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Background: To evaluate the possible major adverse cardiovascular events (MACE) associated with second-line hormonal therapy in patients with metastatic castration-resistant prostate cancer (mCRPC)., Methods: We performed a population-based real-world cohort study of 4962 prostate cancer patients between 2014 and 2017 utilizing the Chang Gung Research Database of Taiwan. The second-line hormonal therapies included enzalutamide and abiraterone acetate. The outcomes of interest were MACE, including acute coronary syndrome (ACS), ischemic stroke (IS), and heart failure (HF) events that resulted in hospitalization. Cox proportional-hazards models with inverse probability of treatment weighting (IPTW) with propensity scores were used., Results: After IPTW, 288 patients were prescribed second-line hormonal therapy and 1575 received first-line androgen-deprivation therapy (ADT). Of all patients diagnosed with MACE, the event rates were 2.92% in the second-line hormonal group and 2.22% in the first-line ADT group. The mean follow-up period was 9.52 months for the second-line hormonal group. Patients who received second-line hormonal therapy exhibited a significantly increased risk for MACE (hazard ratio [HR]: 3.15; 95% confidence interval [CI]: 2.03-4.89), ACS (HR: 4.94; 95% CI: 2.36-10.33), and HF (HR: 2.83; 95% CI: 1.53-5.25), compared with the first-line ADT group, but a similar risk for IS was observed in both groups (HR: 1.70; 95% CI: 0.95-3.04)., Conclusions: The real-world evidence study revealed increased risks for MACE in mCRPC patients receiving second-line hormonal therapy., (© 2020 Wiley Periodicals LLC.)

Background: Compared to tamoxifen, adjuvant treatment with aromatase inhibitors improves disease outcomes of postmenopausal women with hormone receptor-positive early breast cancer. In the international, randomized, double-blind BIG 1-98 trial, 8010 women were randomized to receive tamoxifen, letrozole, or sequential use of the agents for 5 years. With a focus on switching between agents, we investigated cardiovascular events over the entire 5-year treatment period., Methods: Of the 6182 patients enrolled, 6144 started trial treatment and were included in this analysis. Adverse events occurring during study treatment until 30 days after cessation were considered. Eight cardiovascular event types were defined. Cumulative incidence of events were estimated using the Kaplan-Meier method, without consideration for competing events. Multivariable Cox models estimated hazard ratios (HR) with 95% confidence intervals (CI) for pairwise comparisons of treatment arms., Results: While on study treatment, 6.5% of patients (n = 397) had any cardiac events reported; for 2.4%, the event was grades 3-5, of which 11 (0.2%) were grade 5. Letrozole monotherapy was associated with higher risk of grade 1-5 ischemic heart disease (HR = 1.81; 95% CI, 1.06-3.08) compared with tamoxifen monotherapy. Patients assigned sequential tamoxifen →letrozole (HR = 1.59; 95% CI, 0.92-2.74) or sequential letrozole → tamoxifen (HR = 1.20; 95% CI, 0.68-2.14) showed a lesser degree of risk elevation. Patients assigned to tamoxifen-containing regimens had significantly higher risk of grade 1-5 thromboembolic events (tamoxifen monotherapy HR = 2.10; 95% CI, 1.42-3.12; tamoxifen → letrozole HR = 1.96; 95% CI, 1.32-2.92; letrozole → tamoxifen HR = 1.56; 95% CI 1.03-2.35) as compared with patients assigned letrozole alone., Conclusion: When initiating or switching between adjuvant endocrine treatments in postmenopausal patients, age and medical history, with special attention to prior cardiovascular events, should be balanced with expected benefit of the treatment.

Purpose: For high-risk prostate cancer, standard treatment options include radical prostatectomy (RP) or radiotherapy plus androgen deprivation therapy (ADT). Despite definitive therapy, many patients will have disease recurrence. Imaging has the potential to better define characteristics of response and resistance. In this study, we evaluated prostate multiparametric MRI (mpMRI) before and after neoadjuvant enzalutamide plus ADT., Patients and Methods: Men with localized intermediate- or high-risk prostate cancer underwent a baseline mpMRI and mpMRI-targeted biopsy followed by a second mpMRI after 6 months of enzalutamide and ADT prior to RP. Specimens were sectioned in the same plane as mpMRI using patient-specific 3D-printed molds to permit mpMRI-targeted biopsies to be compared with the same lesion from the RP. Specimens were analyzed for imaging and histologic correlates of response., Results: Of 39 patients enrolled, 36 completed imaging and RP. Most patients (92%) had high-risk disease. Fifty-eight lesions were detected on baseline mpMRI, of which 40 (69%) remained measurable at 6-month follow-up imaging. Fifty-five of 59 lesions (93%) demonstrated >50% volume reduction on posttreatment mpMRI. Three of 59 lesions (5%) demonstrated growth in size at follow-up imaging, with two lesions increasing more than 3-fold in volume. On whole-mount pathology, 15 patients demonstrated minimal residual disease (MRD) of <0.05 cc or pathologic complete response. Low initial mpMRI relative tumor burden was most predictive of MRD on final pathology., Conclusions: Low relative lesion volume at baseline mpMRI was predictive of pathologic response. A subset of patients had limited response. Selection of patients based on these metrics may improve outcomes in high-risk disease., (©2020 American Association for Cancer Research.)

Objective: As the genetic and molecular profiles of triple negative breast carcinoma (TNBC) are elucidated, multiple therapeutic targets have been produced. TNBC with less than 1% androgen receptor (AR) expression may respond to enzalutamide with greater response association in higher levels. A metronomic dose of capecitabine and docetaxel are effective developed drugs for angiogenic process inhibition. We aimed to demonstrate the treatment outcome of triple-negative breast cancer patients in correlation to their clinicopathological features., Materials and Methods: A retrospective cohort study of 80 TNBC patients was conducted. The patients underwent proper observation with the reporting of their treatment and follow-up data. Patients with a metastatic disease, neoadjuvant chemotherapy, follow-up drop or data shortage were excluded from the survival analysis., Results: The study results revealed a significant association between negative androgen expression and younger age ≤35 years, premenopausal status, higher grade, extracapsular extension, lymphovascular invasion, Ki 67, and CA15-3 (p=0.003, 0.02, < 0.001, 0.001, 0.027, 0.005, 0.009 respectively). The three-year overall survival (OS) in patients who received bicalutamide was better than those patients who received capecitabine or docetaxel but of no significance (p=0.46). The three-year disease free survival (DFS) was significantly better in the bicalutamide arm versus the other two groups (p=0.012)., Conclusions: We concluded that extended adjuvant antiandrogen such as bicalutamide and metronomic capecitabine are well tolerated with accepted compliance and affordability compared to docetaxel and are warranted for problem-solving and better DFS and OS in some TNBC patients.

Introduction: Currently, severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection is a major public health problem worldwide. Although most patients present a mild infection, effective strategies are required for patients who develop the severe disease. Anti-inflammatory treatment with JAK inhibitors has been considered in SARS-CoV-2., Methods: In this study, we presented our experience in a group of severe SARS-CoV-2 Chilean patients. This prospective study was performed on consecutive patients presenting severe respiratory failure owing to COVID-19 or high-risk clinical condition associated with SARS-CoV-2, and who were treated with ruxolitinib for management of associated inflammation. Overall, 18 patients presenting SARS-CoV-2 viral-induced hyperinflammation were treated with ruxolitinib, with 16 patients previously treated with steroids, 4 with tocilizumab, and 3 with both treatments., Results: Ten patients evolved with favorable response, including 7 patients admitted with severe respiratory failure (PaFi less than 200 mm Hg in high-flow nasal cannula), presenting complete regression of hyperinflammation, regression of the lung lesions, and subsequent discharge. In the remaining 8 patients, 25% showed reduced inflammation, but early discharge was not achieved owing to the slow evolution of respiratory failure. Unfortunately, 3 patients demonstrated a severe respiratory failure. The early initiation of ruxolitinib was found to be associated with better clinical evolution (p < 0.005)., Conclusion: In this study, ruxolitinib resolved hyperinflammatory state in 55% of the patients, regardless of the previous steroid or tocilizumab therapy. Unfortunately, few patients demonstrated severe evolution despite ruxolitinib therapy. Notably, the treatment starting time appears to play an important role in achieving good outcomes. Further validation in randomized controlled trials is crucial., (© 2021 S. Karger AG, Basel.)

&lt;b&gt;Background and Objective:&lt;/b&gt; The continuous use of pesticides in the ecosystem is of great concern, as some of them are highly stable and impact non-target organisms. The effect was tested of different concentrations of insecticides such as (Deltamethrin and Malathion) and natural products, Including, lemongrass oil on Fruit Fly (&lt;i&gt;Drosophila melanogaster&lt;/i&gt;), to calculate the concentration at which the highest mortality occurred and death half the number of individuals after 96 hrs, as well as calculating the half-lethal time for individuals. &lt;b&gt;Materials and Methods:&lt;/b&gt; This study, which evaluated the toxicity of five different concentrations (0.75, 1.00, 1.25, 1.50 and 1.75 mg L&lt;sup&gt;1&lt;/sup&gt;) of Malathion, (0.05, 0.10, 0.21, 0.53 and 1.48 mg L&lt;sup&gt;1&lt;/sup&gt;) of Deltamethrin and lemongrass oil (0.25, 0.50, 0.75, 1.00 and 1.50 mg L&lt;sup&gt;1&lt;/sup&gt;) on the insect of &lt;i&gt;Drosophila melanogaster&lt;/i&gt; after 96 hrs of treatment. &lt;b&gt;Results:&lt;/b&gt; From the results of this study, the concentration (LC&lt;sub&gt;50 &lt;/sub&gt;= 2.938 mg L&lt;sup&gt;1&lt;/sup&gt;) of Malathion leads to kills half of the individuals, compared to Deltamethrin a higher concentration (LC&lt;sub&gt;50 &lt;/sub&gt;= 4.8673 mg L&lt;sup&gt;1&lt;/sup&gt;) that leads to killing half of the individuals. While lemongrass oil the concentration (LC&lt;sub&gt;50 &lt;/sub&gt;= 9.7478 mg L&lt;sup&gt;1&lt;/sup&gt;) leads to kills half of individuals. Also, when used Deltamethrin it takes (LT&lt;sub&gt;50 &lt;/sub&gt;= 660.277) hours to kill half of the individuals compared to Malathion, which takes approximately (LT&lt;sub&gt;50&lt;/sub&gt; = 321.862) hours to death half of the individuals. But lemongrass oil (LT&lt;sub&gt;50 &lt;/sub&gt;= 819.745) hours to kill half of the individuals. &lt;b&gt;Conclusion:&lt;/b&gt; In conclusion, the lemon plant and its components have excellent potential for being used in the control of &lt;i&gt;Drosophila melanogaster&lt;/i&gt;, which had an effective role in biological control.

Introduction: In this real-world study, the incidence of cardiovascular events (CV) including major adverse cardiac events (MACE), arterial occlusive events (AOE), and venous occlusive events (VOE) was evaluated in chronic myeloid leukemia (CML) patients treated with ponatinib or bosutinib in a US commercial database population., Materials and Methods: CML patients aged ≥18 years with use of 1 or 2 prior tyrosine kinase inhibitors prescribed bosutinib or ponatinib were selected from the IBM® MarketScan® Research database. Cox proportional hazard model analyses were conducted to examine any difference in CV event risk., Results: Ponatinib and bosutinib was associated with similar incidence and risk of CV events, including MACEs (HR: 1.02; 95% CI: 0.35, 3.01), AOEs (HR: 0.90; 95% CI: 0.43, 1.85) and VOEs (HR: 0.92; 95% CI: 0.44, 1.94)., Conclusion: Treatment with ponatinib or bosutinib was not associated with significant differences in the incidence of CV events in CML patients., (Copyright © 2021. Published by Elsevier Ltd.)

Introduction: Parkinson's disease (PD) is a progressive, chronic neurodegenerative disorder. The main neuropathological cause of the disease is the death of dopaminergic neurons in the substantia nigra. Unfortunately, there is no curative treatment yet. The gold-standard of the treatment is levodopa (LD). During the course of the disease, motor complications develop, which postulates the addition of entacapone (ENT) to the dopaminergic medication. Previous studies have suggested that patients have a better quality of life when entacapone is added in a combination with LD., Areas Covered: A systematic literature search was performed. Articles were identified through PubMed (MEDLINE), Web of Science, Ovid, and ClinicalTrials.gov databases. The following search terms were used: 'Levodopa' AND 'Carbidopa' OR 'Benserazide' AND 'Entacapone'. The search period was between 2000 and 2020. Twenty randomized and 10 non-randomized clinical trials (12,893 subjects) were included in the qualitative analysis. The systematic review was written in line with the PRISMA guideline., Expert Opinion: ENT administered in combination with LD resulted in a better quality of life compared to separate tablets. Therefore, in PD patients where impaired motor performance develops and the application of entacapone is necessary, it is suggested to be administered in a single tablet form.

Chlorothalonil (CT) is a commonly used fungicide and its excessive application seriously threatens aquatic life and human health. Resveratrol (RSV) is a natural polyphenol and can be used as a therapeutic and preventive agent for the treatment of various diseases. To explore the toxic mechanism of CT exposure on fish kidney cell, as well as the alleviation effect of RSV, we established CT poisoning and/or RSV treatment fish kidney cell models. Ctenopharyngodon idellus kidney (CIK) cell line was treated with CT (5 μg/L) and/or RSV (10 μM) for 48 h. The results showed that CT exposure activated cytochromeP450s (CYPs) including CYP1A1, CYP1B1 and CYP1C, caused malondialdehyde (MDA) accumulation, inhibited glutathione (GSH) levels and glutathione peroxidase (GPX) activities, increased the expression of miR-15a and downregulated BCL2 and TNFα-induced protein 3 (TNFAIP3, A20), triggered mitochondrial pathway mediated apoptosis and receptor interacting serine/threonine kinase (RIP)-dependent necroptosis in CIK cells. However, cell death under CT exposure could be relieved by RSV treatment through inhibiting the expression of CYP1 family genes and restoring miR-15a/BCL2-A20 axis disorders. Overall, we conclude that RSV could relieve CT-induced apoptosis and necroptosis through miR-15a/Bcl2-A20 axis in CIK cells. These results enrich the toxicological mechanisms of the CT and confirm that RSV can be used as a potential antidote for CT poisoning., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: Most patients with prostate cancer receiving enzalutamide or abiraterone develop resistance. Clinical evidence indicates that serum levels of dehydroepiandrosterone sulfate (DHEAS) and biologically active DHEA remain in the high range despite antiandrogen treatment. The conversion of DHEAS into DHEA by steroid sulfatase (STS) may contribute to sustained intracrine androgen synthesis. Here, we determine the contribution of STS to treatment resistance and explore the potential of targeting STS to overcome resistance in prostate cancer., Experimental Design: STS expression was examined in patients and cell lines. In vitro , STS activity and expression were modulated using STS-specific siRNA or novel STS inhibitors (STSi). Cell growth, colony formation, androgen production, and gene expression were examined. RNA-sequencing analysis was conducted on VCaP cells treated with STSi. Mice were treated with STSis with or without enzalutamide to determine their effects in vivo ., Results: STS is overexpressed in patients with castration-resistant prostate cancer (CRPC) and resistant cells. STS overexpression increases intracrine androgen synthesis, cell proliferation, and confers resistance to enzalutamide and abiraterone. Inhibition of STS using siRNA suppresses prostate cancer cell growth. Targeting STS activity using STSi inhibits STS activity, suppresses androgen receptor transcriptional activity, and reduces the growth of resistant C4-2B and VCaP prostate cancer cells. STSis significantly suppress resistant VCaP tumor growth, decrease serum PSA levels, and enhance enzalutamide treatment in vitro and in vivo ., Conclusions: These studies suggest that STS drives intracrine androgen synthesis and prostate cancer proliferation. Targeting STS represents a therapeutic strategy to treat CRPC and improve second-generation antiandrogen therapy., (©2020 American Association for Cancer Research.)

Abstract: The NLRP3 inflammasome has been implicated in the development and progression of heart failure. The aim of this study was to determine the safety of an oral inhibitor of the NLRP3 inflammasome, dapansutrile (OLT1177), in patients with heart failure and reduced ejection fraction (HFrEF). This was a phase 1B, randomized, double-blind, dose escalation, single-center, repeat dose safety and pharmacodynamics study of dapansutrile in stable patients with HFrEF (New York Heart Association Class II-III). Subjects were randomized to treatment with dapansutrile for up to 14 days at a ratio of 4:1 into 1 of 3 sequential ascending dose cohorts (500, 1000, or 2000 mg) each including 10 patients. Subjects underwent clinical assessment, biomarker determination, transthoracic echocardiogram, and maximal cardiopulmonary exercise testing at baseline, day 14, and day 28 to ascertain changes in clinical status. Placebo cases (N = 2 per cohort) were used as a decoy to reduce bias and not for statistical comparisons. Thirty participants (20 men) were treated for 13 (12-14) days. No serious adverse events during the study were recorded. All clinical or laboratory parameters at day 14 compared with baseline suggested clinical stability without significant within-group differences in the dapansutrile-pooled group or the 3 dapansutrile cohorts. Improvements in left ventricular EF [from 31.5% (27.5-39) to 36.5% (27.5-45), P = 0.039] and in exercise time [from 570 (399.5-627) to 616 (446.5-688) seconds, P = 0.039] were seen in the dapansutrile 2000 mg cohort. Treatment with dapansutrile for 14 days was safe and well tolerated in patients with stable HFrEF., Competing Interests: B. W. Van Tassell has served as a consultant for Novartis and Serpin Pharma. A. Abbate has served as a consultant for AstraZeneca, Janssen, Kiniksa Pharmaceuticals Ltd, Merck, Novartis, Olatec, and Serpin Pharma. A. Bonaventura and A. Vecchié received a travel grant from Kiniksa Pharmaceuticals Ltd to attend the 2019 American Heart Association Scientific Sessions. S. Carbone is supported by a Career Development Award 19CDA34660318 from the American Heart Association. The remaining authors report no conflicts of interest., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: ZEN-3694 is a bromodomain extraterminal inhibitor (BETi) with activity in androgen-signaling inhibitor (ASI)-resistant models. The safety and efficacy of ZEN-3694 plus enzalutamide was evaluated in a phase Ib/IIa study in metastatic castration-resistant prostate cancer (mCRPC)., Patients and Methods: Patients had progressive mCRPC with prior resistance to abiraterone and/or enzalutamide. 3+3 dose escalation was followed by dose expansion in parallel cohorts (ZEN-3694 at 48 and 96 mg orally once daily, respectively)., Results: Seventy-five patients were enrolled ( N = 26 and 14 in dose expansion at low- and high-dose ZEN-3694, respectively). Thirty (40.0%) patients were resistant to abiraterone, 34 (45.3%) to enzalutamide, and 11 (14.7%) to both. ZEN-3694 dosing ranged from 36 to 144 mg daily without reaching an MTD. Fourteen patients (18.7%) experienced grade ≥3 toxicities, including three patients with grade 3 thrombocytopenia (4%). An exposure-dependent decrease in whole-blood RNA expression of BETi targets was observed (up to fourfold mean difference at 4 hours post-ZEN-3694 dose; P ≤ 0.0001). The median radiographic progression-free survival (rPFS) was 9.0 months [95% confidence interval (CI), 4.6-12.9] and composite median radiographic or clinical progression-free survival (PFS) was 5.5 months (95% CI, 4.0-7.8). Median duration of treatment was 3.5 months (range, 0-34.7+). Lower androgen receptor (AR) transcriptional activity in baseline tumor biopsies was associated with longer rPFS (median rPFS 10.4 vs. 4.3 months)., Conclusions: ZEN-3694 plus enzalutamide demonstrated acceptable tolerability and potential efficacy in patients with ASI-resistant mCRPC. Further prospective study is warranted including in mCRPC harboring low AR transcriptional activity., (©2020 American Association for Cancer Research.)

Purpose: To date, there has not been a single randomized controlled trial (RCT) conducted to directly compare the efficacy and safety of perampanel to brivaracetam in the adjunctive treatment of focal-onset seizures. This study makes these comparisons through the use of indirect treatment comparison (ITC) methods., Methods: A systematic review was conducted to identify RCTs that evaluated either one of perampanel or brivaracetam in the treatment of patients with focal-onset seizures. The Bucher ITC method was then used to compare efficacy and safety outcomes between perampanel and brivaracetam. Additional subgroup analyses, by levetiracetam usage (prior or concomitant), were conducted., Results: Eight RCTs (four comparing perampanel to placebo, four comparing brivaracetam to placebo) were included in the ITC. For patients taking concomitant levetiracetam, perampanel showed a significantly better responder rate compared to brivaracetam [relative risk (RR) and 95 % confidence interval (CI): 2.62 (1.15, 5.99)]. For patients who had previously, or never, taken levetiracetam, there was no difference in the responder rate. In the overall population, both perampanel and brivaracetam were more effective than placebo in terms of responder rate, seizure freedom, and secondarily generalized tonic-clonic seizure responder rate; however, for these outcomes, no evidence of a difference between perampanel and brivaracetam was found. Patients taking brivaracetam showed significantly less dizziness compared to patients taking perampanel. No differences for any other safety outcome were found., Conclusion: Perampanel and brivaracetam are effective for the adjunctive treatment of focal-onset seizures and display similar adverse event profiles. Perampanel demonstrated an improved focal-onset seizure responder rate compared to brivaracetam in patients taking concomitant levetiracetam. This may be due to the similarity in the mechanism of action between brivaracetam and levetiracetam., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The FDA has approved three androgen receptor inhibitors-enzalutamide, apalutamide, and darolutamide-for the treatment of patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). These approvals were all based on randomized, double blind, placebo-controlled trials demonstrating large improvements in metastasis-free survival (MFS) and internally consistent evidence of benefit seen across secondary endpoints. In this article, we summarize the FDA regulatory history of MFS and we describe the design, conduct, and results of the three pivotal trials supporting these important treatment options for patients with nmCRPC., (©2020 American Association for Cancer Research.)

Background and Objectives: Topiroxostat, a selective xanthine oxidoreductase inhibitor, is used for the management of hyperuricemic patients with or without gout in Japan. Accumulating evidence has demonstrated the efficacy of topiroxostat for the treatment of hyperuricemia with or without gout. However, the safety and efficacy of topiroxostat in the clinical setting remain unclear, and there is little large-scale clinical evidence. We conducted a post-marketing observational study over 54 weeks., Patients and Methods: Patients were centrally enrolled, and case report forms of 4491 patients were collected between April 2014 and March 2019 from 825 medical sites., Results: Overall, 4329 patients were assessed for safety and 4253 patients for effectiveness. The overall incidence of adverse drug reactions was 6.95%, and the incidence rates of adverse drug reactions of gouty arthritis, hepatic dysfunction, and skin disorders, which are of special interest in this study, were 0.79%, 1.73%, and 0.95%, respectively. No case of serious gouty arthritis was observed. Serum urate levels decreased stably over time and showed a significant reduction rate at 54 weeks (21.19% ± 22.07%) and on the final visit (19.91% ± 23.35%) compared to the baseline. The rates for subjects who achieved serum uric acid levels ≤ 6.0 mg/dL at 18 and 54 weeks after administration were 43.80% and 48.28%, respectively., Conclusions: This study suggests that there is no particular concern about adverse drug reactions or the efficacy of topiroxostat for hyperuricemic patients with or without gout in a post-marketing setting in Japan.

Background: In the PREVAIL study, enzalutamide significantly improved clinical outcomes versus placebo in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC)., Objective: To evaluate long-term benefits and risks of enzalutamide in the final prespecified PREVAIL analysis., Design, Setting, and Participants: We conducted a final 5-yr survival analysis of PREVAIL in men with chemotherapy-naïve mCRPC from the enzalutamide (n = 689) and placebo (n = 693) arms., Outcome Measurements and Statistical Analysis: Predictors of the primary outcome of overall survival were estimated using the Kaplan-Meier method. Long-term adverse events over time were analyzed., Results and Limitations: At the 5-yr data cutoff, 1382 of 1717 (80%) men had died. Enzalutamide reduced the hazard of death by 17% (hazard ratio 0.83; 95% confidence interval [CI] 0.75-0.93; p < 0.001), despite 65%, 54%, and 43% of placebo-treated patients receiving subsequent docetaxel, abiraterone, and enzalutamide, respectively. Median overall survival was 36 mo (95% CI 34-38) in the enzalutamide arm versus 31 mo (95% CI 29-34) in the placebo arm, with a median follow-up of 69 mo. Prognostic modeling showed 5-yr survival rates of 42%, 24%, and 5% for low-, intermediate-, and high-risk groups, respectively. Greater degrees of confirmed prostate-specific antigen declines (≤3 mo) were associated with greater 5-yr survival. A higher incidence of fatal treatment-emergent adverse events was observed with enzalutamide (6.9% vs 3.8%), with an increase in fatal cardiovascular events (1.6% vs 0.4%)., Conclusions: With >5 yr of follow-up, enzalutamide continued to demonstrate improved survival in patients with mCRPC despite crossover and multiple subsequent effective therapies, balanced against a slightly higher rate of fatal cardiovascular events. PREVAIL is registered on ClinicalTrials.gov as NCT01212991., Patient Summary: We report a maintained long-term survival benefit with enzalutamide and risks with >5 yr of enzalutamide treatment and follow-up in men with metastatic prostate cancer, and identify groups of men with widely different outcomes based on clinical factors., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The TROFEO trial demonstrated that febuxostat causes greater and more rapid reduction of serum uric acid (s-UA) than topiroxostat. We compared these drugs in patients with chronic kidney disease (CKD) by sub-analysis of the TROFEO trial., Methods: This sub-analysis targeted patients with an estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73 m 2 . The primary endpoint was the s-UA level. Secondary endpoints included creatinine, eGFR, urinary albumin, cystatin-C, oxidized low-density lipoprotein (Ox-LDL), eicosapentaenoic acid/arachidonic acid ratio, lipid biomarkers, high-sensitivity C-reactive protein, and B-type natriuretic peptide (BNP)., Results: There was no significant difference of s-UA between the two groups either before or after treatment. However, s-UA did not exceed 6.0 mg/dL in febuxostat group during the study period, but it exceeded this level in seven patients from topiroxostat group, with the number being significantly higher in topiroxostat group. Serum creatinine (s-Cr) and eGFR were significantly better after 6 months of febuxostat treatment compared with topiroxostat Cystatin-C was significantly lower after 6 months of febuxostat treatment compared with topiroxostat. The Ox-LDL was significantly lower after 3 and 6 months of febuxostat treatment compared with topiroxostat., Conclusion: Febuxostat had stronger renoprotective and antioxidant effects than topiroxostat in patients with hyperuricemia and CKD.

Bosutinib is approved for newly diagnosed Philadelphia chromosome-positive (Ph+) chronic phase (CP) chronic myeloid leukemia (CML) and for Ph+ CP, accelerated (AP), or blast (BP) phase CML after prior treatment with tyrosine kinase inhibitors (TKIs). In the ongoing phase 4 BYOND study (NCT02228382), 163 CML patients resistant/intolerant to prior TKIs (n = 156 Ph+ CP CML, n = 4 Ph+ AP CML, n = 3 Ph-negative/BCR-ABL1+ CML) received bosutinib 500 mg once daily (starting dose). As of ≥1 year after last enrolled patient (median treatment duration 23.7 months), 56.4% of Ph+ CP CML patients remained on bosutinib. Primary endpoint of cumulative confirmed major cytogenetic response (MCyR) rate by 1 year was 75.8% in Ph+ CP CML patients after one or two prior TKIs and 62.2% after three prior TKIs. Cumulative complete cytogenetic response (CCyR) and major molecular response (MMR) rates by 1 year were 80.6% and 70.5%, respectively, in Ph+ CP CML patients overall. No patient progressed to AP/BP on treatment. Across all patients, the most common treatment-emergent adverse events were diarrhea (87.7%), nausea (39.9%), and vomiting (32.5%). The majority of patients had confirmed MCyR by 1 year and MMR by 1 year, further supporting bosutinib use for Ph+ CP CML patients resistant/intolerant to prior TKIs.

Background: Kidney transplantation is the preferred management for patients with end-stage kidney disease (ESKD). However, it is often complicated by worsening or new-onset diabetes. The safety and efficacy of glucose-lowering agents after kidney transplantation is largely unknown. This is an update of a review first published in 2017., Objectives: To evaluate the efficacy and safety of glucose-lowering agents for treating pre-existing and new onset diabetes in people who have undergone kidney transplantation., Search Methods: We searched the Cochrane Kidney and Transplant Register of Studies up to 16 January 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov., Selection Criteria: All randomised controlled trials (RCTs), quasi-RCTs and cross-over studies examining head-to-head comparisons of active regimens of glucose-lowering therapy or active regimen compared with placebo/standard care in patients who have received a kidney transplant and have diabetes were eligible for inclusion., Data Collection and Analysis: Four authors independently assessed study eligibility and quality and performed data extraction. Continuous outcomes were expressed as post-treatment mean differences (MD) or standardised mean difference (SMD). Adverse events were expressed as post-treatment absolute risk differences (RD). Dichotomous clinical outcomes were presented as risk ratios (RR) with 95% confidence intervals (CI)., Main Results: Ten studies (21 records, 603 randomised participants) were included - three additional studies (five records) since our last review. Four studies compared more intensive versus less intensive insulin therapy; two studies compared dipeptidyl peptidase-4 (DPP-4) inhibitors to placebo; one study compared DPP-4 inhibitors to insulin glargine; one study compared sodium glucose co-transporter 2 (SGLT2) inhibitors to placebo; and two studies compared glitazones and insulin to insulin therapy alone. The majority of studies had an unclear to a high risk of bias. There were no studies examining the effects of biguanides, glinides, GLP-1 agonists, or sulphonylureas. Compared to less intensive insulin therapy, it is unclear if more intensive insulin therapy has an effect on transplant or graft survival (4 studies, 301 participants: RR 1.12, 95% CI 0.32 to 3.94; I 2 = 49%; very low certainty evidence), delayed graft function (2 studies, 153 participants: RR 0.63, 0.42 to 0.93; I 2 = 0%; very low certainty evidence), HbA1c (1 study, 16 participants; very low certainty evidence), fasting blood glucose (1 study, 24 participants; very low certainty evidence), kidney function markers (1 study, 26 participants; very low certainty evidence), death (any cause) (3 studies, 208 participants" RR 0.68, 0.29 to 1.58; I 2 = 0%; very low certainty evidence), hypoglycaemia (4 studies, 301 participants; very low certainty evidence) and medication discontinuation due to adverse effects (1 study, 60 participants; very low certainty evidence). Compared to placebo, it is unclear whether DPP-4 inhibitors have an effect on hypoglycaemia and medication discontinuation (2 studies, 51 participants; very low certainty evidence). However, DPP-4 inhibitors may reduce HbA1c and fasting blood glucose but not kidney function markers (1 study, 32 participants; low certainty evidence). Compared to insulin glargine, it is unclear if DPP-4 inhibitors have an effect on HbA1c, fasting blood glucose, hypoglycaemia or discontinuation due to adverse events (1 study, 45 participants; very low certainty evidence). Compared to placebo, SGLT2 inhibitors probably do not affect kidney graft survival (1 study, 44 participants; moderate certainty evidence), but may reduce HbA1c without affecting fasting blood glucose and eGFR long-term (1 study, 44 participants, low certainty evidence). SGLT2 inhibitors probably do not increase hypoglycaemia, and probably have little or no effect on medication discontinuation due to adverse events. However, all participants discontinuing SGLT2 inhibitors had urinary tract infections (1 study, 44 participants, moderate certainty evidence). Compared to insulin therapy alone, it is unclear if glitazones added to insulin have an effect on HbA1c or kidney function markers (1 study, 62 participants; very low certainty evidence). However, glitazones may make little or no difference to fasting blood glucose (2 studies, 120 participants; low certainty evidence), and medication discontinuation due to adverse events (1 study, 62 participants; low certainty evidence). No studies of DPP-4 inhibitors, or glitazones reported effects on transplant or graft survival, delayed graft function or death (any cause)., Authors' Conclusions: The efficacy and safety of glucose-lowering agents in the treatment of pre-existing and new-onset diabetes in kidney transplant recipients is questionable. Evidence from existing studies examining the effect of intensive insulin therapy, DPP-4 inhibitors, SGLT inhibitors and glitazones is mostly of low to very low certainty. Appropriately blinded, larger, and higher quality RCTs are needed to evaluate and compare the safety and efficacy of contemporary glucose-lowering agents in the kidney transplant population., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Aim: To provide an overview on the available treatments to prevent and reduce gynecomastia and/or breast pain caused by antiandrogen therapy for prostate cancer., Methods: The German Society of Radiation Oncology (DEGRO) expert panel summarized available evidence published and assessed the validity of the information on efficacy and treatment-related toxicity., Results: Eight randomized controlled trials and one meta-analysis were identified. Two randomized trials demonstrated that prophylactic radiation therapy (RT) using 1 × 10 Gy or 2 × 6 Gy significantly reduced the rate of gynecomastia but not breast pain, as compared to observation. A randomized dose-finding trial identified the daily dose of 20 mg tamoxifen (TMX) as the most effective prophylactic dose and another randomized trial described that daily TMX use was superior to weekly use. Another randomized trial showed that prophylactic daily TMX is more effective than TMX given at the onset of gynecomastia. Two other randomized trials described that TMX was clearly superior to anastrozole in reducing the risk for gynecomastia and/or breast pain. One comparative randomized trial between prophylactic RT using 1 × 12 Gy and TMX concluded that prophylactic TMX is more effective compared to prophylactic RT and furthermore that TMX appears to be more effective to treat gynecomastia and/or breast pain when symptoms are already present. A meta-analysis confirmed that both prophylactic RT and TMX can reduce the risk of gynecomastia and/or breast pain with TMX being more effective; however, the rate of side effects after TMX including dizziness and hot flushes might be higher than after RT and must be taken into account. Less is known regarding the comparative effectiveness of different radiation fractionation schedules and more modern RT techniques., Conclusions: Prophylactic RT as well as daily TMX can significantly reduce the incidence of gynecomastia and/or breast pain. TMX appears to be an effective alternative to RT also as a therapeutic treatment in the presence of gynecomastia but its side effects and off-label use must be considered.

This open-label, single-arm, phase 2 study (ClinicalTrials.gov, NCT03128411) evaluated the efficacy, safety, and pharmacokinetics of bosutinib at a starting dose of 400 mg once daily (QD) in Japanese patients with newly diagnosed chronic phase chronic myeloid leukemia (CP CML). The primary endpoint was major molecular response (MMR) at Month 12 in the modified as-treated population (Philadelphia chromosome-positive [Ph+] patients with e13a2/e14a2 transcripts). Sixty Japanese patients with CP CML were treated with bosutinib; median age was 55 years (range 20-83), 60.0% were males, and all were Ph+ and had e13a2/e14a2 transcripts. After median follow-up of 16.6 months (range 11.1-21.9), 41 (68.3%) patients remained on bosutinib. The MMR rate at Month 12 was 55.0% (2-sided 90% confidence interval: 44.4-65.6). There were no on-treatment transformations to accelerated/blast phase, and no patient died on treatment or within 28 days of the last bosutinib dose. The most common treatment-emergent adverse events were diarrhea (86.7%), increased alanine aminotransferase (55.0%), and increased aspartate aminotransferase (46.7%). The primary objective of this phase 2 study was met, and there were no new safety signals for bosutinib. These data suggest bosutinib is an effective first-line treatment option for Japanese patients with newly diagnosed CP CML.

Motor fluctuations are frequently seen in Parkinson disease patients on chronic treatment with levodopa. Management of motor fluctuation includes the addition of catechol-O-methyl transferase (COMT) inhibitors. Opicapone is a recent and selective third-generation COMT inhibitor which achieves marked increase in the bioavailability of levodopa. We present a consensus of a group of Spanish neurologists with extensive experience in the clinical management of motor fluctuations. The clinical experience of this group of experts is in line with clinical trials and confirms that opicapone is an effective drug in the control of motor fluctuations, regardless of the daily levodopa dose, or the use of other antiparkinsonian drugs. However, in the opinion of these experts, the ideal patient with Parkinson's disease to initiate treatment with opicapone is the one with mild motor fluctuations, since the ratio between clinical efficacy and adverse effects is more favorable. In general, it is an easy-to-use drug both in those first treated with a COMT inhibitor or those already on entacapone. In any case, the secondary side effects are easily managed.

Background: Teriflunomide is contraindicated in pregnancy. Some pregnancies have occurred despite guidance to use effective contraception., Objectives: To report outcomes of pregnancies occurring in teriflunomide clinical trials and the post-marketing setting., Methods: Outcomes are summarized for pregnancies in teriflunomide monotherapy clinical trials and the post-marketing setting (data cutoff: December 2017)., Results: Of 437 confirmed teriflunomide-exposed pregnancies, 222 had known outcomes (70 from clinical trials; 152 from the post-marketing setting); 161 were reported prospectively and 61 retrospectively. There were 107 (48.2%) live births, 63 (28.4%) elective abortions, 47 (21.2%) spontaneous abortions, 3 (1.4%) ectopic pregnancies, 1 (0.5%) stillbirth, and 1 (0.5%) maternal death leading to fetal death. Four birth defects were reported among cases with known pregnancy outcome: ureteropyeloectasia (only defect considered major); congenital hydrocephalus; ventricular septal defect; and malformation of right foot valgus. A case of cystic hygroma was identified on antenatal ultrasound (pregnancy outcome unknown). One elective abortion followed prenatal diagnosis of fetal anomaly (blighted ovum). The risk of major birth defects in prospectively reported live birth/stillbirth outcomes was 3.6% (1/28) in clinical trials and 0.0% (0/51) in post-marketing reports., Conclusions: Outcomes were consistent with the general population. Current human data do not indicate a teratogenic signal in teriflunomide-exposed pregnancies.

In this study, we aimed to compare changes in cavernosal tissues in rats with antiandrogen treatment and orchiectomy. A total of 42 Wistar albino rats were divided into four groups. Group I, control group, Group II, LH-RH was given for 1 month, Group III-LH-RH + Bicalutamide was given for 1 month, and Group IV was defined as orchiectomy and followed up for 1 month. Measurements of intracavernosal pressure with different electrical stimuli and pathological findings of smooth muscle collagen in cavernosal tissues were examined. While the cavernosal pressure response in all the different electrical stimuli given in the control group and in all other groups was significantly lower than that in the other groups, it was statistically significant at 7.5 and 10 V (p = .005, p < 0001). According to the pathologic evaluation, the density of tissue collagen increased significantly in the other groups according to the control group. In groups 3 and 4, the density of 4+ collagen was found to be increased according to Groups 1 and 2. In the LH-RH alone group, it appears that there are no 4+ colloid density and less damage. According to these findings, the negative effect of LH-RH treatment on cavernosal tissues appears to be less., (© 2020 Blackwell Verlag GmbH.)

Purpose: In a mouse model, degarelix generated the least metabolic consequences via low follicle-stimulating hormone (FSH) levels compared with orchiectomy and leuprolide after 4 months of androgen deprivation therapy (ADT). Here, we comparatively investigated the influence of ADT with degarelix or leuprolide on the development of metabolic syndrome in patients with prostate cancer (PCa)., Methods: Patients with hormone-naive PCa were recruited. Eligible patients were randomized (1:1) to monthly degarelix or monthly leuprolide for 6 months. Key trial variables were monitored monthly. The primary endpoint was changes in fasting blood sugar (FBS). Secondary endpoints were changes in body weight, abdominal circumference, lipid profiles, and hemoglobin A1c (HbA1c) and FSH levels. Computed tomography was performed to measure subcutaneous and visceral fat areas before and after 6 months of ADT. Data were analyzed using the χ 2 test, Student's t test, and analysis of variance., Results: From the 100 patients registered, 85 completed the trial (degarelix: 40 patients; leuprolide: 45 patients). Mean increases in FBS did not differ between the two arms. Similarly, there were no differences between the arms in mean increases in body weight, abdominal circumference, lipid profiles, HbA1c, or subcutaneous and visceral fat areas. Follicle-stimulating hormone levels were significantly lower in the degarelix arm than in the leuprolide arm (p < 0.05)., Conclusions: Lipid and glucose metabolism did not differ significantly between the arms, while FSH levels were significantly lower in the degarelix arm.

Introduction: Bicalutamide is widely used in the treatment of prostate cancer. Among its side effects, central nervous system disorders are relatively rare, and the information about bicalutamide-associated hallucinations is limited., Case Report: We report an uncommon case of a patient with metastatic prostate cancer, who had hallucinations due to the use of bicalutamide., Management and Outcome: The patient accepted to receive only hormonal therapy (bicalutamide and leuprolide acetate). But he developed hallucinations due to bicalutamide use. His hallucinations disappeared after discontinuation of bicalutamide. A good response was obtained with the use of luteinizing hormone-releasing hormone agonist monotherapy., Discussion: The pathophysiology of bicalutamide-induced hallucinations is unclear. We hypothesize that antiandrogens can indirectly cause hallucinations through changes in plasma testosterone and cerebral reelin expression. Additionally, luteinizing hormone-releasing hormone agonist monotherapy is a good option in metastatic prostate cancer patients who have intolerable side effects due to the use of antiandrogens.

Aim: To evaluate the effect of adding the dipeptidyl-peptidase-4 inhibitor vildagliptin to insulin on the glycaemic control of patients with type 2 diabetes undergoing haemodialysis., Methods: Overall, 65 insulin-treated patients with type 2 diabetes undergoing haemodialysis (HbA1c: 7.3% ± 1.1%; age: 70.5 ± 8.5 years) were randomized (1:1) either to receive vildagliptin 50 mg/day in addition to insulin (vildagliptin-insulin group) or to pursue their usual insulin regimen (insulin-only group). Continuous glucose monitoring (CGM) was performed for 48 ± 6 hours at baseline and at week 12. The primary study endpoint was change from baseline in mean interstitial glucose using CGM. The secondary endpoints included other CGM variables and glucose control markers., Results: After 12 weeks, a greater reduction in mean CGM glucose from baseline was observed in the vildagliptin-insulin group compared with the insulin-only group, although the between-treatment difference was not statistically significant (mean difference [CI 95%]: -0.96 mmol/L [-2.09; 0.18] vs. -0.29 mmol/L [-1.29; 0.76], P = 0.32). However, a significant decrease from baseline in HbA1c, glycated albumin and insulin daily doses was observed in the vildagliptin-insulin group versus the insulin-only group (-0.6% [-1.19; -0.1], P < 0.01), in the vildagliptin-insulin group versus no change in the insulin-only group (-130.6 μmol/L [-271; 10.7] vs. +36.2 μmol/L [-164.4; 236.9], P = 0.04 and - 5.9 IU/day [-1.8; 7.1] vs. +1.1 IU/day [-14.5; 16.6], P = 0.01, respectively). There was no significant difference in the percentage of time spent in hypoglycaemia using CGM, occurrence of severe hypoglycaemia or number of adverse events., Conclusion: In this study, vildagliptin added to insulin improved glycaemic control with an associated insulin-sparing effect in patients with type 2 diabetes undergoing haemodialysis and was well tolerated., (© 2020 John Wiley & Sons Ltd.)

Background: Chronic obstructive pulmonary disease (COPD) is associated with cough, sputum production or dyspnoea, and a reduction in lung function, quality of life, and life expectancy. Apart from smoking cessation, no other treatments that slow lung function decline are available. Roflumilast and cilomilast are oral phosphodiesterase-4 (PDE₄) inhibitors proposed to reduce the airway inflammation and bronchoconstriction seen in COPD. This Cochrane Review was first published in 2011, and was updated in 2017 and 2020., Objectives: To evaluate the efficacy and safety of oral PDE₄ inhibitors for management of stable COPD., Search Methods: We identified randomised controlled trials (RCTs) from the Cochrane Airways Trials Register (date of last search 9 March 2020). We found other trials at web-based clinical trials registers., Selection Criteria: We included RCTs if they compared oral PDE₄ inhibitors with placebo in people with COPD. We allowed co-administration of standard COPD therapy., Data Collection and Analysis: We used standard Cochrane methods. Two independent review authors selected trials for inclusion, extracted data, and assessed risk of bias. We resolved discrepancies by involving a third review author. We assessed our confidence in the evidence by using GRADE recommendations. Primary outcomes were change in lung function (minimally important difference (MID) = 100 mL) and quality of life (scale 0 to 100; higher score indicates more limitations)., Main Results: We found 42 RCTs that met the inclusion criteria and were included in the analyses for roflumilast (28 trials with 18,046 participants) or cilomilast (14 trials with 6457 participants) or tetomilast (1 trial with 84 participants), with a duration between six weeks and one year or longer. These trials included people across international study centres with moderate to very severe COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades II to IV), with mean age of 64 years. We judged risks of selection bias, performance bias, and attrition bias as low overall amongst the 39 published and unpublished trials. Lung function Treatment with a PDE₄ inhibitor was associated with a small, clinically insignificant improvement in forced expiratory volume in one second (FEV₁) over a mean of 40 weeks compared with placebo (mean difference (MD) 49.33 mL, 95% confidence interval (CI) 44.17 to 54.49; participants = 20,815; studies = 29; moderate-certainty evidence). Forced vital capacity (FVC) and peak expiratory flow (PEF) were also improved over 40 weeks (FVC: MD 86.98 mL, 95% CI 74.65 to 99.31; participants = 22,108; studies = 17; high-certainty evidence; PEF: MD 6.54 L/min, 95% CI 3.95 to 9.13; participants = 4245; studies = 6; low-certainty evidence). Quality of life Trials reported improvements in quality of life over a mean of 33 weeks (St George's Respiratory Questionnaire (SGRQ) MD -1.06 units, 95% CI -1.68 to -0.43; participants = 7645 ; moderate-certainty evidence). Incidence of exacerbations Treatment with a PDE₄ inhibitor was associated with a reduced likelihood of COPD exacerbation over a mean of 40 weeks (odds ratio (OR) 0.78, 95% CI 0.73 to 0.84; participants = 20,382; studies = 27; high-certainty evidence), that is, for every 100 people treated with PDE₄ inhibitors, five more remained exacerbation-free during the study period compared with those given placebo (number needed to treat for an additional beneficial outcome (NNTB) 20, 95% CI 16 to 27). No change in COPD-related symptoms nor in exercise tolerance was found. Adverse events More participants in the treatment groups experienced an adverse effect compared with control participants over a mean of 39 weeks (OR 1.30, 95% CI 1.22 to 1.38; participants = 21,310; studies = 30; low-certainty evidence). Participants experienced a range of gastrointestinal symptoms such as diarrhoea, nausea, vomiting, or dyspepsia. Diarrhoea was more commonly reported with PDE₄ inhibitor treatment (OR 3.20, 95% CI 2.74 to 3.50; participants = 20,623; studies = 29; high-certainty evidence), that is, for every 100 people treated with PDE₄ inhibitors, seven more suffered from diarrhoea during the study period compared with those given placebo (number needed to treat for an additional harmful outcome (NNTH) 15, 95% CI 13 to 17). The likelihood of psychiatric adverse events was higher with roflumilast 500 µg than with placebo (OR 2.13, 95% CI 1.79 to 2.54; participants = 11,168; studies = 15 (COPD pool data); moderate-certainty evidence). Roflumilast in particular was associated with weight loss during the trial period and with an increase in insomnia and depressive mood symptoms. Participants treated with PDE₄ inhibitors were more likely to withdraw from trial participation; on average, 14% in the treatment groups withdrew compared with 8% in the control groups. Mortality No effect on mortality was found (OR 0.98, 95% CI 0.77 to 1.24; participants = 19,786; studies = 27; moderate-certainty evidence), although mortality was a rare event during these trials., Authors' Conclusions: For this current update, five new studies from the 2020 search contributed to existing findings but made little impact on outcomes described in earlier versions of this review. PDE₄ inhibitors offered a small benefit over placebo in improving lung function and reducing the likelihood of exacerbations in people with COPD; however, they had little impact on quality of life or on symptoms. Gastrointestinal adverse effects and weight loss were common, and the likelihood of psychiatric symptoms was higher, with roflumilast 500 µg. The findings of this review provide cautious support for the use of PDE₄ inhibitors in COPD. In accordance with GOLD 2020 guidelines, they may have a place as add-on therapy for a subgroup of people with persistent symptoms or exacerbations despite optimal COPD management (e.g. people whose condition is not controlled by fixed-dose long-acting beta₂-agonist (LABA) and inhaled corticosteroid (ICS) combinations). More longer-term trials are needed to determine whether or not PDE₄ inhibitors modify FEV₁ decline, hospitalisation, or mortality in COPD., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Purpose: Primary objective is to evaluate safety of isavuconazonium sulfate (ISA) in pediatrics below 18 years old. Exploratory endpoint includes mortality due to probable and proven invasive fungal infection (IFI) and overall morality in this population., Patients and Methods: Retrospective review of patients below 18 years receiving ISA for ≥7 days for possible, probable, or proven IFI or prophylaxis between June 2015 and March 2018. Descriptive analysis performed to calculate median, frequency, and percentages., Results: Safety analysis included 18 patients and a subgroup of 11/18 patients were assessed for efficacy. Median age 12.5 years (4 to 17 y), median weight 50.25 kg (19 to 118 kg), 50% male, 77% acute leukemias, 94% hematopoietic cell transplant recipients, 50% matched unrelated donors and 78% in remission. Elevated alanine aminotransferase 3 times baseline within 30 days of ISA occurred in 22% (4/18). No patients had elevated bilirubin or increase in serum creatinine. All-cause mortality at 90 days was 22% (4/18) and 27% (3/11) in patients with probable or proven IFI. Clinical response rates: 14-day: 45% (5/11) partial, 27% (3/11) stable; 30-day: 45% (5/11) partial, 36% (4/11) stable; 90-day: 54% (6/11) had either partial (n=3) or complete (n=3) response to ISA., Conclusions: ISA is safe in pediatric patients for the treatment of IFI. Prospective, randomized controlled trials are warranted to determine efficacy and safety of ISA in pediatric patients with hematologic malignancies and hematopoietic cell transplant.

Background: Limited information is available regarding the rate of long-term cardiovascular (CV) mortality in chronic myeloid leukaemia (CML) patients treated with second- and third-generation tyrosine kinase inhibitors (2 ndG /3 rdG TKIs) in the real-life practice., Methods: We identified 656 consecutive CML patients treated with nilotinib, dasatinib, bosutinib and ponatinib., Results: The 15-year CV-mortality free survival was 93 ± 2.8%. Age ≥65 years (p = 0.005) and a positive history of CV disease (p = 0.04) were significantly associated with a lower CV-mortality free survival. CV disease accounted for 16.5% and 5% of potential years of life lost (PYLL) in male and female patients, respectively. The standard mortality ratio (SMR) following ischemic heart disease (IHD) was 3.9 in males and 3.8 in female patients, meaning an excess of IHD deaths observed, in comparison with the population of control., Conclusion: Prevention strategies based on CV risk factors, in particular in those patients with a previous history of CV disease, should be considered., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Deltamethrin (DM) is widely used in agriculture, veterinary medicine and control of domestic pests. Epidemiological studies suggest that DM exposure is a risk factor for neurodegenerative disorders such as Parkinson's (PD) and Alzheimer diseases; however the mechanisms are elusive. In the present study we evaluated the effects of intracerebroventricular (i.c.v.) administration of DM on locomotion activity, spatial working memory and dopaminergic pathway in the rat. Middle-aged male Wistar rats received three i.c.v. injections of DM 0.5 μg, DM 5 μg or vehicle, every other day. Across the treatment, the animals were submitted to behavioral evaluation in the catalepsy test, open field test, and spontaneous alternation task. Following completion of behavioral tests, rats were perfused and their brains were processed to tyrosine hydroxylase (TH) immunohistochemistry. We observed that i.c.v. administration of DM 5 μg increased locomotion activity (open field) and caused spatial working memory impairment (spontaneous alternation task). These alterations were accompanied by reduction TH immunoreactivity in the substantia nigra pars compacta (SNpc), ventral tegmental area (VTA) and dorsal striatum. Conversely, no motor change was observed in the catalepsy test. These results indicate that i.c.v. administration of DM can cause hyperactivity and cognitive alteration which may be related to disruption of the dopaminergic pathway., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In a 3-year cohort study of adult patients with proven or probable IA, fewer patients initially treated with isavuconazole experienced adverse events compared with voriconazole, but more patients required a change in therapy due to lack of clinical efficacy., (© 2019 Blackwell Verlag GmbH.)

Purpose: To compare the effectiveness and safety between abiraterone and enzalutamide in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC)., Methods: We systematically searched for relevant articles from PubMed, Cochrane, Embase from their inception through November 4, 2019. Available articles from conferences were searched. The endpoints were prostate-specific antigen (PSA) response, overall survival (OS), progression-free survival (PFS), number of patients with any adverse event (AE)., Results: 15 cohort studies involving 3546 participants were included in this meta-analysis. Pooled result showed that PSA response rate in the enzalutamide group was significantly greater than that in the abiraterone group (867 patients, risk ratio (RR) 0.69, 95% confidence interval (CI) 0.61-0.79, p＜0.00001, I2=29%). There was no significant difference in the total incidence of AEs between two groups (730 patients, RR 0.42, 95% CI 0.14-1.31, p = 0.14, I2=84%). The common adverse events observed in the published articles were fatigue and perceived cognitive impairments. Patients who received enzalutamide had the higher risk to have the feeling of fatigue compared with abiraterone group (2555 patients, RR 0.45, 95% CI 0.24-0.85, p=0.01, I2=92%). And there was no statistical difference between two groups respect to the side effect of perceived cognitive impairments (1856 patients, RR 0.94, 95% CI 0.47-1.88, p=0.85, I2=15%)., Conclusions: Our results demonstrated that enzalutamide was associated with higher PSA response rate compared to abiraterone in patients with mCRPC, and no significant difference was found between two groups in the overall AE. But enzalutamide use induced higher risk of the AE of fatigue.

Since their introduction, tyrosine kinase inhibitors (TKIs, eg, imatinib, nilotinib, dasatinib, bosutinib, ponatinib) have revolutionized the treatment of chronic myeloid leukemia (CML). However, long-term treatment with TKIs is associated with serious adverse events including both bleeding and thromboembolism. Experimental studies have shown that TKIs can cause platelet dysfunction. Herein, we present the first side-by-side investigation comparing the effects of currently used TKIs on platelet function and thrombin generation when used in clinically relevant concentrations. A flow cytometry multiparameter protocol was used to study a range of significant platelet activation events (fibrinogen receptor activation, alpha granule, and lysosomal exocytosis, procoagulant membrane exposure, and mitochondrial permeability changes). In addition, thrombin generation was measured in the presence of TKIs to assess the effects on global hemostasis. Results show that dasatinib generally inhibited platelet function, while bosutinib, nilotinib, and ponatinib showed less consistent effects. In addition to these general trends for each TKI, we observed a large degree of interindividual variability in the effects of the different TKIs. Interindividual variation was also observed when blood from CML patients was studied ex vivo with whole blood platelet aggregometry, free oscillation rheometry (FOR), and flow cytometry. Based on the donor responses in the side-by-side TKI study, a TKI sensitivity map was developed. We propose that such a sensitivity map could potentially become a valuable tool to help in decision-making regarding the choice of suitable TKIs for a CML patient with a history of bleeding or atherothrombotic disease., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The causative chemicals responsible for nitrile rubber glove-induced allergic contact dermatitis have not been fully elucidated., Subject: This case involved a 36-year-old female, who developed an erythematous rash on her hands after one and a half months of wearing nitrile rubber gloves at her workplace., Methods: Patch tests were performed using the gloves as is, and the Japanese standard allergen 2008 and their components. The gloves were chemically analyzed and several detected substances were subjected to further patch testing., Results: The patient exhibited positive patch test reactions to nitrile rubber gloves as is, as well as to the dithiocarbamate mix and thiuram mix in the Japanese standard allergen 2008. Further patch testing revealed positive reactions to zinc diethyldithiocarbamate (ZDEC) and tetraethylthiuram disulfide (TETD) and weak positive reactions to zinc dimethyldithiocarbamate (ZDMC) and tetramethylthiuram monosulfide (TMTM). Chemical analysis revealed that ethyl isothiocyanate (EITC) and butyl isothiocyanate (BITC), which might have been produced from dithiocarbamate-type accelerators (DTCs) or thiuram-type accelerators (thiurams) during the vulcanization process, were present in the nitrile rubber gloves the patient used at her workplace, as was ZDBC. No other DTCs or thiurams were detected. Patch testing of the detected materials produced positive reactions to EITC and BITC, but not to ZDBC., Conclusion: We diagnosed the patient with allergic contact dermatitis due to the EITC and BITC present in nitrile rubber gloves, and considered that alkyl isothiocyanate might also have played a causative role. We propose that nitrile rubber gloves should be produced without using vulcanization accelerators.

Polymeric carbon nitride (PCN), which demonstrates unique properties, has been widely explored, mostly in photocatalysis; however, the evaluation of its biocompatibility is still needed. Herein, the cytocompatibility of PCN with different lateral size distributions (A-PCN with 160 nm, B-PCN with 20 nm, and C-PCN with 10 nm dominating lateral sizes) was investigated. The viability of three cell lines (L929, MCF-7, and HepG2) has been determined using cell counting kit-8 (CCK-8), neutral red uptake (NRU), and lactate dehydrogenase (LDH) leakage assays. It was found that the highest cytotoxicity of PCN was observed for flakes with a lateral size of ∼20 nm (B-PCN) in three cell lines after 48 h of exposition. The uptake process of B-PCN sheets labeled with fluorescein isothiocyanate (FITC) by cells was also the most effective. Confocal laser scanning microscopy and atomic force microscopy revealed the nanomaterial distribution throughout the cytoplasm and perinuclear region. The results demonstrated the correlation among size, internalization process, and cytocompatibility of the tested polymeric carbon nitride structures.

Background/aim: Radiotherapy (RT) with adjuvant hormone therapy (HT) improves prognosis in prostate cancer (PC) patients. Gonadotrophin-releasing hormone agonist (GnRHa) with luteinizing hormone-releasing hormone (LH-RH) analogues is the standard HT. High-dose antiandrogen therapy also improves survival in patients with locally advanced PC. The aim of this study was to compare the results of patients treated with RT plus GnRHa and patients treated with RT plus bicalutamide., Patients and Methods: Our institutional PC database was used to identify patients treated with definitive or postoperative RT +/- HT which were included in this study., Results: Three hundred and eighteen patients were retrospectively reviewed (median follow-up=56 months). Five-year biochemical relapse-free survival was 85.5% and 88.3% in patients treated with GnRHa and bicalutamide, respectively (p=0.712)., Conclusion: Bicalutamide may be offered as an adjuvant treatment to RT in patients who refuse GnRHa because of related side effects. Furthermore, our study justifies randomized trials comparing RT plus GnRHa and RT plus bicalutamide., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Prolonged courses of isavuconazole (ISA) are increasingly utilized in immunocompromised patients. Toxicities have been reported with long-term use of the other triazoles. We report the first real-life tolerability data in 50 patients with hematologic malignancy receiving ≥6 months of ISA. ISA was well tolerated in our ill patient population., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Isavuconazole is a new azole approved for adults with invasive aspergillosis and mucormycosis, with a favorable hepatic tolerability reported in Phase III trials. Here, we report on a case of drug-induced liver failure related to isavuconazole in a pediatric patient treated for invasive aspergillosis after bone marrow transplant.