Pancreatic hamartoma: detection of harbouring NAB2::STAT6 fusion gene.

Hamartomas in the pancreas are rare and are often histologically and morphologically similar to solitary fibrous tumours (SFTs). We examined the differences between hamartomas and SFTs at the molecular level. METHODS AND RESULTS: Thirteen patients histopathologically diagnosed with pancreatic hamartoma were included in the study. We also performed STAT6 immunohistochemistry (IHC), which is used in the diagnosis of SFT. Furthermore, for the three cases in which RNA was extracted, reverse transcription polymerase chain reaction to search for NAB2::STAT6 fusions was used. Macroscopically, 13 patients had well-demarcated tumour lesions. Histologically, no islets of Langerhans were observed in the lesions, acinar tissue and ducts were unevenly distributed and elastic fibres were not observed around the ducts by Elastica van Gieson staining. One case contained a lipomatous hamartoma composed mainly of adipose tissue. Seven of the 13 cases demonstrated expression of STAT6 in the nuclei of intervening spindle cells. NAB2::STAT6 fusions were observed in two of the three cases in which RNA was extracted. These two cases also demonstrated STAT6 expression in spindle cells using STAT6 IHC. In one case of lipomatous hamartoma, we did not confirm NAB2::STAT6 fusion or STAT6 expression in STAT6 IHC. CONCLUSION: Of the 13 patients histopathologically diagnosed with hamartoma, two demonstrated NAB2::STAT6 fusions, suggesting the existence of pancreatic hamartomas with molecular-level components identical to those of SFT.

[Carcinoma of the gallbladder which progress on the mucosa of choledochocolonic fistula].

A 70-year-old man was admitted to our hospital for further examination of pneumobilia and atrophy in the gallbladder. Abdominal CT scan and EUS revealed that the atrophic gallbladder was occupied by a tumor lesion. In addition, ERCP showed choledochocolonic fistula. Colonoscopy revealed an elevated lesion in the colonic side of fistula, and biopsy of the elevated lesion revealed adenocarcinoma. Cholecystectomy and right hemicolectomy was performed under a preoperative diagnosis of gallbladder carcinoma with choledochocolonic fistula. Pathologically, most of the tumor was localized in the gallbladder, and grew along the mucosa of choledchocolonic fistula. This case was of interest with regard to the relationship between the choledochocolonic fistula and gallbladder carcinoma.

Multicenter, randomized, open-label Phase II study comparing S-1 alternate-day oral therapy with the standard daily regimen as a first-line treatment in patients with unresectable advanced pancreatic cancer.

PURPOSE: Non-inferiority for overall survival (OS) following alternate-day treatment with the oral anticancer drug S-1 compared with standard daily treatment was assessed in Japanese patients with unresectable advanced pancreatic cancer in a multicenter, randomized, phase II study. This trial was registered at the UMIN Clinical Trials Registry (no. 000008604). METHODS: Chemotherapy-naïve patients with locally advanced or metastatic pancreatic cancer were randomly assigned 2:1 to treatment with alternate-day (twice daily on alternate days from days 1 through 42 of a 42-day cycle) or daily (twice daily on days 1 through 28 of a 42-day cycle) treatment with S-1. The primary endpoint was OS. Secondary endpoints were progression-free survival (PFS), time to treatment failure, response rate, quality of life assessments, and safety. RESULTS: A total of 190 patients were enrolled, of which 185 were included in the final analysis (alternate-day: 121; daily: 64). Median OS was 9.4 for the alternate-day group and 10.4 months for the daily group [hazard ratio (HR), 1.19; 95% credible interval, 0.86 to 1.64], indicating that non-inferiority of alternate-day treatment to daily treatment was not demonstrated. Median PFS was 3.0 for the alternate-day group and 4.2 months for the daily group (HR, 1.65; 95% credible interval, 1.20-2.29). The incidence of anorexia, fatigue, neutrophils, pigmentation, and pneumonitis was lower in alternate-day treatment compared with daily treatment. CONCLUSION: S-1 for advanced pancreatic cancer should be taken daily as recommended, based on the decreased OS and PFS and marginal improvement in safety observed in the alternate-day group.

Differential roles of alterations of p53, p16, and SMAD4 expression in the progression of intraductal papillary-mucinous tumors of the pancreas.

Intraductal papillary-mucinous tumors (IPMTs) of the pancreas are characterized by dilated pancreatic ducts and ductules that are lined by tall columnar mucin-producing neoplastic epithelial cells. IPMTs have been suggested to be distinct neoplasms with a less aggressive phenotype than that of conventional ductal adenocarcinomas of the pancreas. Molecular mechanisms underlying tumorigenesis of IPMTs are beginning to be characterized. Allelic losses have frequently been detected at 9p, 17p, and 18q, suggesting that inactivation of tumor suppressor genes at these loci play a role in tumorigenesis of IPMTs. Using immunohistochemistry, we analyzed 38 IPMTs, including 9 hyperplasia, 16 adenoma, and 13 carcinoma tissues, for expression of p53, Ki-67, p16, and SMAD4. Nuclear p53 expression was observed in 5 (38%) of 13 carcinoma tissues but not in hyperplasia or adenoma tissues. Partial loss of p16 expression was observed in 9 (56%) and 12 (92%) of the 16 adenoma and 13 carcinoma tissues, respectively. Partial loss of p16 expression was observed even in adenomas with mild atypia. Partial loss of SMAD4 expression was observed in 6 (38%) and 12 (92%) of the 16 adenoma and 13 carcinoma tissues, respectively. The SMAD4 negative index was significantly higher in invasive carcinomas than in non-invasive carcinomas. Our results suggest that loss of p16 is an early event and p53 alteration is a late event during the progression of IPMTs. SMAD4 inactivation appears to be an early event but also involved in invasive tumor growth. Our results suggest that these alterations accumulate during the progression of IPMTs, reflecting results of analysis of allelic losses that showed a stepwise accumulation of genetic changes during progression.

A multicenter phase II study of S-1 for gemcitabine-refractory biliary tract cancer.

PURPOSE: Gemcitabine (GEM)-based chemotherapy has been used worldwide as the first-line treatment for advanced biliary tract cancer (BTC). However, no standard regimens have been established yet for patients with GEM-refractory BTC. A previous phase II trial of S-1 as a first-line treatment in patients with advanced BTC revealed promising activity of this drug. The present study was conducted to evaluate the efficacy and safety of S-1 in patients with GEM-refractory BTC. METHODS: The subjects were patients with pathologically proven BTC who had shown disease progression while receiving GEM-based chemotherapy. Each treatment cycle consisted of administration of S-1 orally at the dose of 40 mg/m(2) twice daily for 28 days, followed by a rest period of 14 days. The primary endpoint of this study was objective response, and the secondary endpoints were the toxicity, progression-free survival (PFS), and overall survival (OS). RESULTS: Forty patients were assessed for efficacy and safety from 8 hospitals in Japan between June 2007 and September 2008. There were 3 cases of confirmed partial response (7.5 %) and 22 patients (55 %) of stable disease. The median PFS and OS were 2.5 and 6.8 months, respectively. Toxicity was generally mild, and the most common grade 3 or 4 toxicities were anorexia (10.0 %), anemia (7.5 %), mucositis (7.5 %), hypoalbuminemia (5.0 %), and pneumonia (5.0 %). There were no treatment-related deaths. CONCLUSIONS: Monotherapy with S-1 was well tolerated, but showed modest efficacy in patients with GEM-refractory BTC.

Distinctive histopathologic findings of pancreatic hamartomas suggesting their "hamartomatous" nature: a study of 9 cases.

Pancreatic hamartoma is a rare tumor, and its characteristic histopathologic features have not yet been fully evaluated. In this study, we collected 9 cases of pancreatic hamartoma to elucidate distinctive histopathologic features that can serve to establish this tumor as a clear disease entity and thus formulate useful histopathologic criteria for this tumor. The cases comprised 4 men and 5 women with a mean age of 62.7 years. The average tumor diameter was 3.3 cm. All patients underwent surgical treatment, and none showed any recurrence postoperatively. Macroscopically, pancreatic hamartomas were well-demarcated tumors with a solid or solid and cystic appearance. Microscopically, these tumors comprised mature acini and small-sized to medium-sized ducts showing a distorted architecture with various amounts of fibrous stroma. Strikingly, the tumors consistently lacked concentric elastic fibers in their duct walls, peripheral nerves, and well-formed islets of Langerhans, all of which exist in both the normal and atrophic pancreas. Immunohistochemically, scattered chromogranin A-positive neuroendocrine cells were observed in the acinar and ductal components. Ductal components were positive for S-100 protein. Spindle-shaped stromal cells expressed CD34 and/or c-kit. These histopathologic features were distinct from those of 5 cases of pancreatic ductal adenocarcinoma, 3 cases of type 1 autoimmune pancreatitis (lymphoplasmacytic sclerosing pancreatitis), 3 cases of alcoholic chronic pancreatitis, and 5 cases of normal pancreas. In conclusion, pancreatic hamartomas share some distinctive histopathologic features and clinical outcomes (neither recurrence nor metastasis) that allow them to be interpreted as malformative lesions. The term "hamartoma" is appropriate for these unique lesions.