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.

Comparison of 68Ga-PSMA-617 PET/CT and 68Ga-RM2 PET/CT in Patients with Localized Prostate Cancer Who Are Candidates for Radical Prostatectomy: A Prospective, Single-Arm, Single-Center, Phase II Study.

Considering the wide range of therapeutic options for localized prostate cancer (e.g., active surveillance, radiation-beam therapy, focal therapy, and radical prostatectomy), accurate assessment of the aggressiveness and localization of primary prostate cancer lesions is essential for treatment decision making. National Comprehensive Cancer Network guidelines recognize prostate-specific membrane antigen (PSMA) PET/CT for use in initial staging of high-risk primary prostate cancer. The gastrin-releasing peptide receptor (GRP-R) is a neuropeptide receptor overexpressed by low-risk prostate cancer cells. We aimed to perform the first (to our knowledge) prospective head-to-head comparison of PSMA- and GRP-R-targeted imaging at initial staging to understand how PSMA PET and GRP-R PET can be used or combined in clinical practice. Methods: This was a prospective, single-center, diagnostic cross-sectional imaging study using anonymized, masked, and independent interpretations of paired PET/CT studies in 22 patients with 68Ga-PSMA-617 (a radiolabeled PSMA inhibitor) and 68Ga-RM2 (68Ga-DOTA-4-amino-1-carboxymethylpiperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2, a radiolabeled GRP-R antagonist). We enrolled patients with newly diagnosed, biopsy-proven prostate cancer. None had received neoadjuvant hormone therapy or chemotherapy, and all underwent extended pelvic lymph node dissection. Histologic findings served as a reference. Results: On a lesion-based analysis (including lesions < 0.1 cm3), 68Ga-PSMA-617 PET/CT detected 74.3% (26/35) of all tumor lesions and 68Ga-RM2 PET/CT detected 78.1% (25/32; 1 patient could not be offered 68Ga-RM2 PET/CT). Paired examinations showed positive uptake of the 2 tracers in 21 of 32 lesions (65.6%), negative uptake in 5 of 32 lesions (15.6%), and discordant uptake in 6 of 32 lesions (18.8%). Uptake of 68Ga-PSMA-617 was higher when the International Society of Urological Pathology (ISUP) score was at least 4 versus at least 1 (P < 0.0001) or 2 (P = 0.0002). There were no significant differences in uptake between ISUP scores for 68Ga-RM2. Median 68Ga-RM2 SUVmax was significantly higher than median 68Ga-PSMA-617 SUVmax in the ISUP-2 subgroup (P = 0.01). Conclusion: 68Ga-PSMA-617 PET/CT is useful to depict higher, more clinically significant ISUP score lesions, and 68Ga-RM2 PET/CT has a higher detection rate for low-ISUP tumors. Combining PSMA PET and GRP-R PET allows for better classification of intraprostatic lesions.

Feasibility of robotic-assisted partial nephrectomy for complete remission of metastatic renal cell carcinoma after long exposure to immune checkpoint inhibitors (UroCCR-106).

Immune checkpoint inhibitors used for metastatic clear cell renal cell carcinoma treatment show significant rates of complete response on metastatic sites. Feasibility of delayed surgery on primitive tumors remains questionable, especially regarding conservative procedures. We present here the first reported case of robotic-assisted partial nephrectomy (RAPN) and concomitant metastasectomy after long exposure to immunotherapy. We performed an imperative salvage RAPN and metastasectomy in a 79-year-old woman with history of right radical nephrectomy for oligometastatic clear cell renal cell carcinoma, previous open partial nephrectomy and ablative treatment on the remaining left kidney. In fact, after complete response on the metastatic sites, the patient experienced progression on the solitary kidney despite immunotherapy. This limited experience of RAPN and metastasectomy after long exposure to immunotherapy appears to be feasible safe and efficient both on the oncological and functional point of view.

ELANE neutropenia and solid tumors: Four cases from the French severe chronic neutropenia registry.

Neutropenia related to ELANE gene mutations predisposes patients to infection and leukemia/myelodysplasia, but little is known about the predisposition to cancer. Among a cohort of 147 patients, we identified four with malignant solid tumors (papillary thyroid cancer, anal squamous cell cancer, papillary renal cell carcinoma, and adrenocortical carcinoma), all aged 25-50 years. Three occurred with cyclic neutropenia, and one occurred with severe chronic neutropenia. Previous radiotherapy was identified as a risk factor in one patient. No genetic predisposition was identified in the three other patients.

Incidental prostate cancer after holmium laser enucleation of the prostate: incidence and predictive factors for clinical progression.

OBJECTIVES: To describe the incidental prostate cancer (iPCa) rate and identify predictive factors for PCa progression after holmium laser enucleation of the prostate (HoLEP). METHODS: A retrospective review of all iPCa cases diagnosed after HoLEP procedures between April 2012 and May 2020 was conducted. iPCa was defined as a symptom-free cancer diagnosed after HoLEP in patients without any diagnosis or suspicion of PCa before surgical treatment. PCa progression was suspected by rise in PSA from baseline after HoLEP and confirmed by progressive disease detected on transrectal needle biopsy or by the appearance of metastatic disease. Univariate and multivariate logistic regression were used to identify predictive factors for cancer progression. RESULTS: The iPCa rate in our cohort was 10.7% (n = 134). Among patients with iPCa, 25 (18.6%) progressed with a mean follow-up of 32 months. Regarding predictive factors, post-operative PSA (OR 2.35, p < 0.001) was significantly associated with PCa progression in multivariate analysis. The cutoff value for post-operative PSA was determined at 2 ng/mL. Among iPCa cases, 14 patients (10.4%) had both T1b stage disease and PSA ≥ 2 ng/mL, while 68 (50.7%) had neither of these factors. Univariate logistic regression analysis showed that patients with both factors had the highest risk of progression (OR 49.4; p < 0.001). CONCLUSION: In this study, post-operative PSA above 2 ng/mL was the only independent risk factor for iPCa progression after HoLEP. Patients with post-operative PSA ≥ 2 ng/mL must be considered to be at risk of progression and may require early curative treatment or closer follow-up in the post-operative period, especially when this is associated with T1b stage disease.

Aseptic cystitis induced by nivolumab and ipilimumab combination for metastatic melanoma.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced melanoma. Combination of ICI with ipilimumab cytotoxic T-lymphocyte antigen-4 and nivolumab [anti-programmed cell death-1 (PD-1)] improves tumoral response compared to anti-PD1 monotherapy in melanoma patients, but is associated with more severe and multiple immune-related adverse events. We report the first case of aseptic cystitis induced by ipilimumab and nivolumab combination in a 61-year-old melanoma patient. She described after two infusions, diarrhea, pollakiuria, intense bladder pain, urinary urgency, and nocturia. Repeated negative urine culture tests led to perform cystoscopy. Mucosal bladder biopsies showed lymphocytic T-cells infiltration in intraepithelial and in subepithelial connective tissue, which were consistent with the diagnosis of immune-related aseptic cystitis. Aseptic cystitis is a rare and poorly known side-effect related to ICI. Only four other cases with anti-PD1 monotherapy were found in literature, only in Japanese patients. It simulates bacterial cystitis with negative urinary tests, and is often associated with atypical symptoms like diarrhea, which may delay the diagnosis. Oral steroids appear to be the most efficient therapeutic options.

Current management and future perspectives of penile cancer: An updated review.

Penile cancer (PeCa) is a rare disease worldwide, accounting for less than one percent of all malignancies in men. It usually presents as a painless ulcer or lump on the head of the penis. Squamous cell carcinoma represents the most common histological subtype of PeCa, with pathogenesis intimately linked to chronic Human Papilloma Virus (HPV) infection. Surgery is the cornerstone for the treatment of primary PeCa with potential mutilating outcome depending on the nodal extension of the disease. However, in case of extensive lymph node involvement, multidisciplinary treatment including perioperative chemotherapy and inclusion in clinical trial should be considered. To date, advanced or metastatic disease still have poor prognosis and are a therapeutic challenge with limited options, highlighting the need of new treatments and further investigations. Growing efforts to identify molecular alterations, understand the role of HPV and characterize immune contexture have expanded over the past years, providing further perspectives in prognostication, predictive biomarkers and therapeutic intervention. In this review, we provide an updated overview of current management of PeCa focusing on perioperative strategy. We discuss about new insights of the biology of PeCa and comment future directions in the field.

68Ga-PSMA-617 Compared With 68Ga-RM2 and 18F-FCholine PET/CT for the Initial Staging of High-Risk Prostate Cancer.

Ga-labeled prostate-specific membrane antigen inhibitors and Ga-labeled gastrin-releasing peptide receptor antagonists showed interesting results for staging biochemically recurrent prostate cancer. In this case, Ga-prostate-specific membrane antigen-617 PET/CT, Ga-RM2 PET/CT, and F-choline PET/CT were performed in a patient (66-year-old man, prostate-specific antigen = 6.7 ng/mL) with biopsy-proven Gleason 9 (5 + 4) prostate cancer, candidate for radical prostatectomy and lymph node dissection.

Comparison of the radiolabeled PSMA-inhibitor 111In-PSMA-617 and the radiolabeled GRP-R antagonist 111In-RM2 in primary prostate cancer samples.

PURPOSE: Prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRP-R) are expressed in prostate cancer and can be targeted with radiolabeled inhibitors and antagonists. Their performances for the initial characterization of prostatic tumors have been barely evaluated but never compared. We aimed to gather comparative preclinical data of the role of PSMA and GRP-R targeting in prostate cancer. PROCEDURES: We retrospectively studied 20 frozen prostatectomy samples with various metastatic risks of the D'Amico classification. Tissue samples were investigated by tissular microimaging using the radiolabeled PSMA inhibitor 111In-PSMA-617 and the radiolabeled GRP-R antagonist 111In-RM2. Bindings of the two radiopharmaceuticals were compared to histology and clinico-biological data (Gleason score, PSA values, metastatic risks). RESULTS: Binding of 111In-PSMA-617 was high whatever the metastatic risk (p = 0.665), Gleason score (p = 0.555), or PSA value (p = 0.404) while 111In-RM2 exhibited a significantly higher binding in the low metastatic risk group (p = 0.046), in the low PSA value group (p = 0.001), and in samples with Gleason 6 score (p = 0.006). CONCLUSION: PSMA and GRP-R based imaging might have complementary performances for the initial characterization of prostatic tumors. Prospective clinical studies comparing the two tracers in this setting are needed.

Antigenic Mimicry in Paraneoplastic Immune Thrombocytopenia.

The association of immune thrombocytopenia (ITP) with cancer has been reported, but the causality of tumor cells in paraneoplastic ITP pathogenesis and maintenance has never been established. We analyzed the unusual case of refractory ITP and coincident urothelial tumor of the kidney with circulating high titer anti-GPIIBIIIA autoantibodies. Intriguingly, after nephrectomy, the patient recovered fully and her anti-GPIIBIIIA autoantibodies disappeared. Proteomic and immunohistochemistry analyses revealed erratic GPIIB expression by the tumor cells, suggesting possible antigenic mimicry chronically stimulating the immune system and leading to this patient's refractory ITP. Such previously unreported findings provide proof-of-concept that requires further confirmation with the prospective study of a larger number of patients.

Metastatic Clear-cell Renal Cell Carcinoma With a Long-term Response to Sunitinib: A Distinct Phenotype Independently Associated With Low PD-L1 Expression.

BACKGROUND: Long-term responders (LTRs) are defined by at least 18 months of response to sunitinib in metastatic clear-cell renal cell carcinoma (ccRCC). Well-described by clinical studies, the phenotype of these tumors has never been explored. PATIENTS AND METHODS: In a retrospective and multicenter study, 90 ccRCCs of patients with metastatic disease were analyzed. Immunohistochemistry (carbonic anhydrase IX, vascular endothelial growth factor, c-MET, programmed death-ligand 1 [PD-L1], and PD-1) and VHL status were performed. Progression-free survival and overall survival were calculated from sunitinib introduction and from progression. LTRs and their corresponding tumors were compared with others using univariate and multivariate analysis. RESULTS: Twenty-eight patients were LTRs. They had a median progression-free survival of 28 months versus 4 months for other patients (P < .001). Similarly, LTRs had a median overall survival of 49 months versus 14 months (P < .001), even from progression (median, 21 vs. 7 months; P = .029). They were associated with a favorable or intermediate risk (International Metastatic Renal Cell Carcinoma Database Consortium model) (P = .007) and less liver metastasis (P = .036). They experienced more frequent complete or partial responses at the first radiologic evaluation (P = .035). The corresponding ccRCCs were associated with less nucleolar International Society for Urological Pathology grade 4 (P = .037) and hilar fat infiltration (P = .006). They were also associated with low PD-L1 expression (P = .02). Only the International Metastatic Renal Cell Carcinoma Database Consortium model and PD-L1 expression remained significant after multivariate analysis (P = .014 and P = .029, respectively). CONCLUSION: Primary tumor characteristics of LTRs were studied for the first time and demonstrated a different phenotype. Interestingly, they were characterized by low expression of PD-L1, suggesting a potentially lower impact of targeted immunotherapy in these patients.

Contemporary assessment of the correlation between Bosniak classification and histological characteristics of surgically removed atypical renal cysts (UroCCR-12 study).

PURPOSE: To evaluate and compare pathological characteristics of renal cysts Bosniak IIF, III and IV in light of recent histological classification. PATIENTS AND METHODS: The French research network for kidney cancer UroCCR conducted a multicentre study on patients treated surgically for a renal cyst between 2007 and 2016. Independent radiological and centralized pathological reviews were performed for every patient. Pathological characteristics were compared to the Bosniak classification. RESULTS: Of a total 216 patients included, 175 (81.0%) tumours (90.9% of Bosniak IV, 69.8% of Bosniak III) were malignant or had a low malignant potential, with 60% of clear cell renal cell carcinoma (CCRCC), 24% of papillary RCC (PRCC) and 6.9% of multilocular cystic renal tumour of low malignant potential (MCRTLMP). Malignancies were mostly of low pT stage (86.4% of pT1-2), and low ISUP grade (68.0% of 1-2). Bosniak III cysts had a lower rate of CCRCC (46.7 vs. 67.3%), higher rate of PRCC (30 vs. 20.9%) and MCRTLMP (18.3 vs. 0.9%) compared to Bosniak IV (p < 0.001). Low-malignant potential lesions were less likely Bosniak IV and pT3-4 stage was more frequent in Bosniak IV vs. III (15.7 vs. 3.5%; p = 0.04). There were two recurrences (1.1%) and no cancer-related death occurred during follow-up. CONCLUSION: These results confirmed that cystic renal malignancies have excellent prognosis. Bosniak III cysts had a low malignant potential, which suggests surveillance could be an option for these lesions.

Hilar fat infiltration: A new prognostic factor in metastatic clear cell renal cell carcinoma with first-line sunitinib treatment.

INTRODUCTION: The selection of patients with metastatic clear cell renal cell carcinoma (ccRCC) who may benefit from targeted tyrosine kinase inhibitors has been a challenge, even more so now with the advent of new therapies. Hilar fat infiltration (HFI) is a validated prognostic factor in nonmetastatic ccRCC (TNM 2009 staging system) but has never been studied in metastatic patients. We aimed to assess its phenotype and prognostic effect in patients with metastatic ccRCC treated with first-line sunitinib. MATERIALS AND METHODS: In a multicentric study, we retrospectively included 90 patients and studied the corresponding ccRCC at the pathological, immunohistochemical, and molecular levels. Patient and tumor characteristics were compared using univariate and multivariate analysis. All the features were then studied by Cox models for prognostic effect. RESULTS: HFI was found in 42 patients (46.7%), who had worse prognosis (Heng criteria) (P = 0.003), liver metastases (P = 0.036), and progressive diseases at first radiological evaluation (P = 0.024). The corresponding ccRCC was associated with poor pathological prognostic factors that are well known in nonmetastatic ccRCC. For these patients, median progression-free survival was 4 months vs. 13 months (P = 0.02), and median overall survival was 14 months vs. 29 months (P = 0.006). In a multivariate Cox model integrating all the variables, only poor prognosis, according to the Heng criteria and HFI, remained independently associated with both progression-free survival and overall survival. CONCLUSION: HFI was demonstrated for the first time to be an independent poor prognostic factor. Its potential role in predicting resistance to antiangiogenic therapy warrants further investigation.

Correlation of c-MET Expression with PD-L1 Expression in Metastatic Clear Cell Renal Cell Carcinoma Treated by Sunitinib First-Line Therapy.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is highly metastatic. Cabozantinib, an anti-angiogenic tyrosine kinase inhibitor that targets c-MET, provided interesting results in metastatic ccRCC treatment. OBJECTIVE: To understand better the role of c-MET in ccRCC, we assessed its status in a population of patients with metastatic ccRCC. PATIENTS AND METHODS: For this purpose, tumor samples were analyzed for c-MET expression by immunohistochemistry (IHC), for c-MET copy number alterations by fluorescence in situ hybridization (FISH), and for c-MET mutations by next generation sequencing (NGS) in a retrospective cohort of 90 primary ccRCC of patients with metastases treated by first-line sunitinib. The expression of c-MET was correlated with pathological, immunohistochemical (VEGFA, CAIX, PD-L1), clinical, and molecular criteria (VHL status) by univariate and multivariate analyses and to clinical outcome using Kaplan-Meier curves compared by log-rank test. RESULTS: Of ccRCC, 31.1% had low c-MET expression (absent to weak intensity by IHC) versus 68.9% with high expression (moderate to strong intensity). High expression of c-MET was associated with a gain in FISH analysis (p=0.0284) without amplification. No mutations were detected in NGS. Moreover, high c-MET expression was associated with lymph node metastases (p=0.004), sarcomatoid component (p=0.029), VEGFA (p=0.037), and PD-L1 (p=0.001) overexpression, the only factor that remained independently associated (p<0.001) after logistic regression. No difference was observed in clinical outcomes. CONCLUSION: This study is the first to analyse c-MET status in metastatic ccRCC. The high expression of c-MET in the majority of ccRCC and its independent association with PD-L1 expression, may suggest a potential benefit from combining c-MET inhibitors and targeted immunotherapy.

Renal Intravascular Large B-cell Lymphoma: A Case Report and Review of the Literature.

We herein report the case of a 52-year-old woman who consulted us because of a 2-month history of a fever, anorexia and weight loss. A physical examination was unremarkable. The blood count showed mild anemia and lymphopenia, and lactate dehydrogenase was elevated. Creatinine clearance was normal and proteinuria was undetectable. CT showed enlarged kidneys. A bone marrow biopsy was normal. PET-CT showed an intense uptake of 18fluorodeoxyglucose in both kidneys. A kidney biopsy provided the diagnosis of intravascular large B-cell lymphoma (IVLBCL). Kidney-limited IVLBCL without an impairment in the renal function or proteinuria has not been described. We analyzed the 38 published cases of IVLBCL involving the kidney to describe the main features of this entity.

Is Multiparametric MRI Useful for Differentiating Oncocytomas From Chromophobe Renal Cell Carcinomas?

OBJECTIVE: The purpose of this study was to retrospectively evaluate the diagnostic accuracy of multiparametric MRI to differentiate oncocytoma from chromophobe renal cell carcinoma (RCC). MATERIALS AND METHODS: In this retrospective study, 26 histologically confirmed oncocytomas and 16 chromophobe RCCs that underwent full MRI examination were identified in 42 patients (25 men and 17 women) over a 6-year period. Demographic data were recorded. Double-echo chemical-shift, dynamic contrast-enhanced T1- and T2-weighted images, and apparent diffusion coefficient (ADC) maps were reviewed independently by two radiologists blinded to pathologic results. Signal-intensity index (SII), tumor-to-spleen signal-intensity ratio, ADC ratio, three wash-in indexes, and two washout indexes were calculated and compared using univariate and ROC analyses. Sensitivity and specificity analyses were performed to calculate diagnostic accuracy. RESULTS: All carcinomas and nine oncocytomas were resected; the remaining 17 oncocytomas were biopsied. Patient age (for oncocytomas: mean, 68.2 years; range, 43-84 years; for RCCs: mean, 60.8 years; range, 20-79 years) and tumor size (for oncocytomas: mean, 35.5 mm; range, 12-98 mm; for RCCs: mean, 37.2 mm; range, 9-101 mm) did not differ significantly across groups (p = 0.132 and 0.265, respectively). Good interobserver agreement was observed for all measurements but four. Oncocytomas presented significantly higher ADC (p = 0.002) and faster enhancement (p = 0.007-0.012) but lower SII (p = 0.03) than carcinomas. This combination provided sensitivity of 92.3% (24/26), specificity of 93.8% (15/16), and accuracy of 92.9% (39/42) for the detection of oncocytomas. CONCLUSION: Multiparametric MRI helps to accurately differentiate oncocytomas from chromophobe RCCs with high sensitivity and specificity.

Unique Transcriptomic Profile of Collecting Duct Carcinomas Relative to Upper Tract Urothelial Carcinomas and other Kidney Carcinomas.

Collecting duct carcinoma (CDC) is a kidney cancer subtype that is thought to arise from principal cells in distal parts of the collecting ducts. Some studies suggested an overlap of CDC with upper tract urothelial carcinoma (UTUC), making the pathological diagnosis challenging. Herein, we performed for the first time transcriptome sequencing of CDC and compared them to UTUC and renal cell carcinoma subtypes. We discovered that CDC displays a unique transcriptomic signature among kidney cancer subtypes, with a putative cell of origin in the distal convoluted tubules. Hierarchical unsupervised clustering reveals that the CDC signature is closer to that of other RCC subtypes than to UTUC, which is similar to that of bladder carcinoma. CDC is characterized by a metabolic shift, with impairment of oxidoreductase activity, pyruvate metabolism and the tricarboxlyic acid cycle, as well as an immunogenic response consistent with increased tumor infiltrating lymphocytes, particularly within metastatic cases. In addition, pathways differentially altered between CDC and UTUC point to a basal-like phenotype of CDC in contrast to the luminal-like signature of UTUC. We conclude that CDC harbors a pathognomonic transcriptomic signature characterized by immunogenic and a metabolic aberrations, indicating that targeting these processes might provide therapeutic options for patients.

A germline mutation in PBRM1 predisposes to renal cell carcinoma.

BACKGROUND: Many cases of familial renal cell carcinoma (RCC) remain unexplained by mutations in the known predisposing genes or shared environmental factors. There are therefore additional, still unidentified genes involved in familial RCC. PBRM1 is a tumour suppressor gene and somatic mutations are found in 30-45% of sporadic clear cell (cc) RCC. METHODS: We selected 35 unrelated patients with unexplained personal history of ccRCC and at least one affected first-degree relative, and sequenced the PBRM1 gene. RESULTS: A germline frameshift mutation (c.3998_4005del [p.Asp1333Glyfs]) was found in one patient. The patient's mother, his sister and one niece also had ccRCC. The mutation co-segregated with the disease as the three affected relatives were carriers, while an unaffected sister was not, according with autosomal-dominant transmission. Somatic studies supported these findings, as we observed both loss of heterozygosity for the mutation and loss of protein expression in renal tumours. CONCLUSIONS: We show for the first time that an inherited mutation in PBRM1 predisposes to RCC. International studies are necessary to estimate the contribution of PBRM1 to RCC susceptibility, estimate penetrance and then integrate the gene into routine clinical practice.

Real-time contrast-enhanced transrectal US-guided prostate biopsy: diagnostic accuracy in men with previously negative biopsy results and positive MR imaging findings.

PURPOSE: To retrospectively evaluate diagnostic accuracy of real-time contrast material-enhanced (CE) ultrasonography (US) transrectal US-guided biopsies in patients with persistently elevated prostate-specific antigen (PSA) levels, previous negative systematic transrectal US-guided biopsy results, and positive prostate multiparametric magnetic resonance (MR) findings. MATERIALS AND METHODS: Institutional review board approval was obtained for this retrospective study. Informed consent was waived. From 2007 to 2011, 178 patients with increased PSA levels (mean, 10.7 ng/mL [10.7 µg/L]), previous negative findings of random biopsies, and targets depicted at multiparametric MR imaging underwent transrectal US-guided prostate biopsies after injection of sulfur hexafluoride microbubbles. CE US-targeted biopsies were performed systematically in cancer-suggestive regions, followed by random acquisition of 12 nontargeted cores in all other regions. Diagnostic accuracy of CE US-targeted biopsies was measured with sensitivity, specificity, and positive and negative predictive values. Fisher exact and Mann-Whitney U tests were used to compare subgroups of patients. Potential predictive variables were examined with a logistic regression model. RESULTS: CE US findings were positive in a first group of 158 patients and negative in a second group of 20 patients. Prostate carcinoma (PCa) was detected in 75 patients in the first group (47.5%) and in eight of the second group (40.0%). Overall cancer detection rate was 46.6% (83 of 178). In the first group, PCa was detected with targeted biopsies alone in 18 patients (24%), with nontargeted biopsies alone in 23 (30.7%), and with both in 34 (45.3%). Mean number of CE US-targeted cores per cancer-suggestive region was 2.2. CE US-targeted biopsies had a positive overall detection rate of 30.9%, while it was 6.9% for 12-core nontargeted biopsies (P < .001). PSA level and Gleason score were associated with positivity of CE US-targeted biopsies (P = .031 and P = .015, respectively). CONCLUSION: Real-time CE US-targeted transrectal US biopsy offers excellent sensitivity for PCa detection in men with previous negative biopsy results and positive findings at multiparametric MR imaging. It may be combined with conventional random biopsies to increase specificity.