Detection of tetraploidization in chromophobe renal cell carcinoma: Insights and pitfalls.

Chromosomal losses resulting in a marked hypodiploidy are a specificity of chromophobe renal cell carcinoma (ChRCC), the third most frequent type of kidney cancer. Its detection is useful in challenging cases. However some ChRCC, especially the eosinophilic variant, do not exhibit hypodiploidy and deserve to be better explored. Using comparative genomic hybridization (array-CGH) we observed chromosomal gains in five cases of nonmetastatic ChRCC. Our objective was to determine whether these apparent chromosomal gains were instead losses within a near-polyploid genome. We performed a retrospective and prospective molecular study of 26 cases of ChRCC retrieved among 643 renal tumors (2012-2019). All tumors were analyzed using array-CGH (Agilent) and array-CGH (Affymetrix) coupled to single nucleotide polymorphism analysis (array-SNP). In silico manual centralization of the fluorescence ratio, fluorescence in situ hybridization (FISH) and next generation sequencing were made in the five cases suspected of polyploidy. Tetraploidization was observed in 19% of our series of ChRCC. None of the methods used individually could identify both chromosomal losses and tetraploidy. Only the combination of manual recentring of array-CGH and FISH provided relevant results. B-allele frequency results indicated that tetraploidization occurred secondarily to chromosomal losses in four cases while it preceded losses in one case. Tetraploidization is a frequent but underestimated phenomenon in ChRCC that may be overlooked using the individual standard genomic methods. Its potential clinical consequences are not identified yet. Whether the mechanisms that induce chromosomal losses in ChRCC are the same that generate tetraploidization is not known.

The combination of bevacizumab/Avastin and erlotinib/Tarceva is relevant for the treatment of metastatic renal cell carcinoma: the role of a synonymous mutation of the EGFR receptor.

Metastatic clear cell renal cell carcinomas (mRCC) over-express the vascular endothelial growth factor (VEGF). Hence, the anti-VEGF antibody bevacizumab/Avastin (BVZ) combined with interferon alpha (IFN) was approved for the treatment of mRCC. However, approval was lost in July 2016 due to the absence of sustained efficacy. We previously showed that BVZ accelerates tumor growth in experimental models of mRCC in mice, results in part explained by down-regulation of the phospho tyrosine phosphatase receptor kappa (PTPRκ) in tumor cells. The epidermal growth factor receptor (EGFR) is a direct target of PTPRκ. Its down-regulation leads to constitutive activation of EGFR, an observation which prompted us to test the effect of the EGFR inhibitor erlotinib/Tarceva (ERLO) in addition to BVZ/IFN. The influence of the long non-coding RNA, EGFR-AS1, on ERLO efficacy was also addressed. Methods: The effect of BVZ/IFN/ERLO was tested on the growth of experimental tumors in nude mice. The presence of germline mutation in the EGFR was evaluated on cell lines and primary RCC cells. In vitro translation and transfections of expression vectors coding the wild-type or the EGFR mutated gene in HEK-293 cells were used to test the role of EGFR mutation of the ERLO efficacy. Correlation between EGFR/EGFR-AS1 expression and survival was analyzed with an online available data base (TCGA). Results: Tumor growth was strongly reduced by the triple combination BVZ/IFN/ERLO and linked to reduced levels of pro-angiogenic/pro-inflammatory cytokines of the ELR+CXCL family and to subsequent inhibition of vascularization, a decreased number of lymphatic vessels and polarization of macrophages towards the M1 phenotype. Cells isolated from surgical resection of human tumors presented a range of sensitivity to ERLO depending on the presence of a newly detected mutation in the EGFR and to the presence of EGFR-AS1. Conclusions: Our results point-out that the BVZ/IFN/ERLO combination deserves testing for the treatment of mRCC that have a specific mutation in the EGFR.

Age-related schwannomatosis with potential exosome-mediated contribution to prostate hyperplasia: a case report and mini-review.

A 72-year-old Caucasian man incurring a prostate hypertrophy presented with a right forearm nodule, the growth of which appeared to parallel the rise in his blood prostate-specific antigen (PSA) level. Echographic examination was consistent with a median-nerve schwannoma, and was confirmed upon magnetic resonance imaging (MRI). Excision of the nodule was readily performed without significant neural damage, and its schwannoma nature was confirmed upon immunohistochemistry analysis. Importantly, blood PSA dropped abruptly from ≈13 to ≈5 ng/ml within 2 months postschwannoma resection, a swift drastic reduction unachievable with oral dutasteride alone. However, 6 weeks later, a new nodule became apparent on the back of the left knee and was identified as a second schwannoma, thereby suggesting that its growth could have been stimulated by the resection of the first schwannoma, as previously described for vestibular schwannomas. The second schwannoma was in fact two: the bigger one was in the common fibular nerve and the smaller one in the tibial nerve. Both echography and MRI results were confirmed upon surgical resection of the bigger knee schwannoma. Although the third schwannoma has not yet been resected and formally characterized, we face a schwannomatosis case with an unexpected potential exosome-mediated stimulating effect on PSA secretion (PSA immunohistochemistry was negative on both schwannomas). On the other hand, preliminary genomic analysis showed a deficient balance for chromosome 22, the very chromosome carrying the three main genes involved in schwannomatosis. This age-related schwannomatosis case is thus discussed in light of the following: age-related DNA repair deficiency culminating in loss of chromosome/heterozygosity; CpG methylation/demethylation-based epigenetic aging; age-related functional decline of the immune system responsible for inefficient elimination of abnormal cells and subsequent tumorigenic cell turn-over; exosome-mediated pathologic intercellular communications; and prostate-invading brain neural progenitors as pathologic peripheral nervous system (PNS) cells.

Safety of dual kidney transplantation compared to single kidney transplantation from expanded criteria donors: a single center cohort study of 39 recipients.

Our objective was to compare the outcomes of dual kidney transplanataion (DKT) to single kidney transplantation (SKT) performed with grafts from expanded criteria donors (ECD) in recipients ≥65 years, focusing on surgical complications. All kidney transplantations (KT) performed between 2006 and 2014 in our institution were analysed. DKT was indicated according to the criteria of the French national Agence de la Biomedecine. Thirty-nine DKT and 155 SKT were included, with a median follow-up of 36 and 26.5 months, respectively. The rate of early surgical revisions was not significantly higher after DKT (23.1% vs 15.5% (P = 0.2593)) but more venous graft thromboses (12.8% vs 3.2% (P = 0.02)) were reported. The glomerular filtration rate (GFR) 24 months after KT was significantly higher after DKT (45.0 ± 16.3 vs 39.8 ± 13.8 ml/min/1.73m2 ; P = 0.04) and allowed shorter waiting time without a significant increased risk of surgical revision, excepted for venous graft thrombosis, more frequent after DKT. Graft survivals were not significantly different and GFR was higher after DKT. DKT seems to remain an appropriate strategy to address the growing graft shortage in elderly patients.

Clinicopathological characteristics of urothelial bladder cancer in patients less than 40 years old.

Urothelial bladder cancer (UBC) is rare in young patients and as a result little information as to tumor type and clinical course are available. We present clinicopathological data of a large series of patients less than 40 years with bladder carcinoma. We included in this retrospective study covering the period from 1992 to 2013 patients less than 40 years with a first diagnosis of bladder cancer. Lesions were classified according to the WHO 2004 classification by uropathologists of ten centers. Stage, grade, multifocality, smoking habits, recurrence, and survival were studied. The cohort comprised of 152 patients, 113 males and 39 females with a mean age of 33.2 years. The large majority of the patients (142) was diagnosed with an urothelial carcinoma, the ten others with various histopathological diagnoses. In the age group less than 30 years old, 40.3 % of the cases concerned a papillary urothelial neoplasia of low malignant potential (PUNLMP). In the age group over 30 years, the proportion of PUNLMP decreased to 27.2 %. Only 5.6 % of the UBC was associated with carcinoma in situ. In 14.1 %, a high grade muscle invasive UC was found; 7.0 % had lymph node and 4.9 % distant metastasis at time of presentation. Four patients presented with a history of schistosomiasis; all had an infiltrating carcinoma. After initial resection, 36 patients relapsed, 17 % as PUNLMP, 53 % as pTa low grade, and 30 % as pTa-pT2 high grade UC. During follow-up, 6 % of the patients died. PUNLMP is the most frequent entity in this patient group. It is important that the PUNLMP entity is maintained in future classification systems.

Prostate cancer incidence on cystoprostatectomy specimens is directly linked to age: results from a multicentre study.

OBJECTIVE: To assess the incidence and age-related histopathological characteristics of incidentally diagnosed prostate cancer from specimens obtained via radical cystoprostatectomy (RCP) for muscle-invasive bladder cancer. PATIENTS AND METHODS: A retrospective review of the histopathological features of 2424 male patients who underwent a RCP for bladder cancer was done at eight centres between January 1996 and June 2012. No patient had preoperative suspicion of prostate cancer. Statistical analyses were performed in different age-related groups. RESULTS: Overall, prostate cancer was diagnosed in 518 men (21.4%). Incidences varied significantly according to age (5.2% in those aged <50 years to 30.5% in those aged >75 years, P < 0.001). Most of the prostate cancers were considered as 'non-aggressive', that is to say organ-confined (≤pT2) and well-differentiated (Gleason score <7). Tumour-Node-Metastasis (TNM) stage and proportion with a Gleason score of ≥7 were significantly greater in older patients (P < 0.001). Apart from age, there were no preoperative predictive factors for 'non-aggressive' prostate-cancer status. At the end of the follow-up, only nine patients (1.7%) had biochemical recurrence of prostate cancer, and no preoperative predictive factors were identified. CONCLUSION: The rate of incidentally diagnosed prostate cancer from RCP specimens is ≈20%, most of them being organ-confined and well-differentiated. The probability of having a 'non-aggressive' prostate cancer decreases in older men.

Clinicopathological characteristics of incidental prostate cancer discovered from radical cystoprostatectomy specimen: a multicenter French study.

PURPOSE: The present study assessed the incidence and histopathological features of incidentally diagnosed prostate cancer (PCa) in specimens from radical cystoprostatectomy (RCP) for bladder cancer. The patient outcomes also were evaluated. METHODS: We retrospectively reviewed the histopathological features and survival data of 4,299 male patients who underwent a RCP for bladder cancer at 25 French centers between January 1996 and June 2012. No patients had preoperative clinical or biological suspicion of PCa. RESULTS: Among the 4,299 RCP specimens, PCa was diagnosed in 931 patients (21.7%). Most tumors (90.1%) were organ-confined (pT2), whereas 9.9% of them were diagnosed at a locally advanced stage (≥pT3). Gleason score was <6 in 129 cases (13.9%), 6 in 575 cases (61.7%), 7 (3 + 4) in 149 cases (16.0%), 7 (4 + 3) in 38 cases (4.1%), and >7 in 40 cases (4.3%). After a median follow-up of 25.5 months (interquartile range 14.2-47.4), 35.4% of patients had bladder cancer recurrence and 23.8% died of bladder cancer. Only 16 patients (1.9%) experienced PCa biochemical recurrence during follow-up, and no preoperative predictive factor was identified. No patients died from PCa. CONCLUSIONS: The rate of incidentally diagnosed PCa in RCP specimens was 21.7%. The majority of these PCas were organ-confined. PCa recurrence occurred in only 1.9% of cases during follow-up.

Laparoscopic seminal vesicle and pelvic lymph node resection before high-dose three-dimensional conformal radiation therapy for localized prostate cancer. Results of a dosimetric study.

PURPOSE: To analyze the dosimetric implications of seminal vesicle (SV) resection at the time of laparoscopic pelvic lymph node (PLN) dissection in patients presenting with high-risk prostate cancer regarding PLN and SV involvement. PATIENTS AND METHODS: Between June and September 2005, twelve patients underwent laparoscopic SV resection and PLN dissection before delivering a total dose of 80 Gy through a three-dimensional conformal radiation therapy (3D-CRT). Dose-volume histograms (DVHs; rectum, bladder, femoral heads) were obtained from G1 (group 1 with SV) and G2 (group 2 without SV) according to either three- dimensional or intensity-modulated treatment planning. All DVH medians were compared using the nonparametric sign test. RESULTS: SV resection during laparoscopic PLN dissection was performed in all twelve patients without major complications. DVH obtained with three-dimensional and intensity-modulated treatment planning showed that the median doses of RV(25%) (25% of rectal volume), RV(50%), RFHV(5%) (5% of right femoral head volume) and LFHV(5%) (5% of left femoral head volume) in G1 were significantly higher compared to those obtained in G2. CONCLUSION: For patients presenting with high-risk prostate cancer, SV resection performed at the time of laparoscopic PLN dissection allows to significantly decrease the dose delivered to the rectum, using either three-dimensional or intensity-modulated treatment planning, and to reduce the risk of acute and late rectal toxicity.