A Decade of Robotic-Assisted Radical Nephrectomy with Inferior Vena Cava Thrombectomy: A Systematic Review and Meta-Analysis of Perioperative Outcomes.

PURPOSE: Open radical nephrectomy with inferior vena cava thrombectomy (O-CT) is standard management for renal cell carcinoma with inferior vena cava thrombus. First reported a decade ago, robotic-assisted radical nephrectomy with inferior vena cava thrombectomy (R-CT) is a minimally invasive option for this disease. We aimed to perform a systematic review to assess the safety and feasibility of R-CT in terms of perioperative outcomes and compare the outcomes between R-CT and O-CT. MATERIALS AND METHODS: The PubMed®, Scopus®, Cochrane Central Register of Controlled Trials and Web of ScienceTM databases were searched using the free-text and MeSH terms "renal cell carcinoma," "inferior vena cava," "thrombosis" or "thrombus," "robot" and "thrombectomy." Studies reporting perioperative outcomes of R-CT and studies comparing R-CT with O-CT were included. The review was done in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. RESULTS: The search retrieved 28 articles describing R-CT, including 7 comparative studies. This systematic review included 1,375 patients, out of which 329 patients were in single-arm studies and 1,046 patients were in comparative studies. Of the 329 patients who underwent R-CT, 14.7% were level I, 60.9% level II, 20.4% level III and 2.5% level IV thrombus. Operative time ranged from 150 to 530 minutes; blood transfusion was administered in 38.2% (126). The overall complication rate was 30.3% (99). R-CT, in comparison to O-CT, was associated with a lower blood transfusion rate (18.4% vs 64.3%, p=0.002) and a lower complication rate (14.5% vs 36.7%, p=0.005). Major complication and 30-day mortality rates were similar in both groups. CONCLUSIONS: R-CT has acceptable perioperative outcomes in carefully selected patients. Compared with O-CT, R-CT is associated with a lower blood transfusion rate and fewer overall complications. In experienced hands with carefully selected patients, R-CT is feasible and safe, with acceptable outcomes; however, selection bias limits definitive inference of these results, and optimal patient selection criteria remain to be described.

Impact of facility type and volume on survival in patients with metastatic renal cell carcinoma.

INTRODUCTION: To investigate the impact of facility type and volume on survival in patients with metastatic renal cell carcinoma (mRCC). MATERIALS AND METHODS: We investigated the National Cancer Database for patients with mRCC. Patients were stratified according to treatment facility type (academic vs. non-academic) and facility volume (high, intermediate, and low). Kaplan-Meier survival estimates and Cox proportional hazard models were fitted to evaluate overall survival (OS) as a function of facility type, volume, and different treatment modalities. RESULTS: A total of 27,598 patients were identified, of which 10,938 (40%) were treated at academic centers (AC) and 16,131 (60%) at non-academic centers (non-AC). Overall, 19,904 patients (72%) were treated in high-volume hospitals (HVH). Among patients treated at AC, 94% were treated at HVHs. Patients treated at AC were more likely to receive immunotherapy, undergo cytoreductive nephrectomy (CN) and metastasectomy. The 2 and 5 year OS rates for patients treated in AC were 29.7% (CI 28.8%-30.6%) and 13% (CI 12%-14%) vs. 21.7% (CI 21%-22.4%) and 8.4% (CI %7.91-%8.99) in the Non-AC, respectively (p < 0.001). Multivariate Cox regression analysis identified treatment at AC as an independent predictor of survival (HR 0.85, 95% CI 0.81-0.91, p < 0.001). Undergoing CN and receipt of immunotherapy was also associated with a survival benefit (HR 0.41, CI 0.40-0.43 and HR 0.63, CI 0.59-0.68 respectively, p < 0.001). CONCLUSIONS: Treatment at ACs and HVHs was associated with a survival benefit in patients with mRCC. Patients treated at AC were more likely to receive immunotherapy, undergo CN and metastasectomy.

Impact of tumor microenvironment composition on therapeutic responses and clinical outcomes in cancer.

The tumor microenvironment (TME) plays an important role in cancer growth and progression. Paradoxically, the TME is capable of acting as both a potential barrier and facilitator of tumor proliferation by affecting various processes including local growth resistance, immune system interactions, and the formation of distant metastases. This important interaction between cancer cells and their local environment, composed of immune cells, angiogenic cells, lymphatic endothelial cells and cancer-associated fibroblasts is paramount to determine a cancer cell's ability to grow and ultimately metastasize. It is essential to understand this complex interplay in order to define treatment modalities to target the TME as part of anti-cancer therapy.

Managing adverse effects of immunotherapy.

Remarkable efficacy has been achieved in a variety of cancer types by targeting immune checkpoints. The cytotoxic T-lymphocyte-associated antigen 4 inhibitor ipilimumab, the programmed death 1 inhibitors nivolumab and pembrolizumab, and the programmed death ligand 1 inhibitors atezolizumab, avelumab, and durvalumab are the agents currently approved by the US Food and Drug Administration for the treatment of certain advanced malignancies. These agents mark a departure from both standard cytotoxic chemotherapy and targeted therapy. However, they are associated with a unique set of immune-related adverse events (irAEs), which can manifest as a wide range of autoimmune phenomena. The irAEs can affect any system in the body and in rare cases are life-threatening. It is critical for the practicing medical oncologist to recognize and promptly treat any irAEs that may develop.

Immune-Related Adverse Events as a Biomarker in Non-Melanoma Patients Treated with Programmed Cell Death 1 Inhibitors.

BACKGROUND: The programmed death 1 (PD-1) checkpoint inhibitors (CKIs) can lead to immune-related adverse events (irAEs). We sought to evaluate whether the development of irAEs correlates with treatment response in non-melanoma malignancies. MATERIALS AND METHODS: We conducted a retrospective study of patients who received anti-PD-1 CKI monotherapy at Fox Chase Cancer Center. Endpoints included overall response rate (ORR), time to next therapy or death (TTNTD), and overall survival (OS). Fisher's exact tests and logistic regression models were used to determine the association between irAE incidence and ORR, and Kaplan-Meier curves with log-rank tests and Cox regression models were used for the comparison of TTNTD and OS. RESULTS: Between November 2011 and November 2016, 160 patients were treated with >1 dose of an anti-PD-1 CKI. Seventy-three (46%) were treated on a clinical trial. Immune-related adverse events were noted in 64 patients (40%), with steroids required in 36 (23%). Of the 142 patients evaluable for clinical response, 28 patients (20%) achieved a partial response at first scan. An association between irAEs and ORR was seen in clinical trial patients (p = .007), but not in non-trial patients (p = .13). When controlling for clinical trial participation and cancer type using multivariate analysis, low-grade irAEs had higher ORR (p = .017) and longer TTNTD (p = .008). No association between irAE incidence and OS was seen (p = .827). Immune-related adverse events that required steroid treatment were marginally associated with increased TTNTD (p = .05, hazard ratio 0.62) but were not associated with OS (p = .13). CONCLUSION: We demonstrate several positive associations between the development of irAEs and clinical outcomes in non-melanoma patients treated with PD-1 CKIs, for which further validation is required. IMPLICATIONS FOR PRACTICE: This study evaluated whether the development of immune-related adverse events in non-melanoma patients treated with programmed cell death 1 checkpoint inhibitors correlates with improved clinical outcomes. The results indicate that for a subset of patients, in particular those with low-grade immune-related adverse events, immune-related adverse events predicted for an improved response rate and longer time to next therapy or death.

Immune Checkpoint Inhibitor Therapy: What Line of Therapy and How to Choose?

OPINION STATEMENT: Immunotherapy is now an established part of the treatment paradigm for advanced non-small cell lung cancer (NSCLC), but the line of therapy and the sequence of agents are still in flux. In this time when much is to be learned, the optimal therapy for most patients in both the first-line and previously treated settings is in the context of a clinical trial. For standard therapy, however, there are good data to support the practice of programmed death-ligand 1 (PD-L1) testing in the front-line advanced setting and to use pembrolizumab as first-line therapy for those with ≥50% PD-L1 expression. In those who have progressed after receiving platinum-based chemotherapy in the first-line, multiple PD-1/PD-L1 agents are available and currently approved, including nivolumab, pembrolizumab, and atezolizumab. There are no data to suggest that one agent is more efficacious than the others, but pembrolizumab should be reserved for patients with PD-L1 expression ≥1%. Prescribers and patients must be cognizant of the toxicity profile of these agents, as severe immune-related adverse events can occur with therapy. At this time, this practice pattern for immunotherapy in the first- and second-line can be considered the standard of care, but new data are likely to impact the role of immunotherapy as monotherapy or in combination in the near future.

Perioperative Immune Checkpoint Blockade for Muscle-Invasive and Metastatic Bladder Cancer.

Checkpoint inhibitors offer promise in treating muscle-invasive and metastatic bladder cancer, but the optimal timing of their administration-neoadjuvant or adjuvant-remains unclear. To determine the efficacy of combining checkpoint inhibition with standard cisplatin-based chemotherapy, we conducted a phase II trial of neoadjuvant anti-PD-1 (αPD-1) and anti-CTLA-4 (αCTLA-4), in combination with cisplatin-gemcitabine, for patients with muscle-invasive bladder cancer prior to radical cystectomy. In addition, a novel murine model of spontaneous metastatic bladder cancer was used to compare the efficacy of neoadjuvant versus adjuvant anti-PD-L1 (αPD-L1) treatment. The clinical trial was closed prematurely due to the industry's withdrawal of drug provision. Adverse events were observed in all patients; however, serious adverse events were not observed in any patient. A complete pathologic response was observed in 50% of the 4 patients enrolled. Response to treatment was significantly associated with elevated urinary T cells including CD8+ and IFNγ+ CD4+ T cells, suggesting potential reinforcement of immune responses by neoadjuvant αPD-1 and αCTLA-4 against bladder tumor cells. These findings suggest that combining chemotherapy and immunotherapy in the neoadjuvant setting could be safe. However, the complete response rate of this four-drug regimen was modest and emphasizes the need for randomized controlled trials to properly assess immunotherapy efficacy in the neoadjuvant setting. In corresponding murine studies, the MB49-met model consistently displayed widespread metastasis, including tumor growth in the lungs, liver, and bowel mesentery, within 20 days of subcutaneous transplantation. Mice receiving surgery plus neoadjuvant αPD-L1 or adjuvant αPD-L1 exhibited improved survival compared to those receiving only αPD-L1. However, no significant difference in survival was observed between the neoadjuvant and adjuvant αPD-L1 cohorts. Furthermore, the timing of neoadjuvant therapy administration (early vs. late) did not significantly impact survival. This study highlights the potential of perioperative immunotherapy in the treatment of locally advanced and metastatic bladder cancer.

Sacituzumab Govitecan in Combination With Pembrolizumab for Patients With Metastatic Urothelial Cancer That Progressed After Platinum-Based Chemotherapy: TROPHY-U-01 Cohort 3.

PURPOSE: Pembrolizumab is standard therapy for patients with metastatic urothelial cancer (mUC) who progress after first-line platinum-based chemotherapy; however, only approximately 21% of patients respond. Sacituzumab govitecan (SG) is a trophoblast cell surface antigen-2-directed antibody-drug conjugate with US Food and Drug Administration-accelerated approval to treat patients with locally advanced or mUC who previously received platinum-based chemotherapy and a checkpoint inhibitor (CPI). Here, we report the primary analysis of TROPHY-U-01 cohort 3. METHODS: TROPHY-U-01 (ClinicalTrials.gov identifier: NCT03547973) is a multicohort, open-label phase II study. Patients were CPI-naïve and had mUC progression after platinum-based chemotherapy in the metastatic setting or ≤12 months in the (neo)adjuvant setting. Patients received 10 mg/kg of SG once on days 1 and 8 and 200 mg of pembrolizumab once on day 1 of 21-day cycles. The primary end point was objective response rate (ORR) per central review. Secondary end points included clinical benefit rate (CBR), duration of response (DOR) and progression-free survival (PFS) per central review, and safety. RESULTS: Cohort 3 included 41 patients (median age 67 years; 83% male; 78% visceral metastases [29% liver]). With a median follow-up of 14.8 months, the ORR was 41% (95% CI, 26.3 to 57.9; 20% complete response rate), CBR was 46% (95% CI, 30.7 to 62.6), median DOR was 11.1 months (95% CI, 4.8 to not estimable [NE]), and median PFS was 5.3 months (95% CI, 3.4 to 10.2). The median overall survival was 12.7 months (range, 10.7-NE). Grade ≥3 treatment-related adverse events occurred in 61% of patients; most common were neutropenia (37%), leukopenia (20%), and diarrhea (20%). CONCLUSION: SG plus pembrolizumab demonstrated a high response rate with an overall manageable toxicity profile in patients with mUC who progressed after platinum-based chemotherapy. No new safety signals were detected. These data support further evaluation of SG plus CPI in mUC.

Patient-Reported Outcomes in Patients With Advanced Urothelial Cancer Who Are Ineligible for Cisplatin and Treated With First-Line Enfortumab Vedotin Alone or With Pembrolizumab.

PURPOSE: Locally advanced/metastatic urothelial cancer (la/mUC) affects patients' quality of life (QOL) and functioning. We describe the impact of first-line (1L) enfortumab vedotin (EV) alone or with pembrolizumab (P) on QOL/functioning/symptoms in patients with la/mUC who were cisplatin-ineligible from EV-103 Cohort K. METHODS: In this phase Ib/II trial, patients were randomly assigned 1:1 to EV + P or EV monotherapy (mono). Exploratory patient-reported outcomes (PROs) were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Questionnaire (EORTC QLQ-C30) and Brief Pain Inventory Short Form (BPI-SF) at baseline, once per week for cycles 1-3, and then in every cycle through the end of treatment. Changes in scores from baseline to week 24, reported as least squares mean (standard error), were assessed by mixed models for repeated measures. There were no formal statistical comparisons between treatment arms. RESULTS: Of 149 patients treated, 65 (EV + P) and 63 (EV mono) comprised the PRO analysis set. For EV + P, EORTC QLQ-C30 QOL was maintained through week 24 with improvements in emotional functioning, pain, and insomnia. Clinically meaningful improvements were seen in EORTC QLQ-C30 pain after EV + P at weeks 12 (-14.41 [3.14]) and 24 (-14.99 [3.56]) and BPI-SF worst pain at week 24 (-2.07 [0.37]). For EV mono, EORTC QLQ-C30 QOL remained stable with clinically meaningful improvements in EORTC QLQ-C30 pain (-12.55 [4.27]), insomnia (-14.46 [4.69]), and constipation (-10.09 [4.35]) at week 24. There were small-to-moderate improvements in BPI-SF worst pain at week 24. CONCLUSION: EV + P in patients with la/mUC who were cisplatin-ineligible was associated with preservation or improvement of QOL/functioning/symptoms. Improvement in pain was seen in both PRO instruments and treatment arms. These data complement clinical outcomes of 1L EV + P.

Hippocampal volumes in patients with chronic combat-related posttraumatic stress disorder: a systematic review.

The authors and others have recently demonstrated that veterans with chronic combat-related PTSD (CR-PTSD) have a twofold increased risk of dementia. To understand this increased incidence, they performed a systematic review of the literature on neuroanatomical differences between veterans with chronic CR-PTSD and control subjects (22 included studies). The hippocampus was most commonly and consistently reported to differ between groups, thereby suggesting the hypothesis that PTSD is associated with smaller hippocampi, which increases the risk for dementia. However, an alternate hypothesis is that smaller hippocampal volumes are a preexisting risk factor for PTSD and dementia. Studies are clearly needed to differentiate between these important possibilities.

Cost-Effectiveness Analysis for Therapy Sequence in Advanced Cancer: A Microsimulation Approach with Application to Metastatic Prostate Cancer.

PURPOSE: Patients with advanced cancer may undergo multiple lines of treatment, switching therapies as their disease progresses. We developed a general microsimulation framework to study therapy sequence and applied it to metastatic prostate cancer. METHODS: We constructed a discrete-time state transition model to study 2 lines of therapy. Using digitized published survival curves (progression-free survival, time to progression, and overall survival [OS]), we inferred event types (progression or death) and estimated transition probabilities using cumulative incidence functions with competing risks. We incorporated within-patient dependence over time; first-line therapy response informed subsequent event probabilities. Parameters governing within-patient dependence calibrated the model-based results to a target clinical trial. We applied these methods to 2 therapy sequences for metastatic prostate cancer, wherein both docetaxel (DCT) and abiraterone acetate (AA) are appropriate for either first- or second-line treatment. We assessed costs and quality-adjusted life-years (5-y QALYs) for 2 treatment strategies: DCT → AA versus AA → DCT. RESULTS: Models assuming within-patient independence overestimated OS time, which corrected with the calibration approach. With generic pricing, AA → DCT dominated DCT → AA, (higher 5-y QALYs and lower costs), consistent for all values of calibration parameters (including no correction). Model calibration increased the difference in 5-y QALYs between treatment strategies (0.07 uncorrected v. 0.15 with base-case correction). Applying the correction decreased the estimated difference in cost (-$5,360 uncorrected v. -$3,066 corrected). Results were strongly affected by the cost of AA. Under a lifetime horizon, AA → DCT was no longer dominant but still cost-effective (incremental cost-effectiveness ratio: $19,463). CONCLUSIONS: We demonstrate a microsimulation approach to study the cost-effectiveness of therapy sequences for advanced prostate cancer, taking care to account for within-patient dependence. HIGHLIGHTS: We developed a discrete-time state transition model for studying therapy sequence in advanced cancers.Results are sensitive to dependence within patients.A calibration approach can introduce dependence across lines of therapy and closely match simulation outcomes to target trial outcomes.

Effects of vortioxetine on hippocampal-related cognitive impairment induced in rats by androgen deprivation as a model of prostate cancer treatment.

Advances in prostate cancer treatment have significantly improved survival, but quality of life for survivors remains an under-studied area of research. Androgen deprivation therapy (ADT) is a foundational treatment for advanced prostate cancer and is used as an adjuvant for prolonged periods in many high-risk, localized tumors. More than half of patients treated with ADT experience debilitating cognitive impairments in domains such as spatial learning and working memory. In this study, we investigated the effects of androgen deprivation on hippocampal-mediated cognition in rats. Vortioxetine, a multimodal antidepressant, has been shown to improve cognition in depressed patients. Thus, we also tested the potential efficacy of vortioxetine in restoring impaired cognition after ADT. We further investigated mechanisms that might contribute to these effects, measuring changes in the circuitry and gene expression within the dorsal hippocampus. ADT via surgical castration induced impairments in visuospatial cognition on the novel object location test and attenuated afferent-evoked local field potentials recorded in the CA1 region of the dorsal hippocampus. Chronic dietary administration of vortioxetine effectively reversed these deficits. Castration significantly altered gene expression in the hippocampus, whereas vortioxetine had little effect. Pathway analysis revealed that androgen depletion altered pathways related to synaptic plasticity. These results suggest that the hippocampus may be vulnerable to ADT, contributing to cognitive impairment in prostate cancer patients. Further, vortioxetine may be a candidate to improve cognition in patients who experience cognitive decline after androgen deprivation therapy for prostate cancer and may do so by restoring molecular and circuit-level plasticity-related mechanisms compromised by ADT.

Understanding the Challenges Faced by Esophageal and Gastroesophageal Junction Cancer Survivors.

The primary aim of this study is to characterize long-term quality of life (QOL) in patients with esophageal and gastroesophageal junction (EGEJ) cancers who underwent curative intent treatment. EGEJ survivors were recruited to participate in a one-time cross-sectional survey study using validated questionnaires assessing QOL. Chart review was conducted for patient demographics and clinical characteristics. Spearman correlation coefficients, Wilcoxon signed-rank test, and Fisher's exact test were used to assess relationships between patient characteristics and long-term outcomes. QOL was relatively high in this sample, as evidenced by high median scores on the functional scales and low median scores in the symptom domains of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30, with an overall median global health score of 75.0 (range 66.7-83.3). Patients using opiates at the time of survey reported lower role functioning (P = .004), social functioning (P = .052), and overall global health (P = .041). Younger patients had significantly higher rates of reflux (P = .019), odynophagia (P = .045), choking (P = .005), and cough (P = .007). Patients using opiates or of younger age had lower QOL and higher symptoms in this cohort of long-term EGEJ survivors.

Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer.

PURPOSE: Patients with locally advanced or metastatic urothelial cancer (la/mUC) who are ineligible for cisplatin-based therapy have limited first-line (1L) treatment options and significant need for improved therapies. Enfortumab vedotin (EV) and pembrolizumab (Pembro) individually have shown a survival benefit in urothelial cancer in second-line + la/mUC settings. Here, we present data from the pivotal trial of EV plus Pembro (EV + Pembro) in the 1L setting. PATIENTS AND METHODS: In Cohort K of the EV-103 phase Ib/II study, cisplatin-ineligible patients with previously untreated la/mUC were randomly assigned 1:1 to receive EV as monotherapy or in combination with Pembro. The primary end point was confirmed objective response rate (cORR) per blinded independent central review. Secondary end points included duration of response (DOR) and safety. There were no formal statistical comparisons between treatment arms. RESULTS: The cORR was 64.5% (95% CI, 52.7 to 75.1) and 45.2% (95% CI, 33.5 to 57.3) for patients treated with EV + Pembro (N = 76) and EV monotherapy (N = 73), respectively. The median DOR was not reached for the combination and was 13.2 months for monotherapy; 65.4% and 56.3% of patients who responded to the combination and monotherapy, respectively, maintained a response at 12 months. The most common grade 3 or higher treatment-related adverse events (TRAEs) in patients treated with the combination were maculopapular rash (17.1%), fatigue (9.2%), and neutropenia (9.2%). EV TRAEs of special interest (any grade) in the combination arm included skin reactions (67.1%) and peripheral neuropathy (60.5%). CONCLUSION: EV + Pembro showed a high cORR with durable responses as 1L treatment in cisplatin-ineligible patients with la/mUC. Patients who received EV monotherapy had a response and safety profile consistent with previous studies. Adverse events for EV + Pembro were manageable, with no new safety signals observed.

Hereditary Cancer Gene Variants in Hispanic Men With a Personal or Family History of Prostate Cancer.

BACKGROUND: Mutations in several common hereditary cancer genes are associated with prostate cancer, but there is limited information on the prevalence of these mutations in Hispanic men. MATERIALS AND METHODS: We selected men at high risk for genetic mutations from 1515 Hispanic men enrolled in the San Antonio Biomarkers of Risk for prostate cancer (SABOR) cohort. Inclusion criteria included men with a diagnosis of prostate cancer or a first-degree family history of prostate cancer. We performed germline genetic testing using the Color Genomics platform, sequencing 30 genes associated with hereditary cancer risk. Additionally, we assessed ancestral informative markers to determine the admixture of the ethnically unique cohort. RESULTS: Of the 275 subjects who met selection criteria, 263 patients had sufficient samples for sequencing. We identified 3.8% of patients (10 of 263) with a pathogenic or likely pathogenic mutation in the 30 genes tested, of whom 70% would not have met established criteria for genetic testing. Six of these mutations were in BRCA1/2 or ATM. There was a significant inverse association between the percentage of Native American ancestry and the risk of prostate cancer, OR 0.11 (95% CI 0.02-0.76, P = .025). CONCLUSION: Hispanic men with either a personal or family history of prostate cancer carry mutations in hereditary cancer genes at a significant rate, on par with non-Hispanic counterparts with similar risk factors.

Prevalence of pathogenic germline cancer risk variants in testicular cancer patients: Identifying high risk groups.

BACKGROUND: Germline studies in testicular cancer have focused on unselected populations but so far have not led to recommendations for testicular cancer screening. OBJECTIVE: Herein, we hypothesized that men with testicular cancer and an additional risk factor for hereditary cancer predisposition carry a higher rate of pathogenic variants than men with testicular cancer without another risk factor. METHODS AND RESULTS: 187 patients with a personal history of testicular cancer underwent germline testing via Invitae. Patients were divided into low-risk and high-risk patients. Low-risk patients (n=83) had testicular cancer as their only primary malignancy without a family history of testicular cancer. High-risk patients (n=104) had additional primary malignancies and/or a family history of testicular cancer. 23.1% of patients harbored pathogenic germline variants with 19.6% carrying actionable variants. Among low-risk patients, 13.5% carried pathogenic variants versus 29.9% in the high-risk cohort. Of patients with a family history of non-testicular cancers and a personal history of additional primary malignancies, 32% harbored pathogenic variants. CONCLUSION: High-risk patients are twice as likely to harbor pathogenic variants compared to low-risk patients. Importantly, patients with a family history of cancer and other primary malignancies represent a subset of patients that may benefit from genetic evaluation.

Disparities in Cancer Genetic Testing and Variants of Uncertain Significance in the Hispanic Population of South Texas.

PURPOSE: Racial and ethnic disparities have included a lack of access to both genetic testing and research, resulting in poor understanding of the genomic architecture in under-represented populations. The South Texas population is primarily of Hispanic background and has been largely devoid of genetic services. We extended access to this underserved population and uncovered genetic variants previously not observed, emphasizing the need to continually improve both genomic databases and clarification of variant significance to provide meaningful patient counseling. METHODS: This study consisted of a retrospective cohort review of patients seen through a cancer genetics education and service program across 24 counties in South Texas. In total, 1,595 individuals were identified as appropriate for cancer genetic counseling and 1,377 completed genetic testing. RESULTS: Eighty percent of those receiving genetic counseling self-identified as Hispanic, 16% as non-Hispanic White (NHW), 3% as African American, and 1% as other race/ethnicity. Of reported variants, 18.8% were pathogenic and 13.7% were reported as a variant of uncertain significance (VUS). VUS was reported in 17.2% of the Hispanic individuals compared with 9% NHW (P = .005). CONCLUSION: Individuals of Hispanic ethnicity were significantly more likely to harbor a VUS compared with NHW. The extended reach into our regional communities revealed a gap in the ability to accurately interpret genomic variation with implications for advising patients on screening, prevention, and management strategies. A higher percentage of VUS also emphasizes the challenge of continued follow-up amid existing barriers that led to disparities in access. As understanding of the variants develops, hopefully gaps in knowledge of the genomic landscape will be lessened with increased clarity to provide accurate cancer risk assessment and recommendations for implementing prevention initiatives.

Rapamycin enhances BCG-specific γδ T cells during intravesical BCG therapy for non-muscle invasive bladder cancer: a randomized, double-blind study.

BACKGROUND: Although intravesical BCG is the standard treatment of high-grade non-muscle invasive bladder cancer (NMIBC), response rates remain unsatisfactory. In preclinical models, rapamycin enhances BCG vaccine efficacy against tuberculosis and the killing capacity of γδ T cells, which are critical for BCG's antitumor effects. Here, we monitored immunity, safety, and tolerability of rapamycin combined with BCG in patients with NMIBC. METHODS: A randomized double-blind trial of oral rapamycin (0.5 or 2.0 mg daily) versus placebo for 1 month was conducted in patients with NMIBC concurrently receiving 3 weekly BCG instillations (NCT02753309). The primary outcome was induction of BCG-specific γδ T cells, measured as a percentage change from baseline. Post-BCG urinary cytokines and immune cells were examined as surrogates for local immune response in the bladder. Secondary outcomes measured were adverse events (AEs) and tolerability using validated patient-reported questionnaires. RESULTS: Thirty-one patients were randomized (11 placebo, 8 rapamycin 2.0 mg, and 12 rapamycin 0.5 mg). AEs were similar across groups and most were grade 1-2. One (12.5%) patient randomized to 2.0 mg rapamycin was taken off treatment due to stomatitis. No significant differences in urinary symptoms, bowel function, or bother were observed between groups. The median (IQR) percentage change in BCG-specific γδ T cells from baseline per group was as follows: -26% (-51% to 24%) for placebo, 9.6% (-59% to 117%) for rapamycin 0.5 mg (versus placebo, p=0.18), and 78.8% (-31% to 115%) for rapamycin 2.0 mg (versus placebo, p=0.03). BCG-induced cytokines showed a progressive increase in IL-8 (p=0.02) and TNF-α (p=0.04) over time for patients on rapamycin 2.0 mg, whereas patients receiving placebo had no significant change in urinary cytokines. Compared with placebo, patients receiving 2.0 mg rapamycin had increased urinary γδ T cells at the first week of BCG (p=0.02). CONCLUSIONS: Four weeks of 0.5 and 2.0 mg oral rapamycin daily is safe and tolerable in combination with BCG for patients with NMIBC. Rapamycin enhances BCG-specific γδ T cell immunity and boosts urinary cytokines during BCG treatment. Further study is needed to determine long-term rapamycin safety, tolerability and effects on BCG efficacy.