The Risks of Stone Diagnosis and Stone Removal Procedure After Different Bariatric Surgeries.

Introduction: Nephrolithiasis is common after malabsorptive bariatric surgery; however, the comparative risk of stone formation after different bariatric surgeries remains unclear. We seek to compare the risk of stone diagnosis and stone procedure after gastric banding (GB), sleeve gastrectomy (SG), short-limb Roux-en-Y (SLRY), long-limb Roux-en-Y (LLRY), and biliopancreatic diversion with duodenal switch (BPDDS). Patients and Methods: Using an administrative database, we retrospectively identified 116,304 patients in the United States, who received bariatric surgery between 2007 and 2014, did not have a known kidney stone diagnosis before surgery, and were enrolled in the database for at least 1 year before and after their bariatric surgery. We used diagnosis and procedural codes to identify comorbidities and events of interest. Our primary analysis was performed with extended Cox proportional hazards models using time to stone diagnosis and time to stone procedure as outcomes. Results: The adjusted hazard ratio of new stone diagnosis from 1 to 36 months, compared to GB, was 4.54 for BPDDS (95% confidence interval [CI] 3.66-5.62), 2.12 for LLRY (95% CI 1.74-2.58), 2.15 for SLRY (95% CI 2.02-2.29), and 1.35 for SG (95% CI 1.25-1.46). Similar results were observed for risk of stone diagnosis from 36 to 60 months, and for risk of stone removal procedure. Male sex was associated with an overall 1.63-fold increased risk of new stone diagnosis (95% CI 1.55-1.72). Conclusions: BPDDS was associated with a greater risk of stone diagnosis and stone procedures than SLRY and LLRY, which were associated with a greater risk than restrictive procedures. Nephrolithiasis is more common after more malabsorptive bariatric surgeries, with a much greater risk observed after BPDDS and for male patients.

Dual-frequency setting for urinary stone fragmentation during shock wave lithotripsy: an in vitro study.

Extracorporeal shock wave lithotripsy (SWL) is less invasive compared to the other invasive modalities of stone treatment that are gaining popularity. Hence, methods to improve the efficacy of SWL are desirable. We studied the effectiveness of dual frequency on the efficacy of stone fragmentation, but minimizing treatment time. A phantom 10 mm spherical BegoStone was fragmented in vitro in a kidney model using an electromagnetic lithotripter (Storz MODULITH®SLX-F2). A total of 78 stones were fragmented each with 3000 shocks at 60 Hz or 120 Hz or a dual frequency (DF) of 60-120 Hz. For the DF setting, the first 1000 shocks were delivered at 60 Hz and the next 2000 at 120 Hz. Total weight and number of significant fragments of > 3 mm (TWSF and TNSF, respectively) and also > 2 mm was measured. Results: The mean TWSF was 0.1, 0.16, and 0.08 g for 60 Hz, 120 Hz, and DF 60-120 Hz, respectively. The TWSF of DF 60-120 Hz was significantly lower than that of 120 Hz (p = 0.02), but same as the 60 Hz (p = 0.32). The mean TNSF of > 3 mm was 2.6, 3.0, and 2.0 for 60 Hz, 120 Hz, and DF 60-120 Hz, respectively, without significant differences between each setting. However, increasing trend of TWSF, TW2 mm and TN2 mm was seen in the order of DF, 60 Hz and 120 Hz (p = 0.019, p = 0.004 and 0.017, respectively). Treatment time for 60 Hz, 120 Hz, and DF 60-120 Hz was 50, 25, and 34 min, respectively. Dual-frequency setting produced effective stone fragmentation compared to the recommended 60 Hz, while decreasing treatment time. DF variation is one other factor that may be tailored for effective stone comminution and needs clinical evaluation.

Analysis of renal cancer cell lines from two major resources enables genomics-guided cell line selection.

The utility of cancer cell lines is affected by the similarity to endogenous tumour cells. Here we compare genomic data from 65 kidney-derived cell lines from the Cancer Cell Line Encyclopedia and the COSMIC Cell Lines Project to three renal cancer subtypes from The Cancer Genome Atlas: clear cell renal cell carcinoma (ccRCC, also known as kidney renal clear cell carcinoma), papillary (pRCC, also known as kidney papillary) and chromophobe (chRCC, also known as kidney chromophobe) renal cell carcinoma. Clustering copy number alterations shows that most cell lines resemble ccRCC, a few (including some often used as models of ccRCC) resemble pRCC, and none resemble chRCC. Human ccRCC tumours clustering with cell lines display clinical and genomic features of more aggressive disease, suggesting that cell lines best represent aggressive tumours. We stratify mutations and copy number alterations for important kidney cancer genes by the consistency between databases, and classify cell lines into established gene expression-based indolent and aggressive subtypes. Our results could aid investigators in analysing appropriate renal cancer cell lines.

Bilateral Testicular Germ Cell Tumors in the Era of Multimodal Therapy.

OBJECTIVE: To characterize the incidence, presentation, management, and relapse of a large population of bilateral testicular germ cell tumors (TGCT) from a single institution. PATIENTS AND METHODS: We identified bilateral TGCT diagnosed between January 1989 and February 2014. We categorized synchronous and metachronous TGCT, noting time between first and second TGCT, histology (seminoma vs nonseminoma [NSGCT]), stage, and treatments. Kaplan-Meier survival estimates characterized relapse. RESULTS: Of 5132 patients with TGCT, 128 (2.5%) had bilateral TGCT. Bilateral TGCT increased over time-1.7% in 1989-1994 up to 3.8% in 2010 to February 2014. The 35 (27%) synchronous cases of TGCT had 20 (57%) concordant seminoma, 5 (14%) concordant NSGCT, and 10 (29%) discordant NSGCT. The 93 (73%) metachronous cases had median time interval to second TGCT of 73 months (range: 5 months-28.6 years). Compared with first TGCT, 39 (42%) had discordant histology, 29 (31%) had concordant seminoma, and 25 (27%) had concordant NSGCT. Stage at first tumor was statistically similar to second TGCT (second stage I, II, II in 69%, 22%, 10%). Increasing duration between first and second TGCT was not associated with higher stage (II or III) at second TGCT (P = .09). Treatment at first tumor was not associated with stage at second tumor. Relapse following bilateral diagnosis was 16.8% (95% confidence interval 10.5%-26.2%) at 5 years. CONCLUSION: Incidence of bilateral TGCT increased with >25% of metachronous TGCT presenting ≥10 years after first TGCT; possible causes include increased survivorship and referral bias. Stage was statistically similar at first and second tumor; stage at second tumor was not associated with time interval between tumors or prior treatment modality at first tumor.

Genomic Biomarkers of a Randomized Trial Comparing First-line Everolimus and Sunitinib in Patients with Metastatic Renal Cell Carcinoma.

BACKGROUND: Metastatic renal cell carcinoma (RCC) patients are commonly treated with vascular endothelial growth factor (VEGF) inhibitors or mammalian target of rapamycin inhibitors. Correlations between somatic mutations and first-line targeted therapy outcomes have not been reported on a randomized trial. OBJECTIVE: To evaluate the relationship between tumor mutations and treatment outcomes in RECORD-3, a randomized trial comparing first-line everolimus (mTOR inhibitor) followed by sunitinib (VEGF inhibitor) at progression with the opposite sequence in 471 metastatic RCC patients. DESIGN, SETTING, AND PARTICIPANTS: Targeted sequencing of 341 cancer genes at ∼540× coverage was performed on available tumor samples from 258 patients; 220 with clear cell histology (ccRCC). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Associations between somatic mutations and median first-line progression free survival (PFS1L) and overall survival were determined in metastatic ccRCC using Cox proportional hazards models and log-rank tests. RESULTS AND LIMITATIONS: Prevalent mutations (≥ 10%) were VHL (75%), PBRM1 (46%), SETD2 (30%), BAP1 (19%), KDM5C (15%), and PTEN (12%). With first-line everolimus, PBRM1 and BAP1 mutations were associated with longer (median [95% confidence interval {CI}] 12.8 [8.1, 18.4] vs 5.5 [3.1, 8.4] mo) and shorter (median [95% CI] 4.9 [2.9, 8.1] vs 10.5 [7.3, 12.9] mo) PFS1L, respectively. With first-line sunitinib, KDM5C mutations were associated with longer PFS1L (median [95% CI] of 20.6 [12.4, 27.3] vs 8.3 [7.8, 11.0] mo). Molecular subgroups of metastatic ccRCC based on PBRM1, BAP1, and KDM5C mutations could have predictive values for patients treated with VEGF or mTOR inhibitors. Most tumor DNA was obtained from primary nephrectomy samples (94%), which could impact correlation statistics. CONCLUSIONS: PBRM1, BAP1, and KDM5C mutations impact outcomes of targeted therapies in metastatic ccRCC patients. PATIENT SUMMARY: Large-scale genomic kidney cancer studies reported novel mutations and heterogeneous features among individual tumors, which could contribute to varied clinical outcomes. We demonstrated correlations between somatic mutations and treatment outcomes in clear cell renal cell carcinoma, supporting the value of genomic classification in prospective studies.

Surgical Treatment of Tumors Involving Kidneys With Fusion Anomalies: A Contemporary Series.

OBJECTIVE: To report a contemporary series of surgically treated patients with tumors involving kidneys with fusion anomalies. MATERIALS AND METHODS: We retrospectively reviewed the medical records of all 10 patients treated at a single tertiary care institution for tumors involving kidneys with fusion anomalies between the years 2000 and 2015. One patient, diagnosed with lymphoma, did not undergo surgical treatment and was therefore excluded. Data regarding patient, tumor, and treatment characteristics were collected and described. RESULTS: The study cohort included 7 male and 2 female patients, at a median age of 52 years. Seven patients underwent open partial nephrectomy. Nephroureterectomy was performed on 2 patients; 1 open and 1 laparoscopic. All patients had localized disease at diagnosis. Tumor histologies were renal cell carcinoma in 5 patients, renal oncocytoma in 1 patient, urothelial carcinoma in 2 patients, and a well-differentiated liposarcoma involving the kidney in 1 patient. Accessory blood vessels were identified in 8 of 9 patients. Median estimated blood loss was 300 mL (interquartile range: 150-1000). Four patients had postoperative complications, including 3 major (Clavien grade ≥ 3) and 3 minor (Clavien grade ≤ 2) complications. During a median follow-up of 19.2 months (interquartile range: 3-34.8), 1 patient with urothelial carcinoma developed a bladder recurrence. None of the patients developed new-onset chronic kidney disease during the early postoperative period. CONCLUSION: Localized renal cortical tumors in kidneys with fusion anomalies may be treated with partial nephrectomy; however, complication rates are relatively high. Preoperative imaging of the blood vessels is necessary, as most patients have an accessory blood supply.

Impact of Ureteroscopy Before Nephroureterectomy for Upper Tract Urothelial Carcinoma on Oncologic Outcomes.

OBJECTIVE: To compare the oncologic outcomes of patients with upper tract urothelial carcinoma undergoing nephroureterectomy (NU) with and without prior ureteroscopy (URS). METHODS: We reviewed records of all patients with no prior history of bladder cancer who underwent NU at our institution (n = 201). We compared patients who underwent URS before NU with patients who proceeded directly to NU based on imaging alone. After excluding patients undergoing URS with therapeutic intent, we used multivariable Cox proportional hazards models, adjusting for tumor characteristics with cancer-specific survival (CSS), intravesical recurrence-free survival, metastasis-free survival (MFS), and overall survival (OS) as end points. This study received institutional review board approval. RESULTS: A total of 144 (72%) patients underwent URS before NU, and 57 (28%) patients proceeded directly to NU. The median follow-up time for survivors was 5.4 years from diagnosis. The performance of diagnostic URS before NU was significantly associated with IR (hazard ratio 2.58; 95% CI 1.47, 4.54; P = .001), although it was not associated with CSS, MFS, or OS. The adjusted intravesical recurrence-free survival probability 3 years after diagnosis is 71% and 42% for patients who did not and did receive URS before NU, respectively (adjusted risk difference 30%; 95% CI 13%, 47%). CONCLUSION: We did not find evidence that URS adversely impacts disease progression and survival in patients with upper tract urothelial carcinoma. Although patients are at higher risk for IR after NU when they have undergone prior diagnostic URS, their CSS, MFS, and OS are not significantly affected.

Low yield of surveillance imaging after surgery for T1 kidney cancer.

PURPOSE: To examine the mode of relapse detection and subsequent treatment after partial or radical nephrectomy in patients with low-risk (pT1, N0, Nx) kidney cancer. METHODS: Retrospective study on 1404 patients treated with partial or radical nephrectomy for low-risk kidney cancer from the years 2000-2012. Scans for chest imaging (X-ray or CT) and abdominal imaging (CT, MRI, or ultrasound) are tabulated. For those patients with relapse, the site, mode of detection, and symptoms were recorded. RESULTS: Twenty-one patients relapsed with a median follow-up of 4.1 years for patients who did not relapse. In 17 (81 %) patients, relapse was detected by imaging alone, while 4 (19 %) patients presented with symptoms. Of the patients who relapsed by imaging, 13 (76 %) were treated immediately, while 4 (24 %) continued observation. During the first 3 years of follow-up, 5762 imaging studies were performed to detect 8 relapses, with 6 patients receiving immediate treatment. The median number of imaging studies per patient per year for the first 3 years was 1.7 (interquartile range 1.0, 2.3) including 30 % CT, 3 % MRI, 36 % X-ray, and 31 % ultrasounds. CONCLUSION: We found a low yield of surveillance imaging in the first 3 years for pT1 kidney cancer. Nearly 1000 imaging studies were performed to detect one relapse that required treatment. Further studies are needed to evaluate the clinical impact of imaging surveillance according to recent guidelines.

Partial and Radical Nephrectomy for Unilateral Synchronous Multifocal Renal Cortical Tumors.

OBJECTIVE: To evaluate clinicopathologic characteristics and treatment outcomes of patients undergoing partial nephrectomy (PN) or radical nephrectomy (RN) for unilateral synchronous multifocal renal tumors. METHODS: We retrospectively reviewed medical records for 128 patients with nonmetastatic, unilateral, synchronous, multifocal renal tumors who underwent surgical resection at our institution from 1995 to 2012. Five patients with hereditary renal cell carcinoma were excluded. Differences between patient and tumor characteristics from the 2 nephrectomy groups were evaluated. Outcomes in terms of recurrence-free survival, overall survival, and chronic kidney disease upstaging were estimated using Kaplan-Meier methods. The log-rank test was used for group comparisons. RESULTS: The study cohort included 78 PN patients (63%) and 45 RN patients (37%); 17 of 95 planned PN (18%) were converted to RN. Tumor diameter and RENAL nephrometry scores were greater in RN patients (P <.0001 and P = .0002, respectively). Pathologic stage T3 was seen in 40% of RN patients and 10% of PN patients (P = .0002). Histologic concordance was apparent in 60 of 123 patients (49%). Median follow-up for patients alive without a recurrence was 4 years. Five-year recurrence-free survival was 98% for PN and 85% for RN. Five-year overall survival was 96% for PN and 86% for RN (P = .5). Five-year freedom from chronic kidney disease upstaging was 74% for PN and 55% for RN (P = .11). CONCLUSION: Partial nephrectomy for the treatment of unilateral, synchronous, multifocal, renal tumors with favorable characteristics was associated with a low recurrence rate. These findings suggest PN is an appropriate management strategy for this group of carefully selected patients.

Pathological Stage T3a Significantly Increases Disease Recurrence across All Tumor Sizes in Renal Cell Carcinoma.

PURPOSE: Tumor size and stage are important prognostic parameters in renal cell carcinoma. While pathological stage T1 and T2 are defined by size alone, the presence of certain intrinsic features can up stage a tumor to pathological stage T3a regardless of size. We investigate the effect of pathological tumor stage on the relationship between tumor size and risk of disease recurrence. MATERIALS AND METHODS: Data were reviewed on patients who underwent nephrectomy at our institution between 2006 and 2013 to identify all those with pathological stage T1, T2 and T3a tumors. A proportional hazards Cox model was built with time to recurrence as outcome, and pathological stage and tumor size as covariates. An interaction term for stage and tumor size was included. RESULTS: The final cohort included 1,809 patients. On multivariable analysis, when adjusted for tumor size, patients with pT3a tumors had a greater risk of tumor recurrence compared to those with pT1/T2 tumors (HR 3.70; 95% CI 2.31, 5.92; p <0.0001). The risk of disease recurrence increased more rapidly as tumor size increased only with the presence of perinephric fat invasion (p=0.006). CONCLUSIONS: Using the AJCC 2010 staging criteria we validated pathological stage T3a as a poor prognostic factor in renal cell carcinoma regardless of tumor size. Our results also demonstrated an increased rate of risk of recurrence with perinephric fat invasion. Given this increased risk of recurrence, even in tumors less than 4 cm, closer surveillance is warranted in such cases and the role of perinephric involvement necessitates further investigation.

Subcentimeter pulmonary nodules are not associated with disease progression in patients with renal cell carcinoma.

PURPOSE: Renal cell carcinoma most commonly metastasizes to the lung. Indeterminate pulmonary nodules develop preoperatively in half of the patients with localized renal cell carcinoma but clinical significance remains poorly defined. We determined whether the presence of indeterminate pulmonary nodules, or nodule size or number is associated with renal cell carcinoma outcomes. MATERIALS AND METHODS: We reviewed data on 1,102 patients with renal cell carcinoma in whom chest computerized tomography was done within 6 months before nephrectomy from 2002 to 2012. Patients with metastatic disease at presentation, benign tumors, pulmonary nodules greater than 2 cm or concurrent pulmonary disease were excluded, leaving 748 available for analysis. Study outcomes included lung metastasis, any distant metastasis or death from renal cell carcinoma. Cox proportional hazards models were used to assess whether the presence of indeterminate pulmonary nodules, or nodule size or number was associated with outcomes. Models were evaluated by comparing discrimination using the Harrell c-index. RESULTS: Indeterminate pulmonary nodules were present in 382 of 748 patients (51%). Median followup was 4.1 years (IQR 2.2-6.1). The presence of indeterminate pulmonary nodules was not associated with distant metastasis or death from kidney cancer. However, compared to subcm indeterminate pulmonary nodules the nodules greater than 1 cm were associated with metastatic disease after adjusting for tumor histology, stage and size (HR 2.48, 95% CI 1.08-5.68, p = 0.031). The outcome c-index increased slightly after adding nodule size to a predictive model adjusted for tumor characteristics. CONCLUSIONS: No evidence in the current study suggested that indeterminate pulmonary nodules less than 1 cm are associated with renal cell carcinoma progression, although large nodules significantly predicted metastatic disease. Patients with subcm indeterminate pulmonary nodules would be unlikely to benefit from extensive postoperative chest imaging surveillance, which should be reserved for patients with nodules greater than 1 cm.

The impact of genetic heterogeneity on biomarker development in kidney cancer assessed by multiregional sampling.

Primary clear cell renal cell carcinoma (ccRCC) genetic heterogeneity may lead to an underestimation of the mutational burden detected from a single site evaluation. We sought to characterize the extent of clonal branching involving key tumor suppressor mutations in primary ccRCC and determine if genetic heterogeneity could limit the mutation profiling from a single region assessment. Ex vivo core needle biopsies were obtained from three to five different regions of resected renal tumors at a single institution from 2012 to 2013. DNA was extracted and targeted sequencing was performed on five genes associated with ccRCC (von-Hippel Lindau [VHL], PBRM1, SETD2, BAP1, and KDM5C). We constructed phylogenetic trees by inferring clonal evolution based on the mutations present within each core and estimated the predictive power of detecting a mutation for each successive tumor region sampled. We obtained 47 ex vivo biopsy cores from 14 primary ccRCC's (median tumor size 4.5 cm, IQR 4.0-5.9 cm). Branching patterns of various complexities were observed in tumors with three or more mutations. A VHL mutation was detected in nine tumors (64%), each time being present ubiquitously throughout the tumor. Other genes had various degrees of regional mutational variation. Based on the mutations' prevalence we estimated that three different tumor regions should be sampled to detect mutations in PBRM1, SETD2, BAP1, and/or KDM5C with 90% certainty. The mutational burden of renal tumors varies by region sampled. Single site assessment of key tumor suppressor mutations in primary ccRCC may not adequately capture the genetic predictors of tumor behavior.