Hervé Wallerand

The epithelial-mesenchymal transition-inducing factor TWIST is an attractive target in advanced and/or metastatic bladder and prostate cancers.

PURPOSE Metastasis remains the main cause of death in both bladder (BCa) and prostate (PCa) cancers. The results of chemotherapy did not show any significant improvement of the survival the past years. Cancer research has led to the identification of signaling pathways involved and molecular targets that could change the natural history. The epithelial-mesenchymal transition (EMT), critical during embryonic development, becomes potentially destructive in many epithelial tumors progression where it is inappropriately activated. The cell-cell and cell-extracellular matrix interactions are altered to release cancer cells, which are able to migrate toward metastatic sites. Hallmarks of EMT include the down-regulation of E-cadherin expression, which is the main component of the adherens junctions. The protein TWIST is a transcriptional repressor of E-cadherin, tumor progression, and metastasis, and could be used as a molecular target to restore the chemosensitivity in BCa and PCa. MATERIALS AND METHODS We selected the last 5-year basic research literature on EMT and TWIST but also clinical studies on BCa and PCa in which TWIST is overexpressed and could be considered as an efficient prognostic marker and molecular target. RESULTS TWIST is considered as a potential oncogene promoting the proliferation and inhibiting the apoptosis. TWIST promotes the synthesis of the pro-angiogenic factor, vascular endothelial growth factor (VEGF) involved in tumor progression and metastasis. Apoptosis and angiogenesis are two essential cancer progression steps in many epithelial tumors, including BCa and PCa. CONCLUSIONS With the targeted therapy, oncology has entered into a new era, which is going to be critical in cancer treatment in combination with traditional anticancer drugs.

N-Cadherin as a Novel Prognostic Marker of Progression in Superficial Urothelial Tumors

Purpose: Loss of intercellular adhesion and increased cell motility promote tumor cell invasion and spreading. In bladder cancer, loss or reduced E-cadherin expression has been associated with poor survival, and aberrant expression of N-cadherin has been associated with the invasive phenotype of bladder carcinoma cells. The purpose of this study was to investigate whether N-cadherin expression was associated with the bladder tumor progression. Experimental Design: E-cadherin and N-cadherin expression was evaluated by immunohistochemistry in 101 tumors (pT1 and pT2-T3) and by reverse transcription-PCR analysis and immunohistochemistry in 28 other fresh frozen tumors (pTa, pT1, and pT2-T3). Results: N-cadherin expression was absent in normal urothelium, appeared in stage pT1, and increased in pT2-pT3 tumors. In most cases, increased N-cadherin expression in invasive tumors was associated with loss of E-cadherin expression. Progression-free survival and multivariate analyses revealed that N-cadherin expression is an independent prognostic marker for pT1 tumor progression. Analysis of the 28 frozen tumors by immunohistochemistry and reverse transcription-PCR showed a good correlation between protein and gene expression in pT1 and pT2-T3 tumors. Interestingly, in pTa tumors, N-cadherin was not immunodetected, whereas mRNA was present in 50% of cases. Conclusion: Regulatory defects in the N-cadherin promoter, abnormalities at the translational, or protein processing levels could explain the discrepancies between protein and mRNA expression. Most importantly, this study identified N-cadherin as a novel prognostic marker of progression in superficial urothelial tumors. Clearly, N-cadherin acts in an invasive mode in bladder cancer, but whether it has a primary role in urothelial neoplastic progression has yet to be investigated.

THE PREDICTIVE VALUE OF MUSCULARIS MUCOSAE INVASION AND p53 OVER EXPRESSION ON PROGRESSION OF STAGE T1 BLADDER CARCINOMA

PURPOSE We determine the significance of muscularis mucosae invasion and nuclear p53 over expression on the progression of stage T1 transitional cell bladder cancer. MATERIALS AND METHODS The pathological findings in 149 cases of T1 tumors diagnosed between 1973 and 1996 were reviewed. Diagnosis was stage T1 in 94 tumors in which the muscular layer was clearly identifiable and disease-free. Mean followup was 64.9 months (range 5 to 288). T1 bladder cancers were subclassified into 2 groups, with (T1b) or without (T1a) muscularis mucosae invasion. The p53 nuclear antibody immunoreactivity was determined with antibody D07 and a cutoff point at 15%. RESULTS T1 subclassification was possible in all 94 patients. Of all tumors 37.2% expressed p53 nuclear over expression. Univariate statistical analysis showed that p53 expression (p <0.05) and tumor invasion depth (p <0.001) significantly correlated with progression. However, on multivariate analysis only invasion depth (p <0.0001) and associated carcinoma in situ (p <0.03) remained independently significant as predictors of progression. CONCLUSIONS In our study the depth of tumor invasion was a significant independent predictor of progression in patients with T1 bladder cancer. This result suggests that the depth of invasion in stage T1 should be included in the histopathological report.

Interpretation of Positive Flow Cytometric Crossmatch in the Era of the Single-antigen Bead Assay

Background. Prognosis of renal transplants with positive flow cytometric crossmatch (FCXM) remains controversial. Methods. We analyzed the outcome of these kidney transplant recipients by human leukocyte antigen (HLA) donor-specific antibodies (HLA-DSA) using single-antigen bead (SAB) assays in major histocompatibility complex classes I and II. We compared them with controls with a negative FCXM. Results. Forty-five patients consecutively transplanted with a positive FCXM had significantly more acute rejection episodes than the control patients (33.3% vs. 8.9%, P=0.002). Risk of acute rejection was increased with day 0 (D0) positive T-cell FCXM (odds ratio [OR]=9.04, P=0.002), D0 positive B-cell FCXM (OR=7.43, P=0.02), and D0 HLA-DSA identified by SAB assay (OR=6.5, P=0.03). The 21 patients with D0 positive FCXM and D0 HLA-DSA had more acute rejection (62%, P=0.0001) and a lower estimated glomerular filtration rate 1-year posttransplantation (P=0.0001), when compared with controls. Mainly anti-Cw and anti-DP HLA-DSA were found in patients displaying acute rejection. The remaining FCXM-positive patients displayed short-term outcomes similar to controls. The presence of HLA-DSA detected only by the SAB assay in the context of a negative FCXM crossmatch was not associated with increased risk of acute rejection. Conclusion. Identification of HLA-DSA in D0 sera by the two sensitive techniques FCXM and SAB assay indicates which patients are at highest risk of subsequent acute allograft rejection and chronic allograft dysfunction.

Relationship between expansion of the CAG repeat in exon 1 of the androgen receptor gene and idiopathic male infertility

OBJECTIVE To determine whether expansion of CAG repeats in exon 1 of the androgen receptor is correlated with impaired spermatogenesis in patients with male idiopathic infertility. DESIGN A retrospective study. SETTING Medical school in Besançon, France. PARTICIPANT(S) Thirty-seven infertile patients with azoospermia or oligospermia and 50 fertile controls. INTERVENTION(S) History, physical, hormonal assays, semen analysis, and collection of blood samples in order to study the androgen receptors gene. MAIN OUTCOME MEASURE(S) Blood samples were collected from each infertile patient and control. The length of the CAG repeat segment was evaluated by using polymerase chain reaction (PCR) electrophoresis in exon 1 and PCR single-strand conformation polymorphism in exons 2-8. RESULT(S) The mean length of the CAG repeats was significantly different between infertile and fertile patients (23.91 +/- 0.5 vs. 22.20 +/- 0.4). No mutation was detected in exons 2-8 of the androgen receptor gene in infertile patients. CONCLUSION(S) Expansion of the CAG repeat segment of the androgen receptor is correlated with male idiopathic infertility. The number of CAG repeats may therefore have a modulatory effect on normal androgen receptor function.

Update on the Medical Treatment of Metastatic Renal Cell Carcinoma

CONTEXT Metastatic renal cell carcinoma (mRCC) has long been treated only by immunotherapy with good results only in a small population of patients. In recent years, major improvements in treatment possibilities have occurred with the advent of anti-angiogenic drugs. In the past 2 yr, pivotal phase III trials have confirmed this major breakthrough by increasing the progression-free survival rates and/or overall survival rates provided by sunitinib, sorafenib, and bevacizumab, and more recently by the mTOR (mammalian target of rapamycin) inhibitors temsirolimus and everolimus. OBJECTIVE To update the previous review on smart drugs published in the European Journal in 2006 (Patard JJ, et al. Understanding the importance of smart drugs in renal cell carcinoma. Eur Urol 2006; 49:633-43). EVIDENCE ACQUISITION Critical review of published literature 2006-2008 (Pubmed website search words: renal cell carcinoma and/or targeted therapy and prospective trials) and more recent meeting abstracts (American Society of Clinical Oncology 2007). Quality assessment included prospective phase I-III trials and critical evaluations with low numbers of patients, retrospective analyses, and slide presentations of meeting abstracts. EVIDENCE SYNTHESIS This review presents the current situation and provides more recent data on sequential treatment, the association of targeted drugs, and the treatment of non-clear-cell histologies. CONCLUSIONS Treatment of mRCC with targeted therapy centers on at least two major pathways: angiogenesis and mTOR involving inhibiting drugs that may be used alone, in combination, or sequentially.

The expression of Twist has an impact on survival in human bladder cancer and is influenced by the smoking status

OBJECTIVES Twist is considered as transcription factor that regulates epithelial mesenchymal transition (EMT) by at least inhibition of E-cadherin expression. EMT is a key event in the tumor invasion process. The purpose of this study is to investigate the expression of Twist but also those of E- and N-cadherin in human primary bladder tumor and to evaluate its prognostic value. As smoking cigarettes is a strong bladder cancer risk factor, we tried to evaluate the impact of the tobacco status on these molecular abnormalities. MATERIALS AND METHODS To delineate on the oncogenic role for Twist in human bladder cancer, we evaluated the E- and N-cadherin but also Twist expression (n = 70) by immunohistochemistry. We evaluated the prognostic value of these expressions. Moreover, we tried to correlate these protein expressions to the smoking status of the patients. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method, and multivariate analysis was performed using the Cox proportional hazard analysis. RESULTS Of the 70 bladder tumors, 28 (40%) cases were positive for Twist expression, 16 (23%) cases were negative for E-cadherin expression, and 12 (17%) were positive for N-cadherin expression. When categorized into negative vs. positive expression, Twist was associated with the stage (P = 0.001), the grade (P < 0.001), the progression (P = 0.02), and the E-cadherin expression (P = 0.01). Moreover, positive Twist expression clearly predicted poorer PFS (P = 0.02). In the multivariate analysis, both positive Twist expression and loss of E-cadherin expression were independent prognostic factors for PFS (P = 0.046 and P = 0.001, respectively) and only loss of E-cadherin expression for the OS (P < 0.001). We also demonstrated that almost 60% (16/28) of patients with Twist-positive expression were current smokers at the time of the diagnosis, corroborating the fact that smoking modulates the expression of EMT markers including Twist. CONCLUSION Positive Twist expression may be a useful prognostic marker for patients with bladder cancer. Its expression seems to be correlated to the tobacco status of the patients.

Renal Cell Carcinoma (RCC) in Patients With End-Stage Renal Disease Exhibits Many Favourable Clinical, Pathologic, and Outcome Features Compared With RCC in the General Population

BACKGROUND Patients with end-stage renal disease (ESRD) are at risk of developing renal tumours. OBJECTIVE Compare clinical, pathologic, and outcome features of renal cell carcinomas (RCCs) in ESRD patients and in patients from the general population. DESIGN, SETTING, AND PARTICIPANTS Twenty-four French university departments of urology participated in this retrospective study. INTERVENTION All patients were treated according to current European Association of Urology guidelines. MEASUREMENTS Age, sex, symptoms, tumour staging and grading, histologic subtype, and outcome were recorded in a unique database. Categoric and continuous variables were compared by using chi-square and student statistical analyses. Cancer-specific survival (CSS) was assessed by Kaplan-Meier and Cox methods. RESULTS AND LIMITATIONS The study included 1250 RCC patients: 303 with ESRD and 947 from the general population. In the ESRD patients, age at diagnosis was younger (55 ± 12 yr vs 62 ± 12 yr); mean tumour size was smaller (3.7 ± 2.6 cm vs 7.3 ± 3.8 cm); asymptomatic (87% vs 44%), low-grade (68% vs 42%), and papillary tumours were more frequent (37% vs 7%); and poor performance status (PS; 24% vs 37%) and advanced T categories (≥ 3) were more rare (10% vs 42%). Consistently, nodal invasion (3% vs 12%) and distant metastases (2% vs 15%) occurred less frequently in ESRD patients. After a median follow-up of 33 mo (range: 1-299 mo), 13 ESRD patients (4.3%), and 261 general population patients (27.6%) had died from cancer. In univariate analysis, histologic subtype, symptoms at diagnosis, poor PS, advanced TNM stage, high Fuhrman grade, large tumour size, and non-ESRD diagnosis context were adverse predictors for survival. However, only PS, TNM stage, and Fuhrman grade remained independent CSS predictors in multivariate analysis. The limitation of this study is related to the retrospective design. CONCLUSIONS RCC arising in native kidneys of ESRD patients seems to exhibit many favourable clinical, pathologic, and outcome features compared with those diagnosed in patients from the general population.

Complete Histologic Remission after Sunitinib Neoadjuvant Therapy in T3b Renal Cell Carcinoma

The authors present the first case report of complete histologic remission after neoadjuvant sunitinib treatment on primary renal tumour and vena cava thrombus. A 78-yr-old woman with an Eastern Cooperative Oncology Group (ECOG) score of 0 presented with a T3b renal tumour. She refused surgical treatment but agreed to percutaneous biopsy and medical treatment. A Fuhrman III renal cell carcinoma was histologically confirmed on percutaneous biopsy, and sunitinib treatment was administered over 6 mo. A significant objective response was observed for tumour size and thrombus. The patient finally accepted surgical treatment. Pathologic examination concluded with a complete response of primary tumour and thrombus.

Therapeutic Management of De Novo Urological Malignancy in Renal Transplant Recipients: The Experience of the French Department of Urology and Kidney Transplantation from Bordeaux

OBJECTIVES To determine and analyze the incidence, prognosis, and therapeutic strategy of de novo urological malignancies in a series of renal transplant recipients (RTRs). METHODS A retrospective study of 1350 recipients between January 1998 and January 2008 was carried out; we reviewed the data of 42 de novo urological malignancies in 39 recipients. RESULTS There were 21 cases of prostate cancer, 13 cases of renal cell carcinoma in 10 patients, 3 cases of renal graft tumors, and 5 cases of transitional cell carcinoma of the bladder. The overall incidence of urological neoplasms was 3.1%. The mean age of cancer diagnosis was 60 +/- 8.3 years. The mean duration of dialysis before cancer diagnosis was 35 +/- 37.5 months. About 92% of patients underwent hemodialysis (34/39) and the remaining underwent peritoneal dialysis (5/39). All the 39 recipients received cadaveric kidneys. The mean follow-up period for this study was 33 +/- 34.4 months (range 2-160 months). There appears to be a greater risk of urological neoplasm in RTRs. Prostate cancer and renal carcinoma can be treated in a similar manner than in general population with encouraging oncological results and low morbidity. However, the transitional cell carcinoma of the bladder remains particularly aggressive requiring optimal treatment despite the morbidity concerning the intravesical therapy. CONCLUSIONS We can apply the standard medical and surgical treatment in RTRs, with encouraging oncological results if a strict screening program is established and followed by the patients.