Association of Second-generation Antiandrogens With Cognitive and Functional Toxic Effects in Randomized Clinical Trials: A Systematic Review and Meta-analysis.

Importance: The use of second-generation antiandrogens (AAs) in the treatment of prostate cancer is increasing. Retrospective evidence suggests an association between second-generation AAs and adverse cognitive and functional outcomes, but further data from prospective trials are needed. Objective: To examine whether evidence from randomized clinical trials (RCTs) in prostate cancer supports an association between second-generation AAs and cognitive or functional toxic effects. Data Sources: PubMed, EMBASE, and Scopus (inception to September 12, 2022). Study Selection: Randomized clinical trials of second-generation AAs (abiraterone, apalutamide, darolutamide, or enzalutamide) among individuals with prostate cancer that reported cognitive toxic effects, asthenic toxic effects (eg, fatigue, weakness), or falls were evaluated. Data Extraction and Synthesis: Study screening, data abstraction, and bias assessment were completed independently by 2 reviewers following the Preferred Reporting Items for Systematic Reviews and Meta-analyses and Enhancing the Quality and Transparency of Health Research reporting guidelines. Tabular counts for all-grade toxic effects were determined to test the hypothesis formulated before data collection. Main Outcomes and Measures: Risk ratios (RRs) and SEs were calculated for cognitive toxic effects, asthenic toxic effects, and falls. Because fatigue was the asthenic toxic effect extracted from all studies, data on fatigue are specified in the results. Meta-analysis and meta-regression were used to generate summary statistics. Results: The systematic review included 12 studies comprising 13 524 participants. Included studies had a low risk of bias. An increased risk of cognitive toxic effects (RR, 2.10; 95% CI, 1.30-3.38; P = .002) and fatigue (RR, 1.34; 95% CI, 1.16-1.54; P < .001) was noted among individuals treated with second-generation AAs vs those in the control arms. The findings were consistent in studies that included traditional hormone therapy in both treatment arms for cognitive toxic effects (RR, 1.77; 95% CI, 1.12-2.79; P = .01) and fatigue (RR, 1.32; 95% CI, 1.10-1.58; P = .003). Meta-regression supported that, across studies, increased age was associated with a greater risk of fatigue with second-generation AAs (coefficient, 0.75; 95% CI, 0.04-0.12; P < .001). In addition, the use of second-generation AAs was associated with an increased risk of falls (RR, 1.87; 95% CI, 1.27-2.75; P = .001). Conclusions and Relevance: The findings of this systematic review and meta-analysis suggest that second-generation AAs carry an increased risk of cognitive and functional toxic effects, including when added to traditional forms of hormone therapy.

Green nail syndrome complicated by pseudomonal keratitis in a teenager with artificial nails.

Green nail syndrome (GNS) is a pseudomonal nail infection that presents with characteristic green nail discoloration. It typically affects patients with preexisting nail conditions or chronic exposure to wet environments but can also be seen with local trauma. Our patient presented with a pseudomonal corneal ulcer of the left eye and was incidentally found to have GNS, which developed after home artificial nail application. This unusual case of extensive pediatric GNS illustrates a rare and serious infectious complication of prolonged artificial nails.

An infant with LUMBAR syndrome complicated by severe perineal ulceration managed with diverting colostomy.

Infantile hemangiomas are the most common childhood vascular lesions. LUMBAR syndrome (lower body hemangioma, urogenital abnormalities/ulceration, myelopathy, bony deformities, anorectal malformations/arterial anomalies, and rectal anomalies) warrants special treatment considerations. Here we describe a case of an infant with LUMBAR syndrome who presented with severe perineal ulceration refractory to standard medical therapy and was managed with a temporary diverting sigmoid colostomy. This case demonstrates that adjunctive surgical management can be considered in infants with aggressive perineal wounds refractory to standard medical therapy.

Association of clonal hematopoiesis mutations with clinical outcomes: A systematic review and meta-analysis.

Clonal hematopoiesis (CH) mutations are common among individuals without known hematologic disease. CH mutations have been associated with numerous adverse clinical outcomes across many different studies. We systematically reviewed the available literature for clinical outcomes associated with CH mutations in patients without hematologic disease. We searched PubMed, EMBASE, and Scopus for eligible studies. Three investigators independently extracted the data, and each study was verified by a second author. Risk of bias was assessed using the Newcastle-Ottawa Scale. We identified 32 studies with 56 cohorts that examine the association between CH mutations and clinical outcomes. We conducted meta-analyses comparing outcomes among individuals with and without detectable CH mutations. We conducted meta-analyses for cardiovascular diseases (nine studies; HR = 1.61, 95% CI = 1.26-2.07, p = .0002), hematologic malignancies (seven studies; HR = 5.59, 95% CI = 3.31-9.45, p < .0001), therapy-related myeloid neoplasms (four studies; HR = 7.55, 95% CI = 4.3-13.57, p < .001), and death (nine studies; HR = 1.34, 95% CI = 1.2-1.5, p < .0001). The cardiovascular disease analysis was further stratified by variant allele fraction (VAF) and gene, which showed a statistically significant association only with a VAF of ≥ 10% (HR = 1.42, 95% CI = 1.24-1.62, p < .0001), as well as statistically significant associations for each gene examined with the largest magnitude of effect found for CH mutations in JAK2 (HR = 3.5, 95% CI = 1.84-6.68, p < .0001). Analysis of the association of CH mutations with hematologic malignancy demonstrated a numeric stepwise increase in risk with increasing VAF thresholds. This analysis strongly supports the association of CH mutations with a clinically meaningful increased risk of adverse clinical outcomes among individuals without hematologic disease, particularly with increasing VAF thresholds.

Association of Second-generation Antiandrogens With Depression Among Patients With Prostate Cancer.

Importance: Previous studies have shown a consistent association between hormone therapy (HT), such as androgen deprivation therapy, to treat prostate cancer and depression risk. However, the association between second-generation antiandrogens (AAs) and depression is unknown. Objective: To test the a priori hypothesis that second-generation AAs are associated with an increased risk of depression, including compared with traditional forms of HT. Design, Setting, and Participants: This retrospective cohort study analyzed patients aged 66 years and older who were diagnosed with prostate cancer without a second cancer in 12 months from January 2011 to December 2015. Patients with continuous Medicare Parts A, B, and D coverage were included. Individuals who received any form of HT prior to prostate cancer diagnosis and those previously diagnosed with depression were excluded. Data were collected from the Surveillance, Epidemiology, and End Results-Medicare and Texas Cancer Registry-Medicare linked databases. Data were analyzed from February to May 2021. Exposures: The following treatment groups were compared: (1) no HT group, (2) traditional HT group (HT without second-generation AA exposure), and (3) second-generation AA group. Main Outcomes and Measures: Risk of depression in the second-generation AA group compared with the no HT and traditional HT groups, determined prior to data collection, stratified by diagnosis stage. Results: Of 210 804 patients diagnosed with prostate cancer during the study window, 30 069 men (11 484 [38%] aged 66-70 years; 22 594 [75%] White) who met inclusion criteria were identified. Overall, 17 710 (59%) received no HT, 11 311 (38%) received traditional HT only, and 1048 (3%) received a second-generation AA. Those receiving a second-generation AA were more likely to be older (aged ≥81 years: second-generation AA group, 246 [24%]; traditional HT group, 1997 [18%]; no HT group, 1173 [7%]) and present with advanced disease (eg, distant disease: second-generation AA group, 562 [24%]; traditional HT group, 876 [8%]; no HT group, 129 [0.7%]). Multivariable Cox proportional hazards analysis showed that the second-generation AA group had an increased risk of depression compared with the no HT group (hazard ratio [HR], 2.15; 95% CI, 1.79-2.59; P < .001) and the traditional HT group (HR, 2.26; 95% CI, 1.88-2.73; P < .001), including specifically among those with metastatic disease at diagnosis (HR, 2.40; 95% CI, 1.38-4.15; P = .002). Conclusions and Relevance: In this cohort study, patients with prostate cancer who received a second-generation AA had a large and clinically significant increased risk of depression compared with patients who received traditional HT alone or no HT, including when limiting our analysis to individuals with metastatic disease at diagnosis.

Association of statin use with clinical outcomes in patients with triple-negative breast cancer.

BACKGROUND: Previous studies have examined the association of statin therapy and breast cancer outcomes with mixed results. The objective of this study was to investigate the clinical effects of incident statin use among individuals with triple-negative breast cancer (TNBC). METHODS: Data from the Surveillance, Epidemiology, and End Results-Medicare and Texas Cancer Registry-Medicare databases were used, and women aged ≥66 years who had stage I, II, and III breast cancer were identified. Multivariable Cox proportional hazards regression models were used to examine the association of new statin use in the 12 months after a breast cancer diagnosis with overall survival (OS) and breast cancer-specific survival (BCSS). RESULTS: When examining incident statin use, defined as the initiation of statin therapy in the 12 months after breast cancer diagnosis, a significant association was observed between statin use and improved BCSS (standardized hazard ratio, 0.42; 95% confidence interval [CI], 0.20-0.88; P = .022) and OS (hazard ratio, 0.70; 95% CI, 0.50-0.99; P = .046) among patients with TNBC (n = 1534). No association was observed with BCSS (standardized hazard ratio, 0.99; 95% CI, 0.71-1.39; P = .97) or OS (hazard ratio, 1.04; 95% CI, 0.92-1.17; P = .55) among those without TNBC (n = 15,979). The results were consistent when examining statin exposure as a time-varying variable. CONCLUSIONS: Among women with I, II, and III TNBC, initiation of statin therapy in the 12 months after breast cancer diagnosis was associated with an OS and BCSS benefit. Statins may have a role in select patients with breast cancer, and further investigation is warranted.