The introduction of targeted therapy (TT) and immuno-oncology (IO) agents have revolutionized the treatment of metastatic renal cell carcinoma (mRCC). However, despite the significant improvements in survival and clinical response yielded by these agents, a significant percentage of patients still experience progressive disease. Evidence now suggests that microorganisms living in the gut (i.e., the gut microbiome) could be used as a biomarker for response and may also have utility in increasing response to these treatments. In this review, we present an overview of the role of the gut microbiome in cancer and its potential implications in the treatment of mRCC.

RORγt is known to instruct the differentiation of T helper 17 (T _H 17) cells that mediate the pathogenesis of autoimmune diseases. However, it remains unknown whether RORγt plays a distinct role in the differentiation and effector function of T _H 17 cells. Here, we show that mutation of RORγt lysine-256, a ubiquitination site, to arginine (K256R) separates the RORγt role in these two functions. Preventing ubiquitination at K256 via arginine substitution does not affect RORγt-dependent thymocyte development, and T _H 17 differentiation in vitro and in vivo, however, greatly impaired the pathogenesis of T _H 17 cell–mediated experimental autoimmune encephalomyelitis (EAE). Mechanistically, K256R mutation impairs RORγt to bind to and activate Runx1 expression critical for T _H 17-mediated EAE. Thus, RORγt regulates the effector function of T _H 17 cells in addition to T _H 17 differentiation. This work informs the development of RORγt-based therapies that specifically target the effector function of T _H 17 cells responsible for autoimmunity.

Adamantinoma-like Ewing sarcoma typically shows t(11;22) EWSR1::FLI1 translocation and complex epithelial differentiation. It poses a diagnostic challenge, especially in the head and neck region, due to its under-recognition and significant histologic overlap with other malignancies. Neoadjuvant and adjuvant treatment information on head and neck Adamantinoma-like Ewing sarcoma is limited. Herein, we report a case of a 78-year-old female with Adamantinoma-like Ewing sarcoma of the parotid gland, including the imaging findings and clinical response to neoadjuvant therapy followed by surgery. The efficacy of neoadjuvant therapy in the treatment of Adamantinoma-like Ewing sarcoma is discussed in the context of a review of pertinent literature. Adamantinoma-like Ewing sarcoma in the head and neck is frequently misdiagnosed as poorly differentiated squamous cell carcinoma or a basaloid salivary gland carcinoma. Adamantinoma-like Ewing sarcoma is a EWS1::FLI1 translocation driven tumor; frequently misdiagnosed on head and neck biopsies as poorly differentiated carcinoma, or squamous cell carcinoma. Ewing sarcoma-specific chemoregimen appears effective for this entity. If diagnosed early, patient may be amenable to neoadjuvant therapy, which may improve surgical and cosmetic outcomes. This is especially important in head and neck regions.

Objectives: To characterise the restrictiveness of eligibility criteria in contemporary renal cell carcinoma (RCC) trials, using recommendations from the American Society of Clinical Oncology (ASCO)‐Friends of Cancer Research (FCR) initiative. Methods: vPhase I–III trials assessing systemic therapies in patients with RCC starting between 30 June 2012 and 30 June 2022 were identified. Eligibility criteria regarding brain metastases, prior or concurrent malignancies, hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, and human immunodeficiency virus (HIV) infection were identified and stratified into three groups: exclusion, conditional inclusion, and not reported. Descriptive statistics were used to determine the frequency of eligibility criteria. Fisher's exact test or chi‐square test were used to calculate their associations with certain trial characteristics. Results: A total of 423 RCC trials were initially identified of which 112 (26.5%) had sufficient accessible information. Exclusion of patients with HIV infection, HBV/HCV infection, brain metastases, and prior or concurrent malignancies were reported in 74.1%, 53.6%, 33.0%, and 8.0% of trials, respectively. In the context of HIV and HBV/HCV infection, patients were largely excluded from trials evaluating immunotherapy (94.4% and 77.8%, respectively). In addition, brain metastases were excluded in trials assessing targeted therapy (36.4%), combined therapy (33.3%), and immunotherapy (22.2%). Exclusion of patients with prior or concurrent malignancies was less frequently reported, accounting for 9.1%, 8.3%, and 5.6% targeted therapy, combined therapy and immunotherapy trials, respectively. Conclusion: A substantial proportion of RCC trials utilise restrictive eligibility criteria, excluding patients with fairly prevalent comorbidities. Implementing the ASCO‐FCR recommendations will ensure resulting data are more inclusive and aligned with patient populations in the real‐world.

Introduction: In a joint statement, Friends of Cancer Research and the American Society of Clinical Oncology affirmed the need for broadening clinical trial eligibility criteria to expand patient access to investigational treatments and enroll cohorts more representative of the general population. Our study aimed to characterize and analyze the prevalence of overly exclusionary eligibility criteria in contemporary clinical trials involving patients with locally advanced and metastatic urothelial cancer.Methods: Utilizing MeSH query terms “(metastatic OR advanced OR stage IV OR unresectable) AND (bladder cancer OR upper tract urothelial carcinoma OR upper tract urothelial cancer)” in ClinicalTrials.gov, we identified 205 interventional urothelial cancer trials activated between June 30, 2012 through June 30, 2022. We investigated the prevalence of four potentially restrictive criteria: the presence of brain metastases, HIV infection, hepatitis B/C infection, and the presence of concurrent malignancies. Fisher's Exact test was utilized to ascertain significant associations between criteria and trial characteristics.Results: Of 205 trials found initially, 37 (18%) contained sufficient data for analysis. Overall, HIV infection and Hepatitis B/C infection were most restrictive, with most trials completely excluding patients with these conditions (89.2%; 56.8%). Restrictiveness for HIV infection and type of therapy were significantly associated, with most exclusionary trials involving combination or immunotherapies (39.4%; 33.3%; p = 0.003). Brain metastases were totally excluded by 35.1% of trials and had 18.9% of trials provide no explicit criteria or guidelines. Most trials specified conditions for the inclusion of patients with concurrent malignancies (91.9%). Variant histology was also underrepresented, with most trials not specifying or totally excluding all variant histology (43.2%; 8.1%).Conclusion: HIV infection and hepatitis B/C infection were commonly identified in exclusion criteria across these trials despite limited evidence suggesting these criteria significantly impact therapy efficacy and tolerability. Broadening and modernization of eligibility criteria will ensure more inclusive clinical trials.