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.

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.

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.

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.

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.

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.

Biological significance of perineural invasion (PNI) in prostate cancer.

BACKGROUND: In order to better understand the biological significance of perineural invasion (PNI) in prostate cancer, we aimed to analyze in situ the expression of molecules involved in tumor growth or nerve trophicity. METHODS: Tissues from 66 radical prostatectomies performed for prostate cancer (40 with PNI and 26 without PNI) were selected and included in a tissue microarray (TMA): PNI areas (when available), cancer far from nerves, and nerves far from cancer. The expression of the following molecules was analyzed using immunohistochemistry on TMA slides: macrophage migration inhibitory factor (MIF) and its receptor CD74, EGF receptor (EGFR), heregulin (HRG) and its receptor ErbB3, and the proliferation marker Ki67. RESULTS: Cancer cells in the PNI areas showed increased proliferation, EGFR and CD74 expression, when compared to cells far from nerves (P = 0.009, 0.0005, and 0.02, respectively). Moreover, cell proliferation and CD74 staining were increased in cancers with PNI features compared to cancers without PNI (P = 0.001), even when adjusting for Gleason score, tumor size, and pathological stage. CONCLUSIONS: These results suggest that cancer cells in the PNI areas could acquired a growth advantage that could be triggered by the growth factor receptors EGFR and CD74.