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Background: Gastrointestinal stromal tumors (GISTs) are believed to originate from the interstitial cells of Cajal (ICCs) or from the precursors of ICCs. Most GISTs show an activating mutation in either the c-kit or platelet-derived growth factor receptor alpha (PDGFRA) gene that results in a constitutive, ligand-independent activation of receptor tyrosine kinases. These gene mutations may play an important role in transforming a GIST progenitor cell into a tumor cell during the early phase of GIST tumorigenesis. However, the precise mechanism of the tumorigenesis is not known., Methods: We examined ten patients with sporadic GIST for mutations in the tumor and its adjacent ICC cells, and compared the mutational status of ICC cells with that of the GIST cells in each patient. All cases were screened for mutations in the c-kit gene (exons 9, 11, 13, and 17) and in the PDGFRA gene (exons 12 and 18). Samples were limited to GIST cases from the small intestine, where ICCs were present in bundles and were considered suitable for isolation by laser capture microdissection., Results: Of the ten tumors screened, eight had mutations in the c-kit gene (all in exon 11) and two were wild-type, whereas none of the ICCs exhibited mutations in these genes., Conclusions: Our results suggest that ICCs adjacent to overt GISTs did not have mutations in the c-kit or PDGFRA genes, and overt GISTs may develop after the local and sporadic acquisition of these gene mutations, together with additional events.

Background: Recently, the novel gene DOG1 has been found to be overexpressed in most gastrointestinal stromal tumors (GISTs) specifically within the field of soft tissue tumors. DOG1 might play a role in development of GISTs and have potential as a diagnostic marker and therapeutic target, but the biological function and the overexpression mechanism have not yet been investigated. In this study we examined whether the DOG1 gene mutation occurs as with the KIT gene and PDGFRA gene., Methods: We investigated ten resected primary GIST tissues. All cases were examined for immunoreactivity for KIT and DOG1 and screened for mutation in the KIT gene (exons 9, 11, 13, and 17) and the PDGFRA gene (exons 12, 14, and 18) by direct DNA sequencing. Four cases with relatively good quality DNA were analyzed for the DOG1 gene (exons 1-26) mutation., Results: All ten GISTs showed immunoreactivity for KIT. Although all cases expressed DOG1 in immunohistochemistry, we could not find any mutations within all 26 exons (a total of 104 exons) of the DOG1 gene in the four analyzed cases., Conclusions: Based on four cases, the DOG1 gene was found not to be mutated in GISTs.

Background: We performed hepatectomy without lymph node (LN) dissection for intrahepatic cholangiocarcinoma (ICC) limited to the peripheral region of the liver, and hepatectomy with extrahepatic bile duct resection and regional LN dissection for any types of ICC extending to the hepatic hilum. Surgical outcomes were evaluated to elucidate the prognostic factors that influence patient survival with respect to intrahepatic recurrence., Methods: Forty-one patients underwent resection of ICC with no macroscopic evidence of residual cancer., Results: Significant risk factors for poorer survival included preoperative jaundice (P = 0.0115), serum CA19-9 levels >37 U/ml (P = 0.0089), tumor diameter >4.5 cm (P = 0.017), ICC extending to the hepatic hilum (P = 0.0065), mass-forming with periductal-infiltrating type (P = 0.003), poorly differentiated adenocarcinoma, portal vein involvement (P = 0.0785), LN metastasis at initial hepatectomy (P < 0.0001), and positive surgical margin (P = 0.023). Intrahepatic recurrence, which was the predominant manner of recurrence, was detected in 20 patients (74.1%). Patients with intrahepatic recurrence had a significantly high incidence of high serum CA19-9 levels (>37 U/ml; P = 0.0006), preoperative jaundice (P = 0.0262), ICC extended to the hepatic hilum (P = 0.0349), large tumors (>4.5 cm; P = 0.0351), portal vein involvement (P = 0.0423), and LN metastasis at initial hepatectomy (P = 0.009) compared with disease-free patients. The multiple logistic regression analysis revealed that preoperative CA19-9 elevation and obstructive jaundice influenced intrahepatic recurrence of ICC., Conclusions: Although LN metastasis is a significant prognostic factor, the most obvious recurrence pattern after surgery was intrahepatic recurrence, which could be predicted preoperatively by a combination of elevated serum CA19-9 levels and manifestation of obstructive jaundice.