Characterization of Sonic Hedgehog/Gli1 Signal Expression in Human Ureter Either Un-Stented or Fitted with Double-Pigtail Stent or a Thread.

INTRODUCTION: The Sonic Hedgehog/Gli1 signal is involved in smooth muscle activity. An experiment showed that the double-pigtail stent caused ureteral inflammation and decreased Gli1 expression in smooth muscle cells. The innovative pigtail-suture stent (JFil® or MiniJFil®) with a thin 0.3F suture thread significantly decreased stent-related symptoms. Fortuitously, a dilation of the ureter containing the sutures was discovered, and a previous study confirmed that the sutures caused less ureteral inflammation than the double-pigtail stent. However, the mechanisms involved in the ureteral dilation are still unknown. In this study, we assessed ureteral Gli1 expression in the human ureter when it was un-stunted or when fitted with a double-pigtail stent or a suture thread. MATERIAL AND METHODS: After consent and inclusion of patients in the protocol, nine segments of ureters were collected during cystectomy procedures for bladder cancers. There was no selection or exclusion, and patients with large tumors were included. Gli1 expression was assessed on the histological section to control the reflection of an active hedgehog signal. The expression of Gli1 in smooth muscle cells of the stented ureter was subjectively compared to un-stented ureter. RESULTS: A decrease in the intensity of Gli1 expression of smooth muscle cells was observed in all cases of ureter fitted with a double-pigtail stent. For the un-stunted ureters and the ureters fitted with the thin 0.3F suture thread, Gli1 staining of smooth muscle cells was heterogeneous, and the small number of cases did not allow us to conclude. CONCLUSION: Apart from the cases of ureters fitted with the double-pigtail stent, Gli1 expression of smooth muscle was heterogeneous. The Shh/Gli1 pathway may not be involved in ureteral dilation by the thread. A broader exploration of molecular mechanisms could make it possible to obtain the mechanisms involved in the dilation of the ureter by the thread.

Histological Inflammation in Human Ureter either Healthy or Fitted with Double-Pigtail Stent or a Thin 0.3 F Suture Thread: A Preliminary Study.

BACKGROUND: Ureteral stent intolerance reduces patients' quality of life. It has been suggested that changes in the shape of stents could decrease discomfort. In previous studies, the innovative pigtail-suture stent (i.e., JFil® or MiniJFil®) with a thin 0.3 F suture thread significantly decreased stent-related symptoms. Fortuitously, a dilation of the ureter containing the sutures was discovered. In addition, no inflammation was seen on the ureter wall around the suture in endoscopy. In this preliminary study, we assessed ureteral inflammation in the human ureter when it was healthy or when fitted with a double-pigtail stent or a thread. MATERIALS AND METHODS: After consent and inclusion of patients in the protocol, fifteen segments of ureters were collected during cystectomy procedures for bladder tumors. Ureteral inflammation was assessed on the histological section stained with hematoxylin-eosin. Histological grading (cumulative range of 0 to 6) assessing inflammation was performed on the ureter section for mucosa inflammation and inflammation in the muscle layer. RESULTS: A marked ureteral inflammatory reaction was observed in all cases of ureters fitted with a double-pigtail stent with a mean inflammation score of 4.8 ± 0.4. The ureter fitted with the thin suture thread showed inflammation in only one case with a mean inflammation score of 1.8 ± 1.3 (p=0.001). CONCLUSION: Although the study was limited by the small number of patients, it confirmed that the double-pigtail stent induced ureteral inflammation in all cases and the thin 0.3 F suture thread caused less ureteral inflammation than the double-pigtail stent. The concept of material reduction within the urinary tract seems necessary in order to decrease mucosal irritation. The JFil® or the MiniJFil® thread could meet this requirement.

ß-catenin activation is associated with specific clinical and pathologic characteristics and a poor outcome in adrenocortical carcinoma.

PURPOSE: Activation of the Wnt/ß-catenin signaling pathway is frequent in adrenocortical carcinoma (ACC) and might be associated with a more aggressive phenotype. The objective of this study was to assess the prognostic value of ß-catenin immunohistochemistry and CTNNB1 (ß-catenin gene)/APC (adenomatous polyposis coli gene) mutations in patients with resected primary ACC. EXPERIMENTAL DESIGN: In 79 patients with resected primary ACC from a French cohort (Cochin-COMETE), ß-catenin expression was assessed on tumor specimens by immunohistochemistry. For patients with available DNA (n = 49), CTNNB1, and APC hotspot (mutation cluster region), were sequenced. Association between these results and the clinicopathologic characteristics of the ACC and overall and disease-free survival were studied. Results were confirmed on a tissue microarray from an independent multicentric cohort of 92 ACC from Germany (German-ENSAT cohort). RESULTS: In the Cochin-COMETE cohort, the presence of a ß-catenin nuclear staining was significantly associated with a higher ENSAT tumor stage (i.e., stages III and IV), higher Weiss score, more frequent necrosis, mitoses, and CTNNB1/APC mutations. ß-Catenin nuclear staining and the presence of CTNNB1/APC mutations were both associated with decreased overall and disease-free survival, and were independent predictive factors of survival in multivariate analysis. The same results were observed in the German-ENSAT cohort. CONCLUSIONS: Wnt/ß-catenin activation, confirmed by the presence of ß-catenin nuclear staining, is an independent prognostic factor of overall and disease-free survival in patients with resected primary ACC.

Wnt/ß-catenin pathway activation in adrenocortical adenomas is frequently due to somatic CTNNB1-activating mutations, which are associated with larger and nonsecreting tumors: a study in cortisol-secreting and -nonsecreting tumors.

BACKGROUND: Abnormal ß-catenin immunohistochemistry and mutations of the ß-catenin gene (CTNNB1) have been reported in adrenocortical adenomas (ACAs), but the frequencies of these defects and the phenotype of such tumors have not been clearly determined. OBJECTIVE: The objective of the study was to describe the Wnt/ß-catenin pathway alterations in 100 ACAs and their association with clinicopathological characteristics. PATIENTS AND METHODS: One hundred consecutive ACAs (excluding Conn's adenomas) were studied clinically by ß-catenin immunohistochemistry and direct sequencing of CTNNB1. RESULTS: Thirty-five ACAs were nonsecreting adenomas (NSAs), 19 were subclinical cortisol secreting adenomas (SCSAs), and 46 were cortisol secreting adenomas (CSAs). Fifty-one tumors had abnormal cytoplasmic and/or nuclear ß-catenin immunohistochemical staining, indicating Wnt/ß-catenin pathway alteration. Thirty-six tumors showed CTNNB1 mutations, which all showed abnormal immunohistochemical ß-catenin accumulation. Among the 64 nonmutated tumors, only 15 (23%) showed cytoplasmic and/or nuclear ß-catenin staining (P < 0.0001). Tumors with CTNNB1 mutations were predominantly nonsecreting (61% NSAs, 22% SCSAs, 16% CSAs) whereas nonmutated tumors were predominantly secreting (20% NSAs, 17% SCSAs, 62% CSAs) (P < 0.0001). Mean tumor size and weight were, respectively, 4.2 cm (± 1.3) and 28.4 g (± 21.4) for tumors with CTNNB1 mutations vs. 3.4 cm (± 0.9) and 18.2 g (± 8.2) for nonmutated tumors (P < 0.01). CONCLUSIONS: Abnormal cytoplasmic and/or nuclear ß-catenin immunohistochemical staining occurs in about half of ACAs. This suggests the activation of the Wnt/ß-catenin pathway, which could be explained by activating mutations of CTNNB1 in 70% of the cases. CTNNB1 mutations are mainly observed in larger and nonsecreting ACAs, suggesting that the Wnt/ß-catenin pathway activation is associated with the development of less differentiated ACAs.