting 8, 9.5+, 17+, and 21+ months. Three of these patients have had complete disappearance of their pulmonary metastases and one has had resolution of a large left-sided pelvic wall mass. Two additional patients (14%) had a partial response to therapy, each lasting 1.5 months. The median survival for these 14 patients was 9.0 months. The chemotherapy regimen was well tolerated. There were no drug-related deaths and no instances of severe or irreversible renal dysfunction or peripheral neuropathy. The mean lowest white blood cell and platelet counts were 4540 and 205,000 per mm3, respectively. Although severe or life-threatening thrombocytopenia occurred in only 36% patients, it appeared to be the dose-limiting toxicity of this drug combination.

https://pubmed.ncbi.nlm.nih.gov/6169465/

3f692f14fd1dc7ff15258ac63e7d03a7

Co-injection of the lowest doses of levobupivacaine and lidocaine dramatically increased the paw withdrawal latency .

Modification of local anesthetic-induced antinociception by fentanyl in rats. In clinical practice, using the lowest doses of drugs for anesthesia or analgesia is the main goal. Opioid combinations with local anesthetics can be preferable for achieving adequate anesthesia or analgesia. The primary purpose of this study was to examine possible thermal antinociceptive effects of the opioid -fentanyl and the amide local anesthetics levobupivacaine and lidocaine when locally administered alone or in combination. The paw withdrawal latencies to noxious thermal stimuli in rats were measured to assess the antinociceptive actions of drugs after subcutaneous intraplantar injection into the hind paw. All drugs examined in this study produced dose- and time-dependent increases in the paw withdrawal latencies. Fentanyl is approximately 125 and 500 times more potent than levobupivacaine and lidocaine, respectively. At the same dose, the antinociceptive potency of levobupivacaine was 3.6-fold higher than that of lidocaine. Co-injection of the lowest doses of levobupivacaine and lidocaine dramatically increased the paw withdrawal latency . However, in the presence of fentanyl, the effects of levobupivacaine and lidocaine were different. Although co-injection of levobupivacaine with fentanyl both enhanced and prolonged antinociceptive action, the lidocaine-fentanyl combination did not significantly change the paw withdrawal latency. These results suggest that intraplantar co-administration of fentanyl with levobupivacaine, but not lidocaine, may provide more effective antinociception without increasing the dose requirements.

https://pubmed.ncbi.nlm.nih.gov/22358090/

cc67bf6e7bbf69b13b54908cf76fe9d7

Inflammatory breast cancer ( IBC ) is a rare , aggressive form of breast cancer associated with HER2 amplification , with high risk of metastasis and an estimated median survival of 2.9 y. We performed an open-label , single-arm phase II clinical trial ( ClinicalTrials.gov NCT01325428 ) to investigate the efficacy and safety of afatinib , an irreversible ErbB family inhibitor , alone and in combination with vinorelbine in patients with HER2-positive IBC .

Clonal Evolutionary Analysis during HER2 Blockade in HER2-Positive Inflammatory Breast Cancer: A Phase II Open-Label Clinical Trial of Afatinib +/- Vinorelbine. Inflammatory breast cancer ( IBC ) is a rare , aggressive form of breast cancer associated with HER2 amplification , with high risk of metastasis and an estimated median survival of 2.9 y. We performed an open-label , single-arm phase II clinical trial ( ClinicalTrials.gov NCT01325428 ) to investigate the efficacy and safety of afatinib , an irreversible ErbB family inhibitor , alone and in combination with vinorelbine in patients with HER2-positive IBC . This trial included prospectively planned exome analysis before and after afatinib monotherapy. ### Methods And Findings HER2-positive IBC patients received afatinib 40 mg daily until progression, and thereafter afatinib 40 mg daily and intravenous vinorelbine 25 mg/m2 weekly. The primary endpoint was clinical benefit; secondary endpoints were objective response (OR), duration of OR, and progression-free survival (PFS). Of 26 patients treated with afatinib monotherapy, clinical benefit was achieved in 9 patients (35%), 0 of 7 trastuzumab-treated patients and 9 of 19 trastuzumab-naïve patients. Following disease progression, 10 patients received afatinib plus vinorelbine, and clinical benefit was achieved in 2 of 4 trastuzumab-treated and 0 of 6 trastuzumab-naïve patients. All patients had treatment-related adverse events (AEs). Whole-exome sequencing of tumour biopsies taken before treatment and following disease progression on afatinib monotherapy was performed to assess the mutational landscape of IBC and evolutionary trajectories during therapy. Compared to a cohort of The Cancer Genome Atlas (TCGA) patients with HER2-positive non-IBC, HER2-positive IBC patients had significantly higher mutational and neoantigenic burden, more frequent gain-of-function TP53 mutations and a recurrent 11q13.5 amplification overlapping PAK1. Planned exploratory analysis revealed that trastuzumab-naïve patients with tumours harbouring somatic activation of PI3K/Akt signalling had significantly shorter PFS compared to those without (p = 0.03). High genomic concordance between biopsies taken before and following afatinib resistance was observed with stable clonal structures in non-responding tumours, and evidence of branched evolution in 8 of 9 tumours analysed. Recruitment to the trial was terminated early following the LUX-Breast 1 trial, which showed that afatinib combined with vinorelbine had similar PFS and OR rates to trastuzumab plus vinorelbine but shorter overall survival (OS), and was less tolerable. The main limitations of this study are that the results should be interpreted with caution given the relatively small patient cohort and the potential for tumour sampling bias between pre- and post-treatment tumour biopsies. ### conclusions afatinib, with or without vinorelbine, showed activity in trastuzumab-naïve HER2-positive IBC patients in a planned subgroup analysis. HER2-positive IBC is characterized by frequent TP53 gain-of-function mutations and a high mutational burden. The high mutational load associated with HER2-positive IBC suggests a potential role for checkpoint inhibitor therapy in this disease. ### Trial Registration ClinicalTrials.gov NCT01325428.

https://pubmed.ncbi.nlm.nih.gov/27923043/

bce7b05d7aeb7352b707222c1976fbdf

Carboplatin and paclitaxel versus cisplatin , paclitaxel and doxorubicin for first-line chemotherapy of advanced ovarian cancer : a Hellenic Cooperative Oncology Group ( HeCOG ) study .

Carboplatin and paclitaxel versus cisplatin , paclitaxel and doxorubicin for first-line chemotherapy of advanced ovarian cancer : a Hellenic Cooperative Oncology Group ( HeCOG ) study . The combination of carboplatin and paclitaxel is considered the standard of care as initial chemotherapy for Advanced Ovarian Cancer (AOC). We compared this regimen with the combination of cisplatin, paclitaxel and doxorubicin. ### Patients And Methods Patients with AOC were randomised to either six courses of paclitaxel 175mg/m(2) plus carboplatin 7AUC or paclitaxel at the same dose plus cisplatin 75mg/m(2) plus doxorubicin 40mg/m(2). ### results Analysis was performed on 451 patients. The treatment groups were well balanced with regard to patient and disease characteristics. Performance status (PS) was better in the anthracycline arm. In terms of severe toxicity, the only significant difference between the two groups was the development of febrile neutropaenia in the anthracycline arm. Overall response rate was similar in both groups. With a median follow-up of 57.5 months, a marginal significance towards improved Progression-Free Survival (PFS) was noted in favour of the anthracycline arm, whilst there was no difference in overall survival. In multivariate analysis the hazard of disease progression at any time was significantly decreased by 25.5% for patients of the anthracycline arm. ### conclusion The combination of cisplatin, paclitaxel and doxorubicin demonstrates a marginal PFS improvement, but no additional survival benefit when compared with the standard carboplatin/paclitaxel regimen.

https://pubmed.ncbi.nlm.nih.gov/18691879/

513c3d2bb7d335b2cb1527a1775af10c

For susceptibility testing , DS-8587 exhibited more effective antibacterial activity when compared with ciprofloxacin and levofloxacin .

Characteristics of antibiotic resistance and sequence type of Acinetobacter baumannii clinical isolates in Japan and the antibacterial activity of DS-8587. DS-8587 is a novel broad-spectrum fluoroquinolone with extended antimicrobial activity against both Gram-positive and Gram-negative pathogens. In this study, we evaluated the antibacterial activity and mechanism of DS-8587 in 31 quinolone-resistant Acinetobacter baumannii clinical isolates. Efflux pump and qnr genes, mutations in quinolone resistance-determining regions of target enzymes, and sequence types determined by multilocus sequence typing were analyzed. Forty-two quinolone-susceptible clinical isolates were analyzed for comparison. For susceptibility testing , DS-8587 exhibited more effective antibacterial activity when compared with ciprofloxacin and levofloxacin . When combined with the efflux pump inhibitor 1-(1-napthylmethyl)-piperazine, the MIC of DS-8587 was less affected when compared with the MIC exhibited by combined ciprofloxacin and 1-(1-napthylmethyl)-piperazine. The efflux pump genes adeA/adeB/adeC and regulatory elements adeR/adeS were detected in 23 of 31 quinolone-resistant isolates. The qnrA/qnrB/qnrS genes were not detected in any A. baumannii isolates analyzed. Mutations in quinolone resistance-determining regions were observed in all 31 quinolone-resistant isolates. Multilocus sequence typing analyses revealed that 22 of 31 quinolone-resistant isolates belonged to ST-2, corresponding to international clonal lineage II. In conclusion, DS-8587 exhibits potent antibacterial activity against quinolone-resistant A. baumannii isolates that harbor mutations in quinolone resistance-determining regions. In the presence of the efflux pump inhibitor 1-(1-napthylmethyl)-piperazine, no significant changes were observed in the MIC for DS-8587. DS-8587 should be considered as a treatment option for A. baumannii including ST-2 strains that are predominant among the quinolone-resistant A. baumannii isolates found in Japan.

https://pubmed.ncbi.nlm.nih.gov/24709045/

43b1b9a41604d7aa5ad660cb80fe319a

Since 1987 , we have evaluated carboplatin alone or in combination with etoposide in two separate phase II trials of patients with non-small cell lung cancer ( NSCLC ) who had not received prior chemotherapy .

Phase II studies with carboplatin in non-small cell lung cancer. Since 1987 , we have evaluated carboplatin alone or in combination with etoposide in two separate phase II trials of patients with non-small cell lung cancer ( NSCLC ) who had not received prior chemotherapy . Single-agent carboplatin produced a 20% response rate in 51 patients treated with 390 mg/m2 intravenously every 4 weeks. A 3-day schedule of etoposide 140 mg/m2 on days 2, 3, and 4, and carboplatin 150 mg/m2 on days 1 and 5 also resulted in a 26.7% response rate in 46 patients. Myelosuppressive toxicity associated with carboplatin/etoposide was substantially greater than that seen with carboplatin alone. carboplatin as a single agent is active in previously untreated patients with advanced NSCLC. The two-drug combination of carboplatin and etoposide also shows activity in NSCLC similar to other combination chemotherapeutic regimens based on comparable prognostic factors in untreated patients. Further evaluation of carboplatin as part of combination chemotherapy in NSCLC is warranted.

https://pubmed.ncbi.nlm.nih.gov/2154856/

f3ca6904190590488d651122c505034a

Oral formulations of paclitaxel and docetaxel are of great interest , but have yet to receive regulatory approval in this disease .

Taxanes, past, present, and future impact on non-small cell lung cancer. Taxanes are novel microtubule-stabilizing agents and have shown efficacy in non-small cell lung cancer (NSCLC) since the 1990s. paclitaxel and docetaxel have been used either as single agents or in combination with a platinum compound. The newer generation albumin-bound taxane, nab-paclitaxel, has also shown similar efficacy in advanced NSCLC, both as a single agent and in combination with a platinum compound. Nab-paclitaxel, being Cremophor EL free, appears to have a better toxicity profile than paclitaxel. Taxane/platinum combinations still remain the foundation of treatment for advanced or metastatic NSCLC. docetaxel and paclitaxel as single agents have also shown efficacy in the second-line setting in advanced/metastatic NSCLC. Oral formulations of paclitaxel and docetaxel are of great interest , but have yet to receive regulatory approval in this disease . The phase I-II trials have shown that these formulations are feasible in the clinical setting.

https://pubmed.ncbi.nlm.nih.gov/24463482/

02baf8db20b9dcdda7efc4ece6762c6d

FLAIE ( fludarabine , cytarabine , idarubicin , and etoposide ) , a four drug induction chemotherapy for adult acute myeloid leukemia : A single center experience .

FLAIE ( fludarabine , cytarabine , idarubicin , and etoposide ) , a four drug induction chemotherapy for adult acute myeloid leukemia : A single center experience .

https://pubmed.ncbi.nlm.nih.gov/19731308/

0d77af88b5d27b2a2a55fbdc6b44750e

Overall , our study shows that the combination of dabrafenib and cetuximab results in increased antitumor activity and decreased stem cell capacities in BRAF(V600E)-mutant CRC cells .

BRAF and EGFR inhibitors synergize to increase cytotoxic effects and decrease stem cell capacities in BRAF(V600E)-mutant colorectal cancer cells. Mutations in the oncogene BRAF(V600E) are found in ~10% of colorectal cancers (CRCs) and are associated with poor prognosis. However, BRAF(V600E) has a limited response to the small-molecule drug, vemurafenib, a BRAF inhibitor, and BRAF inhibition is thought to cause a feedback activation of EGFR signaling that supports continued proliferation. In this study, we explored the effect of combined use of dabrafenib, a BRAF inhibitor, and cetuximab, an EGFR inhibitor, on BRAF(V600E)-mutant CRC stem cells and its possible mechanisms. Through cell viability analysis, flow cytometry, sphere forming, and western blot analysis, we found that the dabrafenib can synergize with cetuximab to reduce cell viability, induce enhanced apoptotic rates and cell cycle arrest in BRAF(V600E)-mutant HT-29 cells and inhibits stem cell capacities. Further, western blot analysis revealed that PTEN/Src/c-Myc pathway is possibly involved in the synergism between dabrafenib and cetuximab. Overall , our study shows that the combination of dabrafenib and cetuximab results in increased antitumor activity and decreased stem cell capacities in BRAF(V600E)-mutant CRC cells .

https://pubmed.ncbi.nlm.nih.gov/29534162/

35f40d091be6cc1509c9e9ac25d22237

Forty-seven patients with previously untreated metastatic or unresectable colorectal adenocarcinoma received capecitabine 1000 mg/m2 twice daily on days 2 - 15 and intravenous irinotecan 100 mg/m2 on days 1 and 8 , every 21 days .

Multicenter phase II study of oral capecitabine plus irinotecan as first-line chemotherapy in advanced colorectal cancer: a Korean Cancer Study Group trial. A phase II study was conducted to assess the efficacy and tolerability of capecitabine in combination with irinotecan (CAPIRI) in advanced colorectal cancer. Forty-seven patients with previously untreated metastatic or unresectable colorectal adenocarcinoma received capecitabine 1000 mg/m2 twice daily on days 2 - 15 and intravenous irinotecan 100 mg/m2 on days 1 and 8 , every 21 days . A total of 268 cycles of chemotherapy (median 6: range 1-11) were administered. According to an intent-to-treat analysis, the overall response rate was 49% (95% CI, 35-63%). Median time to progression and overall survival were 7.5 months (95% CI, 4.8-10.2) and 19.5 months (95% CI, 15.7-23.8), respectively. The most common grade 3/4 adverse events were diarrhea (24%) and neutropenia (11%). There were no treatment-related deaths. These results indicate that CAPIRI has comparable activity and tolerability to FOLFIRI as first-line treatment for advanced colorectal cancer.

https://pubmed.ncbi.nlm.nih.gov/16076694/

905b604d62ba8d7f64c81a504648e942

Amphotericin B plus flucytosine were initially given to 4 patients , all of them developed liver and renal abnormalities to some degree after therapy .

[Retrospective analysis of seven cases of pulmonary cryptococcosis]. To understand the diagnosis and treatment of pulmonary cryptococcosis. ### methods Patients diagnosed as having pulmonary cryptococcosis in the past 15 years were retrospectively studied. Their demographic data, respiratory symptoms, diagnostic methods, chest radiograph, immune state, antifungal therapy and follow-up results were analyzed. ### results Thirty cases of cryptococcosis were diagnosed, of which 7 were diagnosed as having pulmonary cryptococcosis, one of them presented with concomitant meningitis. Of the 7 patients, 4 were male and 3 were female, with a median age of 41.8. All were HIV negative; one case was immunocompromised with a history of colon cancer and glucocorticoid therapy for 8 months, while others were immunocompetent. Three patients complained of low fever or cough and sputum, while 4 others presented no symptoms. The X-ray and chest CT showed unilateral or bilateral patches, nodules or cavities. The diagnosis was made by pathology and bacterial culture of sputum or bronchoalveolar lavage fluid. Amphotericin B plus flucytosine were initially given to 4 patients , all of them developed liver and renal abnormalities to some degree after therapy . Three patients were given fluconazole or itraconazole initially. All the 7 patients with pulmonary cryptococcosis responded favorably to antifungal therapy and the prognosis was good. ### conclusions Clinically pulmonary cryptococcosis was less common than cryptococcal meningitis. Pathology and cryptococcal culture were essential to the diagnosis. For immunocompetent patients with pulmonary cryptococcosis, the prognosis was good.

https://pubmed.ncbi.nlm.nih.gov/12490129/

cd7f36f8e535377e9822cc17ee70ab0a

Liposomes were surface modified with transferrin ( Tf ) for receptor targeting , and cell penetrating peptide PFVYLI ( PFV ) to increase translocation of doxorubicin ( Dox ) and Erlotinib ( Erlo ) across the BBB into glioblastoma ( U87 ) tumor cells .

Co-delivery of doxorubicin and erlotinib through liposomal nanoparticles for glioblastoma tumor regression using an in vitro brain tumor model. Glioma is a highly malignant tumor that starts in the glial cells of brain. Tumor cells reproduce quickly and infiltrate rapidly in high grade glioma. Permeability of chemotherapeutic agents into brain is restricted owing to the presence of blood brain barrier (BBB). In this study, we developed a dual functionalized liposomal delivery system for efficient transport of chemotherapeutics across BBB for the treatment of glioma. Liposomes were surface modified with transferrin ( Tf ) for receptor targeting , and cell penetrating peptide PFVYLI ( PFV ) to increase translocation of doxorubicin ( Dox ) and Erlotinib ( Erlo ) across the BBB into glioblastoma ( U87 ) tumor cells . In vitro cytotoxicity and hemolysis studies were performed to assess biocompatibility of liposomal nanoparticles. Cellular uptake studies demonstrated efficient internalization of Dox and Erlo in U87, brain endothelial (bEnd.3), and glial cells. In addition, dual functionalized liposomes showed significantly (p < 0.05) higher apoptosis in U87 cells. Significantly (p < 0.05) higher translocation of dual functionalized liposomes across the BBB and delivering chemotherapeutic drugs to the glioblastoma tumor cells inside PLGA-Chitosan scaffold resulted in approximately 52% tumor cell death, using in vitro brain tumor model.

https://pubmed.ncbi.nlm.nih.gov/30261346/

41bf69e0eca5a16659fc722436c1365d

Endpoints were determination of maximum tolerated dose of doxorubicin and etoposide , treatment tolerability , and survival .

A prospective, non-randomised phase 1-2 trial of VACOP-B with filgrastim support for HIV-related non-Hodgkin's lymphoma. Non-Hodgkin's lymphoma (NHL) remains an important complication of associated HIV infection despite advances in antiretroviral therapy (ART), and the optimum chemotherapy regimen for this disease remains to be defined. A dose-escalation trial was performed to determine the maximum tolerated doses of etoposide and doxorubicin as part of the 12-week VACOP-B regimen, supported by filgrastim (r-metHuG-CSF). Patients with aggressive histology HIV-related NHL who were previously untreated with chemotherapy, and who had no active opportunistic infection were eligible for the study. Chemotherapy consisted of cyclophosphamide 350 mg/m2, vincristine 2 mg, bleomycin 10 U/m2; and prednisone 100 mg q2 days x 12 weeks, with increasing doses of doxorubicin 25-50 mg/m2 and etoposide 25-50 mg/m2 intravenously and 50-100 mg/m2 orally. Central nervous system prophylaxis (intrathecal cytarabine 50 mg x 4 doses), antifungal, and Pneumocystis carinii prophylaxis were used, and filgrastim was administered to prevent neutropenic complications. One dose level was expanded to permit the concomitant use of ART. Endpoints were determination of maximum tolerated dose of doxorubicin and etoposide , treatment tolerability , and survival . Forty-seven patients were enrolled, most with diffuse large-cell or immunoblastic NHL. Protocol-defined maximum tolerated dose was not reached and the limits of dose-limiting toxicity were not exceeded, even in patients receiving ART. Thirty-two cycles (4.9%) were delayed >6 days because of toxicity; 30 patients (64%) completed all 12 weeks of treatment. After completion of therapy, 14 patients had a complete response (30%), and 4 had a partial response (8%). Median time to progression was 9 months. At 42 months, progression-free survival was 25% and overall survival was 28%.

https://pubmed.ncbi.nlm.nih.gov/16216784/

546f5069e5a5df509d89decc6fa0ab10

Multiple ongoing clinical trials are currently evaluating the role of immune checkpoint inhibitors in ACC ( pembrolizumab , combination pembrolizumab and relacorilant , nivolumab , combination nivolumab and ipilimumab ) .

The Role of Immunotherapy in the Treatment of Adrenocortical Carcinoma. Adrenocortical carcinoma (ACC) is a rare epithelial neoplasm, with a high tendency for local invasion and distant metastases, with limited treatment options. Surgical treatment is the method of choice. For decades, the mainstay of pharmacological treatment has been the adrenolytic drug mitotane, in combination with chemotherapy. Immunotherapy is the latest revolution in cancer therapy, however preliminary data with single immune checkpoint inhibitors showed a modest activity in ACC patients. The anti-neoplastic activity of immune checkpoint inhibitors such as anti-cytotoxic-T-lymphocyte-associated-antigen 4 (anti-CTLA-4), anti-programmed death-1 (anti-PD-1), and anti-PD-ligand-1 (PD-L1) antibodies in different solid tumors has aroused interest to explore the potential therapeutic effect in ACC as well. Multiple ongoing clinical trials are currently evaluating the role of immune checkpoint inhibitors in ACC ( pembrolizumab , combination pembrolizumab and relacorilant , nivolumab , combination nivolumab and ipilimumab ) . The primary and acquired resistance to immunotherapy continue to counter treatment efficacy. Therefore, attempts are made to combine therapy: anti-PD-1 antibody and anti-CTLA-4 antibody, anti-PD-1 antibody and antagonist of the glucocorticoid receptor. The inhibitors of immune checkpoints would benefit patients with antitumor immunity activated by radiotherapy. Immunotherapy is well tolerated by patients; the most frequently observed side effects are mild. The most common adverse effects of immunotherapy are skin and gastrointestinal disorders. The most common endocrinopathy during anti-CTLA treatment is pituitary inflammation and thyroid disorders.

https://pubmed.ncbi.nlm.nih.gov/33498467/

801965c4cbde0556f5d76bb35ff1c9e0

Treatments including the monoclonal antibodies showed a cost per month of PFS gained of 2823 € ( FOLFIRI with cetuximab in KRAS wild-type patients and liver-only metastases ) , of € 15,822 ( FOLFOX with panitumumab in KRAS wild type ) , and of 13,383 € ( FOLFOX with bevacizumab ) .

First-line therapies in metastatic colorectal cancer: integrating clinical benefit with the costs of drugs. In light of the relevant expenses of pharmacological interventions, it might be interesting to make a balance between the cost of the new drugs administered and the added value represented by the improvement in progression free survival (PFS) in first-line for metastatic colorectal cancer CRC (mCRC). ### methods Phase III randomized controlled trials (RCTs) that compared at least two first-line chemotherapy regimens for mCRC patients were evaluated. Differences in PFS between the different arms were compared with the pharmacological costs (at the pharmacy of our hospital). The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) was applied to the above RCTs. ### results Overall 28 phase III RCTs, including 19,958 patients, were analyzed. The FOLFOX resulted the least expensive (56 € per month of PFS gained) while the addition of irinotecan to FOLFOX (FOLFOXIRI) increased only marginally the costs (90 € per month of PFS gained). Treatments including the monoclonal antibodies showed a cost per month of PFS gained of 2823 € ( FOLFIRI with cetuximab in KRAS wild-type patients and liver-only metastases ) , of € 15,822 ( FOLFOX with panitumumab in KRAS wild type ) , and of 13,383 € ( FOLFOX with bevacizumab ) . According to the ESMO-MCBS, the treatments including an EGFR-inhibitor (cetuximab or panitumumab) were associated with a score of 4, while the inclusion of bevacizumab reached a score of 3. ### conclusions Our data demonstrate a huge difference in cost per month of PFS gained in modern first-line treatments in mCRC.

https://pubmed.ncbi.nlm.nih.gov/30196427/

bfd9d42e3f083e5d336c1c3786cac47d

Several liposomal anthracyclines have been extensively studied in humans with a variety of cancer types , including TLC D-99 ( Myocet ; The Liposome Company , Elan Corporation , Princeton , NJ ) , liposomal daunorubicin ( Daunoxome ; NeXstar Pharmaceuticals , Inc , San Dimas , CA ) , and pegylated liposomal doxorubicin ( Doxil ; Alza Pharmaceuticals , Palo Alto , CA , Caelyx ; Schering Corporation , Kenilworth , NJ ) .

Liposomal anthracyclines for breast cancer. doxorubicin and other anthracyclines are an important class of agents for the treatment of early and advanced stage breast cancer, but produce substantial acute and chronic toxicities. One strategy for reducing anthracycline-associated toxicity is packaging them in liposomes. Liposomes are closed vesicular structures that envelop water-soluble molecules. They may serve as vehicles for delivering cytotoxic agents more specifically to tumor, and limit exposure of normal tissues to the drug. Liposomal anthracyclines are more effective and less toxic in a number of preclinical models compared with conventional anthracyclines. Several liposomal anthracyclines have been extensively studied in humans with a variety of cancer types , including TLC D-99 ( Myocet ; The Liposome Company , Elan Corporation , Princeton , NJ ) , liposomal daunorubicin ( Daunoxome ; NeXstar Pharmaceuticals , Inc , San Dimas , CA ) , and pegylated liposomal doxorubicin ( Doxil ; Alza Pharmaceuticals , Palo Alto , CA , Caelyx ; Schering Corporation , Kenilworth , NJ ) . Although none of these agents are currently approved for the treatment of breast cancer in the United States, the liposomal doxorubicin preparations seem to have comparable activity and less cardiac toxicity than conventional doxorubicin. Furthermore, they have been safely combined with other cytotoxic agents, including cyclophosphamide, 5-fluorouracil, vinorelbine, paclitaxel, and docetaxel. Further studies will be required do determine their role in the treatment of breast cancer.

https://pubmed.ncbi.nlm.nih.gov/11552228/

4a2f57276f745307d489ba43f622a866

In this study , combined drug action from the combination of Oxa with the phytochemicals andrographolide ( Andro ) , epigallocatechin-3-gallate ( EGCG ) , chlorophyllin ( Chl ) , colchicines ( Col ) , curcumin ( Cur ) and paclitaxel ( Tax ) was evaluated in the human ovarian cancer cell lines A2780 and A2780(cisR ) .

Synergism from the combination of oxaliplatin with selected phytochemicals in human ovarian cancer cell lines. oxaliplatin (Oxa) is a third generation platinum drug currently in clinical use for the treatment against colorectal cancer. Although it has a somewhat different spectrum of activity than cisplatin (Cis), it too has two major limitations, namely problems of side-effects and drug resistance. In this study , combined drug action from the combination of Oxa with the phytochemicals andrographolide ( Andro ) , epigallocatechin-3-gallate ( EGCG ) , chlorophyllin ( Chl ) , colchicines ( Col ) , curcumin ( Cur ) and paclitaxel ( Tax ) was evaluated in the human ovarian cancer cell lines A2780 and A2780(cisR ) . The combination index (CI) was used as a measure of synergism (CI<1), addictiveness (CI=1) and antagonism (CI>1). Generally, all the combinations showed greater synergism at a lower concentration (ED(50)) than at higher concentrations (ED(75) and ED(90)). Oxa in binary combination with Col and Tax showed the highest synergism in both the cancer cell lines, when administered 4 h after the phytochemical, with CI at ED(50) ranging from 0.004 to 0.1. The combination of Oxa with the other phytochemicals generally showed greater synergism when Oxa was administered 4 h before the phytochemical. Appropriately sequenced combination of Oxa with tumor active phytochemicals produces marked synergistic effects in cisplatin resistant as well as non-resistant ovarian cancer cell lines and may offer the means of overcoming drug resistance in ovarian cancer.

https://pubmed.ncbi.nlm.nih.gov/22199293/

9ef762a2a01d3569685f5e98013ae2a6

Bevacizumab and intetumumab can be administered safely in combination .

A Phase I/biomarker study of bevacizumab in combination with CNTO 95 in patients with advanced solid tumors. Inhibition of tumor angiogenesis is an effective mechanism to limit tumor growth; dual inhibition may result in additional benefit. bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor (VEGF), and intetumumab is a fully humanized monoclonal antibody that blocks αv integrins when complexed with β integrins. We evaluated the safety, tolerability, and efficacy of the combination of bevacizumab plus intetumumab in patients with refractory solid tumors. We also explored the effects of these agents on plasma-based biomarkers and wound angiogenesis. ### methods Patients with refractory solid tumors, Karnofsky performance status ≥70%, and adequate organ function were eligible. Plasma samples and wound biopsies were obtained at baseline and on-treatment. ### results Twelve patients were enrolled and received study drug. No tumor responses were noted. Observed toxicities included three cases of transient uveitis likely related to intetumumab and one case of reversible posterior leukoencephalopathy syndrome likely related to bevacizumab. Biomarker analysis revealed changes in soluble endoglin, soluble E-cadherin, and soluble E-selectin as well as PlGF and VEGF-D while on treatment. There was no observed impact of bevacizumab plus intetumumab on the phosphorylated or total levels of paxillin in wound tissue; however, an increase in the ratio of phospho/total paxillin levels was noted. ### conclusions Bevacizumab and intetumumab can be administered safely in combination . bevacizumab plus intetumumab treatment resulted in changes in the plasma levels of several extracellular matrix interacting proteins and angiogenic factors.

https://pubmed.ncbi.nlm.nih.gov/25527204/

7768631e00096b41ac8aa6992665bf23

The key findings were that amsacrine produced comparable levels of cell killing with both alpha and beta , whilst etoposide , doxorubicin and mitoxantrone produced higher degrees of cell killing with alpha than with beta or yeast topoisomerase II .

Complementation of temperature-sensitive topoisomerase II mutations in Saccharomyces cerevisiae by a human TOP2 beta construct allows the study of topoisomerase II beta inhibitors in yeast. We show herein that human DNA topoisomerase II beta is functional in yeast. It can complement a yeast temperature-sensitive mutation in topoisomerase II. The effect on human topoisomerase II beta of a number of topoisomerase II inhibitors was analysed in a yeast in vivo system and compared with that of human topoisomerase II alpha and wild-type yeast topoisomerase II. A drug permeable yeast strain (JN394 top2-4) was used to analyse the in vivo effects of known anti-topoisomerase II agents on human topoisomerase II beta transformants. A parallel analysis on human topoisomerase II alpha transformants provides the first in vivo analysis of the responses of yeast bearing the individual isoforms to these drugs. The strain was analysed at 35 degrees C, a non-permissive temperature at which only plasmid-borne topoisomerase II is active. A shuttle vector with either human topoisomerase II beta, human topoisomerase II alpha or yeast topoisomerase II under the control of a GAL1 promoter was used. The key findings were that amsacrine produced comparable levels of cell killing with both alpha and beta , whilst etoposide , doxorubicin and mitoxantrone produced higher degrees of cell killing with alpha than with beta or yeast topoisomerase II . Merbarone had the greatest effect on the yeast strain bearing plasmid-borne yeast topoisomerase II. Suramin, quercetin and genistein showed little cell killing in this system. This yeast in vivo system provides a powerful way to analyse the effects of anti-topoisomerase II agents on transformants bearing the individual human isoforms. This system also provides a means of analysing putative drug-resistance mutations in human topoisomerase II beta or to select for drug-resistance mutations in human topoisomerase II beta.

https://pubmed.ncbi.nlm.nih.gov/9025779/

3bd47c43bdafcc2ae400aa4d28b3022a

In the full study population , there were significant improvements in the anastrozole group compared with the tamoxifen group for disease-free survival ( hazard ratio [ HR ] 0·91 , 95 % CI 0·83 - 0·99 ; p=0·04 ) , time to recurrence ( 0·84 , 0·75 - 0·93 ; p=0·001 ) , and time to distant recurrence ( 0·87 , 0·77 - 0·99 ; p=0·03 ) .

Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. The Arimidex, tamoxifen, Alone or in Combination (ATAC) trial was designed to compare the efficacy and safety of anastrozole (1 mg) with tamoxifen (20 mg), both given orally every day for 5 years, as adjuvant treatment for postmenopausal women with early-stage breast cancer. In this analysis, we assess the long-term outcomes after a median follow-up of 120 months. ### methods We used a proportional hazards model to assess the primary endpoint of disease-free survival, and the secondary endpoints of time to recurrence, time to distant recurrence, incidence of new contralateral breast cancer, overall survival, and death with or without recurrence in all randomised patients (anastrozole n=3125, tamoxifen n=3116) and hormone-receptor-positive patients (anastrozole n=2618, tamoxifen n=2598). After treatment completion, we continued to collect data on fractures and serious adverse events in a masked fashion (safety population: anastrozole n=3092, tamoxifen n=3094). This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN18233230. ### findings Patients were followed up for a median of 120 months (range 0-145); there were 24,522 woman-years of follow-up in the anastrozole group and 23,950 woman-years in the tamoxifen group. In the full study population , there were significant improvements in the anastrozole group compared with the tamoxifen group for disease-free survival ( hazard ratio [ HR ] 0·91 , 95 % CI 0·83 - 0·99 ; p=0·04 ) , time to recurrence ( 0·84 , 0·75 - 0·93 ; p=0·001 ) , and time to distant recurrence ( 0·87 , 0·77 - 0·99 ; p=0·03 ) . For hormone-receptor-positive patients, the results were also significantly in favour of the anastrozole group for disease-free survival (HR 0·86, 95% CI 0·78-0·95; p=0·003), time to recurrence (0·79, 0·70-0·89; p=0·0002), and time to distant recurrence (0·85, 0·73-0·98; p=0·02). In hormone-receptor-positive patients, absolute differences in time to recurrence between anastrozole and tamoxifen increased over time (2·7% at 5 years and 4·3% at 10 years) and recurrence rates remained significantly lower on anastrozole than tamoxifen after treatment completion (HR 0·81, 95% CI 0·67-0·98; p=0·03), although the carryover benefit was smaller after 8 years. There was weak evidence of fewer deaths after recurrence with anastrozole compared with tamoxifen treatment in the hormone-receptor-positive subgroup (HR 0·87, 95% CI 0·74-1·02; p=0·09), but there was little difference in overall mortality (0·95, 95% CI 0·84-1·06; p=0·4). Fractures were more frequent during active treatment in patients receiving anastrozole than those receiving tamoxifen (451 vs 351; OR 1·33, 95% CI 1·15-1·55; p<0·0001), but were similar in the post-treatment follow-up period (110 vs 112; OR 0·98, 95% CI 0·74-1·30; p=0·9). Treatment-related serious adverse events were less common in the anastrozole group than the tamoxifen group (223 anastrozole vs 369 tamoxifen; OR 0·57, 95% CI 0·48-0·69; p<0·0001), but were similar after treatment completion (66 vs 78; OR 0·84, 95% CI 0·60-1·19; p=0·3). No differences in non-breast cancer causes of death were apparent and the incidence of other cancers was similar between groups (425 vs 431) and continue to be higher with anastrozole for colorectal (66 vs 44) and lung cancer (51 vs 34), and lower for endometrial cancer (six vs 24), melanoma (eight vs 19), and ovarian cancer (17 vs 28). No new safety concerns were reported. ### interpretation These data confirm the long-term superior efficacy and safety of anastrozole over tamoxifen as initial adjuvant therapy for postmenopausal women with hormone-sensitive early breast cancer.

https://pubmed.ncbi.nlm.nih.gov/21087898/

74cc59748549558a9b00fd53720fdd4a

The optimal correlation coefficients for norfloxacin , enrofloxacin , and ofloxacin in the prediction set were obtained with multiple linear regression that combined absorption peaks with wavelengths selected by stepwise regression , which were 0.867 , 0.828 , and 0.964 , respectively .

Analysis of fluoroquinolones antibiotic residue in feed matrices using terahertz spectroscopy. As antibiotic residue becomes more and more serious all over the world, a rapid and effective detection method is needed to evaluate the antibiotic residue in feed matrices to ensure food safety for consumers. In this study, three different kinds of fluoroquinolones (norfloxacin, enrofloxacin, and ofloxacin) in feed matrices were analyzed using terahertz (THz) spectroscopy, respectively. Meanwhile, pure fluoroquinolones and pure feed matrices were also measured in the same way. Then, the absorption spectra of all of the samples were extracted in the transmission mode. Pure norfloxacin has two absorption peaks at 0.825 and 1.187 THz, and they could still be observed when mixing norfloxacin with feed matrices. Also, there was an obvious and strong absorption peak for ofloxacin at 1.044 THz. However, no obvious absorption peak for enrofloxacin was observed, and only a weak absorption peak was located at 0.8 THz. Then, the different models were established with different chemometrics to identify the fluoroquinolones in feed matrices and determined the fluoroquinolones content in the feed matrices. The least squares support vector machines, Naive Bayes, Mahalanobis distance, and back propagation neural network (BPNN) were used to build the identification model with a Savitzky-Golay filter and standardized normal variate pretreatments. The results show that the excellent classification model was acquired with the BPNN combined with no pretreatment. The optimal classification accuracy was 80.56% in the testing set. After that, multiple linear regression and stepwise regression were used to establish the quantitative detection model for different kinds of fluoroquinolones in feed matrices. The optimal correlation coefficients for norfloxacin , enrofloxacin , and ofloxacin in the prediction set were obtained with multiple linear regression that combined absorption peaks with wavelengths selected by stepwise regression , which were 0.867 , 0.828 , and 0.964 , respectively . Overall, this research explored the potential of identifying the fluoroquinolones in feed matrices using THz spectroscopy without a complex pretreatment process and then quantitatively detecting the fluoroquinolones content in feed matrices. The results demonstrate that THz spectra could be used to identify fluoroquinolones in feed matrices and also detect their content quantitatively, which has great significance for the food safety industry.

https://pubmed.ncbi.nlm.nih.gov/29400779/

333bbd0b71066c038075b72815a68105

The protocol consisted of oral gefitinib 250 mg daily for 1 year plus intravenous oxaliplatin 85 or 100 mg/m(2 ) on days 1 , 15 , and 29 , and RT ( 50.4 Gy in 28 1.8-Gy fractions ) .

Pilot study of gefitinib, oxaliplatin, and radiotherapy for esophageal adenocarcinoma: tissue effect predicts clinical response. Overexpression of epidermal growth factor receptor (EGFR) in esophageal cancer is associated with poor prognosis. Preclinical studies indicate synergism between the EGFR inhibitor gefitinib and oxaliplatin or radiotherapy (RT). We report here early results of a planned phase I/II study of gefitinib, oxaliplatin, and RT for locally advanced, unresectable esophageal cancer. ### Methods And Materials The protocol consisted of oral gefitinib 250 mg daily for 1 year plus intravenous oxaliplatin 85 or 100 mg/m(2 ) on days 1 , 15 , and 29 , and RT ( 50.4 Gy in 28 1.8-Gy fractions ) . Four-quadrant biopsies were obtained at 1-cm intervals along the length of the tumor before and after treatment and the specimens were immunostained for EGFR, Erk, Akt, and their phosphorylated (activated) forms. ### results Enrollment was halted at 6 evaluable cases [all male; median age, 72.5 years (range, 51-75); and all with Eastern Cooperative Oncology Group performance status of 1]. All 6 tumors were adenocarcinomas; 5 were stage III and 1 stage IVA. oxaliplatin was given at 85 mg/m(2) in 3 cases and at 100 mg/m(2) in 3 cases. gefitinib therapy lasted a median 24 weeks; the median number of oxaliplatin doses was 6.5. Best responses were mucosal complete response (n = 1), partial response (n = 1), stable disease (n = 1), and progressive disease (n = 3). EGFR was expressed by tumor in 5 cases and Erk and Akt in 6 cases before treatment; no changes were noted after treatment. EGFR expression did not correlate with survival or response. No grade 4 toxicities were noted; grade 3 toxicities were diarrhea (n = 1), vomiting (n = 1), fatigue (n = 1), and constipation (n = 2). Median overall and disease-free survival times were 10.8 months and 8.4 months. ### conclusions gefitinib in combination with oxaliplatin and RT was tolerable, but had limited clinical activity and did not down-regulate total or activated EGFR, Akt, or Erk in esophageal tumor samples.

https://pubmed.ncbi.nlm.nih.gov/18845990/

63a2b77527a0d3a6b7af107f664cf52b

The efflux curves observed for both verapamil and prochlorperazine could be mathematically modeled by assuming

The cationic lipid stearylamine reduces the permeability of the cationic drugs verapamil and prochlorperazine to lipid bilayers: implications for drug delivery. The therapeutic activity of a wide variety of drugs is significantly improved when their longevity in the circulation is extended by encapsulation in liposomes. To improve the retention of cationic drugs in liposomes, we have investigated the effect of the cationic lipid stearylamine on the permeability of the calcium channel blocker verapamil and the antipsychotic drug prochlorperazine, both of which are also multidrug resistance modulators. Both drugs were efficiently incorporated into liposomes composed of DSPC/cholesterol that possessed a transmembrane pH gradient (inside acidic). However, the efflux of the loaded drugs was relatively rapid (i.e., 50% of the encapsulated verapamil was released after 4 h at 37 degrees C), despite the presence of a 3 unit pH gradient (pHi = 4.0, pHo = 7.5). Drug retention within the liposomes was improved by increasing the magnitude of the transmembrane pH gradient to approx. 5 units (pHi = 2.0, pHo = 7.5). Further improvements in drug retention were achieved by the addition of 10 mol% of the cationic lipid stearylamine in the DSPC/cholesterol liposomes. The combination of the 5 unit pH gradient and stearylamine resulted in increases of the retention of verapamil and prochlorperazine by approx. 20- and 5-fold, respectively. Calculation of the permeability coefficients for the charged (cationic) and neutral forms of the drugs indicated that the neutral forms of both drugs were approx. 10(4)-fold more permeable than were the cationic forms of the drugs. Further, the presence of stearylamine reduced the permeability coefficient for the cationic species of the drugs by approximately an order of magnitude, but had no effect on the neutral species of the drugs. The efflux curves observed for both verapamil and prochlorperazine could be mathematically modeled by assuming that the primary influence of stearylamine was on the development of a positive surface charge density on the inner monolayer of the liposome. Taken in sum, these results indicate that stearylamine is effective at decreasing the leakage of cationic drugs from liposomes, and may prove to be a valuable component of liposomal drug formulations.

https://pubmed.ncbi.nlm.nih.gov/7548129/

1f087a954b04aab5fc7970966aca70cd

The in vitro concentration-effect relationships for , chloroquine , mefloquine , lumefantrine and artesunate , were derived from clinical isolates obtained from patients on the western border of Thailand .

Nonlinear mixed-effects modelling of in vitro drug susceptibility and molecular correlates of multidrug resistant Plasmodium falciparum. The analysis of in vitro anti-malarial drug susceptibility testing is vulnerable to the effects of different statistical approaches and selection biases. These confounding factors were assessed with respect to pfmdr1 gene mutation and amplification in 490 clinical isolates. Two statistical approaches for estimating the drug concentration associated with 50% effect (EC50 ) were compared: the commonly used standard two-stage (STS) method, and nonlinear mixed-effects modelling. The in vitro concentration-effect relationships for , chloroquine , mefloquine , lumefantrine and artesunate , were derived from clinical isolates obtained from patients on the western border of Thailand . All isolates were genotyped for polymorphisms in the pfmdr1 gene. The EC50 estimates were similar for the two statistical approaches but 15-28% of isolates in the STS method had a high coefficient of variation (>15%) for individual estimates of EC50 and these isolates had EC50 values that were 32 to 66% higher than isolates derived with more precision. In total 41% (202/490) of isolates had amplification of pfmdr1 and single nucleotide polymorphisms were found in 50 (10%). Pfmdr1 amplification was associated with an increase in EC50 for mefloquine (139% relative increase in EC50 for 2 copies, 188% for 3+ copies), lumefantrine (82% and 75% for 2 and 3+ copies respectively) and artesunate (63% and 127% for 2 and 3+ copies respectively). In contrast pfmdr1 mutation at codons 86 or 1042 were associated with an increase in chloroquine EC50 (44-48%). Sample size calculations showed that to demonstrate an EC50 shift of 50% or more with 80% power if the prevalence was 10% would require 430 isolates and 245 isolates if the prevalence was 20%. In conclusion, although nonlinear mixed-effects modelling did not demonstrate any major advantage for determining estimates of anti-malarial drug susceptibility, the method includes all isolates, thereby, potentially improving confirmation of candidate molecular markers of anti-malarial drug susceptibility.

https://pubmed.ncbi.nlm.nih.gov/23894496/

6621bb3ae6f16fa28ac7aea66b0ff743

Forty-eight patients were treated with mitoxantrone alone , 40 with mitoxantrone plus beta-interferon , 11 with fluorouracil plus folinic acid and the remaining four with adriamycin .

Prognostic factors in patients affected by hepatocellular carcinoma treated with systemic chemotherapy: the experience of the National Cancer Institute of Milan. Survival times and overall response rates are generally poor in patients with unresectable hepatocellular carcinoma submitted to systemic chemotherapy. Limited data are reported in the literature concerning the factors influencing survival among this subset of patients but the distribution of these variables may affect the results of clinical trials. ### Patients And Methods The data on 103 patients undergoing systemic chemotherapy at the Istituto Nazionale Tumori from January 1988 through July 1991 have been analyzed using univariate and Cox multivariate analysis. Forty-eight patients were treated with mitoxantrone alone , 40 with mitoxantrone plus beta-interferon , 11 with fluorouracil plus folinic acid and the remaining four with adriamycin . ### results Median survival time, and 6-month and 12-month survival rates, were 7.1, 55% and 29%, respectively. Lactate dehydrogenase value (P = 0.0009), TNM stage (P = 0.001), vascular invasion (P = 0.001), bilirubin (P = 0.008), Child status (P = 0.01), aspartate amino-transferase (P = 0.02), extent of liver involvement (P = 0.02) and performance status (P = 0.03) were the most significant factors influencing survival in univariate analysis. In the multivariate analysis, aspartate amino-transferase (P = 0.02) and, particularly, TNM stage (p = 0.0009) were confirmed as independent variables correlating with survival. A prognostic index was calculated on the basis of these factors and high- and low-risk groups were identified. Median survival time and 12-month survival were 11.1 months and 43% for the low-risk group, and 4.0 months and 9% for the high-risk group (p = 0.0005). ### conclusion The results of this analysis may provide guidance for the design of future therapeutic trials in unresectable hepatocellular carcinoma. In particular, patient stratification should be considered for further clinical trials.

https://pubmed.ncbi.nlm.nih.gov/8394736/

6556ed7ec43351f47276edd66fb4a943

Fifty-one HIV-negative patients with an average age of 50.3 years were treated with chemotherapy regimen included 2500 mg/m(2 ) MTX with Leucovorin rescue and 1.4 mg/m(2 ) vincristine ( day two ) , which was administered every other week for 6 weeks .

Treatment of Primary Central Nervous System Lymphoma with High-dose Methotrexate and Radiotherapy in HIV-negative Patients. We assessed the outcome of high-dose methotrexate (HD-MTX) chemotherapy with or without radiotherapy (RT) in primary central nervous system lymphoma (PCNSL) patients. ### methods Fifty-one HIV-negative patients with an average age of 50.3 years were treated with chemotherapy regimen included 2500 mg/m(2 ) MTX with Leucovorin rescue and 1.4 mg/m(2 ) vincristine ( day two ) , which was administered every other week for 6 weeks . Only the patients who were younger than 60 years received RT. All patients received two cycles of 3000 mg/m(2) cytarabine at the end of the treatment for two successive days. ### results Diffuse large B-cell lymphoma was the most common histologic subtype (90.2%), and twenty-six (51.0%)patients had multiple brain lesions. The median survival of patients who were younger than 60 years was 37 months. For patients who were older than 60 years, the median survival was 20 months. The median survival of men and women were 30 and 34 months, respectively. There was no significant difference in survival of patients in terms of age and sex. Overall, sixteen patients (31%) out of fifty-one patients died, five of them were older than 60 years and eleven were younger than 60 years. Twenty-five (49%) of all patients experienced relapse, and 10 (40%) of them died after rechemotherapy. ### conclusions The base of our chemotherapy regimen was HD-MTX as the regular doses of MTX cannot penetrate the blood brain barrier (BBB). Our results indicated that the combination of HD-MTX with RT may not influence the outcome of PCNSL; thus, RT cannot be the first line therapy.

https://pubmed.ncbi.nlm.nih.gov/26317598/

aa64cc4e50f7476207f460edbe742bba

Phase I study of decitabine with doxorubicin and cyclophosphamide in children with neuroblastoma and other solid tumors : a Children 's Oncology Group study .

Phase I study of decitabine with doxorubicin and cyclophosphamide in children with neuroblastoma and other solid tumors : a Children 's Oncology Group study . Demethylating agents may alter the expression of genes involved in chemotherapy resistance. We conducted a phase I trial to determine the toxicity and molecular effects of the demethylating agent, decitabine, followed by doxorubicin and cyclophosphamide in children with refractory solid tumors. ### procedure Stratum A included children with any solid tumor; Stratum B included neuroblastoma patients only. Patients received a 1-hr decitabine infusion for 7 days, followed by doxorubicin (45 mg/m(2)) and cyclophosphamide (1 g/m(2)) on day 7. Pharmacokinetic studies were performed after the first dose of decitabine. Biological studies included methylation and gene expression analyses of caspase-8, MAGE-1 and fetal hemoglobin (HbF), and expression profiling of pre- and post-treatment peripheral blood and bone marrow cells. ### results The maximum-tolerated dose of decitabine was 5 mg/m(2)/day for 7 days. Dose-limiting toxicities at 10 mg/m(2)/day were neutropenia and thrombocytopenia. decitabine exhibited rapid clearance from plasma. Three of 9 patients in Stratum A and 4/12 patients in Stratum B had stable disease for > or = 4 months. Sustained MAGE-1 demethylation and increased HbF expression were observed in the majority of patients post-treatment (12/20 and 14/16, respectively). Caspase-8 promoter demethylation and gene expression were seen in 2/7 bone marrow samples. Differentially expressed genes were identified by microarray analysis. ### conclusion Low-dose decitabine when combined with doxorubicin/cyclophosphamide has tolerable toxicity in children. However, doses of decitabine capable of producing clinically relevant biologic effects were not well tolerated with this combination. Alternative strategies of combining demethylating agents with non-cytotoxic, biologically targeted agents such as histone deacetylase inhibitors should be explored.

https://pubmed.ncbi.nlm.nih.gov/20589651/

13876a1ea5fd417c7bfb9f3330b8c313

Tail-flick test showed that tramadol produced better antinociceptive effect than gabapentin .

The antinociceptive effects of systemic administration of tramadol, gabapentin and their combination on mice model of acute pain. The aim of the present study was to investigate the possible antinociceptive effects of systemic administration of tramadol and gabapentin either alone or in combination on acute pain models in mice. ### methods After obtaining the approval of Animal Ethics Committee; 96 BALB/c albino male mice were divided into 12 groups: (I) control without injection, (II) control treated with saline, (III)-(IV) mice treated with tramadol 10 mg/kg or 30 mg/kg, (V)-(VIII) mice treated with gabapentin; 30, 100, 200, 300 mg/kg respectively. In order to determine possible interactions between tramadol gabapentin and; mice received four different combinations of tramadol + gabapentin (30+30, 30+100, 30+200 and 30+300 mg/kg) (Groups IX-XII respectively). Mice received 0.1 ml solution for every 10 g of their weight. The drug was injected into peritonea. Thirty minutes after the drug injection, tail-flick and hot-plate tests were conducted. ### results Ten and 30 mg/kg tramadol produced dose dependent antinociceptive effect in tail-flick and hot plate tests. gabapentin had no antinociceptive effect in the tail flick test except 300 mg/kg dose, and had dose dependent antinociceptive effect in hot-plate test. In both tests, various combinations of tramadol and gabapentin produced an antinociceptive effect that is greater than that produced by tramadol and gabapentin alone. But, just 30 mg/kg tramadol + 300 mg/kg gabapentin combination caused statistically significant increase in both tests (p<0.05). ### conclusion When gabapentin and tramadol were used in combination, gabapentin had no additive antinociceptive effect except for 300 mg/kg in tail-flick and hot-plate tests. Tail-flick test showed that tramadol produced better antinociceptive effect than gabapentin .

https://pubmed.ncbi.nlm.nih.gov/22865488/

84db443a60cee772007ee38cd9fe366f

Our study involves a preliminary phase II trial , which evaluates the activity , feasibility and tolerability of a sequential combination of docetaxel and gemcitabine followed by docetaxel and carboplatin , as first-line treatment for inoperable NSCLC .

A phase II study of sequential docetaxel and gemcitabine followed by docetaxel and carboplatin as first-line therapy for non-small cell lung cancer. Our study involves a preliminary phase II trial , which evaluates the activity , feasibility and tolerability of a sequential combination of docetaxel and gemcitabine followed by docetaxel and carboplatin , as first-line treatment for inoperable NSCLC . Twenty-six chemo-naïve patients aged less than 75 years with histologically or cytologically confirmed unresectable stage IIIB, IV or relapsed post-operative metastatic NSCLC were included in the study. gemcitabine 1,250 mg/m(2) was administered and was followed by docetaxel 65 mg/m(2). Treatment was administered on days 1 and 14 in a 28-day cycle for three consecutive cycles. If patients had no progressive disease after three cycles of chemotherapy, they received another three cycles of docetaxel 65 mg/m(2) followed by carboplatin AUC5 on day 1 in a 21-day cycle. Recombinant human granocyte colony-stimulating factor (rhG-CSF) was given prophylactically. In addition, all patients received standard pre- and post- treatment with oral dexamethasone. Response rates at three cycles were: 19% achieved a partial response (PR), 46% had stable disease (SD) and 23% had progressive disease. At six cycles, 8% of the patients maintained PR, 19% showed SD and 35% had progressive disease. The median time-to-disease progression was 6 months. The median survival time of patients was 10 months while, at the end of the first year, the patients who managed to get through the complete therapy (20 patients) had a survival rate of 38%. This detailed analysis of 20 patients showed that 80% of the patients survived for up to 6 months, 38% up to 12 months and 19% for more than a year. The only risk factor associated with the hazard of death among the factors studied was the performance status of the patients. Patients with PS=0 presented a median survival time of 13 months and those with PS=1, it was only 9 months. Non-haematological and haematological toxic effects were generally mild to moderate and entirely manageable.

https://pubmed.ncbi.nlm.nih.gov/18204976/

72f38214c809afe54fa6dec8941d6ce8

The combination of galunisertib and sorafenib showed acceptable safety and a prolonged OS outcome .

A Phase 2 Study of Galunisertib (TGF-β1 Receptor Type I Inhibitor) and Sorafenib in Patients With Advanced Hepatocellular Carcinoma. Inhibition of tumor growth factor-β (TGF-β) receptor type I potentiated the activity of sorafenib in preclinical models of hepatocellular carcinoma (HCC). galunisertib is a small-molecule selective inhibitor of TGF-β1 receptor type I, which demonstrated activity in a phase 2 trial as second-line HCC treatment. ### methods The combination of galunisertib and sorafenib (400 mg BID) was tested in patients with advanced HCC and Child-Pugh A liver function without prior systemic therapy. galunisertib dose was administered 80 or 150 mg b.i.d. orally for 14 days every 28 days in safety lead-in cohorts; in the expansion cohort, all patients received galunisertib 150 mg b.i.d. Objectives included time-to-tumor progression, changes in circulating alpha fetoprotein and TGF-β1, safety, overall survival (OS), response rate, and pharmacokinetics (PK). ### results Patients (n = 47) were enrolled from 5 non-Asian countries; 3 and 44 patients received the 80 mg and 150 mg b.i.d. doses of galunisertib, respectively. The pharmacokinetics and safety profiles were consistent with monotherapy of each drug. For the 150 mg b.i.d. galunisertib cohort, the median time-to-tumor progression was 4.1 months; the median OS was 18.8 months. A partial response was seen in 2 patients, stable disease in 21, and progressive disease in 13. TGF-β1 responders (decrease of >20% from baseline) vs nonresponders had longer OS (22.8 vs 12.0 months, P = 0.038). ### discussion The combination of galunisertib and sorafenib showed acceptable safety and a prolonged OS outcome .

https://pubmed.ncbi.nlm.nih.gov/31295152/

e011193be897784c42a549400738bd35

All the patients were conditioned with busulfan ( BU ) 12 mg.kg-1 and cyclophosphamide ( CY ) 3.6 g.m-2 , of whom 4 were conditioned with additioned antithymocyte globulin(ATG ) .

[Human leukocyte antigen mismatched hemopietic stem cell transplants for the treatment of leukemia]. To explore the feasibility of HLA mismatched hemopietic stem cell transplants for the treatment of leukemia. ### methods Between July 2000 and December 2001, seven patients received hemopietic stem cell transplants(HSCT) with HLA mismatched family donors, including 3 chronic myelocytic leukemia (CML), 3 acute nonlymphocytic leukemia (ANLL), and 1 acute lymphocytic leukemia (ALL). Stem cell sources were bone marrow(n = 1) or G-CSF mobilized peripheral blood (n = 6). All the patients were conditioned with busulfan ( BU ) 12 mg.kg-1 and cyclophosphamide ( CY ) 3.6 g.m-2 , of whom 4 were conditioned with additioned antithymocyte globulin(ATG ) . Graft versus host disease (GVHD) prophylaxis regimen consisted of cyclosporin-A (CSA), methotrexate (MTX) and mycophenolate mofetil(MMF). ### results One patients received 3.41 x 10(8) kg-1 mononuclear cells(MNC) from bone marrow; six patients received a mean number of 8.46 x 10(8) kg-1 (4.3 x 10(8)-15.4 x 10(8) kg-1) MNC from peripheral blood. The mean time of ANC > 0.5 x 10(9) L-1 was day 13 (11-16), and BPC > 20.0 x 10(9) L-1 was day 16 (11-23). All the patients got engraftment successfully and attained CR. Acute I-II GVHD occurred in 3(42.9%) patients, no acute III-IV GVHD occurred and extensive chronic GVHD did in 2(28.6%) patients. All the patients were alive and well after 6-24 months' follow-up. ### conclusion (1) BU/CY plus ATG appears to be an effective conditioning regimen for HLA mismatched allogenic stem cell transplants. (2) G-CSF mobilized peripheral blood stem cells may be the source of stem cells even for HLA mismatched hemopietic stem cell transplants.

https://pubmed.ncbi.nlm.nih.gov/12920822/

9a1b4790ee47a73210561eb4db593e83

Phase II study of an intensive combination chemotherapy with cisplatin , adriamycin , etoposide and cyclophosphamide ( CAVE ) in small cell lung cancer .

Phase II study of an intensive combination chemotherapy with cisplatin , adriamycin , etoposide and cyclophosphamide ( CAVE ) in small cell lung cancer . One hundred and twelve patients with small cell lung cancer (SCLC) were treated with a combination (CAVE) of cisplatin (60 mg/m2 day 1), adriamycin (45 mg/m2 day 1), etoposide (80 mg/m2 days 1-2-3) and cyclophosphamide (1 g/m2 day 1) given every 4 weeks. A total of 10 courses were given. Response evaluation was initially evaluated after the first two courses of CAVE and repeated at least after treatment completion. This regimen was associated with severe hematological toxicity, mainly leucopenia; five toxic deaths related to sepsis were observed. One hundred and one patients were evaluable for response: 63 with limited disease and 49 with extensive disease. Overall complete and partial response rates after the first two courses of chemotherapy were 16% and 63% respectively but 14 late complete responses were documented, leading to a 30% total complete response rate; 38% in patients with limited disease and 19% in those with disseminated disease. Median overall survival was 46 weeks with a 17% 2 year survival. The only significant prognostic factor for survival was the type of response. There was no survival difference between 'early' and 'late' complete responders. Complete responders had a 75 week median survival time with a 34% 2 year survival. CAVE is thus an effective regimen for SCLC, but with a considerable toxicity.

https://pubmed.ncbi.nlm.nih.gov/2838289/

e75884e8d96c3040a948221a74fcc92f

These trials were compared with a broader set of trials examining the effectiveness of other AADs for AF : amiodarone , sotalol and class 1c agents ( flecainide and propafenone ) .

Dronedarone for the treatment of atrial fibrillation: a NICE single technology appraisal. The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of dronedarone (Multaq®, Sanofi-Aventis Limited, UK) to submit evidence on the clinical and cost effectiveness of the anti-arrhythmic drug (AAD) for the treatment of atrial fibrillation (AF) and atrial flutter, as part of the Institute's single technology appraisal (STA) process. The Centre for Reviews and Dissemination and the Centre for Health Economics, both at the University of York, were commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and NICE's subsequent decisions regarding the use of dronedarone within the UK NHS. The ERG review comprised a critique of the submitted evidence on the clinical effectiveness and cost effectiveness of dronedarone. The ERG examined the search strategy used to obtain relevant evidence, the selection of studies included in the assessment, outcome measures chosen and statistical methods employed. The ERG also validated the manufacturer's decision analytic model and used it to explore the robustness of the cost-effectiveness results to key assumptions. The main clinical effectiveness evidence supporting the use of dronedarone as a treatment for AF came from four randomized controlled trials. These trials were compared with a broader set of trials examining the effectiveness of other AADs for AF : amiodarone , sotalol and class 1c agents ( flecainide and propafenone ) . The evidence suggested that all AADs decreased the recurrence of AF but dronedarone had the smallest effect. A mixed treatment comparison analysis of the trials showed that dronedarone was associated with a lower risk of all-cause mortality than other AADs, but this was highly uncertain. There was limited evidence to assess the effect of dronedarone on stroke, and no statistically significant differences between dronedarone and other AADs were found for treatment discontinuation. From the evidence presented by the manufacturer, dronedarone appeared highly cost effective in each of the population groups examined compared with using standard baseline therapy alone as first-line treatment, or compared with sotalol or amiodarone as first-line AAD, with incremental cost-effectiveness ratios (ICERs) well below £20,000 per QALY gained. The ICER for dronedarone relative to class 1c agents was around £19,000 per QALY. Although the evidence presented by the manufacturer indicated that dronedarone was cost effective, the estimates of treatment effect relative to other AADs and safety in the longer term were highly uncertain. The NICE Appraisal Committee in its preliminary guidance did not recommend the use of dronedarone for AF. However, following the response from a large number of consultees and commentators, NICE revised its preliminary guidance to allow the use of the drug in a specific subgroup of AF patients with additional cardiovascular risk factors.

https://pubmed.ncbi.nlm.nih.gov/22136303/

e83777d937c0c9e8b04aebf93acb357b

First-line PFS for sorafenib , sunitinib , temsirolimus , everolimus , and " other " was 6.9 , 8.9 , 4.2 , not analyzed ( too few patients ) , and 10.8 months , respectively .

"Real world" treatment of metastatic renal cell carcinoma in a joint community-academic cohort: progression-free survival over three lines of therapy. New targeted therapeutics approved for metastatic renal cell carcinoma (mRCC) offer multiple options in each line of therapy; however, there are few prospective data beyond the first-line settings, and overall comparative effectiveness data are limited. In the targeted therapy era, progression-free survival (PFS) has been the most common regulatory end point for demonstrating the benefit of new therapies. ### Patients And Methods Drawing on a joint community-academic retrospective mRCC registry, we analyzed all patients who had undergone at least 1 line of systemic therapy (N = 325) for PFS. Patients were grouped according to treatment choice (sorafenib, sunitinib, temsirolimus, everolimus, and "other") for up to 3 lines of therapy. PFS by treatment choice and line of therapy was evaluated using Kaplan-Meier and Cox regression analyses. ### results PFS was longest in patients treated with sunitinib in the first and second lines of therapy. First-line PFS for sorafenib , sunitinib , temsirolimus , everolimus , and " other " was 6.9 , 8.9 , 4.2 , not analyzed ( too few patients ) , and 10.8 months , respectively . Second-line PFS was 4.6, 7.0, 3.2, 3.8, and 4.1 months, respectively. Third-line PFS was 4.5, 4.6, 9.9, 4.2, and 2.9, months, respectively. The risk of progression in patients treated with temsirolimus was about twice that of patients treated with sunitinib in the first and second lines of therapy. ### conclusion Patients treated with sunitinib had the longest PFS in the first and second lines of therapy. PFS from practice-based data appear consistent with trial-based expectations; however, practice variation was still evident.

https://pubmed.ncbi.nlm.nih.gov/23856102/

dcf22d47d862a9e7ca895b583d3061dc

Simultaneous treatment with gefitinib and pemetrexed enhanced cell growth inhibition and cell death and prevented the appearance of gefitinib resistance mediated by T790 M mutation or epithelial-to-mesenchymal transition ( EMT ) in PC9 and HCC827 cells , respectively .

Combination of Gefitinib and Pemetrexed Prevents the Acquisition of TKI Resistance in NSCLC Cell Lines Carrying EGFR-Activating Mutation. Development of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors is a clinical issue in patients with epidermal growth factor receptor gene (EGFR)-mutated non-small cell lung cancer (NSCLC). The aim of this study was to investigate the potential of combining gefitinib and pemetrexed in preventing the acquisition of resistance to EGFR tyrosine kinase inhibitors in NSCLC cell lines harboring EGFR exon 19 deletion. ### methods The effect of different combinatorial schedules of gefitinib and pemetrexed on cell proliferation, cell cycle, apoptosis, and acquisition of gefitinib resistance in PC9 and HCC827 NSCLC cell lines and in PC9 xenograft models was investigated. ### results Simultaneous treatment with gefitinib and pemetrexed enhanced cell growth inhibition and cell death and prevented the appearance of gefitinib resistance mediated by T790 M mutation or epithelial-to-mesenchymal transition ( EMT ) in PC9 and HCC827 cells , respectively . In PC9 cells and in PC9 xenografts the combination of gefitinib and pemetrexed, with different schedules, prevented gefitinib resistance only when pemetrexed was the first treatment, given alone or together with gefitinib. Conversely, when gefitinib alone was administered first and pemetrexed sequentially alternated, a negative interaction was observed and no prevention of gefitinib resistance was documented. The mechanisms of resistance that developed in vivo included T790M mutation and EMT. The induction of EMT was a feature of tumors treated with gefitinib when given before pemetrexed, whereas T790M was recorded only in tumors treated with gefitinib alone. ### conclusions The combination of gefitinib and pemetrexed is effective in preventing gefitinib resistance; the application of intermittent treatments requires that gefitinib not be administered before pemetrexed.

https://pubmed.ncbi.nlm.nih.gov/27006151/

f23c04d1cfa9c526da88afe28383d0e8

Two courses of eight drugs in 1 day followed by two courses of etoposide plus carboplatin ( 500 and 800 mg/m(2 ) per course , respectively ) were administered after surgery .

Standard-risk medulloblastoma treated by adjuvant chemotherapy followed by reduced-dose craniospinal radiation therapy: a French Society of Pediatric Oncology Study. The primary objective of this study was to decrease the late effects of prophylactic radiation without reducing survival in standard-risk childhood medulloblastoma. ### Patients And Methods Inclusion criteria were as follows: children between the ages of 3 and 18 years with total or subtotal tumor resection, no metastasis, and negative postoperative lumbar puncture CSF cytology. Two courses of eight drugs in 1 day followed by two courses of etoposide plus carboplatin ( 500 and 800 mg/m(2 ) per course , respectively ) were administered after surgery . Radiation therapy had to begin 90 days after surgery. Delivered doses were 55 Gy to the posterior fossa and 25 Gy to the brain and spinal canal. ### results Between November 1991 and June 1998, 136 patients (median age, 8 years; median follow-up, 6.5 years) were included. The overall survival rate and 5-year recurrence-free survival rate were 73.8% +/- 7.6% and 64.8% +/- 8.1%, respectively. Radiologic review showed that 4% of patients were wrongly included. Review of radiotherapy technical files demonstrated a correlation between the presence of a major protocol deviation and treatment failure. The 5-year recurrence-free survival rate of patients included in this study with all optimal quality controls of histology, radiology, and radiotherapy was 71.8% +/- 10.5%. In terms of sequelae, 31% of patients required growth hormone replacement therapy and 25% required special schooling. ### conclusion Reduced-dose craniospinal radiation therapy can be proposed in standard-risk medulloblastoma provided staging and radiation therapy are performed under optimal conditions.

https://pubmed.ncbi.nlm.nih.gov/16034048/

060d0d773e51ed4d195d2697f39b9d90

Azithromycin , doxycycline , and moxifloxacin hydrochloride were shown to relieve symptoms but were not as effective after continuous usage .

A case of human infection with a novel Babesia species in China. Babesiosis is an uncommon but emerging tick-borne disease caused by the genus Babesia. In this case study, we report a case of human infection with a novel Babesia sp. in China. ### findings The patient in question had been suffering from repetitive occurrences of mild fever of unknown origin and fatigue for 10 years. Ring forms, tetrads, and one or two dots of chromatin or trophozoite-like organisms were observed in the patient's thin blood smears and bone marrow smears. Using a confocal laser-scanning microscope, it was observed that the patient's serum had reactivity with the surface proteins of the B. microti strain. Electron microscopy revealed oval red blood cells with 1 ~ 2 μm of knob protrusions in the cellular membrane. The results of the Babesia-specific nested PCR assay for 18S rRNA confirmed the presence of Babesia infection. The construction of a phylogenetic relationship showed clustering with B. microti and B. duncani, which was identified as a novel Babesia species and named as Babesia sp. XXB/HangZhou. Azithromycin , doxycycline , and moxifloxacin hydrochloride were shown to relieve symptoms but were not as effective after continuous usage . After atovaquone (Mepron®) administration, the patient recovered from fever and tested negative for detection of Babesia-specific genes. ### conclusion Babesia sp. XXB/HangZhou is a novel Babesia species, which causes mild babesiosis in an immunocompetent patient.

https://pubmed.ncbi.nlm.nih.gov/27025290/

0222ad5a8d7b268dfac452940ab10aae

Travellers used doxycycline ( 15 % ) for malaria prophylaxis , 11 % took an antibiotic for travellers ' diarrhoea ( TD ) treatment ( fluoroquinolone 7 % , azithromycin 4 % ) .

Travel-associated multidrug-resistant organism acquisition and risk factors among US military personnel. International travel is a risk factor for incident colonization with extended spectrum beta-lactamase (ESBL)-producing organisms. These and other multidrug-resistant (MDR) bacteria are major pathogens in combat casualties. We evaluated risk factors for colonization with MDR bacteria in US military personnel travelling internationally for official duty. ### methods TravMil is a prospective observational study enrolling subjects presenting to military travel clinics. We analysed surveys, antimicrobial use data, and pre- and post-travel perirectal swabs in military travellers to regions outside the continental USA, Canada, Western or Northern Europe, or New Zealand, presenting to one clinic from 12/2015 to 12/2017. Recovered Gram-negative isolates underwent identification and susceptibility testing (BD Phoenix). Characteristics of trip and traveller were analysed to determine risk factors for MDR organism colonization. ### results 110 trips were planned by 99 travellers (74% male, median age 38 years [IQR 31, 47.25]); 72 trips with returned pre- and post-travel swabs were completed by 64 travellers. Median duration was 21 days (IQR 12.75, 79.5). 17% travelled to Mexico/Caribbean/Central America, 15% to Asia, 57% to Africa and 10% to South America; 56% stayed in hotels and 50% in dormitories/barracks. Travellers used doxycycline ( 15 % ) for malaria prophylaxis , 11 % took an antibiotic for travellers ' diarrhoea ( TD ) treatment ( fluoroquinolone 7 % , azithromycin 4 % ) . Incident MDR organism colonization occurred in 8 travellers (incidence density 3.5/1000 travel days; cumulative incidence 11% of trips [95% CI: 4-19%]), all ESBL-producing Escherichia coli. A higher incidence of ESBL-producing E. coli acquisition was associated with travel to Asia (36% vs 7%, P = 0.02) but not with travel to other regions, TD or use of antimicrobials. No relationship was seen between fluoroquinolone or doxycycline exposure and resistance to those antimicrobials. ### conclusions Incident colonization with MDR organisms occurs at a lower rate in this military population compared with civilian travellers, with no identified modifiable risk factors, with highest incidence of ESBL acquisition observed after South Asia travel.

https://pubmed.ncbi.nlm.nih.gov/33675647/

2b93901ec2000c5b67bd9da8cb04762d

3 . When timolol was administered concomitantly with hydrochlorothiazide , plasma renin activity was suppressed and blood pressure was significantly lowered .

Enhancement of the antihypertensive effect of hydrochlorothiazide in dogs after suppression of renin release by beta-adrenergic blockade. 1. Renal hypertensive dogs were treated with hydrochlorothiazide (8-2 mumol/kg or 33 mumol/kg daily for 7 days), or timolol (4-6 mumol/kg daily for 4 days), a potent beta-adrenergic blocking agent, or combinations of these drugs). Changes in mean arterial blood pressure and plasma renin activity were measured over the treatment period. 2. Neither drug significantly lowered arterial blood pressure when administered alone. Plasma renin activity, which did not change during treatment with timolol, was substantially elevated during treatment with hydrochlorothiazide. 3 . When timolol was administered concomitantly with hydrochlorothiazide , plasma renin activity was suppressed and blood pressure was significantly lowered . 4. These observations suggest that compensatory activation of the renin-angiotensin system limits the antihypertensive activity of hydrochlorothiazide in renal hypertensive dogs and suppression of diuretic-induced renin release by timolol unmasks the antihypertensive effect of the diuretic.

https://pubmed.ncbi.nlm.nih.gov/234821/

33dd0f530003bdb85acc6415460c70ba

Phase I study combining treatment with temsirolimus and sunitinib malate in patients with advanced renal cell carcinoma .

Phase I study combining treatment with temsirolimus and sunitinib malate in patients with advanced renal cell carcinoma . Concurrent inhibition of multiple oncogenic signaling pathways might improve the efficacy of anticancer agents and abrogate resistance mechanisms. This phase I study evaluated temsirolimus in combination with sunitinib in patients with advanced RCC. ### Patients And Methods Eligibility included advanced RCC and <or= 2 previous systemic regimens. At the starting dose, temsirolimus 15 mg was administered by intravenous (I.V.) infusion once weekly, and sunitinib 25 mg was administered orally once daily for 4 weeks, followed by a 2-week rest period. ### results In the first cohort, dose-limiting toxicities (grade 3 treatment-related toxicities that lasted >or= 7 days) were observed in 2 of 3 patients. One patient experienced grade 3 rash during week 3, which led to treatment discontinuation. A second patient had grade 3 thrombocytopenia (platelet count, 48,000/microL), cellulitis, and gout during week 3 and was hospitalized; platelets recovered to 109,000/microL 4 days after discontinuation of protocol therapy. A third patient experienced rash, asthenia, diarrhea, stomatitis, constipation, fever, and rectal hemorrhage, all of which were mild in severity. The study was terminated because of dose-limiting toxicity observed at low starting doses of both agents. ### conclusion Concomitant use of I.V. temsirolimus 15 mg weekly and oral sunitinib 25 mg daily (4 weeks on, 2 weeks off) is not recommended.

https://pubmed.ncbi.nlm.nih.gov/19213664/

50a955738574e2180ca53947a32832d7

Both anastrozole ( 1.0 mg/d ) and letrozole ( 2.5 mg/d ) have now been approved as second-line treatment for hormone-dependent breast cancer in postmenopausal women in whom disease has progressed following tamoxifen treatment .

Emerging role of aromatase inhibitors in the treatment of breast cancer. The new generation of potent steroidal and nonsteroidal inhibitors of the enzyme aromatase act by decreasing estrogen production throughout the body in postmenopausal women. The most potent of these agents may also inhibit estrogen synthesis within metastatic breast cancer tissue. The newly developed, orally administered, nonsteroidal competitive inhibitors, such as anastrozole (Arimidex), letrozole (Femara), and vorozole (Rizivor), are a thousand times more potent inhibitors of aromatase than is aminoglutethimide. Furthermore, these agents are highly selective. In several large randomized trials, the new inhibitors produced similar response rates as megestrol acetate (160 mg/d) in postmenopausal women with hormone-dependent breast cancer, but showed a trend toward improved response duration and survival. They also produced less weight gain and fewer cardiovascular and thromboembolic side effects. In addition, letrozole proved superior to aminoglutethimide in another randomized trial. Both anastrozole ( 1.0 mg/d ) and letrozole ( 2.5 mg/d ) have now been approved as second-line treatment for hormone-dependent breast cancer in postmenopausal women in whom disease has progressed following tamoxifen treatment . Either drug should replace the routine use of megestrol acetate in this setting. Ongoing clinical studies are comparing anastrozole and letrozole to antiestrogens as first-line endocrine therapy for metastatic breast cancer. Other trials will study the possible roles of these compounds as adjuvant therapy and chemoprevention for breast cancer.

https://pubmed.ncbi.nlm.nih.gov/9556789/

435964f6f8ee59908d3297556750e0bd

P-glycoprotein effluxes a variety of anticancer drugs , such as doxorubicin , vinca alkaloids , etoposide and taxol , and thereby allows cancer cells to show resistance to these drugs .

Therapeutic approach to drug resistant tumors. Drug resistance is a major problem in cancer chemotherapy. P-glycoprotein plays a major role in multidrug resistance in cancer cells. P-glycoprotein is expressed in some normal tissues and has physiological functions. These include protecting the brain against toxic substances at the blood-brain barrier site, excreting toxic substances from the liver, kidney, and gastrointestinal tracts, and transporting steroidal hormones in the adrenal grand. Once expressed in cancer cells. P-glycoprotein effluxes a variety of anticancer drugs , such as doxorubicin , vinca alkaloids , etoposide and taxol , and thereby allows cancer cells to show resistance to these drugs .

https://pubmed.ncbi.nlm.nih.gov/9780138/

897f9a3302265c3ceed1ad42cae9f915

The H2-receptor antagonists dose-dependently inhibited the histamine-stimulated acid production ( IC50 for cimetidine = 10(-5 ) M and 10(-6 ) M and for ranitidine = 10(-5 ) M and 2 X 10(-7 ) M for high and low concentrations of histamine , respectively ) .

Omeprazole, cimetidine, and ranitidine: inhibition of acid production in isolated human parietal cells. The antisecretory properties of omeprazole, cimetidine, and ranitidine were studied in vitro, using human gastric mucosal cells, which were obtained by sequential pronase and collagenase incubation of small tissue specimens obtained by endoscopic biopsy. Acid production was measured as the accumulation of radioactive aminopyrine in the acid compartments of the parietal cells. Acid production was stimulated via H2-receptors by histamine (10(-4) M or 5 X 10(-6) M) and via intracellular mechanisms by db-cAMP (10(-3) M). omeprazole induced a dose-dependent inhibition of acid production for all stimulators (IC50 = 2 X 10(-7) M and 3 X 10(-8) M with high and low concentrations of histamine, respectively, and 5 X 10(-6) M with db-cAMP). The H2-receptor antagonists dose-dependently inhibited the histamine-stimulated acid production ( IC50 for cimetidine = 10(-5 ) M and 10(-6 ) M and for ranitidine = 10(-5 ) M and 2 X 10(-7 ) M for high and low concentrations of histamine , respectively ) . Neither cimetidine nor ranitidine inhibited acid production after intracellular stimulation with db-cAMP. omeprazole reduced the aminopyrine accumulation stimulated by histamine (10(-4) M) already within 5-10 min, whereas cimetidine (10(-3) M and ranitidine (10(-4) M) required 20-30 min. The unstimulated level of acid production was also inhibited by omeprazole but not by the H2-receptor antagonists.

https://pubmed.ncbi.nlm.nih.gov/4081628/

c16e11de09ac91bbdcce0ab321ac08d2

To examine the cost-effectiveness of aripiprazole , quetiapine , and olanzapine/fluoxetine in adults with MDD who are refractory to antidepressant therapy .

Cost-effectiveness of adjunctive therapy with atypical antipsychotics for acute treatment of major depressive disorder. While the clinical utility of atypical antipsychotics has been established in patients with major depressive disorder (MDD) who are refractory to antidepressant therapy, their cost-effectiveness is unknown. ### objective To examine the cost-effectiveness of aripiprazole , quetiapine , and olanzapine/fluoxetine in adults with MDD who are refractory to antidepressant therapy . ### methods Using techniques of decision analysis, we estimated expected outcomes and costs over 6 weeks in adults with MDD receiving (1) aripiprazole 2-20 mg/day and antidepressant therapy; (2) quetiapine 150 mg/day or 300 mg/day and antidepressant therapy; (3) the fixed-dose combination of olanzapine 6, 12, or 18 mg/day with fluoxetine 50 mg/day; or (4) antidepressant therapy alone. Cost-effectiveness was assessed in terms of the cost per additional responder at 6 weeks, defined as the ratio of the difference in the cost of MDD-related care over 6 weeks versus antidepressant therapy alone to the difference in the number of patients achieving clinical response by 6 weeks. We estimated the model using data from Phase 3 clinical trials of atypical antipsychotics along with other secondary data sources. ### results With antidepressant therapy alone, the estimated clinical response rate at 6 weeks was 30%. aripiprazole, quetiapine 150 mg/day, quetiapine 300 mg/day, and olanzapine/fluoxetine were estimated to increase clinical response at 6 weeks to 49%, 34%, 38%, and 45%, respectively. Costs of MDD-related care over 6 weeks were estimated to be $192 for antidepressant therapy, $847 for aripiprazole, $541 for quetiapine 150 mg/day, $672 for quetiapine 300 mg/day plus antidepressant therapy, and $791 for olanzapine/fluoxetine. Costs per additional responder (vs antidepressant therapy) over a 6-week period were estimated to be $3447 for aripiprazole, $8725 for quetiapine 150 mg/day, $6000 for quetiapine 300 mg/day, and $3993 for olanzapine/fluoxetine. ### conclusions Atypical antipsychotics substantially increase clinical response at 6 weeks. Cost per additional responder is lower for aripiprazole than for quetiapine or olanzapine/fluoxetine.

https://pubmed.ncbi.nlm.nih.gov/22550279/

438212a88b4990ac96ee4e56a46dd644

2 . The two combination treatment regimes lowered the 12 h post-dose blood pressure more effectively than did atenolol alone , but the high dose nifedipine combination was no more effective than the low dose nifedipine combination .

Atenolol-nifedipine combinations compared to atenolol alone in hypertension: efficacy and tolerability. 1. In a double-blind, randomised, three-way-crossover study, 25 patients with sitting diastolic blood pressure between 95 and 120 mm Hg (Phase V) after 4 weeks' run-in on atenolol 50 mg twice daily, received atenolol 50 mg twice daily alone, atenolol 50 mg plus nifedipine 20 mg each twice daily and atenolol 50 mg plus nifedipine 40 mg each twice daily in three treatment periods each lasting 4 weeks. 'Washout' periods were not included. 2 . The two combination treatment regimes lowered the 12 h post-dose blood pressure more effectively than did atenolol alone , but the high dose nifedipine combination was no more effective than the low dose nifedipine combination . Sitting systolic BP (+/- s.e. mean) at the end of each period was 174 +/- 5 mm Hg after the atenolol run-in, 170 +/- 5 mm Hg with atenolol alone, 156 +/- 5 mm Hg with the low dose combination and 158 +/- 4 mm Hg with the high dose combination. Corresponding diastolic BP readings were 106 +/- 2 mm Hg, 106 +/- 2 mm Hg, 97 +/- 2 mm Hg and 99 +/- 2 mm Hg respectively. 3. Side-effects tended to occur less commonly with the low dose of the fixed combination than with atenolol alone. An increased number of side-effects occurred with the 40 mg twice daily doses of nifedipine, particularly flushing/erythema, oedema of the ankles/feet, and a hot feeling in the legs. These differences did not reach significance. 4. Overall compliance was good (98 +/- 0.7 s.e. mean %) and was similar within the different treatment regimes.(ABSTRACT TRUNCATED AT 250 WORDS)

https://pubmed.ncbi.nlm.nih.gov/3289598/

27cd3f43b9cbb557253aeb707e8c59ce

In addition , a variety of systemic chemotherapeutic agents have been tested in HCC , including various combinations of 5-fluorouracil , doxorubicin , epirubicin , etoposide , cisplatin , and mitoxantrone , as well as interferon , tamoxifen , capecitabine , thalidomide , and octreotide .

Nonsurgical treatment of hepatocellular carcinoma. While surgical resection and tumor ablation are the preferred therapies for hepatocellular carcinoma (HCC), these are available or appropriate in only a minority of patients. This reflects the usual comorbidity of severe underlying liver disease that either precludes surgery or makes the surgical approach extremely dangerous. Nonetheless, regional control of HCC is highly relevant and many regional strategies have been explored, including hepatic intra-arterial chemotherapy transarterial chemoembolization, lipiodol chemoembolization, radiation therapy, cryosurgery, percutaneous ethanol injection, and radiofrequency ablation. In addition , a variety of systemic chemotherapeutic agents have been tested in HCC , including various combinations of 5-fluorouracil , doxorubicin , epirubicin , etoposide , cisplatin , and mitoxantrone , as well as interferon , tamoxifen , capecitabine , thalidomide , and octreotide . Published data regarding these regional and systemic therapies will be discussed in this review.

https://pubmed.ncbi.nlm.nih.gov/11685743/

1841564f5c327bd81bb7274a6552a054

A very reasonable first-choice antidepressant is either sertraline or paroxetine .

Depression in Parkinson's Disease. Depression is very common in Parkinson's disease (PD), but its severity and particular symptoms vary. It can often be difficult to diagnose because many of the symptoms typically associated with depression (eg, sleep difficulties, fatigue) can be seen in nondepressed patients with PD, and signs thought to represent depression (eg, lack of facial expression, slowness) can be produced by PD itself. Apathy, although a possible feature of depression, can exist apart from depression and is often associated with cognitive impairment. Therefore, when evaluating patients with PD for possible depression, one should concentrate on the psychological or ideational aspects of the illness. One must determine whether the patient feels sad or hopeless or has a marked inability to enjoy life. Once it has been determined that the patient has clinically significant depressive symptoms, it is important to let him or her know that depression is an aspect of PD requiring treatment, just like the motor manifestations of the disease. The idea of adding antidepressant medications and the possibility of psychotherapy should be introduced. A very reasonable first-choice antidepressant is either sertraline or paroxetine . Because of isolated case reports of worsening motor function associated with institution of a selective serotonin reuptake inhibitor (SSRI), one should keep track of when the medication was started so that the patient can be seen again within a month. It is important from a psychological perspective to have regular follow-up visits when treating depression. If the SSRIs are ineffective or not tolerated, nortriptyline is a good next choice. It has fewer anticholinergic effects and is less likely to cause or worsen orthostatic hypotension than other tricyclic antidepressants. amitriptyline, although an old favorite of neurologists, is very sedating and has too much anticholinergic activity to be well tolerated in the higher doses needed to treat depression. If a patient could benefit from a dopamine agonist from a motor standpoint and his or her depressive symptoms are mild, consider using pramipexole, which may improve mood and motivation (although this has not yet been proven in a well-controlled trial). It is a good idea to keep patients on antidepressant therapy at least 6 months; many patients require long-term treatment. If a patient is severely depressed, he or she should be referred to a psychiatrist, who may consider admission to the hospital and possible electroconvulsive therapy.

https://pubmed.ncbi.nlm.nih.gov/11096753/

33a31447659a13473eb60f58152b458e

It is concluded that plasma lipid regulators which elevate HDL in this model might do so by altering the metabolism and hence plasma concentration of apoAI ( fenofibrate , ciprofibrate ) or both apo E and A-I ( gemfibrozil ) .

Gemfibrozil increases both apo A-I and apo E concentrations. Comparison to other lipid regulators in cholesterol-fed rats. HDL cholesterol (HDL-C) was increased by gemfibrozil (+3.6-fold), fenofibrate (+1.3-fold) and ciprofibrate (+1.2-fold) but not clofibrate or bezafibrate when dosed PO at 50 mg/kg for 2 weeks in cholesterol-fed rats. Cholesterol in apo B-containing lipoproteins decreased with gemfibrozil (-76%), clofibrate (-12%) and ciprofibrate (-12%). Plasma apo B decreased to the greatest extent with gemfibrozil (-86%) followed by ciprofibrate (-47%), fenofibrate (-40%), clofibrate (-24%) and bezafibrate (-20%). Only gemfibrozil increased plasma apo E levels which are characteristically low in this rat model. gemfibrozil, fenofibrate and ciprofibrate increased apo A-I concentrations. It is concluded that plasma lipid regulators which elevate HDL in this model might do so by altering the metabolism and hence plasma concentration of apoAI ( fenofibrate , ciprofibrate ) or both apo E and A-I ( gemfibrozil ) . It is hypothesized that drugs which alter the metabolism of both HDL peptides result in the greatest HDL-C elevation in the rat.

https://pubmed.ncbi.nlm.nih.gov/3081014/

6ba484620193fedfad6ddb775e6184f3

To evaluate the effect of switching to bevacizumab or ranibizumab after developing tachyphylaxis during anti-vascular endothelial growth factor ( VEGF ) therapy for choroidal neovascularisation ( CNV ) .

Bevacizumab and ranibizumab tachyphylaxis in the treatment of choroidal neovascularisation. To evaluate the effect of switching to bevacizumab or ranibizumab after developing tachyphylaxis during anti-vascular endothelial growth factor ( VEGF ) therapy for choroidal neovascularisation ( CNV ) . ### methods The authors reviewed the records of all patients who received both ranibizumab and bevacizumab for treatment of CNV to identify those who developed tachyphylaxis, defined as optical coherence tomography evidence of initial decreased exudation followed by lack of further reduction or an increase in exudation. Signs of exudation included subretinal fluid (SRF), pigment epithelial detachment (PED) and/or cystoid macular oedema (CMO). ### results 26 eyes were included. 10 were initially treated with bevacizumab and then changed to ranibizumab for persistent SRF, PED and/or CMO. Of these, seven had occult CNV and three had predominantly classic CNV. One eye in the occult CNV group did not respond after being switched to ranibizumab. Six eyes had a positive therapeutic response, after one injection in four eyes, and after two or three injections in one eye each. In the classic group, two responded to ranibizumab and one did not. Sixteen eyes were initially treated with ranibizumab before changing to bevacizumab. Of these, 15 had occult CNV and 1 was predominantly classic. Three of the 16 eyes failed to respond to bevacizumab; 6 improved after one injection and 5 after two injections. ### conclusions Patients with CNV who develop tachyphylaxis to ranibizumab or bevacizumab may respond to another anti-VEGF drug. The majority of cases (81%) in this series demonstrated at least some response after switching therapies.

https://pubmed.ncbi.nlm.nih.gov/21791509/

18c6d31cc386a2c4a4842f2ba9325548

Low-risk patients received three cycles of modified CODOX-M ( cyclophosphamide , doxorubicin , adriamycin , vincristine with intrathecal methotrexate and cytarabine followed by high-dose systemic methotrexate , regimen A ) .

Modified magrath regimens for adults with Burkitt and Burkitt-like lymphomas: preserved efficacy with decreased toxicity. Burkitt and Burkitt-like lymphomas are rapidly growing tumors which require specialized therapy. Although intensive, multi-agent regimens have been effective in children, results are more variable in adults. Magrath et al. previously described a regimen that was highly effective in children and young adults. This phase II study of a modified Magrath regimen was designed to assess its efficacy in older adults and reduce treatment-related toxicity. Fourteen patients with Burkitt/Burkitt-like lymphoma and median age of 47 years were stratified into two categories: low-risk (normal LDH and a single focus of disease measuring less than 10 cm, 3 patients) and high risk (all other, 11 patients). Low-risk patients received three cycles of modified CODOX-M ( cyclophosphamide , doxorubicin , adriamycin , vincristine with intrathecal methotrexate and cytarabine followed by high-dose systemic methotrexate , regimen A ) . High-risk patients received four alternating cycles of regimens A and B (A-B-A-B). Regimen B consisted of ifosfamide, cytarabine, etoposide and intrathecal methotrexate (IVAC). The modified treatment regimen was associated with no grade 3/4 neuropathy and only one episode of grade 3/4 mucositis. All patients completed protocol therapy and there were no treatment-related deaths. Twelve patients (86%, 90% CI: 61 97%) achieved a complete response; 1 patient achieved a PR and 1 patient died of progressive disease. Nine patients (64%) are alive and disease free at a median follow-up of 29 months. This modified Magrath regimen is effective and well-tolerated in a representative group of older adult patients.

https://pubmed.ncbi.nlm.nih.gov/15160953/

2ab0adbbe0f3976d64dcdaa3e633966e

Background The National Wilms Tumor Study ( NWTS ) approach to treating stage III favorable-histology Wilms tumor ( FHWT ) is Regimen DD4A ( vincristine , dactinomycin , and doxorubicin ) and radiation therapy .

Outcome and Prognostic Factors in Stage III Favorable-Histology Wilms Tumor: A Report From the Children's Oncology Group Study AREN0532. Background The National Wilms Tumor Study ( NWTS ) approach to treating stage III favorable-histology Wilms tumor ( FHWT ) is Regimen DD4A ( vincristine , dactinomycin , and doxorubicin ) and radiation therapy . Further risk stratification is required to improve outcomes and reduce late effects. We evaluated clinical and biologic variables for patients with stage III FHWT without combined loss of heterozygosity (LOH) at chromosomes 1p and 16q treated in the Children's Oncology Group protocol AREN0532. Methods From October 2006 to August 2013, 588 prospectively treated, centrally reviewed patients with stage III FHWT were treated with Regimen DD4A and radiation therapy. Tumor LOH at 1p and 16q was determined by microsatellite analysis. Ineligible patients (n = 5) and those with combined LOH 1p/16q (n = 40) were excluded. Results A total of 535 patients with stage III disease were studied. Median follow-up was 5.2 years (range, 0.2 to 9.5). Four-year event-free survival (EFS) and overall survival estimates were 88% (95% CI, 85% to 91%) and 97% (95% CI, 95% to 99%), respectively. A total of 58 of 66 relapses occurred in the first 2 years, predominantly pulmonary (n = 36). Eighteen patients died, 14 secondary to disease. A better EFS was associated with negative lymph node status ( P < .01) and absence of LOH 1p or 16q ( P < .01), but not with gross residual disease or peritoneal implants. In contrast, the 4-year EFS was only 74% in patients with combined positive lymph node status and LOH 1p or 16q. A total of 123 patients (23%) had delayed nephrectomy. Submitted delayed nephrectomy histology showed anaplasia (n = 8; excluded from survival analysis); low risk/completely necrotic (n = 7; zero relapses), intermediate risk (n = 63; six relapses), and high-risk/blastemal type (n=7; five relapses). Conclusion Most patients with stage III FHWT had good EFS/overall survival with DD4A and radiation therapy. Combined lymph node and LOH status was highly predictive of EFS and should be considered as a potential prognostic marker for future trials.

https://pubmed.ncbi.nlm.nih.gov/29211618/

ee13fff13e99f5f1f6204552cc001ecc

The role of serotonergic neurons in foot shock-induced jumping behavior was evaluated by studying the effects of serotonin agonists and depletors under conditions of increasing activity of catecholaminergic neurons by combining different shock intensities with methamphetamine or clonidine pretreatment .

Serotonergic-catecholaminergic interactions and foot shock-induced jumping behavior in rats. The role of serotonergic neurons in foot shock-induced jumping behavior was evaluated by studying the effects of serotonin agonists and depletors under conditions of increasing activity of catecholaminergic neurons by combining different shock intensities with methamphetamine or clonidine pretreatment . Low shock (40 V) jumping was suppressed by three different kinds of serotonergic agonists: 5-hydroxytryptophan (50 and 100 mg/kg), 5-methoxydimethyltryptamine (1 and 5 mg/kg) and clomipramine (5 mg/kg) but these drugs did not suppress high shock (60 V) jumping. A depletor of brain serotonin, p-chlorophenylalanine (200 mg/kg), failed to affect the jumping induced by both shock intensities. The inhibitory effect of serotonergic agonists on low shock jumping was abolished by pretreatment with methamphetamine (1 mg/kg) or clonidine (100 micrograms/kg). Furthermore, 5-methoxydimethyltryptamine (5 mg/kg), a serotonergic postsynaptic receptor stimulant, potentiated high shock jumping in rats pretreated with methamphetamine (3 and 5 mg/kg). The results indicated that activation of serotonergic neurons has a differential effect on jumping behavior ranging from inhibitory to facilitatory, depending upon the increasing activity of catecholaminergic neurons.

https://pubmed.ncbi.nlm.nih.gov/6653659/

efaf3b6f6b5f664849d17e9c57112c6a

Enrolled patients received ADT in the form of leuprolide every 12 weeks for 24 months with bicalutamide initiating after the completion of chemotherapy .

A phase II trial of androgen deprivation therapy (ADT) plus chemotherapy as initial treatment for local failures or advanced prostate cancer. Long-term hormonal ablation in prostate cancer is associated with decreased overall health and quality of life. Few reports emphasized the role of chemotherapy in the management of early stage prostate cancer. This study analyzed the safety and efficacy of androgen deprivation therapy (ADT) plus chemotherapy as initial treatment for patients identified as local failures or not eligible for prostatectomy or radiation therapy due to advanced disease presentation. ### methods Enrolled patients received ADT in the form of leuprolide every 12 weeks for 24 months with bicalutamide initiating after the completion of chemotherapy . Chemotherapy consisted of ketoconazole and doxorubicin for weeks 1, 3, and 5 and estramustine and docetaxel and for weeks 2, 4 and 6. During weeks 7 and 8, no treatment was received. ### results Forty-six patients were enrolled, and forty-five patients were evaluable. Median progression-free survival (PFS) was 23.4 months. Median overall survival (OS) was 53.7 months. Out of 45 patients with measurable disease, 22 patients had an objective response: 9 patients achieved a complete response; 2 patients achieved a partial response; 10 patients achieved stable disease. Frequent grade 3 adverse events included elevated ALT (17 %), hypokalemia (13 %), and hypophosphatemia (13 %). Grade 4 adverse events were rare and included low bicarbonate (2 %), hypokalemia (2 %), leukocytopenia (2 %), and neutropenia (2 %). ### conclusions The treatment demonstrated clinical benefit in all patient subsets with minimal reversible treatment-related adverse events. Subgroup analysis suggests that having prior local therapy resulted in greater PFS and OS.

https://pubmed.ncbi.nlm.nih.gov/23604530/

310fe5ed4e6b2d907d28ff5f621520b5

Clinical studies have indicated the following relative potency differences : fluticasone propionate > budesonide = beclomethasone dipropionate > triamcinolone acetonide = flunisolide .

Establishing a therapeutic index for the inhaled corticosteroids: part I. Pharmacokinetic/pharmacodynamic comparison of the inhaled corticosteroids. The inhaled corticosteroids contain physicochemical differences that alter both glucocorticoid receptor-binding characteristics and the pharmacokinetic variables of these drugs. Differences in receptor-binding affinity translate into differences in potency for different drugs. Differences in pharmacokinetics, however, determine the topical effect to systemic effect ratio, or the "pulmonary targeting" of the drug. Beneficial pharmacokinetic properties that may improve pulmonary targeting include low oral bioavailability, rapid systemic clearance, and slow absorption from the lung. Delivery devices can produce clinically significant differences in topical activity by altering the dose deposited in the lung and, for orally absorbed drugs, the amount deposited in the oropharynx and swallowed. Clinical trials have confirmed that differences in potency or drug delivery of 2-fold or more can be detected in patients with asthma. However, because of the relatively flat nature of the dose-response curve for morning peak expiratory flow and forced expiratory volume in 1 second, the trials must be adequately powered and well controlled. The use of bronchial provocation measures are problematic because of the prolonged lag time for response. Study design flaws can lead to misinterpretation of results. Clinical studies have indicated the following relative potency differences : fluticasone propionate > budesonide = beclomethasone dipropionate > triamcinolone acetonide = flunisolide . Current evidence suggests that potency differences can be overcome by giving larger doses of the less potent drug. However, because of these potency differences, studies of systemic effects should not be done in isolation of adequate topical activity studies to define the pulmonary targeting of the drugs.

https://pubmed.ncbi.nlm.nih.gov/9798722/

92547edbc8aa1ee6250ed5d19f1b04cf

To evaluate the efficacy and safety of lapatinib ( L ) and trastuzumab ( T ) combination in HER2-positive metastatic breast cancer ( MBC ) patients previously treated with T and/or L.

A retrospective, multicenter study of the efficacy of lapatinib plus trastuzumab in HER2-positive metastatic breast cancer patients previously treated with trastuzumab, lapatinib, or both: the Trastyvere study. To evaluate the efficacy and safety of lapatinib ( L ) and trastuzumab ( T ) combination in HER2-positive metastatic breast cancer ( MBC ) patients previously treated with T and/or L. ### Materials And Methods We conducted a retrospective, post-authorized, multicenter study including patients with HER2-positive MBC or locally advanced breast cancer (ABC) treated with the combination of L-T. Concomitant endocrine therapy, as well as brain metastasis and/or prior exposure to L, were allowed. ### results One hundred and fifteen patients from 14 institutions were included. The median age was 59.8 years. The median number of prior T regimens in the advanced setting was 3 and 73 patients had received a prior L regimen. The clinical benefit rate (CBR) was 34.8% (95% CI 26.1-43.5). Among other efficacy endpoints, the overall response rate was 21.7%, and median progression-free survival (PFS) and overall survival were 3.9 and 21.6 months, respectively. Heavily pretreated and ≥ 3 metastatic organ patients showed lower CBR and PFS than patients with a low number of previous regimens and < 3 metastatic organs. Moreover, CBR did not significantly change in L-pretreated compared with L-naïve patients (31.5% versus 40.5% for L-pretreated versus L-naïve). Grade 3/4 adverse events were reported in 19 patients (16.5%). ### conclusion The combination of L-T is an effective and well-tolerated regimen in heavily pretreated patients and remains active among patients progressing on prior L-based therapy. Our study suggests that the L-T regimen is a safe and active chemotherapy-free option for MBC patients previously treated with T and/or L.

https://pubmed.ncbi.nlm.nih.gov/31203575/

49701c7a424eb30b64f745b9d5bdf83e

Meloxicam combined with sorafenib synergistically inhibits tumor growth of human hepatocellular carcinoma cells via ER stress-related apoptosis .

Meloxicam combined with sorafenib synergistically inhibits tumor growth of human hepatocellular carcinoma cells via ER stress-related apoptosis . sorafenib (SOR) is a promising treatment for advanced hepatocellular carcinoma (HCC). However, the precise mechanisms of toxicity and drug resistance have not been fully explored and new strategies are urgently needed for HCC therapy. meloxicam (MEL) is a selective cyclooxygenase-2 (COX-2) inhibitor which elicits antitumor effects in human HCC cells. In the present study, we investigated the interaction between MEL and SOR in human SMMC‑7721 cells and the role endoplasmic reticulum (ER) stress exerts in the combination of SOR with MEL treatment-induced cytotoxicity. Our results revealed that the combination treatment synergistically inhibited cell proliferation and enhanced apoptosis. Furthermore, the combination treatment enhanced ER stress-related molecules which involved in SMMC-7721 cell apoptosis. GRP78 knockdown by siRNA or co-treatment with MG132 significantly increased this combination treatment-induced apoptosis. In addition, we found that the combination treatment suppressed tumor growth by way of activation of ER stress in in vivo models. We concluded that the combination of SOR with MEL treatment-induced ER stress, and eventually apoptosis in human SMMC-7721 cells. Knockdown of GRP78 using siRNA or proteosome inhibitor enhanced the cytotoxicity of the combination of SOR with MEL-treatment in SMMC-7721 cells. These findings provided a new potential treatment strategy against HCC.

https://pubmed.ncbi.nlm.nih.gov/26252057/

9509f8edbe454f9760ad599d91515702

We validated these initial findings in samples collected in a clinical trial comparing the nucleoside analog fludarabine alone or in combination with the alkylating agent cyclophosphamide in untreated CLL samples collected prior to starting therapy ( E2997 ) .

The long noncoding RNA, treRNA, decreases DNA damage and is associated with poor response to chemotherapy in chronic lymphocytic leukemia. The study of long noncoding RNAs (lncRNAs) is an emerging area of cancer research, in part due to their ability to serve as disease biomarkers. However, few studies have investigated lncRNAs in chronic lymphocytic leukemia (CLL). We have identified one particular lncRNA, treRNA, which is overexpressed in CLL B-cells. We measured transcript expression in 144 CLL patient samples and separated samples into high or low expression of treRNA relative to the overall median. We found that high expression of treRNA is significantly associated with shorter time to treatment. High treRNA also correlates with poor prognostic indicators such as unmutated IGHV and high ZAP70 protein expression. We validated these initial findings in samples collected in a clinical trial comparing the nucleoside analog fludarabine alone or in combination with the alkylating agent cyclophosphamide in untreated CLL samples collected prior to starting therapy ( E2997 ) . High expression of treRNA was independently prognostic for shorter progression free survival in patients receiving fludarabine plus cyclophosphamide. Given these results, in order to study the role of treRNA in DNA damage response we generated a model cell line system where treRNA was over-expressed in the human B-CLL cell line OSU-CLL. Relative to the vector control line, there was less cell death in OSU-CLL over-expressing treRNA after exposure to fludarabine and mafosfamide, due in part to a reduction in DNA damage. Therefore, we suggest that treRNA is a novel biomarker in CLL associated with aggressive disease and poor response to chemotherapy through enhanced protection against cytotoxic mediated DNA damage.

https://pubmed.ncbi.nlm.nih.gov/28412730/

aecf217b9cc205de69a52ac110a4aa53

The antiviral agents ganciclovir and foscarnet are effective against CMV retinitis and gastrointestinal diseases , although dose-limiting adverse effects and the need for long-term maintenance therapy may hinder their use in many patients .

Treatment and prophylaxis of cytomegalovirus disease. The diseases caused by cytomegalovirus (CMV) may threaten the life or sight of immunocompromised individuals such as patients undergoing transplantation and those with the acquired immunodeficiency syndrome. The management of CMV disease can be difficult. The antiviral agents ganciclovir and foscarnet are effective against CMV retinitis and gastrointestinal diseases , although dose-limiting adverse effects and the need for long-term maintenance therapy may hinder their use in many patients . When used to treat CMV pneumonitis in bone marrow transplant recipients, ganciclovir alone is not as effective as when it is combined with immune globulin. Since CMV disease can be fatal, several protocols have been developed for the transplant patient population, including administration of acyclovir, ganciclovir, screened blood products, and immune globulins.

https://pubmed.ncbi.nlm.nih.gov/1325636/

42fcd1c1fa5ccff740b1a69412b2de1f

Switching between metronidazole and clarithromycin seems to be a sensible strategy as these two are the most effective anti-Helicobacter agents .

Where are We with current therapy? Despite intensive research and widely publicized recommendations from consensus meetings in different continents, the public and primary care physicians are relatively slow in picking up the impact of Helicobacter pylori infection and identifying optimal therapies. The treatment of H. pylori infection has evolved from bismuth-containing regimens, 2-week proton pump inhibitor (PPI)-dual therapies, and now, the widely accepted PPI/ranitidine bismuth citrate (RBC) single week triple therapies. There is a wealth of evidence showing that these regimens are highly efficacious and well tolerated by patients. The MACH-2 studies have confirmed that the addition of a PPI to two antimicrobials has significantly improved the cure rate of H. pylori infection and reduced the impact of antimicrobial resistance. Attempts to use shorter regimens ranging from 1 to 3 days should be resisted because of their unacceptably low therapeutic efficacy. In the United States, there are some indications that 10-14 days of treatment may be required. While the first-line therapies for H. pylori infection is well established, we are still struggling with the choice of optimal regimen in retreatment after the first attempt fails. Quadruple therapy combining PPI with bismuth, metronidazole and tetracycline has achieved a respectable success of around 85%. Switching between metronidazole and clarithromycin seems to be a sensible strategy as these two are the most effective anti-Helicobacter agents . Changing between PPI and RBC in the triple therapy would not make much difference without replacing some of the antimicrobials. rifabutin-containing regimens and high-dose PPI-amoxicillin dual therapy deserve more studies with large-scale studies. Data on anti-Helicobacter therapy for children are few. Most studies based on bismuth derivatives in combination with amoxicillin or tinidazole and were limited by the small number of cases. Recent studies showed 1-week bismuth-based triple therapy and 2-week PPI-based triple therapy are highly efficacious. Reinfection in children > 5 years of age after successful cure is rare. It is worthwhile to refine the optimal therapy for children as the treatment of this group would, theoretically, prevent the development gastric cancer in the long term.

https://pubmed.ncbi.nlm.nih.gov/10828750/

caec1f330b4ff88064928cbdfe2d04ae

Therefore , downregulation of bcl-2 or xIAP by RNAi enhances the effects of etoposide and doxorubicin .

Specific downregulation of bcl-2 and xIAP by RNAi enhances the effects of chemotherapeutic agents in MCF-7 human breast cancer cells. Antiapoptotic genes such as bcl-2 or xIAP may be responsible for resistance to apoptosis induced by cytotoxic drugs. The aim of this study was to investigate if downregulation of bcl-2 or xIAP by RNA interference (RNAi) would sensitize MCF-7 cells to etoposide and doxorubicin. FITC-siRNAs uptake was verified by fluorescence microscopy and downregulation of Bcl-2 or XIAP was confirmed by Western Blotting. Both siRNAs reduced the number of viable cells and increased cellular apoptosis. Treatment with siRNAs followed by treatment with etoposide or doxorubicin further reduced the number of viable cells, when compared to either of the treatments alone. Therefore , downregulation of bcl-2 or xIAP by RNAi enhances the effects of etoposide and doxorubicin .

https://pubmed.ncbi.nlm.nih.gov/15031723/

e64a65a04bf8a854d6a211efc8068c61

Cetuximab is a monoclonal antibody against EGFR with additive preclinical activity with irinotecan .

N0436 (Alliance): A Phase II Trial of Irinotecan With Cetuximab in Patients With Metastatic Breast Cancer Previously Exposed to Anthracycline and/or Taxane-Containing Therapy. irinotecan has a 20% to 25% response rate (RR) in patients with previously treated metastatic breast cancer (MBC). Epidermal growth factor receptor (EGFR) is overexpressed in some MBC, especially in triple-negative breast cancer (TNBC). Cetuximab is a monoclonal antibody against EGFR with additive preclinical activity with irinotecan . ### Patients And Methods We report a 1-stage phase II study on MBC, measurable disease, and previous anthracycline and/or taxane therapy. Patients received cetuximab 400 mg/m(2) on day 1 cycle 1 then 250 mg/m(2) weekly thereafter and irinotecan 80 mg/m(2) on days 1 and 8 of each 21-day cycle. The primary end point was overall RR (ORR) according to Response Evaluation Criteria in Solid Tumors criteria (version 1.1). ### results Of 19 eligible patients enrolled from February to September 2006, 14 patients (74%) had visceral disease, seven patients (37%) were hormone receptor-positive, two patients (11%) HER2-positive, and 11 patients (58%) were triple-negative. Patients received a median of 2 cycles (range, 1-37). Confirmed ORR was 11% (95% confidence interval [CI], 1%-33%), with 1 partial response and 1 complete response. One patient had stable disease for 8 months. RR for TNBC versus non-TNBC was 18% versus 0% (P = .49). Median time to progression was 1.4 months (95% CI, 1.0-2.2) and median overall survival was 9.4 months (95% CI, 2.8-16.1). Twelve patients had disease progression within 2 cycles during therapy. Because of a low RR and rapid disease progression, the study leadership decided to close the trial early. ### conclusion The tolerability of the combination of cetuximab and irinotecan is acceptable but demonstrated low overall activity. Potentially promising results were noted in patients with TNBC and further studies of these patients might be considered.

https://pubmed.ncbi.nlm.nih.gov/26381420/

650a70ac002563b1aea29279e3f6a48a

A non-specific inhibitor of 5-HT reuptake , imipramine , did not produce this amnesic effect , nor did the combination of fenfluramine with the MAOI tranylcypromine , although it produced , as expected , the " serotonergic syndrome . " Results for the metabolic precursor of 5-HT , 5-HTP , also administered peripherally , were inconsistent , with amnesic effects seen at 5 and 20 mg/kg but none at 10 mg/kg .

Manipulations of 5-HT activity and memory in the rat. The activity of 5-HT was manipulated by means of the peripheral injection of 5-HT reuptake inhibitors, fenfluramine and fluoxetine. These drug treatments, at doses higher than 1 mg/kg, produced retrograde amnesia in a one-trial appetitive learning task in rats. A non-specific inhibitor of 5-HT reuptake , imipramine , did not produce this amnesic effect , nor did the combination of fenfluramine with the MAOI tranylcypromine , although it produced , as expected , the " serotonergic syndrome . " Results for the metabolic precursor of 5-HT , 5-HTP , also administered peripherally , were inconsistent , with amnesic effects seen at 5 and 20 mg/kg but none at 10 mg/kg .

https://pubmed.ncbi.nlm.nih.gov/3873076/

db1c10486c4e7c99ceaac0fc14a353cf

Activity of irinotecan and temozolomide in the presence of O6-methylguanine-DNA methyltransferase inhibition in neuroblastoma pre-clinical models .

Activity of irinotecan and temozolomide in the presence of O6-methylguanine-DNA methyltransferase inhibition in neuroblastoma pre-clinical models . The combination of temozolomide (TMZ) and irinotecan is a regimen used in neuroblastoma patients with recurrent disease. O(6)-methylguanine-DNA methyltransferase (MGMT) may have a function in resistance to TMZ. Using neuroblastoma pre-clinical models, we determined whether the inhibition of MGMT by O(6)-benzylguanine (O6-BG) could enhance the anti-tumour activity of TMZ and irinotecan. ### methods The cytotoxicity of TMZ and irinotecan, either alone or in combination, was measured in five neuroblastoma cell lines in the presence or absence of O6-BG with a fluorescence-based cell viability assay (DIMSCAN). Anti-tumour activity was measured in three neuroblastoma xenograft models. ### results MGMT mRNA and protein were expressed in 9 out of 10 examined cell lines. Pretreatment of cells with 25 μM O6-BG decreased MGMT protein expression and enhanced The TMZ cytotoxicity by up to 0.3-1.4 logs in four out of five tested cell lines. TMZ (25 mg kg(-1) per day for 5 days every 3 weeks for four cycles) did not significantly improve mice survival, whereas the same schedule of irinotecan (7.5 mg kg(-1) per day) significantly improved survival (P<0.0001) in all three xenograft models. Combining O6-BG and/or TMZ with irinotecan further enhanced survival. ### conclusion Our in vitro and in vivo findings suggest that irinotecan drives the activity of irinotecan and TMZ in recurrent neuroblastoma. Inhibitors of MGMT warrant further investigation for enhancing the activity of regimens that include TMZ.

https://pubmed.ncbi.nlm.nih.gov/20924375/

c5b1038c47002a14dda922096cd0be58

This is a phase II study of etoposide , vincristine , and doxorubicin , administered as a 96-hour continuous infusion , with intravenous ( IV ) bolus cyclophosphamide and oral prednisone ( EPOCH ) in 74 consecutive patients who relapsed from or failed to respond to most of the same drugs administered on a bolus schedule .

EPOCH chemotherapy: toxicity and efficacy in relapsed and refractory non-Hodgkin's lymphoma. Based on in vitro evidence that tumor cells are less resistant to prolonged exposure to low concentrations of the natural product class, compared with brief higher concentration exposure, we developed a chemotherapy regimen (etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone [EPOCH]) in which the natural products are administered as a continuous infusion. ### Patients And Methods This is a phase II study of etoposide , vincristine , and doxorubicin , administered as a 96-hour continuous infusion , with intravenous ( IV ) bolus cyclophosphamide and oral prednisone ( EPOCH ) in 74 consecutive patients who relapsed from or failed to respond to most of the same drugs administered on a bolus schedule . Patients with aggressive lymphomas who achieved a good response after EPOCH were eligible to undergo bone marrow transplantation. ### results Patients with intermediate- or high-grade lymphoma comprised 76% of this series and 77% had stage IV disease. Seventy-one percent had previously received all of the drugs contained in the EPOCH regimen and 92% had received at least four of the drugs. Seventy patients were assessable for response, of whom 19 (27%) achieved a complete remission (CR) and 42 (60%) a partial remission (PR). Among 21 patients who had no response to prior chemotherapy, 15 (71%) responded, but only one achieved a CR. Patients who relapsed from an initial CR had a 100% response rate, with 76% CRs. With a median potential follow-up duration of 19 months, there was a 28% probability of being event-free at 1 year. Toxicity was primarily hematologic with neutropenia during 51% of cycles, but only a 17% incidence of febrile neutropenia. Gastrointestinal, neurologic, and cardiac toxicity were minimal. ### conclusion EPOCH chemotherapy was well tolerated and highly effective in patients who were resistant to or relapsed from the same drugs administered on a bolus schedule, suggesting that continuous infusion of the natural drug component of this regimen is capable of partially reversing drug resistance and reducing toxicity. Dose-intensity (DI) was > or = that achieved in primary treatment regimens for aggressive lymphomas.

https://pubmed.ncbi.nlm.nih.gov/7687667/

525796501d9304f57265c5bab837ebe3

Based on the FIRM-ACT trial , mitotane plus etoposide , doxorubicin , and cisplatin is now the established first-line cytotoxic therapy .

Update in adrenocortical carcinoma. Adrenocortical carcinoma (ACC) is an orphan malignancy that has attracted increasing attention during the last decade. Here we provide an update on advances in the field since our last review published in this journal in 2006. The Wnt/β-catenin pathway and IGF-2 signaling have been confirmed as frequently altered signaling pathways in ACC, but recent data suggest that they are probably not sufficient for malignant transformation. Thus, major players in the pathogenesis are still unknown. For diagnostic workup, comprehensive hormonal assessment and detailed imaging are required because in most ACCs, evidence for autonomous steroid secretion can be found and computed tomography or magnetic resonance imaging (if necessary, combined with functional imaging) can differentiate benign from malignant adrenocortical tumors. Surgery is potentially curative in localized tumors. Thus, we recommend a complete resection including lymphadenectomy by an expert surgeon. The pathology report should demonstrate the adrenocortical origin of the lesion (eg, by steroidogenic factor 1 staining) and provide Weiss score, resection status, and quantitation of the proliferation marker Ki67 to guide further treatment. Even after complete surgery, recurrence is frequent and adjuvant mitotane treatment improves outcome, but uncertainty exists as to whether all patients benefit from this therapy. In advanced ACC, mitotane is still the standard of care. Based on the FIRM-ACT trial , mitotane plus etoposide , doxorubicin , and cisplatin is now the established first-line cytotoxic therapy . However, most patients will experience progress and require salvage therapies. Thus, new treatment concepts are urgently needed. The ongoing international efforts including comprehensive "-omic approaches" and next-generation sequencing will improve our understanding of the pathogenesis and hopefully lead to better therapies.

https://pubmed.ncbi.nlm.nih.gov/24081734/

b419ddb50eed7610d1d9c4e619f1b6bb

Additionally , thorough analysis of the available literature indicates no correlation between dasatinib nor nilotinib dose , length of exposure , trimester of use , and deleterious patient or fetal outcomes can be concluded .

Experience with dasatinib and nilotinib use in pregnancy. Pregnancy in a patient with chronic myeloid leukemia presents a therapeutic challenge. Both dasatinib and nilotinib are indicated for first-line treatment as well as for treatment-resistant chronic myeloid leukemia. Animal studies with dasatinib or nilotinib demonstrate fetal skeletal malformations as well as significant mortality during organogenesis. The goal of this article is to review the experience to date of dasatinib and nilotinib in human pregnancy, specifically dasatinib and nilotinib dose, length of exposure, trimester of use, as well as patient and fetal outcomes. Based on the limited data, both dasatinib and nilotinib may cause fetal harm. Additionally , thorough analysis of the available literature indicates no correlation between dasatinib nor nilotinib dose , length of exposure , trimester of use , and deleterious patient or fetal outcomes can be concluded . Therefore, health care professionals need to regularly counsel women of child bearing potential with chronic myeloid leukemia regarding the risks of taking dasatinib or nilotinib during pregnancy. The safest potential therapeutic options for the management of chronic myeloid leukemia in pregnancy include temporary discontinuation of the tyrosine kinase inhibitor followed by observation or intervention with interferon alfa and/or leukapheresis.

https://pubmed.ncbi.nlm.nih.gov/29284357/

93ead62c1d4c59ac6ea81f118b1343b5

The principal toxicity was myelosuppression ; grade 4 neutropenia was more frequent with topotecan ( 81.4 % of patients ) than with paclitaxel ( 22.9 % of patients ) .

Clinical evidence for topotecan-paclitaxel non--cross-resistance in ovarian cancer. A large, randomized study comparing the efficacy and safety of topotecan versus paclitaxel in patients with relapsed epithelial ovarian cancer showed that these two compounds have similar activity. In this study, a number of patients crossed over to the alternative drug as third-line therapy, ie, from paclitaxel to topotecan and vice versa. We therefore were able to assess the degree of non-cross-resistance between these two compounds. ### Patients And Methods Patients who had progressed after one platinum-based regimen were randomized to either topotecan (1.5 mg/m(2)/d) x 5 every 21 days (n = 112) or paclitaxel (175 mg/m(2) over 3 hours) every 21 days (n = 114). A total of 110 patients received cross-over therapy with the alternative drug (61 topotecan, 49 paclitaxel) as third-line therapy. ### results Response rates to third-line cross-over therapy were 13.1% (8 of 61 topotecan) and 10.2% (5 of 49 paclitaxel; P =.638). Seven patients who responded to third-line topotecan and four patients who responded to paclitaxel had failed to respond to their second-line treatment. Median time to progression (from the start of third-line therapy) was 9 weeks in both groups, and median survival was 40 and 48 weeks for patients who were receiving topotecan or paclitaxel, respectively. The principal toxicity was myelosuppression ; grade 4 neutropenia was more frequent with topotecan ( 81.4 % of patients ) than with paclitaxel ( 22.9 % of patients ) . ### conclusion topotecan and paclitaxel have similar activity as second-line therapies with regard to response rates and progression-free and overall survival. We demonstrated that the two drugs have a degree of non-cross-resistance. Thus, there is a good rationale for incorporating these drugs into future first-line regimens.

https://pubmed.ncbi.nlm.nih.gov/11283120/

e18f53a72ef354dc4bf0992f2d580682

Consistent with previous reports , genistein combined with doxorubicin had a synergistic effect on MCF-7/Adr cells , and genistein reduced the chemoresistance of these cells .

Synergistic cytotoxic effect of genistein and doxorubicin on drug-resistant human breast cancer MCF-7/Adr cells. The molecular mechanisms underlying genistein-mediated reversal of chemoresistance remains unknown. In the present study, we investigated the molecular mechanisms by which genistein overcomes chemoresistance and its effect on doxorubicin-induced cytotoxicity. Consistent with previous reports , genistein combined with doxorubicin had a synergistic effect on MCF-7/Adr cells , and genistein reduced the chemoresistance of these cells . genistein treatment increased the intracellular accumulation of doxorubicin but did not influence P-gp function. The combination of genistein and doxorubicin significantly induced cell cycle arrest and apoptosis. genistein treatment strongly inhibited HER2/neu but not MDR-1 expression at both the mRNA and protein levels. Therefore, our results demonstrated that genistein combined with doxorubicin had a synergistic effect on MCF-7/Adr cells, and the mechanisms likely involve an increase in the intracellular accumulation of doxorubicin and suppression of HER2/neu expression.

https://pubmed.ncbi.nlm.nih.gov/25109508/

400902e0b2c154edcc0b488ee004fddb

This historical cohort study evaluated the association of efavirenz ( EFV ) compared to nevirapine ( NVP ) with post-ART TB among patients initiated on first-line ART from 2005 to 2009 in a large , urban HIV clinic in Uganda .

Risk of tuberculosis after antiretroviral treatment initiation: a comparison between efavirenz and nevirapine using inverse probability weighting. There is a high incidence of tuberculosis (TB) early after antiretroviral therapy (ART) initiation. This historical cohort study evaluated the association of efavirenz ( EFV ) compared to nevirapine ( NVP ) with post-ART TB among patients initiated on first-line ART from 2005 to 2009 in a large , urban HIV clinic in Uganda . ### methods Hazard ratios (HR) for developing TB were computed using multivariable Cox proportional hazards models with inverse weighting of the probability of being prescribed NVP or EFV (calculated by a multivariable logistic regression model), stratifying by baseline CD4+ T-cell count. Adjustment for time-updated CD4+ T-cell count, restriction of the analysis to patients remaining in follow-up and a TB-free survival analysis were performed as sensitivity analyses. ### results ART was initiated in 5,797 patients; 66% were women with a mean age of 37 years (SD 9) and a median baseline CD4+ T-cell count of 117 cells/mm3 (IQR 43-182). Overall, 60% (n = 3,484) were initiated on NVP and 40% (n = 2,313) on EFV. In the first 2 years of ART, 377 patients developed TB. The use of EFV compared to NVP was independently associated with higher TB incidence in patients with a baseline CD4+ T-cell count < 100 cells/mm3 (HR 2.05 [95% CI 1.29, 3.27]; P = 0.003), but not at higher CD4+ T-cell counts (HR 0.71 [95% CI 0.39, 1.31]; P = 0.428). These estimates were robust to all sensitivity analyses. ### conclusions There was a higher incidence of TB in patients with baseline CD4+ T-cell counts < 100 cells/mm3 initiated on EFV compared to those initiated on NVP. Further research in a trial setting or a larger multisite observational cohort is needed to confirm these findings.

https://pubmed.ncbi.nlm.nih.gov/23423604/

04b4d94b76cbe96ab4d75a4e83e53da1

Combination of ibrutinib and ublituximab ( n = 64 ) had an ORR of 78 % ( CR 7 % ) in a phase 3 study .

Efficacy of Ibrutinib-Based Regimen in Chronic Lymphocytic Leukemia: A Systematic Review. ibrutinib has shown to have better efficacy than standard chemoimmunotherapy in del17 positive chronic lymphocytic leukemia (CLL) patients; however its role in del17 negative patients is less clear. We aim to evaluate the efficacy of ibrutinib-based regimens in CLL. Seven databases were searched in accordance with PRISMA statement guidelines using the following keywords: chronic lymphocytic leukemia, CLL, Bruton tyrosine kinase inhibitor, BTK inhibitor, ibrutinib, and PCI-32765. Data from only prospective clinical trials was included. In a phase 3 trial (n = 136), the overall response rate (ORR) with ibrutinib was 92% whereas 18% patients had a complete response (CR). Progression free survival (PFS) and overall survival (OS) at 2 years were 89% and 95% respectively. Phase 3 trial (n = 195) with single agent ibrutinib showed ORR of 63%. PFS at 6 months and OS at 12 months were 88% and 90% respectively. In a phase 2 trial of relapsed and/or refractory (R/R) or high risk treatment naive (TN) patients, combination of ibrutinib and rituximab (n = 104) achieved an ORR of 100% (CR 28%) as compared to ORR 98% (CR 21%) with ibrutinib monotherapy (n = 102) with no significant difference in PFS. Combination of ibrutinib and ublituximab ( n = 64 ) had an ORR of 78 % ( CR 7 % ) in a phase 3 study . In del17p negative R/R patients, combination of bendamustine/rituximab (BR) and ibrutinib (n = 289) achieved an ORR of 83% (CR/CRi 10%) and the 18 month PFS was 79%. In a phase 2 trial treated with ibrutinib (n = 145), patients with del17p R/R disease achieved an ORR of 64% and the 24 month PFS and OS was 63% and 75% respectively. In TN del17p patients (n = 35), ORR was 97% (CR-0) and the 24 month PFS and OS were 82% and 84% respectively with single agent ibrutinib. ibrutinib is the treatment of choice for patients with del17p mutation and has good efficacy in RR/TN patients without del17p mutation. ibrutinib is being evaluated in combination with rituximab for del17p mutations. Future prospects include combination of ibrutinib with frontline chemotherapy and other novel agents for TN and RR del17p negative patients.

https://pubmed.ncbi.nlm.nih.gov/32300434/

0db914a1836322dc765a2945b4cfb1c9

Overall median effective concentration ( EC50 ) values ranged from 0.22 mg/L to 86 mg/L. Pseudomonas putida was the most sensitive organism ( EC50 values for 16-h growth inhibition were 0.22 and 0.82 mg/L for oxytetracycline and flumequine , respectively ) , followed by duckweed Lemna minor ( 7-d growth inhibition , EC50 2.1 and 3.0 mg/L ) and green alga Pseudokirchneriella subcapitata ( 4-d growth inhibition , EC50 3.1 and 2.6 mg/L ) .

Complex evaluation of ecotoxicity and genotoxicity of antimicrobials oxytetracycline and flumequine used in aquaculture. Ecotoxicity and genotoxicity of widely used veterinary antimicrobials oxytetracycline and flumequine was studied with six model organisms (Vibrio fischeri, Pseudomonas putida, Pseudokirchneriella subcapitata, Lemna minor, Daphnia magna, Escherichia coli). Overall median effective concentration ( EC50 ) values ranged from 0.22 mg/L to 86 mg/L. Pseudomonas putida was the most sensitive organism ( EC50 values for 16-h growth inhibition were 0.22 and 0.82 mg/L for oxytetracycline and flumequine , respectively ) , followed by duckweed Lemna minor ( 7-d growth inhibition , EC50 2.1 and 3.0 mg/L ) and green alga Pseudokirchneriella subcapitata ( 4-d growth inhibition , EC50 3.1 and 2.6 mg/L ) . The least sensitive organism was Daphnia magna (48-h immobilization, lowest-observed-effect concentration [LOEC] of oxytetracycline of 400 mg/L). oxytetracycline showed limited genotoxicity (SOS-chromotest with Escherichia coli, minimal genotoxic concentration of 500 mg/L), and flumequine was genotoxic at 0.25 mg/L. Based on the reported measured concentrations (MECs) and predicted no-effect concentrations (PNECs), oxytetracycline may be concluded to be of ecotoxicological concern (calculated risk quotient = 8), whereas flumequine seems to represent lower risk.

https://pubmed.ncbi.nlm.nih.gov/21312248/

958cbca38ea92887cc70337ca7273e47

This review therefore aims to overview the prognostic value of MRD eradication in CLL , the role of post-remission intervention with " passive " immunotherapy ( alemtuzumab or rituximab ) so as to eliminate persistent MRD or prevent MRD relapse , the impact of these strategies on disease-free survival and their possible adverse consequences .

Post-remission intervention with alemtuzumab or rituximab to eradicate minimal residual disease in chronic lymphocytic leukemia: where do we stand? The introduction of purine nucleoside analogs, later in combination with alkylating moieties and anti-CD20 immunotherapy, has profoundly improved the response rate and response duration in patients with chronic lymphocytic leukemia (CLL). The quality of clinical response following treatment may be improved to a level where residual leukemic cells become undetectable. As patients with this type of response appear to have extended survival rates, minimal residual disease (MRD) eradication is considered a new objective in CLL treatment with the aim of improving progression-free survival (PFS) and potentially overall survival (OS). This review therefore aims to overview the prognostic value of MRD eradication in CLL , the role of post-remission intervention with " passive " immunotherapy ( alemtuzumab or rituximab ) so as to eliminate persistent MRD or prevent MRD relapse , the impact of these strategies on disease-free survival and their possible adverse consequences . The data indicate a potential for post-remission alemtuzumab or rituximab to prolong PFS in CLL, although more investigations and longer follow-up are required before MRD-guided strategies can be recommended outside of clinical trials.

https://pubmed.ncbi.nlm.nih.gov/21854093/

6b0c167b3ee8a9f88fdb82ebaff2c407

Paclitaxel , 5-fluorouracil , hydroxyurea , and concomitant radiation therapy for poor-prognosis head and neck cancer .

Paclitaxel , 5-fluorouracil , hydroxyurea , and concomitant radiation therapy for poor-prognosis head and neck cancer . A series of phase I and phase II studies investigating multiagent concomitant chemoradiotherapy in patients with poor-prognosis head and neck cancer have been conducted at the University of Chicago. Drug combinations initially included 5-fluorouracil (5-FU) and hydroxyurea, with the more recent addition of cisplatin; in the most recent trial, paclitaxel was substituted for cisplatin. The primary end point of these trials was definition of maximum tolerated doses in combination with radiation therapy. All radiation therapy was given concomitantly with chemotherapy on an every-other-week schedule (total dose, hydroxyurea and 5-FU were defined at 1 g given orally twice daily for a total of 11 doses and 800 mg/m2/d for 5 days (by continuous intravenous infusion), respectively. When cisplatin was added to this regimen, the observed myelosuppression necessitated the addition of granulocyte colony-stimulating factor. The recommended phase II doses for the three-drug combination were cisplatin 100 mg/m2 every 28 days, 5-FU 800 mg/m2/d for 5 days, and hydroxyurea 1 g orally twice daily for 11 doses. The feasibility of administering radiation at 1.5 Gy twice daily with chemotherapy was also established, which allowed the administration of 75 Gy over 5 cycles (10 weeks). The initial review of this trial suggested substantial toxicity, particularly mucositis and myelosuppression; however, local and regional control rates also were high. Most recently, paclitaxel has replaced cisplatin in this regimen. Recommended phase II doses were hydroxyurea 0.5 g orally twice daily for 11 doses, 5-FU 600 mg/m2/d for 5 days, and paclitaxel 20 mg/m2/d for 5 days, with radiation therapy administered twice daily in 1. 5-Gy fractions. A formal phase II study of this regimen in previously untreated patients with stage IV disease has recently completed accrual and is awaiting analysis. Evaluation of a simplified paclitaxel administration schedule (1-hour infusion on day 1 of chemoradiotherapy between the two radiation fractions) is under way. In addition, the feasibility of substituting gemcitabine for hydroxyurea is undergoing evaluation. Future trials in this disease should focus on developing new combinations that are less toxic and have similar efficacy.

https://pubmed.ncbi.nlm.nih.gov/10210543/

0fd66b6397cebf2424a79a0642146c4d

The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up , and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories .

Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting. ### methods In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment. ### findings Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32·4 months [IQR 13·4-36·3]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35·6-not estimable] vs 26·6 months [22·1-33·4]; hazard ratio [HR] 0·66 [95% CI 0·54-0·80], p<0·0001), progression-free survival (median 8·2 months [95% CI 6·9-10·0] vs 8·3 months [7·0-8·8]; HR 0·77 [95% CI 0·65-0·90], p=0·0014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0·0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37·9 months [32·2-not estimable]; HR 0·71 [95% CI 0·59-0·86], p=0·0003), progression-free survival (median 9·7 months [95% CI 8·1-11·1] vs 9·7 months [8·3-11·1]; HR 0·85 [95% CI 0·73-0·98], p=0·027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0·015). In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related. ### interpretation The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up , and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories . ### funding Bristol-Myers Squibb and ONO Pharmaceutical.

https://pubmed.ncbi.nlm.nih.gov/31427204/

478ed5b3c75c19eb591ce2aa273d8129

Clonogenic assays showed that preexposure to hypoxia leads to resistance to various classes of chemotherapeutic agents , including anthracyclines ( daunorubicin and doxorubicin ) , epipodophyllotoxins ( etoposide ) , and anthracenediones ( mitoxantrone ) .

Hypoxia-induced resistance to anticancer drugs is associated with decreased senescence and requires hypoxia-inducible factor-1 activity. Hypoxia in solid tumors is associated with the development of chemoresistance. Although many studies have focused on the effect of hypoxia on drug-induced apoptosis, the effect of nonapoptotic pathways on hypoxia-induced drug resistance has not been previously investigated. Here, we determined the effects of hypoxia on multiple forms of drug-induced death in human MDA-MB-231 breast carcinoma cells. Clonogenic assays showed that preexposure to hypoxia leads to resistance to various classes of chemotherapeutic agents , including anthracyclines ( daunorubicin and doxorubicin ) , epipodophyllotoxins ( etoposide ) , and anthracenediones ( mitoxantrone ) . Results revealed a high degree of heterogeneity in nuclear and cytoplasmic alterations in response to acute drug exposure; however, the majority of exposed cells displayed morphologic and biochemical changes consistent with drug-induced senescence. Hypoxia decreased only the proportion of cells in the senescent population, whereas the small proportion of cells exhibiting features of apoptosis or mitotic catastrophe were unaffected. Similar results were obtained with human HCT116 colon carcinoma cells, indicating that the protective effect of hypoxia on drug-induced senescence is not unique to MDA-MB-231 cells. Treatment of MDA-MB-231 cells with small interfering RNA targeting the alpha-subunit of hypoxia-inducible factor-1 (HIF-1), a key regulator of cellular adaptations to hypoxia, prevented hypoxia-induced resistance. HIF-1alpha small interfering RNA also selectively abolished the hypoxia-induced changes in the senescent population, indicating that the increased survival was due to protection against drug-induced senescence. These results support a requirement for HIF-1 in the adaptations leading to drug resistance and reveal that decreased drug-induced senescence is also an important contributor to the development of hypoxia-induced resistance.

https://pubmed.ncbi.nlm.nih.gov/18645006/

8189632e01c53b8d9f394d39b352a314

Hence , the aim of this study was to conduct an economic evaluation of anastrozole versus tamoxifen in early stage breast cancer .

Economic Evaluation of Anastrozole Versus Tamoxifen for Early Stage Breast Cancer in Singapore. In Singapore, breast cancer is the leading female malignancy and its incidence has increased threefold over the past decades. For treatment of postmenopausal, hormone receptor positive early stage breast cancer, tamoxifen or aromatase inhibitors such as anastrozole are prescribed either as first-line therapy or sequentially. Currently, anastrozole is patented with a higher drug cost compared with tamoxifen. Hence , the aim of this study was to conduct an economic evaluation of anastrozole versus tamoxifen in early stage breast cancer . ### methods A Markov model with a lifetime horizon was developed by using results from the Arimidex, tamoxifen, Alone or in Combination trial. Direct medical costs were estimated by billing data obtained via financial electronic databases. Utility scores were elicited from 20 experienced oncology nurses using the visual analogue scale. Cost per quality-adjusted life-years was calculated by using the societal perspective. A discount rate of 3% for both charges (expressed in 2010 Singapore dollars) and benefits was used. ### results At an additional cost of S $17,597, anastrozole treatment resulted in a gain of 0.085 life-year survival and 0.154 quality-adjusted life-year. The incremental cost-effectiveness ratio of anastrozole was S $207,402 per life-year gained and S $114,061 per quality-adjusted life-year gained compared with tamoxifen. ### conclusion This is the first economic evaluation that used 10-year results from the Arimidex, tamoxifen, Alone or in Combination trial and utility elicited from the local population. If the World Health Organization's recommendation of 1 to 3 gross domestic product range is an acceptable threshold, anastrozole is deemed cost-effective compared with tamoxifen in the treatment of early stage breast cancer.

https://pubmed.ncbi.nlm.nih.gov/29702826/

122abf6ba48902522485dec0fbfcdd2d

A randomized trial of mobilization of peripheral blood stem cells with cyclophosphamide , etoposide , and granulocyte colony-stimulating factor with or without cisplatin in patients with malignant lymphoma receiving high-dose chemotherapy .

A randomized trial of mobilization of peripheral blood stem cells with cyclophosphamide , etoposide , and granulocyte colony-stimulating factor with or without cisplatin in patients with malignant lymphoma receiving high-dose chemotherapy . The purpose of this study was to evaluate the addition of cisplatin to cyclophosphamide, etoposide, and granulocyte colony-stimulating factor (G-CSF) for the mobilization of peripheral blood stem cells (PBSC). Eighty-one patients with malignant lymphoma were randomized to receive either cyclophosphamide 4 g/m2 and etoposide 600 mg/m2 (CE), and G-CSF 6 microg/kg/day (n = 41), or the same drugs with cisplatin 105 mg/m2 (CEP; n = 40) followed by collection of PBSC. Seventy-eight of 81 patients (96%) had apheresis performed and 70 (86%) received high-dose chemotherapy (HDC) with PBSC support. The median number of CD34+ cells collected after CE was 19.77 compared with 9.39 x 10(6)/kg after CEP (p = 0.09). More patients receiving CEP had grade 3-4 gastrointestinal (p = 0.03) and neurologic toxicities (p = 0.05), had significant delays in recovery of neutrophils (p = 0.0001) and platelets (p = 0.009), and received more red blood cell (p = 0.03) and platelet (p = 0.08) transfusions than patients receiving CE. There were no significant differences in treatment-related deaths, relapse, survival, or event-free survival between patients receiving CE or CEP when all 81 patients or the 70 patients receiving HDC were evaluated. It was concluded that the addition of cisplatin to CE did not improve CD34+ cell yields, was associated with more morbidity and resource utilization, and was not associated with improvement in outcomes.

https://pubmed.ncbi.nlm.nih.gov/9708644/

d93a605049539ee873eb80044935d4ba

Treatment of pancreatic cancer with a combination of docetaxel , gemcitabine and granulocyte colony-stimulating factor : a phase II study of the Greek Cooperative Group for Pancreatic Cancer .

Treatment of pancreatic cancer with a combination of docetaxel , gemcitabine and granulocyte colony-stimulating factor : a phase II study of the Greek Cooperative Group for Pancreatic Cancer . To evaluate the tolerance and efficacy of front-line docetaxel plus gemcitabine treatment in patients with inoperable pancreatic cancer. ### Patients And Methods Fifty-four patients with locally advanced or metastatic pancreatic cancer were enrolled. gemcitabine (1000 mg/m2) was administered on days 1 and 8 and docetaxel (100 mg/m2) on day 8, every three weeks; rh-G-CSF (150 ig/m2 s.c.) was given prophylactically on days 9-15. ### results Seven (13%) patients achieved partial response and 18 (33%) stable disease (intent-to-treat). The median duration of response was 24 weeks, time to tumour progression 32 weeks, and overall survival 26 weeks. Performance status was improved in 33% of patients, pain in 43%, asthenia in 16%, weight gain in 28% and appetite in 27%. Grade 3-4 neutropenia occurred in 17 (31%) patients and grade 3-4 thrombocytopenia in four (4%). Six (11%) patients developed febrile neutropenia and one of them died from sepsis. ### conclusions This combination is a relatively well-tolerated out-patient regimen for patients with inoperable pancreatic cancer.

https://pubmed.ncbi.nlm.nih.gov/11249034/

668cf1cd34592609ac6c5a94033486b9

Such situations are known as exposing to pneumococcal meningitis and to resistance of the strain involved to penicillin G. Both patients were cured by vancomycin in continuous infusion associated with rifampicin or fosfomycin .

[Vancomycin in meningitis caused by penicillin G resistant Streptococcus pneumoniae]. We report two cases of penicillin G-resistant pneumococcal meningitis in adults, with clinical and bacteriological failure of amoxicillin and negative or incomplete response to third generation cephalosporins. Meningitis occurred in a man treated for myeloma and in an elderly woman under prolonged intermittent amoxicillin therapy for chronic otitis. Such situations are known as exposing to pneumococcal meningitis and to resistance of the strain involved to penicillin G. Both patients were cured by vancomycin in continuous infusion associated with rifampicin or fosfomycin . Contrary to third generation cephalosporins, which have higher minimal inhibitory concentrations, vancomycin and rifampicin are still fully active against penicillin G-resistant pneumococcal strains. Thus, vancomycin administered in continuous infusion and associated with rifampicin and fosfomycin deserves to be tried as first-line treatment of pneumococcal meningitis in patients at risk of resistance to penicillin G.

https://pubmed.ncbi.nlm.nih.gov/8309909/

d9618273421b43d587ebe3aff81f5bf6

We recently identified a unique site within the MLL bcr that is highly susceptible to DNA double-strand cleavage by classic topo II inhibitors ( e.g. , etoposide and doxorubicin ) .

DNA cleavage within the MLL breakpoint cluster region is a specific event which occurs as part of higher-order chromatin fragmentation during the initial stages of apoptosis. A distinct population of therapy-related acute myeloid leukemia (t-AML) is strongly associated with prior administration of topoisomerase II (topo II) inhibitors. These t-AMLs display distinct cytogenetic alterations, most often disrupting the MLL gene on chromosome 11q23 within a breakpoint cluster region (bcr) of 8.3 kb. We recently identified a unique site within the MLL bcr that is highly susceptible to DNA double-strand cleavage by classic topo II inhibitors ( e.g. , etoposide and doxorubicin ) . Here, we report that site-specific cleavage within the MLL bcr can be induced by either catalytic topo II inhibitors, genotoxic chemotherapeutic agents which do not target topo II, or nongenotoxic stimuli of apoptotic cell death, suggesting that this site-specific cleavage is part of a generalized cellular response to an apoptotic stimulus. We also show that site-specific cleavage within the MLL bcr can be linked to the higher-order chromatin fragmentation that occurs during the initial stages of apoptosis, possibly through cleavage of DNA loops at their anchorage sites to the nuclear matrix. In addition, we show that site-specific cleavage is conserved between species, as specific DNA cleavage can also be demonstrated within the murine MLL locus. Lastly, site-specific cleavage during apoptosis can also be identified at the AML1 locus, a locus which is also frequently involved in chromosomal rearrangements present in t-AML patients. In conclusion, these results suggest the potential involvement of higher-order chromatin fragmentation which occurs as a part of a generalized apoptotic response in a mechanism leading to chromosomal translocation of the MLL and AML1 genes and subsequent t-AML.

https://pubmed.ncbi.nlm.nih.gov/9199342/

33cfcb3cd74eb5b8b3d9504e685db473

In 2011 , the combination of rituximab with bendamustine ( 31 % ) was most frequent used followed by the rituximab-fludarabine-cyclophosphamide ( 22 % ) regime .

Altered treatment of chronic lymphocytic leukemia in Germany during the last decade. Chronic lymphocytic leukemia (CLL) is the most common subtype of adult leukemia in the western world. We here report a nationwide survey monitoring the treatment decisions concerning CLL patients in Germany in 2011 and compare treatment trends to sequential surveys performed previously during the last decade. The rate of patients diagnosed in early stages (Binet A/B) notably increased (2006: 66 %, 2009: 71 %, 2011: 77 %) over the years. From 2006 to 2009, the most frequent applied regime switched from chlorambucil to fludarabine containing regimes (2006 chlorambucil: 32 %, 2009: 14 %, fludarabine 2006: 23 %, 2009: 37 %). In 2011 , the combination of rituximab with bendamustine ( 31 % ) was most frequent used followed by the rituximab-fludarabine-cyclophosphamide ( 22 % ) regime . Further, immune-chemotherapies were administered significantly more often over the observation period (2006: 15 %, 2011: 73 %). Taken together, this data reflects the change of treatment strategies over the last decade in clinical reality.

https://pubmed.ncbi.nlm.nih.gov/27021305/

8ef1062bde923a162f10e0bedec07669

The combination of ofatumumab and bendamustine in elderly patients with diffuse large B-cell lymphoma demonstrated modest efficacy compared with standard of care .

Phase II Study of Bendamustine and Ofatumumab in Elderly Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma Who Are Poor Candidates for R-CHOP Chemotherapy. The combination of ofatumumab and bendamustine in elderly patients with diffuse large B-cell lymphoma demonstrated modest efficacy compared with standard of care .The poor response may have been due to patient age and the high rate of treatment discontinuation. ### background This phase II trial evaluated the efficacy of bendamustine and ofatumumab in elderly patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) who were not candidates for rituximab cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). ### methods Patients received IV 90 mg/m ### results Twelve of 21 enrolled patients completed treatment; median age was 83 years. The most common reasons for treatment discontinuation were disease progression (three patients), intercurrent illness (two patients), and death (one patient due to drug-related sepsis and bowel necrosis and one patient due to unknown cause). Thrombocytopenia (14%), neutropenia (10%), diarrhea (10%), vomiting (10%), and dehydration (10%) were the most common grade ≥3 treatment-related adverse events. The overall response rate was 90.5% and the CRR was 33.3%. Median progression-free survival (PFS) and overall survival (OS) were 8.6 and 12.0 months, respectively. ### conclusion The combination of ofatumumab and bendamustine is feasible in elderly patients with DLBCL.

https://pubmed.ncbi.nlm.nih.gov/31073022/

795339d0baa8752d627554fdf49cadaf

Imatinib and nilotinib directly inhibit the kinase activity of KIT , while RAD001 ( everolimus ) inhibits mTOR .

Preclinical evaluation of KIT/PDGFRA and mTOR inhibitors in gastrointestinal stromal tumors using small animal FDG PET. Primary and secondary drug resistance to imatinib and sunitinib in patients with gastrointestinal stromal tumors (GISTs) has led to a pressing need for new therapeutic strategies such as drug combinations. Most GISTs are caused by mutations in the KIT receptor, leading to upregulated KIT tyrosine kinase activity. Imatinib and nilotinib directly inhibit the kinase activity of KIT , while RAD001 ( everolimus ) inhibits mTOR . We report a preclinical study on drug combinations in a xenograft model of GIST in which effects on tumor dimensions and metabolic activity were assessed by small animal PET imaging. ### methods Rag2-/-; γcommon -/- male mice were injected s.c. into the right leg with GIST 882. The animals were randomized into 6 groups of 6 animals each for different treatment regimens: No therapy (control), imatinib (150 mg/kg b.i.d.) by oral gavage for 6 days, then once/day for another 7 days, everolimus (10 mg/kg/d.) by oral gavage, everolimus (10 mg/kg/d.) + imatinib (150 mg/kg b.i.d.) by oral gavage for 6 days, then once/day for another 7 days, nilotinib (75 mg/kg/d.) by oral gavage, nilotinib (75 mg/kg/d.) + imatinib (150 mg/kg b.i.d) by oral gavage for 6 days, then once/day for another 7 days. Tumor growth control was evaluated by measuring tumor volume (cm3). Small animal PET (GE Explore tomography) was used to evaluate tumor metabolism and performed in one animal per group at base-line then after 4 and 13 days of treatment. ### results After a median latency time of 31 days, tumors grew in all animals (volume 0,06-0,15 cm3) and the treatments began at day 38 after cell injection. Tumor volume control (cm3) after 13 days of treatment was > 0.5 for imatinib alone and nilotinib alone, and < 0.5 for the 2 combinations of drugs and for everolimus alone. The baseline FDG uptake was positive in all animals. FDG/SUV/TBR was strongly reduced over time by everolimus both as a single agent and in combination with imatinib respectively: 3.1 vs. 2.3 vs. 1.9 and 2.5 vs 2.3 vs 0. ### conclusions As single agents, all drugs showed an anti-tumor effect in GIST xenografts but everolimus was superior. The everolimus plus imatinib combination appeared to be the most active regimen both in terms of inhibiting tumor growth and tumor metabolism. The integration of everolimus in GIST treatment merits further investigation.

https://pubmed.ncbi.nlm.nih.gov/21192792/

9a8e6801e6379528eff10d0f0abe84bc

In this study the antiproliferative effects of Paclitaxel ( PAC ) , Epirubicin ( EPI ) and Tamoxifen ( TAM ) on growth kinetics of Ehrlich Ascites Tumor ( EAT ) cells were examined in culture .

Evaluation of the effect of paclitaxel, epirubicin and tamoxifen by cell kinetics parameters in estrogen-receptor-positive ehrlich ascites tumor (eat) cells growing in vitro. In this study the antiproliferative effects of Paclitaxel ( PAC ) , Epirubicin ( EPI ) and Tamoxifen ( TAM ) on growth kinetics of Ehrlich Ascites Tumor ( EAT ) cells were examined in culture . An estrogen-receptor-positive ER (+) hyperdiploid EAT cell line growing in vitro was also analysed in the present study. IC50 doses of PAC, EPI and TAM (12 microg/ml, 12 microg/ml and 2 microg/ml, respectively) were used. Cells were treated with the above doses for 0, 4, 8, 16, 24 and 32 hrs. At the end of these periods, living cell numbers were determined by collecting EAT cells in every group for growth study rate and for MTT assay. Therefore, the mitotic index was determined in the same experimental groups. The proliferation of EAT cells, inhibited by PAC, EPI and TAM concentrations was compared to control with increasing treatment time (4-32 hrs). Treatment of PAC, EPI and TAM alone for 24 hrs decreased the proliferation rate of EAT cells by 50% with respect to control. The inhibition of proliferation rate was higher in double drug treatment than that in single drug treatment with increased treatment time. In the treatment of three drugs applied for 32 hrs, this effect reached a maximum and proliferation rate decreased by 12% as compared to the (100%) control. In our studies, when the mitotic index parameter data were evaluated to determine which phase of the cell cycle was affected by PAC to cause the repression of cell reproduction, it was found that PAC exerted of its cytotoxic effect by causing cell accumulation at mitosis. The accumulation of the cells resulted in an increase in mitotic index values, which was an expected consequence of PAC treatment. It was observed that depending on the drug treatments, inhibition of proliferation rate and mitotic index in EAT cells were increased with respect to control, being with statistically significant occurrence (p < 0.01 - p < 0.001). As a result, concomitant treatment combined with hormonal therapy has given improved results compared with single treatment and PAC + EPI + TAM treatments had a maximum synergistic effect for 32 hrs (p < 0.001).

https://pubmed.ncbi.nlm.nih.gov/17385543/

9102d006b4fd44a3746292aafa45c3af

The most common chemotherapy and route of administration for systemic treatment is paclitaxel plus carboplatin given intravenously .

Systemic therapy for non-serous ovarian carcinoma. Ovarian cancer is one of the top ten most common cancers in women around the world, with high-grade serous epithelial cancer being the most frequent type. However, around a quarter of cases consist of non-serous epithelial ovarian cancer (EOC), which is a heterogeneous group of malignancies that includes endometroid, mucinous, clear cell carcinoma (CCC), and carcinosarcoma. Another relevant group of nonepithelial tumors are those arising from germ cells or sex-cord stromal cells, which account for about 10% of all ovarian cancers. Although there are similarities in the presentation, evaluation, and management of these tumors, they have unique characteristics in terms of epidemiology, tumor biology, tumor marker expression, and response to treatment, warranting a different approach to each one of them. Collectively, the treatment of most of EOC include surgical cytoreduction followed by adjuvant systemic platinum-based chemotherapy. The most common chemotherapy and route of administration for systemic treatment is paclitaxel plus carboplatin given intravenously . However, the treatment of EOC has been rapidly evolving and emerging targeted therapies such as poly (adenosine diphosphate-ribose) polymerase inhibitors, immune checkpoint inhibitors, and antiangiogenic agents are also available. On the other hand, non-EOC responds well to combination chemotherapy used to treat testicular cancer (bleomycin, etoposide, cisplatin) and has a good prognosis. Frontline chemotherapeutic regimen selection differs according to histological subtype, molecular alterations, and patient characteristics. Here, we review specific characteristics of non-serous and non-EOC emphasizing the peculiarities of systemic therapy for each subtype.

https://pubmed.ncbi.nlm.nih.gov/32787339/

fac0370d3f121156119782b95e4b40ee

Finally , the ability of givinostat , belinostat and panobinostat to reactivate latent HIV-1 expression in primary T-cells was investigated employing a CCL19-induced latent primary CD4 + T cell infection model .

Comparison of HDAC inhibitors in clinical development: effect on HIV production in latently infected cells and T-cell activation. We aimed to compare the potential for inducing HIV production and the effect on T-cell activation of potent HDAC inhibitors undergoing clinical investigation. ### design In vitro study ### results The various HDAC inhibitors displayed significant potency differences in stimulating HIV-1 expression from the latently infected cell lines with panobinostat>givinostat ≈belinostat>vorinostat>valproic acid. panobinostat was significantly more potent than all other HDAC inhibitors and induced virus production even in the very low concentration range 8-31 nM. The proportion of primary T-cells expressing the early activation marker CD69 increased moderately in all HDAC inhibitor-treated cells compared with untreated cells. Finally, proof was obtained that panobinostat, givinostat and belinostat induce virus production in latently infected primary cells at therapeutic concentrations with panobinostat being the most potent stimulator. ### methods The latently infected cell lines ACH2 and U1 were treated with the HDAC inhibitors panobinostat, givinostat, belinostat, vorinostat and valproic acid. Viral induction was estimated by p24 production. Peripheral blood mononuclear cells from uninfected donors were treated with the HDAC inhibitors and the expression of activation markers on T-cell phenotypes was measured using flow cytometry. Finally , the ability of givinostat , belinostat and panobinostat to reactivate latent HIV-1 expression in primary T-cells was investigated employing a CCL19-induced latent primary CD4 + T cell infection model . ### conclusion At therapeutic concentrations panobinostat stimulate HIV-1 expression in latently infected cells with greater potency than other HDAC inhibitors undergoing clinical investigation. These findings warrant further investigation and panobinostat is now being advanced into clinical testing against latent HIV infection.

https://pubmed.ncbi.nlm.nih.gov/23370291/

86044cf678d60a50e49f28a5d757323e

Aflibercept has been used in combination with folinic acid (leucovorin)-fluorouracil-irinotecan ( FOLFIRI ) chemotherapy in mCRC patients and among patients with mCRC with wild-type KRAS , the outcomes were significantly improved by panitumumab in combination with folinic acid (leucovorin)-fluorouracil-oxaliplatin ( FOLFOX ) or FOLFIRI .

Molecularly targeted drugs for metastatic colorectal cancer. The survival rate of patients with metastatic colorectal cancer (mCRC) has significantly improved with applications of molecularly targeted drugs, such as bevacizumab, and led to a substantial improvement in the overall survival rate. These drugs are capable of specifically targeting the inherent abnormal pathways in cancer cells, which are potentially less toxic than traditional nonselective chemotherapeutics. In this review, the recent clinical information about molecularly targeted therapy for mCRC is summarized, with specific focus on several of the US Food and Drug Administration-approved molecularly targeted drugs for the treatment of mCRC in the clinic. Progression-free and overall survival in patients with mCRC was improved greatly by the addition of bevacizumab and/or cetuximab to standard chemotherapy, in either first- or second-line treatment. Aflibercept has been used in combination with folinic acid (leucovorin)-fluorouracil-irinotecan ( FOLFIRI ) chemotherapy in mCRC patients and among patients with mCRC with wild-type KRAS , the outcomes were significantly improved by panitumumab in combination with folinic acid (leucovorin)-fluorouracil-oxaliplatin ( FOLFOX ) or FOLFIRI . Because of the new preliminary studies, it has been recommended that regorafenib be used with FOLFOX or FOLFIRI as first- or second-line treatment of mCRC chemotherapy. In summary, an era of new opportunities has been opened for treatment of mCRC and/or other malignancies, resulting from the discovery of new selective targeting drugs.

https://pubmed.ncbi.nlm.nih.gov/24204124/

d81343860cdb91f3f2271e6e992965f8

The current mainstay of systemic treatment for patients with metastatic or unresectable disease remains doxorubicin with or without ifosfamide in the first-line setting .

Systemic Therapy in Metastatic or Unresectable Well-Differentiated/Dedifferentiated Liposarcoma. Liposarcoma is one of the most common subtypes of soft-tissue sarcoma and consists of three main subtypes, of which well-differentiated liposarcoma and dedifferentiated liposarcoma account for 40-45%. The current mainstay of systemic treatment for patients with metastatic or unresectable disease remains doxorubicin with or without ifosfamide in the first-line setting . Recently, eribulin and trabectedin have been approved by the US Food and Drug Administration for recurrent liposarcomas and progress in molecular characterization of these tumors has opened up new and potential novel treatment targets. This review will focus on the evidence base for current treatment strategies and will also discuss potential future options.

https://pubmed.ncbi.nlm.nih.gov/29250486/

f4fd1204cff04f98797ea524bf93568c

All patients received intravenous heparin after PTCA and aspirin was begun on the day prior to PTCA .

Effect of angiotensin converting enzyme inhibition on the incidence of restenosis after percutaneous transluminal coronary angioplasty. To determine whether angiotensin converting enzyme (ACE) inhibition may reduce the incidence of restenosis after percutaneous transluminal coronary angioplasty (PTCA), we retrospectively identified 322 consecutive patients who underwent a successful procedure from June 1988 to December 1989. No patients developed chest pain, ST segment elevation, positive cardiac enzymes, or other evidence of abrupt vessel closure following the PTCA. All patients received intravenous heparin after PTCA and aspirin was begun on the day prior to PTCA . Patients were separated into two groups: those at hospital discharge incidentally treated for hypertension or heart failure with ACE inhibitors (n = 36), and those treated with a drug regimen which did not include ACE inhibitors (n = 286). The two groups were similar with respect to age (61 +/- 13.5 vs. 60 +/- 12.5, p = NS) and other demographic characteristics. Restenosis, defined as the presentation to a physician with symptoms of angina within 6 months of the PTCA and the finding on repeat catheterization of a significant restenosis at the site of the PTCA, occurred in 30% of the patients who were discharged on a drug regimen which did not include ACE inhibitors vs. 3% (p less than .05) in those treated with an ACE inhibitor. Thus, it appears that the use of ACE inhibitors may significantly reduce the incidence of restenosis after successful PTCA.

https://pubmed.ncbi.nlm.nih.gov/1653645/

8486206d9c09508997f2a5a84ff5a6a4

In this article , we summarize available literature evidence on different chemotherapy agents used beyond the first-line , in locally advanced or MBC patients , including rechallenge with anthracyclines and taxanes , antimetabolite and antimicrotubule agents , such as vinorelbine , capecitabine , eribulin , ixabepilone , and the newest developed agents , such as vinflunine , irinotecan , and etirinotecan .

Chemotherapy Options beyond the First Line in HER-Negative Metastatic Breast Cancer. Despite the recent advances in the biological understanding of breast cancer (BC), chemotherapy still represents a key component in the armamentarium for this disease. Different agents are available as mono-chemotherapy options in patients with locally advanced or metastatic BC (MBC) who progress after a first- and second-line treatment with anthracyclines and taxanes. However, no clear indication exists on what the best option is in some populations, such as heavily pretreated, elderly patients, triple-negative BC (TNBC), and those who do not respond to the first-line therapy. In this article , we summarize available literature evidence on different chemotherapy agents used beyond the first-line , in locally advanced or MBC patients , including rechallenge with anthracyclines and taxanes , antimetabolite and antimicrotubule agents , such as vinorelbine , capecitabine , eribulin , ixabepilone , and the newest developed agents , such as vinflunine , irinotecan , and etirinotecan .

https://pubmed.ncbi.nlm.nih.gov/33312203/

569f2de3df24afb409bf9d3ae3878d96

After an initial 6 - 8 weeks of metformin , they received either letrozole ( 2.5 mg ) or clomiphene ( 100 mg ) from day 3 - 7 of their menstrual cycle .

Efficacy of combined metformin-letrozole in comparison with metformin-clomiphene citrate in clomiphene-resistant infertile women with polycystic ovarian disease. Adding metformin to clomiphene citrate in clomiphene-resistant polycystic ovary syndrome (PCOS) patients increases ovulatory response. However, because of anti-estrogenic effects of clomiphene it may be associated with lower pregnancy rate, offsetting the ovulation rate benefit. letrozole is an aromatase inhibitor which induces ovulation without anti-estrogenic effects. ### methods Infertile women with PCOS were randomly divided into metformin-letrozole (29 patients) and metformin-clomiphene groups (30 patients). After an initial 6 - 8 weeks of metformin , they received either letrozole ( 2.5 mg ) or clomiphene ( 100 mg ) from day 3 - 7 of their menstrual cycle . Estradiol (E2) levels, number of follicles, pregnancy rates and endometrial thickness were measured on the day of HCG administration. ### results Mean total E2 and E2 per mature follicle were significantly higher in clomiphene group without a difference in mean number of mature follicles >18 mm and ovulation rate. Endometrial thickness was significantly higher in letrozole group. The pregnancy rate in letrozole group (10 patients, 34.50%) as compared with clomiphene group (5 patients, 16.67%) did not show significant difference, whereas full-term pregnancies were higher in letrozole group [10 patients (34.50%) versus 3 patients (10%)]. ### conclusion In clomiphene-resistant PCOS patients, the combination of letrozole and metformin leads to higher full-term pregnancies.

https://pubmed.ncbi.nlm.nih.gov/16478764/

1aa150f13e8dd0036b14b0794d17455c

No study has evaluated the significance of CD30 expression in DLBCL patients treated with rituximab , etoposide , prednisone , vincristine , cyclophosphamide , and doxorubicin ( R-EPOCH ) .

CD30 expression and prognostic significance in R-EPOCH-treated patients with diffuse large B-cell lymphoma. A few recent studies investigated the prognostic impact of CD30 expression in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. No study has evaluated the significance of CD30 expression in DLBCL patients treated with rituximab , etoposide , prednisone , vincristine , cyclophosphamide , and doxorubicin ( R-EPOCH ) . In a group of 97 patients with DLBCL and high-risk features who received R-EPOCH induction therapy, we studied CD30 expression by immunohistochemistry using different cutoff values (>0% and ≥20% of lymphoma cells, respectively) and correlated with prognosis. CD30 expression was detected in 24 (25%) cases using a cutoff greater than 0% and in 12 (12%) cases using a cutoff of 20% or greater. The clinicopathological features were similar between CD30+ and CD30-negative groups. A major difference was that MYC rearrangement was infrequent in the CD30+ group: 2 (9%) of 23 in CD30+ versus 25 (35%) of 72 in CD30-negative group (P=.02). CD30 expression was not associated with germinal center B-cell-like (GCB) or non-GCB type. Overall survival (OS) was not significantly different between patients with CD30+ and patients with CD30-negative DLBCL, either for all patients or for the subset of patients without MYC rearrangement, regardless of cutoff (P>.05). CD30 expression was not associated with OS in either GCB or non-GCB subtype (P>.05, > 0% cutoff). In conclusion, CD30 expression was detected in up to 25% of cases of DLBCL and was more frequent in tumors without MYC rearrangement. CD30 expression was not associated with OS in R-EPOCH-treated de novo DLBCL patients.

https://pubmed.ncbi.nlm.nih.gov/27816715/