Role of Gut Microbiome in Neoadjuvant Chemotherapy Response in Urothelial Carcinoma: A Multi-Institutional Prospective Cohort Evaluation.

Neoadjuvant chemotherapy (NAC) is linked with clinical advantages in urothelial carcinoma for patients with muscle-invasive bladder cancer (MIBC). Despite comprehensive research into the influence of tumor mutation expression profiles and clinicopathological factors on chemotherapy response, the role of the gut microbiome (GM) in bladder cancer(BC) chemotherapy response remains poorly understood. This study examines the variance in the gut microbiome(GM) of BC patients compared to healthy adults, and investigates GM compositional differences between patients who respond to chemotherapy versus those who exhibit residual disease. Our study reveals distinct clustering, effectively separating the BC and healthy cohorts. However, no significant differences were observed between chemotherapy responders and non-responders within community subgroups. Machine Learning models based on responder status outperformed clinical variables in predicting complete response (AUC 0.88 vs AUC 0.50), although no single microbial species emerged as a fully reliable biomarker. The evaluation of short-chain fatty acid (SCFA) concentration in blood and stool revealed no correlation with responder status. Still, SCFA analysis showed a higher abundance of Akkermansia (rs = 0.51, p = 0.017) and Clostridia (rs = 0.52, p = 0.018), which correlated with increased levels of detectable fecal isobutyric acid. Higher levels of fecal Lactobacillus (rs = 0.49, p=0.02) and Enterobacteriaceae (rs = 0.52, p < 0.03) correlated with increased fecal propionic acid. In conclusion, our study constitutes the first large-scale, multi-center assessment of GM composition, suggesting the potential for a complex microbial signature to predict patients more likely to respond to NAC based on multiple taxa.

Targeting NPC1 in Renal Cell Carcinoma.

Rapidly proliferating cancer cells have a greater requirement for cholesterol than normal cells. Tumor cells are largely dependent on exogenous lipids given that their growth requirements are not fully met by endogenous pathways. Our current study shows that ccRCC cells have redundant mechanisms of cholesterol acquisition. We demonstrate that all major lipoproteins (i.e., LDL, HDL, and VLDL) have a comparable ability to support the growth of ccRCC cells and are equally effective in counteracting the antitumor activities of TKIs. The intracellular trafficking of exogenous lipoprotein-derived cholesterol appears to be distinct from the movement of endogenously synthesized cholesterol. De novo synthetized cholesterol is transported from the endoplasmic reticulum directly to the plasma membrane and to the acyl-CoA: cholesterol acyltransferase, whereas lipoprotein-derived cholesterol is distributed through the NPC1-dependent endosomal trafficking system. Expression of NPC1 is increased in ccRCC at mRNA and protein levels, and high expression of NPC1 is associated with poor prognosis. Our current findings show that ccRCC cells are particularly sensitive to the inhibition of endolysosomal cholesterol export and underline the therapeutic potential of targeting NPC1 in ccRCC.

Localised non-metastatic sarcomatoid renal cell carcinoma: a 31-year externally verified study.

OBJECTIVE: To evaluate post-nephrectomy outcomes and predictors of cancer-specific survival (CSS) between patients with localised sarcomatoid renal cell carcinoma (sRCC) and those with Grade 4 RCC (non-sRCC), as most sRCC research focuses on advanced or metastatic disease with limited studies analysing outcomes of patients with localised non-metastatic sRCC. PATIENTS AND METHODS: A total of 564 patients with localised RCC underwent partial or radical nephrectomy between June 1988 to March 2019 for sRCC (n = 204) or World Health Organization/International Society of Urological Pathology Grade 4 non-sRCC (n = 360). The CSS at every stage between groups was assessed. Phase III ASSURE clinical trial data were used to externally validate the CSS findings. The Mann-Whitney U-test and chi-squared test compared outcomes and the Kaplan-Meier method evaluated CSS, overall survival (OS) and recurrence-free survival. Clinicopathological features associated with RCC death were evaluated using Cox proportional hazards regression. RESULTS: The median follow-up was 31.5 months. The median OS and CSS between the sRCC and Grade 4 non-sRCC groups was 45 vs 102 months and 49 vs 152 months, respectively (P < 0.001). At every stage, sRCC had worse CSS compared to Grade 4 non-sRCC. Notably, pT1 sRCC had worse CSS than pT3 Grade 4 non-sRCC. Negative predictors of CSS were sarcomatoid features, non-clear cell histology, positive margins, higher stage (pT3/pT4), and use of minimally invasive surgery (MIS). ASSURE external verification showed worse CSS in patients with sRCC (hazard ratio [HR] 1.63, 95% confidence interval [CI] 1.12-2.36; P = 0.01), but not worse outcomes in MIS surgery (HR 1.39, 95% CI 0.75-2.56; P = 0.30). CONCLUSIONS: Localised sRCC had worse CSS compared to Grade 4 non-sRCC at every stage. Negative survival predictors included positive margins, higher pathological stage, use of MIS, and non-clear cell histology. sRCC is an aggressive variant even at low stages requiring vigilant surveillance and possible inclusion in adjuvant therapy trials.

Real-time estimation of nephron activity with a linear measurement system (RENAL-MS) predicts postoperative estimated glomerular filtration rate.

OBJECTIVE: To determine whether a simple point-of-care measurement system estimating renal parenchymal volume using tools ubiquitously available could be used to replace nuclear medicine renal scintigraphy (NMRS) in current clinical practice to predict estimated glomerular filtration rate (eGFR) after nephrectomy by estimating preoperative split renal function. PATIENTS AND METHODS: We performed a retrospective review of patients who underwent abdominal cross-sectional imaging (computed tomography/magnetic resonance imaging) and mercaptoacetyltriglycine (MAG3) NMRS prior to total nephrectomy at a single institution. We developed the real-time estimation of nephron activity with a linear measurement system (RENAL-MS) method of estimating postoperative renal function via the following technique: renal parenchymal volume of the removed kidney relative to the remaining kidney was estimated as the product of renal length and the average of six renal parenchymal thickness measurements. The utility of this value was compared to the utility of the split renal function measured by MAG3 for prediction of eGFR and new onset Stage 3 chronic kidney disease (CKD) at ≥90 days after nephrectomy using uni- and multivariate linear and logistic regression. RESULTS: A total of 57 patients met the study criteria. The median (interquartile range [IQR]) age was 69 (61-80) years. The median (IQR) pre- and postoperative eGFR was 74 (IQR 58-90) and 46 (35-62) mL/min/1.73 m2 , respectively. [Correction added on 29 December 2023, after first online publication: The data numbers in the preceding sentence have been corrected.] Correlations between actual and predicted postoperative eGFR were similar whether the RENAL-MS or NMRS methods were used, with correlation using RENAL-MS being slightly numerically but not statistically superior (R = 0.82 and 0.76; P = 0.138). Receiver operating characteristic curve analysis using logistic regression estimates incorporating age, sex, and preoperative creatinine to predict postoperative Stage 3 CKD were similar between RENAL-MS and NMRS (area under the curve 0.93 vs. 0.97). [Correction added on 29 December 2023, after first online publication: The data numbers in the preceding sentence have been corrected.] CONCLUSION: A point-of-care tool to estimate renal parenchymal volume (RENAL-MS) performed equally as well as NMRS to predict postoperative eGFR and de novo Stage 3 CKD after nephrectomy in our population, suggesting NMRS may not be necessary in this setting.

Transition to Value-based Healthcare: Development, Implementation, and Results of an Optimal Surgical Care Framework at a National Cancer Institute-designated Comprehensive Cancer Center.

BACKGROUND: The continued rise in healthcare expenditures has not produced commensurate improvements in patient outcomes, leading US healthcare stakeholders to emphasize value-based care. Transition to such a model requires all team members to adopt a new strategic and organizational framework. OBJECTIVE: To describe and report a strategy for the implementation of a novel patient-centered value-based "optimal surgical care" (OSC) framework, with validation and cost analysis in kidney surgery. DESIGN, SETTING, AND PARTICIPANTS: An observational study of care episodes at a single institution from 2014 to 2019 was conducted. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multidisciplinary teams defined OSC by core and procedure-specific metrics using a combination of provider-based ("bottom-up") and "clinical leadership"-based ("top-down") strategies. Baseline OSC rates across were established, while identifying proportions of OSC achieved by coefficient of variation (CV) in total direct costs. Multivariable linear regression comparing cost between OSC and non-OSC encounters was performed, adjusting for patient characteristics. RESULTS AND LIMITATIONS: An analysis of 30 261 perioperative care episodes was performed. Following the implementation of an OSC framework, there was an increase in OSC rates across all procedure buckets using core (25%) and procedure-specific (26%) metrics. Among the tumors tested, kidney cancer surgical episodes held the highest OSC rate improvement (67%) with lowest variability in cost (CV 0.5). OSC was associated with significant total cost savings across all tumor types after adjusting for inflation (p < 0.05). Compared with non-OSC episodes, a significant reduction in the cost ratio of OSC was noted for renal surgery (p < 0.01), with estimated costs savings of $2445.87 per OSC encounter. CONCLUSIONS: Institutional change directing efforts toward optimizing surgical care and emphasizing value rather than focusing solely on expense reduction is associated with improved outcomes, while potentially reducing costs. The strategy for implementation requires serial performance analyses, engaging and educating providers, and continuous ongoing adjustments to achieve durable results. PATIENT SUMMARY: In this study, we report our strategy and outcomes for transitioning to a value-based healthcare model using a novel "optimal surgical care" framework at a National Cancer Institute-designated comprehensive cancer center. We observed an increase in optimal surgical care episodes across all specialties after 5 yr, with a potential associated reduction in cost expenditure. We conclude that the key to a successful and sustained transition is the implementation strategy, focusing on continual review and provider engagement.

Molecular Characterization of TFE3-Rearranged Renal Cell Carcinoma: A Comparative Study With Papillary and Clear Cell Renal Cell Carcinomas.

TFE3-rearranged renal cell carcinoma (rRCC) is a rare subtype of renal cell carcinomas belonging to the MiT family translocation RCC. To further elucidate the co-alterations that occur along with TFE3 fusions in rRCC, we characterized the genomic, transcriptional, and immune landscapes in comparison to clear cell (ccRCC) and papillary renal cell carcinoma (pRCC). Next-generation sequencing of RNA (whole transcriptome) and DNA (592-gene panel or whole exome) for rRCC (N = 20), pRCC (N = 20), and ccRCC samples (N = 392) was performed. Patients with rRCC were significantly younger and more frequently female (median 44.5 years, 75.0% female) as compared with patients with pRCC (68.5 years, 25.0% female; P < .05) and ccRCC (62.0 years, 27.8% female; P < .05). A total of 8 unique fusion partners were observed, including a novel fusion with SRRM2::TFE3 in 2 patients. ccRCC exhibited significantly higher mutation rates of VHL (0% rRCC, 0% pRCC, 78.7% ccRCC; P < .05) and PBMR1 (0% rRCC, 5.0% pRCC, 49.4% ccRCC; P < .05). The genomic landscapes of rRCC were sparse with no mutations occurring with a prevalence higher than 10% other than pTERT (18.2% rRCC, 0% pRCC, 9.2% ccRCC). rRCC were associated with significantly less M1 macrophages (0.8%) as compared with pRCC (1.4%) and ccRCC (2.7%) (P < .05), suggesting a cold tumor-immune microenvironment. However, rRCC were more commonly PD-L1+ (rRCC 50%, pRCC 19.0%, ccRCC 12.2%; P < .05). Gene set enrichment analysis showed that rRCC are enriched in genes related to oxidative phosphorylation when compared with both ccRCC and pRCC. Despite having a colder tumor-immune microenvironment than pRCC and ccRCC, increased PDL1+ rates in rRCC suggest a potential benefit from immune checkpoint inhibitor therapy.

A sheep in wolf's clothing; a case of renal leiomyoma masquerading as hereditary leiomyomatosis and renal cell carcinoma.

Active surveillance has become a standard of care for the management of small renal masses. Decision to transition from surveillance to intervention relies on several factors including growth kinetics, histologic grade on biopsy and patient comorbidities. Management of renal masses in pregnancy presents a unique change when clinical triggers must be weighed with risk to fetus. We present the case of a third trimester patient with an enlarging and enhancing renal mass managed with robotic assisted laparoscopic partial nephrectomy. Histologic analysis was consistent with renal leiomyoma. Renal leiomyomas are a rare benign mesenchymal tumor influenced by changes in progesterone-estrogen axis.

Partial versus radical nephrectomy for complex renal mass: multicenter comparative analysis of functional outcomes (Rosula collaborative group).

BACKGROUND: Utility of partial nephrectomy (PN) for complex renal mass (CRM) is controversial. We determined the impact of surgical modality on postoperative renal functional outcomes for CRM. METHODS: We retrospectively analyzed a multicenter registry (ROSULA). CRM was defined as RENAL Score 10-12. The cohort was divided into PN and radical nephrectomy (RN) for analyses. Primary outcome was development of de-novo estimated glomerular filtration rate (eGFR)<45 mL/min/1.73 m2. Secondary outcomes were de-novo eGFR<60 and ΔeGFR between diagnosis and last follow-up. Cox proportional hazards was used to elucidate predictors for de-novo eGFR<60 and <45. Linear regression was utilized to analyze ΔeGFR. Kaplan-Meier Analysis (KMA) was performed to analyze 5-year freedom from de-novo eGFR<60 and <45. RESULTS: We analyzed 969 patients (RN=429/PN=540; median follow-up 24.0 months). RN patients had lower BMI (P<0.001) and larger tumor size (P<0.001). Overall postoperative complication rate was higher for PN (P<0.001), but there was no difference in major complications (Clavien III-IV; P=0.702). MVA demonstrated age (HR=1.05, P<0.001), tumor-size (HR=1.05, P=0.046), RN (HR=2.57, P<0.001), and BMI (HR=1.04, P=0.001) to be associated with risk for de-novo eGFR<60 mL/min/1.73 m2. Age (HR=1.03, P<0.001), BMI (HR=1.06, P<0.001), baseline eGFR (HR=0.99, P=0.002), tumor size (HR=1.07, P=0.007) and RN (HR=2.39, P<0.001) were risk factors for de-novo eGFR<45 mL/min/1.73 m2. RN (B=-10.89, P<0.001) was associated with greater ΔeGFR. KMA revealed worse 5-year freedom from de-novo eGFR<60 (71% vs. 33%, P<0.001) and de-novo eGFR<45 (79% vs. 65%, P<0.001) for RN. CONCLUSIONS: PN provides functional benefit in selected patients with CRM without significant increase in major complications compared to RN, and should be considered when technically feasible.

Diabetes, Obesity, and Pathological Upstaging in Renal Cell Carcinoma: Results From a Large Multi-institutional Consortium.

PURPOSE: We sought to determine whether clinical risk factors and morphometric features on preoperative imaging can be utilized to identify those patients with cT1 tumors who are at higher risk of upstaging (pT3a). MATERIALS AND METHODS: We performed a retrospective international case-control study of consecutive patients treated surgically with radical or partial nephrectomy for nonmetastatic renal cell carcinoma (cT1 N0) conducted between January 2010 and December 2018. Multivariable logistic regression models were used to study associations of preoperative risk factors on pT3a pathological upstaging among all patients, as well as subsets with those with preoperative tumors ≤4 cm, renal nephrometry scores, tumors ≤4 cm with nephrometry scores, and clear cell histology. We also examined association with pT3a subsets (renal vein, sinus fat, perinephric fat). RESULTS: Among the 4,092 partial nephrectomy and 2,056 radical nephrectomy patients, pathological upstaging occurred in 4.9% and 23.3%, respectively. Among each group independent factors associated with pT3a upstaging were increasing preoperative tumor size, increasing age, and the presence of diabetes. Specifically, among partial nephrectomy subjects diabetes (OR=1.65; 95% CI 1.17, 2.29), male sex (OR=1.62; 95% CI 1.14, 2.33), and increasing BMI (OR=1.03; 95% CI 1.00, 1.05 per 1 unit BMI) were statistically associated with upstaging. Subset analyses identified hilar tumors as more likely to be upstaged (partial nephrectomy OR=1.91; 95% CI 1.12, 3.16; radical nephrectomy OR=2.16; 95% CI 1.44, 3.25). CONCLUSIONS: Diabetes and higher BMI were associated with pathological upstaging, as were preoperative tumor size, increased age, and male sex. Similarly, hilar tumors were frequently upstaged.

Adjuvant everolimus after surgery for renal cell carcinoma (EVEREST): a double-blind, placebo-controlled, randomised, phase 3 trial.

BACKGROUND: Patients undergoing resection of renal cell carcinoma are at risk of disease relapse. We evaluated the effectiveness of the mammalian target of rapamycin inhibitor everolimus administered after surgery. METHODS: In this randomised, double-blind, phase 3 trial, we enrolled adults with histologically confirmed renal cell carcinoma who had undergone a full surgical resection and were at intermediate-high or very high risk of recurrence at 398 academic and community institution centres in the USA. After nephrectomy, patients were randomly assigned (1:1) via a central web-based application using a dynamic balancing algorithm to receive 10 mg oral everolimus daily or placebo for 54 weeks. The primary endpoint was recurrence-free survival. Efficacy analyses included all eligible, randomly assigned patients; safety analysis included all patients who received treatment. This trial is registered with ClinicalTrials.gov, NCT01120249 and is closed to new participants. FINDINGS: Between April 1, 2011, and Sept 15, 2016, a total of 1545 patients were randomly assigned to receive everolimus (n=775) or placebo (n=770), of whom 755 assigned to everolimus and 744 assigned to placebo were eligible for inclusion in the efficacy analysis. With a median follow-up of 76 months (IQR 61-92), recurrence-free survival was longer with everolimus than with placebo (5-year recurrence-free survival 67% [95% CI 63-70] vs 63% [60-67]; stratified log-rank p=0·050; stratified hazard ratio [HR] 0·85, 95% CI 0·72-1·00; p=0·051) but did not meet the prespecified p value for statistical significance of 0·044. Recurrence-free survival was longer with everolimus than with placebo in the very-high-risk group (HR 0·79, 95% CI 0·65-0·97; p=0·022) but not in the intermediate-high-risk group (0·99, 0·73-1·35; p=0·96). Grade 3 or higher adverse events occurred in 343 (46%) of 740 patients who received everolimus and 79 (11%) of 723 who received placebo. INTERPRETATION: Postoperative everolimus did not improve recurrence-free survival compared with placebo among patients with renal cell carcinoma at high risk of recurrence after nephrectomy. These results do not support the adjuvant use of everolimus for renal cell carcinoma after surgery. FUNDING: US National Institutes of Health, National Cancer Institute, National Clinical Trials Network, Novartis Pharmaceuticals Corporation, and The Hope Foundation.

Impact of Variant Histology on Oncological Outcomes in Upper Tract Urothelial Carcinoma: Results From the ROBUUST Collaborative Group.

INTRODUCTION: Oncologic implications of variant histology (VH) have been extensively studied in bladder cancer; however, further investigation is needed in upper tract urothelial carcinoma (UTUC). Our study aims to evaluate the impact of VH on oncological outcomes in UTUC patients treated with radical nephroureterectomy (RNU). METHODS: A retrospective analysis was performed on patients who underwent a robotic or laparoscopic RNU for UTUC using the ROBUUST database, a multi-institutional collaborative including 17 centers worldwide. Logistic regression was used to assess the effect of VH on urothelial recurrence (bladder, contralateral upper tract), metastasis, and survival following RNU. RESULTS: A total of 687 patients were included in this study. Median (IQR) age was 71 (64-78) years and 470 (68%) had organ confined disease. VH was present in 70 (10.2%) patients. In a median follow-up of 16 months, the incidence of urothelial recurrence, metastasis, and mortality was 26.8%, 15.3%, and 11.8%, respectively. VH was associated with increased risk of metastasis (HR 4.3, P <.0001) and death (HR 2.0, P =.046). In multivariable analysis, VH was noted to be an independent risk factor for metastasis (HR 1.8, P =.03) but not for urothelial recurrence (HR 0.99, P =.97) or death (HR 1.4, P =.2). CONCLUSION: Variant histology can be found in 10% of patients with UTUC and is an independent risk factor for metastasis following RNU. Overall survival rates and the risk of urothelial recurrence in the bladder or contralateral kidney are not affected by the presence of VH.

Clinical Performance of Technetium-99m-Sestamibi SPECT/CT Imaging in Differentiating Oncocytic Tumors From Renal Cell Carcinoma in Routine Clinical Practice.

PURPOSE: Technetium-99m-sestamibi single-photon emission CT/x-ray CT is an emerging clinical tool to differentiate oncocytic tumors from renal cell carcinomas. We report data from a large institutional cohort of patients who underwent technetium-99m-sestamibi scans during evaluation of renal masses. MATERIALS AND METHODS: Patients who underwent technetium-99m-sestamibi single-photon emission CT/x-ray CT between February 2020 and December 2021 were included in the analysis. Scans were defined as "hot" for oncocytic tumor when technetium-99m-sestamibi uptake was qualitatively equivalent or higher between the mass of interest and normal renal parenchyma, suggesting oncocytoma, hybrid oncocytic/chromophobe tumor, or chromophobe renal cell carcinoma. Demographic, pathological, and management strategy data were compared between "hot" and "cold" scans. For individuals who underwent diagnostic biopsy or extirpative procedures, the concordance between radiological findings and pathology was indexed. RESULTS: A total of 71 patients (with 88 masses) underwent technetium-99m-sestamibi imaging with 60 (84.5%) patients having at least 1 "cold" mass on imaging and 11 (15.5%) patients exhibiting only "hot" masses. Pathology was available for 7 "hot" masses, with 1 biopsy specimen (14.3%) being discordant (clear cell renal cell carcinoma). Five patients with "cold" masses underwent biopsy. Out of 5 biopsied masses, 4 (80%) were discordant oncocytomas. Of the extirpated specimens, 35/40 (87.5%) harbored renal cell carcinoma and 5/40 (12.5%) yielded discordant oncocytomas. In sum, 20% of pathologically sampled masses that were "cold" on technetium-99m-sestamibi imaging still harbored oncocytoma/hybrid oncocytic/chromophobe tumor/chromophobe renal cell carcinoma. CONCLUSIONS: Further work is needed to define utility of technetium-99m-sestamibi in real-world clinical practice. Our data suggest this imaging strategy is not yet ready to replace biopsy.

Distinguishing lipid-poor angiomyolipoma from renal carcinoma using tumor shape.

OBJECTIVES: To validate the "overflowing beer sign" (OBS) for distinguishing between lipid-poor angiomyolipoma (AML) and renal cell carcinoma, and to determine whether it improves the detection of lipid-poor AML when added to the angular interface sign, a previously-validated morphologic feature associated with AML. METHODS: Retrospective nested case-control study of all 134 AMLs in an institutional renal mass database matched 1:2 with 268 malignant renal masses from the same database. Cross-sectional imaging from each mass was reviewed and the presence of each sign was identified. A random selection of 60 masses (30 AML and 30 benign) was used to measure interobserver agreement. RESULTS: Both signs were strongly associated with AML in the total population (OBS: OR 17.4 95% CI 8.0-42.5, p < 0.001; angular interface: OR 12.6, 95% CI 5.9-29.7, p < 0.001) and the population of patients excluding those with visible macroscopic fat (OBS: OR 11.2, 95% CI 4.8-28.7, p < 0.001; angular interface: 8.5, 95% CI 3.7-21.1, p < 0.001). In the lipid-poor population, the specificity of both signs was excellent (OBS: 95.6%, 95% CI 91.9%-98%; angular interface: 95.1%, 95% CI 91.3%-97.6%). Sensitivity was low for both signs (OBS: 31.4%, 95% CI 24.0-45.4%; angular interface: 30.5%, 95% CI 20.8%-41.6%). Both signs showed high levels of inter-rater agreement (OBS 90.0% 95% CI 80.5 - 95.9; angular interface 88.6, 95% CI 78.7-94.9) Testing for AML using the presence of either sign in this population improved sensitivity (39.0%, 95% CI 28.4%-50.4%, p = 0.023) without significantly reducing specificity (94.2%, 95% CI 90%-97%, p = 0.2) relative to the angular interface sign alone. CONCLUSIONS: Recognition of the OBS increases the sensitivity of detection of lipid-poor AML without significantly reducing specificity.

Pathological and Clinical Outcomes in a Large Surveillance and Intervention Cohort of Radiographically Cystic Renal Masses.

PURPOSE: We evaluated oncologic risks in a large cohort of patients with radiographic cystic renal masses who underwent active surveillance or intervention. MATERIALS AND METHODS: A single-institutional database of 4,340 kidney lesions managed with either active surveillance or intervention between 2000-2020 was queried for radiographically cystic renal masses. Association of radiographic tumor characteristics and high-grade pathology was evaluated. RESULTS: We identified 387 radiographically confirmed cystic lesions in 367 patients. Of these, 247 were resected (n=240) or ablated (n=7; n=247, 203 immediate vs 44 delayed intervention). Pathologically, 23% (n=56) demonstrated high-grade pathology. Cystic features were explicitly described by pathology in only 18% (n=33) of all lesions and in 7% (n=4) of high-grade lesions. Of the intervention cohort, African American race, male gender, and Bosniak score were associated with high-grade pathology (P < .05). On active surveillance (n=184), Bosniak IV lesions demonstrated faster growth rates than IIF and III lesions (2.7 vs 0.6 and 0.5 mm/y, P ≤ .001); however, growth rates were not associated with high-grade pathology (P = .5). No difference in cancer-specific survival was identified when comparing intervention vs active surveillance at 5 years (99% vs 100%, P = .2). No difference in recurrence was observed between immediate intervention vs delayed intervention (P > .9). CONCLUSIONS: A disconnect between "cystic" designation on imaging and pathology exists for renal lesions. Over 80% of radiographic Bosniak cystic lesions are not described as "cystic" on pathology reports. More than 1 in 5 resected cystic renal lesions demonstrated high-grade disease. Despite this finding, judiciously managed active surveillance ± delayed intervention is a safe and effective management option for most radiographic cystic renal masses.

Examining the Effect of PARP-1 Inhibitors on Transcriptional Activity of Androgen Receptor in Prostate Cancer Cells.

Since the early 1940s, androgen ablation has been the cornerstone of treatment for prostate cancer (PC). Importantly, androgen receptor (AR) signaling is vital not only for the initiation of PC, which is initially androgen-dependent, but also for castration-resistant disease. Recent studies demonstrated clear promise of the poly(ADP-ribose) polymerase 1 (PARP-1) inhibitors for targeting prostate cancer cells harboring mutations in DNA damage-repair genes. In addition, it has been established that PARP-1 inhibition suppresses growth of AR-positive prostate cancer cells in cell and animal models. Thus, prostate cancer represents a particularly promising disease site for targeting PARP-1, given that both DNA repair and AR-mediated transcription depend on PARP-1 function. Here, we describe the development and use of cell-based assay to evaluate the impact of PARP-1 inhibitors on the AR signaling in prostate cancer cells.

Long-Term Results of a Phase 3 Randomized Prospective Trial of Erectile Tissue-Sparing Intensity-Modulated Radiation Therapy for Men With Clinically Localized Prostate Cancer.

PURPOSE: The objective of this study was to determine whether limiting the doses delivered to the penile bulb (PB) and corporal bodies with intensity modulated radiation therapy (IMRT) preserves erectile function compared with standard IMRT in men with prostate cancer. METHODS AND MATERIALS: A total of 117 patients with low- to intermediate-risk, clinical T1a-T2c prostate adenocarcinoma were enrolled in a single-institution, prospective, single-blind, phase 3 randomized trial. All received definitive IMRT to 74 to 80 Gy in 37 to 40 fractions and standard IMRT (s-IMRT) or erectile tissue-sparing IMRT (ETS-IMRT), which placed additional planning constraints that limited the D90 to the penile bulb and corporal bodies to ≤15 Gy and ≤7 Gy, respectively. Erectile potency was assessed with components of the International Index of Erectile Function and phosphodiesterase type 5 inhibitor (PDE5) medication records. RESULTS: Sixty-two patients received ETS-IMRT, and 54 received s-IMRT; 1 patient did not receive radiation therapy. Before treatment, all patients reported erectile potency. No patients received androgen deprivation therapy. In the intention-to-treat analysis, treatment arms did not differ in potency preservation at 24 months (37.1% ETS-IMRT vs 31.5% s-IMRT, P = .53). Of 85 evaluable patients with International Index of Erectile Function and PDE5 medication follow-up, erectile potency was seen in 47.9% of patients in the ETS-IMRT arm and 46.0% of patients in the s-IMRT arm (P = .86). PDE5 inhibitors were initiated in 41.7% of ETS-IMRT patients and 35.1% of s-IMRT patients (P = .54). Among all patients enrolled, there was no difference in freedom from biochemical failure between those treated with ETS-IMRT and s-IMRT (5-year 91.8% vs 90.7%, respectively, P = .77), with a median follow-up of 7.4 years. There were no differences in acute or late gastrointestinal or genitourinary toxicity. An unplanned per-protocol analysis demonstrated no differences in potency preservation or secondary endpoints between patients who exceeded erectile tissue-sparing constraints and those who met constraints, although power was limited by attrition and unplanned dosimetric crossover. CONCLUSIONS: ETS-IMRT that strictly limits dose to the penile bulb and corporal bodies is safe and feasible. Use of this planning technique did not show an effect on potency preservation outcomes at 2 years, though power to detect a difference was limited.

No difference in renal function outcomes for patients with oncocytoma managed with active surveillance vs. partial nephrectomy.

OBJECTIVES: To investigate the difference in renal function outcomes for patients with oncocytomas undergoing active surveillance (AS) vs. partial nephrectomy (PN). METHODS: We reviewed our institutional database for patients with biopsy/surgically confirmed oncocytoma from 2000-2020. The primary outcome was to assess for differences in renal function outcomes in patients undergoing AS vs. PN. We fit two generalized estimating equation (GEE) with an interaction term between follow up time and management strategy to predict 1) mean eGFR for patients managed with AS and PN and 2) the probability of progression to CKD stage III or greater. RESULTS: We identified 114 eligible patients, of which 32 were managed with AS. Median follow-up was 21 months vs. 44 months for PN vs. AS patients. AS patients tended to be older (median: 72 years vs. 65 years, P<0.001) and have lower baseline renal function (median: eGFR: 71 mL/min/1.73m2 vs. 82 mL/min/1.73m2, P<0.001) compared with PN patients. Renal mass size from baseline imaging was similar between patients undergoing PN vs. AS (2.8 cm vs. 2.9 cm, P=0.634). For patients undergoing PN vs. AS, there was not a significant difference in predicted longitudinal eGFR (-0.079, 95% CI -0.18-0.023, P=0.129) or predicted probability of progression to CKD stage III or greater (OR: 0.61, 95% CI: 0.16-2.33, P=0.47). CONCLUSIONS: In our institutional dataset, patients undergoing AS or PN with an oncocytoma had similar long-term renal function outcomes. Given similar renal function outcomes in patients undergoing AS and PN, surgery should remain reserved for select patients with oncocytomas.

Acetyl-CoA Counteracts the Inhibitory Effect of Antiandrogens on Androgen Receptor Signaling in Prostate Cancer Cells.

The commonly used therapeutic management of PC involves androgen deprivation therapy (ADT) followed by treatment with AR signaling inhibitors (ARSI). However, nearly all patients develop drug-resistant disease, with a median progression-free survival of less than 2 years in chemotherapy-naïve men. Acetyl-coenzyme A (acetyl-CoA) is a central metabolic signaling molecule with key roles in biosynthetic processes and cancer signaling. In signaling, acetyl-CoA serves as the acetyl donor for acetylation, a critical post-translational modification. Acetylation affects the androgen receptor (AR) both directly and indirectly increasing expression of AR dependent genes. Our studies reveal that PC cells respond to the treatment with ARSI by increasing expression of ATP-citrate lyase (ACLY), a major enzyme responsible for cytosolic acetyl-CoA synthesis, and up-regulation of acetyl-CoA intracellular levels. Inhibition of ACLY results in a significant suppression of ligand-dependent and -independent routes of AR activation. Accordingly, the addition of exogenous acetyl-CoA, or its precursor acetate, augments AR transcriptional activity and diminishes the anti-AR activity of ARSI. Taken together, our findings suggest that PC cells respond to antiandrogens by increasing activity of the acetyl-coA pathway in order to reinstate AR signaling.

Human Gut Mycobiome and Fungal Community Interaction: The Unknown Musketeer in the Chemotherapy Response Status in Bladder Cancer.

Background: Until recently, the properties of microbiome and mycobiome in humans and its relevance to disease have largely been unexplored. While the interest of microbiome and malignancy over the past few years have burgeoned with advent of new technologies, no research describing the composition of mycobiome in bladder cancer has been done. Deciphering of the metagenome and its aggregate genetic information can be used to understand the functional properties and relationships between the bacteria, fungi, and cancer. Objective: The aim of this project is to characterize the compositional range of the normal versus bladder cancer mycobiome of the gut. Design setting and participants: An internal transcribed spacer (ITS) survey of 52 fecal samples was performed to evaluate the gut mycobiome differences between noncancer controls and bladder cancer patients. Outcome measurements and statistical analysis: Our study evaluated the differences in mycobiome among patients with bladder cancer, versus matched controls. Our secondary analysis evaluated compositional differences in the gut as a function of response status with neoadjuvant chemotherapy. Data demultiplexing and classification were performed using the QIIME v.1.1.1.1 platform. The Ion Torrent-generated fungal ITS sequence data were processed using QIIME (v.1.9.1), and the reads were demultiplexed, quality filtered, and clustered into operation taxonomic units using default parameters. Alpha and beta diversity were computed and plotted in Phyloseq, principal coordinate analysis was performed on Bray-Curtis dissimilarity indices, and a one-way permutational multivariate analysis of variance was used to test for significant differences between cohorts. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) was applied to infer functional categories associated with taxonomic composition. Results and limitations: We found distinctive mycobiome differences between control group (n = 32) and bladder cancer (n = 29) gut flora, and identified an increasing abundance of Tremellales, Hypocreales, and Dothideales. Significant differences in alpha and beta diversity were present between the groups (control vs bladder; p = 0.002), noting distinct compositions within each cohort. A subgroup analysis by sex and neoadjuvant chemotherapy status did not show any further differences in mycobiome composition and diversity. Our results indicate that the gut mycobiome may modulate tumor response to preoperative chemotherapy in bladder cancer patients. We propose that patients with a "favorable" mycobiome composition (eg, high diversity, and low abundance of Agaricomycetes and Saccharomycetes) may have enhanced systemic immune response to chemotherapy through antigen presentation. Conclusions: Our study is the first to characterize the enteric mycobiome in patients with bladder cancer and describe complex ecological network alterations, indicating complex bacteria-fungi interactions, particularly highlighted among patients with complete neoadjuvant chemotherapy response. Patient summary: Our study has demonstrated that the composition of stool mycobiome (fungal inhabitants of the gastrointestinal tract) in patients with bladder cancer is different from that in noncancer individuals. Furthermore, when evaluating how patients respond to chemotherapy given prior to their surgery, our study noted significant differences between patients who responded and those who did not.