Solène-Florence Kammerer-Jacquet

Cytoplasmic PAR-3 protein expression is associated with adverse prognostic factors in clear cell renal cell carcinoma and independently impacts survival.

Clear cell renal cell carcinomas (ccRCCs) represent 70% of renal cancers, and several clinical and histolopathological factors are implicated in their prognosis. We recently demonstrated that the overexpression of PAR-3 protein encoded by the PARD3 gene could be implicated in renal oncogenesis. The object of this work was to study the association of intratumoral PAR-3 expression with known prognostic parameters and clinical outcome. In this aim, PAR-3 expression was assessed by immunohistochemistry in ccRCC tumors of 101 patients from 2003 to 2005. The immunostaining of PAR-3 was scored either as membranous (mPAR-3) or as both membranous and cytoplasmic (cPAR-3). Cytoplasmic PAR-3 was significantly associated with worse histopathological and clinical prognostic factors: Fuhrman grades 3 and 4, tumor necrosis, sarcomatoid component, adrenal invasion, renal and hilar fat invasion, eosinophilic component, a noninactivated VHL gene, higher tumor grade, lymph node involvement, metastasis, and worse clinical Eastern Cooperative Oncology Group and S classification scores. After multivariate analysis, 2 parameters were independently associated with cPAR-3: necrosis and eosinophilic components. In addition, cPAR-3 patients had shorter overall and progression-free survivals independently from strong prognostic validated factors like metastases. A cytoplasmic expression of PAR-3 is therefore implicated in worse clinical and pathological cancer features in ccRCC and could be useful to identify patients with high-risk tumors.

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.

Differential diagnosis of atypical lipomatous tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma: utility of p16 in combination with MDM2 and CDK4 immunohistochemistry

The differential diagnosis between atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDLPS) and dedifferentiated liposarcoma (DDLPS) from their morphologic counterparts is challenging. Currently, the diagnosis is guided by MDM2 and CDK4 immunohistochemistry (IHC) and is confirmed by the amplification of the corresponding genes. Recently, p16 IHC has been proposed as a useful diagnostic biomarker. The objective was to assess the utility of p16 IHC in the differential diagnosis of ALT/WDLPS and DDLPS. Our series included 101 tumors that were previously analyzed using fluorescence in situ hybridization for MDM2 and CDK4 amplification. We compared sensitivity and specificity of p16 IHC to MDM2 and CDK4 IHC in the differential diagnosis of ALT-WDLPS (n=19) versus benign adipocytic tumors (n=44) and DDLPS (n=18) versus mimicking sarcomas (n=20). In the differential diagnosis of ALT-WDLPS, p16 had a sensitivity of 89.5% but a specificity of 68.2%, which was impaired by false-positive lipomas with secondary changes, especially in biopsies. Likewise, in the differential diagnosis of DDLPS, p16 had a sensitivity of 94.4% and a specificity of 70%, which hampered its use as a single marker. However, adding p16 to MDM2 and/or CDK4 increased diagnostic specificity. Indeed, MDM2+/p16+ tumors were all ALT-WDLPS, and MDM2-/p16- tumors were all benign adipocytic tumors. Moreover, all MDM2+/CDK4+/p16+ tumors were DDLPS, and the MDM2-/CDK4-/p16- tumor was an undifferentiated sarcoma. Although the use of p16 as a single immunohistochemical marker is limited by its specificity, its combination with MDM2 and CDK4 IHC may help discriminate ALT-WDLPS/DDLPS.

Role of routine computed tomography scan in the oncological follow up of patients treated by radical cystectomy for bladder cancer

To assess the impact of a prolonged follow‐up schedule using computed tomography scan on oncological outcomes after radical cystectomy for bladder cancer.

Wild-type VHL Clear Cell Renal Cell Carcinomas Are a Distinct Clinical and Histologic Entity: A 10-Year Follow-up

BACKGROUND Clear cell renal cell carcinoma (ccRCC) is an aggressive tumor with 50% risk of metastases at initial diagnosis or at follow-up. An inactivation of the tumor-suppressor gene von Hippel-Lindau (VHL) is present in >70% of sporadic cases by two of three different mechanisms: locus deletion, gene mutation, or promoter hypermethylation. OBJECTIVE To correlate the complete status of the VHL gene with clinical and pathologic criteria. DESIGN, SETTING, AND PARTICIPANTS We retrospectively included 98 patients with ccRCC who underwent surgery between 2002 and 2005. VHL gene deletions (71 of 98; 72.4%), mutations (68 of 98; 69.4%), and promoter hypermethylations (13 of 98; 13.3%) were screened by gene copy analysis, gene sequencing, and methylation-specific multiplex ligation-dependent probe amplification, respectively. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Relationships between VHL subgroups and the studied criteria were analyzed using chi-square and Student t tests. Survival was analyzed with the log-rank test and Kaplan-Meier curves. RESULTS AND LIMITATIONS Compared with ccRCCs with two events (66.3%), tumors with no or one genetic event (33.6%) were associated with a higher nuclear grade IV (p=0.02), metastases (p=0.04), sarcomatoid component (p=0.01), dense lymphocyte infiltrate (p=0.013), and vascular endothelial growth factor overexpression (>30%) (p=0.003), which was also an independent factor after multivariate analysis. Furthermore, wild-type VHL tumors (no inactivating event, 11.2%) were associated with nodal involvement (p=0.019), and patients with this type of tumor had a specific survival of 33 mo compared with patients with ccRCCs having one or two VHL inactivating events (107 mo; p=0.016). The retrospective design with small number of wild-type tumors was a limitation of this work. CONCLUSIONS This long-term study (10-yr clinical follow-up) confirms that ccRCCs with wild-type VHL are highly aggressive tumors that need to be formally identified. PATIENT SUMMARY Among activated VHL tumors, the wild-type subgroup defines an aggressive phenotype with worse survival rates, suggesting that these tumors must be more thoroughly screened.

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

To evaluate the impact of fellows’ involvement on the peri‐operative outcomes of robot‐assisted partial nephrectomy (RAPN).

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

BackgroundClear 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.ObjectiveTo understand better the role of c-MET in ccRCC, we assessed its status in a population of patients with metastatic ccRCC.Patients and MethodsFor 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.ResultsOf 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.ConclusionThis 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.

Genomics in upper tract urothelial carcinoma.

Purpose of review Upper tract urothelial carcinoma (UTUC) is a relatively rare and poorly investigated disease. The objective of this review was to discuss recent advances in genomics and their implication regarding prognosis and treatment. Recent findings UTUC were compared with urothelial carcinoma of the bladder (UCB) at genomic and transcriptomic levels. Molecular studies focused on identifying new prognostic biomarkers that were often initially described in UCB and extrapolated to UTUC. Some of them could be interesting to improve the management of UTUC. Summary Recent studies improved our understanding of UTUC as a distinct entity compared with UCB. Although UTUC shares many of the same genomic alterations with UCB, some key differences have been identified as oncogenic drivers of these cancers. This better comprehension of genomics could lead to new prognostic markers that may refine UTUC treatment.

Predicting morbidity after robotic partial nephrectomy: The effect of tumor, environment, and patient-related factors

PURPOSE To investigate the effect of tumor and nontumor related parameters on perioperative outcomes of robotic partial nephrectomy (RPN). PATIENTS AND METHODS Patients who underwent RPN for a localized renal tumor at 2 institutions between June 2010 and November 2016 were reviewed. RENAL and Mayo adhesive probability (MAP) scores were calculated and information on comorbid conditions including ASA score, performance status, Charlsons comorbidity index (CCI), and history of cardiovascular disease was collected. Correlations between each variable and warm ischemia time, estimated blood loss (EBL), operative time, change in estimated glomerular filtration rate, and length of hospital stay were assessed. Logistic regression analyses were performed to identify the best predictors of overall complications, major complications, risk of conversion, and Trifecta achievement. RESULTS A total of 500 patients were included. RENAL score was found to have a statistically significant (P<0.05) correlation with warm ischemia time, EBL, and change in estimated glomerular filtration rate. MAP score showed significant association (P<0.05) with operative time and EBL. CCI had a significant correlation (P<0.05) with length of hospital stay and postoperative complications. In multivariable analyses, MAP score as a continuous variable (OR = 7.66; P<0.001) and MAP risk group stratification (OR = 3.29; P = 0.005) were independent predictors of the risk of conversion. Major complications were significantly associated with the cardiovascular disease in both univariable (OR = 2.35; P = 0.01) and multivariable analysis (OR = 4.52, P = 0.01). Finally, the MAP score as a continuous variable was an independent factor of Trifecta achievement (OR = 0.56; P = 0.04). CONCLUSION Patients related factors were the most important determinants of postoperative complications after RPN. RENAL and MAP scores had some influence on intraoperative parameters.

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

To assess the reliability of urinary cytology and cystoscopy to screen and diagnose bladder cancer in patients with NB.