Autopsy of anaplastic carcinoma of the pancreas producing granulocyte colony-stimulating factor.

A 50-year-old man presented to a nearby hospital with high fever and anorexia. An abdominal tumor was detected, and he was referred to our hospital. A pancreatic tumor was detected by computed tomography and abdominal ultrasonography. He had high fever, leukocytosis, and high serum granulocyte colony-stimulating factor (G-CSF). We performed a tumor biopsy and histological examination revealed anaplastic carcinoma of the pancreas. Based on the diagnosis, we initiated chemotherapy using gemcitabine plus S-1. However, the tumor rapidly progressed and he deteriorated and died 123 days after admission. As immunohistochemical study showed positive staining for G-CSF in the tumor cell, we diagnosed the tumor producing G-CSF during autopsy. Anaplastic carcinoma of the pancreas producing G-CSF is very rare, with 10 cases, including ours, reported in the literature.

[Histopathological Study of the Relationship between Lymphoid Follicles and Different Endoscopic Types of Nodular Gastritis].

Nodular gastritis is characterized histologically by hyperplasia and enlargement of lymphoid follicles in the lamina propria. With the objective of elucidating the relationship between different endoscopic types of nodular gastritis and lymphoid follicles, distributions of lymphoid follicles in the lamina propria were investigated in young gastric cancer patients with nodular gastritis. For the study, whole-mucosal step sectioning of each resected stomach was performed, the densities of lymphoid follicles of all specimens were measured microscopically, and the horizontal and depth distributions were calculated. For assessment in the horizontal direction, density distribution diagrams of lymphoid follicles were created. For assessment in the depth direction, the different endoscopic types of nodular gastritis were compared in the five different analysis sites. In the assessment of the horizontal distribution, no characteristic distribution tendencies were observed in either the granular type group or the scattered type group; however, it was found that areas with relatively high densities of lymphoid follicles generally coincided with the areas where nodular gastritis was observed endoscopically. These results suggested that hyperplasia and aggregation of lymphoid follicles in the lamina propria are involved at the sites where nodular gastritis is observed endoscopically. In the assessment of the depth distribution, lymphoid follicles tended to be more unevenly distributed in the upper lamina propria in the granular type group than in the scattered type at the three different analysis sites where nodular gastritis was observed endoscopically. These results suggested the possibility of a granular type characteristic.

Plaunotol induces a comparative increase of acidic mucin fraction in gastric juice.

BACKGROUND/AIMS: Gastric mucus protects the gastric mucosa. Plaunotol, a gastroprotective agent, has been shown to increase mucus production in animal models. However, it is unclear whether plaunotol benefits human gastric mucus secretion. METHODOLOGY: Twenty-five patients with atrophic gastritis were studied. All patients underwent gastroendoscopy and gastric juice was collected before and after plaunotol treatment for 3 months. Gastric juice mucin was examined by gel filtration as well as anion-exchange chromatography. The identification of each fraction was examined by enzyme-linked immunosorbent assay (ELISA) with the use of HGM75 and HIK1083, antibodies against mucin from surface mucus cells and from gastric glandular mucus cells, respectively. RESULTS: Plaunotol significantly increased the total gastric juice volume (7.8mL before vs. 10.7mL, after administration; p=0.03). By anion exchange chromatography, we detected three mucin fractions (Fr I-III). Fr I strongly reacted with HGM75 but did not react with HIK1083. The other fractions (Fr II, III) reacted with HIK1083 but weakly reacted with HGM75. After administration of plaunotol, a significant increase in Fr III (acidic mucin) was observed (p=0.02). CONCLUSIONS: Long-term administration of plaunotol changes the composition of gastric juice mucin, including a significant increase in the proportion of acidic mucin fraction.

Clinical significance of mucosal suppressors of cytokine signaling 3 expression in ulcerative colitis.

AIM: To investigate the clinical significance of mucosal expression of suppressors of cytokine signaling 1 (SOCS1) and SOCS3 in human ulcerative colitis (UC). METHODS: Biopsy specimens for histological analysis and mRNA detection were obtained endoscopically from the rectum of 62 patients with UC (36 men; age 13-76 years). The patients were classified endoscopically according to Matts' grade (grade 1 to 4). Expression of SOCS1 and SOCS3 mRNAs was quantified in samples by competitive reverse transcription-polymerase chain reaction (RT-PCR). GAPDH was used as an internal control for efficiency of RT-PCR and amount of RNA. RESULTS: SOCS3 mRNA expression was significantly higher in inflamed mucosa of UC than in inactive mucosa. The level of expression was well correlated with the degree of both endoscopic and histologic inflammation. Interestingly, among the patients in remission, the group with relatively low expression of SOCS3 showed a higher rate of remission maintenance over a 12-mo period. In contrast, SOCS1 mRNA was expressed in both inflamed and non-inflamed colonic mucosa and was not correlated with the activity of colonic mucosa or prognosis. CONCLUSION: These observations suggest that increased expression of mucosal SOCS3, but not of SOCS1, may play a critical role in the development of the colonic inflammation of UC.

Cavernous hemangioma in the ascending colon treated by endoscopic mucosal resection.

Hemangioma of the large intestine is rare, but it is a clinically important entity because of the possibility of massive hemorrhage. The case is reported of a patient with a formed, sessile, polypoid-type cavernous hemangioma in the ascending colon that was removed successfully by endoscopic mucosal resection.

Basis of decreased risk of gastric cancer in severe atrophic gastritis with eradication of Helicobacter pylori.

Helicobacter pylori infection induces chronic gastritis and lowers gastric juice ascorbic acid concentrations. We investigated how H. pylori eradication affected multiple variables that could prevent or delay development of new or occult gastric cancer in patients with early gastric cancer treated by endoscopic mucosal resection. Gastric juice pH, nitrite concentrations, and total vitamin C concentrations, serum concentrations of vitamin C and specific H. pylori antibody, and intensity of neutrophil infiltration in gastric mucosa were determined before and after successful H. pylori eradication. Successful eradication increased acid output and ascorbic acid secretion into gastric juice, accompanied by disappearance of polymorphonuclear infiltration from the surface epithelium and decreased gastric juice nitrite concentrations. Our data suggest that H. pylori eradication decreases the nitrosation rate as the ratio of vitamin C to nitrite increases. This decreases reactive oxygen species and nitric oxide, eliminating their damaging effect on DNA and reducing cell turnover.

A combination of the Helicobacter pylori stool antigen test and urea breath test is useful for clinical evaluation of eradication therapy: a multicenter study.

BACKGROUND: Helicobacter pylori stool antigen (HpSA) test is a new tool for evaluating the H. pylori infection. The present study was carried out to investigate the clinical usefulness of the HpSA test in the evaluation of eradication therapy by comparing it with the (13)C-urea breath test (UBT). METHODS: One hundred and five patients received eradication therapy for H. pylori. After more than 8 weeks, the success of the therapy was evaluated by the HpSA test and the UBT. Concordant results were regarded as a final diagnosis, but when the results were discordant, histological examination was carried out. RESULTS: Of the 105 patients receiving eradication therapy for H. pylori, 25 patients were regarded as H. pylori positive by the UBT and and 20 patients were regarded as H. pylori positive by the the HpSA test. Nine patients (8.6%) showed discordant results (seven cases with UBT(+) and HpSA(-), and two with UBT(-) and HpSA(+)). Five cases out of nine were ultimately judged as having a false-positive result of the UBT, and in these cases the UBT values were relatively low (below 10 per thousand). The final diagnostic accuracies of the UBT and the HpSA test were 94.3% (88.0-97.9%; 95% CI) and 97.1% (91.9-99.4%), respectively. When we used the HpSA test in cases with weakly positive UBT values, we were able to diagnose the correct status of H. pylori infection after eradication in 99% of all patients (94.8-100.0%). CONCLUSION: The HpSA test is a useful tool for the evaluation of eradication therapy and a combination of the HpSA test and UBT is clinically recommended.

Single dose of OCH improves mucosal T helper type 1/T helper type 2 cytokine balance and prevents experimental colitis in the presence of valpha14 natural killer T cells in mice.

BACKGROUND AND AIMS: Valpha14 natural killer T (NKT) cells seem to play important roles in the development of various autoimmune diseases. However, the pathophysiologic role of NKT cells in inflammatory bowel disease remains unclear. To clarify the mechanism by which the activation of NKT cells mediates protection against intestinal inflammation, we investigated the antiinflammatory role of specifically activated Valpha14 NKT cells by glycolipids in a mouse experimental model of colitis induced by dextran sulfate sodium (DSS). METHODS: Colitis was induced in C57BL/6 mice by the oral administration of 1.5% DSS for 9 days. A single dose of OCH or alpha-galactosylceramide, a ligand for NKT cells, was administered on day 3 after the induction of colitis. Body weights and colonic mucosal injury were assessed in each glycolipid-treated group. Interferon-gamma and interleukin-4 levels in the supernatants from colonic lamina propria lymphocytes (LPLs) were measured by enzyme-linked immunosorbent assay. RESULTS: The administration of a single dose of OCH attenuated colonic inflammation, as defined by body weights and histologic injury. The protective effects of OCH could not be observed in Valpha14 NKT cell-deficient mice. In vivo treatment with OCH had improved the interferon-gamma/interleukin-4 ratio from colonic LPLs on day 9 after DSS treatment. CONCLUSION: The present data indicated that the activation of Valpha14 NKT cells by OCH plays a pivotal role in mediating intestinal inflammation via altered mucosal T-helper type 1/type 2 responses. Therapeutic strategies that are designed to activate specifically Valpha14 NKT cells may prove to be beneficial in treating intestinal inflammation.

Magnifying colonoscopic features of ulcerative colitis reflect histologic inflammation.

BACKGROUND: Colonoscopy plays an important role in the diagnosis of ulcerative colitis and the determination of disease activity. Standard colonoscopic findings, however, do not often agree with histologic findings. The aim of this study was to clarify the relation between magnifying colonoscopic features and histologic inflammation in the course of ulcerative colitis. METHODS: We performed magnifying colonoscopy examinations in 60 patients with ulcerative colitis. We classified the features into six types and analyzed the relations among these features, standard colonoscopic features (Matts grades), and pathohistological findings. RESULTS: It was difficult to distinguish the remission stage from the active stage by standard colonoscopy in cases of Matts grade 2 disease. There was a relation, however, between the magnifying colonoscopic types and the degrees of histologic inflammation. The magnifying colonoscopic types reflected histologic inflammation status more accurately than did standard colonoscopic findings. CONCLUSION: Magnifying colonoscopy is useful for determining the degree of histologic change without biopsy in patients with ulcerative colitis.

Effects of aged garlic extract (AGE) on colorectal adenomas: a double-blinded study.

Aged garlic extract (AGE) is a material that has the possibility of a cancer-preventive effect according to epidemiologic and animal studies. In order to confirm the effects of AGE on colorectal adenomas, we conducted a double-blinded randomized study using high-AGE (AGE 2.4 ml/day) and low-AGE (AGE 0.16 ml/day) doses 1 groups. Fifty-one patients who were diagnosed as having colorectal adenomas by colonoscopy were randomly assigned to the high-AGE and low-AGE groups. The number and size of adenomas before intake (0 month) and 6 and 12 months after intake were measured using colonoscopy. In 37 patients chosen as efficacy evaluated subjects, 47.4% (9/19) in the high-AGE and 66.7% (12/18) in the low-AGE group had at least one new adenoma for the first and second interval (0 to 12 months after intake), and its relative risk was 0.71. The decrease rate of at least one adenoma was 50.0% (7/14) in the high-AGE group for the second interval (6 to 12 months after intake), whereas there was no decrease in subjects in the low-AGE group (p=0.02). The difference from the base-line for total size of adenomas increased in the low-AGE group, whereas an increase in the high-AGE group was suppressed for the second interval (p=0.04). The difference from the base-line for the total size of adenomas in subjects who had adenomas on the base-line increased in the low-AGE group and decreased in the high-AGE group for the second interval (p=0.03). The results of this study suggest the possibility of preventive and therapeutic effects of AGE on colorectal adenomas, though it is necessary to investigate these in larger-scale and longer-term trials.

Does intragastric nitrite concentration reflect gastric carcinogenesis in Japanese Helicobacter pylori-infected patients?

Established risk factors for gastric cancer include a diet high in nitrate or nitrite and low in vitamin C and the presence of achlorhydria or hypochlorhydria. The aim of this study was to investigate the relationship between intragastric nitrite concentration and atrophic change of the stomach or gastric carcinogenesis in Japanese Helicobacter pylori-infected patients. Gastric juice pH, nitrite, and total vitamin C concentrations in gastric juice, serum pepsinogen I and II concentrations, and specific Helicobacter pylori antibody were analyzed. Intragastric total vitamin C concentration was decreased by Helicobacter pylori infection of the gastric mucosa and with progression of the atrophic grade. There was a significant positive correlation between atrophic grade and intragastric nitrite concentration. In conclusion, the levels of nitrite in gastric juice play a causal role in the development of cancer in Helicobacter pylori-associated atrophic gastric mucosa.

Somatic mutation in mitochondrial DNA and nuclear microsatellite instability in gastric cancer.

It was reported that somatic mutations in the mitochondrial DNA (mtDNA) are associated with high-frequency microsatellite instability (MSI-H) of the nuclear in gastric cancers. However, no correlation between mtDNA mutations and nuclear MSI-H was found in colorectal, breast, and renal cancers. Therefore, the association between mtDNA mutations and nuclear MSI-H in gastric cancers is controversial. We examined mtDNA mutations and nuclear MSI in a large panel of gastric cancers. One-hundred and five gastric cancers were selected. Mutations in the mononucleotide repeat (D310) of mtDNA and nuclear MSI at 5 microsatellite loci were examined by microsatellite assay. Somatic mutations in the mtDNA and nuclear MSI-H were detected in 16 (15%) and 14 (13%) of the gastric cancers, respectively. mtDNA mutations were detected in 2 of the 14 (14%) and 14 of the 91 (15%) tumors with and without nuclear MSI-H, respectively. There was no significant difference between them. These results suggest that somatic mutations in the mtDNA and nuclear MSI-H play important roles in gastric carcinogenesis, and that mtDNA mutations may not be associated with nuclear MSI-H in gastric cancers.

Prevalence of Helicobacter pylori resistance to clarithromycin and metronidazole determined by 23S ribosomal RNA and rdxA gene analyses in Hiroshima, Japan.

BACKGROUND AND AIMS: Resistance to antibiotics in Helicobacter pylori is increasing and becoming a serious problem in eradication treatment of H. pylori. The prevalence of H. pylori infections that are resistant to clarithromycin, metronidazole, or both were determined in H. pylori isolates in Hiroshima, Japan. METHODS: Sixty Japanese patients with H. pylori infection were collected between 1999 and 2000. To detect the resistance to clarithromycin and metronidazole, mutations of the 23S ribosomal RNA (rRNA) and rdxA genes that are responsible for resistance in H. pylori, were examined by direct sequencing analysis. RESULTS: Resistance to clarithromycin and metronidazole was detected in 12 (20.0%) and nine (15.0%) of the patients, respectively. Dual resistance to clarithromycin and metronidazole was detected in five (8.3%) patients. CONCLUSION: These results indicate that the relatively high prevalence of the dual resistance in H. pylori isolates may need special attention and new therapeutic approaches in Japan.

Clinical significance of Fhit expression in development of colorectal carcinoma of various macroscopic types.

It is unclear how expression of the FHIT (fragile histidine triad) gene by the colorectal neoplasm correlates with histogenesis and progression of the disease. We studied the association between expression of Fhit protein and development of colorectal carcinoma (CRC). We also examined relations between Fhit protein expression, macroscopic type, Ki-67 labeling index (LI), and p53 overexpression in carcinoma in situ. We examined 27 colorectal adenomas, 82 carcinomas in situ and 21 invasive CRCs resected endoscopically or surgically. The carcinomas in situ comprised three macroscopic types: polypoid (n=27), superficial (flat elevated, n=27; depressed, n=10) and granulonodular laterally spreading tumor (G-LST, n=23). Fhit, Ki-67, and p53 overexpression were examined immunohistochemically. Levels of Fhit protein were lower in invasive CRC than in adenoma and carcinoma in situ (p<0.01). In carcinoma in situ, reduced Fhit expression was observed in 7 of 22 (31.8%) polypoid types, 13 of 27 (48.1%) superficial flat elevated types, 8 of 10 (80%) superficial depressed types and 7 of 23 (30.4%) G-LST. Frequencies of reduced Fhit expression were significantly higher in the polypoid type and G-LST lesions than in the depressed type (p<0.05). Reduced expression of Fhit protein was related significantly to Ki-67 LI and p53 overexpression in carcinoma in situ (p<0.01). The present findings suggest that reduced expression of Fhit protein is related to development of colorectal neoplasm. Polypoid CRC and G-LST appear to differ from superficial depressed CRC in terms of Fhit expression.

p53 expression, K-ras gene mutation and microsatellite instability in gastric B-cell lymphomas.

BACKGROUND AND AIMS: Genetic mechanisms involved in the development of gastric B-cell lymphomas remain unclear. The aim of the present study was to clarify the roles of mutations of the p53 and K-ras genes, and microsatellite instability (MSI) in the development of gastric B-cell lymphomas. METHODS: We investigated p53 immunoreactivity, mutations of the K-ras gene, and MSI in 27 gastric marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue type (MZBCL) and 24 diffuse large B-cell lymphomas (DLBCL). p53 immunoreactivity was examined using a monoclonal antibody, DO-7. Mutation of the K-ras gene was detected by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. MSI was examined at five microsatellite loci with a microsatellite assay. Cases were classified as having high-frequency MSI (MSI-H) (>/= 2 loci showing instability), low-frequency MSI (MSI-L) (only one locus showing instability), or as microsatellite stable. RESULTS: p53 immunoreactivity was detected in 1 of 16 (6%) MZBCL and 8 of 19 (42%) DLBCL. Frequency of p53 immunoreactivity in DLBCL was significantly higher than that in MZBCL (P = 0.018). MSI-H was detected only in 1 of 20 (5%) DLBCL. None of the cases examined showed mutation of the K-ras gene. CONCLUSIONS: These data suggest that mutations of the p53 gene may play an important role in the development of gastric DLBCL, and that mutations of the K-ras gene and MSI may be involved in little part of the development of gastric B-cell lymphomas.

Gastric juice nitrite and vitamin C in patients with gastric cancer and atrophic gastritis: is low acidity solely responsible for cancer risk?

BACKGROUND: N-nitroso compounds are carcinogens formed from nitrite, a process that is inhibited by vitamin C in gastric juice. Helicobacter pylori infection has been reported to increase nitrite and decrease vitamin C in gastric juice. Therefore, susceptibility to gastric cancer in H. pylori-infected patients may be derived from increased N-nitroso compounds in gastric juice. However, most H. pylori-infected patients do not develop gastric cancer. OBJECTIVE: To investigate additional factors that may affect susceptibility to gastric cancer, we compared nitrite and vitamin C levels in gastric juice from H. pylori-infected patients with and without gastric cancer. METHODS: Serum and gastric juice were obtained from 95 patients undergoing diagnostic endoscopy, including those with normal findings, duodenal ulcer, gastric ulcer, atrophic gastritis and gastric cancer. Serum was analysed for H. pylori antibody, nitrate and nitrite, gastrin and pepsinogens; gastric juice was analysed for pH, nitrite and vitamin C. RESULTS: pH and nitrite levels were increased and vitamin C levels decreased in the gastric juice of patients with atrophic gastritis and gastric cancer compared with other patients. However, in patients with a similar gastric acidity (pH 5-8), nitrite concentrations in the gastric juice were significantly higher and vitamin C levels significantly lower in patients with gastric cancer than in those with atrophic gastritis. CONCLUSION: Although hypochlorhydria increases intraluminal nitrite and decreases intraluminal vitamin C, which increases the intraluminal formation of N-nitroso compounds, our results indicate that patients with gastric cancer may have additional factors that emphasize these changes.

Food deprivation enhances somatostatin and somatostatin receptor subtype expression in rat colon.

Somatostatin, a peptide distributed widely throughout the gut, inhibits a variety of gastrointestinal functions. We previously reported that fasting for 48 h increased gastric somatostatin peptide and mRNA content. Thus, somatostatin could contribute to the inhibition of gastric G cells during fasting. To investigate the effect of fasting on intestinal somatostatin, we determined tissue somatostatin concentration by radioimmunoassay, somatostatin mRNA expression by Northern analysis and reverse transcription polymerase chain reaction (RT-PCR), and mRNA expression for somatostatin receptor subtypes (sst) 1-5 by RT-PCR in ileum and colon of rats either freely fed or food-deprived for 48 h. In the colon, fasting increased somatostatin concentration, somatostatin mRNA expression, and mRNA expression for two receptor subtypes (sst2 and sst3). In the ileum, no change of somatostatin peptide concentration and receptor subtype mRNA expression was demonstrated; only somatostatin mRNA expression was augmented by fasting. These results suggest that in rat colon, fasting for 48 h increases somatostatin synthesis and receptor subtype expression. These changes may be important in maintaining homeostasis during starvation.

Somatic mutation of mitochondrial DNA in Helicobacter pylori-associated chronic gastritis in patients with and without gastric cancer.

Somatic mutations of the mitochondrial DNA (mtDNA) are associated with development of various types of human cancer. To elucidate the significance of somatic mutations of the mtDNA in gastric carcinogenesis, we examined mtDNA mutations in gastric cancers and in Helicobacter pylori-associated chronic gastritis (H. pylori-CG), which is associated with an increased risk for gastric cancer development. Specimens of gastric cancer and gastric mucosa were obtained from 73 gastric cancer patients with H. pylori-CG, 75 cancer-free H. pylori-CG patients and 30 H. pylori-negative healthy subjects. Mutations of a specific mononucleotide repeat (D310) of the mtDNA were examined by microsatellite assay. mtDNA mutations were detected in 9 of 56 (16%) gastric cancers, in 10 of 148 (7%) H. pylori-CG and none of the 30 H. pylori-negative healthy subjects. mtDNA mutations in H. pylori-CG were significantly more frequent in gastric cancer patients than in cancer-free patients (12% vs. 1%, p=0.008). In addition, mtDNA mutations in H. pylori-CG were significantly more frequent in patients with mtDNA mutated gastric cancer than in patients with mtDNA unmutated gastric cancer (66% vs. 4%, p<0.001). These data suggest that somatic mutations of the mtDNA may be involved in the early stages of gastric carcinogenesis.