Cystic Renal Cell Carcinoma: A Report on Outcomes of Surgery and Active Surveillance in Patients Retrospectively Identified on Pretreatment Imaging.

PURPOSE: We evaluated the outcomes of surgical intervention and active surveillance in patients diagnosed with cystic renal cell carcinoma at our hypothesized radiological cutoff of greater than 50% cystic. MATERIALS AND METHODS: We identified all 430 patients with a pathologically confirmed cystic renal mass that fit our criteria from 2000 to 2015. The 292 patients with a lack of computerized tomography, tumors less than 50% cystic on imaging, multifocal tumors and prior renal cell carcinoma were excluded from study. Patients were stratified into benign or malignant subgroups, and radiological, clinicopathological and oncologic features were determined. Univariate and multivariate associations between clinicoradiological parameters in each group were analyzed. We similarly reviewed the records of a separate cohort of patients treated with active surveillance for cystic renal cell carcinoma. RESULTS: Of the 138 identified cases of cystic renal cell carcinoma 102 (73.9%) were renal cell carcinoma and 36 (26.1%) were benign masses. Of the tumors 77.5% were Fuhrman grade 1-2, 83.4% were stage pT2 or less and 65.9% showed clear cell histology. On univariate analysis male gender, a solid component and increasing Bosniak classification were significant for malignancy. In a separate cohort we identified 38 patients on active surveillance. The growth rate was 1.0 mm per year overall and 2.3 mm per year for the solid component. At a median followup of more than 4 years in all cohorts there was no evidence of recurrence or metastasis of cystic renal cell carcinoma. CONCLUSIONS: Patients with unifocal cystic renal cell carcinoma evaluated using a standardized radiological threshold of greater than 50% cystic had an excellent prognosis on active surveillance and after surgical resection.

The association of renal cell carcinoma with gastrointestinal stromal tumors.

BACKGROUND AND OBJECTIVES: Prior small studies have reported a possible association between renal cell carcinoma (RCC) and gastrointestinal stromal tumors (GISTs). In the largest known series, our objective was to describe the prevalence of RCC among patients with GISTs over 26 years at Memorial Sloan Kettering Cancer Center (MSKCC). METHODS: We retrospectively reviewed MSKCC's prospectively maintained sarcoma and RCC databases and identified all patients with both RCC and GIST between 1980 and 2016. Demographic and clinicopathological characteristics were obtained. RESULTS: A total of 9/405 (2.2%) GIST patients were identified with RCC, with a mean follow-up of 9.2 (range 3.8-28.4) years. Five out of nine (55.6%) patients had RCC and GIST diagnosis within 6 months of each other. Mean RCC tumor size was 3.0 (range 1.8-8) cm and 8/9 (88.9%) patients were RCC stage 1. A total of 4/9 (44.4%) patients had papillary RCC (pRCC) histology, 5/9 (55.6%) had additional alternative malignancies, and 4/9 (44.4%) had primary small bowel GIST. CONCLUSIONS: Our series suggests a possible association of RCC with GISTs. In addition, we found a high frequency of pRCC histology, alternative malignancies, and small bowel GISTs in co-occurring RCC-GIST patients. Further investigation to identify genetic mutations, in this population, would assist in surveillance and treatment.

Masked pneumothorax: risk of valveless trocar systems.

PURPOSE: Unlike traditional valved trocars, the valveless trocar maintains pneumoperitoneum during laparoscopy by forming a CO(2) curtain at the proximal end of the trocar. This gas barrier instantaneously maintains exact intraperitoneal pressure that yields to the transient physiological changes seen with breathing. Due to this different mechanism of action, pneumothorax development may be masked by the valveless trocar system. MATERIALS AND METHODS: We retrospectively reviewed 850 transperitoneal laparoscopic kidney and adrenal surgeries in which a valveless trocar system was used to determine any record of pneumothorax detected intraoperatively or postoperatively. A patient with pneumothorax was considered a case and anesthetic parameters were reviewed. A matched control group was generated from patients treated with transperitoneal laparoscopic kidney and adrenal surgery using the valveless trocar with no complications. RESULTS: Pneumothorax was diagnosed in 10 patients (1.2%). Two cases were the result of intentional excision of the diaphragm, which were repaired intraoperatively, while 8 were not recognized until the postoperative period. Five of the patients (63%) with unintentional pneumothorax required chest tube placement for a mean of 2.4 days. The remaining 3 patients (37%) were treated conservatively and followed with serial chest x-rays. The only anesthetic variable that was significantly different between the groups was Δ end tidal CO(2) with greater fluctuations in end tidal CO(2) in the pneumothorax group than in controls (p = 0.03). CONCLUSIONS: Pneumothorax is a rare complication of laparoscopic urological surgery that is usually recognized intraoperatively through physiological changes. Valveless trocar systems mask these findings and can delay identification until the postoperative period.

Fulguration for Hunner ulcers: long-term clinical outcomes.

PURPOSE: Cystoscopic fulguration of Hunner ulcers in patients with interstitial cystitis/bladder pain syndrome is a recommended therapy because it has the potential to rapidly ameliorate symptoms. We reviewed our experience with Hunner ulcer fulguration. MATERIALS AND METHODS: We retrospectively reviewed the records of patients with interstitial cystitis/bladder pain syndrome treated with Hunner ulcer fulguration who were seen at our pelvic pain referral center between 1993 and 2011. Patient demographics, clinical characteristics, intraoperative findings and long-term clinical outcomes were assessed. The Kaplan-Meier product limit method was used to evaluate time to the first repeat procedure. Potential risk factors associated with repeat procedures were examined using the log rank test. RESULTS: A total of 106 procedures were performed in 59 patients. The mean history of illness before first fulguration was 5 years and overall median followup was 44.8 months (IQR 52.2), as calculated from the time of the first fulguration. There were no significant associations between time to the first repeat procedure and any demographic criteria analyzed, patient reported interstitial cystitis/bladder pain syndrome associated conditions or the number of Hunner ulcers fulgurated at the initial session. A total of 27 patients (45.8%) required repeat fulguration. Time to event analysis demonstrated that 12 months after the initial fulguration 13.1% of patients required repeat treatment. This rate increased to 57.2% at 48 months, when it plateaued. CONCLUSIONS: Fulguration of Hunner ulcers can be an effective treatment for patients with interstitial cystitis/bladder pain syndrome and focal Hunner ulcers involving less than 25% of the bladder who have symptoms refractory to other therapies. However, a significant subset requires repeat treatment and some patients may even go on to require cystectomy.

Variability of transrectal ultrasound-guided prostate biopsy prophylactic measures.

INTRODUCTION: To assess the variability of pre-prostate biopsy prophylaxis among American urologists. MATERIALS AND METHODS: A survey was electronically mailed to 3355 urologists around the country. Urologists were surveyed on their antibiotic prophylaxis choice, the route and duration of antimicrobial prophylaxis. Additionally they were questioned about their knowledge of local antimicrobial resistance and if rectal enemas were routinely used. RESULTS: There were 679 (21%) responses to the survey. The survey revealed differences in pre-prostate biopsy prophylaxis among urologists. Ten different classes of antibiotics were used orally, 4 classes intramuscular, 5 classes intravenous, and there was also 14 different duration regimens. CONCLUSION: Despite the initiation of the 2008 American Urological Association Guidelines on this topic, there still is a lack of uniformity in prostate biopsy prophylaxis.

Somatic mutations as preoperative predictors of metastases in patients with localized clear cell renal cell carcinoma - An exploratory analysis.

OBJECTIVE: Recurrent genomic alterations in clear cell renal cell carcinoma (ccRCC) have been associated with treatment outcomes; however, current preoperative predictive models do not include known genetic predictors. We aimed to explore the value of common somatic mutations in the preoperative prediction of metastatic disease among patients treated for localized ccRCC. MATERIALS AND METHODS: After obtaining institutional review board approval, data of 254 patients with localized ccRCC treated between 2005 and 2015 who underwent genetic sequencing was collected. The mutation status of VHL, PBRM1, SETD2, BAP1 and KDM5C were evaluated in the nephrectomy tumor specimen, which served as a proxy for biopsy mutation status. The Raj et al. preoperative nomogram was used to predict the 12-year metastatic free probability (MFP). The study outcome was MFP; the relationship between MFP and mutation status was evaluated with Cox-regression models adjusting for the preoperative nomogram variables (age, gender, incidental presentation, lymphadenopathy, necrosis, and size). RESULTS: The study cohort included 188 males (74%) and 66 females (26%) with a median age of 58 years. VHL mutations were present in 152/254 patients (60%), PBRM1 in 91/254 (36%), SETD2 in 32/254 (13%), BAP1 in 19/254 (8%), and KDM5C in 19/254 (8%). Median follow-up for survivors was 8.1 years. Estimated 12-year MFP was 70% (95% CI: 63%-75%). On univariable analysis SETD2 (HR: 3.30), BAP1 (HR: 2.44) and PBRM1 (HR: 1.78) were significantly associated with a higher risk of metastases. After adjusting for known preoperative predictors in the existing nomogram, SETD2 mutations remained associated with a higher rate of metastases after nephrectomy (HR: 2.09, 95% CI: 1.19-3.67, P = 0.011). CONCLUSION: In the current exploratory analysis, SETD2 mutations were significant predictors of MFP among patients treated for localized ccRCC. Our findings support future studies evaluating genetic alterations in preoperative renal biopsy samples as potential predictors of treatment outcome.

Preoperative nomogram predicting 12-year probability of metastatic renal cancer - evaluation in a contemporary cohort.

OBJECTIVES: Preoperative models, based on patient and tumor characteristics, predict risk for adverse outcomes after nephrectomy. Changes in renal tumor characteristics over the last decades, warrant further evaluation using contemporary cohorts. We aimed to validate a previously published preoperative nomogram predicting 12-year metastasis-free probability after nephrectomy for localized renal tumors in a contemporary cohort. PATIENTS AND METHODS: After obtaining institutional review board approval, data of 1,760 patients who underwent nephrectomy for a localized renal mass between 2005 and 2011 were reviewed. Preoperative images were evaluated for the presence of tumor necrosis, lymphadenopathy, and tumor size. The study outcome was metastatic-free probability. Model discrimination was assessed with Gönen and Heller's concordance probability estimate, and calibration was evaluated. RESULTS: The cohort included 1,102 male and 658 female patients with a median age of 60 years. Most patients presented incidentally (84%). On imaging, 3% had evidence of lymphadenopathy, 55% had necrosis and median tumor diameter was 3.7 cm (interquartile range [IQR]: 2.5, 5.5). Median follow-up in non-metastatic patients was 7.7 years (IQR: 5.3, 9.7). Estimated 12-year metastatic-free probability was 88% (86%-90%). The model showed strong discrimination (concordance probability estimate [CPE]: 0.77), and fair calibration. The time-dependent receiver operating characteristic (ROC) curves showed strong discrimination at all-time points and the area under the curve (AUC) for year 12 was 0.83 (95% Confidence Interval: 0.78-0.89). CONCLUSIONS: We validated the preoperative nomogram of 12-year metastasis-free probability in a contemporary cohort despite different tumor characteristics. Future studies should evaluate the role of preoperative risk stratification in patient selection for neoadjuvant treatment.

Characterization and Impact of TERT Promoter Region Mutations on Clinical Outcome in Renal Cell Carcinoma.

BACKGROUND: Mutations in the promoter region of the TERT gene have been detected in a variety of cancers. These mutations can potentially lead to unlimited cell divisions and result in poor clinical prognosis. OBJECTIVE: To determine the role and relevance of TERT promoter region mutations in both clear cell (ccRCC) and non-clear cell (nccRCC) renal cell carcinoma using ultra-deep and whole-genome sequencing methods on primary tumor samples. DESIGN, SETTING, AND PARTICIPANTS: DNA from 281 kidney tumors (147 ccRCC and 134 nccRCC) was sequenced between 2013 and 2015, and clinical outcomes for these patients from a single institution were retrospectively analyzed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Differences in patient characteristics and mutational status were tested using Fisher's exact test for categorical variables and the Wilcoxon rank sum test for continuous variables. Survival times were estimated using the Kaplan-Meier method and differences were tested using the log-rank test. RESULTS AND LIMITATIONS: TERT mutations occurred in 12.2% of ccRCC and 10.4% of nccRCC cases. In >80% of the cases, mutations were located at C228T and were found to co-occur only rarely with other relevant RCC driver genes. The median follow-up among survivors overall was 2.5 yr (range 0.1-18.3). TERT promoter mutations were significantly associated with cancer-specific survival in ccRCC (hazard ratio 2.68, 95% confidence interval 1.19-6.01; p=0.013). In nccRCC, TERT mutations were significantly associated with larger tumors and metastatic development. Assessment of further relevant clinical associations was precluded in the nccRCC group by the heterogeneous and small sample size. CONCLUSIONS: Our data suggests that TERT mutational status reflects a distinct pathogenesis with an aggressive disease course in RCC. Stratifying patients with this unique tumorigenesis that leads to poor clinical outcomes could be a putative target for novel therapeutics. PATIENT SUMMARY: We show a previously unrecognized frequency of TERT promoter mutations in both clear cell and non-clear cell renal cell carcinoma. TERT promoter mutations were associated with some worse outcomes in patients with clear cell renal cell carcinoma.

Characterizing recurrent and lethal small renal masses in clear cell renal cell carcinoma using recurrent somatic mutations.

INTRODUCTION: Small renal masses (SRMs) with evidence of clear cell renal cell carcinoma (ccRCC) are understudied. Current algorithms for the management of SRMs include surgical resection, ablation, and active surveillance. We sought to identify genomic biomarkers that could potentially refine the management of ccRCC in SRMs, especially in patients being evaluated for active surveillance. METHODS: We identified patients who had SRMs (4cm or less) at time of surgery, had sequencing performed on their primary tumor and had a diagnosis of ccRCC. Patients were selected from 3 publicly available cohorts, The Cancer Genome Atlas (n = 110), University of Tokyo (n = 37), The International Cancer Genome Consortium (n = 31), and from our own institutional prospective database (n = 25). Among this cohort we analyzed mutations present in at least 5% of tumors, assessing for the enrichment of mutations and progression-free survival using the composite endpoint of recurrence or death of disease. Analysis was adjusted for multiple testing. A Cox regression model was used to assess clinical variables with significant mutations. RESULTS: In total, 203 patients were available for analysis. Median follow-up was 43.1 months among survivors. Mutations in VHL, PBRM1, SETD2, BAP1, KDM5C, and MTOR were present in more than 5% of tumors. Twenty-three patients (11.3%) had recurrence or died of their disease. Mutations in KDM5C were associated with inferior survival from either recurrence or death from disease, adjusted P 0.033. CONCLUSIONS: We identified mutations in SRMs in ccRCC that are associated with recurrence and lethality. The strongest association was seen in those with KDM5C mutations. Use of these genomic biomarkers may improve stratification of patients with SRMs and for those who may be appropriate for active surveillance. Prospective evaluation of these markers is needed.

Plasma Glycosaminoglycans as Diagnostic and Prognostic Biomarkers in Surgically Treated Renal Cell Carcinoma.

BACKGROUND: Plasma glycosaminoglycan (GAG) measurements, when aggregated into diagnostic scores, accurately distinguish metastatic clear-cell renal cell carcinoma (RCC) from healthy samples and correlate with prognosis. However, it is unknown if GAG scores can detect RCC in earlier stages or if they correlate with prognosis after surgery. OBJECTIVE: To explore the sensitivity and specificity of plasma GAGs for detection of early-stage RCC and prediction of recurrence and death after RCC surgery. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective case-control study consisting of a consecutive series of 175 RCC patients surgically treated between May 2011 and February 2014 and 19 healthy controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Plasma GAGs in preoperative and postoperative RCC and healthy samples were measured using capillary electrophoresis with laser-induced fluorescence in a single blinded laboratory. A discovery set was first analyzed to update the historical GAG score. The sensitivity of the new GAG score for RCC detection versus healthy subjects was validated using the remaining samples. The correlation of the new GAG score to histopathologic variables, overall survival, and recurrence-free survival was evaluated using nonparametric and log-rank tests and multivariable Cox regression analyses. RESULTS AND LIMITATIONS: The RCC cohort included 94 stage I, 58 stage II-III, and 22 stage IV cases. In the first discovery set (n=67), the new GAG score distinguished RCC from healthy samples with an area under the receiver operating characteristic curve (AUC) of 0.999. In the validation set (n=108), the GAG score achieved an AUC of 0.991, with 93.5% sensitivity. GAG scores were elevated in RCC compared to healthy samples, irrespective of and uncorrelated to stage, grade, histology, age, or gender. The total chondroitin sulfate concentration was an independent prognostic factor for both overall and recurrence-free survival (hazard ratios 1.51 and 1.25) with high concordance when combined with variables available at pathologic diagnosis (C-index 0.926 and 0.849) or preoperatively (C-index 0.846 and 0.736). Limitations of the study include its retrospective nature and moderate variability in GAG laboratory measurements. CONCLUSIONS: Plasma GAGs are highly sensitive diagnostic and prognostic biomarkers in surgically treated RCC independent of stage, grade, or histology. Prospective validation studies on GAG scores for early detection, prediction, and surveillance for RCC recurrence are thus warranted. PATIENT SUMMARY: In this study, we examined if a new molecular blood test can detect renal cell carcinoma in the early stages and predict if the cancer might relapse after surgery. The trial is registered on ClinicalTrial.gov as NCT03471897.

Comparison of Postradical Cystectomy Ileus Rates Using GIA-80 Versus GIA-60 Intestinal Stapler Device.

OBJECTIVE: To assess the impact on recovery of bowel function using an 80 mm versus 60 mm gastrointestinal anastomosis (GIA) stapler following radical cystectomy and urinary diversion (RC/UD) for bladder cancer. METHODS: We identified 696 patients using a prospectively maintained RC/UD database from January 2006 to November 2010. Two nonrandomized consecutive cohorts were compared. Patients between January 2006- and December 2007 (n = 180) were treated using a 60 mm GIA stapler, and 331 patients between January 2008 and December 2010 were subject to an 80 mm GIA stapler. All patients were treated on the same standardized postoperative recovery pathway. After accounting for baseline patient and perioperative characteristics, using a multivariable logistic regression model, we directly compared rates of postoperative ileus using a standardized definition. RESULTS: Of 511 evaluable patients, ileus was observed in 32% (57/180) for 60 mm GIA versus 33% (110/331) for the 80 mm GIA. Preoperative renal function, age, gender, body mass index, and type of diversion were comparable between cohorts. On multivariate analysis, stapler size was not significantly associated with the development of ileus (GIA-60 vs GIA-80: OR 1.11; 95% CI 0.75, 1.66; P = .6). Positive fluid balance was associated with an increased risk (P = .019) and female sex a decreased risk (P = .008) of developing ileus compared to patients with negative fluid balance. CONCLUSION: The size of the intestinal bowel anastomosis (GIA 80 mm vs 60 mm) does not independently impact the time to bowel recovery following RC/UD.

Comparative Genomic Profiling of Matched Primary and Metastatic Tumors in Renal Cell Carcinoma.

BACKGROUND: Next-generation sequencing (NGS) studies of matched pairs of primary and metastatic tumors in renal cell carcinoma (RCC) have been limited to small cohorts. OBJECTIVE: To evaluate the discordance in somatic mutations between matched primary and metastatic RCC tumors. DESIGN, SETTING, AND PARTICIPANTS: Primary tumor (P), metastasis (M), and germline DNA from 60 patients with RCC was subjected to NGS with a targeted exon capture-based assay of 341 cancer-associated genes. Somatic mutations were called using a validated pipeline. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Mutations were classified as shared (S) or private (Pr) in relation to each other within individual P-M pairs. The concordance score was calculated as (S-Pr)/(S+Pr). To calculate enrichment of Pr/S mutations for a particular gene, we calculated a two-sided p value from a binomial model for each gene with at least ten somatic mutation events, and also implemented a separate permutation test procedure. We adjusted p values for multiple hypothesis testing using the Benjamini-Hochberg procedure. The mutation discordance was calculated using Mann-Whitney U tests according to gene mutations or metastatic sites. RESULTS AND LIMITATIONS: Twenty-one pairs (35%) showed Pr mutations in both P and M samples. Of the remaining 39 pairs (65%), 14 (23%) had Pr mutations specific to P samples, 12 (20%) had Pr mutations to M samples, and 13 (22%) had identical somatic mutations. No individual gene mutation was preferentially enriched in either P or M samples. P-M pairs with SETD2 mutations demonstrated higher discordance than pairs with wild-type SETD2. We observed that patients who received therapy before sampling of the P or M tissue had higher concordance of mutations for P-M pairs than patients who did not (Mann-Whitney p=0.088). CONCLUSIONS: Our data show mutation discordance within matched P-M RCC tumor pairs. As most contemporary precision medicine trials do not differentiate mutations detected in P and M tumors, the prognostic and predictive value of mutations in P versus M tumors warrants further investigation. PATIENT SUMMARY: In this study we evaluated the concordance of mutations between matched primary and metastatic tumors for 60 kidney cancer patients using a panel of 341 cancer genes. Forty-seven patients carried nonidentical cancer gene mutations within their matched primary-metastatic pair. The mutation profile of the primary tumor alone could compromise precision in selecting effective targeted therapies and result in suboptimal clinical outcomes.

Use of desipramine for the treatment of overactive bladder refractory to antimuscarinic therapy.

PURPOSE: To evaluate the use of desipramine in the treatment of overactive bladder (OAB). MATERIALS AND METHODS: We retrospectively evaluated 43 patients who were treated with desipramine for OAB refractory to antimuscarinic therapy. These OAB patients were stratified by the presence or absence of bladder pain. RESULTS: Forty-three patients were evaluated with a mean follow up time of 12.2 ± 4.6 months. The mean age of the patients was 71 ± 16 years. Twelve patients (28%) discontinued desipramine, 9 due to perceived lack of efficacy, 2 due to central anticholinergic side effects, and 1 due to the development of oropharyngeal sores. Patients were stratified into two subgroups based upon treatment with desipramine for OAB alone (n = 29) or OAB and bladder pain (n = 14). There was no difference between the groups in regard to sex (P = .34), prior history of radiation (P = .19), side effects (P = .16), and specifically evaluated central anti-cholinergic side effects (P = .66). There was no statistical difference in the self-reported success rate of the medication (P = .48). In the OAB plus bladder pain subgroup, 71% of patients reported improvement in their pain. Overall, 13 (30%) patients had history of prior pelvic radiation and 10 of those (77%) reported improvement with desipramine. CONCLUSION: Desipramine is a potential useful treatment for patients with OAB. In addition, it can be used in patients with OAB and bladder pain and patients with complex OAB such as OAB caused by pelvic radiation.

Outcomes of reduction cystoplasty in men with impaired detrusor contractility.

OBJECTIVE: To report surgical outcomes in patients with impaired detrusor contractility (IDC) treated with reduction cystoplasty (RC). METHODS: This was a retrospective study of consecutive patients with IDC who underwent RC. IDC was defined as a bladder contractility index of <100 and/or a detrusor contraction of insufficient duration resulting in a postvoid residual volume (PVR) >600 mL. Bladder outlet obstruction was defined by a bladder outlet obstruction index (BOOI) >40. All patients had preoperative International Prostate Symptom Score, maximum uroflow (Qmax), PVR, bladder diary, videourodynamics, and cystoscopy. Patients with prostatic obstruction underwent synchronous open prostatectomy. Postoperative Qmax, PVR, need for clean intermittent catheterization (CIC), and Patient Global Impression of Improvement (PGII) score were obtained. Follow-up was at 3 months, 1 year, and yearly thereafter. RESULTS: Eight men met inclusion criteria (mean age, 60; range, 43-75 years). Preoperatively, 3 of 8 patients (37.5%) had moderate-sized bladder diverticula, 4 of 8 (50%) had a bladder contractility index <100, and 6 of 8 (75%) had a BOOI <40. Two patients (25%) fulfilled criteria for bladder outlet obstruction (BOOI, 67 and 72). Three (37.5%) underwent synchronous bladder diverticulectomy, and 3 (37.5%) underwent suprapubic prostatectomy. All patients were available for follow-up at 1 year. Seven of 8 (88%) had a successful outcome (PGII ≤2). One patient was unchanged (PGII, 4) and still needed CIC. CONCLUSION: All but 1 patient who met specific criteria for RC had excellent outcomes after surgery based on the PGII, PVR, Qmax, and need for CIC. RC is a viable option for properly selected patients with IDC.