Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing plasma cells in renal cell cancer.

The presence of intratumoral tertiary lymphoid structures (TLS) is associated with positive clinical outcomes and responses to immunotherapy in cancer. Here, we used spatial transcriptomics to examine the nature of B cell responses within TLS in renal cell carcinoma (RCC). B cells were enriched in TLS, and therein, we could identify all B cell maturation stages toward plasma cell (PC) formation. B cell repertoire analysis revealed clonal diversification, selection, expansion in TLS, and the presence of fully mature clonotypes at distance. In TLS+ tumors, IgG- and IgA-producing PCs disseminated into the tumor beds along fibroblastic tracks. TLS+ tumors exhibited high frequencies of IgG-producing PCs and IgG-stained and apoptotic malignant cells, suggestive of anti-tumor effector activity. Therapeutic responses and progression-free survival correlated with IgG-stained tumor cells in RCC patients treated with immune checkpoint inhibitors. Thus, intratumoral TLS sustains B cell maturation and antibody production that is associated with response to immunotherapy, potentially via direct anti-tumor effects.

Is "Kidney Stone Calculator" efficient in predicting ureteroscopic lithotripsy duration? A holmium:YAG and thulium fiber lasers comparative analysis.

PURPOSE: This study aimed to evaluate the ability of Kidney Stone Calculator (KSC), a flexible ureteroscopy surgical planning software, to predict the lithotripsy duration with both holmium:YAG (Ho:YAG) and thulium fiber laser (TFL). METHODS: A multicenter prospective study was conducted from January 2020 to April 2023. Patients with kidney or ureteral stones confirmed at non-contrast computed tomography and treated by flexible ureteroscopy with laser lithotripsy were enrolled. "Kidney Stone Calculator" provided stone volume and subsequent lithotripsy duration estimation using three-dimensional segmentation of the stone on computed tomography and the graphical user interface for laser settings. The primary endpoint was the quantitative and qualitative comparison between estimated and effective lithotripsy durations. Secondary endpoints included subgroup analysis (Ho:YAG-TFL) of differences between estimated and effective lithotripsy durations and intraoperative outcomes. Multivariate analysis assessed the association between pre- and intraoperative variables and these differences according to laser source. RESULTS: 89 patients were included in this study, 43 and 46 in Ho:YAG and TFL groups, respectively. No significant difference was found between estimated and effective lithotripsy durations (27.37 vs 28.36 min, p = 0.43) with a significant correlation (r = + 0.89, p < 0.001). Among groups, this difference did not differ (p = 0.68 and 0.07, respectively), with a higher correlation between estimated and effective lithotripsy durations for TFL compared to Ho:YAG (r = + 0.95, p < 0.001 vs r = + 0.81, p < 0.001, respectively). At multivariate analysis, the difference was correlated with preoperative (volume > 2000 mm3 (Ho:YAG), 500-750 mm3 SV and calyceal diverticulum (TFL)), operative (fragmentation setting (p > 0.001), and basket utilization (p = 0.05) (Ho:YAG)) variables. CONCLUSION: KSC is a reliable tool for predicting the lithotripsy duration estimation during flexible ureteroscopy for both Ho:YAG and TFL. However, some variables not including laser source may lead to underestimating this estimation.

Open versus robotic partial nephrectomy in obese patients: a multi-institutional propensity score-matched analysis (UroCCR 43-Robese study).

INTRODUCTION: There is limited evidence on the outcomes of robotic partial nephrectomy (RPN) and open partial nephrectomy (OPN) in obese patients (BMI ≥ 30 kg/m2). In this study, we aimed to compare perioperative and oncological outcomes of RPN and OPN. METHODS: We relied on data from patients who underwent PN from 2009 to 2017 at 16 departments of urology participating in the UroCCR network, which were collected prospectively. In an effort to adjust for potential confounders, a propensity-score matching was performed. Perioperative outcomes were compared between OPN and RPN patients. Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: Overall, 1277 obese patients (932 robotic and 345 open were included. After propensity score matching, 166 OPN and 166 RPN individuals were considered for the study purposes; no statistically significant difference among baseline demographic or tumor-specific characteristics was present. A higher overall complication rate and major complications rate were recorded in the OPN group (37 vs. 25%, p = 0.01 and 21 vs. 10%, p = 0.007; respectively). The length of stay was also significantly longer in the OPN group, before and after propensity-score matching (p < 0.001). There were no significant differences in Warm ischemia time (p = 0.66), absolute change in eGFR (p = 0.45) and positive surgical margins (p = 0.12). At a median postoperative follow-up period of 24 (8-40) months, DFS and OS were similar in the two groups (all p > 0.05). CONCLUSIONS: In this study, RPN was associated with better perioperative outcomes (improvement of major complications rate and LOS) than OPN. The oncological outcomes were found to be similar between the two approaches.

A novel VCP::TFE3 gene fusion resulting from t(X;9)(p11.23;p13.3) chromosome translocation in TFE3 rearranged renal cancer cell carcinoma.

Renal cell carcinoma (RCC) with rearrangement of transcription factor for immunoglobulin heavy-chain enhancer 3 (TFE3; TFE3-rearranged RCC) at Xp11.2 is a rare tumor entity but the most frequent among the microphthalmia transcription factor family translocation RCCs. Here, we report the identification of a new VCP::TFE3 fusion gene as the result of a t(X;9)(p11.23;p13.3) translocation identified by whole transcriptome sequencing. No other relevant molecular alteration was identified by whole exome sequencing. This case showed typical morphological features of TFE3-rearranged RCC with positive TFE3 immunostaining and positive TFE3 break-apart fluorescence in situ hybridization. MET was also overexpressed on immunohistochemistry. The patient had metastatic disease and was treated by surgery and five lines of therapy, including 24 months of stable disease on the mesenchymal epithelial transition (MET) inhibitor cabozantinib, with an overall survival of 7 years. In addition to expanding the spectrum of TFE3 rearrangement partners, this report highlights the complexity of these tumors and supports the development of translational programs in renal cancer.

Clinical outcomes of adapted hypofractionated radiotherapy for bladder cancer in elderly patients.

OBJECTIVE: To investigate the feasibility, efficacy, and safety of trimodal therapy (TMT) using a bifractionated split-course hypofractionated radiotherapy (RT) for non-metastatic muscle-invasive bladder cancer (MIBC) in elderly patients. PATIENTS AND METHODS: We retrospectively reviewed the characteristics and outcomes of patients aged >75 years with non-metastatic MIBC suitable or not for radical cystectomy (RC) and treated with transurethral resection of bladder tumour followed by concomitant radio-chemotherapy (platinum salt and 5-fluorouracil) at two institutions (Saint Louis Hospital, Paris, France and European Georges Pompidou Hospital, Paris, France) between 1990 and 2021. RT consisted of an adapted bifractionated split-course hypofractionated RT. Acute toxicities were reported according to Common Terminology Criteria for Adverse Events version 5.0 and late toxicities were reported according to the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer late radiation morbidity scoring schema. The primary end-point was overall survival (OS). Secondary end-points included other survivals outcomes and safety. RESULTS: A total of 122 patients were identified, with a median (range) follow-up of 51.1 (0.5-210.8) months. In all, 83.5% of patients completed radio-chemotherapy. The OS rate was 61.7% at 3 years and 51.2% at 5 years. In multivariate analysis, the completion of RT and concomitant chemotherapy were significantly associated with better OS and cancer-specific survival. For patients fit for RC, a complete histological response was achieved for 77 patients (91.7%) with radio-chemotherapy and the bladder conservation rate was 90.5%. Acute and late Grade ≥3 toxicities were <5%. CONCLUSION: Bifractionated split-course hypofractionated RT with concomitant chemotherapy regimen appears to be well-tolerated and effective. Trimodal treatment seems to be a curative option for elderly patients unfit for radical surgery compared with palliative care and may contribute to improved survival in these patients.

A prospective descriptive 1-year study in France of all BCG therapy dispensations for non-muscle-invasive bladder cancer.

OBJECTIVES: To describe the clinico-pathological characteristics of non-muscle-invasive bladder cancer (NMIBC) treated in metropolitan France over 1 year when bacille Calmette-Guérin (BCG) was subject to a national quota, and to document, in the context of recurrent shortages of intravesical BCG for NMIBC, the real-life indications for adjuvant treatment. MATERIALS AND METHODS: Between February 2021 and February 2022, the French National Agency for the Safety of Medicines (ANSM) asked the French Association of Urology to propose a science-based quota solution for BCG using a clinical score. The ANSM then asked the distributor of the drug, MEDAC, to collect the scores for all patients for whom BCG was requested by healthcare institutions and to prioritize the requests for patients with the highest scores. Tumour stage, grade, size, number, time to recurrence, carcinoma in situ, age, accessibility of alternative treatments (total cystectomy, radio-chemotherapy, thermo-chemotherapy) and BCG treatment progress (initiation or maintenance) were documented for each intravesical BCG prescription. A descriptive analysis of the data collected during the quota year was performed. RESULTS: During the 1-year quota, 25 878 requests for BCG were made for 19 024 patients, 60.5% of whom were aged ≥70 years. Requests for induction and maintenance treatment accounted for 12 704 (49.1%) and 13 174 prescriptions (50.9%), respectively. NMIBC treated with BCG maintenance therapy was more frequently high-risk NMIBC (91.7% vs 90.2%; P < 0.0001) than NMIBC for which induction therapy was requested. The number of cases of NMIBC leading to BCG adjuvant treatment was estimated at 12 704 cases/66 062 188 inhabitants over 1 year in metropolitan France. CONCLUSIONS: Our data suggest that the incidence of NMIBC at high risk of recurrence and progression is underestimated in reference epidemiological studies. These results should help to better define future care needs.

Nephrectomy for kidney tumour increases the risk of de novo arterial hypertension.

OBJECTIVE: To evaluate prospectively the effects of surgical excision of renal tumours on blood pressure (BP). PATIENTS AND METHODS: In a multicentre prospective study, we evaluated 200 patients who underwent nephrectomy for renal tumour between 2018 and 2020 at seven departments of the French Network for Kidney Cancer, the UroCCR. All patients had localized cancer without pre-existing hypertension (HTN). Blood pressure was measured the week before nephrectomy, and at 1 month and 6 months after nephrectomy, according to the recommendations for home BP monitoring. Plasma renin was measured 1 week before surgery and 6 months after surgery. The primary endpoint was the occurrence of de novo HTN. The secondary endpoint was clinically significant increase in BP at 6 months, defined by an increase in systolic and/or diastolic ambulatory BP ≥10 mmHg or requirement for medical antihypertensive treatment. RESULTS: Blood pressure and renin measurements were available for 182 (91%) and 136 patients (68%), respectively. We excluded from the analysis 18 patients who had undeclared HTN detected on preoperative measurements. At 6 months, 31 patients (19.2%) had de novo HTN and 43 patients (26.3%) had a significant increase in their BP. Type of surgery was not associated with an increased risk of HTN (21.7% partial nephrectomy [PN] vs 15.7% radical nephrectomy [RN]; P = 0.59). There was no difference between plasmatic renin levels before and after surgery (18.5 vs 16; P = 0.46). In multivariable analysis, age (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.02-1.12; P = 0.03) and body mass index (OR 1.14, 95% CI 1.03-1.26; P = 0.01) were the only predictors of de novo HTN. CONCLUSION: Surgical treatment of renal tumours is associated with significant changes in BP, with de novo HTN occurring in almost 20% of the patients. These changes are not impacted by the type of surgery (PN vs RN). Patients who are scheduled to undergo kidney cancer surgery should be informed of these findings and have their BP closely monitored after the operation.

Machine-learning approach for prediction of pT3a upstaging and outcomes of localized renal cell carcinoma (UroCCR-15).

OBJECTIVES: To assess the impact of pathological upstaging from clinically localized to locally advanced pT3a on survival in patients with renal cell carcinoma (RCC), as well as the oncological safety of various surgical approaches in this setting, and to develop a machine-learning-based, contemporary, clinically relevant model for individual preoperative prediction of pT3a upstaging. MATERIALS AND METHODS: Clinical data from patients treated with either partial nephrectomy (PN) or radical nephrectomy (RN) for cT1/cT2a RCC from 2000 to 2019, included in the French multi-institutional kidney cancer database UroCCR, were retrospectively analysed. Seven machine-learning algorithms were applied to the cohort after a training/testing split to develop a predictive model for upstaging to pT3a. Survival curves for disease-free survival (DFS) and overall survival (OS) rates were compared between PN and RN after G-computation for pT3a tumours. RESULTS: A total of 4395 patients were included, among whom 667 patients (15%, 337 PN and 330 RN) had a pT3a-upstaged RCC. The UroCCR-15 predictive model presented an area under the receiver-operating characteristic curve of 0.77. Survival analysis after adjustment for confounders showed no difference in DFS or OS for PN vs RN in pT3a tumours (DFS: hazard ratio [HR] 1.08, P = 0.7; OS: HR 1.03, P > 0.9). CONCLUSIONS: Our study shows that machine-learning technology can play a useful role in the evaluation and prognosis of upstaged RCC. In the context of incidental upstaging, PN does not compromise oncological outcomes, even for large tumour sizes.

Predictive factors of recurrence after surgery in patients with non-metastatic renal cell carcinoma with venous tumor thrombus (UroCCR-56 Study).

PURPOSE: To assess the oncological outcomes of renal cell carcinoma (RCC) associated with tumor thrombus and identify predictive factors of recurrence. METHODS: Multi-institutional study that included patients with cT3-4N0-1M0 RCC with tumoral thrombus identified in the prospective UroCCR database (CNIL DR 2013-206; NCT03293563). pT3a without involvement of the renal vein were excluded. All patients underwent radical nephrectomy and a thrombectomy of the renal vein ± inferior vena cava ± right atrium. The primary endpoint was recurrence-free survival (RFS). Thirty-two patients who had adjuvant therapies (tyrosine kinase inhibitors or mTOR inhibitor) were compared to control group (surveillance) in a propensity score-matched 1:1 sub-analysis RESULTS: A total of 432 patients were included: 70.4% pT3a, 20.1% pT3b, 4.2% pT3c and 5.3% pT4. Tumor characteristics were: 90.7% clear cell RCC, 13.9% pN1, and 87.1% high Fuhrman grade. 173 patients (40%) had disease recurrence, and median RFS was 37.3 months (95% CI, 26.4-46.7). In a multivariate analysis (Cox model), predictive factors of recurrence were: pT4 (HR 2.66; 95% CI, 1.42-4.99; p = 0.002), pN1 (HR 2.53; 95% CI, 1.46-4.39; p < 0.001), tumor necrosis (HR 2.92; 95% CI, 1.85-4.62; p < 0.001), tumor size > 10 cm (HR 1.56; 95% CI, 1.08-2.24; p = 0.018). Adjuvant therapy was a protective factor of cancer recurrence (HR 0.33; 95% CI, 0.17-0.66; p = 0.002). Propensity score-matched sub-analysis of adjuvant vs control (surveillance) confirmed adjuvant treatment as a protective factor of cancer recurrence (Log rank p = 0.015). CONCLUSIONS: In this contemporary multi-institutional cohort of RCC + tumor thrombus, we reported higher recurrence rate shortly after surgical excision and demonstrated an oncological benefit of adjuvant treatment.

Late complications and 5 years outcomes of robotic partial nephrectomy in France: prospective assessment in the French Kidney Cancer Research Network (UroCCR 10).

PURPOSE: To describe the practice of robotic-assisted partial nephrectomy (RAPN) in France and prospectively assess the late complications and long-term outcomes. METHODS: Prospective, multicenter (n = 16), observational study including all patients diagnosed with a renal tumor who underwent RAPN. Preoperative, intraoperative, postoperative, and follow-up data were collected and stored in the French research network for kidney cancer database (UroCCR). Patients were included over a period of 12 months, then followed for 5 years. RESULTS: In total, 466 patients were included, representing 472 RAPN. The mean tumor size was 3.4 ± 1.7 cm, most of moderate complexity (median PADUA and RENAL scores of 8 [7-10] and 7 [5-9]). Indication for nephron-sparing surgery was relative in 7.1% of cases and imperative in 11.8%. Intraoperative complications occurred in 6.8% of patients and 4.2% of RAPN had to be converted to open surgery. Severe postoperative complications were experienced in 2.3% of patients and late complications in 48 patients (10.3%), mostly within the first 3 months and mainly comprising vascular, infectious, or parietal complications. At 5 years, 29 patients (6.2%) had chronic kidney disease upstaging, 21 (4.5%) were diagnosed with local recurrence, eight (1.7%) with contralateral recurrence, 25 (5.4%) with metastatic progression, and 10 (2.1%) died of the disease. CONCLUSION: Our results reflect the contemporary practice of French expert centers and is, to our knowledge, the first to provide prospective data on late complications associated with RAPN. We have shown that RAPN provides good functional and oncologic outcomes while limiting short- and long-term morbidity. TRIAL REGISTRATION: NCT03292549.

Contrast enhancement early after renal malignancy cryoablation: imaging findings associated with benignity.

OBJECTIVES: Contrast enhancement by MRI done early after cryoablation for renal malignancies may suggest residual tumor (RT). However, we have observed MRI enhancement within 48 h of cryoablation in patients who had no contrast enhancement 6 weeks later. Our purpose was to identify features of 48-h contrast enhancement in patients without RT. METHODS: This single-center retrospective study included consecutive patients who underwent percutaneous cryoablation of renal malignancies in 2013-2020, exhibited cryoablation-zone MRI contrast enhancement 48 h later, and had available 6-week MRI scans. Persistent or growing CE at 6 weeks vs. 48 h was classified as RT. A washout index was calculated for each 48-h MRI, and its performance for predicting RT was assessed by receiver operating characteristic curve analysis. RESULTS: We included 60 patients with 72 cryoablation procedures and 83 cryoablation zones exhibiting 48-h contrast enhancement; mean age was 66 ± 17 years. Clear-cell renal cell carcinoma accounted for 95% of tumors. Of the 83 48-h enhancement zones, RT was observed in eight while 75 were benign. The 48-h enhancement was consistently visible at the arterial phase. Washout was significantly associated with RT (p < 0.001) and gradually increasing contrast enhancement with benignity (p < 0.009). A washout index below - 1.1 predicted RT with 88% sensitivity and 84% specificity. CONCLUSION: MRI contrast enhancement 48 h after cryoablation of renal malignancies was usually benign. Washout was associated with residual tumor, with a washout index value below - 1.1 exhibiting good performance in predicting residual tumor. These findings may help to guide decisions about repeat cryoablation. CLINICAL RELEVANCE STATEMENT: Magnetic resonance imaging contrast enhancement 48 h after cryoablation of renal malignancies rarely indicates residual tumor, which is characterized by washout with a washout index lower than - 1.1. KEY POINTS: • Contrast enhancement at the arterial phase of magnetic resonance imaging done 48 h after cryoablation of a renal malignancy is usually benign. • Residual tumor manifesting as contrast enhancement at the arterial phase is characterized by subsequent marked washout. • A washout index below - 1.1 has 88% sensitivity and 84% specificity for residual tumor.

Nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors as first-line treatment for metastatic clear-cell renal cell carcinoma (BIONIKK): a biomarker-driven, open-label, non-comparative, randomised, phase 2 trial.

BACKGROUND: We previously reported a 35-gene expression classifier identifying four clear-cell renal cell carcinoma groups (ccrcc1 to ccrcc4) with different tumour microenvironments and sensitivities to sunitinib in metastatic clear-cell renal cell carcinoma. Efficacy profiles might differ with nivolumab and nivolumab-ipilimumab. We therefore aimed to evaluate treatment efficacy and tolerability of nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors (VEGFR-TKIs) in patients according to tumour molecular groups. METHODS: This biomarker-driven, open-label, non-comparative, randomised, phase 2 trial included patients from 15 university hospitals or expert cancer centres in France. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had previously untreated metastatic clear-cell renal cell carcinoma. Patients were randomly assigned (1:1) using permuted blocks of varying sizes to receive either nivolumab or nivolumab-ipilimumab (ccrcc1 and ccrcc4 groups), or either a VEGFR-TKI or nivolumab-ipilimumab (ccrcc2 and ccrcc3 groups). Patients assigned to nivolumab-ipilimumab received intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by intravenous nivolumab 240 mg every 2 weeks. Patients assigned to nivolumab received intravenous nivolumab 240 mg every 2 weeks. Patients assigned to VEGFR-TKIs received oral sunitinib (50 mg/day for 4 weeks every 6 weeks) or oral pazopanib (800 mg daily continuously). The primary endpoint was the objective response rate by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1. The primary endpoint and safety were assessed in the population who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02960906, and with the EU Clinical Trials Register, EudraCT 2016-003099-28, and is closed to enrolment. FINDINGS: Between June 28, 2017, and July 18, 2019, 303 patients were screened for eligibility, 202 of whom were randomly assigned to treatment (61 to nivolumab, 101 to nivolumab-ipilimumab, 40 to a VEGFR-TKI). In the nivolumab group, two patients were excluded due to a serious adverse event before the first study dose and one patient was excluded from analyses due to incorrect diagnosis. Median follow-up was 18·0 months (IQR 17·6-18·4). In the ccrcc1 group, objective responses were seen in 12 (29%; 95% CI 16-45) of 42 patients with nivolumab and 16 (39%; 24-55) of 41 patients with nivolumab-ipilimumab (odds ratio [OR] 0·63 [95% CI 0·25-1·56]). In the ccrcc4 group, objective responses were seen in seven (44%; 95% CI 20-70) of 16 patients with nivolumab and nine (50% 26-74) of 18 patients with nivolumab-ipilimumab (OR 0·78 [95% CI 0·20-3·01]). In the ccrcc2 group, objective responses were seen in 18 (50%; 95% CI 33-67) of 36 patients with a VEGFR-TKI and 19 (51%; 34-68) of 37 patients with nivolumab-ipilimumab (OR 0·95 [95% CI 0·38-2·37]). In the ccrcc3 group, no objective responses were seen in the four patients who received a VEGFR-TKI, and in one (20%; 95% CI 1-72) of five patients who received nivolumab-ipilimumab. The most common treatment-related grade 3-4 adverse events were hepatic failure and lipase increase (two [3%] of 58 for both) with nivolumab, lipase increase and hepatobiliary disorders (six [6%] of 101 for both) with nivolumab-ipilimumab, and hypertension (six [15%] of 40) with a VEGFR-TKI. Serious treatment-related adverse events occurred in two (3%) patients in the nivolumab group, 38 (38%) in the nivolumab-ipilimumab group, and ten (25%) patients in the VEGFR-TKI group. Three deaths were treatment-related: one due to fulminant hepatitis with nivolumab-ipilimumab, one death from heart failure with sunitinib, and one due to thrombotic microangiopathy with sunitinib. INTERPRETATION: We demonstrate the feasibility and positive effect of a prospective patient selection based on tumour molecular phenotype to choose the most efficacious treatment between nivolumab with or without ipilimumab and a VEGFR-TKI in the first-line treatment of metastatic clear-cell renal cell carcinoma. FUNDING: Bristol Myers Squibb, ARTIC.

Low-grade oncocytic renal tumor (LOT): mutations in mTOR pathway genes and low expression of FOXI1.

Low-grade oncocytic renal tumor (LOT) is an emerging provisional entity, described as rare solid renal oncocytic/eosinophilic tumor sharing diffuse CK7 and negative CD117 immunoprofile. The links between LOT and other eosinophilic chromophobe like-renal cell carcinomas (RCC) are currently discussed. We sequenced tumoral DNA with a next generation sequencing panel for kidney cancer and carried out immunohistochemical analyses with CK7, CD117, SDHB, 4EBP1-P, S6K-P, and FOXI1 antibodies in a series of ten cases of LOT (9 females, 1 male; mean age at surgery: 66 years, 42.3 to 83.4) retrospectively diagnosed from a cohort of 272 tumors initially classified as chromophobe RCC (CHRCC). All LOT were single, without known hereditary predisposition, classified stage pT1 (70%), pT2 (20%) or pT3a (10%). Morphological features were similar to previous descriptions and clinical behavior was indolent for the six cases with available follow-up. We identified genetic variations in mTOR pathway related genes in 80% of cases, MTOR (7 cases) or TSC1 (1 case). Expression of FOXI1 was absent in all cases. In 9 LOT, 4EBP1-P and S6K-P were overexpressed, suggesting mTOR pathway activation.Our data highlights the major role of mTOR pathway in tumorigenesis of LOT mostly due to activating MTOR gene variations. Absence of FOXI1 expression is a strong argument to distinguish LOT from eosinophilic CHRCC and to bring them closer to other recently described FOXI1 negative eosinophilic-CHRCC like with MTOR/TSC mutations. Altogether, our data argue to consider LOT as a distinct entity with a favorable clinical outcome. However, in case of metastasis, an accurate diagnosis of LOT would be essential for the patient's management and could allow targeted therapy.

Using Contrast-Enhanced Ultrasound in Addition to Cross-Sectional Imaging for Indeterminate Renal Cysts May Lead to Overclassification in Bosniak III Category: A Case-Control Study.

INTRODUCTION: Indeterminate renal cysts may require several imaging modalities before clinical decision. The aim of this study was to investigate the effect of the imaging modality used to characterize indeterminate renal cysts on the pathological findings after surgical resection. METHODS: From our institutional database, we identified all patients surgically treated for Bosniak III renal masses between January 2008 and January 2018. All complex renal cysts were characterized with a combination of computed tomography (CT) and/or magnetic resonance imaging (MRI), and/or contrast-enhanced ultrasound (CEUS) and discussed during a multidisciplinary tumor board. Potential association between clinical/radiological characteristics and the pathological findings were investigated, using univariate and multivariate analyses. RESULTS: Of the 52 renal cystic lesions surgically removed, with a preoperative diagnosis of Bosniak III renal cyst, 19 (37%) were malignant and 33 (63%) were benign. The proportion of malignant lesions decreased from 47% when the renal cyst was characterized with cross-sectional imaging (CT and/or MRI) to 17% when the diagnosis required CEUS in addition to cross-sectional imaging. In multivariate analysis, prior history of renal cell carcinoma was associated with a higher risk of malignancy (p = 0.016) and diagnosis made with CEUS was associated with a lower risk of malignancy (p = 0.040). CONCLUSION: We found that using CEUS in addition to cross-sectional imaging to characterize indeterminate renal cysts tends to redefine Bosniak III as lesions with a lower risk of malignancy and can lead to overclassification.

Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma.

BACKGROUND: Cytoreductive nephrectomy has been the standard of care in metastatic renal-cell carcinoma for 20 years, supported by randomized trials and large, retrospective studies. However, the efficacy of targeted therapies has challenged this standard. We assessed the role of nephrectomy in patients with metastatic renal-cell carcinoma who were receiving targeted therapies. METHODS: In this phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with confirmed metastatic clear-cell renal-cell carcinoma at presentation who were suitable candidates for nephrectomy to undergo nephrectomy and then receive sunitinib (standard therapy) or to receive sunitinib alone. Randomization was stratified according to prognostic risk (intermediate or poor) in the Memorial Sloan Kettering Cancer Center prognostic model. Patients received sunitinib at a dose of 50 mg daily in cycles of 28 days on and 14 days off every 6 weeks. The primary end point was overall survival. RESULTS: A total of 450 patients were enrolled from September 2009 to September 2017. At this planned interim analysis, the median follow-up was 50.9 months, with 326 deaths observed. The results in the sunitinib-alone group were noninferior to those in the nephrectomy-sunitinib group with regard to overall survival (stratified hazard ratio for death, 0.89; 95% confidence interval, 0.71 to 1.10; upper boundary of the 95% confidence interval for noninferiority, ≤1.20). The median overall survival was 18.4 months in the sunitinib-alone group and 13.9 months in the nephrectomy-sunitinib group. No significant differences in response rate or progression-free survival were observed. Adverse events were as anticipated in each group. CONCLUSIONS: Sunitinib alone was not inferior to nephrectomy followed by sunitinib in patients with metastatic renal-cell carcinoma who were classified as having intermediate-risk or poor-risk disease. (Funded by Assistance Publique-Hôpitaux de Paris and others; CARMENA ClinicalTrials.gov number, NCT00930033 .).

MET alterations in biphasic squamoid alveolar papillary renal cell carcinomas and clinicopathological features.

Biphasic squamoid alveolar papillary renal cell carcinoma (BSA-PRCC) is a recently studied lesion considered a morphologic variant of papillary renal cell carcinoma (RCC), more closely related to type 1. Considering the role of proto-oncogene MET in both sporadic type 1 papillary RCC and hereditary papillary RCC, we aimed to explore the role of MET activation in the oncogenesis of BSA-PRCC. We identified 17 patients with either unique (n = 14) or multiple (n = 3) BSA-PRCC, all localized, and performed an integrative analysis of MET status in 18 formalin-fixed paraffin-embedded tumors combining next-generation sequencing analysis, fluorescent in situ hybridization and immunohistochemistry. Trisomy 7 was found in 86% of tumors (14/16) without MET amplification at 7q31 (15/15). A pathogenic MET genetic variant was identified in 60% (9/15) of cases, at the germline level in 57% (4/7) of tested patients or at the somatic level (5/11). MET expression was observed in all tumors with a higher value of combined score in large cells (mean 97%, range 80-100%) than in small cells (mean 74%, range 10-100%) and was lower in two cases without MET copy number gain. In conclusion, our study provides additional evidence to consider biphasic squamoid alveolar papillary RCC as a morphological variant of type 1 papillary renal RCC. Our data strongly suggest that MET represents a major oncogenic driver gene in BSA-PRCC, harboring a higher frequency of MET mutation that encourages to further explore the benefice of anti-MET targeted therapies for aggressive BSA-PRCC.

Evaluation of a free 3D software for kidney stones' surgical planning: "kidney stone calculator" a pilot study.

INTRODUCTION: Kidney Stone Calculator (KSC) is a free, three-dimensional (3D) planning software for flexible ureteroscopy(fURS) with Holmium:YAG(Ho:YAG) endocorporeal lithotripsy (EL). KSC provides the stone volume (SV) and expected duration of lithotripsy (ExDL) estimations based on non-enhanced-CT scan (NECT) DICOM series. We aimed to provide a preclinical and clinical evaluation of KSC. PATIENTS AND METHODS: A preclinical evaluation measured the SV by three operators (resident, endourology expert and research engineer) among 17 NECT cases. Between January and March 2020, a multicentric, prospective, observational double-blind clinical evaluation was conducted in patients presenting with renal stones treated with Ho:YAG-EL during fURS and preoperative NECT. Demographic and surgical data were collected. The primary endpoint was a significant median difference between ExDL and EffectiveDL (EfDL). Second, efficiency (J/mm3) and efficacy (mm3/min) ratios were calculated. RESULTS: The preclinical evaluation showed no significant difference in the SV measurements among operators (p > 0.05). Pearson and Kendall coefficients of 0.99 and 0.98, respectively, were found. Twenty-six patients were included in the clinical evaluation, with a median age of 55 years. In 66% of cases, there was a single stone located in the lower pole, with a density > 1000 Hounsfield Unit observed in 42% and 85% of cases. A 14% [Q1-Q3 (5.4-24.8); p = 0.36] median difference between ExDL and EfDL was noted, which was greater in the case of lower pole stones with no possible relocation (p = 0.008). Median values of 17.6 J/mm3 and 0.4 (0.32-0.56) mm3/s EL were also noted. CONCLUSIONS: Kidney Stone Calculator is a reproducible and accurate software that allows for an estimation of the stone burden and provides an ExDL for URSf. Defining the influencing factors of EL will improve its ExDL.

Persistent orchialgia after laparoscopic living-donor nephrectomy: an underestimated complication requiring information adjustment.

PURPOSE: Laparoscopic living-donor nephrectomy (LLDN) is the gold-standard procedure for kidney procurement. Ipsilateral orchialgia has barely been described. Some authors reported that ligation of gonadal vein (GV) above iliac vessel bifurcation could prevent orchialgia. We aimed to assess incidence and duration of orchialgia after LLDN in male donors despite distal ligation of GV. METHODS: Patients who underwent LLDN from 2014 to 2017 were included. Standard procedure consisted in distal ligation of GV, close to the renal vein confluence and proximal ureteral ligation. Patients' demographics, per-operative data, and post-operative consultation reports were retrospectively reviewed. Orchialgia and scrotal symptoms were assessed through a non-validated questionnaire by phone interview. RESULTS: Sixty-nine donors were included. Orchialgia incidence and testicular swelling were 31.9% (n = 22) and 15.9% (n = 11), respectively. Median symptom duration was 15.5 months. Orchialgia led to medical consultation in 41.7% (n = 10) of cases. All patients declared having been informed, prior to donation, about possible residual pain but not specifically orchialgia. CONCLUSION: Orchialgia after LLDN affects more than 30% of donors, despite distal ligation of GV and led less than 50% of them to medical consultation, suggesting a large underestimation in clinical practice. Emphasis should be put on this complication during pre-donation information.

Long-term outcomes after bladder-preserving tri-modality therapy for patients with muscle-invasive bladder cancer.

PURPOSE: To evaluate trimodal conservative treatment as an alternative to radical surgery for urothelial muscle-invasive bladder cancer (MIBC). PATIENTS AND METHODS: This retrospective study reported the carcinologic and functional results of patients (pts) presenting a cT2/T3 N0M0 operable MIBC and fit for surgery, treated by a conservative strategy. Treatment consisted of a transurethral resection (TURB) followed by concomitant bi-fractionated split-course radiochemotherapy (RCT) with 5FU-Cisplatine. A control cystoscopy was performed six weeks after the induction RCT (eq45Gy) with systematic biopsies. Patients with complete histologic response achieved RCT protocol. Salvage surgery was proposed to pts with persistent tumor. RESULTS: 313 pts (83% cT2 and 17% cT3) treated between 1988 and 2013 were included, with a median follow-up of 59 months and 67-year mean age. After the induction RCT, the histologic response rate was 83%. After five years, overall, disease-free, and functional bladder-intact survival rates were respectively 69%, 61%, and 69%, significantly better for pts in complete response after induction RCT. Late urinary and digestive toxicities were limited, with respective rates of 4% and 1.5% of grade 3 toxicity. CONCLUSION: Trimodal strategy with RCT after TURB showed interesting functional and oncologic results and should be considered as an alternative to surgery in well-selected pts.

Apalutamide, darolutamide and enzalutamide in nonmetastatic castration-resistant prostate cancer: a meta-analysis.

Aim: Comparison of the efficacy/safety/health-related quality of life of apalutamide, enzalutamide and darolutamide in Phase III clinical trials involving patients with nonmetastatic castration-resistant prostate cancer was performed. Materials & methods: Relevant studies were identified by searching PubMed as well as conference abstracts reporting updated overall survival. Three pivotal trials were identified, SPARTAN (apalutamide), PROSPER (enzalutamide) and ARAMIS (darolutamide), and form the basis of this analysis. Results: All three drugs significantly prolonged metastasis-free survival, prostate-specific antigen response and overall survival versus placebo, and were generally well tolerated. Conclusion: Drug selection will likely be influenced by tolerability/safety and other factors, such as the propensity for drug-drug interactions and the presence of comorbidities, that affect the risk-benefit balance in individual patients.