Françoise Gobet

Prognostic Interest in Discriminating Muscularis Mucosa Invasion (T1a vs T1b) in Nonmuscle Invasive Bladder Carcinoma: French National Multicenter Study with Central Pathology Review

PURPOSE Predictive factors of T1 nonmuscle invasive bladder cancer evolution that could guide treatment decision making are lacking. We assessed the prognostic value of muscularis mucosa invasion in nonmuscle invasive bladder cancer. MATERIALS AND METHODS In a national multicenter study patients with primary T1 nonmuscle invasive bladder cancer were recruited from 6 French hospitals. All patients had undergone transurethral resection of bladder tumor. All T1 tumors were substaged according to muscularis mucosa invasion as T1a-no invasion beyond the muscularis mucosa or T1b-invasion beyond the muscularis mucosa with muscle preservation. Subsequent central pathology review was then done by a single referent uropathologist. Muscularis mucosa invasion was tested as a prognostic factor for survival on univariate and multivariate analysis. RESULTS A total of 587 patients were enrolled in the study, including 388 (66%) with T1a and 199 (34%) with T1b tumors. Median followup after transurethral resection of bladder tumor was 35 months (IQR 14-54). There was no significant difference between groups T1a and T1b except high tumor grade in T1b cases (p <0.0001). After central review, initial pathological substaging was confirmed in 84% of cases. On multivariate analysis muscularis mucosa invasion (T1b substage) was significantly associated with recurrence-free (p = 0.03), progression-free (p = 0.0002) and cancer specific (p = 0.02) survival. The main study limitation was absent systematic subsequent transurethral resection of bladder tumor. CONCLUSIONS Muscularis mucosa invasion appears to be highly predictive of T1 nonmuscle invasive bladder cancer behavior. Consequently, systematic T1a vs T1b discrimination should be highly advocated by urologists and pathologists. We believe that it could aid in crucial decision making when choosing between conservative management and radical cystectomy remains a moot point.

The orexin type 1 receptor is overexpressed in advanced prostate cancer with a neuroendocrine differentiation, and mediates apoptosis

AIM In the present study, we have examined the presence of orexins and their receptors in prostate cancer (CaP) and investigated their effects on the apoptosis of prostate cancer cells. METHODS We have localised the orexin type 1 and 2 receptors (OX1R and OX2R) and orexin A (OxA) in CaP sections of various grades and we have quantified tumour cells containing OX1R. Expression of OX1R was evaluated in the androgeno-dependent (AD) LNCaP and the androgeno-independent (AI) DU145 prostate cancer cells submitted or not to a neuroendocrine differentiation. The effects of orexins on the apoptosis and viability of DU145 cells were also investigated. RESULTS OX1R is strongly expressed in carcinomatous foci exhibiting a neuroendocrine differentiation, and the number of OX1R-stained cancer cells increases with the grade of the CaP. In contrast, OX2R is only detected in scattered malignant cells in high grade CaP. OX1R is expressed in the AI DU145 cells but is undetectable in the LNCaP cells. Acquisition of a neuroendocrine phenotype by the DU145 cells is associated with an overexpression of OX1R. Orexins induce the apoptosis of DU145 cells submitted to a neuroendocrine differentiation. CONCLUSION The present data indicate that OX1R-driven apoptosis is overexpressed in AI CaP exhibiting a neuroendocrine differentiation opening a gate for novel therapies for these aggressive cancers which are incurable until now.

Mast Cell Hyperplasia Is Associated With Aldosterone Hypersecretion in a Subset of Aldosterone-Producing Adenomas

CONTEXT Adrenal mast cells can stimulate aldosterone secretion through the local release of serotonin (5-HT) and activation of the 5-HT4 receptor (5-HT4). In aldosterone-producing adenomas (APAs), 5-HT4 receptor is overexpressed and the administration of 5-HT4 receptor agonists to patients with APA increases plasma aldosterone levels. These data and the well-documented role of mast cells in tumorigenesis suggest that mast cells may be involved in the pathophysiology of APA. OBJECTIVE The study aimed at investigating the occurrence of mast cells in a series of APA tissues and to examine the influence of mast cells on aldosterone secretion. DESIGN The occurrence of mast cells in APAs was investigated by immunohistochemistry. Mast cell densities were compared with clinical data. The influence of mast cells on aldosterone production was studied by using cultures of human mast cell and adrenocortical cell lines. RESULTS In APA tissues, the density of mast cells was found to be increased in comparison with normal adrenals. Mast cells were primarily observed in adrenal cortex adjacent to adenomas or in the adenomas themselves, distinguishing two groups of APAs. A subset of adenomas was found to contain a high density of intratumoral mast cells, which was correlated with aldosterone synthase expression and in vivo aldosterone secretory parameters. Administration of conditioned medium from cultures of human mast cell lines to human adrenocortical cells induced a significant increase in aldosterone synthase (CYP11B2) mRNA expression and aldosterone production. CONCLUSION APA tissues commonly contain numerous mast cells that may influence aldosterone secretion through the local release of regulatory factors.

The neuropeptide 26RFa is expressed in human prostate cancer and stimulates the neuroendocrine differentiation and the migration of androgeno-independent prostate cancer cells.

AIM Accumulating data suggest that neuropeptides produced by neuroendocrine cells play a crucial role in the progression and aggressiveness of hormone refractory prostate cancer (CaP). In this study, we have investigated the presence and function of the neuropeptide 26RFa in CaP. METHODS We have localised and quantified tumour cells containing 26RFa and its receptor, GPR103, in CaP sections of various grades. In vitro experiments were performed to investigate the effects of 26RFa on the migration, proliferation and neuroendocrine differentiation of the androgeno-independent (AI) prostate cancer cell line DU145. RESULTS 26RFa and GPR103 are present in carcinomatous foci exhibiting a neuroendocrine differentiation, and the number of 26RFa and GPR103-immunoreactive cancer cells increases with the grade of CaP. 26RFa stimulated the migration of native or transdifferentiated AI DU145 cells, but had no effect on their proliferation. Furthermore, 26RFa induced the neuroendocrine differentiation of DU145 cells as assessed by the occurrence of neurite-like extensions and the increase of the expression of the neuroendocrine marker chromogranin A. CONCLUSION The present data indicate that 26RFa may participate to the development of CaP at the AI state by promoting the neuroendocrine differentiation and the migration of cancer cells via autocrine/paracrine mechanisms.

Early-onset low-grade papillary carcinoma of the bladder associated with Apert syndrome and a germline FGFR2 mutation (Pro253Arg)†

Andréas Andreou, Aude Lamy, Valérie Layet, Daniel Cailliez, Françoise Gobet, Christian Pfister, Michel Menard, and Thierry Frebourg* Department of Urology, Rouen University Hospital, Rouen, France Department of Pediatric Surgery, Le Havre Hospital, Le Havre, France Department of Pathology, Rouen University Hospital, Rouen, France Department of Genetics, Le Havre Hospital, Le Havre, France Department of Pathology, Le Havre Hospital, Le Havre, France Department of Genetics, Rouen University Hospital and Inserm U614, Faculty of Medicine, Rouen, France

Concomitant unilateral and synchronous bilateral testis cancer in azoospermic dizygotic twins: differential management of fertility preservation.

OBJECTIVE To optimize fertility preservation management in unilateral or bilateral testicular cancer. DESIGN Case series. SETTING Urology department and reproductive biology laboratory. PATIENT(S) Dizygotic azoospermic twins presenting unilateral and bilateral synchronous testicular tumors. INTERVENTION(S) Testicular sperm extraction (TESE) and orchiectomy. MAIN OUTCOME MEASURE(S) Semen analysis, histologic diagnosis. RESULT(S) No spermatozoa were cryopreserved for the first case, because fertility preservation was proposed after orchiectomy. Spermatozoa were retrieved after TESE for his brother with bilateral tumor. CONCLUSION(S) Clinicians should be aware of the need to recommend sperm banking before treatments may alter spermatogenesis. TESE may be the sole option for fertility preservation in bilateral testicular cancer.

Hypothalamic Neuropeptide 26RFa Acts as an Incretin to Regulate Glucose Homeostasis

26RFa is a hypothalamic neuropeptide that promotes food intake. 26RFa is upregulated in obese animal models, and its orexigenic activity is accentuated in rodents fed a high-fat diet, suggesting that this neuropeptide might play a role in the development and maintenance of the obese status. As obesity is frequently associated with type 2 diabetes, we investigated whether 26RFa may be involved in the regulation of glucose homeostasis. In the current study, we show a moderate positive correlation between plasma 26RFa levels and plasma insulin in patients with diabetes. Plasma 26RFa concentration also increases in response to an oral glucose tolerance test. In addition, we found that 26RFa and its receptor GPR103 are present in human pancreatic β-cells as well as in the gut. In mice, 26RFa attenuates the hyperglycemia induced by a glucose load, potentiates insulin sensitivity, and increases plasma insulin concentrations. Consistent with these data, 26RFa stimulates insulin production by MIN6 insulinoma cells. Finally, we show, using in vivo and in vitro approaches, that a glucose load induces a massive secretion of 26RFa by the small intestine. Altogether, the present data indicate that 26RFa acts as an incretin to regulate glucose homeostasis.

Testicular metastasis of prostatic cancer.

Secondary testicular tumors are rare, we report a case of a solitary testicular metastasis of prostate cancer in 58-year-old man treated using hormonal therapy associated with radiotherapy. Ultrasound is the imaging modality of choice, but metastasis might be difficult to differentiate from primary tumors. The diagnosis confirmed by histologic examination includes routine microscopic and immunohistochemical findings, and therefore systemic treatment was required.

La gangrène de la verge : une rare complication de la calciphylaxie systémique, à dépister

Gangrene of the penis is a rare and serious complication of end stage renal disease, being an expression of systemic calciphylaxis. We report the case of a 58-year-old patient with chronic renal failure and diabetes, who presented with a necrosis of the gland. MRI defined the limits of necrosis. The treatment consisted in partial amputation of the penis. Histological examination found a calciphylaxis.

Scrotal metastasis from a nonmuscle-infiltrative bladder cancer: a surprising clinical evolution.

We report the rare case of a 58-year-old man treated for a nonmuscle-invasive bladder cancer with 1 similar recurrence 3 years later. He presented another 3 years after his last recurrence with a urothelial cell scrotal metastasis. This case is of particular interest because it occurred without any diagnosis of invasive tumor or carcinoma in situ. Scrotal (particularly tunical) localization of metastases from urothelial carcinoma is rare. In 2004, a 58-year-old man developed nonmuscleinvasive bladder tumor (urothelial carcinoma Stage pTa, WHO-1973, grade 2), localized on the dome. Transure-