Evaluation of Artificial Intelligence-Based Gleason Grading Algorithms "in the Wild".

The biopsy Gleason score is an important prognostic marker for prostate cancer patients. It is, however, subject to substantial variability among pathologists. Artificial intelligence (AI)-based algorithms employing deep learning have shown their ability to match pathologists' performance in assigning Gleason scores, with the potential to enhance pathologists' grading accuracy. The performance of Gleason AI algorithms in research is mostly reported on common benchmark data sets or within public challenges. In contrast, many commercial algorithms are evaluated in clinical studies, for which data are not publicly released. As commercial AI vendors typically do not publish performance on public benchmarks, comparison between research and commercial AI is difficult. The aims of this study are to evaluate and compare the performance of top-ranked public and commercial algorithms using real-world data. We curated a diverse data set of whole-slide prostate biopsy images through crowdsourcing containing images with a range of Gleason scores and from diverse sources. Predictions were obtained from 5 top-ranked public algorithms from the Prostate cANcer graDe Assessment (PANDA) challenge and 2 commercial Gleason grading algorithms. Additionally, 10 pathologists (A.C., C.R., J.v.I., K.R.M.L., P.R., P.G.S., R.G., S.F.K.J., T.v.d.K., X.F.) evaluated the data set in a reader study. Overall, the pairwise quadratic weighted kappa among pathologists ranged from 0.777 to 0.916. Both public and commercial algorithms showed high agreement with pathologists, with quadratic kappa ranging from 0.617 to 0.900. Commercial algorithms performed on par or outperformed top public algorithms.

Clinical and histological features of histiocytoid Sweet syndrome associated with VEXAS syndrome.

BACKGROUND: VEXAS (Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is caused by acquired somatic mutations in UBA1. Sweet-syndrome-like skin disorders [and especially histiocytoid Sweet syndrome (HSS)] may be associated with VEXAS syndrome. OBJECTIVES: To characterize the clinical and histopathological features of HSS in patients with VEXAS syndrome. METHODS: Skin biopsies with a histological diagnosis of HSS at Rennes University Medical Center (Rennes, France) between October 2011 and January 2022 were reviewed in this study. Sanger sequencing and digital polymerase chain reaction were used to screen skin, blood and bone marrow samples for UBA1 variants, and thus classify patients as having VEXAS syndrome or not. We evaluated the clinical, histological and molecular (UBA1) characteristics of patients with or without VEXAS syndrome. RESULTS: We compared 15 skin biopsies from 7 patients found to have VEXAS syndrome and 19 skin biopsies from 15 patients without VEXAS syndrome. Persistent C-reactive protein elevation, macrocytosis, anaemia and haematological malignancies were more prevalent in patients with VEXAS syndrome [6/7 (86%), 6/7 (86%), 7/7 (100%) and 6/7 (86%), respectively] than in patients without [5/14 (36%), 6/15 (40%), 8/15 (53%) and 8/15 (53%), respectively]. These features sometimes appeared after the first skin manifestations, and a UBA1 mutation was found in the skin of five patients with VEXAS syndrome. Dermal infiltration by reniform histiocytoid cells (myeloperoxidase-positive and/or CD163-positive) and a periadnexal distribution were more frequently observed in VEXAS syndrome biopsies [15/15 (100%) and 3/15 (20%), respectively, vs. 11/19 (58%) and 0/19 (0%) in non-VEXAS syndrome biopsies, respectively]. CONCLUSIONS: Our findings might help pathologists to consider a diagnosis of VEXAS syndrome and to initiate early genetic testing.

[2022 WHO classification of renal cell carcinomas: Focus on papillary renal cell carcinoma]. / Classification OMS 2022 des cancers du rein : focus sur le carcinome rénal papillaire.

Renal cell carcinomas (RCC) represent a group of heterogeneous tumors whose classification has greatly evolved since 1981. The latest update in 2022 classifies all renal cell carcinomas into six categories according to their morphology or the detection of specific molecular alterations. Molecular disassembly of renal cell carcinomas with papillary features has enabled the identification of new entities characterized by a specific molecular alteration, such as Fumarate Hydratase (FH) deficient RCC, TFE3-rearranged RCC or TFEB-altered RCC. This new classification allows for a more accurate diagnosis but requires a thorough knowledge of the genomic alterations to search for with immunohistochemical or molecular biology techniques. According to the new WHO 2022 classification, papillary renal cell carcinoma (PRC) type 1 or type 2 classification is no longer recommended. A classification based on nucleolar ISUP grade must be preferred: low-grade PRC (ISUP 1-2) or high-grade PRC (ISUP 3-4). The other prognostic factors remain the same: the pTNM stage, lymphovascular invasion, and the presence or absence of dedifferentiated areas referring to sarcomatoid or rhabdoid features. Of note, the presence of necrosis is not currently recognized as a poor prognostic element for this type of carcinoma. The diagnosis of high-grade PRC is from now on a diagnosis of exclusion. It can only be sustained after having ruled out TFE3-rearranged RCC, TFEB-altered RCC, and FH-deficient RCC. For clinicians, the diagnosis of PRC implies suggesting an oncogenetic consultation to screen for an associated genetic tumor syndrome regardless of the patient's age.

Deep Learning for Detecting BRCA Mutations in High-Grade Ovarian Cancer Based on an Innovative Tumor Segmentation Method From Whole Slide Images.

BRCA1 and BRCA2 genes play a crucial role in repairing DNA double-strand breaks through homologous recombination. Their mutations represent a significant proportion of homologous recombination deficiency and are a reliable effective predictor of sensitivity of high-grade ovarian cancer (HGOC) to poly(ADP-ribose) polymerase inhibitors. However, their testing by next-generation sequencing is costly and time-consuming and can be affected by various preanalytical factors. In this study, we present a deep learning classifier for BRCA mutational status prediction from hematoxylin-eosin-safran-stained whole slide images (WSI) of HGOC. We constituted the OvarIA cohort composed of 867 patients with HGOC with known BRCA somatic mutational status from 2 different pathology departments. We first developed a tumor segmentation model according to dynamic sampling and then trained a visual representation encoder with momentum contrastive learning on the predicted tumor tiles. We finally trained a BRCA classifier on more than a million tumor tiles in multiple instance learning with an attention-based mechanism. The tumor segmentation model trained on 8 WSI obtained a dice score of 0.915 and an intersection-over-union score of 0.847 on a test set of 50 WSI, while the BRCA classifier achieved the state-of-the-art area under the receiver operating characteristic curve of 0.739 in 5-fold cross-validation and 0.681 on the testing set. An additional multiscale approach indicates that the relevant information for predicting BRCA mutations is located more in the tumor context than in the cell morphology. Our results suggest that BRCA somatic mutations have a discernible phenotypic effect that could be detected by deep learning and could be used as a prescreening tool in the future.

Osteonecrosis of the jaw under palbociclib: A case series description.

INTRODUCTION: Cases of osteonecrosis of the jaw have been reported by dental surgeons to the pharmacovigilance center in Rennes, France, occurring among patients treated with palbociclib, a cyclin-dependent kinase 4/6 inhibitor. Although this event was not expected with the drug, a safety signal was raised. Describing a local case series, the aim of our study was to identify specific patterns that might suggest a triggering role for these drugs, and to discuss pathophysiological hypotheses. MATERIALS AND METHODS: A retrospective case series of patients exposed to cyclin-dependent kinase 4/6 inhibitors between 2016 and 2020 with a diagnosis of osteonecrosis of the jaw at the Rennes Dental Care Center was analyzed. The descriptive analysis was conducted on patient demographics, breast cancer characteristics, osteonecrosis of the jaw, biological data, and exposure to cyclin-dependent kinase 4/6 inhibitors. RESULTS: We identified eight cases, most of them at stages 0-1 (62.5%). Four patients were still exposed to palbociclib at the time of diagnosis and four had discontinued the treatment before the diagnosis. Chronological imputability could not be excluded given the drug's half-life and the variable intervals of dental monitoring from one patient to another. All patients had at least one dental osteonecrosis risk factor (including dental extraction, dentures, and denosumab exposure at the time of diagnosis). Neutropenia and mucositis were not systematically reported at the time of diagnosis. The anatomopathological characteristics were nonspecific. CONCLUSION: We did not identify a specific pattern that could suggest a triggering role of palbociclib in the development of ONJ.

[FH (Fumarate Hydratase)-deficient renal cell carcinoma: A case report]. / Carcinome à cellules rénales FH (fumarate hydratase)-déficient : à propos d'un cas.

Fumarate hydratase deficient renal cell carcinoma (FH-RCC) is a rare malignant neoplasia caused by constitutive or somatic mutations in the FH gene whose diagnosis is primordial, requiring genetic counselling. Because of histological heterogeneity, such tumors have been in the past misclassified as "type 2 papillary carcinoma", "tubulo-cystic renal cell carcinoma" or "high grade papillary carcinoma". We report here a case of FH deficient renal cell carcinoma (FH-RCC) in a 69years old patient. Through this observation, we precise the epidemiological and histological aspects and diagnosis criteria of this rare tumor.

[Secondary tumors localized in testis]. / Localisations tumorales secondaires testiculaires.

Testis tumors are uncommon in oncology, and testicular metastasis from distant solid tumors are even rarer. We present two cases encountered in our department of pathology in CHU de Rennes, France. Moreover, we collected all reported cases in the Medline/PubMed databases of non-hematopoietic secondary testis tumors in adults, excluding autopsy studies, to propose an integrative study on this topic. In total, we report 98 cases of secondary testis lesions to prostate (n=38, 38.77 %), colorectal (n=19, 19.39%), gastric (n=12, 12.24%), kidney (n=7, 7.14%), lung (n=6, 6.12%) and other primary cancers. The median age at diagnosis was 66.5 years. We identified significantly more prostate adenocarcinoma (P<0.0001) when the primary tumor was known and significantly more colorectal adenocarcinoma (P=0.035) and pancreatic adenocarcinoma (P=0.002) when the primary tumor was unknown. The age at diagnosis was older when the primary tumor was known (P=0.007). We present the challenges for the diagnosis and propose some elements for diagnosis orientation. Finally, we discuss the possible ways of metastatic dissemination from primary site to testis, as illustrated by the two cases we present.

Comprehensive study of nine novel cases of TFEB-amplified renal cell carcinoma: an aggressive tumour with frequent PDL1 expression.

AIMS: First described in 2014, renal cell carcinoma (RCC) with TFEB amplification (6p21) is a rare molecular subgroup whose diagnosis is challenging. The prognosis and therapeutic implications remain unclear. METHODS: We report here the clinical, histological, immunohistochemical, and genetic features of nine novel cases. The pathological and immunohistochemical features were centrally reviewed by expert uropathologists. Fluorescence in situ hybridisation (FISH) confirmed the diagnosis and comparative genomic hybridisation (CGH) was performed to determine quantitative genomic alterations. We also performed an exhaustive review of the literature and compiled our data. RESULTS: TFEB-amplified RCC were locally advanced, with initial lymph node involvement in one case and liver metastasis in another case. They were high-grade eosinophilic tumours with papillary/pseudopapillary architecture, frequent positivity for melanocytic markers, and frequent PDL1 expression. FISH demonstrated high-level TFEB amplification in six cases. One case showed concomitant TFEB translocation. CGH analysis identified complex alterations with frequent losses of 1p, 2q, 3p, 6p, and frequent 6p and 8q gains. VEGFA coamplification was identified in all cases with a lower level than TFEB. The prognosis was poor, with five patients having lymph node or distant metastases. CONCLUSION: TFEB-amplified RCC is a rare molecular subgroup with variable morphology whose diagnosis is confirmed by FISH analysis. The complex alterations identified by CGH are consistent with an aggressive clinical behaviour. The coamplification of VEGFA and the expression of PDL1 could suggest a potential benefit from antiangiogenics and targeted immunotherapy in combination for these aggressive tumours.

Complete Transurethral Resection before Radical Cystectomy May Improve Oncological Outcomes.

OBJECTIVES: The objective of this study was to assess the impact of complete transurethral resection of bladder tumors (TURBTs) before radical cystectomy on pathological and oncological outcomes of patients with muscle-invasive bladder cancer (MIBC) and high-risk non-MIBC. MATERIALS AND METHODS: The charts of all patients who underwent radical cystectomy for bladder cancer in 2 academic departments of urology between 1996 and 2016 were retrospectively reviewed. Patients were divided into 2 groups according to the completeness of the last endoscopic resection before radical cystectomy: macroscopically complete transurethral resection (complete) or macroscopically incomplete transurethral resection (incomplete). The primary end point was the recurrence-free survival (RFS). Secondary end points included cancer-specific survival (CSS) and rates of pT0 and downstaging. RESULTS: Out of 486 patients included for analysis, the TURBT immediately preceding radical cystectomy was considered macroscopically complete in 253 patients (52.1%) and incomplete in 233 patients (47.9%). In multivariate analysis, macroscopically complete TURBT was the strongest predictor of both pT0 disease (OR = 3.1; p = 0.02) and downstaging (OR = 7.1; p < 0.0001). After a median follow-up of 41 months, macroscopically complete TURBT was associated with better RFS (5-year RFS: 57 vs. 37%; p < 0.0001) and CSS (5-year CSS: 70.8 vs. 54.5%; p = 0.002). In multivariate analysis adjusting for multifocality, weight of endoscopic resection specimen, cT4 stage on preoperative imaging, interval between endoscopic resection and radical cystectomy, neoadjuvant chemotherapy, pT stage, and associated carcinoma in situ, macroscopically complete endoscopic resection remained the main predictor of better RFS (HR = 0.4; p = 0.0003) and the only preoperative factor associated with CSS (HR = 0.5; p = 0.01). CONCLUSION: A macroscopically complete TURBT immediately preceding radical cystectomy may improve pathological and oncological outcomes in patients with MIBC and high-risk MIBC.

[Renal carcinoma with leiomyomatous stroma and osseous metaplasia from a patient diagnosed with a tuberous sclerosis complex]. / Carcinome rénal à stroma léiomyomateux avec métaplasie osseuse chez un patient porteur d'une sclérose tubéreuse de Bourneville.

Renal cell carcinoma with leiomyomatous stroma is a rare and poorly described histopathological entity. Here we report a unique case with osseous metaplasia, in a 31-year-old man recently diagnosed with a tuberous sclerosis complex (TSC2 gene mutation). Partial nephrectomy was performed. Histologically, the epithelial component was made up of papillary and alveolar structures with clear to eosinophilic cytoplasm, and basally located nuclei. The cells are surrounded by an abundant smooth muscle stroma with focally osseous metaplasia. The tumor was positive for carbonic anhydrase IX, cytokeratin 7, cytokeratin 20, and CD10, and negative for TFE3. This emerging entity is highly correlated to tuberous sclerosis complex, which justifies a screening for the syndrome when this diagnosis is made.

Implementation of a molecular tumor board at a regional level to improve access to targeted therapy.

BACKGROUND: With the development of precision oncology, Molecular Tumor Boards (MTB) are developing in many institutions. However, the implementation of MTB in routine clinical practice has still not been thoroughly studied. MATERIAL AND METHODS: Since the first drugs approved for targeted therapies, patient tumor samples were centralized to genomic testing platforms. In our institution, all tumor samples have been analyzed since 2014 by Next Generation Sequencing (NGS). In 2015, we established a regional MTB to discuss patient cases with 1 or more alterations identified by NGS, in genes different from those related to drug approval. We conducted a retrospective comparative analysis to study whether our MTB increased the prescriptions of Molecular Targeted Therapies (MTT) and the inclusions of patients in clinical trials with MTT, in comparison with patients with available NGS data but no MTB discussion. RESULTS: In 2014, 86 patients had UGA, but the results were not available to clinicians and not discussed in MTB. During the years 2015 and 2016, 113 patients with an UGA (unreferenced genomic alteration) were discussed in MTB. No patients with an UGA were included in 2014 in a clinical trial, versus 2 (2%) in 2015-2016. 13 patients with an UGA (12%) were treated in 2015-2016 with a MTT whereas in 2014, no patient (p = 0.001). CONCLUSIONS: In this retrospective analysis, we showed that the association of large-scale genomic testing and MTB was feasible, and could increase the prescription of MTT. However, in routine clinical practice, the majority of patients with UGA still do not have access to MTT.

Immunotherapy in Renal Cell Carcinoma: The Future Is Now.

Renal cell carcinoma is the third type of urologic cancer and has a poor prognosis with 30% of metastatic patients at diagnosis. The antiangiogenics and targeted immunotherapies led to treatment remodeling emphasizing the role of the tumour microenvironment. However, long-term responses are rare with a high rate of resistance. New strategies are emerging to improve the efficacy and the emerging drugs are under evaluation in ongoing trials. With the different treatment options, there is an urgent need to identify biomarkers in order to predict the efficacy of drugs and to better stratify patients. Owing to the limitations of programmed death-ligand 1 (PD-L1), the most studied immunohistochemistry biomarkers, and of the tumor mutational burden, the identification of more reliable markers is an unmet need. New technologies could help in this purpose.

Ki-67 is an independent predictor of prostate cancer death in routine needle biopsy samples: proving utility for routine assessments.

Standard clinical parameters fail to accurately differentiate indolent from aggressive prostate cancer. Our previous studies showed that immunohistochemical testing for Ki-67 improved prediction of prostate cancer death in a previous cohort of conservatively treated clinically localized prostate cancer. However there is a need for validation of usage with whole biopsy sections rather than tissue micro-arrays for use in routine diagnostics. Prostate cancer biopsy cases were identified in the UK, between 1990 and 2003, treated conservatively. Tumor extent and prostate-specific antigen (PSA) serum measurements were available. Biopsy cases were centrally reviewed by three uropathologists and Gleason conformed to contemporary ISUP 2014 criteria. Follow-up was through cancer registries up until 2012. Deaths were divided into those from prostate cancer and those from other causes. The percentage of Ki-67 in tumor cells was evaluated by immunohistochemistry on whole biopsy sections and was available for 756 patients. This percentage was used in analysis of cancer specific survival using a Cox proportional hazards model. In univariate analysis, the interquartile hazard ratio (HR) (95% confidence intervals) for continuous Ki-67 was 1.68 (1.49, 1.89), χ12 = 47.975, P < 0.001. In grade groups 1 and 2, continuous Ki-67 was a statistically significant predictor of time to death from prostate cancer, HR (95% CI) = 1.97 (1.34, 2.88), χ12 = 9.017, p = 0.003. In multivariate analysis, continuous Ki-67 added significant predictive information to that provided by grade groups, extent of disease and serum PSA, HR (95% CI) = 1.34 (1.16, 1.54), Δχ12 = 13.703, P < 0.001. We now advocate the introduction of Ki-67 as a viable and practicable prognostic biomarker in clinical practice. The association of Ki-67 with mortality was highest in grade groups 1 and 2, showing that Ki-67 can be used as a routine biomarker in patients being considered for active surveillance.

Does tumour effraction during robotic partial nephrectomy have any impact on recurrence?

OBJECTIVE: To evaluate the impact of accidental surgical incision into the tumour (ASIT) on oncological outcomes in patients undergoing RPN for a malignant tumour. MATERIALS AND METHODS: A retrospective review of our prospectively maintained database was performed to identify all patients who underwent RPN for a localized RCC between June 2010 and July 2016. We stratified our cohort into two groups according to the presence of an ASIT. Perioperative data were compared between the two groups. Logistic regression analyses were used to assess the variables associated with ASIT. Recurrence-free survival was estimated using the Kaplan-Meier method and compared between groups with the log-rank test. RESULTS: A total of 234 patients were identified. 32 (14%) ASIT were observed. Patients' characteristics were similar in the two groups. Most of intraoperative outcomes were comparable between the two groups, but patients in the ASIT group had greater EBL (475 vs. 300 mL; p = 0.01). In multivariate analysis, tumour size (p = 0.02), RENAL score (p = 0.02), EBL (p = 0.05) and low surgeon experience (p = 0.03) were all predictive factors of ASIT. 15 (6%) of recurrences were observed over a median follow-up of 36 months. There was no difference in recurrence-free survival between the two groups (p = 0.57). CONCLUSIONS: In our experience, accidental surgical incision into the tumour during RPN was a common event that did not appear to compromise oncological outcome.

Targeting the PD-1/PD-L1 Pathway in Renal Cell Carcinoma.

Renal cell carcinoma encompass distinct diseases with different pathologic features and distinct molecular pathways. Immune checkpoint inhibitors targeting the programmed death receptor ligand 1 (PD-L1)/programmed death receptor 1 (PD-1) pathway alone or in combination have greatly changed clinical management of metastatic renal cell carcinoma, now competing with antiangiogenic drugs in monotherapy for first-line treatment. However, long-term response rates are low, and biomarkers are needed to predict treatment response. Quantification of PD-L1 expression by immunohistochemistry was developed as a promising biomarker in clinical trials, but with many limitations (different antibodies, tumour heterogeneity, specimens, and different thresholds of positivity). Other biomarkers, including tumour mutational burden and molecular signatures, are also developed and discussed in this review.

Reliability of urinary cytology and cystoscopy for the screening and diagnosis of bladder cancer in patients with neurogenic bladder: A systematic review.

AIMS: To assess the reliability of urinary cytology and cystoscopy to screen and diagnose bladder cancer in patients with NB. PATIENTS AND METHODS: A systematic literature search of the Medline and Embase databases was performed in April 2017. Data extraction was performed by two independent reviewers. A narrative synthesis was made. RESULTS: Out of 220 records assessed, 15 were included in this systematic review. All studies were prospective or retrospective series with no control group. Cystoscopy allowed the detection of asymptomatic bladder cancer in 0-10 patients, with a screening sensitivity (available in only one study) of 0%, a screening specificity ranging from 65% to 90%, and a yield in detecting asymptomatic bladder cancer of 0% in all series where it could be calculated. Urinary cytology allowed the detection of bladder cancer in asymptomatic patients in 0-12 patients, with a screening sensitivity of 71%, a screening specificity ranging from 92% to 97% and a yield ranging from 0% to 1.25%. Sensitivity of cystoscopy for diagnosis of bladder cancer ranged from 27% to 81% and specificity was 54% in the only study where it could be calculated. Sensitivity of urinary cytology for diagnosis of bladder cancer was 0-72% and specificity was 100%. CONCLUSION: There is currently insufficient data to support formal recommendations of using both tools in the screening of bladder cancer in patients with neurogenic bladder. Urinary cytology outperformed cystoscopy for screening and might be the best tool currently available.

[Low-grade eosinophilic unclassified renal cell carcinoma, a recently proposed entity in the spectrum of eosinophilic renal cells tumors: Report of one case and discussion]. / Le carcinome rénal inclassé de bas grade à cellules éosinophiles, une entité récemment proposée dans le spectre des tumeurs rénales à cellules éosinophiles : étude d'un cas et discussion.

Low-grade eosinophilic unclassified renal cell carcinoma is a rare kidney tumor recently described, not included in the WHO classification, which is very close to oncocytoma. It is unknown to most pathologists and clinicians. From a histopathological point of view, this tumor is composed of oncocytic cells arranged in a diffuse and solid pattern, without cell nests, that makes it possible to differentiate it from oncocytoma, and expresses cytokeratin 7 (CK7) heterogeneously. We report a case with a cranial vault metastasis, and present the features to differentiate this entity from oncocytoma. Furthemore, we discuss about unclassified renal cell carcinomas with oncocytic cells.

Independent association of PD-L1 expression with noninactivated VHL clear cell renal cell carcinoma-A finding with therapeutic potential.

Clear cell renal cell carcinoma (ccRCC) is an aggressive tumor that is characterized in most cases by inactivation of the tumor suppressor gene VHL. The VHL/HIF/VEGF pathway thus plays a major role in angiogenesis and is currently targeted by anti-angiogenic therapy. The emergence of resistance is leading to the use of targeted immunotherapy against immune checkpoint PD1/PDL1 that restores antitumor immune response. The correlation between VHL status and PD-L1 expression has been little investigated. In this study, we retrospectively reviewed 98 consecutive cases of ccRCC and correlated PD-L1 expression by immunohistochemistry (IHC) with clinical data (up to 10-year follow-up), pathological criteria, VEGF, PAR-3, CAIX and PD-1 expressions by IHC and complete VHL status (deletion, mutation and promoter hypermethylation). PD-L1 expression was observed in 69 ccRCC (70.4%) and the corresponding patients had a worse prognosis, with a median specific survival of 52 months (p = 0.03). PD-L1 expression was significantly associated with poor prognostic factors such as a higher ISUP nucleolar grade (p = 0.01), metastases at diagnosis (p = 0.01), a sarcomatoid component (p = 0.04), overexpression of VEGF (p = 0.006), and cytoplasmic PAR-3 expression (p = 0.01). PD-L1 expression was also associated with dense PD-1 expression (p = 0.007) and with ccRCC with 0 or 1 alteration(s) (non-inactivated VHL tumors; p = 0.007) that remained significant after multivariate analysis (p = 0.004 and p = 0.024, respectively). Interestingly, all wild-type VHL tumors (no VHL gene alteration, 11.2%) expressed PD-L1. In this study, we found PD-L1 expression to be associated with noninactivated VHL tumors and in particular wild-type VHL ccRCC, which may benefit from therapies inhibiting PD-L1/PD-1.

Does training of fellows affect peri-operative outcomes of robot-assisted partial nephrectomy?

OBJECTIVE: To evaluate the impact of fellows' involvement on the peri-operative outcomes of robot-assisted partial nephrectomy (RAPN). MATERIALS AND METHODS: We analysed 216 patients who underwent RAPN for a small renal tumour. We stratified our cohort into two groups according to the involvement of a fellow surgeon during the procedure: expert surgeon operating alone (expert group) and fellow operating under the supervision of the expert surgeon (fellow group). Peri-operative data were compared between the two groups. Linear and logistic regression analyses were performed to assess the impact of fellows' involvement on peri-operative and postoperative outcomes. Trifecta and margins ischaemia complications (MIC) score achievement rates were used to assess the quality of surgery in both the expert and fellow groups. Trifecta was defined as a combination of warm ischaemia time <25 min, negative surgical margins and no peri-operative complications. MIC score was defined as negative surgical margins, ischaemia time <20 min, and absence of complications grade ≥3. RESULTS: Fellows were involved in a total of 89 procedures (41%). Patients' characteristics were similar in the two groups. Operating time and warm ischaemia time (WIT) were longer in the fellow group (180 vs 120 min, P < 0.001, and 18 vs 14 min, P = 0.002, respectively). Length of hospital stay (LOS) was longer in the fellow group (5 vs 4.3 days; P = 0.05) and patients in this group had higher estimated blood loss (EBL; 400 vs 300 mL; P = 0.01), but this had no impact on transfusion rate (14% vs 11%; P = 0.43). Positive surgical margin rates were similar in the fellow and expert groups (2.2% vs 3.1%; P = 0.70). Major complications were more frequent in the fellow group (12.3% vs 6.3%), but the difference was not significant (P = 0.10). In multivariable analysis, fellow involvement was predictive of longer WIT (ß = 0.22; P = 0.003) and operating time (ß = 0.49; P < 0.001), but was not associated with EBL (ß = 0.12, P = 0.09) or LOS (ß = 0.12, P = 0.11). Finally, fellow involvement was associated with a lower rate of trifecta and MIC score accomplishment (odds ratio [OR] 0.53, P = 0.05 and OR 0.46, P = 0.01, respectively). CONCLUSION: Training fellows to perform RAPN is associated with longer operating time and WIT but does not appear to compromise other peri-operative outcomes.

HER2 overexpression is associated with worse outcomes in patients with upper tract urothelial carcinoma (UTUC).

PURPOSE: The aim of our study was to evaluate the expression pattern of HER2 overexpression in patients with upper tract urothelial carcinoma (UTUC) and to evaluate its association with clinical outcomes. METHODS: This multicenter retrospective study included 732 patients treated with radical nephroureterectomy for UTUC. HER2 expression was assessed using immunohistochemistry and scored according to the HercepTest: Scores of 0 or 1 were considered negative and 2 or 3 as positive. To qualify for 2 scoring, complete membrane staining of more than 10 % of tumor cells at a moderate intensity had to be observed. RESULTS: HER2 was overexpressed in 262 (35.8 %) patients. It was associated with pathologic characteristics such as more advanced T stage (p < 0.001), presence of lymph node metastasis (p = 0.006), high-grade tumor (p < 0.001), tumor necrosis (p = 0.01) and lymphovascular invasion (p = 0.02). Patients with HER2 overexpression had a 1.66-fold increased risk of experiencing disease recurrence (95 % CI 1.24-2.24, p = 0.001), 1.55-fold increased risk of death (95 % CI 1.21-1.99, p = 0.001) and 1.81-fold increased risk of cancer-specific death (95 % CI 1.33-2.48, p < 0.001). On multivariable analysis that adjusted for the effects of standard clinicopathologic variables, HER2 overexpression remained associated with disease recurrence (p = 0.04), overall (p = 0.02) and cancer-specific mortality (p = 0.02). CONCLUSIONS: Approximately, one-third of UTUC patients overexpressed HER2. HER2 overexpression was associated with features of clinically and biologically aggressive disease as well as prognosis. HER2 may represent a good marker for therapeutic risk stratification and potentially a target for therapy in some UTUC tumors.