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Collecting duct carcinoma of the kidney is a rare and aggressive subtype of renal cell carcinoma (RCC) arising from the distal convoluted tubules. At the time of diagnosis, patients are more frequently symptomatic, with advanced locoregional stage, and have metastatic disease. The 2016 WHO Classification of Tumours of the Urinary System defined diagnostic criteria for this entity. However, the diagnostic features continue to evolve, with typical, but not entirely specific, histologic and immunophenotypic characteristics. In addition, the lack of consistent molecular alterations makes collecting duct carcinoma a diagnosis of exclusion, with historical cases being re-classified as fumarate hydratase deficient RCC, ALK rearranged RCC, renal medullary carcinoma or high-grade urothelial carcinoma. The rarity and poor prognosis of the tumor makes it difficult to reach consensus guidelines to guide therapy. In this manuscript we review the clinicopathologic features of collecting duct carcinoma including pathologic diagnostic criteria, molecular characteristics and differential diagnosis, and their possible implications for management.

Plant lectins, a natural source of glycans with a therapeutic potential may lead to the discovery of new targeted therapies. Glycans extracted from plant lectins are known to act as ligands for C-type lectin receptors (CLRs) that are primarily present on immune cells. Plant-derived glycosylated lectins offer diversity in their N-linked oligosaccharide structures that can serve as a unique source of homogenous and heterogenous glycans. Among the plant lectins-derived glycan motifs, Man9GlcNAc2Asn exhibits high-affinity interactions with CLRs that may resemble glycan motifs of pathogens. Thus, such glycan domains when presented along with antigens complexed with a nanocarrier of choice may bewilder the immune cells and direct antigen cross-presentation - a cytotoxic T lymphocyte immune response mediated by CD8+ T cells. Glycan structure analysis has attracted considerable interest as glycans are looked upon as better therapeutic alternatives than monoclonal antibodies due to their cost-effectiveness, reduced toxicity and side effects, and high specificity. Furthermore, this approach will be useful to understand whether the multivalent glycan presentation on the surface of nanocarriers can overcome the low-affinity lectin-ligand interaction and thereby modulation of CLR-dependent immune response. Besides this, understanding how the heterogeneity of glycan structure impacts the antigen cross-presentation is pivotal to develop alternative targeted therapies. In the present review, we discuss the findings on structural analysis of glycans from natural lectins performed using GlycanBuilder2 - a software tool based on a thorough literature review of natural lectins. Additionally, we discuss how multiple parameters like the orientation of glycan ligands, ligand density, simultaneous targeting of multiple CLRs and design of antigen delivery nanocarriers may influence the CLR targeting efficacy. Integrating this information will eventually set the ground for new generation immunotherapeutic vaccine design for the treatment of various human malignancies.

Introduction: Contact tracing is a central public health response to infectious disease outbreaks, especially in the early stages of an outbreak when specific treatments are limited. Current clinical and epidemiological data are insufficient to understand the full extent of the transmission potential of the COVID pandemic. The main advantages are that it can identify potentially infected individuals before severe symptoms emerge, and if conducted sufficiently quickly can prevent onward transmission from the secondary cases. Hence the study was undertaken. Methodology: It was a cross-sectional study conducted by the Department of Community Medicine, Bhopal from 9th May to 30th June 2020. Results: Out of 426 COVID positive patients, 54.93% were asymptomatic and 45.07% symptomatic. Fever was the most common presentation reported by the COVID positive patients. Mean incubation period was 4.68 ±2.63 days. Contact with COVID-19 positive cases was major source of infection identified. Only 9.86% patients had co-morbidity. Out of 10512 contacts traced, 66.65% i.e., 6902 samples were collected. Overall Positivity rate was found to be 4.30%. The positivity of the advanced contact tracing is 2.42%. Conclusion: Contact tracing is a highly effective and robust strategy if given sufficient resources.

Introduction To describe the efficacy of infigratinib, a potent, selective fibroblast growth factor receptor (FGFR) 1-3 tyrosine kinase inhibitor, across lines of therapy (LOT) in patients with metastatic urothelial cancer (mUC). Patients and Methods Eligible patients had mUC and prior platinum-based chemotherapy, unless contraindicated, and activating FGFR3 mutation/fusion. Patients received infigratinib 125 mg orally daily (3 weeks on/1 week off) in a single-arm, open-label study. Primary endpoint: investigator-assessed confirmed objective response rate (ORR). Disease control rate (DCR), progression-free survival (PFS), best overall response (BOR) that included unconfirmed responses, and overall survival (OS) were also assessed. Subgroup analysis of efficacy and safety outcomes by LOT was performed. Results Sixty-seven patients were enrolled; 13 (19.4%) received infigratinib as early-line therapy for mUC due to ineligibility to receive platinum-based chemotherapy. Overall, ORR was 25.4% (95% CI 15.5-37.5) and DCR was 64.2% (95% CI 51.5-75.5). ORR was 30.8% (95% CI 9.1-61.4) with early-line infigratinib and 24.1% (95% CI 13.5-37.6) for ≥2 LOT. DCR was 46.2% (95% CI 19.2-74.9) for early-line and 68.5% (95% CI 54.4-80.5) for ≥2 LOT. PFS and OS appeared similar in both groups. Thirteen of 59 patients with a bladder primary tumor received early-line treatment with an ORR of 30.5% (95% CI 9.1-61.4), and 46 received ≥2 LOT with an ORR of 20.3% (95% CI 9.4-33.9); BOR was 38.5% (95% CI: 13.9-68.4%) and 42.6% (95% CI: 29.2-56.8%) in the early-line and salvage settings, respectively. Eight patients with upper tract urothelial carcinoma received salvage therapy (ORR, 50.0%; DCR, 100.0%). No significant differences in toxicities between LOT were observed. Conclusion Infigratinib has notable activity in patients with mUC regardless of LOT. The findings support the evaluation of infigratinib across different settings in mUC.

Treatment options for metastatic renal cell carcinoma (mRCC) and metastatic urothelial carcinoma (mUC) have increased dramatically over the past decade. However, even when novel approaches have proven to be effective as monotherapy, many patients still develop progressive disease, and different strategies are needed to increase clinical response and quality of life. Strategies combining targeted therapy (TT) and immunotherapy (IO) have emerged as a way to shorten the gap between responders and nonresponders to monotherapy and have reported promising results. In this review, we discuss the current role of cabozantinib in combination with IO agents in the treatment of metastatic RCC and UC and go over future directions in the field.Lay abstract Treatment options for both advanced kidney and bladder cancers have increased significantly over the last decade. However, even when these new approaches have proven to be effective, many patients still experience disease progression. Therefore, different strategies are needed to increase the response to treatment and quality of life. Strategies combining therapies directed to reduce the tumor's blood supply (targeted therapies) and therapies that increase the ability of the body to recognize and attack tumor cells (immunotherapy) have emerged as a way to increase the effectiveness obtained when using these drugs on their own. In this review, we discuss the current role of cabozantinib, a targeted therapy, in combination with immune-based agents in the treatment of advanced kidney and bladder cancers and go over future directions in the field.

The association between tobacco use and urothelial cancer of the bladder is well known. Given the worsening tobacco epidemic, here we make the case for systematic targeted points of intervention for urologists and other professionals to intervene against bladder cancer. Awareness of contemporary checkpoints where we can intervene for counseling patients may help medical education in a tobacco-pandemic difficult setting.

Context Bladder and kidney cancers require invasive procedures for definitive diagnosis, and bladder cancer requires repeated procedures to monitor for disease recurrence. Given the recent work to identify molecular alterations in liquid biopsies to diagnose and monitor these diseases, a synthesis of the growing body of evidence is merited. Objective To review current data on cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) and to synthesize their roles in the diagnosis, monitoring, and prognostication of bladder and kidney cancer. Evidence acquisition A literature review was conducted through August 15, 2020 including prospective and retrospective studies. Keywords included “cell-free DNA”, “circulating tumor DNA”, “kidney cancer”, “renal cell carcinoma”, “bladder cancer”, “upper tract urothelial carcinoma”, and “urothelial carcinoma”. Evidence synthesis Urine tumor DNA (utDNA) has sensitivity of 91% and specificity of 96% for detecting bladder cancer, outperforming cystoscopy and cytology. Increased utDNA and ctDNA are associated with progression from non–muscle-invasive to muscle-invasive disease. In patients undergoing cystectomy, ctDNA detection is associated with worse overall survival and disease recurrence, and with persistent tumor on surgical pathology in those who received neoadjuvant chemotherapy. cfDNA is significantly higher in patients with kidney cancer than in healthy controls or in those with benign lesions, and detectable ctDNA and increased cfDNA are associated with decreased survival. Conclusions Combined data from small studies provide evidence that cfDNA and ctDNA may have the ability to detect, monitor, and prognosticate in patients with bladder, upper tract urothelial, and kidney cancers. Patient summary In this review, we looked at the work that has been published so far on cell-free and circulating tumor DNA in bladder and kidney cancers. We found that while many of the studies were small, there is evidence that cell-free tumor DNA can emerge as a tool for the diagnosis and monitoring of treatment response for patients with these cancers.

BackgroundThe need of agonists and antagonists of β2 adrenoceptor (β2AR) is warranted in various human disease conditions including cancer, cardiovascular and other metabolic disorders. However, the sources of agonists of β2AR are diverse in nature. Interestingly, there is a complete gap in the exploration of agonists of β2AR from serum that is a well-known component of culture media which supports growth and proliferation of normal and cancer cells in vitro.MethodsIn this paper, we employed a novel vertical tube gel electrophoresis (VTGE)-assisted purification of intracellular metabolites of MCF-7 cells grown in vitro in complete media with fetal bovine serum (FBS). Intracellular metabolites of MCF-7 cells were then analyzed by LC-HRMS. Identified intracellular tripeptides of FBS origin were evaluated for their molecular interactions with various extracellular and intracellular receptors including β2AR (PDB ID: 2RH1) by employing molecular docking and molecular dynamics simulations (MDS). A known agonist of β2AR, isoproterenol was used as a positive control in molecular docking and MDS analysesResultsWe report here identification of a few novel intracellular tripeptides, namely Arg-His-Trp, (PubChem CID-145453842), Pro-Ile-Glu, (PubChem CID-145457492), Cys-Gln-Gln, (PubChem CID-71471965), Glu-Glu-Lys, (PubChem CID-11441068) and Gly-Cys-Leu (PubChem CID145455600) of FBS origin in MCF-7 cells. Molecular docking and MDS analyses revealed that among these molecules, the tripeptide Arg-His-Trp shows a favorable binding affinity with β2AR (−9.8 Kcal/mol). Furthermore, agonistic effect of this tripeptide, Arg-His-Trp is significant and comparable with that of a known agonist of β2AR, isoproterenol.ConclusionIn conclusion, we identified a unique Arg-His-Trp tripeptide of FBS origin in MCF-7 cells by employing a novel approach. This unique tripeptide Arg-His-Trp is suggested to be a potential agonist of β2AR and it may have applications in the context of various human diseases like bronchial asthma and chronic obstructive pulmonary disease (COPD).NOVELTY & IMPACT STATEMENTSThis paper reports on a novel vertical tube gel electrophoresis (VTGE) system that assisted in the purification and identification of a few intracellular tripeptides in the in vitro grown breast cancer cells, MCF-7ls.Molecular docking and molecular dynamics simulation analyses strongly suggest that the tripeptide Arg-His-Trp among others forms the most stable ligand-protein complex with β2 adrenoceptor (β2AR). Its binding affinity and the nature of molecular interactions are comparable or even better than the known agonists of β2AR.This tripeptide Arg-His-Trp is predicted to show manyfold less cytotoxicity, mutagenicity, cardiotoxicity, drug-drug interactions, microsomal stability, and drug-induced liver injury over the other known agonists of β2AR.The tripeptide Arg-His-Trp is therefore suggested as an effective agonist of β2AR and this may be validated in future, in preclinical and clinical models.

Background Genomic testing of somatic and germline DNA has transformed cancer care. However, low genetic knowledge among patients may compromise care and health outcomes. Given the rise in genomic testing, we sought to understand patients’ knowledge of their genetic test results. Materials and Methods We conducted a survey‐based study with 85 patients at a comprehensive cancer center. We compared self‐reported recall of (a) having had somatic/germline testing and (b) their specific somatic/germline results to the genomic test results documented in the medical record. Results Approximately 30% of patients did not recall having had testing. Of those who recalled having testing, 44% of patients with pathogenic/likely pathogenic germline mutations and 57% of patients with reported somatic alterations did not accurately recall their specific gene or variant‐level results. Conclusion Given significant knowledge gaps in patients’ recall of genomic testing, there is a critical need to improve patient‐directed education and return‐of‐results strategies., Considering the increase in genomic testing for cancer care, this study aimed to better understand patients’ knowledge of their genetic test results.

Aims: To optimize drying technique for the popular Dutch rose cultivar, Taj Mahal, by evaluating different drying methods and appraising the physical, biochemical and sensory quality of the product. Study Design: Completely Randomized Design. Place and Duration of Study: Department of Floriculture, Medicinal and Aromatic Plants, Faculty of Horticulture, Uttar Banga Krishi Viswavidyalaya, during 2019-2020 Methodology: Flowers of rose cultivar ‘Taj Mahal’, at their prime beauty i.e., half-opened bud stage, were subjected to embedded drying in silica gel at six different conditions viz. at room temperature (T1), in hot air oven at 45°C, (T2) and at 60°C, (T3) in micro-wave oven at 100% power level (T4), 80% power level (T5) and at 60% power level (T6). The quality of the ensuing dehydrated flowers was judged with respect to colour, weight, volume shrinkage and anthocyanin and carotenoid contents. Temperature during drying and time to reach optimum dehydrated condition under different drying techniques were recorded. Sensory evaluation for the quality of the products was done after six months of storage. Results: The time taken for optimum drying ranged from 120 hours in case of room temperature drying (25.1°C) to 3 minutes in microwave oven on high power i.e., 100% (130.4°C). Significant variation in final weight of the product was recorded between 18.34% to 28% of the fresh weight. Minimum shrinkage (42.85%) was noted in room drying (T1) and hot air oven drying at 60°C (43.53%). Maximum anthocyanin concentration (3.528 mg/g) was recorded in flowers dried at room temperature, whereas, minimum among the dried flowers, was recorded in microwave oven drying at 100% power level (1.439 mg/g). Maximum Carotenoid content (16.780 µg/g) was recorded in flowers dried in hot air oven at 45°C. Out of six treatments in the present study, maximum sensory score (30.38 out of 36) was gathered by T2, which was at par with T1 and T5. Conclusion: Dehydrating ‘Taj Mahal’ rose flowers by embedding in silica gel and drying under room temperature (25°C) for 120 hours or hot air oven at 45°C for 27.5 hours or microwave oven at 80% power level for 3.5 minutes can be recommended for commercial dry flower production.

In less than 5years immune checkpoint inhibitors (ICI) went from first FDA approval to become first-line options in advanced renal cell carcinoma. Despite that many patients have benefited from ICI, a significant fraction of individuals are refractory to these new immunological treatments. In this review, we discussed using intratumoral (i.t.) route of drug administration as an alternative to systemic therapy to increase the response rates and to circumvent potential drug-induced systemic adverse events. We provided a historic account of i.t. drug treatments in cancer and reviewed the contemporary experience in local drug delivery. We discussed the potential for enhancing the therapeutic impact of ICI by leveraging hydrogels as drug delivery vehicles and presented an outlook for implementing i.t. in renal cell carcinoma.

5068 Background: Anti-PD-1/PD-L1 immune-checkpoint inhibitors (ICI) are now a standard of care in metastatic renal cell carcinoma (mRCC). Older adults were underrepresented in registration trials and given that immunological senescence may affect the anti-tumor activity of ICIs, there is uncertainty about the efficacy of ICIs in this population. Here we provide real world data on outcomes of older adults with mRCC treated with ICIs. Methods: Patients with mRCC treated with a PD-1/PD-L1 ICI either as monotherapy or as a combination treatment from 2000 to 2019 were included. Older adult was defined as ≥ 70-years at the time of ICI treatment. Descriptive statistics were summarized in means, medians and proportions. Efficacy was assessed by survival analysis, including overall survival (OS), time to treatment failure (TTF), and overall response rate (ORR). Multivariate analyses adjusted for imbalances in IMDC risk factors. P < 0.05 was considered statistically significant. Results: Of 1427 patients, 397 (28%) were older adults. Mean age of older vs. younger adults was 74 (70-92) vs. 60 (22-69) years. Groups were comparable in terms of gender (Female 28.5% vs. 26.1%, p = 0.36), rates of nephrectomy (21% vs. 18.3%, p = 0.24) and presence of sarcomatoid features (12.3% vs. 17.8%, p = 0.14). Proportion of IMDC risk-groups between older vs. younger adults were as follows: 15.4% vs. 18.2% for favorable, 61.2% vs. 59.1% for intermediate, and 23.4% vs. 22.7% for poor; there was no statistical difference (p = 0.55). ICI was used as 1st line in 40%, 2nd line in 48.5% and 3rd line in 11.5% patients; older adults were less likely to be treated with ICI in 1st line (32.2% vs. 43%, p < 0.01). In terms of survival, older adults had poorer median OS (25.1m vs. 30.8m, p < 0.01) but similar median TTF (6.9m vs. 6.9m, p = 0.40) compared to younger adults. In multivariate analyses, older age was not a predictor of either worse OS (aHR = 1.02, p = 0.86) or TTF (aHR = 0.95, p = 0.59). Older adults had a lower ORR compared to younger (24% vs. 31%, p = 0.01), which was mainly driven by responses in 1st line (31% vs. 44%, p = 0.02) and not observed in 2nd/3rd line (20% vs. 20%, p = 0.86). Conclusions: On multivariate analyses, older adults with mRCC treated with ICI had no difference in OS and TTF when compared to younger adults, despite having lower ORR in 1st line. Our data supports that older age is not an independent risk factor for survival; thus, treatment selection should not be based solely on chronological age.

Background The use of immune checkpoint inhibitors combined with vascular endothelial growth factor (VEGF)-targeted therapy as second-line treatment for metastatic clear cell renal cancer (mRCC) has not been evaluated prospectively. Objective To evaluate the efficacy and safety of atezolizumab + bevacizumab following disease progression on atezolizumab or sunitinib monotherapy in patients with mRCC. Design, setting, and participants IMmotion150 was a multicenter, randomized, open-label, phase 2 study of patients with untreated mRCC. Patients randomized to the atezolizumab or sunitinib arm who had investigator-assessed progression as per RECIST 1.1 could be treated with second-line atezolizumab + bevacizumab. Intervention Patients received atezolizumab 1200 mg intravenously (IV) plus bevacizumab 15 mg/kg IV every 3 wk following disease progression on either atezolizumab or sunitinib monotherapy. Outcome measurements and statistical analysis The secondary endpoints analyzed during the second-line part of IMmotion150 included objective response rate (ORR), progression-free survival (PFS), and safety. PFS was examined using Kaplan-Meier methods. Results and limitations Fifty-nine patients in the atezolizumab arm and 78 in the sunitinib arm were eligible, and 103 initiated second-line atezolizumab + bevacizumab (atezolizumab arm, n = 44; sunitinib arm, n = 59). ORR (95% confidence interval [CI]) was 27% (19–37%). The median PFS (95% CI) from the start of second line was 8.7 (5.6–13.7) mo. The median event follow-up duration was 19.4 (12.9–21.9) mo among the 25 patients without a PFS event. Eighty-six (83%) patients had treatment-related adverse events; 31 of 103 (30%) had grade 3/4 events. Limitations were the small sample size and selection for progressors. Conclusions The atezolizumab + bevacizumab combination had activity and was tolerable in patients with progression on atezolizumab or sunitinib. Further studies are needed to investigate sequencing strategies in mRCC. Patient summary Patients with advanced kidney cancer whose disease had worsened during treatment with atezolizumab or sunitinib began second-line treatment with atezolizumab + bevacizumab. Tumors shrank in more than one-quarter of patients treated with this combination, and side effects were manageable.

OBJECTIVE Emotional problem-related distress is a common issue faced by patients with cancer. However, patients suffering with this emotional burden do not typically seek assistance. This study sought to determine the prevalence of emotional problem-related distress by cancer type, and identify factors correlated with the level of assistance requested. METHODS Using the SupportScreen®, patients were screened for emotional problem-related distress at their first or second visit to an NCI designated Comprehensive Cancer Center. General Linear Model was used to test the association between emotional problem-related distress and type of cancer, and the relationship between level of assistance requested and patients' characteristics. RESULTS A total of 2,421 patients were included in this analysis. Patients were mostly female (62%), diagnosed with breast (24%), gynecological (16%) or gastrointestinal (15%) cancers. Highest levels of emotional problem-related distress were reported by patients diagnosed with lung, gynecological, breast and gastrointestinal cancers. Level of assistance requested were significantly associated with problem-related distress scores (p

Context Bladder urothelial carcinoma (BUC) and upper tract urothelial carcinoma (UTUC) have genetic differences, which may influence therapy. Objective The aim of the current review was to summarize the current genetic understanding of upper tract and BUC. Evidence acquisition PubMed, Cochrane, and Web of Science online databases were searched systematically up to February 2020, using the following keywords: urothelial carcinomas, upper urinary tract, renal pelvis, ureter, bladder cancer, and genetics. Evidence synthesis UTUC and BUC share mutations in similar genes, such as FGFR3, TP53, and HRAS, and epigenetic genes, such as KDM6A and KMT2A-C, but at varying frequencies. Furthermore, subtyping of UTUC and BUC has identified similar expression subtypes, but UTUC is more often luminal with more T-cell depletion. Clonal studies indicate that BUC after UTUC is also likely luminal, while UTUC after BUC is often basal. Conclusions UTUC and BUC share many genomic alterations, but at different frequencies, which recapitulate with their metachronous recurrences. These differences likely contribute to the behavior of these two cancers and imply that they and their metachronous recurrences should be treated as two related yet distinct entities. Patient summary Urothelial carcinoma of the bladder has distinct genomic features, which are different from distinct genomic features of urothelial carcinoma of the renal pelvis and/or ureter. These features can be used for tailored treatment options specific to tumors of different locations.

Although predominantly urothelial, some bladder cancer and upper tract urothelial cancer (BC/UTUC) harbor histologic variants. Small cell BC (SCBC) variants comprised ˜5% of The Cancer Genome Atlas BC cohort, with a poor prognosis. We describe genomic profiles of BC/UTUC with small cell/neuroendocrine features identified in the Foundation Medicine database from June 2012 to September 2018. Of 3368 BC/UTUC samples, 3.92% (132) harbored small cell/neuroendocrine features by immunohistochemistry. Mutations were noted in: TP53 (92%), RB1 (75%), combined TP53/RB1 (72%), and TERT promoter (68%). Of the samples, 6.5% had TMB ≥ 10 mutations/Mb. RNA expression profiling of 24 pure SCBC and 51 urothelial BC (UBC) muscle-invasive samples evaluated from a separate cohort revealed a large number of differentially expressed genes with suppression of several inflammatory pathways in SCBC compared with UBC. This largest reported SCBC dataset to date confirms enrichment of signatures in SCBC similar to small cell lung cancer and describes unique gene expression compared with UBC. These findings may explain aggressive SCBC phenotype. Patient summary Small cell bladder cancer (SCBC) is an aggressive subtype that microscopically resembles aggressive small cell lung cancer (SCLC). This study confirms that SCBC shares DNA changes similar to SCLC and that SCBC expresses many genes that urothelial bladder cancer does not, possibly explaining aggressive SCBC activity.

SummaryTAS0728 is an oral covalent binding inhibitor of human epidermal growth factor receptor 2 (HER2). A first-in-human open-label, dose-escalation, phase I study (NCT03410927) was initiated to investigate the safety and dose-limiting toxicity (DLT) and to determine the maximum tolerated dose (MTD) and/or recommended phase II dose of TAS0728 in adults with advanced solid tumors with HER2 or HER3 overexpression, amplification or mutation. In total, 19 patients received TAS0728 at escalating doses from 50 to 200 mg BID for 21-day cycles. Following escalation of the dose to 200 mg BID, a total of two DLTs were observed, both cases of Grade 3 diarrhea (lasting >48 h and not responsive to aggressive antidiarrheal treatment). Following de-escalation of the dose to 150 mg BID, another DLT of Grade 3 diarrhea was observed in one patient. Additionally, at 150 mg BID, one patient had a fatal cardiac arrest after receiving 1 cycle (21 days) of TAS0728. The etiology of the cardiac arrest event was not clear, however causal relationship to TAS0728 could not be excluded due to the temporal association observed. Partial responses were observed in 2 of 14 patients evaluable for TAS0728 treatment response. The study was stopped due to unacceptable toxicity during the dose-escalation as the overall risk-benefit ratio no longer favored the dose level being tested, therefore the MTD was not determined. ClinicalTrials.gov registration number: https://clinicaltrials.gov/ct2/show/NCT03410927; registered on January 25, 2018.

Background Systemic therapy (ST) can be deferred in patients who have metastatic renal cell carcinoma (mRCC) and slow-growing metastases. Currently, this subset of patients managed with active surveillance (AS) is not well described in the literature. Methods This was a prospective observational study of patients with mRCC across 46 US community and academic centers. The objective was to describe baseline characteristics and demographics of patients with mRCC initially managed by AS, reasons for AS, and patient outcomes. Descriptive statistics were used to characterize demographics, baseline characteristics, and patient-related outcomes. Wilcoxon 2-sample rank-sum tests and χ2 tests were used to assess differences between ST and AS cohorts in continuous and categorical variables, respectively. Kaplan-Meier survival curves were used to assess survival. Results Of 504 patients, mRCC was initially managed by AS (n = 143) or ST (n = 305); 56 patients were excluded from the analysis. Disease was present in 69% of patients who received AS, whereas the remaining 31% had no evidence of disease. At data cutoff, 72 of 143 patients (50%) in the AS cohort had not received ST. The median overall survival was not reached (95% CI, 122 months to not estimable) in patients who received AS versus 30 months (95% CI, 25-44 months) in those who received ST. Quality of life at baseline was significantly better in patients who were managed with AS versus ST. Conclusions AS occurs frequently (32%) in real-world clinical practice and appears to be a safe and appropriate alternative to immediate ST in selected patients.

In recent years, incredible progress has been made in the treatment of metastatic renal cell carcinoma, with a paradigm shift from the use of cytokines to tyrosine kinase inhibitors, and more recently, immune checkpoint inhibitors (ICIs). Despite advances in the metastatic setting, effective therapies in the adjuvant setting are a largely unmet need. Currently, sunitinib (Sutent, Pfizer) is the only therapy for the adjuvant treatment of RCC included in the National Comprehensive Cancer Network guidelines, which was approved by the FDA based on the improvement in disease-free survival (DFS) seen in the S-TRAC trial. However, improvement in DFS has not translated into an overall survival (OS) benefit for patients at high-risk of relapse post-nephrectomy, illustrating the need for more effective therapies. This manuscript will highlight attributes of both historical and current drug trials and their implications on the landscape of adjuvant therapy. Additionally, we will outline strategies for selecting patients in whom treatment would be most beneficial, as optimal patient selection is a crucial step towards improving outcomes in the adjuvant setting. This is especially critical, given the financial cost and pharmacological toxicity of therapeutic agents. Furthermore, we will review the design of clinical trials including the value of utilizing OS as an endpoint over DFS. Finally, we will discuss how the incorporation of genomic data into predictive models, the use of more sensitive imaging modalities for more accurate staging, and more extensive surgical intervention involving lymph node dissection, may impact outcomes.

Objective Recent neuroimaging studies have revealed differences in cortical and white matter brain structure in children with self‐limiting rolandic epilepsy (RE). Despite this, reproducibility of the findings has been difficult, and there is no consensus about where and when structural differences are most apparent. We performed a systematic review of quantitative neuroimaging studies in children with RE to explore these questions. Methods Using PRISMA guidelines, we used a multilayered search strategy to identify neuroimaging studies in RE. Publications were included if they were quantitative and derived from controlled group studies and passed a quality assessment. Findings of the studies were presented and stratified by duration of epilepsy and age of participants. Results We identified six gray matter studies and five white matter studies. Consistent findings were found inside and outside the central sulcus, predominantly within the bilateral frontal and parietal lobes, striatal structures, such as the putamen and white matter, mainly involving the left superior longitudinal fasciculus and connections between the left pre‐ and postcentral gyrus. Stratification of the T1 studies by age found that cortical thickness differences varied between the under and over 10 year olds. Furthermore, the longer the duration of epilepsy, the less likely differences were detected. In white matter studies, there was a reduction in differences with increased age and duration of epilepsy. Significance These findings would suggest that the development of regions of the cortex in children with RE is abnormal. These regions are more widespread than the suspected seizure onset zone. Moreover, the findings would suggest that these differences are evidence of neurodevelopmental delay rather than apparent “damage” from the epilepsy.

Tumor heterogeneity is influenced by various factors including genetic, epigenetic and axis of metabolic-epigenomic regulation. In recent years, metabolic-epigenomic reprogramming has been considered as one of the many tumor hallmarks and it appears to be driven by both microenvironment and macroenvironment factors including diet, microbiota and environmental pressures. Epigenetically, histone lysine residues are altered by various post-translational modifications (PTMs) such as acetylation, acylation, methylation and lactylation. Furthermore, lactylation is suggested as a new form of PTM that uses a lactate substrate as a metabolic ink for epigenetic writer enzyme that remodels histone proteins. Therefore, preclinical and clinical attempts are warranted to disrupt the pathway of metabolic-epigenomic reprogramming that will turn pro-tumor microenvironment into an anti-tumor microenvironment. This paper highlights the metabolicepigenomic regulation events including lactylation and its metabolic substrate lactate in the tumor microenvironment.

Purpose: Circulating tumor cells (CTC) are under investigation as a minimally invasive liquid biopsy that may improve risk stratification and treatment selection. CTCs uniquely allow for digital pathology of individual malignant cell morphology and marker expression. We compared CTC features and T-cell counts with survival endpoints in a cohort of patients with metastatic genitourinary cancer treated with combination immunotherapy. Experimental Design: Markers evaluated included pan-CK/CD45/PD-L1/DAPI for CTCs and CD4/CD8/Ki-67/DAPI for T cells. ANOVA was used to compare CTC burden and T-cell populations across timepoints. Differences in survival and disease progression were evaluated using the maximum log-rank test. Results: From December 2016 to January 2019, 183 samples from 81 patients were tested. CTCs were found in 75% of patients at baseline. CTC burden was associated with shorter overall survival (OS) at baseline (P = 0.022), but not on-therapy. Five morphologic subtypes were detected, and the presence of two specific subtypes with unique cellular features at baseline and on-therapy was associated with worse OS (0.9–2.3 vs. 28.2 months; P < 0.0001–0.013). Increasing CTC heterogeneity on-therapy had a trend toward worse OS (P = 0.045). PD-L1+ CTCs on-therapy were associated with worse OS (P < 0.01, cycle 2). Low baseline and on-therapy CD4/CD8 counts were also associated with poor OS and response category. Conclusions: Shorter survival may be associated with high CTC counts at baseline, presence of specific CTC morphologic subtypes, PD-L1+ CTCs, and low %CD4/8 T cells in patients with metastatic genitourinary cancer. A future study is warranted to validate the prognostic utility of CTC heterogeneity and detection of specific CTC morphologies.

Emerging efficacy data have led to the emergency use authorization or approval of COVID-19 vaccines in several countries worldwide. Most trials of COVID-19 vaccines excluded patients with active malignancies, and thus data on the safety, tolerability and efficacy of the vaccines in patients with cancer are currently limited. Given the risk posed by the COVID-19 pandemic, decisions regarding the use of vaccines against COVID-19 in patients participating in trials of investigational anticancer therapies need to be addressed promptly. Patients should not have to choose between enrolling on oncology clinical trials and receiving a COVID-19 vaccine. Clinical trial sponsors, investigators and treating physicians need operational guidance on COVID-19 vaccination for patients with cancer who are currently enrolled or might seek to enrol in clinical trials. Considering the high morbidity and mortality from COVID-19 in patients with cancer, the benefits of vaccination are likely to far outweigh the risks of vaccine-related adverse events. Herein, we provide operational COVID-19 vaccine guidance for patients participating in oncology clinical trials. In our perspective, continued quality oncological care requires that patients with cancer, including those involved in trials, be prioritized for COVID-19 vaccination, which should not affect trial eligibility., Patients with cancer have a high risk of morbidity and mortality from COVID-19. The rapid development of COVID-19 vaccines has provided new hope of mitigating the disease. Herein, the COVID19 and Cancer Clinical Trials Working Group calls for prioritization of patients with cancer, importantly including those participating in oncology clinical trials, for COVID-19 vaccination. The authors also provide operational COVID-19 vaccine guidance for patients participating in oncology clinical trials.

Epidemiological modeling is an important problem around the world. This research presents COVID-19 analysis to understand which model works better for different regions. A comparative analysis of t...

Purpose: Patients with advanced renal cell carcinoma with sarcomatoid features (sRCC) have poor prognoses and suboptimal outcomes with targeted therapy. This post hoc analysis of the phase III CheckMate 214 trial analyzed the efficacy of nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib in patients with sRCC. Patients and Methods: Patients with sRCC were identified via independent central pathology review of archival tumor tissue or histologic classification per local pathology report. Patients were randomized 1:1 to receive nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks (four doses) then nivolumab 3 mg/kg every 2 weeks, or sunitinib 50 mg orally every day (4 weeks; 6-week cycles). Outcomes in patients with sRCC were not prespecified. Endpoints in patients with sRCC and International Metastatic Renal Cell Carcinoma Database Consortium intermediate/poor-risk disease included overall survival (OS), progression-free survival (PFS) per independent radiology review, and objective response rate (ORR) per RECIST v1.1. Safety outcomes used descriptive statistics. Results: Of 1,096 randomized patients in CheckMate 214, 139 patients with sRCC and intermediate/poor-risk disease and six with favorable-risk disease were identified. With 42 months' minimum follow-up in patients with sRCC and intermediate/poor-risk disease, median OS [95% confidence interval (CI)] favored NIVO+IPI [not reached (NR) (25.2-not estimable [NE]); n = 74] versus sunitinib [14.2 months (9.3–22.9); n = 65; HR, 0.45 (95% CI, 0.3–0.7; P = 0.0004)]; PFS benefits with NIVO+IPI were similarly observed [median 26.5 vs. 5.1 months; HR, 0.54 (95% CI, 0.33–0.86; P = 0.0093)]. Confirmed ORR was 60.8% with NIVO+IPI versus 23.1% with sunitinib, with complete response rates of 18.9% versus 3.1%, respectively. No new safety signals emerged. Conclusions: NIVO+IPI showed unprecedented long-term survival, response, and complete response benefits versus sunitinib in previously untreated patients with sRCC and intermediate/poor-risk disease, supporting the use of first-line NIVO+IPI for this population. See related commentary by Hwang et al., p. 5

Background: Obesity is because of excessive fat accumulation that affects health adversely in the form of various diseases such as diabetes, hypertension, cardiovascular diseases, and many other disorders. Our Indian diet is rich in carbohydrates, and hence the sucrose-induced obesity is an apt model to mimic this. Ventromedial hypothalamus (VMH) is linked to the regulation of food intake in animals as well as humans. Purpose: To understand the role of VMHin sucrose-induced obesity on metabolic parameters. Methods: A total of 24 adult rats were made obese by feeding them on a 32% sucrose solution for 10 weeks. The VMH nucleus was ablated in the experimental group and sham lesions were made in the control group. Food intake, body weight, and biochemical parameters were compared before and after the lesion. Results: Male rats had a significant weight gain along with hyperphagia, whereas female rats did not have a significant weight gain inspite of hyperphagia. Insulin resistance and dyslipidemia were seen in both the experimental and control groups. Conclusion: A sucrose diet produces obesity which is similar to the metabolic syndrome with insulin resistance and dyslipidemia, and a VMH lesion further exaggerates it. Males are more prone to this exaggeration.

Background Cabozantinib is approved for metastatic renal cell carcinoma (mRCC) based on the METEOR and CABOSUN trials. However, real‐world effectiveness and dosing patterns of cabozantinib are not well characterized. Methods Patients with mRCC treated with cabozantinib between 2011 and 2019 were identified and stratified using the International mRCC Database Consortium (IMDC) risk groups. First‐ (1L), second‐ (2L), third‐ (3L), and fourth‐line (4L) overall response rate (ORR), time to treatment failure (TTF), and overall survival (OS) were analyzed. Dose reduction rates and their association with TTF and OS were determined. Results A total of 413 patients were identified. The ORRs across 1L to 4L were 32%, 26%, 25%, and 29%, respectively, and the median TTF rates were 8.3, 7.3, 7.0, and 8.0 months, respectively. The median OS (mOS) rates in 1L to 4L were 30.7, 17.8, 12.6, and 14.9 months, respectively. For patients treated with 1L PD(L)1 combination agent (n = 31), 2L cabozantinib had ORR of 22%, median TTF of 5.4 months, and mOS of 17.4 months. About 50% (129/258) of patients required dose reductions. The TTF and mOS were significantly longer for patients who required dose reduction vs. patients who did not, with an adjusted hazard ratio of 0.37 (95% CI 0.202–0.672, p, Cabozantinib demonstrates activity for use in real‐world patients with metastatic renal cell carcinoma across the first‐ to fourth‐line treatment settings.

In this theoretical analysis, our main concern is to explore the physical consequences of hybrid nanoparticle (NP) suspension in blood flowing through an inclined artery with mild stenosis filled with porous substances under the influence of a uniform magnetic field and heat source or sink. Darcy’s law is employed to predict the flow characteristics in the porous medium. The basic transported equations of blood flow in the diseased artery are formulated in a cylindrical coordinate system and simplified under the assumption of mild stenosis. The approximated analytical solutions based on the homotopy perturbation method (HPM) are achieved. Influences of significant physical parameters on the blood flow characteristics are displayed graphically and physical aspects are analyzed in detail. Graphical results based on the semi-analytical solutions reveal that the blood flow is appreciably influenced by the existence of stenosis at the arterial wall. The high concentration of hybrid nanoparticles significantly reduces the resistance impedance to the blood flow in a stenotic artery. The blood temperature due to the suspension of hybrid nanoparticles is found to be lower in comparison to copper blood or pure blood. The blood trapping pattern also manifests that the impulsion of hybrid nanoparticles speeds up the blood flow in the stenotic region. The rheological behavior of blood with hybrid nanoparticle (copper and alumina) suspension is examined because of decisive importance of nanoparticles in biomedicine, diagnosis, and treatment of arterial and cardiovascular diseases. It is believed that the simulated results hold key towards designing and analysis of bio-medical instruments or devices for great potential treatment modalities, nanodrug delivery systems, and anticancer drug industry, etc.

Patients with advanced genitourinary cancers face many challenges throughout their disease trajectory, and many will experience clinically relevant psychosocial distress. Certain groups, including female gender, younger age (and older age for suicide), unmarried status, and non–clear cell histology, remain at a higher risk, and evidence suggests that those with kidney and bladder cancers may be at an increased risk of suicide. Routine psychosocial screening, with brief validated tools, has the ability to identify patients’ unmet needs, assist the health care team in addressing such symptoms, and subsequently improve quality of life, adherence, and clinical outcomes. Effective supportive care modalities are available that address common patient needs in the context of incurable disease (eg, emotional and physical symptoms); however, challenges remain in terms of patient acceptance and access through insurance coverage. As a result, remote home-based interventions have emerged with the potential to mitigate emotional symptom burden and improve disease adjustment. In this study, we highlight studies reporting on the prevalence of psychosocial distress and associated risk factors in advanced genitourinary cancers, and review evidence-based interventions for the management of distress, including distress screening and psychosocial interventions. Patient summary This mini-review reports the prevalence of psychosocial distress and associated risk factors among patients with advanced kidney, bladder, or prostate cancer. We found that patients with these types of advanced genitourinary cancers are at a great risk of distress, including suicide, with consequent impairments in quality of life. We recommend that a distress screening program be incorporated as the standard of care and that referrals to appropriate psychosocial interventions be available to assist patients in greatest need.

PURPOSE We assessed the safety and efficacy of cabozantinib and nivolumab (CaboNivo) and CaboNivo plus ipilimumab (CaboNivoIpi) in patients with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignances. PATIENTS AND METHODS Patients received escalating doses of CaboNivo or CaboNivoIpi. The primary objective was to establish a recommended phase II dose (RP2D). Secondary objectives included objective response rate (ORR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS). RESULTS Fifty-four patients were enrolled at eight dose levels with a median follow-up time of 44.6 months; data cutoff was January 20, 2020. Grade 3 or 4 treatment-related adverse events (AEs) occurred in 75% and 87% of patients treated with CaboNivo and CaboNivoIpi, respectively, and included fatigue (17% and 10%, respectively), diarrhea (4% and 7%, respectively), and hypertension (21% and 10%, respectively); grade 3 or 4 immune-related AEs included hepatitis (0% and 13%, respectively) and colitis (0% and 7%, respectively). The RP2D was cabozantinib 40 mg/d plus nivolumab 3 mg/kg for CaboNivo and cabozantinib 40 mg/d, nivolumab 3 mg/kg, and ipilimumab 1 mg/kg for CaboNivoIpi. ORR was 30.6% (95% CI, 20.0% to 47.5%) for all patients and 38.5% (95% CI, 13.9% to 68.4%) for patients with mUC. Median DoR was 21.0 months (95% CI, 5.4 to 24.1 months) for all patients and not reached for patients with mUC. Median PFS was 5.1 months (95% CI, 3.5 to 6.9 months) for all patients and 12.8 months (95% CI, 1.8 to 24.1 months) for patients with mUC. Median OS was 12.6 months (95% CI, 6.9 to 18.8 months) for all patients and 25.4 months (95% CI, 5.7 to 41.6 months) for patients with mUC. CONCLUSION CaboNivo and CaboNivoIpi demonstrated manageable toxicities with durable responses and encouraging survival in patients with mUC and other GU tumors. Multiple phase II and III trials are ongoing for these combinations.

PURPOSE Evidence-based somatic and germline sequencing has transformed cancer care and improves patient outcomes. However, patients’ low genetic literacy and misunderstanding of their own genomic results poses a threat to the realization of precision oncology. To optimize patient genomic comprehension, we developed a Web-based, patient-directed, genomic sequencing education and return-of-results tool, HOPE-Genomics. METHODS The HOPE-Genomics prototype included somatic and germline sequencing results, embedded multimedia genomic education, and interactive features (eg, request for genetic counseling). Between January and April 2018, we elicited feedback on tool usability and comprehensiveness through participant surveys, 4 focus groups of patients with cancer and their family members, and 3 provider focus groups (comprising 8 patients, 5 family members, and 19 providers). RESULTS We identified themes in patient/family tool-related responses, including the desire to view a patient-friendly report, a desire to receive multiple types of genomic information (eg, prognostic and uncertain), high acceptability of report content, and interest in tool-enabled access to genetic counseling. Major themes from the clinician focus groups included believing the tool could help patients formulate questions and facilitate patients’ communication of results to family members. However, there were diverse responses from all participants in terms of tool implementation (ie, timing and nature of report release). Some participants preferred report release before meeting with the provider, and others preferred it during the appointment. Additionally, some clinicians were concerned about providing prognostic and treatment information through the tool. CONCLUSION There was high acceptability and interest from patients, family members, and providers in a patient-directed genomics report. Future work will determine whether direct-to-patient reporting of genomic results improves patient knowledge, care engagement, and compliance with genomically guided interventions.

PURPOSE: Patients with cancer commonly report distress and fear of cancer recurrence (FCR) impacting quality of life and clinical outcomes. This study aims to test the association between emotional well-being and clinical characteristics of survivors with localized renal cell carcinoma (RCC). MATERIALS AND METHODS: Survivors with localized RCC were invited to participate in this study through social media by the Kidney Cancer Research Alliance. Participants self-reported clinical characteristics, distress (Distress Thermometer), and FCR (Fear of Cancer Recurrence-7). Ordinal regression was used to test the association between emotional well-being and patient characteristics. RESULTS: A total of 412 survivors were included in this analysis. Participants were mostly female (79.4%) and well educated (58.3%), with a median age of 54 years (range, 30-80 years) and median time since diagnosis of 17.5 months. More than one half were diagnosed with stage I disease (56.1%). Most patients (62.3%) had a clear understanding of their diagnosis. A high prevalence of moderate to severe distress (67.0%) and FCR (54.9%) was reported across all survivors of RCC. Higher FCR was associated with female gender, younger age, and lack of understanding of their diagnosis ( P = .001), whereas more recent diagnosis was associated with higher distress levels ( P = .01). CONCLUSION: Our findings suggest that FCR is a common problem that is persistent after therapy and that certain individuals, including female and younger patients, may be at particular risk of experiencing clinically relevant FCR.

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, Our study provides novel evidence regarding gut microbiome modulation with a Bifidobacterium‐containing yogurt in metastatic renal cell carcinoma patients receiving targeted therapies and specifies the microbiota members (Barnesiella intestinihominis, Akkermansia muciniphila) associated with clinical benefit from targeted therapies in mRCC.

BACKGROUND Patient-reported outcomes have been used to assess treatment effectiveness and actively engage patients in their disease management. This study was designed to describe the patient-reported performance status (PS) and the provider-reported PS. METHODS Patients with metastatic genitourinary cancers were recruited from a single cancer center before the initiation of a new line of treatment. PS (Eastern Cooperative Oncology Group [ECOG]), quality of life (Functional Assessment of Chronic Illness Therapy-General), and distress (Patient-Reported Outcomes Measurement Information System Anxiety and Depression) were self-reported by patients. Clinical data (eg, age, sex, diagnosis, and physician-reported ECOG PS) were extracted from medical records. Multivariate analysis was used to determine the association between PS, quality of life, and psychological symptoms. RESULTS One hundred forty-five patients were enrolled (76.6% male, 70.3% White, 81.4% married, and 76.6% well educated). The median age was 67 years; 66.9% were diagnosed with renal cell carcinoma, 20.0% were diagnosed with urothelial carcinoma, and 13.1% were diagnosed with prostate cancer. Clinicians more frequently classified patients' ECOG PS as 0 in comparison with the patients themselves (92.4% vs 64.1%; P = .001). Higher clinician-reported ECOG PS was associated with poorer physical and functional well-being and higher rates of depression (P < .01), whereas higher patient-reported ECOG PS was associated with worse psychosocial outcomes (P < .01). CONCLUSIONS Discrepancies were noted between the patient- and provider-reported ECOG PS, with clinicians overestimating the ECOG PS in comparison with the patients themselves. This study's findings suggest that patients incorporate their social and emotional well-being into their PS score in addition to their physical well-being. This information is not immediately accessible to most clinicians from just a standard patient interview and likely accounts for the overestimation of the patients' ECOG PS by the clinicians.

Precision medicine approaches for managing patients with metastatic castrate-resistant prostate cancer (mCRPC) are lacking. Non-invasive approaches for molecular monitoring of disease are urgently needed, especially for patients suffering from bone metastases for whom tissue biopsy is challenging. Here we utilized baseline blood samples to identify mCRPC patients most likely to benefit from abiraterone plus prednisone (AAP) or enzalutamide. Baseline blood samples were collected for circulating tumor cell (CTC) enumeration and qPCR-based gene expression analysis from 51 men with mCRPC beginning treatment with abiraterone or enzalutamide. Of 51 patients (median age 68 years [51–82]), 22 received AAP (abiraterone 1000 mg/day plus prednisone 10 mg/day) and 29 received enzalutamide (160 mg/day). The cohort was randomly divided into training (n = 37) and test (n = 14) sets. Baseline clinical variables (Gleason score, PSA, testosterone, and hemoglobin), CTC count, and qPCR-based gene expression data for 141 genes/isoforms in CTC-enriched blood were analyzed with respect to overall survival (OS). Genes with expression most associated with OS included MSLN, ARG2, FGF8, KLK3, ESRP2, NPR3, CCND1, and WNT5A. Using a Cox-elastic net model for our test set, the 8-gene expression signature had a c-index of 0.87 (95% CI [0.80, 0.94]) and was more strongly associated with OS than clinical variables or CTC count alone, or a combination of the three variables. For patients with a low-risk vs. high-risk gene expression signature, median OS was not reached vs. 18 months, respectively (HR 5.32 [1.91–14.80], p = 0.001). For the subset of 41 patients for whom progression-free survival (PFS) data was available, the median PFS for patients with a low-risk vs high-risk gene expression signature was 20 vs. 5 months, respectively (HR 2.95 [1.46–5.98], p = 0.003). If validated in a larger prospective study, this test may predict patients most likely to benefit from second-generation antiandrogen therapy.

Preclinical models and early clinical data suggest an interplay between the gut microbiome and response to immunotherapy in solid tumors including metastatic renal cell carcinoma (mRCC). We sought to characterize the stool microbiome of mRCC patients receiving a checkpoint inhibitor (CPI) and to assess treatment-related changes in microbiome composition over the course of CPI therapy. Stool was collected from 31 patients before initiation of nivolumab (77%) or nivolumab plus ipilimumab (23%) therapy, of whom 58% experienced clinical benefit. Greater microbial diversity was associated with clinical benefit from CPI therapy (p = 0.001), and multiple species were associated with clinical benefit or lack thereof. Temporal profiling of the microbiome indicated that the relative abundance of Akkermansia muciniphila increased in patients deriving clinical benefit from CPIs. This study substantiates results from previous CPI-related microbiome profiling studies in mRCC. Temporal changes in microbiome composition suggest potential utility in modulating the microbiome for more successful CPI outcomes. Patient summary We compared the composition and diversity of the gut microbiome in patients receiving immunotherapy for renal cell carcinoma. We found that higher microbial diversity is associated with better treatment outcomes. Treatment response is characterized by changes in microbial species over the course of treatment.

Background An increased osteoprotegerin (OPG) level has been reported in both type-2 diabetes mellitus (T2DM) and cardiovascular diease (CVD) that are linked to sympathovagal imbalance (SVI). We explored the link of osteoprotegerin with cardiovagal modulation in T2DM. Methods We assessed fasting serum OPG, high-sensitive C-reactive protein (hsCRP), glucose, insulin and lipid profile in patients having T2DM receiving oral antidiabetic drugs (OAD) (n = 42) compared with age, gender and body composition-matched healthy participants without diabetes (n = 42). Rate pressure product (RPP), spectral indices of heart rate variability (HRV) and body composition were recorded in both the groups. Association of HOMA-IR and OPG with various parameters were assessed. Results Osteoprotegerin, HOMA-IR, hsCRP, coronary lipid risk factor were significantly increased, markers of cardiovagal modulation (TP, SDNN, RMSSD) were considerably decreased, ratio of low-frequency to high-frequency (LH-HF ratio), the indicator of SVI, and RPP, the marker of myocardial work stress were significantly higher in patients with diabetes, suggesting an overall elevated CVD risks in them. HOMA-IR was correlated with RMSSD, lipid risk factors and OPG. Rise in OPG was correlated with decreased cardiovagal modulation in patients with diabetes. There was significant contribution of OPG in decreasing TP, suggesting impaired cardiovagal modulation. Conclusion T2DM patients receiving OAD had higher cardiometabolic risks compared to age, gender and body composition-matched healthy individuals. Increased level of OPG is linked to decreased cardiovagal modulation in T2DM patients.

BACKGROUND: No study to date has assessed the relationship between treatment-specific therapeutic outcomes and race/ethnicity in metastatic renal cell carcinoma (mRCC). As targeted therapies have formed the backbone of first-line treatment options for mRCC until very recently, we assessed the relationship between race/ethnicity and targeted therapy-related outcomes in mRCC. OBJECTIVE: To retrospectively compare response rates and survival outcomes across ethnicities in patients who received first-line targeted therapies for mRCC. METHODS: Patients with mRCC receiving a first-line targeted therapy were identified from an institutional database encompassing consecutive patients treated between 2009 and 2019. Patient demographics, clinical characteristics and survival outcomes were recorded. The racial/ethnic groups included for analysis were Caucasian American, Hispanic American, and Asian American. Survival and response outcomes including progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and disease control rate (DCR) were calculated and compared across ethnic groups using Kaplan-Meier method and Chi-square test, respectively. RESULTS: In total, 295 patients were included for analysis. There were 184 (62.4%) Caucasian American patients, 82 (27.8%) Hispanic American patients, and 29 (9.8%) Asian American patients. No statistically significant differences in PFS nor OS were found between groups (PFS: 5.6 vs. 4.7 vs. 4.7 months, respectively) (OS: 32 vs. 31.7 vs. 51.7 months, respectively). No significant difference was found in ORR nor DCR across groups. Univariate cox regression analyses demonstrated no independent effect of race/ethnicity on PFS or OS. CONCLUSIONS: The apparent lack of differences in treatment-related outcomes across racial/ethnic groups is encouraging. However, further validation is required in larger series.

LAY SUMMARY Despite longer survival with immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1), metastatic urothelial carcinoma remains lethal. There is an unmet need to further improve the efficacy of these agents. In their phase 2 trial, Zhang et al. evaluated the combination of pembrolizumab (a PD-1 inhibitor) plus acalabrutinib (a novel agent inhibiting an enzyme considered relevant to immunotherapy resistance) based on strong rationale but did not demonstrate clinical benefit compared with pembrolizumab alone. Future trials that examine such promising rational combinations may be able to evaluate selected patients based on validated biomarkers to optimize benefit in an endless pursuit of personalizing therapies.

In an era of several therapeutic options available, optimal treatment sequencing is crucial to providing patients the most effective therapy and promoting quality of life. In clear cell renal cell carcinoma, a combination approach with an immunotherapy backbone, such as nivolumab/ipilimumab or axitinib/pembrolizumab, has a key role in the first-line setting. Safety and activity data support the transition to single-agent targeted therapies in the second-line setting. Nivolumab monotherapy possesses clinical and mechanistic rationale as a second-line therapeutic option for patients treated with targeted therapies in the first-line setting. Gene expression models are being generated from large prospective clinical trial data sets.

The phase 3 JAVELIN Renal 101 trial (NCT02684006) demonstrated significantly improved progression-free survival (PFS) with first-line avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma (aRCC). We report updated efficacy data from the second interim analysis.Treatment-naive patients with aRCC were randomized (1 : 1) to receive avelumab (10 mg/kg) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were PFS and overall survival (OS) among patients with programmed death ligand 1-positive (PD-L1+) tumors. Key secondary end points were OS and PFS in the overall population.Of 886 patients, 442 were randomized to the avelumab plus axitinib arm and 444 to the sunitinib arm; 270 and 290 had PD-L1+ tumors, respectively. After a minimum follow-up of 13 months (data cut-off 28 January 2019), PFS was significantly longer in the avelumab plus axitinib arm than in the sunitinib arm {PD-L1+ population: hazard ratio (HR) 0.62 [95% confidence interval (CI) 0.490-0.777]}; one-sided P0.0001; median 13.8 (95% CI 10.1-20.7) versus 7.0 months (95% CI 5.7-9.6); overall population: HR 0.69 (95% CI 0.574-0.825); one-sided P0.0001; median 13.3 (95% CI 11.1-15.3) versus 8.0 months (95% CI 6.7-9.8)]. OS data were immature [PD-L1+ population: HR 0.828 (95% CI 0.596-1.151); one-sided P = 0.1301; overall population: HR 0.796 (95% CI 0.616-1.027); one-sided P = 0.0392].Among patients with previously untreated aRCC, treatment with avelumab plus axitinib continued to result in a statistically significant improvement in PFS versus sunitinib; OS data were still immature.NCT02684006.

Intra- and inter-tumor heterogeneity (TMH) among colorectal cancer patients is considered as major hurdles to develop precise, potent, and personalized cancer therapeutics. The discernible factors that contribute to the existence of TMH and associated problems are suggested as genetic, molecular, epigenetic, and environmental pressures including shifts in trend from high-fiber diet to high-fat/processed sugar diet. In essence, components of high fat/processed sugar diet potentiate metabolic re-programing of inherent cellular heterogeneity of cancer stem cells (CSCs) by genetic and epigenetic pathways intersected by the farnesoid X receptor (FXR) nuclear receptor. Therefore, choices of dietary components shape up protumor or antitumor microenvironment by the modulation of FXR regulated transcriptional and epigenetic events in CSCs. In this article, we highlight the major understanding emanated from preclinical and clinical studies that indicate the potential contribution of high fiber/saturated sugar diet toward carcinogenesis of colorectal cancer.

BACKGROUND: Twitter has emerged as an important platform for conversation surrounding cancer-related topics. As use has proliferated, a better classification of physicians engaging in cancer discussions on Twitter is warranted. OBJECTIVES: To better characterize the medical specialists involved in disseminating kidney cancer information on social media through academic and Twitter metrics. METHODS: Clinical practitioners with an expertise in kidney cancer were identified. Demographics, metrics of academic rank and productivity, and Twitter usage data were collected. Correlations were calculated for the generation of a model predictive of the number of Twitter followers. Analysis of the experts’ Twitter content was performed. RESULTS: Among 59 kidney cancer experts identified, 14 (23.7%) were assistant professors, 24 (40.7%) were associate professors, and 21 (35.6%) were full professors. A total of 5424 tweets were analyzed, 86% of which were medically-related. We identified several differences between academic rank and Twitter variables. Associate professors registered a greater median number of followers subscribed to their Twitter accounts (2360) versus assistant professors (1253) and full professors (934) (p = 0.03) and a greater median number of accounts they themselves followed (752 vs. 290 vs. 235, respectively; p = 0.0009). Use of a more generalized approach (ANCOVA) showed that the most predictive variables for the number of followers are number of tweets, H-index, and percentage of medical tweets (R2 = 0.70). CONCLUSIONS: This study supported correlations between metrics of academic and Twitter activity. The generation of a model to predict the number of followers on Twitter is novel – future work will validate this in other disease types.

The treatment landscape of metastatic renal cell carcinoma (RCC) has been revolutionized over the past two decades, bringing forth an era in which more than a dozen therapeutic agents are now available to treat patients. As a consequence, personalized care has become a critical part of developing effective treatment guidelines and improving patient outcomes. One of the most important emerging aspects of precision medicine in cancer is matching patients and treatments based on the genomic characteristics of an individual and their tumour. Despite the lack of a single genomic predictor of treatment response or prognostication feature in RCC, emerging research suggests that the identification of such markers remains promising. Mutations in VHL and alterations in its downstream pathways are the mainstay of RCC development and progression. However, the predictive value of VHL mutations has been questioned. Further research has examined mutations in genes involved in chromosome remodelling (for example, PBRM1, BAP1 and SETD2), DNA methylation and DNA damage repair, all of which have been associated with clinical outcomes. Here, we provide a comprehensive overview of genomic evidence in the context of RCC and its potential predictive and prognostic value. Genomic profiling of renal cell carcinoma has demonstrated the clinical relevance of several genetic alterations in different disease subtypes. Pal and colleagues discuss the prognostic and predictive value of these alterations, and how they might help to improve treatment selection and patient outcomes.

BACKGROUND: Tuberculosis (TB) and diabetes mellitus are still of much public health concern. Screening of TB patients for diabetes will ensure early case detection, better management of diabetes, and better TB treatment outcome. The objective of this study was to determine the prevalence and associated factors of diabetes in TB patients and their impact on treatment outcome of TB. MATERIALS AND METHODS: This was a longitudinal follow-up study of registered TB patients under the Revised National Tuberculosis Control Program in all five TB units of Bhopal district. Participants were contacted and the interview was conducted. The blood sugar of all TB patients was checked, and they were followed up to assess the treatment outcome from October 2014 to September 2017. Data were analyzed using SPSS (version 16.0. Chicago, SPSS Inc.). Logistic regression was done to find the factors for diabetes in TB patients. The Chi-square tests were used to find the difference in treatment outcomes and assess the relative risk for poor outcome in diabetic TB patients. RESULTS: Of total 662 TB patients, 82 (12.39%) were diagnosed as diabetic. Age >50 years, males, higher body mass index, pulmonary TB, patients on Category II treatment, and history of smoking were found to be predictors of diabetes in TB patients. The treatment outcome of TB was more unfavorable (defaulter, failure, and death) in diabetic TB patients (16.17%) than in nondiabetic TB patients (5.8%) (risk ratio = 2.78, 1.469–5.284 confidence interval). CONCLUSION: The high prevalence of diabetes and the unfavorable treatment outcome in diabetic TB patients make screening and management of diabetes at an early-stage crucial for a better outcome in TB patients.

PURPOSE Platinum-based chemotherapy for first-line treatment of metastatic urothelial cancer is typically administered for a fixed duration followed by observation until progression. “Switch maintenance” therapy with PD-1 blockade at the time of chemotherapy cessation may be attractive for mechanistic and pragmatic reasons. PATIENTS AND METHODS Patients with metastatic urothelial cancer achieving at least stable disease on first-line platinum-based chemotherapy were enrolled. Patients were randomly assigned double-blind 1:1 to switch maintenance pembrolizumab 200 mg intravenously once every 3 weeks versus placebo for up to 24 months. Patients with disease progression on placebo could cross over to pembrolizumab. The primary objective was to determine the progression-free survival. Secondary objectives included determining overall survival as well as treatment outcomes according to PD-L1 combined positive score (CPS). RESULTS Between December 2015 and November 2018, 108 patients were randomly assigned to pembrolizumab (n = 55) or placebo (n = 53). The objective response rate was 23% with pembrolizumab and 10% with placebo. Treatment-emergent grade 3-4 adverse events occurred in 59% receiving pembrolizumab and 38% of patients receiving placebo. Progression-free survival was significantly longer with maintenance pembrolizumab versus placebo (5.4 months [95% CI, 3.1 to 7.3 months] v 3.0 months [95% CI; 2.7 to 5.5 months]; hazard ratio, 0.65; log-rank P = .04; maximum efficiency robust test P = .039). Median overall survival was 22 months (95% CI, 12.9 months to not reached) with pembrolizumab and 18.7 months (95% CI, 11.4 months to not reached) with placebo. There was no significant interaction between PD-L1 CPS ≥ 10 and treatment arm for progression-free survival or overall survival. CONCLUSION Switch maintenance pembrolizumab leads to additional objective responses in patients achieving at least stable disease with first-line platinum-based chemotherapy and prolongs progression-free survival in patients with metastatic urothelial cancer.