Adjuvant immunotherapy in high-risk muscle invasive urothelial carcinoma: A systematic review and meta-analysis of randomized clinical trials.

Despite surgical resection, many patients with muscle invasive urothelial carcinoma (MIUC) experience recurrence. Adjuvant immune checkpoint inhibition (ICI) following radical resection in patients with MIUC demonstrates disparate outcomes among phase III randomized controlled trials (RCTs). Our objective was to synthesize available data regarding the disease-free survival (DFS) benefit of adjuvant ICIs for patients with MIUC and evaluate the overall safety profile of ICIs in this setting. The protocol was registered with PROSPERO, CRD42022352587. We searched MEDLINE, Embase, CENTRAL, and relevant conference proceedings from inception up to January 29, 2024. Only phase III RCTs comparing adjuvant ICI versus placebo/observation were selected. Study screening and selection, along with data extraction was performed in duplicate according to a predefined registered protocol. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was used. Quality assessment was performed using the Cochrane risk-of-bias (RoB 2) tool for randomized trials. The primary and secondary endpoints were DFS and serious adverse events, respectively. All outcomes were analyzed using random-effects meta-analysis owing to inter-study heterogeneity. Sensitivity and subgroup analyses were performed to identify potential sources of heterogeneity. A priori defined subgroups of interest included positive program death-ligand 1 (PD-L1) expression, previous use of neoadjuvant chemotherapy (NAC), primary tumor origin, pathologic lymph node status, and baseline Eastern Cooperative Oncology Group performance status. Pooled results across the 3 RCTs (2,220 patients) demonstrated significantly improved DFS for patients treated with ICI in the intention-to-treat cohorts (HR 0.76, 95% CI 0.65-0.90). There was considerable clinical and statistical heterogeneity (I2 = 44%) due to differences in inclusion criteria and interventions. Overall, there was a low risk of bias among the RCTs. Regarding subgroup analyses, there was significant benefit among patients with negative PD-L1 expression (HR 0.76, 95% CI 0.64-0.90), those who received prior NAC (HR 0.69, 95% CI 0.52-0.91), and patients with lower tract (HR 0.71, 95% CI 0.55-0.92) but not upper tract disease (HR 1.21, 95% CI 0.87-1.68). This pooled analysis of DFS and safety provides support for ICI utilization in the setting of high-risk resected MIUC.

Evaluation of passive samplers as a cost-effective method to predict the impact of wildfire smoke in grapes and wines.

Wildfire smoke exposure alters grape composition, potentially resulting in "smoke tainted" wines. This has been correlated with elevated levels of smoke-derived volatile phenols (VPs) in grapes and wines. This work sought to create a predictive tool that could correlate levels of VPs in smoke with concentrations in grapes and wines. Therefore, passive samplers and Cabernet Sauvignon grapes were intentionally exposed to various smoke intensities, and wines were made thereafter. As expected, concentrations of VPs in grapes and wines were positively associated with the intensity of smoke exposure. Interestingly, levels of guaiacol in the passive samplers had a strong positive correlation with concentrations in grapes (R2 = 0.9999) and wines (R2 = 0.9998). The passive samplers were able to accurately predict guaiacol levels in smoke exposed grapes and wines with percent errors ranging from 0.08 to 11.3 %. These results suggest the capability of passive samplers to act as a monitoring system in vineyards during smoke events.

Association Between Surgeon Sex and Days Alive at Home Following Surgery: A Population-Based Cohort Study.

Objective: The objective of this study was to measure potential associations between surgeon sex and number of days alive and at home (DAH). Background: Patients treated by female surgeons appear to have lower rates of mortality, complications, readmissions, and healthcare costs when compared with male surgeons. DAH is a validated measure, shown to better capture the patient experience of postoperative recovery. Methods: We conducted a retrospective study of adults (≥18 years of age) undergoing common surgeries between January 01, 2007 and December 31, 2019 in Ontario, Canada. The outcome measures were the number of DAH within 30-, 90-, and 365-days. The data was summarized using descriptive statistics and adjusted using multivariable generalized estimating equations. Results: During the study period, 1,165,711 individuals were included, of which 61.9% (N = 721,575) were female. Those managed by a female surgeon experienced a higher mean number of DAH when compared with male surgeons at 365 days (351.7 vs. 342.1 days; P < 0.001) and at each earlier time point. This remained consistent following adjustment for covariates, with patients of female surgeons experiencing a higher number of DAH at all time points, including at 365 days (343.2 [339.5-347.1] vs. 339.4 [335.9-343.0] days). Multivariable regression modeling revealed that patients of male surgeons had a significantly lower number of DAH versus female surgeons. Conclusions: Patients of female surgeons experienced a higher number of DAH when compared with those treated by male surgeons at all time points. More time spent at home after surgery may in turn lower costs of care, resource utilization, and potentially improve quality of life. Further studies are needed to examine these findings across other care contexts.

Association of chronic kidney disease with postoperative outcomes: a national surgical quality improvement program (NSQIP) multi-specialty surgical cohort analysis.

BACKGROUND: Chronic kidney disease (CKD) is associated with higher incidence of major surgery. No studies have evaluated the association between preoperative kidney function and postoperative outcomes across a wide spectrum of procedures. We aimed to evaluate the association between CKD and 30-day postoperative outcomes across surgical specialties. METHODS: We selected adult patients undergoing surgery across eight specialties. The primary study endpoint was major complications, defined as death, unplanned reoperation, cardiac complication, or stroke within 30 days following surgery. Secondary outcomes included Clavien-Dindo high-grade complications, as well as cardiac, pulmonary, infectious, and thromboembolic complications. Multivariable regression was performed to evaluate the association between CKD and 30-day postoperative complications, adjusted for baseline characteristics, surgical specialty, and operative time. RESULTS: In total, 1,912,682 patients were included. The odds of major complications (adjusted odds ratio [aOR] 2.14 [95% confidence interval (CI): 2.07, 2.21]), death (aOR 3.03 [95% CI: 2.88, 3.19]), unplanned reoperation (aOR 1.57 [95% CI: 1.51, 1.64]), cardiac complication (aOR 3.51 [95% CI: 3.25, 3.80]), and stroke (aOR 1.89 [95% CI: 1.64, 2.17]) were greater for patients with CKD stage 5 vs. stage 1. A similar pattern was observed for the secondary endpoints. CONCLUSION: This population-based study demonstrates the negative impact of CKD on operative outcomes across a diverse range of procedures and patients.

Effect of concomitant medications on treatment response and survival in non-metastatic castrate resistant prostate cancer: Exploratory analysis of the SPARTAN trial.

BACKGROUND: We performed an exploratory analysis of the SPARTAN trial to determine whether concomitant exposure to several classes of commonly prescribed medications influenced the effect of apalutamide on overall survival (OS) and metastasis-free survival (MFS) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). PATIENTS AND METHODS: SPARTAN was a phase III randomized controlled trial in which nmCRPC patients were randomly assigned in a 2:1 ratio to receive androgen deprivation therapy with or without apalutamide. We focused on 5 commonly prescribed classes of medications: metformin, statins, angiotensin converting enzyme inhibitors (ACEI), acetylsalicylic acid (ASA), and proton pump inhibitors (PPI) based on a plausible biological and clinical rationale. To determine the potential effect modification, we applied multivariable Cox regression models for OS and MFS separately with additional interaction terms. To determine the independent association of concomitant medications with OS and MFS, we used IPTW-based log-rank test. A 2-sided p < 0.01 was considered statistically significant. RESULTS: We did not find statistically significant differences in effect from apalutamide on OS across subgroups stratified by concomitant exposure to any of the medication classes. While there was some difference in the treatment effect from apalutamide on MFS between patients with concomitant statins (adjusted hazard ratio [aHR]: 0.20; 95 % CI: 0.15-0.28) versus without concomitant statins (aHR: 0.31 [0.24-0.39]), this did not reach the pre-specified threshold of statistical significance (p = 0.011). On IPTW-based analysis, patients treated concomitantly with metformin (median: not reached versus 31 months; p = 0.002), or ACEI (median: 37 versus 29 months, p = 0.006) had significantly improved MFS. CONCLUSIONS: In this post-hoc exploratory analysis of SPARTAN, effects of apalutamide on MFS and OS were consistent across subgroups stratified by exposure to concomitant medications. Exposure to concomitant metformin and ACEI was independently associated with a significant improvement in MFS.

Opportunities for optimizing fungal biological control agents for long-term and effective management of insect pests of orchards and vineyards: a review.

Novel tactics for controlling insect pests in perennial fruit and nut crops are needed because target pests often display decreased susceptibility to chemical controls due to overreliance on a handful of active ingredients and regulatory issues. As an alternative to chemical controls, entomopathogenic fungi could be utilized as biological control agents to manage insect pest populations. However, development of field ready products is hampered by a lack of basic knowledge. Development of field ready products requires collecting, screening, and characterizing a greater variety of potential entomopathogenic fungal species and strains. Creation of a standardized research framework to study entomopathogenic fungi will aid in identifying the potential mechanisms of biological control activity that fungi could possess, including antibiotic metabolite production; strains and species best suited to survive in different climates and agroecosystems; and optimized combinations of entomopathogenic fungi and novel formulations. This mini review therefore discusses strategies to collect and characterize new entomopathogenic strains, test different potential mechanisms of biocontrol activity, examine ability of different species and strains to tolerate different climates, and lastly how to utilize this information to develop strains into products for growers.

5-α Reductase Inhibitors and Prostate Cancer Mortality.

Importance: 5-alpha-reductase-inhibitors (5-ARIs) are approved for treating benign prostatic hyperplasia (BPH) and have been found to reduce prostate cancer (PCa) risk by 25%. However, trials also have shown 5-ARIs to be associated with high-grade PCa. Whether 5-ARIs increase mortality among those with a diagnosis of PCa remains unclear. Objective: To determine long-term outcomes of clinically localized PCa arising in individuals taking 5-ARIs compared with nonusers. Design, Setting, and Participants: This population-based cohort study was conducted between January 2003 and October 2017. Eligible participants were men aged 65 years or older in Ontario, Canada, who developed clinically localized PCa with complete pathological abstraction from the Ontario Health Administrative Databases. Data analysis occurred from November 2017 to November 2022. Exposure: 5-ARIs before PCa diagnosis. Main Outcomes and Measures: The primary outcomes were overall mortality and PCa-specific mortality. Cause-specific hazard models with inverse probability treatment weights (IPTW) were used to examine associations of 5-ARI use with mortality outcomes. Sensitivity analyses based on prediagnostic 5-ARI use, Gleason score, comorbidity, 5-ARI indication, prostate-specific antigen modeling, and statin use were also performed. Results: The cohort included 19 938 patients with PCa. Of these, 2112 (10.6%; median [IQR] age, 74 [70-79] years) were 5-ARI users and 17 826 (89.4%; median [IQR] age, 71 [68-76] years) were nonusers. During a median (IQR) follow-up of 8.96 (6.28-12.17) years, 6053 (30.4%) died, including 1047 (5.3%) from PCa. 5-ARI use appeared to be associated with increased overall and PCa specific mortality in crude analyses; however, after IPTW, 5-ARI use was not associated with overall mortality (hazard ratio, 0.98; 95% CI, 0.90-1.07; P = .77) or PCa-specific mortality (hazard ratio, 1.02; 95% CI, 0.83-1.25; P = .84). Conclusions and Relevance: In this population-based cohort study of 5-ARI use prior to PCa diagnosis including long-term follow-up and clinicopathologic details, prediagnostic 5-ARI use was not associated with PCa-specific or all-cause mortality. This study offers reassuring safety data for patients using 5-ARIs before PCa diagnosis for both BPH and chemopreventive reasons.

Canadian Association of Radiologists Genitourinary Imaging Referral Guideline.

The Canadian Association of Radiologists (CAR) Genitourinary Expert Panel is made up of physicians from the disciplines of radiology, emergency medicine, family medicine, nephrology, and urology, a patient advisor, and an epidemiologist/guideline methodologist. After developing a list of 22 clinical/diagnostic scenarios, a rapid scoping review was undertaken to identify systematically produced referral guidelines that provide recommendations for one or more of these clinical/diagnostic scenarios. Recommendations from 30 guidelines and contextualization criteria in the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) for guidelines framework were used to develop 65 recommendation statements across the 22 scenarios (2 scenarios point to the CAR Obstetrics and Gynecology Diagnostic Imaging Referral Guideline). This guideline presents the methods of development and the referral recommendations for haematuria, hypertension, renal disease (or failure), renal colic, renal calculi in the absence of acute colic, renal lesion, urinary tract obstruction, urinary tract infection, scrotal mass, or pain, including testicular torsion, adrenal mass, incontinence, urgency, and frequency, chronic pelvic pain, elevated PSA, infertility, and pelvic floor.

Protocol for Delivery of CRISPR/dCas9 Systems for Epigenetic Editing into Solid Tumors Using Lipid Nanoparticles Encapsulating RNA.

Genome editing tools, particularly the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) systems (e.g., CRISPR/Cas9), and their repurposing into epigenetic editing platforms, offer enormous potential as safe and customizable therapies for cancer. Specifically, various transcriptional abnormalities in human malignancies, such as silencing of tumor suppressors and ectopic re-expression of oncogenes, have been successfully targeted with virtually no off-target effects using CRISPR activation and repression systems. In these systems, the nuclease-deactivated Cas9 protein (dCas9) is fused to one or more domains inducing selective activation or repression of the targeted genes. Despite these advances, the efficient in vivo delivery of these molecules into the target cancer cells represents a critical barrier to accomplishing translation into a clinical therapy setting for cancer. Major obstacles include the large size of dCas9 fusion proteins, the necessity of multimodal delivery of protein and gRNAs, and the potential of these formulations to elicit detrimental immune responses.In this context, viral methods for delivering CRISPR face several limitations, such as the packaging capacity of the viral genome, the potential for integration of the nucleic acids into the host cells genome, and immunogenicity of viral proteins, posing serious safety concerns. The rapid development of mRNA vaccines in response to the COVID-19 pandemic has rekindled interest in mRNA-based approaches for CRISPR/dCas9 delivery. Simultaneously, due to their high loading capacity, scalability, customizable surface modification for cell targeting, and low immunogenicity, lipid nanoparticles (LNPs) have been widely explored as nonviral vectors. In this chapter, we first describe the design of optimized dCas9-effector mRNAs and gRNAs for epigenetic editing. We outline formulations of LNPs suitable for dCas9 mRNA delivery. Additionally, we provide a protocol for the co-encapsulation of the dCas9-effector mRNAs and gRNA into these LNPs, along with detailed methods for delivering these formulations to both cell lines (in vitro) and mouse models of breast cancer (in vivo).

Early Prostate-Specific Antigen Response by 6 Months Is Predictive of Treatment Effect in Metastatic Hormone Sensitive Prostate Cancer: An Exploratory Analysis of TITAN Trial.

PURPOSE: Early PSA response has been found to be prognostic of outcomes in metastatic hormone sensitive prostate cancer. We performed a secondary analysis of the TITAN trial to determine if early PSA response was predictive of treatment efficacy in metastatic hormone sensitive prostate cancer patients. MATERIALS AND METHODS: Early PSA response was defined as achieving a PSA level of ≤ 0.2 ng/mL by 6 months of random assignment. A Cox proportional hazard model was constructed in a landmark population with an interaction term between the treatment and early PSA response to determine differential treatment effect on overall survival (OS). We applied multivariable Cox proportional hazard regression model with time to early PSA response fitted with restricted cubic spline to determine the association of time to early PSA response with OS. RESULTS: Approximately 24% (124/524) of patients in the androgen deprivation therapy (ADT) alone group and 61% (321/524) in the apalutamide group had PSA response ≤ 0.2 ng/mL by 6 months. Longer time to early PSA response was associated with significantly superior OS in the apalutamide group. There was a significant difference in treatment effect from apalutamide on OS (P = .03 for interaction) among 6-month PSA responders (HR: 0.66; 95% CI: 0.44-1.00) vs nonresponders (HR: 1.14; 95% CI: 0.89-1.46). This difference in treatment effect was not statistically significant at 3 months (P = .17 for interaction). Among 6-month PSA responders, 3-year confounder-adjusted OS was 84% (80%-88%) for the apalutamide group and 74% (66%-82%) for the ADT alone group. Among nonresponders, 3-year adjusted OS for the 2 treatment arms were 58% (52%-65%) and 56% (51%-60%), respectively. CONCLUSIONS: Early PSA response by 6 months was a predictor of treatment efficacy from ADT plus apalutamide on OS. Longer time to early PSA response was associated with superior OS in the apalutamide arm.

Financial Distress in Genitourinary Cancer: Insights From CDC National Health Interview Survey.

PURPOSE: This study leverages CDC National Health Interview Survey data to examine Financial Distress (FD) among genitourinary (GU) cancer survivors, specifically prostate cancer (PC), kidney cancer (KC), and bladder cancer (BC). It investigates the economic impacts faced by these patients, especially in relation to disparities in insurance coverage and its effects on material, psychological, and behavioral aspects of FD. METHODS: We retrospectively analyzed responses from GU cancer survivors, stratifying by cancer status and age (18-64 years, ≥65 years). Medical financial hardship was divided into three domains: material, psychological, and behavioral. Associations between cancer history, hardship, and clinical factors were assessed using generalized ordinal logistic regressions. RESULTS: Significant health care access disparities were found, particularly for mental health services, with 25% of younger BC survivors and 4.7% of younger KC survivors reporting affordability issues, in contrast to 2.7% of noncancer individuals. Dental care was also problematic, with higher avoidance rates among younger BC (27%) and KC (15%) survivors compared with the general population. Surprisingly, noncancer individuals reported more difficulty in affording prescriptions than BC survivors across both age groups. PC survivors, however, showed lower FD across all domains versus noncancer controls, indicating fewer concerns about medical bills and a lesser tendency to forgo care. CONCLUSION: The study underscores significant gaps in the financial support system for GU cancer survivors, with urgent needs in mental and dental health care access. Policy interventions, including comprehensive insurance reforms, are imperative to alleviate the financial burdens on these individuals.

Superstition in Surgery: A Population-Based Cohort Study to Assess the Association Between Surgery on Friday the 13th and Postoperative Outcomes.

Objective: We sought to examine whether the outcomes of patients who receive a surgical procedure on Friday the 13th differ from patients who receive surgery on flanking Fridays. Background: Numerous studies have demonstrated that increased anxiety from the provider or patient around the time of surgery can lead to worse outcomes. Superstitious patients often express significant concern and anxiety when undergoing a surgical procedure on Friday the 13th. Methods: A retrospective, population-based cohort study of 19,747 adults undergoing 1 of 25 common surgical procedures on Friday the 13th or flanking control Fridays (Friday the 6th and Friday the 20th) between January 1, 2007, and December 31, 2019, with 1 year of follow-up. The main outcomes included death, readmission, and complications at 30 days (short-term), 90 days (intermediate-term), and 1 year (long-term). Results: A total of 7,349 (37.2%) underwent surgery on Friday the 13th, and 12,398 (62.8%) underwent surgery on a flanking Friday during the study period. Patient characteristics were similar between the 2 groups. We found no evidence that patients receiving surgery on Friday the 13th group were more likely to experience the composite primary outcome at 30 days [adjusted odds ratio (aOR) = 1.02 (95% CI = 0.94-1.09)], 90 days [aOR = 0.97 (95% CI = 0.90-1.04)], and 1 year [aOR = 0.99 (95% CI = 0.94-1.04)] after surgery. Conclusion: Patients receiving surgery on Friday the 13th do not appear to fare worse than those treated on ordinary Fridays with respect to the composite outcome.

Development of an effective predictive screening tool for prostate cancer using the ClarityDX machine learning platform.

The current prostate cancer (PCa) screen test, prostate-specific antigen (PSA), has a high sensitivity for PCa but low specificity for high-risk, clinically significant PCa (csPCa), resulting in overdiagnosis and overtreatment of non-csPCa. Early identification of csPCa while avoiding unnecessary biopsies in men with non-csPCa is challenging. We built an optimized machine learning platform (ClarityDX) and showed its utility in generating models predicting csPCa. Integrating the ClarityDX platform with blood-based biomarkers for clinically significant PCa and clinical biomarker data from a 3448-patient cohort, we developed a test to stratify patients' risk of csPCa; called ClarityDX Prostate. When predicting high risk cancer in the validation cohort, ClarityDX Prostate showed 95% sensitivity, 35% specificity, 54% positive predictive value, and 91% negative predictive value, at a ≥ 25% threshold. Using ClarityDX Prostate at this threshold could avoid up to 35% of unnecessary prostate biopsies. ClarityDX Prostate showed higher accuracy for predicting the risk of csPCa than PSA alone and the tested model-based risk calculators. Using this test as a reflex test in men with elevated PSA levels may help patients and their healthcare providers decide if a prostate biopsy is necessary.

Chemotherapy, immunotherapy, or combination first-line treatment for metastatic urothelial carcinoma of the bladder: A large real-world experience.

INTRODUCTION: First-line systemic therapy for metastatic urothelial carcinoma of the bladder (mUC) consists of platinum-based chemotherapy in most patients and PD1/L1 inhibitors in selected patients. Multiple combination chemoimmunotherapy trials failed to show a clear benefit over chemotherapy alone. We used real-world data to evaluate clinical and sociodemographic factors associated with receipt of first-line chemotherapy, immunotherapy, or combination chemoimmunotherapy treatment for metastatic bladder cancer and examined differences in overall survival (OS). MATERIALS AND METHODS: We used the National Cancer Database to identify patients with stage IV mUC diagnosed between 2014 and 2018, who were treated with first-line immunotherapy, chemotherapy, or combination treatment. We performed multivariable logistic regression modeling to determine factors associated with treatment receipt Adjusted Kaplan-Meier survival analysis and multivariable Cox proportional hazards regression were used to evaluate the association between treatment and OS. RESULTS: In our cohort of 4,169 patients, multivariable analysis identified increasing age (RRR: 1.07, 95%CI, 1.06-1.08) and comorbidity burden (, as independent predictors of receiving immunotherapy. Treatment at an academic facility was associated with increased likelihood of combination treatment (RRR: 1.29, 95%CI, 1.01-1.65). After IPTW, we found that combination therapy (hazard ratio [HR]: 0.72; 95%CI, 0.62-0.83) was associated with improved survival compared to chemotherapy. CONCLUSIONS: Patients with older age and more comorbidities were more likely to receive immunotherapy than chemotherapy for first-line treatment of metastatic urothelial carcinoma of the bladder. Utilization of chemoimmunotherapy was observed to be higher in academic centers and was associated with improved survival compared to chemotherapy.

Contemporary morbidity and mortality of open versus robotic cystectomy for bladder cancer: An analysis of the National Surgical Quality Improvement Program (NSQIP) procedure targeted cystectomy database.

OBJECTIVES: To evaluate the association between surgical modality (RARC vs. ORC) and the risk of 30-day complications. MATERIALS AND METHODS: We utilized the American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) Cystectomy-Targeted database from 2019 to 2021. The primary outcome was a composite of major complications including 30-day mortality, reoperation, cardiac events, and stroke. Secondary outcomes included individual major and cystectomy-specific complications. Propensity score matching (PSM) was employed to minimize inherent differences within our cohort. We performed logistic regression to assess the association between outcomes of interest and operative modality. RESULTS: We found no difference between operative modality and the primary outcome, however, RARC was associated with a 70% lower risk of 30-day mortality (OR 0.30, 95% CI 0.13-0.70) and had favorable outcomes with respect to respiratory, deep venous thrombosis, wound complications, and length of stay. Limitations are related to residual confounding given the observational methodology. CONCLUSIONS: RARC was associated with reduced risk of multiple 30-day complications, including mortality, as well as organ system and cystectomy-specific outcomes. These data support the clinical benefit of increased adoption of RARC.