Mokrane Yacoub

Expression of estrogen related proteins in hormone refractory prostate cancer: association with tumor progression.

PURPOSE Despite increasing evidence that estrogen signaling has a key role in prostate cancer development and progression, few studies have focused on the estrogen pathway in the transition from hormone sensitive to hormone refractory tumors. We investigated the expression of proteins related to androgen and estrogen metabolism in paired prostate cancer samples collected before androgen deprivation therapy and after hormonal relapse. MATERIALS AND METHODS The study included 55 patients treated for prostate cancer only with androgen deprivation therapy and in whom tissue was available before treatment induction and after recurrence. Immunohistochemistry was performed using tissue microarray with antibodies directed against androgen receptor, phosphorylated androgen receptor, estrogen receptor α, estrogen receptor β, 5α-reductase 1 and 2, aromatase, BCAR1 and the proliferation marker Ki67. RESULTS Compared to hormone sensitive samples, tissues collected after hormonal relapse were characterized by increased expression of Ki67, androgen receptor, phosphorylated androgen receptor (p <0.001) and BCAR (p = 0.03), and by lower staining for 5α-reductase 2 (p = 0.002), estrogen receptor β (p = 0.016) and aromatase (p <0.001). Shorter time to hormonal relapse was associated with high expression of aromatase and BCAR1 on diagnostic biopsy, together with low staining for estrogen receptor α in stromal cells. Overall survival was significantly shorter when tissues collected after relapse showed a high proliferation index and low estrogen receptor α expression. CONCLUSIONS Results revealed dysregulation of proteins involved in androgen pathways, and in estrogen synthesis and signaling during the development of hormone refractory prostate cancer.

Multiparametric magnetic resonance imaging for the differentiation of low and high grade clear cell renal carcinoma

AbstractPurposeTo retrospectively evaluate the ability of magnetic resonance (MR) imaging to differentiate low from high Fuhrman grade renal cell carcinoma (RCC).Materials and methodsMR images from 80 consecutive pathologically proven RCC (57 clear cell, 16 papillary and 7 chromophobe) were evaluated. Double-echo chemical shift, dynamic contrast-enhanced T1- and T2-weighted images and apparent diffusion coefficient (ADC) maps were reviewed independently. Signal intensity index (SII), tumour-to-spleen SI ratio (TSR), ADC ratio, wash-in (WiI) and wash-out indices (WoI) between different phases were calculated and compared to pathological grade and size. The Fuhrman scoring system was used. Low grade (score ≤2) and high grade (score ≥3) tumours were compared using univariate and multivariate analyses.ResultsNo associations between grade and imaging factors were found for papillary and chromophobe RCCs. For clear cell RCCs, there was a significant association between the grade and parenchymal WiI (WiI2) (P = 0.02) or ADCr (P = 0.03). A significant association between tumour grade and size (P = 0.01), WiI2 (P = 0.02) and ADCr (P = 0.05) remained in multivariate analysis.ConclusionsMultiparametric MRI can be used to accurately differentiate low Fuhrman grade clear cell RCC from high grade. High Fuhrman grade (≥3) RCCs were larger, had lower parenchymal wash-in indices and lower ADC ratios than low grade.Key Points• Fuhrman grade of clear cell RCC can be differentiated with multiparametric MR imaging. • Fuhrman grade significantly differed for size, parenchymal wash-in index and ADC ratio. • No significant associations were found for papillary and chromophobe renal cell carcinoma.

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.

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

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.

Differential expression of the semaphorin 3A pathway in prostatic cancer

Aims:  To analyse the expression pattern of the semaphorin 3A (Sema3A) pathway, including the receptor neuropilin 1 (NRP1) and its ligands the ‘antitumoral’ Sema3A and the ‘protumoral’ vascular endothelial growth factor (VEGF)in prostatic cancer.

Differential Expression of Genes Related to Androgen and Estrogen Metabolism in Hereditary versus Sporadic Prostate Cancer

The hereditary predisposition to prostate cancer is rare and accounts for <5% of cases. Except for younger age at diagnosis, no phenotypic features have been clearly associated with hereditary prostate cancer. The aim of the study was to analyze the expression of genes related to androgen and estrogen metabolism in both hereditary and sporadic prostate cancers in patients matched for clinicopathologic features. Tissues were obtained from patients included in a national familial prostate cancer registry. From the 120 cases of hereditary forms suggesting autosomal dominant Mendelian inheritance, 21 patients were treated by radical prostatectomy for whom formalin-fixed tissue was available. Twenty-one sporadic cases were then matched according to age, Gleason score, and pathologic stage. Immunohistochemistry was done on tissue microarray using antibodies directed against androgen receptor (AR), estrogen receptor α (ERA), estrogen receptor β, 5α-reductase I and II, aromatase, and the proliferation marker Ki67. The percentage of AR-positive cancer cells was higher in hereditary cancer compared with sporadic cases (P < 0.004). In contrast, the mean number of ERA-positive stromal cells was lower in hereditary versus sporadic cancer (P < 0.03). This differential expression of AR and ERA suggests that a specific pattern of hormone receptors is associated with hereditary predisposition to prostate cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1505–9)

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 patients 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.

Epithelial Phenotypes in the Developing Human Prostate

An intermediate population has been identified among prostate glands called transiently amplifying (TA) cells, which are characterized by coexpression of basal and luminal cytokeratins (CKs), high proliferation, and lack of p27 expression. These cells are rare in the normal adult prostate and increase in pretumoral conditions, but their importance in the developing gland remains unknown. We analyzed fetal prostates for the expression of CKs (5/6, 18, 19) and factors involved in proliferation and apoptosis: p63, Ki67, p27, epidermal growth factor (EGFR), Bcl2, androgen receptor (AR). Immunostaining was performed on a tissue microarray, including 40 prostates from fetuses aged 13-42 weeks and normal prostate tissue from 10 adults. In both solid buds and the basal compartment of canalized glands, cells expressed p63, CK5/6, CK19, CK18, BCL2, EGFR and were p27 negative. Luminal cells of fetal canalized glands continue to express CK19, EGFR, and BCL2, without p27 expression. In contrast, adult epithelial luminal cells showed diffuse AR and p27 expression, without CK19, BCL2, and EGFR staining. Proliferation was high and diffuse in fetal glands and rare and restricted to basal cells in adult glands. These results indicate that most fetal epithelial prostatic cells exhibit the phenotype of TA cells, suggesting their regulatory function in prostate development.

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.