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Background: Cancer survivors are at an increased risk of cardiovascular disease (CVD) compared with the general population. We sought to evaluate the impact of mosaic chromosomal alterations (mCA) on death of CVD causes, coronary artery disease (CAD) causes, and of any cause in patients with a cancer diagnosis. Methods: The study was a prospective cohort analysis of 48,919 UK Biobank participants with a cancer diagnosis. mCAs were characterized using DNA genotyping array intensity data and long-range chromosomal phase inference. Multivariable Cox regression models were used to ascertain the associations of mCAs. Exploratory endpoints included various incident cardiovascular phenotypes. Results: Overall, 10,070 individuals (20.6%) carried ≥ 1 mCA clone. In adjusted analyses, mCA was associated with an increased risk of death of CAD causes [HR, 1.37; 95% confidence interval (CI), 1.09–1.71; P = 0.006]. In sub-analyses, we found that carriers of mCAs diagnosed with kidney cancer had an increased risk of death of CVD causes (HR, 2.03; 95% CI, 1.11–3.72; P = 0.022) and CAD causes (HR, 3.57; 95% CI, 1.44–8.84; P = 0.006). Women diagnosed with breast cancer who carried a mCA also had a higher risk of death of CAD causes (HR, 2.46; 95% CI, 1.23–4.92; P = 0.011). Conclusions: Among cancer survivors, carriers of any mCA are at an increased risk of CAD death compared with noncarriers. Mechanistic studies should be considered to better ascertain the biological mechanisms underneath the observed associations between mCAs and cardiovascular events for specific cancer types. Impact: There may be clinical relevance in considering mCAs in patients diagnosed with cancer and undergoing treatment.

Supplementary Figure 2: Visual mapping of mosaic chromosomal alterations

Supplementary Table 6: Cox regression analyses evaluating the effect of mosaic chromosomal alterations on the risk of death of cardiovascular disease causes, coronary artery disease causes, from cancer, and any cause of death by chemotherapy status

Supplementary Table 1: Primary diagnostic codes for selected cancers

Supplementary Table 7: The effect of autosomal mosaic chromosomal alterations on death of cardiovascular disease causes, coronary artery disease causes, from cancer and any cause of death

Background:Cancer survivors are at an increased risk of cardiovascular disease (CVD) compared with the general population. We sought to evaluate the impact of mosaic chromosomal alterations (mCA) on death of CVD causes, coronary artery disease (CAD) causes, and of any cause in patients with a cancer diagnosis.Methods:The study was a prospective cohort analysis of 48,919 UK Biobank participants with a cancer diagnosis. mCAs were characterized using DNA genotyping array intensity data and long-range chromosomal phase inference. Multivariable Cox regression models were used to ascertain the associations of mCAs. Exploratory endpoints included various incident cardiovascular phenotypes.Results:Overall, 10,070 individuals (20.6%) carried ≥ 1 mCA clone. In adjusted analyses, mCA was associated with an increased risk of death of CAD causes [HR, 1.37; 95% confidence interval (CI), 1.09–1.71; P = 0.006]. In sub-analyses, we found that carriers of mCAs diagnosed with kidney cancer had an increased risk of death of CVD causes (HR, 2.03; 95% CI, 1.11–3.72; P = 0.022) and CAD causes (HR, 3.57; 95% CI, 1.44–8.84; P = 0.006). Women diagnosed with breast cancer who carried a mCA also had a higher risk of death of CAD causes (HR, 2.46; 95% CI, 1.23–4.92; P = 0.011).Conclusions:Among cancer survivors, carriers of any mCA are at an increased risk of CAD death compared with noncarriers. Mechanistic studies should be considered to better ascertain the biological mechanisms underneath the observed associations between mCAs and cardiovascular events for specific cancer types.Impact:There may be clinical relevance in considering mCAs in patients diagnosed with cancer and undergoing treatment.

Supplementary Table 5: Cox regression analyses evaluating the effect of mosaic chromosomal alterations on the risk of death of cardiovascular disease causes, coronary artery disease causes, from cancer, and any cause of death stratified by smoking status groups

Supplementary Table 9: The effect of mosaic loss of Y chromosome on death of cardiovascular disease causes, coronary artery disease causes, from cancer and any cause of death

Supplementary Table 8: The effect of mosaic loss of X chromosome on death of cardiovascular disease causes, coronary artery disease causes, from cancer, and any cause of death

Supplementary Table 3: Sensitivity analyses by Cox regression considering additional covariates

Supplementary Figure 1: Visual depiction of the proportion of patients with at least 1 mosaic chromosomal alteration

Supplementary Table 4: Multivariable competing-risks regression model for the prediction of death of CVD causes and CAD causes

Supplementary Table 2: ICD-9 and ICD-10 diagnostic and procedure codes for inpatient cardiovascular-related endpoints and for the primary endpoints

Supplementary Data from Biomarkers of Angiogenesis and Clinical Outcomes to Cabozantinib and Everolimus in Patients with Metastatic Renal Cell Carcinoma from the Phase III METEOR Trial

Supplementary Table from Biomarkers of Angiogenesis and Clinical Outcomes to Cabozantinib and Everolimus in Patients with Metastatic Renal Cell Carcinoma from the Phase III METEOR Trial

Purpose:Antiangiogenic VEGF receptor (VEGFR) inhibitors are approved for metastatic clear cell renal cell carcinoma (mccRCC) and their efficacy is higher in high angiogenic tumors. As cabozantinib inhibits multiple tyrosine kinase receptors, including VEGFRs, we tested whether markers of angiogenesis, including microvascular density (MVD) and mast cell density (MCD), could predict benefit from cabozantinib versus everolimus, using RCC samples from the METEOR (NCT01865747) trial.Experimental Design:MVD and MCD were studied in 430 patients (cabozantinib = 216, everolimus = 214) by double immunohistochemistry for CD31 (vascular marker) and tryptase (mast cell marker) coupled with automated image analysis. Results from evaluable cases (MVD = 360, MCD = 325) were correlated with progression-free survival (PFS), overall survival (OS), and objective response rate (ORR).Results:MVD was positively correlated with MCD. In the whole cohort, high MVD and high MCD were associated with longer PFS; improved PFS was most evident in patients with high levels of both MCD and MVD. Cabozantinib was associated with improved PFS, OS, and ORR compared with everolimus, irrespective of MVD levels. Cabozantinib was also associated with improved ORR compared with everolimus, irrespective of MCD levels. For PFS and OS, the treatment effect for cabozantinib versus everolimus tended to be greater in tumors with low MCD.Conclusions:High MVD and high MCD are associated with improved outcome in mccRCC but do not predict efficacy to cabozantinib versus everolimus. The high efficacy of cabozantinib in low angiogenic tumors allows us to speculate that its antitumor activity is not exclusively mediated by VEGFR inhibition.

Blood cell production is complex, partly genetically determined and influenced by acquired factors. However, there is a paucity of data on how these factors interplay in the context of aging, which is associated with a myeloid proliferation bias, clonal hematopoiesis (CH) and an increased incidence of myeloid cancers. We investigated hereditary and acquired factors underlying blood cell trait variability in a cohort of 2996 related and unrelated women from Quebec aged 55 to 101 years. We performed a genome-wide association study, evaluated the impact of chronic diseases and performed targeted deep sequencing of CH driver genes and X-chromosome inactivation (XCI)-based clonality analyses. Multivariable analyses were conducted using generalized linear mixed models. We document that aging is associated with increasing neutrophil and monocyte counts and decreasing lymphocyte counts. Neutrophil counts were influenced by variants in the region of GSDMA and PSMD3-CSF3 but this association decreased with age. In parallel, aging individuals with cardiometabolic comorbidities exhibited significantly higher neutrophil counts (4.1x109/L vs 3.83x109/L, p-value

Low-dose colchicine is effective in reducing the risks of recurrent cardiovascular events following an acute myocardial infarction (MI). However, the influence of colchicine on inflammation remains inconclusive. In the current study, we conducted a combined analysis using individual patient data from the COLCOT and LoDoCo-MI trials to assess the effect of low-dose colchicine on high-sensitivity C reactive protein (hs-CRP) in patients with acute MI.We performed a combined analysis of individual patient data from two clinical trials (COLCOT, LoDoCo-MI). Paired pre-treatment and post-treatment hs-CRP (mg/L) were available in 222 patients for LoDoCo-MI and 207 patients for COLCOT (nColchicine was not significantly associated with post-treatment hs-CRP when it was considered as a continuous variable (beta: -0.41, P = 0.429). However, the intervention was significantly associated with increased odds of achieving post-treatment hs-CRP values ≤1.0 mg/L compared to placebo (odds ratio: 1.64, 95% confidence interval: 1.07 to 2.51, P = 0.024).Reduction of inflammation may be a key component in the clinical efficacy of low-dose colchicine with respect to decreased risk of recurrent cardiovascular events following MI. Systematic sampling of hs-CRP before and after treatment with colchicine may be relevant.

Cancer survivors are at an increased risk of cardiovascular disease (CVD) compared to the general population. Here, we evaluated the impact of somatic mosaic chromosomal alterations (mCAs) on death of CVD causes, coronary artery disease (CAD) causes, from cancer, and of any cause in patients with a cancer diagnosis within the UK Biobank (n=48 919). mCAs were derived from DNA genotyping array intensity data and long-range chromosomal phase inference from participants. Overall, 10 070 individuals (20.6%) carried ≥1 mCA clone. In adjusted analyses, mCA was associated with an increased risk of death of CAD causes (hazard ratio [HR]: 1.37, 95% confidence interval [CI]: 1.09-1.71, P=0.006), from cancer (HR: 1.06, 95% CI: 1.00-1.11, P=0.041), and death of any cause (HR: 1.07, 95% CI: 1.02-1.12, P=0.005). Among cancer survivors, carriers of any mCA are at an increased risk of death of CAD causes and of any cause as compared to non-carriers.

Objective The objective of this study was to examine the risk of immune-related adverse events (irAEs) in patients with a preexisting autoimmune disease (pAID) presenting with a cutaneous melanoma receiving an immune checkpoint inhibitor (ICI) therapy. Methods Data from the Surveillance, Epidemiology, and End Results cancer registries and linked Medicare claims between January 2010 and December 2015 was used to identify patients diagnosed with cutaneous melanoma who had pAID or received ICI or both. Patients were then stratified into 3 groups: ICI+pAID, non-ICI+pAID, and ICI+non-pAID. Inverse probability of treatment weighted Cox proportional hazards regression models were fitted to assess the risk of cardiac, pulmonary, endocrine, and neurological irAE. Results In total, 3704 individuals were included in the analysis. The majority of patients consisted of non-ICI+pAID patients (N=2706/73.1%), while 106 (2.9%) patients and 892 (24.1%) were classified as ICI+pAID and ICI+non-pAID, respectively. The risk of irAE was higher in the ICI+pAID group compared with the non-ICI+pAID and ICI+non-pAID, respectively (non-ICI: cardiac: hazard ratio [HR]=3.59, 95% confidence interval [CI]: 2.83-4.55; pulmonary: HR=3.94, 95% CI: 3.23-4.81; endocrine: HR=1.72, 95% CI: 1.53-1.93; neurological: HR=3.88, 95% CI: 2.30-6.57/non-pAID: cardiac: HR=3.83, 95% CI: 3.39-4.32; pulmonary: HR=2.08, 95% CI: 1.87-2.32; endocrine: HR=1.23, 95% CI: 1.14-1.32; neurological: HR=3.77, 95% CI: 2.75-5.18). Conclusions Patients with a pAID face a significantly higher risk of irAEs. Further research examining the clinical impact of these events on the patients' oncological outcome and quality of life is urgently needed given our findings of significantly worse rates of adverse events.

We conducted a genome-wide association study of time to remission of COVID-19 symptoms in 1723 outpatients with at least one risk factor for disease severity from the COLCORONA clinical trial. We found a significant association at 5p13.3 (rs1173773; P = 4.94 × 10–8) near the natriuretic peptide receptor 3 gene (NPR3). By day 15 of the study, 44%, 54% and 59% of participants with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. In 851 participants not treated with colchicine (placebo), there was a significant association at 9q33.1 (rs62575331; P = 2.95 × 10–8) in interaction with colchicine (P = 1.19 × 10–5) without impact on risk of hospitalisations, highlighting a possibly shared mechanistic pathway. By day 15 of the study, 46%, 62% and 64% of those with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. The findings need to be replicated and could contribute to the biological understanding of COVID-19 symptom remission.

Previous studies have found an association between androgen deprivation therapy (ADT) and an increased risk of dementia and depression in elderly men. This association remains controversial, and little is known about the effects of ADT in younger men.To examine the association between the receipt of ADT and these outcomes in young men aged 40-64 yr presenting with nonmetastatic prostate cancer (PCa).For this observational study, we identified 9117 men aged 40-64 yr diagnosed with localized PCa between 2007 and 2014, without a pre-existing neurocognitive diagnosis, using the TRICARE military database.Kaplan-Meier curves were fitted to compare ADT versus no ADT. We also performed a subgroup analysis in patients undergoing ADT for ≥12 mo. The association between ADT and new-onset dementia or depression was evaluated using inverse-probability-of treatment-weight-adjusted Cox proportional hazards regression analysis.Patients receiving ADT had a significantly higher incidence of depression (30.2 vs 15.8 per 1000 person years) and dementia (17.9 vs 7.5 per 1000 person years). The risk of developing either outcome was higher in the ADT cohort (depression: hazard ratio [HR] 2.07, p 0.001; dementia: HR 1.70, p = 0.052). Additionally, there was a dose-response relationship between the duration of ADT and either outcome.In our cohort of young men with PCa, the receipt of ADT was associated with an increased risk of developing dementia and depression. Long-term use of ADT was associated with the highest risk of neurocognitive outcomes.In this study, we looked at the risk of dementia and depression in patients65 yr of age undergoing androgen deprivation therapy (ADT) for prostate cancer. We found that these patients had a higher risk of dementia and depression than those who did not undergo ADT.

Clonal hematopoiesis of indeterminate potential (CHIP) is predictive of hematological cancers and cardiovascular diseases, but the etiology of CHIP initiation and clonal expansion is unknown. Several lines of evidence suggest that proinflammatory cytokines may favor mutated hematopoietic stem cell expansion. To investigate the potential link between inflammation and CHIP, we performed targeted deep sequencing of 11 genes previously implicated in CHIP in 1887 subjects aged >70 years from the Montreal Heart Institute Biobank, of which 1359 had prior coronary artery disease (CAD), and 528 controls did not. We assessed association of CHIP with log transformed high-sensitivity C-reactive protein (hs-CRP), a validated biomarker of inflammation. CHIP was identified in 427 of the 1887 subjects (22.6%). CHIP mutations were more frequently identified in DNMT3A (11.6%) and TET2 (6.1%), with a higher proportion of TET2 mutations occurring in controls than in patients with CAD (9.0% vs 4.9%, P < .001). CHIP carriers had 21% higher hs-CRP levels compared with their noncarrier counterparts (eβ = 1.21, 95% confidence interval [CI]: 1.08 to 1.36; P = .001). A similar effect was observed in the subgroup of patients with known CAD (eβ = 1.22, 95% CI: 1.06 to 1.41; P = .005). These findings confirm the association between inflammation and CHIP. This association may open investigational avenues aimed at documenting mechanisms linking inflammation to clonal progression and ultimately supports prevention interventions to attenuate CHIP’s impact on cardiovascular disease and cancer.

PD-1 blockade has transformed the management of advanced clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of the PD-1 response remain incompletely elucidated. Here, we analyzed 592 tumors from patients with advanced ccRCC enrolled in prospective clinical trials of treatment with PD-1 blockade by whole-exome and RNA sequencing, integrated with immunofluorescence analysis, to uncover the immunogenomic determinants of the therapeutic response. Although conventional genomic markers (such as tumor mutation burden and neoantigen load) and the degree of CD8+ T cell infiltration were not associated with clinical response, we discovered numerous chromosomal alterations associated with response or resistance to PD-1 blockade. These advanced ccRCC tumors were highly CD8+ T cell infiltrated, with only 27% having a non-infiltrated phenotype. Our analysis revealed that infiltrated tumors are depleted of favorable PBRM1 mutations and enriched for unfavorable chromosomal losses of 9p21.3, as compared with non-infiltrated tumors, demonstrating how the potential interplay of immunophenotypes with somatic alterations impacts therapeutic efficacy. A pooled genetic, transcriptomic and immunopathologic analysis of over 500 tumors from patients with advanced renal cell cancer suggests that response to PD-1 blockade depends on both CD8+ T cell infiltration and enrichment of tumor-intrinsic somatic alterations.

Evidence for androgen deprivation therapy (ADT) and risk of dementia is both limited and mixed. We aimed to assess the association between ADT and risk of dementia among men with localized and locally advanced prostate cancer (PCa). We conducted a retrospective cohort study using SEER-Medicare-linked data among 100,414 men aged ≥ 66 years and diagnosed with localized and locally advanced PCa (cT1–cT4) between 1992 and 2009. We excluded men with a history of stroke, dementia, or use of psychiatric services. Men were followed until death or administrative end of follow-up at 36 months. Inverse-probability weighted Fine-Gray models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for Alzheimer’s, all-cause dementia, and use of psychiatric services by duration of pharmacologic ADT (0, 1–6, and ≥ 7 months). Among 100,414 men with PCa (median age 73 [IQR: 69–77] years; 84% white, 10% black), 38% (n = 37,911) received ADT within 6 months of diagnosis. Receipt of any pharmacologic ADT was associated with a 17% higher risk of all-cause dementia (HR 1.17, 95% CI 1.07–1.27), 23% higher risk of Alzheimer’s (HR 1.23, 95% CI 1.11–1.37), and 10% higher risk of psychiatric services use, though the confidence interval included the null (HR 1.10, 95% CI 1.00–1.22). Longer duration of ADT (≥7 months) was associated with a 25% higher risk of all-cause dementia, 34% higher risk of Alzheimer’s, and 9% higher risk of psychiatric services, compared with no ADT. Our study supports an association between pharmacologic ADT and higher risk of all-cause dementia, Alzheimer’s, and use of psychiatric services among men with localized and locally advanced PCa.

Background: Insurance coverage is associated with better cancer outcomes; however, the relative importance of insurance coverage may differ between cancers. This study compared the association between insurance coverage at diagnosis and cancer-specific mortality (CSM; insurance sensitivity) in 6 cancers. Patients and Methods: Using the SEER cancer registry, data were abstracted for individuals diagnosed with ovarian, pancreatic, lung, colorectal, prostate, or breast cancer in 2007 through 2010. The association between insurance coverage at diagnosis and CSM was modeled using a Fine and Gray competing-risks regression adjusted for demographics. An interaction term combining insurance status and cancer type was used to test whether insurance sensitivity differed between cancers. Separate models were fit for each cancer. To control for lead-time bias and to assess whether insurance sensitivity may be mediated by earlier diagnosis and treatment, additional models were fit adjusting for disease stage and treatment. Results: Lack of insurance was associated with an increased hazard of CSM in all cancers (PPinteraction=.04), ranging from an adjusted hazard ratio of 1.13 (95% CI, 1.01–1.28) in ovarian and 1.19 (95% CI, 1.11–1.29) in pancreatic cancer to 2.19 (95% CI, 2.02–2.37) in breast and 2.98 (95% CI, 2.54–3.49) in prostate cancer. The benefit of insurance was attenuated after adjusting for stage and treatment (eg, screening/early treatment effect), with the largest reductions in prostate, breast, and colorectal cancers. Conclusions: Greater insurance sensitivity was seen in screening-detected malignancies with effective treatments for early-stage disease (eg, prostate, breast, and colorectal cancers). Given that this differential is significantly reduced after adjusting for stage and treatment, our results suggest that a significant portion (but not all) of the benefit of insurance coverage is due to detection and treatment of certain curable early-stage cancers.

Introduction:Accountable care organizations are designed to financially incentivize efficiency and reduce low value care. To determine if accountable care organizations have impacted prosta...

Background The incidence of brain metastases (BM) in patients with renal cell carcinoma (RCC) is hypothesized to have increased in the last 2 decades. Objective To define incidence trends according to patient and clinical characteristics, to identify risk factors, and to describe outcomes of patients with BM for RCC. Design, setting, and participants Patients diagnosed with RCC between the years 2010 and 2013 within the Surveillance, Epidemiology, and End Results database. An external validation was also considered using patients diagnosed with RCC between 2010 and 2012 within the National Cancer Database. Outcome measurements and statistical analysis Incidence proportions of BM were calculated. Risk factors correlated with BM at diagnosis were identified via a 1000-bootstrap corrected multivariable logistic regression model. A risk model was then developed and evaluated using measures of predictive accuracy. Overall survival was examined using Cox regression analyses. Results and limitations The overall incidence proportions of BM at RCC diagnosis was 1.51% (95% confidence interval: 1.39–1.64%). White/other race, clear cell histology, and sarcomatoid differentiation, T2–4 disease, tumor dimension >10 cm, and N+ disease were significantly associated with BM at RCC diagnosis, and retained within the final prediction model. A risk score was created based on these variables (c-index: 0.803). BM at RCC diagnosis occurred in 0.5%, 3.6%, and 7.7% of patients categorized as low risk, intermediate risk, and high risk. Patients with BM were more likely to succumb to any death than those without BM at diagnosis (median overall survival: 6.4 mo vs not reached, respectively, adjusted hazard ratio: 1.87, 95% confidence interval: 1.67–2.08, p Conclusions Patients with BM at RCC have poor oncological outcomes. We have characterized the epidemiology of BM at RCC diagnosis and developed a clinical risk model for the purpose of predicting the development of BMs in patients diagnosed with a cortical renal mass. Patient summary In this report we examined recent proportions of patients with brain metastases at kidney cancer diagnosis in a large community database originating from the US. We developed a model that may be used during routine clinical practice to predict brain metastases. The urologic-oncological community may consider baseline imaging for brain metastases in patients without any symptoms but at high risk of having brain metastases according to the risk model. However, the proposed model certainly needs further testing and validation in the clinical setting. Future studies on brain metastases survival and treatment options are also needed.

To assess whether Medicare expenditures for men with incident prostate cancer, treated in Accountable Care Organizations (ACOs) differ from those of men treated in non-ACOs. Using the 20% Medicare sample, total charges for 1 year following an initial diagnosis of prostate cancer were abstracted from Medicare claims. Prostate cancer expenditures were calculated by subtracting total charges from the year prior to diagnosis. Propensity score weighting was used to balance baseline characteristics of men treated in ACOs and non-ACOs, and between treatment modalities (radiation, prostatectomy, and expectant management). A propensity score weighted regression model was then used to estimate mean expenditures for men with prostate cancer treated in ACOs and non ACOs and to test the association between ACO status and costs. We identified 3297 men treated in ACOs for localized prostate cancer versus 24,088 in the non-ACO cohort. The weighted total charges for each treatment modality were $32,358 (radiation), $27,662 (prostatectomy), and $11,134 (expectant management). In our propensity score weighted regression model, the association between charges and ACO status was not significant, nor was the interaction between treatment type and costs. This was true both overall, and in a stratified analysis by treatment type. There was no significant difference in Medicare spending on prostate cancer care based on provider ACO affiliation, regardless of treatment type. Although the effects of ACOs on clinical care are complex, this study adds to a growing body of evidence suggesting that ACOs fail to achieve significantly lower charges in certain clinical settings.

Studies have noted contrasting findings with regard to the contemporary incidence of metastatic prostate cancer (PCa) in the USA, especially in light of the United States Preventive Services Task Force (USPSTF) recommendations against prostate-specific antigen (PSA) screening in recent years. We used data from the 18 population- based tumor registries of the Surveillance, Epidemiology and End Results (SEER) 2004-2013 database to study trends in the incidence of metastatic PCa among men stratified by age and race. Joinpoint regression analyses were performed to identify time points associated with any statistically significant change in incidence. Overall, there was a significant increase in incidence between 2009 and 2013 (annual percentage change [APC] 3.10%; p

Aims Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown. Methods and results We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality. Conclusion The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.

We conducted a genome-wide association study of time to remission of COVID-19 symptoms in 1723 outpatients with at least one risk factor for disease severity from the COLCORONA clinical trial. We found a significant association at 5p13.3 (rs1173773; P = 4.94 × 10−8) near the natriuretic peptide receptor 3 gene (NPR3). By day 15 of the study, 44%, 54% and 59% of participants with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. In 851 participants not treated with colchicine (placebo), there was a significant association at 9q33.1 (rs62575331; P = 2.95 × 10−8) in interaction with colchicine (P = 1.19 × 10−5) without impact on risk of hospitalisations, highlighting a possibly shared mechanistic pathway. By day 15 of the study, 46%, 62% and 64% of those with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. The findings need to be replicated and could contribute to the biological understanding of COVID-19 symptom remission.

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC., Sarcomatoid and rhabdoid tumours are highly aggressive forms of renal cell carcinoma that are also responsive to immunotherapy. In this study, the authors perform a comprehensive molecular characterization of these tumours discovering an enrichment of specific alterations and an inflamed phenotype.

Supplemental Digital Content is available in the text., Background: The randomized, placebo-controlled COLCOT (Colchicine Cardiovascular Outcomes Trial) has shown the benefits of colchicine 0.5 mg daily to lower the rate of ischemic cardiovascular events in patients with a recent myocardial infarction. Here, we conducted a post hoc pharmacogenomic study of COLCOT with the aim to identify genetic predictors of the efficacy and safety of treatment with colchicine. Methods: There were 1522 participants of European ancestry from the COLCOT trial available for the pharmacogenomic study of COLCOT trial. The pharmacogenomic study’s primary cardiovascular end point was defined as for the main trial, as time to first occurrence of cardiovascular death, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina requiring coronary revascularization. The safety end point was time to the first report of gastrointestinal events. Patients’ DNA was genotyped using the Illumina Global Screening array followed by imputation. We performed a genome-wide association study in colchicine-treated patients. Results: None of the genetic variants passed the genome-wide association study significance threshold for the primary cardiovascular end point conducted in 702 patients in the colchicine arm who were compliant to medication. The genome-wide association study for gastrointestinal events was conducted in all 767 patients in the colchicine arm and found 2 significant association signals, one with lead variant rs6916345 (hazard ratio, 1.89 [95% CI, 1.52–2.35], P=7.41×10−9) in a locus which colocalizes with Crohn disease, and one with lead variant rs74795203 (hazard ratio, 2.51 [95% CI, 1.82–3.47]; P=2.70×10−8), an intronic variant in gene SEPHS1. The interaction terms between the genetic variants and treatment with colchicine versus placebo were significant. Conclusions: We found 2 genomic regions associated with gastrointestinal events in patients treated with colchicine. Those findings will benefit from replication to confirm that some patients may have genetic predispositions to lower tolerability of treatment with colchicine.

Purpose: Antiangiogenic VEGF receptor (VEGFR) inhibitors are approved for metastatic clear cell renal cell carcinoma (mccRCC) and their efficacy is higher in high angiogenic tumors. As cabozantinib inhibits multiple tyrosine kinase receptors, including VEGFRs, we tested whether markers of angiogenesis, including microvascular density (MVD) and mast cell density (MCD), could predict benefit from cabozantinib versus everolimus, using RCC samples from the METEOR (NCT01865747) trial. Experimental Design: MVD and MCD were studied in 430 patients (cabozantinib = 216, everolimus = 214) by double immunohistochemistry for CD31 (vascular marker) and tryptase (mast cell marker) coupled with automated image analysis. Results from evaluable cases (MVD = 360, MCD = 325) were correlated with progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Results: MVD was positively correlated with MCD. In the whole cohort, high MVD and high MCD were associated with longer PFS; improved PFS was most evident in patients with high levels of both MCD and MVD. Cabozantinib was associated with improved PFS, OS, and ORR compared with everolimus, irrespective of MVD levels. Cabozantinib was also associated with improved ORR compared with everolimus, irrespective of MCD levels. For PFS and OS, the treatment effect for cabozantinib versus everolimus tended to be greater in tumors with low MCD. Conclusions: High MVD and high MCD are associated with improved outcome in mccRCC but do not predict efficacy to cabozantinib versus everolimus. The high efficacy of cabozantinib in low angiogenic tumors allows us to speculate that its antitumor activity is not exclusively mediated by VEGFR inhibition.

e14592 Background: Ipilimumab is a CTLA-4 inhibitor widely used to treat advanced melanoma. While ipilimumab-induced cardiac immune-related adverse events (irAE) have been reported, there is a paucity of data from large cohorts. We investigated the risk and predictors of ipilimumab-associated cardiac irAE in a national cohort of patients with cutaneous melanoma. Methods: Using SEER-Medicare linked data, we compared the risk of cardiac irAE between patients treated with ipilimumab with or without concomitant treatment for cutaneous melanoma and controls not treated with ipilimumab following a primary diagnosis of cutaneous melanoma. We excluded patients ≤65 years and patients with cardiac comorbidities diagnosed within one year prior to the initiation of melanoma treatment. The primary endpoint was the incidence of at least one cardiac irAE after ipilimumab initiation including acute pericarditis, myocarditis, cardiomyopathy, conduction disorders, cardiac dysthymias, acute heart failure, and takotsubo syndrome. To estimate the risk of cardiac irAE, we conducted a multivariable competing-risk analysis adjusting for death of any cause within one year of treatment as a competing event. Then, we constructed a stepwise logistic regression to assess the predictors of having at least one cardiac irAE within one year of ipilimumab initiation. Subgroup analysis was conducted among patients who received ipilimumab only. The models were adjusted for patient demographics, disease stage, Charlson comorbidity index (CCI), history of hypertension, autoimmune disease, end stage renal disease (ESRD), chronic anticoagulant, and steroid use. Results: The cohort included 715 patients treated with ipilimumab and 22,070 controls. In the ipilimumab arm, 23.4% had metastatic disease, 9.5% had a history of autoimmune disease, and 2.2% had CCI≥2. The incidence rates of cardiac irAE among patients who received ipilimumab and among the control group were 23.3 and 13.6 per 1,000 person-years, respectively. We found that patients who received ipilimumab had a higher risk of cardiac irAE compared to controls (adjusted hazard ratio 1.87; 95%CI 1.50-2.32; p < 0.001). In addition to ipilimumab treatment, other predictors of cardiac irAE included male gender, older age, patients with metastatic disease, history of autoimmune disease, hypertension, ESRD, anticoagulant use, and CCI≥2. The predictors of cardiac irAE were also consistent in the subgroup analysis of patients who received ipilimumab only. Conclusions: Patients who received ipilimumab with or without concomitant treatment for cutaneous melanoma had a higher risk for cardiac irAE. Predictors of cardiac irAE help tailor therapy according to patients’ risk profiles.

Context Financial toxicity (FT) refers to the detrimental effects of financial strain caused by a cancer diagnosis on the well-being of patients and their families. It is highly prevalent among cancer patients and has been associated with inferior clinical outcomes. Objective To summarize the literature regarding FT among patients with prostate, bladder, and kidney cancer, and to propose a framework for future FT investigations. Evidence acquisition Primary manuscripts and abstracts reporting FT as a primary or secondary outcome or a covariate in patients with prostate, bladder, or kidney cancer, published before May 2020, were retrieved using the PubMed, Scopus, Embase, CINAHL, and Cochrane databases in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. Of 629 titles identified, 19, ten, and two studies met the inclusion criteria for prostate, bladder, and kidney cancer, respectively, and were included (24 unique articles). Evidence synthesis Significant heterogeneity was observed in covariates, methodology, and measure of FT. Factors commonly associated with FT included younger age at diagnosis, black race, low socioeconomic status, low education attainment, and rurality. FT was commonly associated with lower quality of life and nonadherence. FT was common among patients in countries with universal health coverage as well as those without, although the nature of these costs differed. Conclusions Despite paucity of literature, it is suggested that FT is common among patients with prostate and bladder cancer, and remains uncharacterized in kidney cancer patients. Future work will benefit from the incorporation of a formal FT framework, utilization of validated FT instruments to characterize FT consistently, and inclusion of FT measures in outcomes reported by patients with genitourinary cancers. Patient summary Financial toxicity affects many prostate, bladder, and kidney cancer patients; however, this toxicity is understudied. It is associated with decreased quality of life and lower medication and treatment adherence.

Background Despite randomized data demonstrating better overall survival favoring radical nephrectomy, partial nephrectomy continues to be the treatment of choice for low-stage renal cell carcinoma. Methods We utilized the National Cancer Database to identify patients younger than 50 years diagnosed with low-stage renal cell carcinoma (cT1) treated with radical nephrectomy or partial nephrectomy (2004–2007). Inverse probability of treatment weighting adjustment was performed for all preoperative factors to account for confounding factors. Kaplan-Meier curves and Cox proportional hazards regression analyses were used to compare overall survival of patients in the two treatment arms. Sensitivity analysis was performed to explore the interaction of type of surgery and clinical stage on overall survival. Results Among the 3009 patients (median age = 44 years [interquartile range (IQR) = 40–47 years]), 2454 patients (81.6%) were treated with radical nephrectomy and 555 patients (18.4%) with partial nephrectomy. The median follow-up was 108.6 months (IQR = 80.2–124.3 months) during which 297 patients (12.1%) in the radical nephrectomy arm and 58 patients (10.5%) in the partial nephrectomy arm died. Following inverse probability of treatment weighting adjustment, there was no difference in overall survival between patients treated with partial nephrectomy and radical nephrectomy (hazard ratio = 0.83, 95% confidence interval = 0.63 to 1.10, P = .196). There were no statistically significant interactions between type of surgery and clinical stage on treatment outcome. Conclusions There was no difference in long-term overall survival between radical and partial nephrectomy in young and healthy patients. This patient cohort may have sufficient renal reserve over their lifetime, and preserving nephrons by partial nephrectomy may be unnecessary.

Introduction Designing adjuvant trials is challenging because of uncertainties of prevalence and outcome of high-risk renal cell cancer (RCC) despite use of validated risk scores. Our objective is to investigate how differences in eligibility criteria may impact on potential study results in RCC adjuvant trials. Patients and Methods RECUR is a multicenter European database capturing patient and tumor characteristics, recurrence patterns, and survival of those curatively treated for non-metastatic RCC from 2006 to 2011 without any adjuvant therapy. We used RECUR to evaluate prevalence, disease-free survival (DFS), and overall survival (OS) according to eligibility criteria of immunotherapy-based adjuvant trials IMMotion 010 ( NCT03024996 ), Checkmate 914 ( NCT03138512 ), Keynote-564 ( NCT03142334 ), RAMPART ( NCT03288532 ), and PROSPER ( NCT03055013 ). Results Of 3024 relevant patients in RECUR, 408 (13.5%), 725 (24%), 609 (20.1%), 1363 (45.1%), and 1071 (35.4%) met eligibility criteria for IMMotion-010, CheckMate-914, Keynote-564, RAMPART, and PROSPER, respectively. The median and 5-year DFS Kaplan-Meier estimates in RECUR corresponding to each trial eligibility criteria were: not reached and 69.6% for RAMPART; not reached and 64.5% for PROSPER; 109.3 months (95% confidence interval [CI], 83.9-134.6 months) and 57% for CheckMate-914; 75.8 months (95% CI, 52.7-98.8 months) and 54.3% for Keynote-564; and 43.6 months (95% CI, 30.8-56.4 months) and 45% for IMMotion-010. Our analysis may be limited by the retrospective design. Conclusions RECUR provides estimated DFS and OS benchmarks for placebo arms of adjuvant checkpoint inhibitor studies and hence likely time to trial reporting. Well-documented contemporary registries rather than past risk models should be used to design future adjuvant trials.

Summary Immune checkpoint blockade (ICB) results in durable disease control in a subset of patients with advanced renal cell carcinoma (RCC), but mechanisms driving resistance are poorly understood. We characterize the single-cell transcriptomes of cancer and immune cells from metastatic RCC patients before or after ICB exposure. In responders, subsets of cytotoxic T cells express higher levels of co-inhibitory receptors and effector molecules. Macrophages from treated biopsies shift toward pro-inflammatory states in response to an interferon-rich microenvironment but also upregulate immunosuppressive markers. In cancer cells, we identify bifurcation into two subpopulations differing in angiogenic signaling and upregulation of immunosuppressive programs after ICB. Expression signatures for cancer cell subpopulations and immune evasion are associated with PBRM1 mutation and survival in primary and ICB-treated advanced RCC. Our findings demonstrate that ICB remodels the RCC microenvironment and modifies the interplay between cancer and immune cell populations critical for understanding response and resistance to ICB., Graphical abstract, Highlights • Distinct CD8+ T cell phenotypes are enriched after immune checkpoint blockade (ICB) • Immune checkpoint ligands are upregulated in macrophages and tumor cells after ICB • Two cancer cell subpopulations are conserved across heterogeneous RCC tumors • Cancer cell programs drive distinct immune interactions and predict patient outcomes, Bi et al. dissect the cancer cell and immune microenvironmental transcriptional programs in immune checkpoint blockade-exposed metastatic renal cell carcinoma, revealing immune subpopulation reprogramming and interactions with distinct cancer cell populations in the context of clinical resistance.

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors1–3, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings shed light on the molecular drivers of aggressivity and responsiveness to immune checkpoint inhibitors of S/R RCC tumors.

Background Androgen deprivation therapy (ADT) increases the risk of metabolic adverse effects among patients with prostate cancer. The transformative impact of mobile health (mHealth) apps may benefit men managing activity and nutrition at home. Objective This study aimed to evaluate the usability and patient experience of a newly developed mHealth app among prostate cancer patients on ADT and physicians’ beliefs about the potential benefits of using this app. Methods This study took place over 2 months, beginning in March 2019. A sample of 5 patients (age 45-75 years) initiating ADT participated in a semistructured focus group discussion with a facilitator. The study participants also included 5 specialist physicians who provided in-depth interviews. An institutional review board–approved script was used to guide both the focus group and physician interviews. Usability was tested through specific scenarios presented to the patients, including downloading the mHealth app, entering information on physical activity and meals, and navigating the app. The focus group and interviews were audio recorded and transcribed. Content analysis was used to analyze the transcripts iteratively and exhaustively. Thematic discrepancies between reviewers were resolved through consensus. Results The mean age of the patients was 62 years. This group included 4 White and 1 Latin American patients. The physician specialists included 2 urologists, 2 medical oncologists, and 1 radiation oncologist. Analyses revealed that the patients appreciated the holistic care enabled by the app. Difficulties were observed with registration of the app among 60% (3/5) of the patients; however, all the patients were able to input information about their physical activity and navigate the options within the app. Most patients (4/5, 80%) were able to input data on their recent meal. Among the health care physicians, the dominant themes reflected in the interviews included undermining of patients ability to use technology, patients’ fear of technology, and concern for the ability of older patients to access technology. Conclusions The patients reported an overall positive experience of using an mHealth app to record and track diet and exercise. Usability was observed to be an important factor for adoption and was determined by ease of registration and use, intuitive appearance of the app, and focus on holistic cancer care. The physicians believed that the app was easy to use but raised concerns about usability among older men who may not typically use smartphone apps.

BACKGROUND Androgen deprivation therapy (ADT) increases the risk of metabolic adverse effects among patients with prostate cancer. The transformative impact of mobile health (mHealth) apps may benefit men managing activity and nutrition at home. OBJECTIVE This study aimed to evaluate the usability and patient experience of a newly developed mHealth app among prostate cancer patients on ADT and physicians’ beliefs about the potential benefits of using this app. METHODS This study took place over 2 months, beginning in March 2019. A sample of 5 patients (age 45-75 years) initiating ADT participated in a semistructured focus group discussion with a facilitator. The study participants also included 5 specialist physicians who provided in-depth interviews. An institutional review board–approved script was used to guide both the focus group and physician interviews. Usability was tested through specific scenarios presented to the patients, including downloading the mHealth app, entering information on physical activity and meals, and navigating the app. The focus group and interviews were audio recorded and transcribed. Content analysis was used to analyze the transcripts iteratively and exhaustively. Thematic discrepancies between reviewers were resolved through consensus. RESULTS The mean age of the patients was 62 years. This group included 4 White and 1 Latin American patients. The physician specialists included 2 urologists, 2 medical oncologists, and 1 radiation oncologist. Analyses revealed that the patients appreciated the holistic care enabled by the app. Difficulties were observed with registration of the app among 60% (3/5) of the patients; however, all the patients were able to input information about their physical activity and navigate the options within the app. Most patients (4/5, 80%) were able to input data on their recent meal. Among the health care physicians, the dominant themes reflected in the interviews included undermining of patients ability to use technology, patients’ fear of technology, and concern for the ability of older patients to access technology. CONCLUSIONS The patients reported an overall positive experience of using an mHealth app to record and track diet and exercise. Usability was observed to be an important factor for adoption and was determined by ease of registration and use, intuitive appearance of the app, and focus on holistic cancer care. The physicians believed that the app was easy to use but raised concerns about usability among older men who may not typically use smartphone apps.