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Clear cell renal cell carcinoma (ccRCC) is one of the most immunologically distinct tumor types due to high response rate to immunotherapies, despite low tumor mutational burden. To characterize the tumor immune microenvironment of ccRCC, we applied single-cell-RNA sequencing (SCRS) along with T-cell-receptor (TCR) sequencing to map the transcriptomic heterogeneity of 25,688 individual CD45+ lymphoid and myeloid cells in matched tumor and blood from three patients with ccRCC. We also included 11,367 immune cells from four other individuals derived from the kidney and peripheral blood to facilitate the identification and assessment of ccRCC-specific differences. There is an overall increase in CD8+ T-cell and macrophage populations in tumor-infiltrated immune cells compared to normal renal tissue. We further demonstrate the divergent cell transcriptional states for tumor-infiltrating CD8+ T cells and identify a MKI67 + proliferative subpopulation being a potential culprit for the progression of ccRCC. Using the SCRS gene expression, we found preferential prediction of clinical outcomes and pathological diseases by subcluster assignment. With further characterization and functional validation, our findings may reveal certain subpopulations of immune cells amenable to therapeutic intervention.

Objective The goal of this study was to determine the incidence of major complications following primary and revision functional endoscopic sinus surgery (FESS). Additionally, this study aimed to determine factors associated with the occurrence of complications including patient and provider characteristics and the use of image guidance system (IGS) technology. Study Design Retrospective cohort analysis of California and Florida all-payer databases from 2005–2008. Methods The rates of major surgical complications (skull base, orbital, and hemorrhagic) after primary and revision FESS were calculated, and bivariate analyses were performed to investigate relationships of complications with demographic and clinical characteristics. A multivariate model was used to determine risk factors for the occurrence of major complications. Results Among 78,944 primary FESS cases, 288 major complications were identified representing a complication rate of 0.36% (95% CI 0.32%–0.40%). The major complication rate following revision cases (n = 19; 0.46%) and primary cases (n = 288; 0.36%) was similar (OR=1.26; 95% CI 0.79–2.00). Multivariate analysis showed that patients who were >40 years old, had a primary payer of Medicaid, had surgery involving the frontal sinus, or had image guidance during surgery were at higher risk for major complications. Conclusion The rate of major complications (0.36%) associated with primary FESS is lower than earlier reports. The rate of major complications following revision FESS (0.46%) was found to be similar to primary cases. IGS, insurance status, age, and extent of surgery were found to be associated with an increased risk of major complications following FESS.

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Background:Bacillus Calmette-Guerin (BCG) is the most effective intravesical therapy for non-muscle invasive bladder cancer (NMIBC), but patients can fail or supply shortages can develop. For BCG failures, radical cystectomy is recommended. However, in patients who desire bladder preservation or are poor surgical candidates, alternative salvage intravesical therapies should be explored.Objective:To determine whether dual sequential intravesical gemcitabine and docetaxel is effective in treating NMIBC.Methods:We evaluated our initial experience with 45 patients treated with intravesical gemcitabine and docetaxel between June 2009 and May 2014. Patients were treated with 6 weekly instillations of gemcitabine (1 gram of gemcitabine in 50 ml of sterile water) followed immediately by docetaxel (37.5 mg of docetaxel in 50 mL of saline). Treatment success was defined as no bladder cancer recurrence and no cystectomy. Intention-to-treat analysis was performed using the Kaplan Meier method.Results:Forty-five patients received treatment with a median overall follow-up of 15 months. Median follow up for treatment success was 6 months in all patients and 13 months for responders. Five patients were unable to tolerate a full induction course. Treatment success was 66% at first surveillance, 54% at 1 year, and 34% at 2 years after initiating induction. Ten patients received cystectomy (median of 5.6 months from starting induction) with no positive margins or lymph nodes on final pathology.Conclusions: Sequential dual intravesical gemcitabine and docetaxel can salvage some patients in a challenging NMIBC cohort.

BackgroundObesity is a major risk factor for renal cancer, yet our understanding of its effects on antitumor immunity and immunotherapy outcomes remains incomplete. Deciphering these associations is critical, given the growing clinical use of immune checkpoint inhibitors for metastatic disease and mounting evidence for an obesity paradox in the context of cancer immunotherapies, wherein obese patients with cancer have improved outcomes.MethodsWe investigated associations between host obesity and anti-programmed cell death (PD-1)-based outcomes in both renal cell carcinoma (RCC) subjects and orthotopic murine renal tumors. Overall survival (OS) and progression-free survival (PFS) were determined for advanced RCC subjects receiving standard of care anti-PD-1 who had ≥6 months of follow-up from treatment initiation (n=73). Renal tumor tissues were collected from treatment-naive subjects categorized as obese (body mass index, ‘BMI’ ≥30 kg/m2) or non-obese (BMI <30 kg/m2) undergoing partial or full nephrectomy (n=19) then used to evaluate the frequency and phenotype of intratumoral CD8+ T cells, including PD-1 status, by flow cytometry. In mice, antitumor immunity and excised renal tumor weights were evaluated ±administration of a combinatorial anti-PD-1 therapy. For a subset of murine renal tumors, immunophenotyping was performed by flow cytometry and immunogenetic profiles were evaluated via nanoString.ResultsWith obesity, RCC patients receiving anti-PD-1 administration exhibited shorter PFS (p=0.0448) and OS (p=0.0288). Treatment-naive renal cancer subjects had decreased frequencies of tumor-infiltrating PD-1highCD8+ T cells, a finding recapitulated in our murine model. Following anti-PD-1-based immunotherapy, both lean and obese mice possessed distinct populations of treatment responders versus non-responders; however, obesity reduced the frequency of treatment responders (73% lean vs 44% obese). Tumors from lean and obese treatment responders displayed similar immunogenetic profiles, robust infiltration by PD-1int interferon (IFN)γ+CD8+ T cells and reduced myeloid-derived suppressor cells (MDSC), yielding favorable CD44+CD8+ T cell to MDSC ratios. Neutralizing interleukin (IL)-1β in obese mice improved treatment response rates to 58% and reduced MDSC accumulation in tumors.ConclusionsWe find that obesity is associated with diminished efficacy of anti-PD-1-based therapies in renal cancer, due in part to increased inflammatory IL-1β levels, highlighting the need for continued study of this critical issue.