Impact of an NCCN-Compliant Multidisciplinary Conference on Treatment Decisions for Localized Prostate Cancer.

BACKGROUND: We sought to investigate the impact of an NCCN-compliant multidisciplinary conference on treatment decisions of patients with localized prostate cancer. METHODS: A retrospective review of our quality assurance localized prostate cancer database was performed. All patients with localized prostate cancer who sought a second opinion at Roswell Park Comprehensive Cancer Center between 2009 and 2019 were presented to the multidisciplinary Localized Prostate Cancer Conference (LPCC) that includes urologists, radiation oncologists, pathologists, and patient advocates. Multivariable regression models were fit to evaluate variables associated with concordance between community recommendations, LPCC recommendations, and treatment received by patients. RESULTS: A total of 1,164 patients were identified, of whom 26% had NCCN very low-/low-risk, 27% had favorable intermediate-risk, 25% had unfavorable intermediate-risk, and 22% had high-/very high-risk prostate cancer. Pathology changed in 11% of patients after genitourinary pathologist review, which caused disease reclassification in 9%. Concordance between community and LPCC recommendations occurred in 78%, with lowest concordance for androgen deprivation therapy (21%) and radiotherapy (53%). Concordance between community recommendations and treatment received occurred in 65%, with lowest concordance for androgen deprivation therapy and radiotherapy; among those who were recommended radiotherapy as the only option by their community urologist, only 26% received it. Concordance between LPCC recommendations and treatment received occurred in 92%. CONCLUSIONS: Community recommendations differed from the multidisciplinary NCCN-compliant recommendations in 22% of patients, primarily for radiotherapy. Multidisciplinary recommendations matched the treatment received in 92% of patients compared with 65% for community recommendations.

Active Surveillance for Risk Stratification of All Small Renal Masses Lacking Predefined Clinical Criteria for Intervention.

PURPOSE: Despite general indolence of small renal masses and no known adversity from treatment delays, broad usage of active surveillance as a means to risk-stratify patients with small renal masses for more selective treatment has not been studied. We describe outcomes for a novel approach in which active surveillance was recommended to all patients with small renal masses lacking predefined progression criteria for intervention. MATERIALS AND METHODS: All nondialysis dependent patients with nonmetastatic small renal masses seen by 1 urologist at a comprehensive cancer center during January 2013-September 2017 were managed with active surveillance if standardized progression criteria for intervention were absent, with delayed intervention recommended only upon progression criteria for intervention development. Progression criteria for intervention were defined prospectively as small renal mass-related symptoms, unfavorable histology, cT3a stage or either of the following without benign neoplastic biopsy histology: longest tumor diameter >4 cm; growth rate >5 mm/year for longest tumor diameter ≤3 cm or >3 mm/year for longest tumor diameter >3 cm. RESULTS: In all, 96% (123/128) of patients with small renal masses lacked progression criteria for intervention at presentation and underwent active surveillance. With median/mean 31/34 months followup, none developed metastasis and 30% (37/123) developed progression criteria for intervention, 78% (29/37) of whom underwent delayed intervention. One (1%) patient crossed over to delayed intervention without progression criteria for intervention. Three-year progression criteria for intervention-free and delayed intervention-free rates were 72% and 75%, respectively. Delayed intervention resections were enriched (62%) for pT3 and/or nuclear grade 3-4 malignant pathology, with no benign resections. CONCLUSIONS: Active surveillance using predefined progression criteria for intervention in otherwise unselected patients with small renal masses allows intervention to be focused on at-risk small renal masses with common adverse pathology, avoiding treatment for most patients with small renal masses. Long-term delayed intervention and oncologic safety require study.

Preclinical efficacy of dual mTORC1/2 inhibitor AZD8055 in renal cell carcinoma harboring a TFE3 gene fusion.

BACKGROUND: Renal cell carcinomas (RCC) harboring a TFE3 gene fusion (TfRCC) represent an aggressive subset of kidney tumors. Key signaling pathways of TfRCC are unknown and preclinical in vivo data are lacking. We investigated Akt/mTOR pathway activation and the preclinical efficacy of dual mTORC1/2 versus selective mTORC1 inhibition in TfRCC. METHODS: Levels of phosphorylated Akt/mTOR pathway proteins were compared by immunoblot in TfRCC and clear cell RCC (ccRCC) cell lines. Effects of the mTORC1 inhibitor, sirolimus, and the dual mTORC1/2 inhibitor, AZD8055, on Akt/mTOR activation, cell cycle progression, cell viability and cytotoxicity were compared in TfRCC cells. TfRCC xenograft tumor growth in mice was evaluated after 3-week treatment with oral AZD8055, intraperitoneal sirolimus and respective vehicle controls. RESULTS: The Akt/mTOR pathway was activated to a similar or greater degree in TfRCC than ccRCC cell lines and persisted partly during growth factor starvation, suggesting constitutive activation. Dual mTORC1/2 inhibition with AZD8055 potently inhibited TfRCC viability (IC50 = 20-50 nM) due at least in part to cell cycle arrest, while benign renal epithelial cells were relatively resistant (IC50 = 400 nM). Maximal viability reduction was greater with AZD8055 than sirolimus (80-90% versus 30-50%), as was the extent of Akt/mTOR pathway inhibition, based on significantly greater suppression of P-Akt (Ser473), P-4EBP1, P-mTOR and HIF1α. In mouse xenograft models, AZD8055 achieved significantly better tumor growth inhibition and prolonged mouse survival compared to sirolimus or vehicle controls. CONCLUSIONS: Akt/mTOR activation is common in TfRCC and a promising therapeutic target. Dual mTORC1/2 inhibition suppresses Akt/mTOR signaling more effectively than selective mTORC1 inhibition and demonstrates in vivo preclinical efficacy against TFE3-fusion renal cell carcinoma.

Blinded review of archival radical prostatectomy specimens supports that contemporary Gleason score 6 prostate cancer lacks metastatic potential.

BACKGROUND: Retrospective identification of Gleason pattern 4 in metastatic Gleason score 3 + 3 = 6 (GS6) radical prostatectomy (RP) specimens has suggested true GS6 prostate cancer (CaP) lacks metastatic potential. However, pathologist awareness of study design and metastasis outcomes at the time of RP review might have introduced upgrading bias. We used pathologist-blinded methodology for unbiased characterization of metastasis rates for contemporarily defined pathologic GS6 (pGS6) CaP. METHODS: An institutional RP database was queried to identify pGS6 patients with metastasis or concern for micrometastasis based on: 1) biochemical failure (BF) despite negative surgical margins or 2) incomplete biochemical response to salvage/adjuvant radiation. RP specimens were regraded independently by two genitourinary pathologists blinded to study aims or clinical outcomes. Additional blinding was performed by random inclusion of pGS6 control specimens from BF-free patients. Only upgrading identified independently by both pathologists was considered. RESULTS: Among 451 pGS6 patients identified, none had synchronous lymph node metastases and 43/451 (10%) suffered BF. Two patients (0.4%) developed metachronous metastasis during a 110-month median follow-up for BF patients. Both metastatic cases had Gleason pattern 4 on blinded RP review, as did 88% of cases with concern for micrometastasis versus 38% of control cases (P = 0.02). All BF patients (29/29) undergoing postoperative radiation had a complete biochemical response or Gleason pattern 4 on blinded RP review. CONCLUSIONS: Unbiased pathologist review of archival RP specimens supports absent metastatic potential for contemporarily defined GS6 CaP. Reduced postoperative monitoring is appropriate for pGS6, but may require pathology review to confirm absent Gleason pattern 4.

Implications of High Rates of Metastatic Prostate Cancer in BRCA2 Mutation Carriers.

BACKGROUND: Patients with germline BRCA2 gene mutations (BRCA2mut) have more aggressive prostate cancer. Analysis of all reported germline BRCA2mut prostate cancer cases allows better understanding of the clinicopathologic features and survival outcomes of these men. METHODS: A systematic review was performed with the MEDLINE database to capture articles evaluating clinicopathologic characteristics of men with BRCA2mut associated prostate cancer. Inclusion criteria were at least five subjects, confirmation of BRCA2mut status, and data for at least 2 clinical parameters of disease. Meta-analysis was performed on outcomes data. Chi-squared tests were used to compare disease features among men undergoing formal versus ad hoc screening, as well as an age of diagnosis less than versus greater than 65 years. Rates of metastatic disease among BRCA2mut cases were compared to rates among non-carrier control subjects and the general population using the SEER database. RESULTS: Twelve out of 289 studies met our inclusion criteria, representing 261 BRCA2mut men. Among carriers, the median age at diagnosis was 62 years and median PSA was 15 ng/dl with 95% of men having a PSA>3. Over 40% of BRCA2mut patients had T3/T4 disease and over 25% were metastatic at presentation. Survival was worse in BRCA2mut men with prostate cancer when compared to non-BRCA2mut subjects. BRCA2mut carriers had significantly higher rates of metastatic disease (18%) versus non-carrier controls (8%) and the SEER population (4%). CONCLUSIONS: BRCA2mut carriers are more likely to have poor risk of prostate cancer at presentation and exhibit worse oncologic outcomes relative to non-carriers, including a fourfold increase in metastatic disease. Younger men and those undergoing formal screening present with less advanced disease which supports a need for earlier identification and screening protocols. Additionally, this population may benefit from alternative therapeutic paradigms. Prostate 76:1135-1145, 2016. © 2016 Wiley Periodicals, Inc.

Clinical significance of prospectively assigned Gleason tertiary pattern 4 in contemporary Gleason score 3+3=6 prostate cancer.

OBJECTIVE: To determine the oncologic impact of prospectively assigned tertiary pattern 4 in contemporary Gleason score (GS) 3 + 3 = 6 radical prostatectomy (RP) specimens. PATIENTS AND METHODS: Oncologic outcomes were retrospectively reviewed for 720 consecutive patients from a single National Comprehensive Cancer Network (NCCN) center with at least 6 months follow-up after RP for GS3 + 3 = 6 (GS6, N = 222), GS6 with tertiary pattern 4 (GS6t4, N = 62), or GS3 + 4 = 7 (N = 436) prostate cancer, as prospectively graded since 2006 using the 2005 International Society of Urologic Pathologists criteria. Preoperative NCCN risk category, RP pathology, progression-free survival (PFS) and metastasis-free survival (MFS) were compared among the GS6, GS6t4, and GS3 + 4 = 7 groups using χ(2) , Kaplan-Meier, and log-rank analyses. RESULTS: The incidence of low NCCN preoperative risk classification for GS6t4 patients (63%) was less than that for GS6 patients (77%) while greater than that for GS3 + 4 = 7 patients (30%, P < 0.001). GS6t4 patients had RP pathologic features which were intermediate in risk between that of GS6 and GS3 + 4 = 7 based on extraprostatic extension (27% vs. 6% vs. 31%, respectively, P < 0.001) and mean percentage of prostate gland involvement (13% vs. 10% vs. 16%, respectively, P < 0.001). With a mean overall follow-up of 42 months, PFS for GS6t4 patients (5-year 85%) was intermediate between that of GS6 (5-year 93%) and GS3 + 4 = 7 (5-year 76%) patients (P < 0.001). The 5-year MFS rate was 100% for GS6 and GS6t4 patients compared to 97% for GS3 + 4 = 7 patients (P = 0.07). CONCLUSIONS: This study provides the longest follow-up to date for RP patients with prospectively assigned GS6t4 and supports a risk for adverse RP pathology and postoperative disease progression that is intermediate between GS6 and GS3 + 4 = 7. Whether a tertiary pattern 4 in GS6 disease increases the risk of metastasis is uncertain and requires longer term study. Given favorable oncologic outcomes, less stringent postoperative surveillance for both GS6 and GS6t4 patients may be warranted.

Lack of Impact of Robotic Assisted Laparoscopic Radical Prostatectomy on Intraoperative Levels of Prostate Cancer Circulating Tumor Cells.

PURPOSE: While the significance of circulating tumor cells in clinically localized cancer remains controversial, it has been reported that surgical tumor manipulation can increase circulating tumor cells, including during open prostatectomy. To our knowledge it is unknown whether this cell shedding also occurs during minimally invasive prostatectomy, which minimizes tumor palpation and uses earlier vascular control. We tested the impact of robotic assisted laparoscopic radical prostatectomy on intraoperative circulating tumor cell levels. MATERIALS AND METHODS: Circulating tumor cell counts were compared in peripheral blood specimens from 25 patients treated with robotic assisted laparoscopic radical prostatectomy preoperatively vs intraoperatively after prostate excision, in addition to 11 healthy blood donors. Circulating tumor cell detection was performed using EpCAM immunomagnetic enrichment and multiparametric flow cytometry quantification of viable EpCAM positive/prostate specific membrane antigen positive/CD45 negative cells. Intraoperative cell counts and increases were tested in univariable analyses for associations with perioperative variables, histopathology and postoperative progression. RESULTS: Circulating tumor cells were detected in 0% of healthy controls compared to 48% and 52% of prostatectomy cases preoperatively and intraoperatively, respectively (range 1 to 8 cells). There was no difference in the incidence or mean number of circulating tumor cells preoperatively vs intraoperatively. Of the patients 60% had no intraoperative change from preoperative levels. Intraoperative cell increases vs decreases were equally infrequent (each 20%) with no intraoperative increase greater than 1 circulating tumor cell. Intraoperative circulating tumor cell detection was not significantly associated with prostatectomy operative characteristics, histopathology or early postoperative progression at a median 21-month followup. CONCLUSIONS: Robotic assisted laparoscopic radical prostatectomy does not cause significant intraoperative increases in circulating tumor cells in contrast to historical reports of open prostatectomy. These findings may aid urologists in counseling candidates for robotic assisted laparoscopic radical prostatectomy regarding the possibility of intraoperative tumor cell shedding.

Outcomes of Scheduled vs For-Cause Biopsy Regimens for Prostate Cancer Active Surveillance.

PURPOSE: Active surveillance is a first line treatment option for patients with low risk prostate cancer but standardized regimens are lacking, including uniform protocols for surveillance prostate biopsy. We compared the outcomes of 2 active surveillance regimens that differ in whether a scheduled biopsy was performed in the absence of clinical progression. MATERIALS AND METHODS: We retrospectively reviewed the records of 313 consecutive patients with prostate cancer at a NCCN® (National Comprehensive Cancer Network®) institution who were assigned prospectively to 1 of 2 active surveillance biopsy regimens. A total of 149 patients underwent biopsy only for clinical concern (for-cause only) while 164 underwent for-cause biopsy plus scheduled annual or biannual biopsy. Times to biopsy, clinical progression, pathological reclassification and treatment were compared using Kaplan-Meier methodology. RESULTS: The for-cause only and scheduled plus for-cause biopsy groups were similar in NCCN risk category at active surveillance initiation. Median followup was 48 and 38 months, respectively. No significant difference was observed in prostate specific antigen dynamics or clinical progression rates. However, patients in the scheduled plus for-cause group underwent significantly more frequent biopsies (p <0.001) and experienced more biopsy related complications (p = 0.04), pathological reclassification (p = 0.02) and treatment conversion (p = 0.001). Adverse prostatectomy pathology (pT3 or greater and/or Gleason primary pattern 4) and early metastasis events were rare in both groups. CONCLUSIONS: Omitting a scheduled biopsy during active surveillance is associated with a decreased biopsy burden and treatment conversion. Although no increase in adverse pathology or early metastasis was observed in this study, longer followup in larger cohorts is necessary to determine the impact of scheduled biopsy omission on these adverse outcomes.

Validation of the Kattan Nomogram for Prostate Cancer Recurrence After Radical Prostatectomy.

BACKGROUND: The Kattan postoperative radical prostatectomy (RP) nomogram is used to predict biochemical recurrence-free progression (BCRFP) after RP. However, external validation among contemporary patients using modern outcome definitions is limited. METHODS: A total of 1,931 patients who underwent RP at Roswell Park Cancer Institute (RPCI) between 1993 and 2014 (median follow-up, 47 months; range, 0-244 months) were assessed for NCCN-defined biochemical failure (BF) and RPCI-defined treatment failure (TF). Actual rates of biochemical failure-free survival (BFS; defined as 1 - BF) and treatment failure-free survival (TFS; defined as 1 - TF) were compared with Kattan BCRFP nomogram predictions. RESULTS: The Kattan BCRFP nomogram predictions at 5 and 10 years were predictive of BFS (area under the receiver operating characteristic curve [AUC], 0.772) and TFS (AUC, 0.774). The Kattan BCRFP nomogram tended to underestimate BFS and TFS compared with actual outcomes. The Kattan 5-year BCRFP predictions consistently overestimated actual 5-year BFS outcomes among subgroups of high- and intermediate-risk patients with at least 5-year outcomes. CONCLUSIONS: The Kattan BCRFP nomogram is a robust predictor of NCCN-defined BF in a large sample of patients with RP with substantial follow-up and modern, standardized failure definitions.

Comparative Analysis of Smoking as a Risk Factor among Renal Cell Carcinoma Histological Subtypes.

PURPOSE: Smoking is the best established modifiable risk factor for renal cell carcinoma. However, the risks of individual renal cell carcinoma histological subtypes are unknown. Therefore, we investigated the relationship between smoking and renal cell carcinoma subtype. MATERIALS AND METHODS: Cigarette smoking data were prospectively collected from 816 consecutive patients with nonfamilial renal cell carcinoma (705) or benign pathology (111) undergoing nephrectomy at a single National Comprehensive Cancer Network® cancer center, and were retrospectively tested for an association with histological diagnosis on univariable and propensity adjusted analyses. RESULTS: Smoking was reported by 51% of patients, including 21% active smokers and 30% former smokers. Active smoking was more common with clear cell (23%) or papillary (26%) renal cell carcinoma than benign histology (14%, p <0.05 each), yet strikingly less common with chromophobe renal cell carcinoma (6%, p <0.05 vs clear cell or papillary). Any smoking history (active or former) was also relatively uncommon with chromophobe (26%) vs clear cell (53%, p = 0.003) or papillary (58%, p = 0.001) histology. Smoking extent based on mean pack-years was significantly greater with clear cell (15.3 mean pack-years) or papillary (15.2 mean pack-years) renal cell carcinoma but not chromophobe renal cell carcinoma (9.4 mean pack-years) compared to benign histology (9.4 mean pack-years, p ≤0.05, p <0.05, p = 1.0, respectively). On propensity analyses adjusting for multiple variables, clear cell (OR 2.2, p <0.05) and papillary (OR 2.4, p <0.05) histologies but not chromophobe histology remained independently associated with active smoking. CONCLUSIONS: Traditional understanding of smoking as a renal cell carcinoma risk factor applies to clear cell and papillary renal cell carcinoma but not the chromophobe subtype. These findings underscore distinct carcinogenic mechanisms underlying the various renal cell carcinoma subtypes.

Gleason 6 Prostate Cancer: Translating Biology into Population Health.

PURPOSE: Gleason 6 (3+3) is the most commonly diagnosed prostate cancer among men with prostate specific antigen screening, the most histologically well differentiated and is associated with the most favorable prognosis. Despite its prevalence, considerable debate exists regarding the genetic features, clinical significance, natural history, metastatic potential and optimal management. MATERIALS AND METHODS: Members of the Young Urologic Oncologists in the Society of Urologic Oncology cooperated in a comprehensive search of the peer reviewed English medical literature on Gleason 6 prostate cancer, specifically focusing on the history of the Gleason scoring system, histological features, clinical characteristics, practice patterns and outcomes. RESULTS: The Gleason scoring system was devised in the early 1960s, widely adopted by 1987 and revised in 2005 with a more restrictive definition of Gleason 6 disease. There is near consensus that Gleason 6 meets pathological definitions of cancer, but controversy about whether it meets commonly accepted molecular and genetic criteria of cancer. Multiple clinical series suggest that the metastatic potential of contemporary Gleason 6 disease is negligible but not zero. Population based studies in the U.S. suggest that more than 90% of men newly diagnosed with prostate cancer undergo treatment and are exposed to the risk of morbidity for a cancer unlikely to cause symptoms or decrease life expectancy. Efforts have been proposed to minimize the number of men diagnosed with or treated for Gleason 6 prostate cancer. These include modifications to prostate specific antigen based screening strategies such as targeting high risk populations, decreasing the frequency of screening, recommending screening cessation, incorporating remaining life expectancy estimates, using shared decision making and novel biomarkers, and eliminating prostate specific antigen screening entirely. Large nonrandomized and randomized studies have shown that active surveillance is an effective management strategy for men with Gleason 6 disease. Active surveillance dramatically reduces the number of men undergoing treatment without apparent compromise of cancer related outcomes. CONCLUSIONS: The definition and clinical relevance of Gleason 6 prostate cancer have changed substantially since its introduction nearly 50 years ago. A high proportion of screen detected cancers are Gleason 6 and the metastatic potential is negligible. Dramatically reducing the diagnosis and treatment of Gleason 6 disease is likely to have a favorable impact on the net benefit of prostate cancer screening.

External validation of preoperative and postoperative nomograms for prediction of cancer-specific survival, overall survival and recurrence after robot-assisted radical cystectomy for urothelial carcinoma of the bladder.

OBJECTIVE: To externally validate currently available bladder cancer nomograms for prediction of all-cause survival (ACS), cancer-specific survival (CSS), other-cause mortality (OCM) and progression-free survival (PFS). PATIENTS AND METHODS: Retrospective analysis of a prospectively maintained database of 282 patients who underwent robot-assisted radical cystectomy (RARC) at a single institution was performed. The Bladder Cancer Research Consortium (BCRC), International Bladder Cancer Nomogram Consortium (IBCNC) and Lughezzani nomograms were used for external validation, and evaluation for accuracy at predicting oncological outcomes. The 2- and 5-year oncological outcomes were compared, and nomogram performance was evaluated through measurement of the concordance (c-index) between nomogram-derived predicted oncological outcomes and observed oncological outcomes. RESULTS: The median (range) patient age was 70 (36-90) years. At a mean follow-up of 20 months, local or distant disease recurrence developed in 30% of patients. With an overall mortality rate of 33%, 17% died from bladder cancer. The actuarial 2- and 5-year PFS after RARC was 62% (95% confidence interval [CI] 54-68) and 55% (95% CI 46-63), respectively. The actuarial 2- and 5-year ACS was 66% (95% CI 59-72) and 47% (95% CI 37-55), respectively, and the 2- and 5-year CSS was 81% (95% CI 74-86) and 67% (95% CI 57-76), respectively. The PFS c-index for IBCNC was 0.70 at 5 years, and for BCRC was 0.77 at both the 2 and 5 years. The accuracy of ACS and CSS prediction was evaluated using the BCRC and Lughezzani nomograms. Using the BCRC nomogram, c-indices of for 2- and 5-year ACS were each 0.73 and c-indices for 2- and 5-year CSS were 0.70 each. The performance of Lughezzani nomogram for 5-year ACS, cancer-specific mortality and OCM were 0.73, 0.72 and 0.40, respectively. The BCRC nomogram prediction of advanced pathological stage and lymph node metastasis was modest, with c-indices of 0.66 and 0.61, respectively. CONCLUSIONS: Bladder cancer nomograms available from the current open RC literature adequately predict ACS, CSS and PFS after RARC. However, prediction of advanced tumour stage and lymph node metastasis was modest and the Lughezzani nomogram failed to predict OCM.

Efficacy of robot-assisted radical cystectomy (RARC) in advanced bladder cancer: results from the International Radical Cystectomy Consortium (IRCC).

OBJECTIVE: To characterise the surgical feasibility and outcomes of robot-assisted radical cystectomy (RARC) for pathological T4 bladder cancer. PATIENTS AND METHODS: Retrospective evaluation of a prospectively maintained International Radical Cystectomy Consortium database was conducted for 1118 patients who underwent RARC between 2003 and 2012. We dichotomised patients based on pathological stage (≤pT3 vs pT4) and evaluated demographic, operative and pathological variables in relation to morbidity and mortality. RESULTS: In all, 1000 ≤pT3 and 118 pT4 patients were evaluated. The pT4 patients were older than the ≤pT3 patients (P = 0.001). The median operating time and blood loss were 386 min and 350 mL vs 396 min and 350 mL for p T4 and ≤pT3, respectively. The complication rate was similar (54% vs 58%; P = 0.64) among ≤pT3 and pT4 patients, respectively. The overall 30- and 90-day mortality rate was 0.4% and 1.8% vs 4.2% and 8.5% for ≤pT3 vs pT4 patients (P < 0.001), respectively. The body mass index (BMI), American Society of Anesthesiology score, length of hospital stay (LOS) >10 days, and 90-day readmission were significantly associated with complications in pT4 patients. Meanwhile, BMI, LOS >10 days, grade 3-5 complications, 90-day readmission, smoking, previous abdominal surgery and neoadjuvant chemotherapy were significantly associated with mortality in pT4 patients. On multivariate analysis, BMI was an independent predictor of complications in pT4 patients, but not for mortality. CONCLUSIONS: RARC for pT4 bladder cancer is surgically feasible but entails significant morbidity and mortality. BMI was independent predictor of complications in pT4 patients.

Stratification of Patients with Renal Cell Carcinoma by the Abundance of Sarcomatoid Features Reveals Differences in Survival and the Underlying Pathobiology.

Sarcomatoid renal cell carcinoma (sRCC) is histologically heterogeneous, with variable sarcomatoid amounts intermixed within epithelial carcinoma. However, the current classification for this aggressive disease is homogeneous and agnostic to the sarcomatoid proportion. We investigated whether sRCC subclassification has prognostic value and can reveal the biology underlying dedifferentiation and its clinical aggressiveness. On the basis of the intratumoral abundance of sarcomatoid features, cases were classified as sarcomatoid-high (≥10% sarcomatoid features) or sarcomatoid-low (<10% sarcomatoid features) in a cohort of 104 consecutive patients with sRCC undergoing nephrectomy at a single center. In comparison to sarcomatoid-low patients (n = 52), sarcomatoid-high patients (n = 52) had significantly shorter overall survival (median 14.5 vs 62.9 mo; p < 0.001), which was confirmed on multivariable analysis, and significantly shorter median metastasis-free survival among patients with clinically localized disease (10.7 vs 39.0 mo; p = 0.043). Transcriptomic analyses of 45 sRCC tumors revealed significant upregulation of nine hallmark pathways related to cell cycle/proliferation, epithelial-to-mesenchymal transition, reactive oxidative species, and interferon-α signaling among sarcomatoid-high (n = 24) versus sarcomatoid-low (n = 21) tumors. Categorization into transcriptomic clusters revealed predominance of proliferative, inflammatory, and immune effector phenotypes among sarcomatoid-high tumors, versus a hypoxia/angiogenesis phenotype among sarcomatoid-low tumors. Overall, these findings indicate prognostic value for sRCC subclassification into high versus low sarcomatoid groups and highlight key biology underlying the differences in clinical outcomes. PATIENT SUMMARY: Sarcomatoid renal cell carcinoma (sRCC) is a highly aggressive form of kidney cancer. The percentage of sarcomatoid features varies among tumors, but sRCC is still defined as a single kidney cancer type. Our results show that grouping patients according to their percentage of sarcomatoid features improves prediction of whether their tumors will become metastatic or lethal, and reveal molecular differences that may be important for this disease. Future assignment of sRCC to high and low sarcomatoid groups may help in guiding research and patient management.

Differential effects of obesity on perioperative outcomes in renal cell carcinoma patients based on race and ethnicity and neighborhood-level socioeconomic status.

Background: Obesity is a well-established risk factor of renal cell carcinoma (RCC), however the impact of obesity on surgical outcomes for racial and ethnic minority patients with RCC is unclear. This study investigated whether a higher body mass index (BMI) or obesity (BMI ≥30 kg/m2) was associated with worse perioperative outcomes and if there were heterogeneous effects based on race, ethnicity, and neighborhood-level socioeconomic factor. Methods: In this single-center cross-sectional study, medical records of patients who underwent partial or radical nephrectomy between 2010 and 2022 were retrospectively reviewed. Logistic regression analysis was performed to assess associations of BMI and perioperative outcomes [ischemia time, estimated blood loss (EBL), and length of hospital stay]. Results: A total of 432 patients, including 49.8% non-Hispanic White (NHW), 35.0% Hispanic, and 6.9% American Indian (AI) patients, were included. Median [interquartile range (IQR)] BMI was 30.2 (26.3-35.2) kg/m2, and Hispanic (31.5) and AI (32.5) patients had higher median BMI than NHW (29.1) patients (P=0.006). Median ischemia time, EBL, and length of hospital stay were 18.5 (IQR, 15.0-22.4) minutes, 150 (IQR, 75.0-300.0) mL, and 3 (IQR, 2-5) days. BMI ≥35 kg/m2 was associated with a longer ischemia time [>18.5 minutes; odds ratio (OR), 5.17; 95% confidence interval (CI): 1.81-14.76; P=0.002], and the association was stronger in NHW than Hispanic patients (BMI continuous OR, 1.13; 95% CI: 1.04-1.22; P=0.004 in NHW and OR, 1.07; 95% CI: 0.98-1.17; P=0.12 in Hispanics). Class I and II/III obese patients had over two-fold increased odds of a larger EBL (>150 mL) than patients with normal weight (OR, 2.17; 95% CI: 1.03-4.59; P=0.04 for class I and OR, 2.24; 95% CI: 1.04-4.84; P=0.04 for class II/III obese patients). This association was stronger in patients from neighborhoods with high social deprivation index (SDI) and in NHW patients (BMI ≥30 vs. <30 kg/m2, OR, 3.53; 95% CI: 1.57-7.97; P=0.002 in high SDI neighborhoods and OR, 2.38; 95% CI: 1.10-5.14; P=0.03 in NHW). BMI was not associated with a longer hospital stay. Conclusions: In this study, obesity increased likelihood of worse perioperative outcomes, and the associations varied based on race and ethnicity and neighborhood-level socioeconomic factors.

Germline PTEN mutation Cowden syndrome: an underappreciated form of hereditary kidney cancer.

PURPOSE: Cowden syndrome is a hereditary cancer syndrome associated with a germline mutation in PTEN. Patients are predisposed to multiple malignancies including renal cell carcinoma. MATERIALS AND METHODS: Patients with Cowden syndrome were evaluated as part of a clinical protocol. Those with a history of renal cell carcinoma underwent review of clinical features, tumor characteristics and family history. Renal tumors were evaluated for loss of heterozygosity. RESULTS: Among 24 patients with Cowden syndrome 4 were identified with renal cell carcinoma (16.7%). Three patients had solitary tumors, 2 with papillary type I histology and 1 with clear cell histology. The fourth patient had bilateral, synchronous chromophobe tumors. No patients had a prior family history of renal cell carcinoma. All patients with renal cell carcinoma had dermatologic manifestations of Cowden syndrome and had macrocephaly. Loss of heterozygosity at the PTEN mutation was identified in 4 tumors (80%). No genotype-phenotype association was found, as the same mutation was identified in different renal cell carcinoma histologies. CONCLUSIONS: Renal cell carcinoma is an underappreciated feature of Cowden syndrome. As most patients lack a prior family history or a distinctive renal cell carcinoma histology, recognition of the associated nonrenal features should target referral for genetic counseling. PTEN loss of heterozygosity is common in Cowden syndrome renal tumors. Because loss of PTEN can activate mTOR and mTOR inhibitors are Food and Drug Administration approved to treat renal cell carcinoma, these agents have clinical potential in renal cell carcinoma associated with Cowden syndrome.

Stability of renal parenchymal volume and function during active surveillance of renal oncocytoma patients.

INTRODUCTION AND OBJECTIVE: To evaluate whether significant loss in ipsilateral renal parenchymal volume (IRPV) and renal function occurs during active surveillance (AS) of renal oncocytoma (RO) patients. METHODS: Renal function (estimated glomerular filtration rate, eGFR) dynamics were retrospectively analyzed in 32 consecutive biopsy-diagnosed RO patients managed with AS at a National Comprehensive Cancer Network institute. Three-dimensional kidney and tumor reconstructions were generated and IRPV was calculated using volumetry software (Myrian®) for all patients with manually estimated RO growth >+10 cm3. GFR and IRPV were compared at AS initiation vs. the last follow-up using 2-sided paired t-tests. The correlation between change in IRPV and change in RO size or GFR was tested using a Spearman coefficient. RESULTS: With median follow-up of 37 months, there was no significant change between initial vs. last eGFR (median 71.0 vs. 70.5 ml/min/1.73 m2, P = 0.50; median change -3.0 ml/min/1.73 m2). Among patients (n = 17) with RO growth >+10 cm3 during AS (median growth +28.6 cm3, IQR +16.9- + 46.5 cm3), IRPV generally remained stable (median change +0.5%, IQR -1.2%- + 1.2%), with only 2 cases surpassing 5% loss. No IRPV loss was detected among any patient within the top tertile of RO growth magnitude. RO growth magnitude did not correlate with loss of either IRPV (ρ = -0.30, P = 0.24) or eGFR (ρ = -0.16, P = 0.40), including among patient subsets with lower initial eGFR. Study limitations include a lack of long-term follow-up. CONCLUSIONS: Volumetry is a promising novel tool to measure kidney and tumor tissue changes during AS. Our study using volumetry indicates that clinically significant loss of IRPV or eGFR is uncommon and unrelated to tumor growth among untreated RO patients with intermediate follow-up. These findings support that AS is in general functionally safe for RO patients, however longer study is needed to determine safety durability, particularly among uncommon ≥cT2 RO variants.

A genetic basis for cancer sex differences revealed in Xp11 translocation renal cell carcinoma.

Xp11 translocation renal cell carcinoma (tRCC) is a female-predominant kidney cancer driven by translocations between the TFE3 gene on chromosome Xp11.2 and partner genes located on either chrX or on autosomes. The rearrangement processes that underlie TFE3 fusions, and whether they are linked to the female sex bias of this cancer, are largely unexplored. Moreover, whether oncogenic TFE3 fusions arise from both the active and inactive X chromosomes in females remains unknown. Here we address these questions by haplotype-specific analyses of whole-genome sequences of 29 tRCC samples from 15 patients and by re-analysis of 145 published tRCC whole-exome sequences. We show that TFE3 fusions universally arise as reciprocal translocations with minimal DNA loss or insertion at paired break ends. Strikingly, we observe a near exact 2:1 female:male ratio in TFE3 fusions arising via X:autosomal translocation (but not via X inversion), which accounts for the female predominance of tRCC. This 2:1 ratio is at least partially attributable to oncogenic fusions involving the inactive X chromosome and is accompanied by partial re-activation of silenced chrX genes on the rearranged chromosome. Our results highlight how somatic alterations involving the X chromosome place unique constraints on tumor initiation and exemplify how genetic rearrangements of the sex chromosomes can underlie cancer sex differences.

Postoperative Restrictive Opioid Protocols and Durable Changes in Opioid Prescribing and Chronic Opioid Use.

Importance: Changes in postsurgical opioid prescribing practices may help reduce chronic opioid use in surgical patients. Objective: To investigate whether postsurgical acute pain across different surgical subspecialties can be managed effectively after hospital discharge with an opioid supply of 3 or fewer days and whether this reduction in prescribed opioids is associated with reduced new, persistent opioid use. Design, Setting, and Participants: In this prospective cohort study with a case-control design, a restrictive opioid prescription protocol (ROPP) specifying an opioid supply of 3 or fewer days after discharge from surgery along with standardized patient education was implemented across all surgical services at a tertiary-care comprehensive cancer center. Participants were all patients who underwent surgery from August 1, 2018, to July 31, 2019. Main Outcomes and Measures: Main outcomes were the rate of compliance with the ROPP in each surgical service, the mean number of prescription days and refill requests, type of opioid prescribed, and rate of conversion to chronic opioid use determined via a state-run opioid prescription program. Postsurgical complications were also measured. Results: A total of 4068 patients (mean [SD] age, 61.0 [13.8] years; 2528 women [62.1%]) were included, with 2017 in the pre-ROPP group (August 1, 2018, to January 31, 2019) and 2051 in the post-ROPP group (February 1, 2019, to July 31, 2019). The rate of compliance with the protocol was 95%. After implementation of the ROPP, mean opioid prescription days decreased from a mean (SD) of 3.9 (4.5) days in the pre-ROPP group to 1.9 (3.6) days in the post-ROPP group (P < .001). The ROPP implementation led to a 45% decrease in prescribed opioids after surgery (mean [SD], 157.22 [338.06] mean morphine milligram equivalents [MME] before ROPP vs 83.54 [395.70] MME after ROPP; P < .001). Patients in the post-ROPP cohort requested fewer refills (367 of 2051 [17.9%] vs 422 of 2017 [20.9%] in the pre-ROPP cohort; P = .02). There was no statistically significant difference in surgical complications. The conversion rate to chronic opioid use decreased following ROPP implementation among both opioid-naive patients with cancer (11.3% [143 of 1267] to 4.5% [118 of 2645]; P < .001) and those without cancer (6.1% [19 of 310] to 2.7% [16 of 600]; P = .02). Conclusions and Relevance: In this cohort study, prescribing an opioid supply of 3 or fewer days to surgical patients after hospital discharge was feasible for most patients, led to a significant decrease in the number of opioids prescribed after surgery, and was associated with a significantly decreased conversion to long-term opioid use without concomitant increases in refill requests or significant compromises in surgical recovery.

Iron accumulation typifies renal cell carcinoma tumorigenesis but abates with pathological progression, sarcomatoid dedifferentiation, and metastasis.

Iron is a potent catalyst of oxidative stress and cellular proliferation implicated in renal cell carcinoma (RCC) tumorigenesis, yet it also drives ferroptosis that suppresses cancer progression and represents a novel therapeutic target for advanced RCC. The von Hippel Lindau (VHL)/hypoxia-inducible factor-α (HIF-α) axis is a major regulator of cellular iron, and its inactivation underlying most clear cell (cc) RCC tumors introduces both iron dependency and ferroptosis susceptibility. Despite the central role for iron in VHL/HIF-α signaling and ferroptosis, RCC iron levels and their dynamics during RCC initiation/progression are poorly defined. Here, we conducted a large-scale investigation into the incidence and prognostic significance of total tissue iron in ccRCC and non-ccRCC patient primary tumor cancer cells, tumor microenvironment (TME), metastases and non-neoplastic kidneys. Prussian Blue staining was performed to detect non-heme iron accumulation in over 1600 needle-core sections across multiple tissue microarrays. We found that RCC had significantly higher iron staining scores compared with other solid cancers and, on average, >40 times higher than adjacent renal epithelium. RCC cell iron levels correlated positively with TME iron levels and inversely with RCC levels of the main iron uptake protein, transferrin receptor 1 (TfR1/TFRC/CD71). Intriguingly, RCC iron levels, including in the TME, decreased significantly with pathologic (size/stage/grade) progression, sarcomatoid dedifferentiation, and metastasis, particularly among patients with ccRCC, despite increasing TfR1 levels, consistent with an increasingly iron-deficient tumor state. Opposite to tumor iron changes, adjacent renal epithelial iron increased significantly with RCC/ccRCC progression, sarcomatoid dedifferentiation, and metastasis. Lower tumor iron and higher renal epithelial iron each predicted significantly shorter ccRCC patient metastasis-free survival. In conclusion, iron accumulation typifies RCC tumors but declines toward a relative iron-deficient tumor state during progression to metastasis, despite precisely opposite dynamics in adjacent renal epithelium. These findings raise questions regarding the historically presumed selective advantage for high iron during all phases of cancer evolution, suggesting instead distinct tissue-specific roles during RCC carcinogenesis and early tumorigenesis versus later progression. Future study is warranted to determine how the relative iron deficiency of advanced RCC contributes to ferroptosis resistance and/or introduces a heightened susceptibility to iron deprivation that might be therapeutically exploitable.