Cardiovascular Implications of Vascular Endothelial Growth Factor Inhibition Among Adolescents/Young Adults in ECOG-ACRIN E2805.

BACKGROUND: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality among adolescents and young adults (AYAs) diagnosed with cancer. The aim of this study was to assess the incidence and predictors of left ventricular systolic dysfunction (LVSD) and hypertension among AYAs receiving VEGF inhibition compared with non-AYAs. METHODS: This retrospective analysis used data from the ASSURE trial (ClinicalTrials.gov identifier: NCT00326898), in which participants with nonmetastatic, high-risk, renal cell cancer were randomized to sunitinib, sorafenib, or placebo. The incidence of LVSD (left ventricular ejection fraction decrease >15%) and hypertension (blood pressure ≥140/90 mm Hg) were compared using nonparametric tests. Multivariable logistic regression examined the association between AYA status, LVSD, and hypertension while adjusting for clinical factors. RESULTS: AYAs represented 7% (103/1,572) of the population. Over a study treatment period of 54 weeks, the incidence of LVSD was not significantly different among AYAs (3%; 95% CI, 0.6%-8.3%) versus non-AYAs (2%; 95% CI, 1.2%-2.7%). The incidence of hypertension was significantly lower among AYAs (18%; 95% CI, 7.5%-33.5%) compared with non-AYAs (46%; 95% CI, 41.9%-50.4%) in the placebo arm. In the sunitinib and sorafenib groups, the incidence of hypertension for AYAs compared with non-AYAs was 29% (95% CI, 15.1%-47.5%) versus 47% (95% CI, 42.3%-51.7%), and 54% (95% CI, 33.9%-72.5%) versus 63% (95% CI, 58.6%-67.7%), respectively. AYA status (odds ratio, 0.48; 95% CI, 0.31-0.75) and female sex (odds ratio, 0.74; 95% CI, 0.59-0.92) were each associated with a lower risk of hypertension. CONCLUSIONS: LVSD and hypertension were prevalent among AYAs. CVD among AYAs is only partially explained by cancer therapy. Understanding CVD risk among AYA cancer survivors is important for promoting cardiovascular health in this growing population.

Patterns of Relapse and Implications for Post-Nephrectomy Surveillance in Patients with High Risk Nonclear Cell Renal Cell Carcinoma: Subgroup Analysis of the Phase 3 ECOG-ACRIN E2805 Trial.

PURPOSE: The natural history of nonclear cell renal cell carcinoma following surgery with curative intent remains poorly defined with postoperative surveillance informed by guidelines largely intended for clear cell renal cell carcinoma. We evaluated relapse patterns and potential implications for post-nephrectomy surveillance in patients with nonclear cell renal cell carcinoma enrolled in the E2805 trial, the largest randomized trial of adjuvant antiangiogenic therapy of high risk renal cell carcinoma. MATERIALS AND METHODS: We retrospectively analyzed the records of patients with completely resected nonclear cell renal cell carcinoma. Participants received up to 54 weeks of postoperative therapy with sunitinib, sorafenib or placebo and underwent surveillance imaging at standardized intervals for 10 years. For recurrence rates by site the cumulative incidence was estimated, accounting for competing risks. The adequacy of strict adherence to post-nephrectomy surveillance guidelines was evaluated. RESULTS: A total of 403 patients with nonclear cell renal cell carcinoma were enrolled in the study. During a median followup of 6.2 years 36% of nonclear cell renal cell carcinomas recurred. Five-year recurrence rates were comparable for nonclear and clear cell renal cell carcinoma in the 1,541 patients, including 34.6% (95% CI 29.8-39.4) and 39.5% (95% CI 36.9-42.1), respectively. However, patients with nonclear cell renal cell carcinoma were significantly more likely to have abdominal sites of relapse (5-year recurrence rate 26.4% vs 18.2%, p = 0.0008) and significantly less likely to experience relapse in the chest (5-year recurrence rate 13.7% vs 20.9%, p = 0.0005). Current surveillance guidelines would potentially capture approximately 90% of relapses at any site. CONCLUSIONS: Nonclear cell renal cell carcinoma may show a distinct pattern of relapse compared to clear cell renal cell carcinoma. Our findings emphasize the importance of cross-sectional, long-term imaging in patients with high risk, resected, nonclear cell renal cell carcinoma.

Climate Change and Mental Health: A Review of Empirical Evidence, Mechanisms and Implications.

Anthropogenic climate change is an existential threat whose influences continue to increase in severity. It is pivotal to understand the implications of climate change and their effects on mental health. This integrative review aims to summarize the relevant evidence examining the harm climate change may have on mental health, suggest potential mechanisms and discuss implications. Empirical evidence has begun to indicate that negative mental health outcomes are a relevant and notable consequence of climate change. Specifically, these negative outcomes range from increased rates of psychiatric diagnoses such as depression, anxiety and post-traumatic stress disorder to higher measures of suicide, aggression and crime. Potential mechanisms are thought to include neuroinflammatory responses to stress, maladaptive serotonergic receptors and detrimental effects on one's own physical health, as well as the community wellbeing. While climate change and mental health are salient areas of research, the evidence examining an association is limited. Therefore, further work should be conducted to delineate exact pathways of action to explain the mediators and mechanisms of the interaction between climate change and mental health.

Recent advances in localized RCC: A focus on VEGF and immuno-oncology therapies.

Recent advances in advanced renal cell cancer (RCC) research have produced new drugs and therapies for patients with metastatic disease leading to higher response rates, improvements in progression-free survival, and longer overall survival. These advances have yet to be realized in patients with early-stage kidney cancer, and to date, no drug has been approved for the adjuvant treatment of localized kidney cancer. The current standard of care for localized high-risk kidney cancers is resection of the primary tumor. Here, we review the results of recently completed adjuvant vascular endothelial growth factor receptor 2 (VEGFR2) tyrosine kinase inhibitor (TKI) trials in RCC that have been reported, or are awaiting results. Further, we discuss the new immune checkpoint inhibitor adjuvant trials planned. There is hope that these trials may lead to new options and longer survival for patients with localized high-risk kidney cancer.

Phase 1 Trial of Everolimus and Radiation Therapy for Salvage Treatment of Biochemical Recurrence in Prostate Cancer Patients Following Prostatectomy.

PURPOSE: In up to half of patients treated with salvage radiation therapy (SRT) for rising prostate-specific antigen levels, a second biochemical recurrence ultimately develops. Phosphatase and tensin homolog inactivation is implicated in prostate cancer progression, and upregulation of the mammalian target of rapamycin pathway can lead to tumor hypoxia and radioresistance. Everolimus is a mammalian target of rapamycin inhibitor with both antitumor and radiosensitizing effects. METHODS AND MATERIALS: We performed a phase 1 study using a modified 3 + 3 dose-escalation design to evaluate the safety and tolerability of everolimus in combination with standard SRT for the treatment of biochemical recurrence following prostatectomy. After a 2-week run-in period of everolimus daily therapy, patients received prostate bed irradiation with daily cone beam computed tomography localization in 37 fractions of 1.8 Gy each (total dose, 66.6 Gy). Patients were monitored for both acute (≤90 days) and chronic (>90 days) treatment-related toxicities. RESULTS: Eighteen patients received everolimus at dose levels of 5 mg (n=6), 7.5 mg (n=6), or 10 mg (n=6) daily in conjunction with SRT. No dose-limiting toxicities were observed. Common acute treatment-related toxicities included grade 1 or 2 mucositis (55.6%), grade 1 or 2 fatigue (38.9%), grade 1 or 2 rash (61.1%), and grade 1 urinary symptoms (61.1%). A grade 3 acute toxicity occurred in 4 patients (22.2%) (n=1 for rash, anemia, lymphopenia, and neutropenia), and no patients had a chronic toxicity of grade 3 or greater. After a median follow-up time of 17.8 months (range, 1.2-46.0 months), an undetectable prostate-specific antigen nadir was achieved in 9 patients (56.3%) and a second biochemical recurrence developed in 5 patients (31.3%). CONCLUSIONS: Everolimus at a dose of ≤10 mg daily appears to be safe and tolerable in combination with fractionated post-prostatectomy radiation therapy.