Initial management of testicular cancer: practice survey among urologists and pathologists.

INTRODUCTION: The objective of this study was to conduct a declarative professional practices survey among urologists of the French Association of Urology (AFU) and French pathologists concerning their management of testicular cancer. MATERIALS AND METHODS: A questionnaire was sent to all urologists, members of the AFU, and another questionnaire was sent to French pathologists, members of the International Academy of Pathology, French Division, in June 2010. A total of 289 urologists (29%) and 84 pathologists (19%) returned the questionnaires. RESULTS: Fifty-seven percent of urologists declared that they performed fewer than 5 orchidectomies per year. Pathologists declared that they examined less than 5 orchidectomy specimens per year in 24% of cases. The laboratory work-up (only alpha fetoprotein [AFP], lactate dehydrogenase [LDH], and total human chorionic gonadotropin [hCG]) and the radiological work-up (only testicular ultrasound and chest, abdomen, and pelvis computed tomography [CT] scan) were performed strictly according to guidelines in 15.9% and 65.7% of cases, respectively. A total of 31.8% of urologists declared that they performed the minimum assessment required by guidelines (AFP, LDH, total hCG, testicular ultrasound and chest, abdomen, and pelvis CT scan plus other examinations not recommended). Prognostic factors of stage I tumors, to define the indications for adjuvant therapy, were correctly declared in 7.3% of nonseminomatous germ cell tumors (vascular and/or lymphatic emboli) and in 13.8% of seminomas (tumor size >4 cm and rete testis invasion). CONCLUSION: This survey demonstrated that clinical practice did not comply with guidelines, which raises the question of the measures that can be taken to ensure better application of guidelines or how to develop expert centers for the management of these rare tumors.

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.

Abrogation of de novo lipogenesis by stearoyl-CoA desaturase 1 inhibition interferes with oncogenic signaling and blocks prostate cancer progression in mice.

Increased de novo fatty acid (FA) synthesis is one hallmark of tumor cells, including prostate cancer. We present here our most recent results showing that lipid composition in human prostate cancer is characterized by an increased ratio of monounsaturated FA to saturated FA, compared with normal prostate, and evidence the overexpression of the lipogenic enzyme stearoyl-CoA desaturase 1 (SCD1) in human prostate cancer. As a new therapeutic strategy, we show that pharmacologic inhibition of SCD1 activity impairs lipid synthesis and results in decreased proliferation of both androgen-sensitive and androgen-resistant prostate cancer cells, abrogates the growth of prostate tumor xenografts in nude mice, and confers therapeutic benefit on animal survival. We show that these changes in lipid synthesis are translated into the inhibition of the AKT pathway and that the decrease in concentration of phosphatidylinositol-3,4,5-trisphosphate might at least partially mediate this effect. Inhibition of SCD1 also promotes the activation of AMP-activated kinase and glycogen synthase kinase 3alpha/beta, the latter on being consistent with a decrease in beta-catenin activity and mRNA levels of various beta-catenin growth-promoting transcriptional targets. Furthermore, we show that SCD1 activity is required for cell transformation by Ras oncogene. Together, our data support for the first time the concept of targeting the lipogenic enzyme SCD1 as a new promising therapeutic approach to block oncogenesis and prostate cancer progression.

miR-143 interferes with ERK5 signaling, and abrogates prostate cancer progression in mice.

BACKGROUND: Micro RNAs are small, non-coding, single-stranded RNAs that negatively regulate gene expression at the post-transcriptional level. Since miR-143 was found to be down-regulated in prostate cancer cells, we wanted to analyze its expression in human prostate cancer, and test the ability of miR-43 to arrest prostate cancer cell growth in vitro and in vivo. RESULTS: Expression of miR-143 was analyzed in human prostate cancers by quantitative PCR, and by in situ hybridization. miR-143 was introduced in cancer cells in vivo by electroporation. Bioinformatics analysis and luciferase-based assays were used to determine miR-143 targets. We show in this study that miR-143 levels are inversely correlated with advanced stages of prostate cancer. Rescue of miR-143 expression in cancer cells results in the arrest of cell proliferation and the abrogation of tumor growth in mice. Furthermore, we show that the effects of miR-143 are mediated, at least in part by the inhibition of extracellular signal-regulated kinase-5 (ERK5) activity. We show here that ERK5 is a miR-143 target in prostate cancer. CONCLUSIONS: miR-143 is as a new target for prostate cancer treatment.

Docetaxel and cisplatin in patients with metastatic androgen independent prostate cancer and circulating neuroendocrine markers.

PURPOSE: A link between neuroendocrine cell differentiation and resistance to androgen deprivation has been observed in prostate cancer, suggesting the possible efficacy of specific treatments. We assessed the efficacy and toxicity of a chemotherapy regimen combining docetaxel and cisplatin in men with androgen independent prostatic adenocarcinoma and circulating neuroendocrine markers. MATERIALS AND METHODS: A total of 41 patients were treated with a combination of 75 mg/m(2) docetaxel and 75 mg/m(2) cisplatin every 3 weeks for a maximum of 6 cycles. The primary study end point was the neuroendocrine response rate, defined as a decrease in neuron specific enolase and/or chromogranin A to 50% or greater of the supranormal baseline serum value. Median followup was 40 months. RESULTS: A median of 6 cycles per patient was delivered. A neuroendocrine response was observed in 13 patients (33%). The median response duration was 4 months (range 2 to 10). The prostate specific antigen response rate was 48%. A clinical benefit was observed in 45% of patients who required analgesics at study entry. The objective response rate was 41% in 29 patients with measurable metastases. Five patients had to stop therapy due to toxicity. The main side effects were cumulative asthenia and sensitive neuropathy. Median survival was 12 months (range 1 to 38). CONCLUSIONS: Regarding the disappointing efficacy and significant toxicity observed in this study, the combination of docetaxel and cisplatin cannot be recommended in daily practice. Further studies are necessary to determine whether patients with circulating neuroendocrine markers require specific therapeutic approaches.

[Long-term morbidity of living donor kidney harvesting]. / Prélèvement rénal chez le donneur vivant: morbidité et suivi à long terme.

OBJECTIVE: To evaluate the morbidity of living donor kidney harvesting and the long-term medical consequences and impact on quality of life (QoL). MATERIAL AND METHODS: Retrospective analysis of medical and surgical data for 114 living kidney donors in a single teaching hospital between 1977 and 2005. Complications were evaluated in relation to the surgical approach and body mass index (BMI) using a Chi-square test or Fisher's exact test. Changes in renal function (serum creatinine, creatinine clearance), proteinuria and blood pressure (BP) were studied by Student's t test or a Mann-Whitney U or Wilcoxon nonparametric test. Long-term QoL was evaluated by the MOS SF-36 questionnaire and a local questionnaire and was then compared to that of the French general population. RESULTS: The median follow-up was 63 months. The morbidity of kidney harvesting was significantly correlated with the surgical approach (p = 0.018) and a BMI > or = 25 kg/m2 (p = 0.014). No mortality was observed in this series. A moderate elevation of serum creatinine was observed during follow-up (mean serum creatinine increased from 82.2 micromol/l [+/- 16.3] to 104.5 micromol/l [+/- 19.9]), and mean creatinine clearance decreased from 113.4 ml/min [+/- 27.6] to 76 ml/min [+/- 29.9]. Little impact was observed on proteinuria and BP and QoL was not altered by kidney harvesting. CONCLUSION: The perioperative complication rate is correlated with BMI and a flank incision. Kidney harvesting lowers glomerular filtration, but clearance remained stable during follow-up. Macroalbuminuria or hypertension may be observed, but their frequency is not higher than in the general population. The QoL of living donors is not altered. Clear information for the general public would allow promotion of living donor transplantation.

Liver metastases in prostate carcinoma: clinical characteristics and outcome.

OBJECTIVE: To assess the clinical characteristics and outcome of patients with liver metastases in prostate carcinoma. PATIENTS AND METHODS: From January 1995 to December 2005, 345 patients with metastatic prostate cancer were prospectively recorded in the database of the Montpellier Cancer Centre, France. The clinical characteristics and outcome of 28 patients who developed liver metastases during the course of the disease were analysed. RESULTS: Six patients had liver metastases as the first site of metastatic disease, and for one of them, liver was the only metastatic site. All but one patient had hormone-refractory disease. Serum measurement of neuroendocrine markers showed increased levels of chromogranin A and neurone-specific enolase in 84% and 44% of patients, respectively. Six patients had a pathological analysis; there were two different histological patterns in liver biopsies, i.e. four were adenocarcinomas with a moderate (one patient) or poor (three) differentiation and two were neuroendocrine carcinomas. Three patients had no treatment because of a poor performance status. One patient had hormone therapy for synchronous liver metastases at diagnosis as the first-line treatment; other patients were treated with chemotherapy. The median (range) overall survival was 6 (1-27) months; the median survival of patients for whom liver was part of the initial metastatic pattern was 14 months. CONCLUSION: Liver metastases are not very rare but appear to be a rather late event in the course of the disease. They are frequently associated with neuroendocrine characteristics.

DNA-methylation-dependent alterations of claudin-4 expression in human bladder carcinoma.

The expression pattern of tight junction (TJ) proteins is frequently disrupted in epithelial tumors. In particular, isoform- and organ-specific alterations of claudins have been detected in human cancers, highlighting them as interesting tools for the prognosis or treatment of various carcinomas. However, the molecular mechanisms responsible for these alterations are seldom identified. Here, we analyzed the expression and localization of claudins 1, 4, and 7 in human bladder carcinoma. Claudin-4 expression was significantly altered in 26/39 tumors, contrasting with the rare modifications detected in the expression of claudins 1 and 7. Overexpression of claudin-4 in differentiated carcinomas was followed by a strong downregulation in invasive/high-grade tumors, and this expression pattern was associated to the 1-year survival of bladder tumor patients. A CpG island was identified within the coding sequence of the CLDN4 gene, and treatment with a methyl-transferase inhibitor restored expression of the protein in primary cultures prepared from high-grade human bladder tumors. In addition, claudin-4 expression correlated with its gene methylation profile in healthy and tumoral bladders from 20 patients, and downregulation of claudin-4 expression was detected in the urothelium of mice overexpressing DNA methyl transferase 3a (Dnmt3a). Delocalization of claudins 1 and 4 from TJs was observed in most human bladder tumors and in the bladder tumor cell line HT-1376. Although the CLDN4 gene was unmethylated in these cells, pharmacological inhibition of methyl transferases re-addressed the two proteins to TJs, resulting in an increase of cell polarization and transepithelial resistance. These biological effects were prevented by expression of claudin-4-specific siRNAs, demonstrating the important role played by claudin-4 in maintaining a functional regulation of homeostasis in urothelial cells. Results of this study indicate that the TJ barrier is disrupted from early stages of urothelial tumorigenesis. In addition, we identified hypermethylation as the mechanism leading to the alteration of claudin-4 expression, and maybe also localization, in bladder carcinoma.

[What is the objective of second-line chemotherapy after failure of first-line chemotherapy in hormone-resistant metastatic prostate?]. / Chimiothérapie de deuxième ligne après échec d'une chimiothérapie de première ligne dans le cancer de la prostate métastatique hormono-résistant. Pour quel objectif?

UNLABELLED: Chemotherapy occupies an increasingly important place in the management of hormone-resistant metastatic prostate cancer. For the first time in this disease, docetaxel increases the survival of patients, with a modest, but definite median gain of about 2 months. In everyday practice, the indication for second-line chemotherapy after immediate or delayed failure of first-line chemotherapy is sometimes considered, although objective data concerning its efficacy are limited. The objective of the present study was to retrospectively evaluate the results obtained with second-line chemotherapy in a patient cohort managed at the Montpellier Regional Cancer Centre. PATIENTS AND METHODS: Clinical characteristics, treatments delivered and outcome of 43 patients who received two successive lines of chemotherapy were retrospectively collected by means of a standardized questionnaire. Three groups of patients were defined as a function of the chemotherapy protocols delivered: docetaxel alone or in combination, mitoxantrone and other protocols not comprising either docetaxel or mitoxantrone. Responses to chemotherapy were analysed according to three criteria: objective responses, laboratory responses and palliative responses. RESULTS: At the time of second-line chemotherapy, the median age of the patients was 69 years (range: 46 to 83). The median interval between the end of first-line chemotherapy and the start of second-line chemotherapy was 3 months (range: 1 to 15). The protocols administered comprised docetaxel alone (12 patients) or in combination with cisplatin (4 patients), mitoxantrone in 13 patients, or other cytotoxic molecules such as vinblastine, doxorubicin or etoposide in combination with a platinum salt (14 patients). The median number of cycles delivered was 4 (range: 1 to 10). No objective response was observed. Six (14%) patients obtained a laboratory response. A palliative response was observed in 16 (37%) patients, 7 of whom were treated with a docetaxel-based protocol, 6 were treated with mitoxantrone and 3 were treated by other protocols. The median duration of palliative response was 3 months (range: 1 to 6). The median survival was 8 months (range: 1 to 24), with no significant difference between the various protocols. CONCLUSION: In 2006, the objective of second-line chemotherapy in patients with hormone-resistant prostate cancer appears to be purely palliative. No reference protocol has been defined among currently available cytotoxic molecules. The indication must therefore take into account the benefit/risk balance to avoid compromising the patients quality of life. Therapeutic trials are essential to develop effective new molecules.

Subcutaneous interleukin-2 and interferon-alpha in metastatic renal cell carcinoma: results of a French regional experience in Languedoc.

OBJECTIVES: To assess the efficacy and toxicity of an immunotherapy regimen combining subcutaneous (SC) interleukin-2 (IL-2) and interferon-alpha (IFN) in patients with metastatic renal cell carcinoma (MRCC). METHODS: The present study included 86 patients with MRCC. Data on treatment toxicity and efficacy (responses rates and overall survival) were collected on a hospital database. Treatment consisted of 6-week cycles repeated every 2 months for a maximum of 3 cycles. Each cycle included SC IL-2 20 x 10 MIU/m2 3 times/wk on weeks 1 and 4; 5 x 10 MIU/m2 3 times/wk on weeks 2, 3, 5, and 6, in combination with IFN 6 x 10 MIU/m2 once weekly on weeks 1 and 4; and 3 times/wk on weeks 2, 3, 5, and 6. RESULTS: Seventy (82%) and 71 (83%) patients received more than 80% of the planned doses of IL-2 and IFN during the first cycle, respectively. Ten patients had to stop therapy before the end of the first cycle because of excessive toxicity (7 patients) or rapidly progressive disease (3 patients). Only 17 (28%) proceeded to the second cycle. Main toxicities included fever and asthenia in 86 (100%) patients, nausea/emesis in 83 (96%) patients, skin disorders in 69 (80%) patients, hypotension in 56 (65%) patients, and diarrhea in 50 (58%) patients. Sixty-seven (78%) patients developed at least one episode of grade 3 toxicity. Objective responses were observed in 13 patients, including 4 complete and 9 partial responses (15%; 95% confidence interval, 9.5-20.5%). After a median follow-up of 45 months, the median time to progression was 4 months (range, 1-41) and the median survival was 14 months (range, 1-89). CONCLUSIONS: Only a small subset of patients with MRCC is likely to benefit from treatment with IL-2 and IFN. As toxicity is significant, the refinement of predictive variables for sensitivity to immunotherapy is mandatory.

Prognostic factors for first recurrence in patients with retroperitoneal sarcoma.

BACKGROUND: Retroperitoneal sarcomas are characterized by a high local recurrence rate despite optimal surgical treatment. The definition of prognostic factors for recurrence could help offer high-risk patients a closer follow-up and a multidisciplinary therapeutic approach. PATIENTS AND METHODS: A cohort of 40 patients treated for a primary retroperitoneal sarcoma was retrospectively analyzed. Median follow-up was 24 months. Patient (sex and age), tumor (maximal size, histologic type, tumor localization, and histologic grade), and treatment (complete vs. incomplete surgery) characteristics were included in univariate and multivariate prognostic factor analyses. RESULTS: After a median follow-up of 24 months (range 3-121), the overall recurrence rate was 65%. Median time between initial surgery and recurrence was 15 months (range 11.5-29.5). In univariate analysis, surgical positive margins (P = 0.011), bilateral tumors (P = 0.0034), nonliposarcoma histologic subtypes (P = 0.043), and a high histologic grade (P = 0.0072) were associated with an increased recurrence rate. All these factors except the histologic subtypes retained an independent prognostic value in the multivariate analysis. Death was strongly related to recurrence (P = 0.0033). CONCLUSION: The optimal treatment of patients with primary retroperitoneal sarcoma should be based on radical surgery, with en bloc organ resection if necessary, to minimize the risk of positive margins. In high-risk patients, close follow-up is mandatory to offer optimal subsequent surgical procedures. The impact of a multidisciplinary therapeutic approach remains to be proved.

[Solitary fibrous tumours of the kidney]. / Tumeur fibreuse solitaire du rein.

Solitary fibrous tumours (SFT) are mesenchymal tumours that usually arise from the pleura. Renal SFT are exceptional (9 cases reported in the literature). The authors report a new case discovered during assessment of HT and treated by radical right nephrectomy. The histological appearance is characteristic: a tumour with a fibrous centre, composed of a monomorphic proliferation of spindle cells, with positive CD 34, CD 99, and bcl 2 labelling. The prognosis after complete resection is generally favourable.

[Calculous renal failure and pregnancy]. / Insuffisance rénale lithiasique et grossesse.

Obstructive renal failure is a rare but serious complication of pregnancy. Although most cases are due to extrinsic compression, renal tract obstruction can also be due to intraluminal precipitation of sulfadiazine prescribed for maternofoetal toxoplasmosis. The diagnosis is suggested by clinical history, ultrasound (radiolucent stones situated anywhere in the renal tract) and especially analysis of the urine pellet (wheat sheaf formation of yellowish crystals). Urinary drainage by double J stent or percutaneous nephrotomy is indicated in the absence of clinical improvement in response to symptomatic treatment and adequate alkaline rehydration. The risk of sulfadiazine crystallization must be systematically prevented by a sufficient water intake and urinary alkalinization right from the start of treatment.