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Obesity is associated with an increased risk of developing clear cell renal cell carcinoma (RCC) but, paradoxically, obesity is also associated with improved oncological outcomes in this cancer. Because the biological mechanisms underlying this paradoxical association are poorly understood, we aimed to identify transcriptomic differences in primary tumour and peritumoral adipose tissue between obese patients and those at a normal weight. In this cohort study, we assessed data from five independent clinical cohorts of patients with clear cell RCC aged 18 years and older. Overweight patients were excluded from each cohort for our analysis. We assessed patients from the COMPARZ phase 3 clinical trial, a cohort from the Cancer Genome Atlas (TCGA), and a Memorial Sloan Kettering (MSK) observational immunotherapy cohort for their inclusion into our study. We assessed overall survival in obese patients (those with a body-mass index [BMI] ≥30 kg/m2) and in patients with a normal weight (BMI 18·5–24·9 kg/m2, as per WHO's BMI categories), defined as the time from treatment initiation (in the COMPARZ and MSK immunotherapy cohorts) or surgery (in the TCGA cohort) to the date of any-cause death or of censoring on the day of the last follow-up. We also evaluated and validated transcriptomic differences in the primary tumours of obese patients compared with those of a normal weight. We compared gene-expression differences in peritumoral adipose tissue and tumour tissue in an additional, prospectively collected cohort of patients with non-metastatic clear cell RCC (the MSK peritumoral adipose tissue cohort). We analysed differences in gene expression between obese patients and those at a normal weight in the COMPARZ, TCGA, and peritumoral adipose tissue cohorts. We also assessed the tumour immune microenvironment in a prospective cohort of patients who had nephrectomy for localised RCC at MSK. Of the 453 patients in the COMPARZ trial, 375 (83%) patients had available microarray data, pretreatment BMI measurements, and overall survival data for analyses, and we excluded 119 (26%) overweight patients, leaving a final cohort of 256 (68%) patients from this study for our analyses. From 332 patients in the TCGA cohort, we evaluated clinical and demographic data from 152 (46%) patients with advanced (ie, stages III and IV) clear cell RCC treated by nephrectomy; after exclusion of 59 (39%) overweight patients, our final cohort consisted of 93 (61%) patients. After exclusion of 74 (36%) overweight patients from the initial MSK immunotherapy study population of 203 participants, our final cohort for overall survival analysis comprised 129 (64%) participants. We found that overall survival was longer in obese patients than in those with normal weight in the TCGA cohort, after adjustment for stage or grade (adjusted HR 0·41, 95% CI 0·22–0·75), and in the COMPARZ clinical trial after adjustment for International Metastatic RCC Database (IMDC) risk score (0·68, 0·48–0·96). In the MSK immunotherapy cohort, the inverse association of BMI with mortality (HR 0·54, 95% CI 0·31–0·95) was not significant after adjustment for IMDC risk score (adjusted HR 0·72, 95% CI 0·40–1·30). Tumours of obese patients showed higher angiogenic scores on gene-set enrichment analysis-derived hallmark gene set angiogenesis signatures than did those of patients at a normal weight, but the degree of immune cell infiltration did not differ by BMI. We found increased peritumoral adipose tissue inflammation in obese patients relative to those at a normal weight, especially in peritumoral fat near the tumour. We found aspects of the tumour microenvironment that vary by BMI in the tumour and peritumoral adipose tissue, which might contribute to the apparent survival advantage in obese patients with clear cell RCC compared with patients at a normal weight. The complex interplay between the clear cell RCC tumour and peritumoral adipose tissue microenvironment might have clinical relevance and warrants further investigation. Ruth L Kirschstein Research Service Award, American Society of Clinical Oncology Young Investigator Award, MSK's Ludwig Center, Weiss Family Kidney Research Fund, Novartis, The Sidney Kimmel Center for Prostate and Urologic Cancers, and the National Institutes of Health (National Cancer Institute) Cancer Center Support Grant.

Integrated sequencing analysis identified a group of tumors among clear cell renal cell carcinomas characterized by hotspot mutations in TCEB1 (a gene that contributes to the VHL complex to ubiquitinate hypoxia-inducible factor). We analyzed 11 tumors from two distinct cohorts with TCEB1 mutations along with an expanded cohort to assess whether these should be considered an entity distinct from clear cell renal cell carcinoma and clear cell papillary renal cell carcinoma. All tumors were characterized by hotspot mutations in TCEB1 Y79C/S/F/N or A100P. Morphological and immunohistochemical characteristics of the tumors were assessed by two experienced genitourinary pathologists. Clinical and pathological variables, copy number alterations, mutations, and expression signatures were compared with a cohort of TCEB1 wild-type tumors. All TCEB1 -mutated tumors were VHL and PBRM1 wild type and contained distinct copy number profiles including loss of heterozygosity of chromosome 8, the location of TCEB1 (8q21.11). All tumors lacked the clear cell renal cell carcinoma signature 3p loss and contained distinct gene expression signatures. None of the clear cell papillary tumors harbored TCEB1 mutations. Pathologically, all TCEB1 -mutated tumors shared characteristic features including thick fibromuscular bands transecting the tumor, pure clear cell cytology frequently with cells showing voluminous cytoplasm, and clear cell renal cell carcinoma-like acinar areas associated with infolding tubular and focally papillary architecture. The presence of voluminous cytoplasm, absence of luminal polarization of tumor nuclei, and lack of extensive cup-like distribution of carbonic anhydrase-IX expression distinguish it from clear cell papillary carcinoma. None of the patients developed metastases at last follow-up (median 48 months). In sum, TCEB1 -mutated renal cell carcinoma is a distinct entity with recurrent hotspot mutations, specific copy number alterations, pathway activation, and characteristic morphological features. Further clinical follow-up is needed to determine whether these tumors are more indolent compared with the conventional clear cell renal cell carcinoma.

BackgroundAssessing the extent of disease in newly diagnosed prostate cancer (PC) patients is crucial for tailoring an appropriate treatment approach. Prostate-specific membrane antigen (PSMA)–targeted positron emission tomography/computed tomography (PET/CT) reportedly has greater accuracy than conventional imaging for staging PC. As with any imaging modality, pitfalls and nonspecific findings do occur. The PSMA reporting and data system (PSMA-RADS) version 1.0 offers structured interpretation of PSMA-targeted studies and classifies lesions by likelihood of clinical significance. The aim of this retrospective study was to evaluate the clinical significance of equivocal bone findings on staging PSMA-targeted imaging, as defined by PSMA-RADS version 1.0, in the preoperative setting. Fifteen of 406 consecutive patients staged by PET/CT prior to radical prostatectomy had equivocal bone lesions. The scans were retrospectively scored with the PSMA-RADS version 1.0 system, blinded to disease course and follow-up data. Postoperative persistence of prostate-specific antigen levels supported by imaging and histological findings was used as the reference standard for the true significance of equivocal imaging findings.ResultsThirteen of the 15 patients had an overall PSMA-RADS score of 3B, of whom only two had true metastatic disease. The remaining patients had scores of 4 (n = 1) or 5 (n = 1), all confirmed as true positive prostate-related malignant lesions. A per-lesion analysis identified 29 bone lesions, of which 27 were scored PSMA-RADS 3B, and only three of them were true metastases. Thus, debatable lesions proved to have no clinical significance in 84.6% of cases, and only 11% of equivocal PSMA-RADS 3B bone lesions were true positive.ConclusionsIn intermediate and high-risk patients staged prior to radical prostatectomy, the majority of PSMA-RADS 3B lesions are of no clinical relevance. Bone lesions judged as being highly suspicious for metastases (PSMA-RADS 4/5) were all validated as true positives.

Background The molecular features determining the risk of metachronous metastases in clear cell renal cell carcinoma (ccRCC) are poorly defined. This study aimed to identify molecular factors associated with the risk of metachronous metastasis. Methods Using a systematic tumor transcriptome deconvolution approach, we investigated the genomic and transcriptomic profiles of 192 ccRCC primary tumors with extended clinical follow-up to identify cancer- and stromal cell-specific molecular features associated with metastatic risk. Based on these features, we applied multivariate Cox regression to develop a compact 5-gene predictive model for metachronous metastasis. Results At the genomic level, we identify a significantly higher frequency of copy number loss at 1p31-36 in primary tumors that later progress with metastases. Tumor transcriptome deconvolution identifies significant down-regulation of epithelial cell polarity, including PATJ (1p31), and fatty acid metabolism, including CYP4A11 (1p33), in cancer cells of tumors that develop metastatic progression. We develop and benchmark a compact 5-gene predictive model (5G) that demonstrates improved accuracy over existing ccRCC gene signatures in the prediction of metachronous metastasis risk. Conclusions Overall, our study highlights convergent genomic and transcriptomic alterations in chromosome 1p, driving dysregulation of epithelial cell polarity and fatty acid metabolism, as putative risk factors of metachronous metastasis in ccRCC. Plain Language Summary Clear cell renal cell carcinoma (ccRCC) is a common type of kidney cancer. In around one in three people with ccRCC, the cancer spreads to other parts of the body 100 days or later after surgery. This condition, known as metachronous metastasis (MM), is often difficult to treat. It is unclear which patients are more likely to develop MM. In this study, we analyzed tumor samples from 192 patients with ccRCC to identify molecular changes linked to development of MM. We found that specific changes on chromosome 1 in the tumor’s DNA and RNA were strongly associated with MM. Using these findings, we developed a mathematical model to predict the risk of MM. Our findings may help identify people at high-risk of MM and also guide development of future treatments. Naeini et al. investigate molecular features determining the risk of metachronous metastases in clear cell renal cell carcinoma (ccRCC). They find convergent genomic and transcriptomic alterations in chromosome 1p, linking changes in epithelial cell polarity and fatty acid metabolism dysregulation to metachronous metastases in ccRCC.

Urinary incontinence after robotic-assisted radical prostatectomy (RARP) has been associated with older age, a longer operative time, a higher BMI, a short membranous urethral length and preoperative erectile function. The authors sought to assess the association between the neuromuscular characteristics and postoperative urinary incontinence. Methods: RARP specimens from 29 men who underwent bilateral nerve sparing were reanalyzed. Urinary incontinence was evaluated using the International Consultation on Incontinence Questionnaire—Short Form (ICIQ-SF) at 6 weeks post surgery and last follow-up. Linear and logistic regression analyses were performed to assess neuromuscular characteristics and incontinence. Results: At the 1-year follow-up, 11 patients (38%) reported severe incontinence (>12 ICIQ-SF score). The median number of peripheral nerves observed at the base and apex in the specimens was 52 (IQR 13–139) and 59 (IQR: 28–129), respectively. Ganglia were present in 19 patients (65%) at the base and 12 patients (41%) at the apex. Additionally, the median proportional area of detrusor smooth muscle fibers at the base was 0.54 (IQR 0.31–1), while the median proportional area of striated muscle fibers at the apex was 0.13 (IQR 0.08–0.24). No statistically significant associations were found. Conclusions: Histologic neuromuscular characteristics were not associated with postoperative urinary incontinence. Enhanced intraoperative evaluation and larger-scale studies may prove useful for the prediction of postprostatectomy incontinence.

Background Fascial dehiscence after radical cystectomy may have serious clinical implications. To optimize its management, we sought to describe accompanying intraabdominal findings of post-cystectomy dehiscence repair and determine whether a thorough intraabdominal exploration during its operation is mandatory. Methods We retrospectively reviewed a multi-institutional cohort of patients who underwent open radical cystectomy between 2005 and 2020. Patients who underwent exploratory surgery due to fascial dehiscence within 30 days post-cystectomy were included in the analysis. Data collected included demographic characteristics, the clinical presentation of dehiscence, associated laboratory findings, imaging results, surgical parameters, operative findings, and clinical implications. Potential predictors of accompanying intraabdominal complications were investigated. Results Of 1301 consecutive patients that underwent cystectomy, 27 (2%) had dehiscence repair during a median of 7 days post-surgery. Seven patients (26%) had accompanying intraabdominal pathologies, including urine leaks, a fecal leak, and an internal hernia in 5 (19%), 1 (4%), and 1 (4%) patients, respectively. Accompanying intraabdominal findings were associated with longer hospital stay [20 (IQR 17, 23) vs. 41 (IQR 29, 47) days, P = 0.03] and later dehiscence identification (postoperative day 7 [IQR 5, 9] vs. 10 [IQR 6, 15], P = 0.03). However, the rate of post-exploration complications was similar in both groups. A history of ischemic heart disease was the only predictor for accompanying intraabdominal pathologies (67% vs. 24%; P = 0.02). Conclusions A substantial proportion of patients undergoing post-cystectomy fascial dehiscence repair may have unrecognized accompanying surgical complications without prior clinical suspicion. While cardiovascular disease is a risk factor for accompanying findings, meticulous abdominal inspection is imperative in all patients during dehiscence repair. Identification and repair during the surgical intervention may prevent further adverse, possibly life-threatening consequences with minimal risk for iatrogenic injury.

PurposeCytoreductive nephrectomy (CN) benefits a subset of patients with metastatic renal cell carcinoma (mRCC), however proper patient selection remains complex and controversial. We aim to characterize urologists’ reasons for not undertaking a CN at a quaternary cancer center.MethodsConsecutive patients with mRCC referred to MSKCC urologists for consideration of CN between 2009 and 2019 were included. Baseline clinicopathologic characteristics were used to compare patients selected or rejected for CN. The reasons cited for not operating and the alternative management strategies recommended were extrapolated. Using an iterative thematic analysis, a framework of reasons for rejecting CN was designed. Kaplan–Meier estimates tested for associations between the reasons for not undertaking a CN and overall survival (OS).ResultsOf 297 patients with biopsy-proven mRCC, 217 (73%) underwent CN and 80 (27%) did not. Median follow-up of patients alive at data cut-off was 27.3 months. Non-operative patients were older (p = 0.014), had more sites of metastases (p = 0.008), harbored non-clear cell histology (p = 0.014) and reduced performance status (p < 0.001). The framework comprised seven distinct themes for recommending non-operative management: two patient-fitness considerations and five oncological considerations. These considerations were associated with OS; four of the oncological factors conferred a median OS of less than 12 months (p < 0.001).ConclusionWe developed a framework of criteria by which patients were deemed unsuitable candidates for CN. These new insights provide a novel perspective on surgical selection, could potentially be applicable to other malignancies and possibly have prognostic implications.

Background: 5-alpha reductase inhibitors (5-ARIs) change hormonal pathways and reduce prostate size. We evaluated the effects of 5-ARIs on prostatic multiparametric magnetic resonance imaging (mpMRI) suspicious findings and in the identification of prostate cancer using targeted biopsies. Methods: We conducted a retrospective study including 600 consecutive patients who, between 2017 and 2021, underwent combined transperineal fusion biopsies. Primary outcomes were Prostate Imaging Reporting and Data System version 2 (PIRADS v2) scores and the identification of clinically significant prostate cancer from suspicious lesions (targeted CSPC). Outcomes were compared between patients treated with 5-ARIs for a minimum of 6 months and the other patients. Results: Patients treated with 5-ARIs were older (p < 0.001) with higher rates of previous prostate biopsies (p = 0.004). PIRADS scores were 3, 4, and 5 in 15 (29%), 28 (54%), and 9 (17%) patients among the 5-ARI group and 130 (24%), 308 (56%), and 110 (20%) patients among the others, and the scores were not different between the groups (p = 0.69). The targeted CSPC identification rate among 5-ARI patients was 31%, not different compared to the non-5-ARI group (p = 1). Rates of targeted CSPC for each PIRADS score were not affected by 5-ARI treatment. The 5-ARI was not associated with neither PIRADS ≥ 4 score nor targeted CSPC on logistic regression analyses (OR = 0.76, 95% CI 0.4–1.4 and OR = 1.02, 95% CI 0.5–1.9, respectively). Conclusions: 5-ARI treatment is not associated with PIRADS score alterations or targeted biopsy results. Patients treated by 5-ARIs with suspicious lesions should not be addressed differently during the mpMRI-related diagnostic process.

Introduction Bilateral testicular germ cell tumor (BGCT) is a rare disease, occasionally considered to be more aggressive than unilateral germ cell tumors (GCT) in some reports. Among BGCT, a synchronous disease might be diagnosed at a higher stage than a metachronous disease, resulting in lower cancer-specific survival. Hence, our study aimed to perform a comparative analysis between unilateral testicular GCT, bilateral synchronous GCT, and bilateral metachronous GCT, aiming to verify the possibility that BGCT is diagnosed with a higher stage and may require more aggressive management. Material and methods In our multicenter retrospective study we reviewed medical records of 40 patients with BGCT (24 metachronous and 16 synchronous). Clinical characteristics, pathological features of the primary and secondary tumors, adjuvant treatments (chemotherapy and radiotherapy)and sperm quality were evaluated as well as cancer-specific survival and overall survival. A cohort of one-to-one matched patients with unilateral GCT were used to determine risk factors for developing BGCT. Results Patients with BGCT were slightly younger compared to those with unilateral GCT and had more advanced disease. Despite similar T-stage distribution between the two groups, nodal involvement was nearly twofold more frequent in patients with BGCT disease (42% vs 22%, p = 0.056). Additionally, although similar histological subtypes distribution at presentation among the two groups, the synchronous disease was diagnosed with a higher local T-stage (OR = 3.4), higher proportions of patients with elevated serum BHCG levels, and more frequent nodal involvement (OR = 2.2). This was later translated into an 18% higher disease-specific mortality rate. The median time to develop a contralateral tumor was 92 months. Pathological local T-stage (T2–T3) of the primary tumor predicted a shorter time interval to a diagnosis of a second contralateral tumor (HR 0.92, P < 0.05). Conclusion BGCT presents at a younger age and potentially with more advanced disease. Synchronous BGCT is diagnosed at a later stage compared to metachronous BGCT and has higher disease-specific mortality. Metachronous tumors might have a long time interval for the development of a contralateral neoplasm. The main predictor of developing an early metachronous disease is a high primary T stage.

Objective To assess the influence of COVID‐19‐imposed life changes on presentation and outcomes of patients with obstructing urinary stones complicated by infection. Patients and methods All patients presenting with obstructing urinary stones and infection 1 year before the pandemic (March 2019 to February 2020; n = 66) and 1 year since its onset (March 2020 to February 2021; n = 45) were enrolled. Demographics, clinical presentation, laboratory panel, stone characteristics and outcomes were compared between groups. Univariate and multivariate logistic regression models were performed for analysis. Results The COVID‐19 period was characterised by younger patients, female predominance, higher temperature at presentation and more bilateral obstructing stones (p < 0.05). The admission rate to intensive care units was double that of the pre‐pandemic period, whereas time between diagnosis and treatment was similar. The univariate analysis revealed higher rates of severe sepsis (odds ratio [OR] = 3, p = 0.01), systemic inflammatory response syndrome (SIRS) ≥ 2 (OR = 2.9, p = 0.01) and risk, injury, failure, loss of kidney function and end‐stage kidney (RIFLE) criteria ≥ 1 (OR = 2.2, p = 0.04) in the pandemic period group. The multivariate analyses revealed the COVID‐19 period as being the sole variable associated with severe sepsis (OR = 3.1, p = 0.02), SIRS ≥ 2 (OR = 3.8, p = 0.005) and RIFLE ≥ 1 (OR = 2.6, p = 0.05). Conclusions The pandemic period was characterised by a worse clinical state at presentation of patients with obstructing urinary stones complicated by infection, probably reflecting delay in arrival to emergency services.