Renal cell carcinoma (RCC) is an immunogenic and proangiogenic cancer, and anti-angiogenic therapy is the current mainstay of treatment. RCC patients develop innate or adaptive resistance to anti-angiogenic therapy. There is a need to identify biomarkers that predict therapeutic resistance and guide combination therapy. We assessed the interaction between anti-angiogenic therapy and tumor immune microenvironment, and determined their impact on clinical outcome. We found that anti-angiogenic therapy-treated RCC primary tumors demonstrated increased infiltration of CD4+ and CD8+ T lymphocytes, which was inversely related to patient overall survival (OS) and progression-free survival (PFS). Furthermore, specimens from patients treated with anti-angiogenic therapy showed higher infiltration of CD4+FOXP3+ regulatory T cells (Treg) and enhanced expression of checkpoint ligand programed death-ligand 1 (PD-L1). Both immunosuppressive features were correlated with T-lymphocyte infiltration and were negatively related to patient survival. Treatment of RCC cell lines and RCC xenografts in immunodeficient mice with sunitinib also increased tumor PD-L1 expression. Results from this study indicate that anti-angiogenic treatment may both positively and negatively regulate the tumor immune microenvironment. These findings generate hypotheses on resistance mechanisms to anti-angiogenic therapy, and will guide the development of combination therapy with PD-1/PD-L1 blocking agents.

Purpose To identify sunitinib alternative schedules (AS) that maintained dose intensity while decreasing adverse events (AEs) in patients with metastatic renal cell cancer (mRCC), and to determine impact of AS on clinical outcomes. Patients and Methods A retrospective review of patients ≥ 18 yr of age with clear-cell mRCC who received first-line sunitinib between 1/26/06 and 3/1/11 at a major Comprehensive Cancer Center. Subset of patients switched at first intolerable AE from traditional schedule (28 d on, 14 d off; TS) to 14 d on/7 d off schedule or other AS. Control group underwent standard dose reduction. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Predictors of PFS and OS were analyzed using Cox regression. Results One hundred eighty five patients were included for analysis; 87% were on TS at baseline. During treatment, 53% of patients continued TS and 47% initiated or transitioned to AS. Baseline characteristics were similar. AEs prompting schedule modification included fatigue (64%), hand-foot syndrome (38%) and diarrhea (32%). Median time to AS was 5.6 mo. Median OS was 17.7 mo (95% confidence interval [CI], 10.8-22.2) on TS compared to 33.0 mo (95% CI, 29.3- not estimable) on AS (P < 0.0001). By multivariable analysis; poor ECOG PS, increased LDH, decreased albumin, unfavorable Heng criteria, and TS are associated with decreased OS (P < 0.05). Conclusion Sunitinib administered on AS may mitigate AEs and has comparable outcomes as TS for mRCC patients. Prospective investigations of alternate dosing schemas are warranted.

Modern medical management of comorbid conditions has resulted in escalating use of multiple medications and the emergence of the twin phenomena of multimorbidity and polypharmacy. Current understanding of how the polypharmacy in conjunction with multimorbidity influences trauma outcomes is limited, although it is known that trauma patients are at increased risk for medication-related adverse events. The comorbidity-polypharmacy score (CPS) is a simple clinical tool that quantifies the overall severity of comorbidities using the polypharmacy as a surrogate for the “intensity” of treatment necessary to adequately control chronic medical conditions. Easy to calculate, CPS is derived by counting all known pre-injury comorbid conditions and medications. CPS has been independently associated with mortality, increased risk for complications, lower functional outcomes, readmissions, and longer hospital stays. In addition, CPS may help identify older trauma patients at risk of post-emergency department undertriage. The goal of this article was to review and refine the rationale for CPS and to provide an evidence-based outline of its potential clinical applications.

Objectives To identify the clinical outcomes of mRCC patients with PM treated with either pazopanib or sunitinib and assess whether PM is an independent prognostic variable in the current therapeutic environment. Patients and Methods Retrospective review of mRCC patients in an outpatient clinic was done from January 2006 to November 2011. Patient characteristics including demographics, laboratory data, and outcomes were analyzed. Comparison of baseline characteristics was done using chi2 and t-test and Overall Survival (OS) and Cancer-Specific Survival (CSS) was estimated using Kaplan-Meier methods. Predictors of OS were analyzed using Cox regression. Results A total of 228 patients were reviewed of which 44 (19.3%) had metastases to the pancreas and 184 (81.7%) had metastasis to sites other than the pancreas. The distribution of baseline characteristics was equal in both groups with the exception of a higher incidence of prior nephrectomy, diabetes and number of metastatic sites in the pancreatic metastasis group. 4 patients had isolated metastases to the pancreas, however, the majority of patients (68%) with pancreatic metastases had at least three different organ sites of metastases, as compared to 29% in patients without pancreatic metastases (p<0.01). Distribution of organ sites of metastases was similar (p>0.05), excluding pancreas. Median OS was 39 months (95% confidence interval [CI], 24–57, HR=0.66, 95% CI = 0.42–0.94, p=0.02) for patients with pancreatic metastases, compared to 26 months (95% CI, 21–31) for patients without pancreatic metastases (p-value <0.01). CSS was 42 months (95% CI: 30–57 months) in the PM group and 27 months (95% CI: 22–33 months, p-value = 0.05) in the control group. Conclusions Despite a higher number of affected organ sites in the pancreatic metastasis cohort, mRCC behavior in this cohort appears to be more indolent, as demonstrated by a higher median OS. These findings suggest that host or tumor features associated with pancreatic metastases may represent a less aggressive tumor phenotype.

The lowest GV and lowest hypoglycemia were observed in patients using the combination of basal insulin with a GLP-1 RA, supporting the complementary glycemic action of these agents in type 2 diabetes. These observed benefits in GV and hypoglycemia may contribute to the cardiovascular outcome reduction seen with GLP-1 RA therapy and should be investigated further.