Small cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer with high mortality. We used a systematic drug-repositioning bioinformatics approach querying a large compendium of gene expression profiles to identify candidate FDA-approved drugs to treat SCLC. We found that tricyclic antidepressants and related molecules potently induce apoptosis in both chemonaïve and chemoresistant SCLC cells in culture, in mouse and human SCLC tumors transplanted into immunocompromised mice, and in endogenous tumors from a mouse model for human SCLC. The candidate drugs activate stress pathways and induce cell death in SCLC cells, at least in part by disrupting autocrine survival signals involving neurotransmitters and their G protein-coupled receptors. The candidate drugs inhibit the growth of other neuroendocrine tumors, including pancreatic neuroendocrine tumors and Merkel cell carcinoma. These experiments identify novel targeted strategies that can be rapidly evaluated in patients with neuroendocrine tumors through the repurposing of approved drugs.

Enterococcus status at ICU admission was associated with risk for death or all-cause infection, and rectal carriage of common ICU pathogens predicted specific infections. The gastrointestinal microbiome may have a role in risk stratification and early diagnosis of ICU infections.

Objective The objective of this study was to assess the predictive value of clinical and exercise test variables in patients with peripheral arterial disease (PAD). Methods 725 PAD patients referred for exercise testing at the Palo Alto Veterans Hospital between 1997 and 2011 were subjected to a customized symptom-limited ramp treadmill protocol. Detailed clinical and exercise test data were collected at baseline and patients were followed for a mean of 11.3±6.3 years. Results During follow up, there were 364 deaths. Baseline exercise capacity was 7.0±2.6 Metabolic equivalents (METs) among survivors and 5.5±2.4 METs in those who died (P<.001). Although several physiologic parameters differed between survivors and non-survivors, age-adjusted Cox regression revealed that exercise capacity was the strongest independent predictor of mortality. Each additional MET achieved was associated with age-adjusted 18% and 20% reductions in all-cause and cardiovascular mortality, respectively (P<.001 for both). This variable surpassed all classical risk factors (including smoking and history of congestive heart failure) as well as all measured exercise test responses (including symptoms and ECG abnormalities). Conclusions Amongst PAD patients, reduced exercise capacity is the most powerful harbinger of long term mortality. This factor has predictive power beyond traditional risk factors and confirms the critical importance of fitness in this cohort.

Background 131I-metaiodobenzylguanidine (131I-MIBG) is a targeted radiopharmaceutical with significant activity in high-risk relapsed and chemotherapy-refractory neuroblastoma. Our primary aim was to determine if there are differences in response rates to 131I-MIBG between patients with relapsed and treatment-refractory neuroblastoma. Methods This was a retrospective cohort analysis of 218 patients with refractory or relapsed neuroblastoma treated with 131I-MIBG at UCSF between 1996 and 2014. Results were obtained by chart review and database abstraction. Baseline characteristics and response rates between relapsed patients and refractory patients were compared using Fisher exact and Wilcoxon rank sum tests, and differences in overall survival (OS) were compared using the log-rank test. Results The response rate (complete and partial response) to 131I-MIBG-based therapies for all patients was 27%. There was no difference in response rates between relapsed and refractory patients. However, after 131I-MIBG, 24% of relapsed patients had progressive disease compared to only 9% of refractory patients, and 39% of relapsed patients had stable disease compared to 59% of refractory patients (p = 0.02). Among all patients, the 24-month OS was 47.0% (95% CI 39.9%–53.9%). The 24-month OS for refractory patients was significantly higher at 65.3% (95% CI 51.8%–75.9%), compared to 38.7% (95% CI 30.4%–46.8%) for relapsed patients (p < 0.001). Conclusions Although there was no significant difference in overall response rates to 131I-MIBG between patients with relapsed vs. refractory neuroblastoma, patients with prior relapse had higher rates of progressive disease and had lower 2-year overall survival after 131I-MIBG compared to patients with refractory disease.