Management of Localized Prostate Cancer in Men With Human Immunodeficiency Virus: Analysis of a Large Retrospective Cohort.

INTRODUCTION: We aimed to characterize the clinicopathological characteristics and outcomes of HIV-positive patients with clinically localized, prostate cancer (PCa). METHODS: A retrospective study was conducted of HIV-positive patients from a single institution with elevated PSA and diagnosis of PCa by biopsy. PCa features, HIV characteristics, treatment type, toxicities, and outcomes were analyzed by descriptive statistics. Kaplan-Meier analysis was used to determine progression-free survival (PFS). RESULTS: Seventy-nine HIV-positive patients were included with a median age at PCa diagnosis of 61 years-old and median duration from HIV infection to PCa diagnosis of 21 years. The median PSA level at diagnosis and Gleason Score was 6.85 ng/mL and 7, respectively. The 5-year PFS was 82.5% with the lowest survival observed in patients treated with radical prostatectomy (RP) + radiation therapy (RT), followed by cryosurgery (CS). There were no reports of PCa-specific deaths, and the 5-year overall survival was 97.5%. CD4 count declined post-treatment in pooled treatment groups that included RT (P = .02). CONCLUSION: We present the characteristics and outcomes of the largest cohort of HIV-positive men with prostate cancer in published literature. RP and RT ± ADT is well-tolerated in HIV-positive patients with PCa as seen by the adequate biochemical control and mild toxicity. CS resulted in worse PFS compared to alternative treatments for patients within the same PCa risk group. A decline in CD4 counts was observed in patients treated RT, and further studies are needed to investigate this relationship. Our findings support the use of standard-of-care treatment for localized PCa in HIV-positive patients.

Prostate Cancer Outcomes in Patients Living With HIV/AIDS Treated With Radiation Therapy: A Systematic Review.

Purpose: A consensus has not been reached regarding the treatment and outcomes of prostate cancer (PCa) in people living with HIV/AIDS (PLWHA). This systematic review aims to summarize the evidence on the management of PCa with radiation therapy (RT) in PLWHA diagnosed with PCa. Methods and Materials: Searches were conducted in the PubMed, Cochrane Library, and Scopus databases during September 2021 using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Articles reporting on outcomes of PLWHA treated for PCa with definitive RT were sought for inclusion. Results: A total of 9 studies with 187 patients with HIV who received diagnoses of PCa met inclusion criteria. The duration of HIV infection to PCa diagnosis ranged from 8.5 to 18.6 years with 69% to 100% of patients on highly active antiretroviral therapy at the time of diagnosis. Patients' prostate-specific antigen levels ranged from 8 to 82 ng/mL. The majority of patients (59%) were treated with external beam RT, followed by brachytherapy (20.5%). The 4- or 5-year biochemical failure-free rate was reported to be between 87% and 97% in 3 studies, and 2 studies reported an 84% to 97% 5-year cancer-specific survival. Using Common Terminology Criteria for Adverse Events criteria, 3 studies reported toxicities and grade 3 toxicity was observed in only 2 patients. Conclusions: RT is efficacious and well tolerated in PLWHA as supported by the comparable biochemical control, clinical outcome, and mortality to the general population as well as by the mild reports of radiotoxicity. There is mixed evidence regarding the effect of RT on CD4 count and viral load, and further studies are needed to better understand this relationship. These findings support the use of definitive RT in PLWHA with PCa.

Caspases and therapeutic potential of caspase inhibitors in moderate-severe SARS-CoV-2 infection and long COVID.

BACKGROUND: COVID-19 can present with lymphopenia and extraordinary complex multiorgan pathologies that can trigger long-term sequela. AIMS: Given that inflammasome products, like caspase-1, play a role in the pathophysiology of a number of co-morbid conditions, we investigated caspases across the spectrum of COVID-19 disease. MATERIALS & METHODS: We assessed transcriptional states of multiple caspases and using flow cytometry, the expression of active caspase-1 in blood cells from COVID-19 patients in acute and convalescent stages of disease. Non-COVID-19 subject presenting with various comorbid conditions served as controls. RESULTS: Single-cell RNA-seq data of immune cells from COVID-19 patients showed a distinct caspase expression pattern in T cells, neutrophils, dendritic cells, and eosinophils compared with controls. Caspase-1 was upregulated in CD4+ T-cells from hospitalized COVID-19 patients compared with unexposed controls. Post-COVID-19 patients with lingering symptoms (long-haulers) also showed upregulated caspase-1activity in CD4+ T-cells that ex vivo was attenuated with a select pan-caspase inhibitor. We observed elevated caspase-3/7levels in red blood cells from COVID-19 patients compared with controls that was reduced following caspase inhibition. DISCUSSION: Our preliminary results suggest an exuberant caspase response in COVID-19 that may facilitate immune-related pathological processes leading to severe outcomes. Further clinical correlations of caspase expression in different stages of COVID-19 will be needed. CONCLUSION: Pan-caspase inhibition could emerge as a therapeutic strategy to ameliorate or prevent severe COVID-19.

Defective IgA response to atypical intestinal commensals in IL-21 receptor deficiency reshapes immune cell homeostasis and mucosal immunity.

Despite studies indicating the effects of IL-21 signaling in intestinal inflammation, its roles in intestinal homeostasis and infection are not yet clear. Here, we report potent effects of commensal microbiota on the phenotypic manifestations of IL-21 receptor deficiency. IL-21 is produced highly in the small intestine and appears to be critical for mounting an IgA response against atypical commensals such as segmented filamentous bacteria and Helicobacter, but not to the majority of commensals. In the presence of these atypical commensals, IL-21R-deficient mice exhibit reduced numbers of germinal center and IgA+ B cells and expression of activation-induced cytidine deaminase in Peyer's patches as well as a significant decrease in small intestine IgA+ plasmablasts and plasma cells, leading to higher bacterial burdens and subsequent expansion of Th17 and Treg cells. These microbiota-mediated secondary changes in turn enhance T cell responses to an oral antigen and strikingly dampen Citrobacter rodentium-induced immunopathology, demonstrating a complex interplay between IL-21-mediated mucosal immunity, microbiota, and pathogens.