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Aim: Gastrointestinal stromal tumors (GISTs) are rare. GISTs differ from other mesenchymal tumors of the gastrointestinal tract (e.g. leiomyomas and schwannomas). The purpose of this study was to investigate the role of Ets-1 in the growth and differentiation of GISTs., Methods: Twenty-eight GISTs, nine leiomyomas and six schwannomas were examined by immunohistochemical staining method for Ets-1 in this study. Specimens were selected from surgical pathology archival tissues at Nagasaki University Hospital., Results: Ets-1 protein was expressed in the cytoplasm of cells in all of these tumors. Immunohistochemical staining revealed that 27 GISTs (96.4%), six leiomyomas (66.7%), and five schwannomas (83.3%) were positive for Ets-1. Ets-1 expression was statistically different between GISTs and leiomyomas (P<0.005). However, there was no correlation between Ets-1 expression and clinical risk categories., Conclusion: Ets-1 plays an important role in the growth and differentiation of GISTs, leiomyomas and schwannomas.

Aim: To investigate the incidence of Epstein-Barr virus-associated gastric cancer (EBV-GC) in Kazakhstan and to compare it with that in Russia, Western and Asian countries in order to evaluate the significance of epidemiopathologic and ethnic factors., Methods: In situ hybridization (ISH) of EBV-encoded small RNA-1 (EBER-1) was used to identify the presence of EBER-1 signal in 139 formalin-fixed and paraffin-embedded GC tissues from Kazakhstan., Results: EBER-1 expression was observed in the nuclei of 10% of the cases of GC (14/139), but not in the surrounding normal mucosa. The incidence of the diffuse type of EBV-GC was significantly higher in Kazakhstan (14%, 13/91) than that of the intestinal type (2%, 1/48). Furthermore, the incidence was significantly higher in males (14%, 12/89) than in females (3.7%, 2/53) from all countries. The overall incidence of EBV-GC increased from 6.7% in Asian countries to 8.7% in Russia, 10.1% in Kazakhstan and 16% in Western countries., Conclusion: Geographical differences in the incidence of EBV-GC may reflect the epidemiologic factors and/or dietary habits independent of histological type and sex.

A high incidence of skin cancers has been noted around the Semipalatinsk Nuclear Testing Site (SNTS) in Kazakhstan. Recently, basal cell carcinoma (BCC) susceptibility genes, human homolog of the Drosophila pathed gene (PTCH), and the xeroderma pigmentosa group A-complementing gene (XPA), have been cloned and localized on chromosome 9q22.3. To clarify the effect of low-dose irradiation on the occurrence of BCC, we used microdissection and polymerase chain reaction to identify loss of heterozygosity (LOH) at 9q22.3 using BCC samples obtained from this region. Ten Japanese samples were analyzed as controls. LOH with at least 1 marker was identified in 5 of 14 cases from around SNTS, whereas only 1 case with 1 marker was identified among the 10 Nagasaki cases. The total number of LOH alleles from SNTS (8 of 45) was significantly higher than the number from Nagasaki (1 of 26) (P = 0.03). The higher incidence of LOH on 9q22.3 in BCC from around SNTS suggests involvement of chronic low-dose irradiation by fallout from the test site as a factor in the cancers.

To assess thyroid status among the schoolchildren around Semipalatinsk Nuclear Testing Site (SNTS), Kazakhstan, and to evaluate the current status of iodine deficiency in this area, we performed medical screening of schoolchildren in two villages, Kaynar and Karaul villages, East Kazakhstan Region, Republic of Kazakhstan, located within 100 km of SNTS. A total of 196 schoolchildren were chosen at random. Control groups comprised 250 schoolchildren from Nagasaki, an iodine-rich area, and 100 schoolchildren from Gomel, an iodine-deficient area contaminated by the Chernobyl Nuclear Power Plant accident. Ultrasound screening of thyroid revealed three cases of benign thyroid disease (two cases of goiter and one single cyst), but no cases suspicious of malignancy. The urinary iodine (UI) concentrations of subjects in Kaynar and Karaul ranged from 21.8 to 735.8 microg/L, 4.3% of whom showed low UI concentrations (<50 microg/L), compared with 0% in the Nagasaki group and 52% in the Gomel group. The median UI concentration in Kaynar and Karaul was 153.2 microg/L, which was significantly lower than that in Nagasaki (366.3 microg/L, p<0.0001) but higher than that in Gomel (47.3 microg/L, p<0.0001). In conclusion, there was a low incidence of morphological abnormalities in the thyroid, and no evidence for severe iodine deficiency among the Kazakhstani children studied. These results suggest that there is no transgenerational risk for schoolchildren born from parents irradiated as a result of tests carried out in SNTS.

Activation of c-Jun NH2-terminal kinase (JNK), a member of the mitogen-activated protein kinase (MAPK) family, is involved in apoptosis or cell proliferation. We have previously demonstrated that ionizing radiation or thyroid-stimulating hormone activated JNK without linking to thyroid cell apoptosis. To clarify the involvement of JNK activation in thyroid cell survival, we investigated the effects of various growth factors on induction of JNK activation in cultured human thyroid cells. JNK activation was observed at 30 minutes after fetal bovine serum (FBS) stimulation and returned to basal level at 240 minutes. Epidermal growth factor (EGF), transforming growth factor-beta (TGF-beta) and hepatocyte growth factor (HGF) also induced JNK activation, but did not trigger apoptotic cell death. Furthermore, we observed high basal activation of JNK in four of five human thyroid cancer cell lines. Overexpression of c-Met, an HGF receptor, was observed in two of the four cell lines with high basal JNK activity. Our results suggest that JNK activation does not induce apoptosis but is associated with survival or transformation of human thyroid cells.

Parathyroid hormone-related peptide (PTHrP) is involved in cell proliferation in both neoplastic and non-neoplastic tissues. We describe an autopsy case of gastric cancer in a patient who showed serum hypercalcemia and overexpression of PTHrP and PTH/PTHrP receptor in the metastatic tumor cells. The primary gastric tumor was poorly differentiated adenocarcinoma, and multiple metastases were present in the bone, multiple visceral organs, peritoneum, and lymph nodes. PTHrP and its mRNA were detected only in the metastatic tumor cells, but not in primary gastric tumor. PTH/PTHrP receptor was also demonstrated immunohistologically in metastatic tumor cells. This case suggests that the expression of PTHrP is related to tumor progression and the poor prognosis in tumors associated with humoral hypercalcemia.

Parathyroid hormone-related peptide (PTHrP) is produced by various neoplasms. It has been suggested that it acts as a cytokine for cell proliferation and tumour progression. The purpose of this study was to evaluate PTHrP expression in gastric cancers by immunohistochemistry. PTHrP was expressed in 71 of 92 (77.2 per cent) gastric adenocarcinomas without humoral hypercalcaemia. In contrast, one case (5 per cent) out of 20 adenomas and none of the background non-neoplastic epithelium showed PTHrP immunoreactivity. In carcinomas, PTHrP immunoreactivity was higher in moderately differentiated adenocarcinomas (21/22; 95-5 per cent) and poorly differentiated adenocarcinomas (34/34; 100 per cent) than in well-differentiated adenocarcinomas (10/23; 43 per cent). Furthermore, PTHrP expression was more intense in the deeply invasive portions than in the mucosal carcinomas. High percentages of metastatic tumour cells in regional lymph nodes were immunopositive. PTHrP mRNA expression was confirmed by in situ hybridization in gastric adenocarcinomas. Reverse transcription-polymerase chain reaction (RT-PCR) studies of normal gastric mucosa and four human gastric cancer cell lines detected PTHrP transcription in NUGC-1 (poorly differentiated) and NUGC-3 (poorly differentiated) but not in normal gastric mucosa, MKN-1 (well differentiated), and KATO-III (signet ring cell). These findings suggest that overexpression of PTHrP may be involved in the malignant transformation and progression of gastric carcinomas.

The giant cell tumour of tendon sheath (GCTTS) is mainly composed of mononucleated stromal cells (SC) and multinucleated giant cells (GC), so-called osteoclast-like GC. It is thought that GC are derived from SC, but their precise relationship is not fully understood. Parathyroid hormone (PTH)-related peptide (PTHrP) is now considered to be a cytokine for cell differentiation, which may stimulate osteoclast-like cell formation in haematopoietic cells. Five cases of GCTTS were evaluated immunohistochemically, using a variety of antibodies against PTHrP, PTH/PTHrP receptor, KP-1 as a histiocytic phenotypic antigen, fibronectin as a fibroblastic phenotypic antigen, and proliferating cell nuclear antigen (PCNA). In situ hybridization and immunohistochemistry revealed that in all cases both SC and GC expressed PTHrP. PTH/PTHrP receptor was observed only in histiocytic SC and GC, but not in fibroblastic SC. Almost all GC showed histiocytic features. PCNA immunoreactivity was detected only in the nuclei of SC, and not in GC. Moreover, SC with PTH/PTHrP receptor immunoreactivity were negative for PCNA. These results suggest that GC are derived from histiocytic SC expressing PTH/PTHrP receptor and losing proliferative activity in the process of transition from mononuclear to multinucleated. PTHrP produced by SC and GC may be involved in the formation of osteoclast-like cells in GCTTS by acting in an autocrine/paracrine fashion.