No abstract

Studies suggest a link between the gut microbiome and metastatic renal cell carcinoma (mRCC) outcomes, including evidence that mRCC patients possess a lower abundance of Bifidobacterium spp. compared to healthy adults. We sought to assess if a Bifidobacterium‐containing yogurt product could modulate the gut microbiome and clinical outcome from vascular endothelial growth factor‐tyrosine kinase inhibitors (VEGF‐TKIs). mRCC patients initiating VEGF‐TKIs, regardless of the line of therapy, were randomized to probiotic‐supplemented (two 4 oz. servings of the probiotic yogurt product daily) or probiotic‐restricted arms. Stool samples were collected prior to therapy and at weeks 2, 3, 4, and 12. Microbiome composition was assessed using whole‐metagenome sequencing. A total of 20 patients were randomized. Bifidobacterium animalis, the active ingredient of the probiotic supplement, reached detectable levels in all patients in the probiotic‐supplemented arm versus two patients in the probiotic‐restricted arm. Clinical benefit rate was similar in probiotic‐supplemented versus probiotic‐restricted arms (70% vs. 80%, p = 0.606). Linear discriminant analysis (LDA) effect size analysis of MetaPhIAn2 abundance data predicted 25 enriched species demonstrating an LDA score >3 in either clinical benefit or no clinical benefit. In patients with clinical benefit (vs. no clinical benefit), Barnesiella intestinihominis and Akkermansia muciniphila were significantly more abundant (p = 7.4 × 10−6 and p = 5.6 × 10−3, respectively). This is the first prospective randomized study demonstrating modulation of the gut microbiome with a probiotic in mRCC. Probiotic supplementation successfully increased the Bifidobacterium spp. levels. Analysis of longitudinal stool specimens identified an association between B. intestinihominis, A. muciniphila, and clinical benefit with therapy. Trial Registration: NCT02944617

In December of 2019, a novel coronavirus, SARS-CoV-2, emerged in the city of Wuhan, China, causing severe morbidity and mortality. Since then, the virus has swept across the globe, causing millions of confirmed infections and hundreds of thousands of deaths. To better understand the nature of the pandemic and the introduction and spread of the virus in Arizona, we sequenced viral genomes from clinical samples tested at the TGen North Clinical Laboratory, the Arizona Department of Health Services, and those collected as part of community surveillance projects at Arizona State University and the University of Arizona. Phylogenetic analysis of 84 genomes from across Arizona revealed a minimum of 11 distinct introductions inferred to have occurred during February and March. We show that >80% of our sequences descend from strains that were initially circulating widely in Europe but have since dominated the outbreak in the United States. In addition, we show that the first reported case of community transmission in Arizona descended from the Washington state outbreak that was discovered in late February. Notably, none of the observed transmission clusters are epidemiologically linked to the original travel-related case in the state, suggesting successful early isolation and quarantine. Finally, we use molecular clock analyses to demonstrate a lack of identifiable, widespread cryptic transmission in Arizona prior to the middle of February 2020. IMPORTANCE As the COVID-19 pandemic swept across the United States, there was great differential impact on local and regional communities. One of the earliest and hardest hit regions was in New York, while at the same time Arizona (for example) had low incidence. That situation has changed dramatically, with Arizona now having the highest rate of disease increase in the country. Understanding the roots of the pandemic during the initial months is essential as the pandemic continues and reaches new heights. Genomic analysis and phylogenetic modeling of SARS-COV-2 in Arizona can help to reconstruct population composition and predict the earliest undetected introductions. This foundational work represents the basis for future analysis and understanding as the pandemic continues.

Lessons Learned The combination of enobosarm and pembrolizumab was well tolerated and showed a modest clinical benefit rate of 25% at 16 weeks. Future trials investigating androgen receptor‐targeted therapy in combination with immune checkpoint inhibitors are warranted. Background Luminal androgen receptor is a distinct molecular subtype of triple‐negative breast cancer (TNBC) defined by overexpression of androgen receptor (AR). AR‐targeted therapy has shown modest activity in AR‐positive (AR+) TNBC. Enobosarm (GTx‐024) is a nonsteroidal selective androgen receptor modulator (SARM) that demonstrates preclinical and clinical activity in AR+ breast cancer. The current study was designed to explore the safety and efficacy of the combination of enobosarm and pembrolizumab in patients with AR+ metastatic TNBC (mTNBC). Methods This study was an open‐label phase II study for AR+ (≥10%, 1+ by immunohistochemistry [IHC]) mTNBC. Eligible patients received pembrolizumab 200 mg intravenous (IV) every 3 weeks and enobosarm 18 mg oral daily. The primary objective was to evaluate the safety of enobosarm plus pembrolizumab and determine the response rate. Peripheral blood, tumor biopsies, and stool samples were collected for correlative analysis. Results The trial was stopped early because of the withdrawal of GTx‐024 drug supply. Eighteen patients were enrolled, and 16 were evaluable for responses. Median age was 64 (range 36–81) years. The combination was well tolerated, with only a few grade 3 adverse events: one dry skin, one diarrhea, and one musculoskeletal ache. The responses were 1 of 16 (6%) complete response (CR), 1 of 16 (6%) partial response (PR), 2 of 16 (13%) stable disease (SD), and 12 of 16 (75%) progressive disease (PD). Response rate (RR) was 2 of 16 (13%). Clinical benefit rate (CBR) at 16 weeks was 4 of 16 (25%). Median follow‐up was 24.9 months (95% confidence interval [CI], 17.5–30.9). Progression‐free survival (PFS) was 2.6 months (95% CI, 1.9–3.1) and overall survival (OS) was 25.5 months (95% CI, 10.4–not reached [NR]). Conclusion The combination of enobosarm and pembrolizumab was well tolerated, with a modest clinical benefit rate of 25% at 16 weeks in heavily pretreated AR+ TNBC without preselected programmed death ligand‐1 (PD‐L1). Future clinical trials combining AR‐targeted therapy with immune checkpoint inhibitor (ICI) for AR+ TNBC warrant investigation.

DummyNeratinib has great efficacy in treating HER2+ breast cancer but is associated with significant gastrointestinal toxicity. The objective of this pilot study was to understand the association of gut microbiome and neratinib-induced diarrhea. Twenty-five patients (age ≥ 60) were enrolled in a phase II trial evaluating safety and tolerability of neratinib in older adults with HER2+ breast cancer (NCT02673398). Fifty stool samples were collected from 11 patients at baseline and during treatment. 16S rRNA analysis was performed and relative abundance data were generated. Shannon’s diversity was calculated to examine gut microbiome dysbiosis. An explainable tree-based approach was utilized to classify patients who might experience neratinib-related diarrhea (grade ≥ 1) based on pre-treatment baseline microbial relative abundance data. The hold-out Area Under Receiver Operating Characteristic and Area Under Precision-Recall Curves of the model were 0.88 and 0.95, respectively. Model explanations showed that patients with a larger relative abundance of Ruminiclostridium 9 and Bacteroides sp. HPS0048 may have reduced risk of neratinib-related diarrhea and was confirmed by Kruskal-Wallis test (p ≤ 0.05, uncorrected). Our machine learning model identified microbiota associated with reduced risk of neratinib-induced diarrhea and the result from this pilot study will be further verified in a larger study.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT02673398.