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Background/aim: In gastric cancer, accurate determination of human epidermal growth factor receptor type 2 (HER2) status is crucial for treatment decision-making. However, the optimal formalin fixation time of gastric cancer specimens for HER2 status determination remains unestablished. Here, we investigated real-world data on formalin overfixation and its effect on HER2 status determination in gastric cancer., Patients and Methods: We comprehensively analyzed HER2 testing results in 228 gastric cancer specimens, including those subjected to formalin overfixation. Subsequently, we divided 52 resected specimens of advanced gastric cancer into three groups and studied the effects of short-term (6-72 h) and long-term (1 and 2 weeks) fixation on HER2 status determination using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH)., Results: A total of 21.5% (49/228) of the specimens were HER2-positive, whereas 78.5% (179/228) were negative. Among the HER2-negative specimens, no biopsies were overfixed, whereas 12.5% (9/72) of the surgical resection specimens were overfixed. The HER2 status of the 6-72-h group was 82.7% and 76.9% identical to that of the 1- and 2-week groups, when determined using IHC, and 73.1% and 36.5%, when determined using FISH, respectively. However, HER2 determination was not feasible in 26.9% and 63.5% of the specimens in the 1- and 2-week groups, respectively., Conclusion: Formalin overfixation may hinder the determination of HER2 status and should be avoided in gastric cancer sample preparation., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The patient is a woman in her 80s who underwent a partial gastrectomy for a gastric GIST 14 years ago. This time, she presented our department with upper abdominal distention and computed tomography revealed an 18 cm-sized cystic lesion in the left lobe of the liver. Since a nodule enhancement was observed in the cyst, malignant disease such as hepatic cystadenocarcinoma could not be ruled out and surgical resection was performed. Pathological examination revealed liver metastasis of gastric GIST. In Japan, only 14 cases have been reported showing such late recurrence with liver metastasis more than 10 years after resection of a primary tumor, including our case. In addition, the cystic finding in this case made preoperative diagnosis difficult because a needle biopsy could not be performed to obtain a pathological diagnosis.

The questionnaire survey was conducted on treatment strategies for gastric cancer with peritoneal dissemination at 7 institutions, including 5 designated cancer hospitals in Yamaguchi prefecture. Staging laparotomy was performed at 6 out of 7 institutions. Six out of 7 institutions selected the treatment strategy for P0CY1 cases", upfront resection and adjuvant therapy". The doublet chemotherapy was performed by S-1 plus platinum or taxane. Surgical treatment for P1 cases, conversion gastrectomy was considered at all institutions when it was judged that R0 resection was possible after induction chemotherapy. Chemotherapy for P1 cases was treated according to the guidelines at all institutions, and the regimen was not changed depending on the peritoneal dissemination.

Euglena gracilis is widely utilized as food or supplement to promote human and animal health, as it contains rich nutrients. In this study, we administered spray-dried powder of E. gracilis and paramylon, β-glucan stored in E. gracilis cells, to A4gnt knockout (KO) mice. A4gnt KO mice are a mutant mouse model that spontaneously develops gastric cancer through hyperplasia-dysplasia-adenocarcinoma sequence in the antrum of the stomach, and we observed the effects of E. gracilis and paramylon on the early involvements of A4gnt KO mice. Male and female 10-week-old A4gnt KO mice and their age-matched wildtype C57BL/6J mice were orally administered with 50 mg of E. gracilis or paramylon suspended in saline or saline as a control. After 3-week administration, animals were euthanatized and the stomach was examined histopathologically and immunohistochemically. Gene expression patterns of the stomach, which have been reported to be altered with A4gnt KO, and IgA concentration in small intestine were also analyzed with real-time PCR and ELISA, respectively. Administration of Euglena significantly reduced the number of stimulated CD3-positive T-lymphocytes in pyloric mucosa of A4gnt KO mice and tend to reduce polymorphonuclear leukocytes infiltration. Euglena administration further downregulated the expression of Il11 and Cxcl1 of A4gnt KO mice. Euglena administration also affected IgA concentration in small intestinal contents of A4gnt KO mice. Paramylon administration reduced the number of CD3-positive lymphocytes in pyloric mucosa of A4gnt KO mice, and downregulated the expressions of Il11 and Ccl2 of A4gnt KO mice. Although we found no significant effects on gross and microscopic signs of gastric dysplasia and cell proliferation, the present study suggests that the administration of Euglena and paramylon may ameliorate the early involvements of A4gnt mice through the effects on inflammatory reactions in the gastric mucosa. The cancer-preventing effects should be studied with long-term experiments until actual gastric cancer formation.

Case 1: The patient was a 74-year-old man with a performance status(PS)of 0. He was referred to our department for pyloric gastric cancer with multiple liver, lung, and lymph node metastases. We started chemotherapy after making the diagnosis of an unresectable gastric cancer. During chemotherapy, the hemoglobin level dropped due to bleeding from the tumor. We attempted endoscopic hemostasis, which was not successful; therefore, we attempted a palliative radiotherapy. The total dose was 30 Gy in 10 Fr and hemostasis was achieved on the 10th day from the start of the radiotherapy. There were no adverse events due to the radiation, and the chemotherapy could be restarted 5 days after the end of the radiotherapy. Case 2: The patient was a 78-year-old man with a PS of 2. He was referred to our department because of vomiting and anemia. As a result of a close inspection, we made the diagnosis of an unresectable gastric body cancer with para-aortic lymph node metastasis and peritoneal dissemination, for which chemotherapy was initiated. Anemia was observed at the first visit, and we started radiotherapy to stop the tumor bleeding. The total dose was 30 Gy in 10 Fr, and hemostasis was achieved on the 12th day. There were no adverse events during the radiotherapy, and chemotherapy could be continued. Palliative radiotherapy is an available method of hemostasis that is less invasive than surgery or transcatheter arterial embolization and can be expected to have a certain effect for gastric cancer bleeding, although it takes several days to obtain a therapeutic effect.

A questionnaire survey was conducted on third-line chemotherapy of unresectable or recurrent gastric cancer for 23 doctors involved in gastric cancer treatment in Yamaguchi prefecture. Eighty-seven% of doctors replied that third-line chemotherapy transfer rate was less than 60% of patients, and 13% of doctors replied that third-line chemotherapy transfer rate was more than 60% of patients. Nivolumab was the first-choice regimen for third-line chemotherapy, with 87% of doctors, 4% of doctors each for CPT-11, trifluridine/tipiracil hydrochloride, and docetaxel. Timing of switching from the second-line therapy to the third-line therapy, RECIST PD was the highest in 61% of doctors, with other baseline PD in 43% of doctors, clinical PD in 43% of doctors, and tumor marker elevation in 39% of doctors. The timing of regimen switching after using the immune checkpoint inhibitor was PD at the first CT in 43% of doctors, PD at the second CT in 43% of doctors. Nivolumab was used as the first-choice in more than 80% of the regimens for gastric cancer third-line chemotherapy in Yamaguchi prefecture. There was a difference in consciousness among doctors regarding the timing of switching from second- line to third-line chemotherapy and the timing of switching from nivolumab to fourth-line therapy.

A questionnaire survey was conducted on the administration of secondary chemotherapy for unresectable or recurrent gastric cancer by 43 doctors involved in gastric cancer treatment in the Yamaguchi prefecture. Seventy-one percent of doctors replied that the secondary chemotherapy transfer rate was more than 60%, and 29% of doctors replied that the secondary chemotherapy transfer rate was less than 60%. The reasons why patients could not be transferred to secondary chemotherapy included inferior performance status, poor general condition, and elderly age, among others. Weekly paclitaxel plus ramucirumab therapy was used as the major regimen of secondary chemotherapy by 95% of doctors. In addition, 93% of doctors indicated that weekly nab-paclitaxel would be an option for gastric cancer secondary chemotherapy. Secondary chemotherapy for gastric cancer in the Yamaguchi prefecture has a standard regimen selection according to guidelines.

Background: There have been very few reports of risk score models for the development of gastric cancer. The aim of this study was to develop and validate a risk assessment tool for discerning future gastric cancer risk in Japanese., Methods: A total of 2444 subjects aged 40 years or over were followed up for 14 years from 1988 (derivation cohort), and 3204 subjects of the same age group were followed up for 5 years from 2002 (validation cohort). The weighting (risk score) of each risk factor for predicting future gastric cancer in the risk assessment tool was determined based on the coefficients of a Cox proportional hazards model in the derivation cohort. The goodness of fit of the established risk assessment tool was assessed using the c-statistic and the Hosmer-Lemeshow test in the validation cohort., Results: During the follow-up, gastric cancer developed in 90 subjects in the derivation cohort and 35 subjects in the validation cohort. In the derivation cohort, the risk prediction model for gastric cancer was established using significant risk factors: age, sex, the combination of Helicobacter pylori antibody and pepsinogen status, hemoglobin A1c level, and smoking status. The incidence of gastric cancer increased significantly as the sum of risk scores increased (P trend < 0.001). The risk assessment tool was validated internally and showed good discrimination (c-statistic = 0.76) and calibration (Hosmer-Lemeshow test P = 0.43) in the validation cohort., Conclusions: We developed a risk assessment tool for gastric cancer that provides a useful guide for stratifying an individual's risk of future gastric cancer.

In recent decades, there has been considerable worldwide progress in the treatment of gastric cancer. Gastrectomy with a modified D2 lymphadenectomy (sparing the distal pancreas and spleen) has increasingly gained acceptance as a preferable standard surgical approach among surgeons in the East and the West. Despite growing consensus significant differences still exist in surgical techniques in clinical trials and clinical practices secondary to variations in epidemiology, clinicopathologic features, and surgical outcomes among geographic regions. In addition, Western physicians tend to prefer adjuvant chemotherapy and radiotherapy after surgery instead of using S-1 chemotherapy, as is the preference in the East., (Copyright © 2017 Elsevier Inc. All rights reserved.)

We report a case of heterochronic cervical esophageal cancer with a subcutaneous abscess successfully treated using chemoradiation. A 68-year-old man underwent esophagectomy for middle thoracic esophageal cancer 13 years ago. In April 2015, upper gastrointestinal endoscopy revealed advanced residual cervical esophageal cancer. Enhanced CT showed a massive tumor with a subcutaneous abscess, and the tumor had invaded the left internal jugular vein and the 8th cervical spine. We firstly performed abscess drainage and administered antibiotics. After the inflammation decreased, we started chemora- diation. Chemotherapy consisted of 70mg/m / 2 cisplatin(day 1)and 700 mg/m2 5-FU(days 1-5)combined with almost 60 Gy radiotherapy(1.8 Gy/day, 5 days/week, days 1-49). We administered cisplatin and 5-FU only once because renal dys- function occurred. Consequently, we changed the regimen to weekly 100mg/m2 paclitaxel administration(day 1). After 2 months, a clinical complete response(CR)was obtained and we stopped chemotherapy. Eight months after chemotherapy cessation, the patient shows no sign of recurrence. These results suggest that chemoradiation is an effective treatment for cervical esophageal cancer with a subcutaneous abscess.

A 56-year-old man who underwent a radical operation and adjuvant chemotherapy for recurrent rectal cancer had been followed-up and had no recurrence for one and a half years. Thereafter, CT and upper endoscopy showed a submucosal tumor with a central recess developing in the stomach wall. It was suspected that the gastric tumor was either a metastasis of rectal cancer or a submucosal tumor-like gastric cancer. We performed a radical operation to remove the lesion. In the resected specimen, immunohistopathological findings including HER2 status suggested that the gastric tumor was a primary gastric cancer resembling a submucosal tumor.

Purpose: Free cancer cells shed from the serosal surface of gastric cancer result in peritoneal dissemination. The aim of this study was to clarify the extent of tumor cell implantation due to surgical manipulation during gastrectomy., Methods: The participants comprised 34 patients who underwent curative gastrectomy for gastric cancer with macroscopic serosal invasion. Two types of cytology were obtained from each patient: (1) cytology from the wound dressing material that covered the serosal invasion area during the operation (Covering Cy), and (2) cytology of the intraperitoneal wash samples (Lavage Cy)., Result: Thirteen patients showed no serosal invasion histopathologically, and all of these patients had negative results for both Lavage Cy and Covering Cy. Among the 21 patients with histopathologically confirmed serosal invasion, six had positive results for both Lavage Cy and Covering Cy, three showed positive findings for Covering Cy alone, one had positive Lavage Cy alone and 11 patients had negative results for both Lavage Cy and Covering Cy. Disseminated recurrence developed in 10 patients. Seven of the nine patients with positive Covering Cy developed disseminated recurrence, compared to three of 12 patients with negative Covering Cy. Positive Covering Cy findings were significantly associated with disseminated recurrence (p < 0.05)., Conclusion: We demonstrated that the intraoperative dissemination of gastric cancer can occur during gastrectomy.

Background: Serum pepsinogen (sPG) levels have been established as a good marker of chronic atrophic gastritis and the sequential occurrence of gastric cancer. However, there have been few prospective investigations which investigated the predictive performance of sPG for future gastric cancer incidence., Subjects and Methods: We prospectively followed-up a total of 2446 community-dwelling Japanese aged ≥ 40 years for 10 years and used the Youden's index to determine the cutoff values of the pepsinogen I level and pepsinogen I/II ratio to accurately discriminate gastric cancer events. Predictive performance of sPG was assessed by ROC curve., Results: During the follow-up, 69 subjects developed gastric cancer. The most predictive sPG test criteria were determined to be a pepsinogen I level ≤ 59 ng/ml and pepsinogen I/II ratio ≤ 3.9. The sensitivity and specificity of these criteria to discriminate the actual occurrence of gastric cancer were 71.0% and 69.2%, respectively. The area under the ROC curve for gastric cancer occurrence increased significantly by adding the sPG test to the model that included the status of Helicobater pylori infection and other potential risk factors (from 0.742 to 0.809; p for difference in the area < 0.001)., Conclusions: This study determined the optimal sPG test criteria for predicting gastric cancer occurrence over 10 years in a general Japanese population. These criteria would be effective to screen for individuals at high risk of this disease.

Background: The results of prospective studies examining the association between dietary vitamin A intake and the risk of gastric cancer have often been conflicting. The objective of this study was to investigate this issue in a general Japanese population., Methods: A total of 2,467 community-dwelling Japanese subjects aged 40 years or older were followed up prospectively for 14 years. Dietary vitamin A intake was estimated using a semiquantitative food frequency method., Results: During the follow-up period, gastric cancer developed in 93 subjects. The age- and sex-adjusted incidence of gastric cancer rose progressively with increasing levels of dietary vitamin A intake: at 2.2, 3.0, 3.8, and 4.5 per 1,000 person-years for quartile groups defined by dietary vitamin A intake levels of <639, 639-837, 838-1,061, and >1,061 μg retinol equivalents (RE)/day, respectively (P for trend <0.01). The risk of gastric cancer was significantly higher in the fourth quartile than in the first one even after multivariate adjustment [hazard ratio (HR) = 1.47, 95% confidence interval (CI) = 0.70-3.09, P = 0.30 for the second quartile; HR = 1.85, 95% CI = 0.82-4.18, P = 0.14 for the third quartile; HR = 2.96, 95% CI = 1.12-7.80, P = 0.03 for the fourth quartile]. Comparable effects of vitamin A intake were observed irrespective of the location or histological type of gastric cancer. The HR for gastric cancer increased significantly only in subjects with a combination of high vitamin A intake (>1,061 μg RE/day) and Helicobacter pylori infection., Conclusions: Our findings suggest that dietary vitamin A intake is clearly associated with the risk of gastric cancer in the general Japanese population.

The authors examined the association between white blood cell (WBC) count and the development of gastric cancer in a 19-year follow-up study of 2,558 Japanese subjects aged ≥40 years (1988-2007). The subjects were stratified into 4 groups according to baseline WBC quartile (≤4.4, 4.5-5.2, 5.3-6.3, or ≥6.4 × 10(3) cells/μL). During follow-up, 128 subjects developed gastric cancer. The age- and sex-adjusted incidence of gastric cancer increased linearly with higher WBC level: 1.7, 2.6, 3.9, and 5.4 per 1,000 person-years, respectively, for the 4 quartile groups (P for trend < 0.01). The risk of gastric cancer was 2.22-fold (95% confidence interval: 1.19, 4.14) higher in the highest WBC quartile group than in the lowest group after adjustment for confounding factors. With respect to Helicobacter pylori infection status, H. pylori-seropositive subjects in the highest WBC quartile group showed a significantly greater risk of gastric cancer than those in the lower 3 quartile groups, whereas such an association was not observed in H. pylori-seronegative subjects. There was no evidence of heterogeneity in the association (P for heterogeneity = 0.65). The study findings suggest that higher WBC levels are a risk factor for gastric cancer, especially in subjects with H. pylori infection.

A 80-year-old female was referred to our hospital for hematomesis. An abdominal CT revealed a heterogeneous giant tumor of about 11 cm, rich in vascularity, extending from the gastric fundus, beyond the upper side of the spleen, to the left thoracic diaphragm. Gastroscopy showed a 5 cm submucosal tumor with a visible vessel at the gastric fundus. After biopsy was performed, she was diagnosed with a c-kit-positive gastrointestinal stromal tumor (GIST)of the stomach. Following endoscopic hemostasis for gastric bleeding, imatinib mesilate was administered. The tumor reduced markedly, and vascularity in the tumor was diminished, the visible vessels of the tumor disappeared. For curative resection, total gastrectomy with a distal pancreato -splenectomy and a left diaphgram resection is necessary, but surgery was high-risk for this patient because she was advanced in age. She is now achieving a good partial response without surgery.

Background & Aims: Although diabetes mellitus and hyperglycemia are considered to be possible risk factors for various types of malignancy, the epidemiologic evidence concerning gastric cancer is scarce. The aim of this study was to evaluate the impact of hemoglobin A1c (HbA1c) levels on gastric cancer occurrence and their interaction with Helicobacter pylori infection., Methods: A total of 2603 Japanese subjects aged>or=40 years were stratified into 4 groups according to baseline HbA1c levels (or=7.0%) and followed up prospectively for 14 years., Results: During the follow-up, 97 subjects developed gastric cancer. The age- and sex-adjusted incidence of gastric cancer significantly increased in the 6.0%-6.9% (5.1 per 1000 person-years; P<.05) and >or=7.0% groups (5.5 per 1000 person-years; P<.05) compared with the 5.0%-5.9% group (2.5 per 1000 person-years), whereas it was slightly but not significantly high in the or=7.0% group). Among subjects who had both high HbA1c levels (>or=6.0%) and Helicobacter pylori infection, the risk of gastric cancer was dramatically elevated (interaction term, P=.004)., Conclusions: Our findings suggest that casual hyperglycemia is a risk factor for gastric cancer and is a possible cofactor increasing the risk posed by Helicobacter pylori infection.

The authors assessed the separate and joint influences of cigarette smoking and Helicobacter pylori infection on the development of gastric cancer in a population-based prospective study. A total of 1,071 Japanese men aged > or =40 years were followed up prospectively for 14 years (1998-2002). Compared with that for current nonsmokers, the multivariate-adjusted hazard ratios of gastric cancer for smokers of 1-9, 10-19, and > or =20 cigarettes per day were 1.36 (95% confidence interval (CI): 0.50, 3.71), 1.93 (95% CI: 1.01, 3.67), and 1.88 (95% CI: 1.02, 3.43), respectively. The risk of gastric cancer increased steeply for subjects who had both a smoking habit and H. pylori infection compared with those who did not have both risk factors (hazard ratio = 11.41, 95% CI: 1.54, 84.67). If causal, the estimated population attributable fraction of gastric cancer for cigarette smoking was approximately half that for H. pylori infection (28.4% vs. 56.2%). The overlap of the population attributable fractions for the 2 factors was 49.6%. Findings suggest that cigarette smoking and H. pylori infection are significant risk factors for gastric cancer in Japanese men, and the magnitude of their combined influence is considerable.

We describe a 51-year-old man case of a huge gastric cancer with an initial presentation of isolated brain metastasis. The patient was successfully managed by gamma knife radiotherapy, followed by chemotherapy using 5-fluorouracil and cisplatin. He has continued oral administration of TS-1 on an outpatient basis with disease free survival for more than one year.

Purpose: The pathogenesis and clinical heterogeneity of gastric diffuse large B-cell lymphoma (DLBCL) are poorly understood. We have comprehensively investigated the incidence and clinical significance of lymphoma-associated chromosomal translocations, particularly those involving the immunoglobulin heavy chain (IGH) gene locus, in a large series of gastric DLBCL., Experimental Design: One hundred forty-one cases of primary gastric DLBCL [58 with mucosa-associated lymphoid tissue (MALT) lymphoma and 83 without MALT lymphoma] were enrolled. Translocations involving BCL6, c-MYC, FOXP1, MALT1, and IGH were investigated using interphase fluorescence in situ hybridization. In positive cases, additional fluorescence in situ hybridization was done with appropriate probes for potential partner genes. Cases were classified into germinal center B-cell-like (GCB) or non-GCB subgroups by immunophenotyping with CD10, BCL6, and MUM1., Results: Translocations involving IGH were detected in 36 (32%) of 111 cases; their partner genes included BCL6 (n = 10), c-MYC (n = 5), and FOXP1 (n = 3) but remained unknown in the remaining 18 cases. t(14;18)/IGH-BCL2, t(14;18)/IGH-MALT1, and t(1;14)/BCL10-IGH were not detected in any case. t(11;18)/API2-MALT1 was detected in none of the cases, except for one case of DLBCL with MALT lymphoma, which showed positive signals only in MALT lymphoma cells. IGH-involved translocation was associated with younger age but not with any other clinicopathologic factors including GCB or non-GCB immunophenotypes. Cox multivariate analysis revealed that IGH-involved translocation, in addition to younger age and early stage, was an independent prognostic factor for better overall and EFSs., Conclusion: IGH-involved translocations are frequent in gastric DLBCL and seem to identify cases with favorable prognosis.

The results of prospective studies that have examined the association between serum cholesterol levels and the incidence of gastric cancer remain controversial. To examine this issue in a general population, a total of 2,604 subjects aged 40 years or older were followed up prospectively for 14 years. During the follow-up period, gastric cancer developed in 97 subjects. The age- and sex-adjusted incidence of gastric cancer by quartiles of serum cholesterol level, namely, <4.06, 4.06-5.32, 5.33-6.04 and >or=6.05 mmol/L, were 3.9, 3.3, 3.1 and 2.1 per 1,000 person-years, respectively. The risk of gastric cancer increased with decreasing cholesterol level (age- and sex-adjusted hazard ratio [HR], 1.22; 95% confidence interval [CI], 1.01-1.49; p = 0.04 for a decrease of 1 mmol/L in serum cholesterol level). This inverse association remained unchanged even after adjustment for other confounding factors, namely, Helicobacter pylori infection, atrophic gastritis, family history of malignant neoplasm, smoking habits, body mass index, hemoglobin A1c, white blood cell count and dietary factors (adjusted HR, 1.28; 95% CI, 1.03-1.58; p = 0.02). This association was significant for intestinal-type gastric cancers, but not for diffuse-type. As regards cancer stage, the inverse cholesterol-cancer association was marginally significant for early gastric cancer after multivariate-adjustment (adjusted HR, 1.25; 95% CI, 0.97-1.61; p = 0.09), but was not for advanced gastric cancer probably due to the small number of cases. In conclusion, our findings suggest that low serum cholesterol levels are an independent risk factor for developing gastric cancer, especially intestinal-type gastric cancer., ((c) 2007 Wiley-Liss, Inc.)

Background and Aims: There is a need for genetic biomarkers to guide prognosis and management of gastric mucosa-associated lymphoid tissue (MALT) lymphomas. We assessed the incidence and clinical significance of the MALT lymphoma-associated genetic abnormalities t(11;18)/API2-MALT1, t(1;14)/BCL10-IGH, t(14;18)/IGH-MALT1, t(3;14)/FOXP1-IGH, and extra copies of MALT1 and FOXP1 in gastric MALT lymphomas from Japan., Methods: The presence of translocations and copy number changes involving MALT1, IGH and FOXP1 were assessed in 90 cases of gastric MALT lymphoma using interphase fluorescence in situ hybridisation (FISH). In cases carrying a MALT1 translocation, FISH for API2-MALT1 was performed, whereas in those carrying an IGH translocation, FISH was performed for BCL10, BCL6, BCL2, c-MYC and/or CCND1., Results: t(11;18)/API2-MALT1 was detected in 18 of 87 (21%) cases and was significantly associated with Helicobacter pylori-negativity, resistance to H pylori eradication and Bcl10 nuclear expression. Four of 68 (6%) cases carried a translocation involving IGH and FOXP1 (n = 1), BCL2 (n = 1) or an unknown partner (n = 2). Neither t(1;14)/BCL10-IGH nor t(14;18)/IGH-MALT1 was detected. Extra copies of MALT1 and FOXP1 were detected in 18 of 71 (25%) cases and 10 of 59 (17%) cases, respectively. The presence of extra copies of MALT1 was significantly associated with progression or relapse of lymphoma, and was an independent adverse prognostic factor for event-free survival as determined by multivariate analysis., Conclusions: t(11;18)/API2-MALT1 is frequent, whereas IGH-involved translocations are rare in gastric MALT lymphoma in Japan. The presence of extra copies of MALT1, often suggestive of partial or complete trisomy 18, is a frequent genetic aberration in gastric MALT lymphoma, which appears to predict adverse clinical behaviour.

Two cases of primary gastric T-cell lymphoma associated with human T lymphotropic virus type 1 (HTLV-1) are presented. Case 1 was a 54-year-old man who had multiple ulcerating tumors in the lower corpus and gastric antrum. Case 2, a 60-year-old man, showed a large ulcerating tumor in the upper corpus. Both patients were positive for serum anti-HTLV-1 antibody and for the monoclonal integration of HTLV-1 proviral DNA in the tumor cells by Southern blot analysis. The patients were thus diagnosed as having primary gastric T-cell lymphoma associated with HTLV-1 of stage II(1). Case 1 underwent total gastrectomy followed by chemotherapy, while Case 2 was treated by chemotherapy and radiotherapy. Both patients have been in complete remission for more than 4 years (96 months in Case 1 and 50 months in Case 2) after the treatments. Although primary gastric T-cell lymphomas associated with HTLV-1 is characterized by an extremely poor prognosis, the present cases suggest that in the early stage, long-term survival can possibly be achieved with appropriate treatments.

The aim of this investigation was to clarify the histological characteristics of gastric cancer in the young. Twenty-three surgically resected specimens of young patients (under 30 years of age; young group) with intramucosal cancer of poorly differentiated type and 42 surgically resected specimens of elderly patients (more than 40 years of age; elderly group) with tumors of the identical depth and histological type were examined. The degree of gastritis and Helicobacter pylori (H. pylori) infection was evaluated according to the updated Sydney system. The incidence of H. pylori infection was significantly higher in the young group than in the elderly group (96 vs 36%, P<0.05). Within the background mucosa, antral chronic inflammatory infiltrates with lymphoid-follicle hyperplasia were more severe, and intestinal metaplasia was less frequent in the young group than in the elderly group. Glandular atrophy was not different between the two groups. Intramucosal gastric adenocarcinomas of poorly differentiated type in the young may be associated with H. pylori infection with antral chronic inflammation with lymphoid-follicle hyperplasia, regardless of the existence of intestinal metaplasia within the background gastric mucosa.

The results of prospective studies of the association between dietary salt intake and gastric cancer occurrence remain controversial. To examine this issue in a cohort study of a general population, 2,476 subjects aged 40 years or older were stratified into 4 groups according to the amount of daily salt intake: namely, <10.0, 10.0-12.9, 13.0-15.9, and > or = 16.0 per day and were followed up prospectively for 14 years. During the follow-up period, 93 subjects developed gastric cancer. The age- and sex-adjusted incidence was significantly higher in the second to fourth groups than in the first group (age- and sex-adjusted hazard ratio [95% confidence interval], 2.42 [1.24-4.71] for the second group; 2.10 [1.03-4.30] for the third group; 2.98 [1.53-5.82] for the fourth group). This association remained substantially unchanged even after adjusting for other confounding factors such as age, sex, Helicobacter pylori infection, atrophic gastritis, medical history of peptic ulcer, family history of cancer, body mass index, diabetes, total cholesterol, physical activity, alcohol intake, smoking habit and other dietary factors. In the stratified analysis, a significant salt-cancer association was observed only in subjects who had both Helicobacter pylori infection and atrophic gastritis (age- and sex-adjusted hazard ratio, 2.87 [1.14-7.24]). Our findings suggest that high dietary salt intake is a significant risk factor for gastric cancer; moreover, this association was found to be strong in the presence of Helicobacter pylori infection with atrophic gastritis.

The authors examined whether a serum pepsinogen test (SPT) based on the combination of the serum pepsinogen I level and pepsinogen I/II ratio is a good predictor of gastric cancer occurrence in a general Japanese population. A total of 2,446 subjects aged > or =40 years were classified into negative, positive, and strong-positive SPT groups and were followed prospectively for 14 years (1988-2002). Compared with that for the negative SPT group (26 men, 10 women), gastric cancer incidence increased significantly for both men (n = 17; age-adjusted hazard ratio = 4.56, 95% confidence interval: 2.42, 8.60) and women (n = 6; age-adjusted hazard ratio = 5.84, 95% confidence interval: 2.00, 17.11) in the strong-positive SPT group. It was also significantly higher in the positive SPT group for men (n = 23; age-adjusted hazard ratio = 3.91, 95% confidence interval: 2.23, 6.86). These associations did not attenuate even after adjustment for other comprehensive risk factors. Stratified analysis revealed significant associations between the SPT and development of intestinal-type gastric cancer as well as of cancer in both Helicobacter pylori-negative and -positive subjects. These findings suggest that the SPT can serve as a predictor of intestinal-type gastric cancer, irrespective of H. pylori infection.

A 77-year-old man was admitted to our hospital with complaints of abdominal pain and body weight loss. Esophagogastroduodenoscopy on admission revealed large ulcerative tumor in the entire region from upper to lower body of the stomach. We diagnosed gastric malignant lymphoma, diffuse large B-cell type and determined stage IV according to the Lugano International Conference classification. Due to gastric perforation occurred on day 4 of chemotherapy, total gastrectomy and partial resection of the transverse colon were performed. Complete remission was achieved by 2 cycles of postoperative chemotherapy together with rituximab.

Background: Although caspase recruitment domain (CARD) membrane-associated guanylate kinase (MAGUK) protein 1 (CARMA1) and CARD9 play important roles in lymphocyte activation, the significance of CARMA1 and CARD9 in the pathogenesis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma remains to be elucidated., Methods: By using reverse transcription-polymerase chain reaction analysis, the expression levels of mRNA of CARMA1, CARD9, Bcl10, and the apoptosis inhibitor 2 (API2)-MALT1 chimeric transcript were determined in tissue specimens from 65 patients with primary gastric B-cell lymphoma (43 patients with low-grade MALT lymphoma, 16 patients with MALT lymphoma plus diffuse large B-cell lymphoma [DLBL], and 6 patients with DLBL without MALT lymphoma) and in tissue specimens from 18 patients with chronic gastritis. The expression levels of CARMA1 and BCL10 were examined immunohistochemically in 30 patients with lymphoma., Results: CARMA1 mRNA was detected in 55% of lymphoma patients but in only 17% of chronic gastritis patients. The positive rates for CARD9, Bcl10, and API2-MALT1 chimeric transcript in the lymphoma patients were 48%, 98%, and 8%, respectively, whereas the 3 molecules were not detected in any specimens from patients with chronic gastritis. The expression of CARMA1 and CARD9 was frequent in the Helicobacter pylori-negative patients (100% and 86%, respectively), in the API2-MALT1 chimeric transcript-positive patients (100% and 100%, respectively), and in the specimens from patients who did not respond to H. pylori eradication (76% and 71%, respectively). In addition, CARMA1 expression was positive more frequently in patients of DLBL without MALT lymphoma (100%) than in patients of MALT lymphoma (51%). CARMA1 protein expression was correlated significantly with the expression of CARMA1 mRNA and also with the expression of nuclear BCL10., Conclusions: The overexpression of CARMA1 and CARD9 presumably is associated with the development or progression of gastric B-cell lymphoma, especially among patients who have disease in which the pathogenesis is not related to H. pylori., ((c) 2005 American Cancer Society.)

Background: The goals of the current study were to elucidate the long-term outcome of Helicobacter pylori eradication therapy for gastric mucosa-associated lymphoid tissue (MALT) lymphoma and to clarify the therapeutic efficacy of stomach-conserving treatments for patients not responding to eradication therapy., Methods: Ninety-six patients with gastric MALT lymphoma, including 17 patients with areas of diffuse large B-cell lymphoma, were treated by H. pylori eradication. Patients not responding to eradication therapy underwent either a gastrectomy, multiagent chemotherapy, oral monochemotherapy (OMC), or radiotherapy (RT). Predictive factors for the response to eradication therapy, overall survival (OS), and event-free survival (EFS) were determined by the Kaplan-Meier analysis with the log-rank test. The efficacy of second-line treatment was compared between OMC and RT., Results: After eradication therapy, 62 (65%) patients achieved complete disease remission (CR). Transient histologic disease recurrence was confirmed in 4 (6.5%) of 62 patients with CR during the follow-up (median, 37.5 months). The OS and EFS probabilities after 5 years were 0.96 and 0.80, respectively. Second-line treatment was performed in 31 patients; gastrectomy in 4 patients, multiagent chemotherapy in 5 patients, OMC in 12 patients, and RT in 10 patients. There were no differences in the CR rate, OS, EFS, or toxicity between the OMC and RT groups., Conclusions: H. pylori eradication therapy was an effective first-line treatment for patients with gastric MALT lymphoma, which led to a favorable long-term outcome. OMC and RT had an equivalent efficacy as a second-line treatment in nonresponding patients to eradication therapy., ((c) 2005 American Cancer Society.)

To examine secular trends in the incidence and mortality of gastric cancer in a Japanese community, Hisayama, we established three study-cohorts of Hisayama residents aged > or =40 years in 1961 (1637 subjects), 1974 (2054), and 1988 (2602). Each cohort was followed up for ten years. The age-standardized mortality from gastric cancer significantly decreased from 2.4 per 1000 person-years in the first cohort to 0.8 in the third cohort for men, and from 1.0 to 0.2, respectively, for women (p < 0.01 for trend in both sexes). The five-year survival rate after gastric cancer significantly improved from the first (32.6%) to the third cohort (73.0%, p < 0.01) for men and from 43.2% to 72.3% (p < 0.05), respectively, for women. The age-standardized incidence of cancer in men was not different among the cohorts (4.3 per 1000 person-years in the first, 5.0 in the second, and 4.9 in the third cohort), while it decreased significantly in women (2.0, 1.8, and 1.2, respectively, p < 0.01 for trend). In conclusion, our findings suggest that in a Japanese population, the mortality from gastric cancer declined during the past 40 years, due mainly to the improvement of survival in both sexes and a decrease in the incidence for women.

We treated a 39-year-old woman with hypoproteinemia and anemia who had profuse gastric polyposis. Radiographic and endoscopic examination showed numerous polyps restricted to the stomach. The patient had pulmonary arteriovenous malformations in the left lung. Histological examination of the resected stomach revealed the gastric polyposis to be composed of cystic dilatation of the glands with small areas of adenocarcinoma. These findings were compatible with gastric juvenile polyposis (GJP) accompanied by gastric cancer. Analysis of genomic DNA revealed that the patient had truncating mutation of SMAD4, a responsible gene for juvenile polyposis (JP). Our case suggests that SMAD4 is possibly a responsible gene for GJP.

Objective: Several studies have shown associations between diabetes and various types of cancer other than gastric cancer. The aim of this cohort study was to evaluate the impact of fasting plasma glucose (FPG) levels on gastric cancer occurrence., Research Design and Methods: A total of 2,466 Japanese subjects aged > or =40 years were stratified into three groups according to FPG tertiles (<5.3 mmol/l, low FPG; 5.3-5.8 mmol/l, modest FPG; >5.8 mmol/l, high FPG) and followed up prospectively for 9 years., Results: During the follow-up, 66 subjects experienced gastric cancer. In men, the age-adjusted incidences were significantly higher in the modest-FPG (7.0 per 1,000 person-years, P < 0.05) and high-FPG (7.2, P < 0.05) groups than in the low-FPG group (2.2). In women, the high-FPG group also had a significantly higher age-adjusted incidence of gastric cancer compared with the low-FPG group (2.5 vs. 0.8, P < 0.05). The multivariate analysis with Cox's proportional hazards model revealed that the risks of gastric cancer in the modest-FPG (relative risk [RR] 2.3 [95% CI 1.1-5.0]) and high-FPG (3.1 [1.5-6.4]) groups were significantly higher than that in the low-FPG group, even after adjusting for other comprehensive risk factors, including Helicobacter pylori status, smoking, and dietary factors. However, this FPG-cancer association was observed only among H. pylori-seropositive subjects., Conclusions: Our findings suggest that a modest increase in FPG is a risk factor for gastric cancer and that hyperglycemia is a possible cofactor increasing the risk posed by Helicobacter pylori infection.

While the hyperplasia-neoplasia sequence of enterochromaffin-like (ECL) cells has been proposed in the pathogenesis of type I gastric carcinoids, the criteria for distinction between hyperplastic endocrine cell micronest (ECM) and neoplastic ECM have not been established. The aims of this study were to clarify differences between the hyperplasia and neoplasia of ECL cells and determine the optimal classification system for gastric ECL cell proliferations in type A gastritis. Endocrine cell lesions (n=531) from 8 surgically-resected stomachs with type A gastritis were reclassified as either atrophic ECM (n=333), hyperplastic ECM (n=168), neoplastic ECM (all ECM > or =0.1 mm in size, n=15), or typical carcinoid (n=15). Hematoxylin and eosin-stained sections were semiautomatically analyzed by nuclear morphometry. Immunohistochemical expression of bcl-2, p53 and Ki-67 was also investigated. As the histologic grade of histology advanced, the morphometric values of area, circumference and largest diameter of the nuclei significantly increased (p<0.0005), while the frequency of diffuse expression of bcl-2 significantly decreased (p<0.0001). Significant differences were also observed in all morphometric parameters and in bcl-2 positivity between the hyperplastic ECM and neoplastic ECM group. There was no expression of p53 in any of the lesions. The Ki-67 index did not differ between the neoplastic ECM and typical carcinoid groups. These results suggest that our system of classification for gastric endocrine cell proliferations in type A gastritis is appropriate. Nuclear morphometry and bcl-2 immunoexpression are useful parameters for the distinction of neoplastic ECMs from hyperplastic ECMs.

Background: No population-based cohort studies have been undertaken to evaluate the incidence and prognosis of gastric cancer. The purpose of this investigation was to clarify the incidence and fatal prognosis of gastric cancer and to determine the factors that contribute to the prognosis in a general Japanese population in Hisayama using a prospective study design., Methods: From 1988 to 1998 a total of 2605 subjects aged 40 years or older with no history of gastrectomy or gastric cancer were followed-up prospectively after a health examination. The diagnosis of gastric cancer was based on clinical records or autopsy findings., Results: During the follow-up period, 76 subjects developed gastric cancer. The age-adjusted incidence of gastric cancer for men (4.9 per 1000 person-years) was 4-fold higher than that for women (1.2, P < 0.05). In men, the incidence of gastric cancer increased with advancing age, but this trend was not observed in women. The age- and sex-adjusted 5-year survival rate was significantly higher in cancers of the middle third of the stomach than in those of the upper third of the stomach. The survival rate was higher in cancers of well-differentiated adenocarcinoma than in those of the other histological types. There were no cases of cancer-related death among the early gastric cancers during the follow-up period., Conclusions: Our data suggest that men are at higher risk of gastric cancer than women in the general Japanese population. Clinical stage, histological type, and site of cancer in the stomach contribute to a fatal prognosis.

Alpha-fetoprotein producing gastric cancer (AFP-GC) rarely occurs, but it is classified as a special subtype of gastric cancer (GC). This tumor, as represented by the production of AFP, exhibits not only specific function but also different histology compared with ordinary-GC (O-GC). Clinically, it is likely to metastasize to the liver and, as a consequence, poor prognosis is recognized as one of the features. Recently, AT motif binding factor-1 (ATBF1) was identified as a modulator of AFP production by hepatocellular carcinoma, and the decreased expression of the protein was also reported in AFP-GC. However, little is known about the biological significance of the decreased expression. In this study, to clarify the biological characteristics of AFP-GC, antibody was raised against ATBF1 and immunohistochemistry was carried out. The antibody specifically recognized ATBF1, and the degree of expression could be characterized by immunohistochemistry. ATBF1 was expressed in O-GC and the area of tubular adenocarcinoma components of AFP-GC. On the other hand, the expression pattern varied in the hepatoid carcinoma components of AFP-GC, and AFP was expressed in the area without ATBF1 expression. Taken together, these results corroborated the previous reports that ATBF1 regulated AFP expression and inhibited transcription. Furthermore, in terms of differentiation induction, ATBF1 expression was decreased in the areas with little glandular formation. This may suggest that aberrant expression of ATBF1 induces the expression of various factors that are otherwise suppressed, and that this somehow determines the biological features of AFP-GC.

We have encountered an unusual case of gastric carcinoid tumors. Gastroscopic examination of a 71-year-old male patient showed eight smooth protrusions at the greater curvature of the gastric body, some of which had central depressions. Endoscopic ultrasonography demonstrated that the largest tumor (2.6 cm in diameter) was located in the submucosal layer. The patient had a normal serum gastrin level and was negative for antiparietal cell antibody. The patient was also found to have a pituitary tumor, an adenomatous goiter, and bilateral Warthin's tumors of the parotid glands. Histological examination of the resected stomach identified 12 discrete carcinoid tumors. There was no evidence of atrophic gastritis or of endocrine cell micronests. No mutations of the MEN1 gene were found on genomic DNA analysis. Despite the multiplicity of carcinoid tumors, we diagnosed type 3 gastric carcinoid in this patient.

Background and Study Aims: Endoscopic resection is increasingly being used in the treatment of early gastric cancer. The aim of the present study was to investigate the accuracy of pretherapeutic staging techniques for assessing the appropriateness of endoscopic resection., Patients and Methods: Both endoscopy and endosonography were carried out at our institution in the treatment of 234 early gastric cancers, with histological confirmation of malignancy following surgical resection (137 lesions) or endoscopic resection (97 lesions). The accuracy in detecting intramucosal cancer with each of the diagnostic procedures was assessed., Results: The accuracy rates for detecting intramucosal cancer using endoscopy and endosonography were calculated as 84 % (197 of 234) and 78 % (182 of 234), respectively. The accuracy tended to be lower in lesions located in the upper third of the stomach, in those measuring 2 cm or more in diameter, and in those with an undifferentiated histology with ulcer fibrosis. However, there were no significant differences in the accuracy rates between endoscopy and endosonography. Precise staging was achieved by endoscopy alone in 103 of 109 differentiated adenocarcinomas without ulcer fibrosis, where the lesions measured less than 2 cm in diameter., Conclusions: Endoscopic resection is indicated in intramucosal gastric cancer lesions showing differentiated histology, no ulcer fibrosis and a diameter of less than 2 cm. EUS may additionally be used for further evaluation in these patients.

Background and Aims: The role of Helicobacter pylori and atrophic gastritis in the pathogenesis of gastric lesions in familial adenomatous polyposis (FAP) has not been clarified., Patients: Thirty one patients with FAP., Methods: The presence of fundic gland polyposis (FGP) and gastric adenoma (GA) was determined by upper endoscopy with biopsies. The degree of gastric mucosal atrophy and H pylori status were determined by serological and histological findings. Germline mutation in the adenomatous polyposis coli (APC) gene was determined by polymerase chain reaction based single strand conformation polymorphism and direct sequencing., Results: Gastric lesions were detected in 23 patients (74%). FGP and GA were found in 52% and 39%, respectively. APC gene mutation was identified in 22 of 30 patients. Patients with FGP were less frequently infected with H pylori than those without FGP (13% v 67%). The former patients had a lower degree of atrophy than the latter. Patients with GA tended to be more frequently infected with H pylori and they had higher degrees of atrophy than those without GA. When subjects were subdivided by gastric lesions (FGP alone, FGP+GA, GA alone, and negative groups), the GA alone group had the lowest pepsinogen I/II ratio and the highest seropositivity for H pylori. GA was found more frequently in patients positive for the APC mutation whereas no such a trend was observed in FGP., Conclusions: In FAP, H pylori associated atrophic gastritis contributes negatively to FGP. It seems to contribute positively to GA, especially in patients with truncating APC gene mutation.

Background: While a close association between gastric mucosa associated lymphoid tissue (MALT) lymphoma and Helicobacter pylori infection has been established, there are still cases which do not respond to H pylori eradication., Aims: To investigate the clinicopathological factors which may help predict the therapeutic efficacy of H pylori eradication in gastric MALT lymphoma., Patients: Forty one patients with gastric MALT lymphoma, including low and high grade lesions., Methods: After endosonographic staging was determined, H pylori was eradicated in all patients, and the subsequent gastric pathological course was then investigated., Results: Complete regression of MALT lymphoma was observed in 29(71%) patients, partial regression in five (12%), and no regression in seven (17%). Twenty six (93%) of 28 MALT lymphomas restricted to the mucosa but only three (23%) of 13 lymphomas which invaded the deep portion of the submucosa or beyond completely regressed. Kaplan-Meier analysis for the probability of complete regression of MALT lymphoma revealed a significant difference between tumours restricted to the mucosa and those invading the submucosa deeply or beyond (p<0.05). Neither the presence of a high grade component, perigastric lymphadenopathy, nor clinical staging prior to eradication correlated with the probability of lymphoma regression., Conclusions: Assessment of deep submucosal invasion by endosonography is valuable for predicting the efficacy of H pylori eradication in gastric MALT lymphoma.

Orbital or ocular metastatic tumors may originate from breast cancer. Few studies have been made regarding their histopathological classification. A 71-year-old female noted a tumor in the right orbital region. She had had bilateral breast cancer 2 years before and gastric cancer 5 months before. Histopathology had shown stage II invasive ductal cancer (scirrhus) in the right breast and stage III invasive lobular cancer in the left. Signet-ring cells were present in the breast and gastric cancers. Biopsy of the right lower eyelid showed poorly differentiated adenocarcinoma with signet-ring cells. Indian file pattern, which is specific for invasive lobular cancer, was also present, suggesting that the orbital tumor had metastatized from the left breast cancer. Genetic analysis of the gastric cancer using polymerase chain reaction showed a mutation at exon 8 of the p53 tumor suppressor gene, indicating the cancer to be metastatic. These results led to the conclusion that invasive lobular cancer of the left breast was the primary lesion for the gastric and orbital metastases. This case also illustrates that signet-ring cells, which are usually seen in gastric cancer, may be present in invasive lobular breast cancer and in orbital metastasis.