Differentiation fate of a stem-like CD4 T cell controls immunity to cancer.

The T cell response to cancer controls disease progression and response to immunotherapy1-3. Despite extensive knowledge regarding CD8 T cells, how CD4 T cells contribute to this process is less well understood. Here we identified a population of PD1+TCF1+ CD4 T cells with stem-like properties that are capable of self-renewal and differentiation into canonical CD4 effector cells. Primarily residing in tumour-draining lymph nodes (TDLNs), these tumour-specific CD4 T cells are restricted by T regulatory (Treg) cells to a stem-like fate that predominantly generated induced Treg (iTreg) cells, limiting effector CD8 T cell responses to the tumour. By contrast, upon Treg depletion, stem-like CD4 T cells differentiated into T helper 1 (TH1) cells, and via IFNγ production induced robust effector differentiation from TCF1+ CD8 T cells in TDLNs, a state we defined as 'active'. Notably, enforcing TBET expression in transferred stem-like CD4 T cells was sufficient to overcome the established restricted T cell state. Despite the presence of Treg cells, endogenous stem-like CD4 T cells actively generated TH1 cells, which were required to restore TDLN effector CD8 T cell differentiation, enhance tumour control and rescue response to immunotherapy. In agreement, TH1 differentiation in patients with kidney cancer predicted successful immunotherapy responses and improved progression-free survival. Together, these findings identify a stem-like CD4 T cell population that through alternative differentiation fates controls the switch between restricted and active T cell states with implications for cancer immunotherapies.

2018 Leibovich prognostic model for renal cell carcinoma: Performance in a large population with special consideration of Black race.

BACKGROUND: The 2018 Leibovich prognostic model for nonmetastatic renal cell carcinoma (RCC) combines clinical, surgical, and pathologic factors to predict progression-free survival (PFS) and cancer-specific survival (CSS) for patients with clear cell (ccRCC), papillary (pRCC), and chromophobe (chRCC) histology. Despite high accuracy, <1% of the original cohort was Black. Here, the authors examined this model in a large population with greater Black patient representation. METHODS: By using a prospectively maintained RCC institutional database, patients were assigned Leibovich model risk scores. Survival outcomes included 5-year and 10-year PFS and CSS. Prognostic accuracy was determined using area under the curve (AUC) analysis and calibration plots. Black patient subanalyses were conducted. RESULTS: In total, 657 (29%) of 2295 patients analyzed identified as Black. Declines in PFS and CSS were observed as scores increased. Discrimination for ccRCC was strong for PFS (AUC: 5-year PFS, 0.81; 10-year PFS, 0.78) and for CSS (AUC: 5-year CSS, 0.82; 10-year CSS, 0.74). The pRCC AUC for PFS was 0.74 at 5 years and 0.71 at 10 years; and the AUC for CSS was 0.74 at 5 years and 0.70 at 10 years. In chRCC, better performance was observed for CSS (AUC at 5 years, 0.75) than for PFS (AUC: 0.66 at 5 years; 0.55 at 10 years). Black patient subanalysis revealed similar-to-improved performance for ccRCC at 5 years (AUC: PFS, 0.79; CSS, 0.87). For pRCC, performance was lower for PFS (AUC at 5 years, 0.63) and was similar for CSS (AUC at 5 years, 0.77). Sample size limited Black patient 10-year and chRCC analyses. CONCLUSIONS: The authors externally validated the 2018 Leibovich RCC prognostic model and found optimal performance for ccRCC, followed by pRCC, and then chRCC. Importantly, the results were consistent in this large representation of Black patients. PLAIN LANGUAGE SUMMARY: In 2018, a model to predict survival in patients with renal cell carcinoma (kidney cancer) was introduced by Leibovich et al. This model has performed well; however, Black patients have been under-represented in examination of its performance. In this study, 657 Black patients (29%) were included, and the results were consistent. This work is important for making sure the model can be applied to all patient populations.

Tailoring language for genitourinary function in patients with newly diagnosed prostate cancer to facilitate discussions in diverse populations and overcome health literacy barriers.

BACKGROUND: Poor comprehension of prostate cancer (PCa) medical terms can create barriers to PCa treatment discussions. The authors measured comprehension of PCa terms and its relationship to health literacy in a group of Black men who were newly diagnosed with PCa. They examined whether tailoring communication with alternative colloquial words would be helpful and acceptable. METHODS: Patients were recruited from urology clinics (N = 152). After they met with their providers to discuss PCa treatment options, they participated in an educational supplement delivered as a structured interview. The supplement tailored PCa treatment information by allowing men to choose between colloquial and medical terms for genitourinary (GU) function. Health literacy was measured using the Rapid Estimate of Adult Literacy in Medicine, and comprehension of common PCa terms was assessed using published methods. Pearson correlation was used to estimate the association between health literacy and comprehension of PCa terms. Spearman rank correlation (r) was used to assess the relation between the total number of medical terms preferred (range, 0-10) and Rapid Estimate of Adult Literacy in Medicine scores (range, 0-66). RESULTS: Most patients (62%) had low health literacy, which was strongly correlated with their understanding of PCa terms (r = 0.526; p < .001). Poor comprehension of many PCa terms established the need to use alternative language for GU function (only 20% knew the word incontinence). There was a statistically significant positive association between the number of medical terms preferred and health literacy (r = 0.358; p < .001). A majority of patients (91%) preferred a mixture of medical and colloquial terms. CONCLUSIONS: Tailoring communications with colloquial terms for GU function was preferred by most patients regardless of health literacy.

PD-L1 and nectin-4 expression and genomic characterization of bladder cancer with divergent differentiation.

BACKGROUND: Bladder cancer with divergent differentiation (BCDD) comprises a heterogenous group of tumors with a poor prognosis, and differential expression of nectin-4 and programmed death ligand-1 (PD-L1) has been reported in BCDD. Importantly, nectin-4 expression in bladder cancer is associated with response to enfortumab vedotin, and PD-L1 expression is associated with responses to immune checkpoint inhibitors (ICIs). METHODS: The authors conducted a retrospective review identifying 117 patients with advanced or metastatic BCDD who were treated at Winship Cancer Institute from 2011 to 2021. They performed immunohistochemistry staining for nectin-4 and PD-L1 expression by histologic subtype as well as genomic analysis of these patients, including RNA sequencing, whole-exome sequencing, and fusion detection analysis as well as a subgroup genomic analysis of patients with BCDD who received ICIs. RESULTS: The results indicated that nectin-4 expression was highest in the groups who had the squamous and plasmacytoid subtypes, whereas the group that had the sarcomatoid subtype (70.8%) had the highest proportion of PD-L1-positive patients. Genomic analysis yielded several key findings, including a 50% RB1 mutation rate in patients who had small cell BCDD, targetable PIK3CA mutations across multiple subtypes of BCDD, and significantly higher expression of TEC in responders to ICIs. CONCLUSIONS: In this study, the authors identified clinically relevant data on nectin-4 and PD-L1 expression in patients with rare bladder tumors. They also identified several novel findings in the genomic analysis that highlight the role of precision medicine in this population of patients. Larger, prospective studies are needed to validate these hypothesis-generating data.

Academic publishing requires linguistically inclusive policies.

Scientific knowledge is produced in multiple languages but is predominantly published in English. This practice creates a language barrier to generate and transfer scientific knowledge between communities with diverse linguistic backgrounds, hindering the ability of scholars and communities to address global challenges and achieve diversity and equity in science, technology, engineering and mathematics (STEM). To overcome those barriers, publishers and journals should provide a fair system that supports non-native English speakers and disseminates knowledge across the globe. We surveyed policies of 736 journals in biological sciences to assess their linguistic inclusivity, identify predictors of inclusivity, and propose actions to overcome language barriers in academic publishing. Our assessment revealed a grim landscape where most journals were making minimal efforts to overcome language barriers. The impact factor of journals was negatively associated with adopting a number of inclusive policies whereas ownership by a scientific society tended to have a positive association. Contrary to our expectations, the proportion of both open access articles and editors based in non-English speaking countries did not have a major positive association with the adoption of linguistically inclusive policies. We proposed a set of actions to overcome language barriers in academic publishing, including the renegotiation of power dynamics between publishers and editorial boards.

Predicting Response to Intravesical BCG in High-Risk NMIBC Using an Artificial Intelligence-Powered Pathology Assay: Development and Validation in an International 12-Center Cohort.

PURPOSE: There are few markers to identify those likely to recur or progress after treatment with intravesical bacillus Calmette-Guérin (BCG). We developed and validated artificial intelligence-based histologic assays that extract interpretable features from transurethral resection of bladder tumor digitized pathology images to predict risk of recurrence, progression, development of BCG-unresponsive disease, and cystectomy. MATERIALS AND METHODS: Pre-BCG resection-derived whole-slide images and clinical data were obtained for high-risk NMIBC cases treated with BCG from 12 centers and were analyzed through a segmentation and feature extraction pipeline. Features associated with clinical outcomes were defined and tested on independent development and validation cohorts. Cases were classified into high or low risk for recurrence, progression, BCG-unresponsive disease, and cystectomy. RESULTS: Nine hundred forty-four cases (development: 303, validation: 641, median follow-up: 36 months) representative of the intended use population were included (high-grade Ta: 34.1%, high-grade T1: 54.8%; carcinoma in situ only: 11.1%, any carcinoma in situ: 31.4%). In the validation cohort, "high recurrence risk" cases had inferior high-grade recurrence-free survival vs "low recurrence risk" cases (HR, 2.08, P < .0001). "High progression risk" patients had poorer progression-free survival (HR, 3.87, P < .001) and higher risk of cystectomy (HR, 3.35, P < .001) than "low progression risk" patients. Cases harboring the BCG-unresponsive disease signature had a shorter time to development of BCG-unresponsive disease than cases without the signature (HR, 2.31, P < .0001). AI assays provided predictive information beyond clinicopathologic factors. CONCLUSIONS: We developed and validated AI-based histologic assays that identify high-risk NMIBC cases at higher risk of recurrence, progression, BCG-unresponsive disease, and cystectomy, potentially aiding clinical decision making.

Efficacy of Intravesical Nadofaragene Firadenovec for Patients With Bacillus Calmette-Guérin-Unresponsive Nonmuscle-Invasive Bladder Cancer: 5-Year Follow-Up From a Phase 3 Trial.

PURPOSE: Nadofaragene firadenovec-vncg is a nonreplicating adenoviral vector-based gene therapy for bacillus Calmette-Guérin (BCG)-unresponsive carcinoma in situ (CIS) with/without high-grade Ta/T1. We report outcomes following 5 years of planned follow-up. MATERIALS AND METHODS: This open-label phase 3 trial (NCT02773849) enrolled patients with BCG-unresponsive nonmuscle-invasive bladder cancer in 2 cohorts: CIS ± Ta/T1 (CIS; n = 107) and Ta/T1 without CIS (Ta/T1 cohort; n = 50). Patients received 75 mL (3 × 1011 vp/mL) nadofaragene firadenovec intravesically once every 3 months with cystoscopy and cytology assessments, with continued treatment offered to those remaining high grade recurrence-free (HGRF). RESULTS: One hundred fifty-seven patients were enrolled from 33 US sites (n = 151 included in efficacy analyses). Median follow-up was 50.8 months (interquartile range 39.1-60.0), with 27% receiving ≥ 5 instillations and 7.6% receiving treatment for ≥ 57 months. Of patients with CIS 5.8% (95% CI 2.2-12.2) were HGRF at month 57, and 15% (95% CI 6.1-27.8) of patients with high-grade Ta/T1 were HGRF at month 57. Kaplan-Meier-estimated HGRF survival at 57 months was 13% (95% CI 6.9-21.5) and 33% (95% CI 19.5-46.6) in the CIS and Ta/T1 cohorts, respectively. Cystectomy-free survival at month 60 was 49% (95% CI 40.0-57.1): 43% (95% CI 32.2-53.7) in the CIS cohort and 59% (95% CI 43.1-71.4) in the Ta/T1 cohort. Overall survival at 60 months was 80% (71.0, 86.0): 76% (64.6-84.5) and 86% (70.9-93.5) in the CIS and Ta/T1 cohorts, respectively. Only 5 patients (4 with CIS and 1 with Ta/T1) experienced clinical progression to muscle-invasive disease. CONCLUSIONS: At 60 months, nadofaragene firadenovec-vncg allowed bladder preservation in nearly half of the patients and proved to be a safe option for BCG-unresponsive nonmuscle-invasive bladder cancer.

Immunotherapy for advanced or metastatic urothelial carcinoma: an abridged Cochrane review.

OBJECTIVES: To assess the effects of immunotherapy compared to chemotherapy as first- and second-line treatment of advanced or metastatic urothelial carcinoma. METHODS: Based on a published protocol, we performed a systematic search of multiple databases. Two review authors independently performed the literature selection, identified relevant studies, assessed the eligibility of studies for inclusion, and extracted data. We performed statistical analyses using a random-effects model and assessed the quality of the evidence on a per-outcome basis according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: We included five randomised controlled trials and also identified seven single-arm studies. When used as first-line therapy, immunotherapy probably has little to no effect on the risk of death from any cause compared to chemotherapy (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.87-1.07; moderate-certainty evidence). immunotherapy probably has little to no effect on health-related quality of life (mean difference [MD] 4.10, 95% CI 3.83-4.37; moderate). Immunotherapy probably reduces grade 3-5 adverse events (risk ratio [RR] 0.47, 95% CI 0.29-0.75; moderate). In the second-line setting immunotherapy may reduce the risk of death from any cause (HR 0.72, 95% CI 0.63-0.81; low). Immunotherapy may have little to no effect on health-related quality of life when compared to chemotherapy (MD 4.82, 95% CI -3.11 to 12.75; low). Immunotherapy may reduce grade 3-5 adverse events (RR 0.89, 95% CI 0.81-0.97; low). CONCLUSIONS: Compared to chemotherapy, immunotherapy has little to no effect on the risk of death from any cause in a first-line setting. Nevertheless, it may reduce the risk of death from any cause when used as second-line therapy. The health-related quality of life of participants receiving first- and second-line therapy does not appear to be affected by immunotherapy. Immunotherapy probably reduces or may reduce grade 3-5 adverse events when used as first- and second-line therapy, respectively.

Creatinine to Cystatin-C Ratio in Renal Cell Carcinoma: A Clinically Pragmatic Prognostic Factor and Sarcopenia Biomarker.

INTRODUCTION: Low creatinine to cystatin-C ratio (Cr/Cys-C) may be a biomarker for low-muscle mass. Furthermore, low Cr/Cys-C is associated with decreased overall survival (OS), but to date, has not been examined in patients with renal cell carcinoma (RCC). Our objective is to evaluate associations between low Cr/Cys-C ratio and OS and recurrence-free survival (RFS) in patients with RCC treated with nephrectomy. METHODS: We performed a retrospective review of patients with RCC treated with nephrectomy. Patients with end-stage renal disease and less than 1-year follow up were excluded. Cr/Cys-C was dichotomized at the median for the cohort (low vs. high). OS and RFS for patients with high versus low Cr/Cys-C were estimated with the Kaplan-Meier method, and associations with the outcomes of interest were modeled using Cox proportional Hazards models. Associations between Cr/Cys-C and skeletal muscle mass were assessed with correlations and logistic regression. RESULTS: A total of 255 patients were analyzed, with a median age of 64. Median (IQR) Cr/Cys-C was 1 (0.8-1.2). Low Cr/Cys-C was associated with age, female sex, Eastern Cooperative Oncology Group Performance Status ≥1, TNM stage, and tumor size. Kaplan-Meier and Cox regression analysis demonstrated an association between low Cr/Cys-C and decreased OS (HR = 2.97, 95%CI, 1.12-7.90, P =0.029) and RFS (HR = 3.31, 95%CI, 1.26-8.66, P = .015). Furthermore, a low Cr/Cys-C indicated a 2-3 increase in risk of radiographic sarcopenia. CONCLUSIONS: Lower Cr/Cys-C is associated with inferior oncologic outcomes in RCC and, pending validation, may have utility as a serum biomarker for the presence of sarcopenia in patients with RCC treated with nephrectomy.

Immune-Related Adverse Events and Clinical Outcomes in Advanced Urothelial Cancer Patients Treated With Immune Checkpoint Inhibitors.

BACKGROUND: In advanced urothelial cancers (UC), immune checkpoint inhibitors (ICI) show promise as a durable therapy. Immune-related adverse events (irAEs), a side effect of ICIs, may serve as an indicator of beneficial response. We investigated the relationship between irAEs and clinical outcomes in patients with advanced UC who received ICI. MATERIALS AND METHODS: In this retrospective study, we investigated 70 patients with advanced UC treated with ICIs at Winship Cancer Institute from 2015 to 2020. Data on patients were collected through chart review. Cox's proportional hazard model and logistic regression were applied to estimate the association with overall survival (OS), progression-free survival (PFS), and clinical benefit (CB). The possible lead-time bias was handled in extended Cox regression models. RESULTS: The median age of the cohort was 68. Over one-third (35%) of patients experienced an irAE, with skin being the most frequent organ involved (12.9%). Patients that experienced at least one irAE had significantly enhanced OS (HR: 0.38, 95% CI, 0.18-0.79, P = .009), PFS (HR: 0.27, 95% CI, 0.14-0.53, P < .001), and CB (OR: 4.20, 95% CI, 1.35-13.06, P = .013). Patients who experienced dermatologic irAEs also had significantly greater OS, PFS, and CB. CONCLUSION: Of patients with advanced UC that had undergone ICI therapy, those who had irAEs, especially dermatologic irAEs, had significantly greater OS, PFS, and CB. These results may suggest that irAE's may serve as an important marker of durable response to ICI therapy in urothelial cancer. The findings of this study need to be validated with larger cohort studies in the future.

Prostatic arterial embolisation for men with benign prostatic hyperplasia: a Cochrane review.

OBJECTIVES: To assess the effects of prostatic arterial embolisation (PAE) compared to other procedures for treatment of lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH). METHODS: We included randomised controlled trials (RCTs), as well as non-randomised studies (NRSs) enrolling men with BPH undergoing PAE vs other surgical interventions via a comprehensive search up until 8 November 2021. Two independent reviewers screened the literature, extracted data, assessed risk of bias, performed statistical analyses by using a random-effects model, and rated the certainty of evidence (CoE) of RCTs and NRSs. RESULTS: We found data to inform two comparisons: PAE vs transurethral resection of prostate (TURP; six RCTs and two NRSs), and PAE vs sham (one RCT). This abstract focuses on the primary outcomes in a comparison of PAE vs TURP. Short-term follow-up: based on RCT evidence, there may be little to no difference in urological symptom score improvement (mean difference [MD] 1.72, 95% confidence interval [CI] -0.37 to 3.81; low CoE) and quality of life (QoL; MD 0.28, 95% CI -0.28 to 0.84; low CoE) measured by International Prostatic Symptom Score. We are very uncertain about the effects of PAE on major adverse events (risk ratio [RR] 0.75, 95% CI 0.19-2.97; very low CoE). Long-term follow-up: based on RCT evidence, PAE may result in little to no difference in urological symptom scores (MD 2.58, 95% CI -1.54 to 6.71; low CoE) and QoL (MD 0.50, 95% CI -0.03 to 1.04; low CoE). We are very uncertain about major adverse events (RR 0.91, 95% CI 0.20-4.05; very low CoE). CONCLUSION: Compared to TURP, the impact on urological symptoms and QoL improvement as perceived by patients appears to be similar. This review did reveal major uncertainty as to how major adverse events compare.

Immunotherapy for advanced or metastatic urothelial carcinoma.

BACKGROUND: Immune checkpoint inhibitors are increasingly important in the treatment algorithm for locally advanced and metastatic bladder cancer. Numerous ongoing studies are investigating these agents as first- and second-line therapies, both alone and in combination with chemotherapy or in a maintenance therapy setting. OBJECTIVES: To assess the effects of immune checkpoint inhibitors compared to chemotherapy as first- and second-line treatment of advanced or metastatic urothelial carcinoma. SEARCH METHODS: We performed a comprehensive search including the Cochrane Library, MEDLINE, Embase, three other databases, several trial registers, other sources of gray literature, and conference proceedings, with no restrictions on language of publication. We limited the search period to run from 2000 until August 2022. SELECTION CRITERIA: We included randomized controlled trials (RCTs) using immunotherapy versus chemotherapy and would have considered non-randomized trials in the absence of randomized trial data. Participants had locally advanced inoperable (cT4b or N+, or both) or metastatic (M1) (or both) urothelial carcinoma of the bladder or upper urinary tract. We excluded studies of people in whom immunotherapy was used in combination with chemotherapy or in a surveillance setting. DATA COLLECTION AND ANALYSIS: Two review authors independently classified studies for inclusion and abstracted data from included studies. We performed statistical analyses using a random-effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. We used GRADE guidance to rate the certainty of evidence on a per-outcome basis. MAIN RESULTS: We included five RCTs and identified seven single-armed studies. The RCTs included 3572 participants comparing immunotherapy versus chemotherapy for the treatment of locally advanced and metastatic bladder cancer. First-line therapy Immunotherapy probably has little to no effect on the risk of death from any cause when used as first-line therapy compared to chemotherapy (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.87 to 1.07; I2 = 0%; 3 studies, 2068 participants; moderate-certainty evidence). This corresponds to 750 deaths per 1000 participants with chemotherapy and 11 fewer (45 fewer to 26 more) deaths per 1000 participants with immunotherapy at 36 months. Immunotherapy probably has little to no effect on health-related quality of life (mean difference (MD) 4.10, 95% CI 3.83 to 4.37; 1 study, 393 participants; moderate-certainty evidence), when assuming a minimal clinically important difference (MCID) of at least 6 points (using the Functional Assessment of Cancer Therapy - Bladder [FACT-BL] tool; scale 0 to 156 with higher scores representing better quality of life). Immunotherapy probably reduces adverse events grade 3 to 5 (RR 0.47, 95% CI 0.29 to 0.75; I2 = 97%; 3 studies, 2046 participants; moderate-certainty evidence). This corresponds to 908 grade 3 to 5 adverse events per 1000 participants with chemotherapy, with 481 fewer (644 fewer to 227 fewer) grade 3 to 5 adverse events per 1000 participants with immunotherapy. We found no evidence for the outcome time to death from bladder cancer. Immunotherapy probably increases the risk of time to disease progression (HR 1.33, 95% CI 1.17 to 1.50; I2 = 0%; 2 studies, 1349 participants; moderate-certainty evidence). This corresponds to 660 events per 1000 participants with chemotherapy and 102 more (57 more to 152 more) events per 1000 participants with immunotherapy at 36 months. Immunotherapy may reduce discontinuations due to adverse effects (RR 0.47, 95% CI 0.20 to 1.10; I2 = 94%; 3 studies, 2046 participants; low-certainty evidence). This corresponds to 338 discontinuations per 1000 participants with chemotherapy and 179 fewer (271 fewer to 34 more) discontinuations per 1000 participants with immunotherapy. Second-line therapy Immunotherapy may reduce the risk of death from any cause when used as second-line therapy (HR 0.72, 95% CI 0.63 to 0.81; I2 = 0%; 2 studies, 1473 participants; low-certainty evidence). This corresponds to 920 deaths per 1000 participants with chemotherapy (vinflunine, paclitaxel, docetaxel) and 59 fewer (95 fewer to 28 fewer) deaths per 1000 participants with immunotherapy at 36 months. Immunotherapy may have little to no effect on health-related quality of life when compared to chemotherapy (MD 4.82, 95% CI -3.11 to 12.75; I2 = 85%; 2 studies, 727 participants; low-certainty evidence), assuming an MCID of at least 10 points (using the EORTC QLQ tool; scale 0 to 100 with higher scores representing better quality of life). Immunotherapy may reduce adverse events grade 3 to 5 in participants undergoing second-line therapy (RR 0.89, 95% CI 0.81 to 0.97; I2 = 9%; 2 studies, 1423 participants; low-certainty evidence). This corresponds to 630 grade 3 to 5 adverse events per 1000 participants with chemotherapy and 76 fewer (126 fewer to 25 fewer) grade 3 to 5 adverse events per 1000 participants with immunotherapy. We found no evidence for the outcome of time to death from bladder cancer. We are very uncertain if immunotherapy reduces the risk of disease progression (HR 0.99, 95% CI 0.84 to 1.16; I2 = 0%; 2 studies, 1473 participants; very low-certainty evidence). Immunotherapy may reduce discontinuations due to adverse events in participants undergoing second-line therapy (RR 0.35, 95% CI 0.17 to 0.72; I2 = 69%; 2 studies, 1473 participants; low-certainty evidence). This corresponds to 110 discontinuations per 1000 participants with chemotherapy and 72 fewer (91 fewer to 31 fewer) discontinuations per 1000 participants with immunotherapy. AUTHORS' CONCLUSIONS: Compared to chemotherapy, immunotherapy for treating advanced or metastatic urothelial carcinoma probably has little to no effect on the risk of death from any cause when used as first-line therapy. Still, it may reduce the risk of death from any cause when used as second-line therapy. Health-related quality of life for participants receiving first- and second-line therapy does not appear to be affected by immunotherapy. Immunotherapy probably reduces or may reduce adverse events grade 3 to 5 when used as first- and second-line therapy, respectively.

Sarcopenia and systemic inflammation are associated with decreased survival after cytoreductive nephrectomy for metastatic renal cell carcinoma.

BACKGROUND: This study was aimed at assessing the associations of sarcopenia, muscle density, adiposity, and inflammation with overall survival (OS) after cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma. METHODS: In all, 158 patients undergoing CN from 2001 to 2014 had digitized preoperative imaging for tissue segmentation via Slice-O-Matic software (version 5.0) at the mid-L3 level. The skeletal muscle index was calculated with the skeletal muscle area (cm2 ) normalized for height (m2 ), and the skeletal muscle density (SMD) was calculated with average Hounsfield units. Adiposity was measured with the cross-sectional area (cm2 ) of visceral, subcutaneous, and intramuscular adiposity compartments and was similarly normalized for height. The average fat density was obtained in Hounsfield units. OS was estimated with the Kaplan-Meier method. Associations between body composition, inflammation metrics, and relevant clinicopathology and OS were assessed with univariable and multivariate Cox analyses. RESULTS: Seventy-six of the 158 patients (48%) were sarcopenic. Sarcopenia was associated with elevated neutrophil to lymphocyte ratios (NLRs; P = .02), increased age (P = .001), lower body mass indices (P = .009), greater modified Motzer scores (P = .019), and lower SMD (P = .006). The median OS was 15.0 and 29.4 months for sarcopenic and nonsarcopenic patients, respectively (P = .04). Elevated inflammation (NLR or C-reactive protein), in addition to sarcopenia, was independently associated with OS, with an elevated NLR ≥ 3.5 and sarcopenia associated with the poorest OS at 10.2 months. No associations were observed between measurements of muscle density or adiposity and OS. CONCLUSIONS: Sarcopenia and measures of high systemic inflammation are additively associated with inferior OS after CN and may be of use in preoperative risk stratification. LAY SUMMARY: Body composition and sarcopenia (a deficiency in skeletal musculature) have been shown to affect outcomes in cancer. We found that sarcopenic patients had poor survival in comparison with nonsarcopenic patients in the setting of metastatic renal cell carcinoma (mRCC). Patients with both elevated inflammation and sarcopenia had the poorest survival. Sarcopenia is an objective measure of nutrition that can assist in therapeutic counseling and decision-making for individualized treatment in mRCC.

Genetic and social contributions to sex differences in lifespan in Drosophila serrata.

Sex differences in lifespan remain an intriguing puzzle in evolutionary biology. While explanations range from sex differences in selection to sex differences in the expression of recessive lifespan-altering mutations (via X-linkage), little consensus has been reached. One unresolved issue is the extent to which genetic influences on lifespan dimorphism are modulated by the environment. For example, studies have shown that sex differences in lifespan can either increase or decrease depending upon the social environment. Here, we took an experimental approach, manipulating multiple axes of the social environment across inbred long- and short-lived genotypes and their reciprocal F1s in the fly Drosophila serrata. Our results reveal strong genetic effects and subtle yet significant genotype-by-environment interactions for male and female lifespan, specifically due to both population density and mating status. Further, our data do not support the idea that unconditional expression of deleterious X-linked recessive alleles in heterogametic males accounts for lower male lifespan.

Blue vs white light for transurethral resection of non-muscle-invasive bladder cancer: an abridged Cochrane Review.

OBJECTIVES: To assess the effects of blue-light (BL)-enhanced transurethral resection of bladder tumour (TURBT) compared to white-light (WL)-based TURBT in the treatment of non-muscle-invasive bladder cancer (NMIBC). METHODS: Based on a published protocol, we performed a systematic search of multiple databases from their inception to March 2021. We included randomized controlled trials (RCTs) comparing blue-light (BL) TURBT to white-light (WL) TURBT. Our meta-analysis was based on a random-effects model. We assessed the quality of evidence on a per-outcome basis according to the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach. RESULTS: We included 16 RCTs involving a total of 4325 participants in this review. BL TURBT may reduce the risk of disease recurrence over time (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.54-0.81; low-certainty evidence) depending on baseline risk. For participants with low-, intermediate- and high-risk NMIBC, this corresponded to 48 (66 fewer to 27 fewer), 109 (152 fewer to 59 fewer) and 147 (211 fewer to 76 fewer) fewer recurrences per 1000 participants when compared to WL TURBT, respectively. BL TURBT may also reduce the risk of disease progression over time (HR 0.65, 95% CI 0.50-0.84; low-certainty evidence) depending on baseline risk. For participants with low-, intermediate- and high-risk NMIBC, this corresponded to 1 (1 fewer to 0 fewer), 17 (25 fewer to 8 fewer), and 56 (81 fewer to 25 fewer) fewer progressions per 1000 participants when compared to WL TURBT, respectively. CONCLUSIONS: Our findings suggest a favourable impact of BL TURBT on the risk of disease recurrence and progression; however, whether this risk reduction is clinically relevant greatly depends on the baseline risk of patients. We did not find an increase in severe surgical complications with BL cystoscopy, and we did not find any trial evidence on other, non-surgical adverse events.

Extramammary Paget's Disease of genitourinary origin.

PURPOSE OF REVIEW: Extramammary Paget's Disease (EMPD) is an uncommon intra-epithelial malignancy, affecting primarily apocrine gland-bearing skin. EMPD is often considered an orphan diagnosis given its rarity. This review provides a contemporary overview of EMPD management. RECENT FINDINGS: The mainstay of EMPD treatment centers around a high index of suspicion to allow for an early and accurate diagnosis, wide local or Mohs micrographic surgical excision with care paid toward the margin status, and thoughtful consideration for lymphadenectomy in patients with clinically positive regional disease. There is currently no consensus regarding adjuvant therapies or systemic therapies although with ongoing improvements in tumor biology and genomics, including molecular pathways and alterations specific to EMPD, targeted or combinatorial therapies may be on the horizon. SUMMARY: Clinicians caring for patients with EMPD should seek consultation from or if feasible, consider referral to high-volume, experienced centers with patients counseled and provided with frequent and close follow-up for disease recurrence or progression. Collaboration with groups such as the Global Society for Rare Genitourinary Tumors, and especially patient groups will be vital to designing trials and collaborative databases.

Prostatic arterial embolization for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia.

BACKGROUND: A variety of minimally invasive surgical approaches are available as an alternative to transurethral resection of the prostate (TURP) for management of lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH). Prostatic arterial embolization (PAE) is a relatively new, minimally invasive treatment approach. OBJECTIVES: To assess the effects of PAE compared to other procedures for treatment of LUTS in men with BPH. SEARCH METHODS: We performed a comprehensive search the Cochrane Library, MEDLINE, Embase, three other databases, trials registries, other sources of grey literature, and conference proceedings with no restrictions on language of publication or publication status, up to 8 November 2021. SELECTION CRITERIA: We included parallel-group randomized controlled trials (RCTs), as well as non-randomized studies (NRS, limited to prospective cohort studies with concurrent comparison groups) enrolling men over the age of 40 years with LUTS attributed to BPH undergoing PAE versus TURP or other surgical interventions.  DATA COLLECTION AND ANALYSIS: Two review authors independently classified studies for inclusion or exclusion and abstracted data from the included studies. We performed statistical analyses by using a random-effects model and interpreted them according to the Cochrane Handbook for Systematic Reviews of Interventions. We used GRADE guidance to rate the certainty of evidence of RCTs and NRSs.  MAIN RESULTS: We found data to inform two comparisons: PAE versus TURP (six RCTs and two NRSs), and PAE versus sham (one RCT). Mean age was 66 years, International Prostate Symptom Score (IPSS) was 22.8, and prostate volume of participants was 72.8 mL. This abstract focuses on the comparison of PAE versus TURP as the primary topic of interest. Prostatic arterial embolization versus transurethral resection of the prostate We included six RCTs and two NRSs with short-term (up to 12 months) follow-up, and two RCTs and one NRS with long-term follow-up (13 to 24 months).  Short-term follow-up: based on RCT evidence, there may be little to no difference in urologic symptom score improvement measured by the International Prostatic Symptom Score (IPSS) on a scale from 0 to 35, with higher scores indicating worse symptoms (mean difference [MD] 1.72, 95% confidence interval [CI] -0.37 to 3.81; 6 RCTs, 360 participants; I² = 78%; low-certainty evidence). There may be little to no difference in quality of life as measured by the IPSS-quality of life question on a scale from 0 to 6, with higher scores indicating worse quality of life between PAE and TURP, respectively (MD 0.28, 95% CI -0.28 to 0.84; 5 RCTs, 300 participants; I² = 63%; low-certainty evidence). While we are very uncertain about the effects of PAE on major adverse events (risk ratio [RR] 0.75, 95% CI 0.19 to 2.97; 4 RCTs, 250 participants; I² = 24%; very low-certainty evidence), PAE likely increases retreatments (RR 3.20, 95% CI 1.41 to 7.27; 4 RCTs, 303 participants; I² = 0%; moderate-certainty evidence). PAE may make little to no difference in erectile function measured by the International Index of Erectile Function-5 on a scale from 1 to 25, with higher scores indicating better function (MD -0.50 points, 95% CI -5.88 to 4.88; 2 RCTs, 120 participants; I² = 68%; low-certainty evidence). Based on NRS evidence, PAE may reduce the occurrence of ejaculatory disorders (RR 0.51, 95% CI 0.35 to 0.73; 1 NRS, 260 participants; low-certainty evidence). Long-term follow-up: based on RCT evidence, PAE may result in little to no difference in urologic symptom scores (MD 2.58 points, 95% CI -1.54 to 6.71; 2 RCTs, 176 participants; I² = 73%; low-certainty evidence) and quality of life (MD 0.50 points, 95% CI -0.03 to 1.04; 2 RCTs, 176 participants; I² = 29%; low-certainty evidence). We are very uncertain about major adverse events (RR 0.91, 95% CI 0.20 to 4.05; 2 RCTs, 206 participants; I² = 72%; very low-certainty evidence). PAE likely increases retreatments (RR 3.80, 95% CI 1.32 to 10.93; 1 RCT, 81 participants; moderate-certainty evidence). While PAE may result in little to no difference in erectile function (MD 3.09 points, 95% CI -0.76 to 6.94; 1 RCT, 81 participants; low-certainty evidence), PAE may reduce the occurrence of ejaculatory disorders (RR 0.67, 95% CI 0.45 to 0.98; 1 RCT, 50 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: Compared to TURP, PAE may provide similar improvement in urologic symptom scores and quality of life. While we are very uncertain about major adverse events, PAE likely increases retreatment rates. While erectile function may be similar, PAE may reduce ejaculatory disorders. Certainty of evidence for the outcomes of this review was low or very low except for retreatment (moderate-certainty evidence), signaling that our confidence in the reported effect size is limited or very limited, and that this topic should be better informed by future research.

Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial.

BACKGROUND: BCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive non-muscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer. METHODS: In this phase 3, multicentre, open-label, repeat-dose study done in 33 centres (hospitals and clinics) in the USA, we recruited patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3 × 1011 viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov, NCT02773849. FINDINGS: Between Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53·4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 25 (45·5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3-4 study drug-related adverse event (two [1%] of 157 patients, both grade 3), and there were no treatment-related deaths. INTERPRETATION: Intravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state. FUNDING: FKD Therapies Oy.

Probing Pedomorphy and Prolonged Lifespan in Naked Mole-Rats and Dwarf Mice.

Pedomorphy, maintenance of juvenile traits throughout life, is most pronounced in extraordinarily long-lived naked mole-rats. Many of these traits (e.g., slow growth rates, low hormone levels, and delayed sexual maturity) are shared with spontaneously mutated, long-lived dwarf mice. Although some youthful traits likely evolved as adaptations to subterranean habitats (e.g., thermolability), the nature of these intrinsic pedomorphic features may also contribute to their prolonged youthfulness, longevity, and healthspan.