Kagoshima City Hospital

Six adult patients had a chronic progressive myelopathy that possessed the following features: high antibody titers to human T-lymphotropic virus type I (HTLV-I) in serum and cerebrospinal fluid (CSF); predominantly upper motor neuron disorder, symmetrical, with mild sensory and bladder disturbances; and presence of adult T-cell leukemia-like cells in both peripheral blood and CSF. We refer to this entity as HTLV-I-associated myelopathy (HAM). Electrophoretic studies of immunoglobulin G in CSF using Western blot analysis characteristically demonstrated p24 and p32 bands. Rates of intra-blood-brain barrier synthesis were determined and found increased in the patients with HAM. Corticosteroid treatment produced clinical improvement in all of 4 patients. A retrospective survey of CSF samples was carried out in 287 patients with neurological disorders, and 6 additional patients with HAM were identified.

The authors declare no conflict of interest.

Molecular level studies on platelets deficient in collagen-induced aggregation provide evidence for identifying possible platelet collagen receptors. We investigated platelets from a patient with mild bleeding time prolongation, but otherwise normal coagulation data. Her platelets lacked collagen-induced aggregation and adhesion, but retained normal aggregation and release by other agonists. Labeling her platelets with 125I or 3H and analysis by SDS-PAGE/autoradiography showed normal levels of glycoproteins Ia, Ib, IIa, IIb, IIIa, and IV. However, there were significantly decreased incorporations of both radioactivities into a 61-kD membrane glycoprotein (GP), which was identified as GPVI from its mobility on unreduced-reduced, two-dimensional SDS-PAGE. Sugiyama et al. (1987. Blood. 69: 1712) reported that the serum from an idiopathic thrombocytopenic purpura (ITP) patient contained an antibody against a 62-kD platelet protein. Our patient's platelets lacked the antigen for the ITP patient's antibody, demonstrating that the ITP serum contains a specific antibody against GPVI. The patient's parents' platelets contained approximately 50% the normal amount of GPVI, but still had normal collagen-induced aggregation and adhesion. The patient's platelets did not bind to types I and III collagen fibrils. Our results suggest that GPVI functions as a collagen receptor.

In 1000 primary gastric carcinomas, 70 (7.0%) contained Epstein-Barr virus (EBV) genomic sequences detected by PCR and Southern blots. The positive tumors comprised 8 of 9 (89%) undifferentiated lymphoepithelioma-like carcinomas, 27 of 476 (5.7%) poorly differentiated adenocarcinomas, and 35 of 515 (6.8%) moderately to well-differentiated adenocarcinomas. In situ EBV-encoded small RNA 1 hybridization and hematoxylin/eosin staining in adjacent sections showed that the EBV was present in every carcinoma cell but was not significantly present in lymphoid stroma and in normal mucosa. Two-color immunofluorescence and hematoxylin/eosin staining in parallel sections revealed that every keratin-positive epithelial malignant cell expressed EBV-determined nuclear antigen 1 (EBNA1) but did not significantly express CD45+ infiltrating leukocytes. A single fused terminal fragment was detected in each of the EBNA1-expressing tumors, thereby suggesting that the EBV-carrying gastric carcinomas represent clonal proliferation of cells infected with EBV. The carcinoma cells had exclusively EBNA1 but not EBNA2, -3A, -3B, and -3C; leader protein; and latent membrane protein 1 because of methylation. The patients with EBV-carrying gastric carcinoma had elevated serum EBV-specific antibodies. The EBV-specific cellular immunity was not significantly reduced; however, the cytotoxic T-cell target antigens were not expressed. These findings strongly suggest a causal relation between a significant proportion of gastric carcinoma and EBV, and the virus-carrying carcinoma cells may evade immune surveillance.

BACKGROUND: A warm-water bath (WWB) or sauna bath (SB) has generally been considered inappropriate for patients with severe congestive heart failure (CHF). However, a comprehensive investigation of the hemodynamic effects of thermal vasodilation in CHF has not been previously undertaken. METHODS AND RESULTS: To investigate the acute hemodynamic effects of thermal vasodilation in CHF, we studied 34 patients with chronic CHF (mean age, 58 +/- 14 years). Clinical stages were New York Heart Association functional class II in 2, III in 19, and IV in 13 patients. Mean ejection fraction was 25 +/- 9%. After a Swan-Ganz catheter was inserted via the right jugular vein, the patient had a WWB for 10 minutes at 41 degrees C or an SB for 15 minutes at 60 degrees C. Blood pressure, ECG, echo-Doppler, expiration gas, and intracardiac pressures were recorded before, during, and 30 minutes after each bath. Oxygen consumption increased mildly, pulmonary arterial blood temperature increased by 1.2 degrees C, and heart rate increased by 20 to 25 beats per minute on average at the end of WWB or SB. Systolic blood pressure showed no significant change. Diastolic blood pressure decreased significantly during SB (P < .01). Cardiac and stroke indexes increased and systemic vascular resistances decreased significantly during and after WWB and SB (P < .01). Mean pulmonary artery, mean pulmonary capillary wedge, and mean right atrial pressures increased significantly during WWB (P < .05) but decreased significantly during SB (P < .05). These pressures decreased significantly from the control level after each bath (P < .01). Mitral regurgitation associated with CHF decreased during and 30 minutes after each bath. Cardiac dimensions decreased and left ventricular ejection fraction increased significantly after WWB and SB. In an additional study, plasma norepinephrine increased significantly during SB in healthy control subjects and in patients with CHF and returned to control levels by 30 minutes after SB. CONCLUSIONS: Hemodynamics improve after WWB or SB in patients with chronic CHF. This is attributable to the reduction in cardiac preload and afterload. Thus, thermal vasodilation can be applied with little risk if appropriately performed and may provide a new nonpharmacological therapy for CHF.

BACKGROUND: The value of pancreatoduodenectomy (PD) with extended lymphadenectomy for pancreatic cancer has been evaluated by many retrospective studies and 3 randomized controlled trials (RCT). However, the protocols used and the results found in the 3 RCTs were diverse. Therefore, a multicenter RCT was proposed in 1998 to evaluate the primary end point of long-term survival and the secondary end points of morbidity, mortality and quality of life of patients undergoing standard versus extended lymphadenectomy in radical PD for pancreatic cancer. METHODS: From March 2000 to May 2003, 112 patients with potentially curable pancreatic head cancer were enrolled and intraoperatively randomized to a standard or extended lymphadenectomy group. No resected patients received any adjuvant treatments. RESULTS: A hundred and one eligible patients were analyzed. Demographic and histopathological characteristics of the two groups were similar. The mean operating time, intraoperative blood loss and number of retrieved lymph nodes were greater in the extended group, but the other operative results were comparable. CONCLUSIONS: Although this multicenter RCT was conducted in a strict setting, extended lymphadenectomy in radical PD did not benefit long-term survival in patients with resectable pancreatic head cancer and led to levels of morbidity, mortality and quality of life comparable to those found after standard lymphadenectomy.

HLA haplotypes of 27 patients with human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM) and 12 patients with adult T-cell leukemia/lymphoma (ATLL) were examined by analyzing HLA types of the patients and their family members. Either A11Bw54Cw1DR4DQw3, A24Bw54Cw1DR4DQ–, A24B7Cw7DR1DQw1, or A24Bw52Cw–DR2DQw1 and the related haplotypes were found in 70% of cases with HAM. None of these “HAM-associated” haplotypes was found in patients with ATLL. HLA haplotypes made up of HLA components of A26Bw62Cw3DR5DQw3 and one particular haplotype of Aw33B44Cw–DRw6DQw1 were associated with the ATLL haplotypes. These “ATLL-associated” haplotypes were also found in the patients with HAM who had no previous history of blood transfusion. The in vitro cultures of peripheral blood lymphocytes with HTLV-I virion antigens revealed that the response with HAM peripheral blood lymphocytes was remarkably higher than that with ATLL peripheral blood lymphocytes. Based on this HTLV-I-specific immune responsiveness, we can segregate the high responders in HAM (14 of 16 cases) and the low responders in ATLL (6 of 7 cases). The existence of high and low responders was also confirmed by the normal healthy individuals, whose responses were segregated with HAM-associated and ATLL-associated haplotypes. These results suggested that two ethnic groups in southern Kyushu may get the two different diseases, HAM and ATLL, because of their different immunogenetic backgrounds. The high immune response to HTLV-I seems to be an important genetic factor in the development of HAM.

To reliably estimate the prognoses of patients with hepatocellular carcinoma (HCC), both liver function and tumor-related factors should be accounted for. However, there are few worldwide staging systems that assess prognostic value in the context of selecting individual patients for randomized stratification in therapeutic and clinical trials. We investigated the value of known prognostic systems and verified the usefulness of the new scoring system proposed by the Cancer of the Liver Italian Program (CLIP), as determined from 662 Japanese patients. A retrospective analysis of the HCC diagnoses at 4 Japanese institutions from 1990 and 1998 was performed. Overall survival was the only end point used in the analysis. Discriminatory ability and predictive power of the CLIP score were compared with those of Okuda stage and AJCC TNM stage. Compared with the Okuda and AJCC staging systems, the CLIP score's enhanced discriminatory capacity, which was tested by the linear trend test and Harrels' c-index, revealed a class of patients with an impressively more favorable prognosis and another class with a relatively shorter life expectancy. Moreover, the likelihood ratio test showed that the CLIP score had additional homogeneity of survival within each score above that of the Okuda stage or the AJCC stage. This was true for 3 subgroups of patients who received surgery, transcatheter arterial chemoembolizations, and percutaneous ethanol injections. Collectively, these findings indicate that the CLIP score has the highest stratification ability with regard to prognosis in patients with HCC. The CLIP score could be used internationally to stratify randomization groups in therapeutic and clinical trials.

The clinicopathologic findings of reversible ampulla-like ventriculogram of the left ventricle were studied in 8 elderly women and one middle-aged man. Their coronary arteriograms were normal, even in the 7 patients who had ST elevation on electrocardiogram. Coronary spasm was positive in only 2 of the 7 patients who received provocation tests. Biopsy specimens revealed focal myocyte injury. Normal coronary arteriograms during ST elevation and the presence of pathologic myocardial lesions were not consistent with a concept of stunned myocardium. The presence of myocardial lesions suggested that focal and disseminated myocardial damage had occurred.

PURPOSE: High-grade serous ovarian cancers are heterogeneous not only in terms of clinical outcome but also at the molecular level. Our aim was to establish a novel risk classification system based on a gene expression signature for predicting overall survival, leading to suggesting novel therapeutic strategies for high-risk patients. EXPERIMENTAL DESIGN: In this large-scale cross-platform study of six microarray data sets consisting of 1,054 ovarian cancer patients, we developed a gene expression signature for predicting overall survival by applying elastic net and 10-fold cross-validation to a Japanese data set A (n = 260) and evaluated the signature in five other data sets. Subsequently, we investigated differences in the biological characteristics between high- and low-risk ovarian cancer groups. RESULTS: An elastic net analysis identified a 126-gene expression signature for predicting overall survival in patients with ovarian cancer using the Japanese data set A (multivariate analysis, P = 4 × 10(-20)). We validated its predictive ability with five other data sets using multivariate analysis (Tothill's data set, P = 1 × 10(-5); Bonome's data set, P = 0.0033; Dressman's data set, P = 0.0016; TCGA data set, P = 0.0027; Japanese data set B, P = 0.021). Through gene ontology and pathway analyses, we identified a significant reduction in expression of immune-response-related genes, especially on the antigen presentation pathway, in high-risk ovarian cancer patients. CONCLUSIONS: This risk classification based on the 126-gene expression signature is an accurate predictor of clinical outcome in patients with advanced stage high-grade serous ovarian cancer and has the potential to develop new therapeutic strategies for high-grade serous ovarian cancer patients.

Although Tax protein is the main target of cytotoxic T lymphocyte (CTL) on human T-cell lymphotropic virus type I (HTLV-I)-infected cells, and Tax peptide 11 through 19 binding to HLA-A*02 has been shown to elicit a strong CTL response, there are patients with adult T-cell leukemia (ATL) bearing HLA-A*02. To explore whether there is genetic variation in HTLV-I tax that can escape CTL recognition during the development of ATL, the HTLV-I tax gene was sequenced in 55 patients with ATL, 61 patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and 62 healthy carriers, and it was correlated with the presence of HLA-A*02. First, a premature stop codon in the 5' half of the tax gene that looses transactivation activity on the viral enhancer was observed in 3 patients with acute and 1 patient with chronic ATL. This stop codon was revealed to emerge after the viral transmission to the patient from sequence analysis in family members with ATL. Second, amino acid change in Tax peptide 11-19 was observed in 3 patients with ATL. CTL assays demonstrated that this altered Tax 11-19 peptide, observed in ATL patients with HLA-A*02, was not recognized by Tax 11-19-specific CTL. Two patients with ATL had large deletions in tax by sequencing, and 5 patients with ATL had deletions in HTLV-I by Southern blotting. These findings suggest that at some stage of ATL development, HTLV-I-infected cells that can escape the host immune system are selected and have a chance to accumulate genetic alterations for further malignant transformation, leading to acute ATL.

To elucidate the mechanisms of rapid progression of serous ovarian cancer, gene expression profiles from 43 ovarian cancer tissues comprising eight early stage and 35 advanced stage tissues were carried out using oligonucleotide microarrays of 18,716 genes. By non-negative matrix factorization analysis using 178 genes, which were extracted as stage-specific genes, 35 advanced stage cases were classified into two subclasses with superior (n = 17) and poor (n = 18) outcome evaluated by progression-free survival (log rank test, P = 0.03). Of the 178 stage-specific genes, 112 genes were identified as showing different expression between the two subclasses. Of the 48 genes selected for biological function by gene ontology analysis or Ingenuity Pathway Analysis, five genes (ZEB2, CDH1, LTBP2, COL16A1, and ACTA2) were extracted as candidates for prognostic factors associated with progression-free survival. The relationship between high ZEB2 or low CDH1 expression and shorter progression-free survival was validated by real-time RT-PCR experiments of 37 independent advanced stage cancer samples. ZEB2 expression was negatively correlated with CDH1 expression in advanced stage samples, whereas ZEB2 knockdown in ovarian adenocarcinoma SKOV3 cells resulted in an increase in CDH1 expression. Multivariate analysis showed that high ZEB2 expression was independently associated with poor prognosis. Furthermore, the prognostic effect of E-cadherin encoded by CDH1 was verified using immunohistochemical analysis of an independent advanced stage cancer samples set (n = 74). These findings suggest that the expression of epithelial-mesenchymal transition-related genes such as ZEB2 and CDH1 may play important roles in the invasion process of advanced stage serous ovarian cancer.

BACKGROUND AND AIMS: Immunotherapy has become the standard-of-care treatment for hepatocellular carcinoma (HCC), but its efficacy remains limited. To identify immunotherapy-susceptible HCC, we profiled the molecular abnormalities and tumor immune microenvironment (TIME) of rapidly increasing nonviral HCC. APPROACHES AND RESULTS: We performed RNA-seq of tumor tissues in 113 patients with nonviral HCC and cancer genome sequencing of 69 genes with recurrent genetic alterations reported in HCC. Unsupervised hierarchical clustering classified nonviral HCCs into three molecular classes (Class I, II, III), which stratified patient prognosis. Class I, with the poorest prognosis, was associated with TP53 mutations, whereas class III, with the best prognosis, was associated with cadherin-associated protein beta 1 (CTNNB1) mutations. Thirty-eight percent of nonviral HCC was defined as an immune class characterized by a high frequency of intratumoral steatosis and a low frequency of CTNNB1 mutations. Steatotic HCC, which accounts for 23% of nonviral HCC cases, presented an immune-enriched but immune-exhausted TIME characterized by T cell exhaustion, M2 macrophage and cancer-associated fibroblast (CAF) infiltration, high PD-L1 expression, and TGF-β signaling activation. Spatial transcriptome analysis suggested that M2 macrophages and CAFs may be in close proximity to exhausted CD8+ T cells in steatotic HCC. An in vitro study showed that palmitic acid-induced lipid accumulation in HCC cells upregulated PD-L1 expression and promoted immunosuppressive phenotypes of cocultured macrophages and fibroblasts. Patients with steatotic HCC, confirmed by chemical-shift MR imaging, had significantly longer PFS with combined immunotherapy using anti-PD-L1 and anti-VEGF antibodies. CONCLUSIONS: Multiomics stratified nonviral HCCs according to prognosis or TIME. We identified the link between intratumoral steatosis and immune-exhausted immunotherapy-susceptible TIME.

BACKGROUND: Malignant and benign tumors of the salivary glands have been associated with exposure to ionizing radiation from various sources, including the atomic bombings in Hiroshima and Nagasaki. However, questions remain unanswered regarding the nature and size of the risk and specific types of tumors involved. METHODS: The incidence and pathology of malignant and benign tumors of the salivary glands was studied in the Life Span Study cohort of atomic bomb survivors followed by the Radiation Effects Research Foundation (RERF) in Hiroshima and Nagasaki, Japan. Incident cases diagnosed during the period 1950-1987 were ascertained from the tumor and tissue registries of Hiroshima and Nagasaki and supplemented by additional case findings from autopsy, biopsy, and surgical specimens maintained at RERF and other institutions. Pathology slides and medical documents were reviewed by a panel of four pathologists who classified tumors using the World Health Organization classification scheme. Analyses were performed of histologic features associated with radiation exposure. RESULTS: Of 145 tumors of the salivary glands identified (119 of the major and 26 of the minor salivary glands), 120 (83%) were histologically confirmed by the current investigators. Among 41 malignant tumors, the frequency of mucoepidermoid tumor was disproportionately high at high radiation doses (P = 0.04); among 94 benign tumors, the frequency of Warthin's tumor increased with increasing radiation dose (P = 0.06). The nature of the tumor was undetermined for the remaining ten cases. Mortality from malignant tumors of the salivary gland was inversely related to radiation dose, reflecting the predominance of mucoepidermoid carcinoma at high dose levels in this series. In one case with high radiation exposure, mucoepidermoid carcinoma of the parotid gland was accompanied by a preexisting or coexisting Warthin's tumor. CONCLUSIONS: These findings, supported by population-based analyses in a companion study reported elsewhere, suggest a causal role for ionizing radiation in salivary gland tumorigenesis, particularly for mucoepidermoid carcinoma, and in the induction of one type of benign tumor (Warthin's tumor).

The so-called "conotruncal anomaly face syndrome" (CTAFS) is characterized by a peculiar facial appearance associated with congenital heart disease (CHD), especially cardiac outflow tract defects such as tetralogy of Fallot (TOF), double outlet right ventricle (DORV), and truncus arteriosus (TAC). CTAFS and the DiGeorge anomaly (DGA) have many similar phenotypic characteristics, suggesting that they share a common cause. In many cases DGA is known to be associated with monosomy for a region of chromosome 22q11.2. Fifty CTAFS patients and 10 DGA patients, 11 parents couples and 10 mothers of CTAFS patients, and 3 parents couples and 2 mothers of DGA patients were examined by fluorescent in situ hybridization (FISH) using the N25 (D22S75) DGCR probe (Oncor). Monosomy for a region of 22q11.2 was found in 42 CTAFS, 9 DGA, 4 mothers, and 1 father who had CTAF without CHD. The remaining 8 CTAFS patients 1 DGA patient and 1 mother who had questionable CTAF without CHD, showed no such chromosome abnormality. For the control, 60 patients who had CHD without CTAF or other known malformation syndromes were examined and had no deletion of 22q11.2. Therefore, we conclude that CTAFS is a part of the CATCH 22 syndrome; cardiac defects, abnormal faces, thymic hypoplasia, cleft palate, and hypocalcemia (CATCH) resulting from 22q11.2 deletions.

BACKGROUND: The COVID-19 pandemic led to profound changes in the organization of health care systems worldwide. AIMS: We sought to measure the global impact of the COVID-19 pandemic on the volumes for mechanical thrombectomy, stroke, and intracranial hemorrhage hospitalizations over a three-month period at the height of the pandemic (1 March-31 May 2020) compared with two control three-month periods (immediately preceding and one year prior). METHODS: Retrospective, observational, international study, across 6 continents, 40 countries, and 187 comprehensive stroke centers. The diagnoses were identified by their ICD-10 codes and/or classifications in stroke databases at participating centers. RESULTS: The hospitalization volumes for any stroke, intracranial hemorrhage, and mechanical thrombectomy were 26,699, 4002, and 5191 in the three months immediately before versus 21,576, 3540, and 4533 during the first three pandemic months, representing declines of 19.2% (95%CI, -19.7 to -18.7), 11.5% (95%CI, -12.6 to -10.6), and 12.7% (95%CI, -13.6 to -11.8), respectively. The decreases were noted across centers with high, mid, and low COVID-19 hospitalization burden, and also across high, mid, and low volume stroke/mechanical thrombectomy centers. High-volume COVID-19 centers (-20.5%) had greater declines in mechanical thrombectomy volumes than mid- (-10.1%) and low-volume (-8.7%) centers (p < 0.0001). There was a 1.5% stroke rate across 54,366 COVID-19 hospitalizations. SARS-CoV-2 infection was noted in 3.9% (784/20,250) of all stroke admissions. CONCLUSION: The COVID-19 pandemic was associated with a global decline in the volume of overall stroke hospitalizations, mechanical thrombectomy procedures, and intracranial hemorrhage admission volumes. Despite geographic variations, these volume reductions were observed regardless of COVID-19 hospitalization burden and pre-pandemic stroke/mechanical thrombectomy volumes.

Cryopyrin-associated periodic syndrome (CAPS) is a spectrum of systemic autoinflammatory disorders in which the majority of patients have mutations in the cold-induced autoinflammatory syndrome (CIAS)1 gene. Despite having indistinguishable clinical features, some patients lack CIAS1 mutations by conventional nucleotide sequencing. We recently reported a CAPS patient with mosaicism of mutant CIAS1, and raised the possibility that CIAS1 mutations were overlooked in "mutation-negative" patients, due to a low frequency of mosaicism. To determine whether there were latent mutant cells in "mutation-negative" patients, we sought to identify mutation-associated biologic phenotypes of patients' monocytes. We found that lipopolysaccharide selectively induced necrosis-like cell death in monocytes bearing CIAS1 mutations. Monocyte death correlated with CIAS1 up-regulation, was dependent on cathepsin B, and was independent of caspase-1. Cell death was intrinsic to CIAS1-mutated monocytes, was not mediated by the inflammatory milieu, and was independent of disease severity or anti-IL-1 therapy. By collecting dying monocytes after lipopolysaccharide treatment, we succeeded in enriching CIAS1-mutant monocytes and identifying low-level CIAS1-mosaicism in 3 of 4 "mutation-negative" CAPS patients. Our findings reveal a novel effect of CIAS1 mutations in promoting necrosis-like cell death, and demonstrate that CIAS1 mosaicism plays an important role in mutation-negative CAPS patients.

BACKGROUND: Advanced-stage ovarian cancer patients are generally treated with platinum/taxane-based chemotherapy after primary debulking surgery. However, there is a wide range of outcomes for individual patients. Therefore, the clinicopathological factors alone are insufficient for predicting prognosis. Our aim is to identify a progression-free survival (PFS)-related molecular profile for predicting survival of patients with advanced-stage serous ovarian cancer. METHODOLOGY/PRINCIPAL FINDINGS: Advanced-stage serous ovarian cancer tissues from 110 Japanese patients who underwent primary surgery and platinum/taxane-based chemotherapy were profiled using oligonucleotide microarrays. We selected 88 PFS-related genes by a univariate Cox model (p<0.01) and generated the prognostic index based on 88 PFS-related genes after adjustment of regression coefficients of the respective genes by ridge regression Cox model using 10-fold cross-validation. The prognostic index was independently associated with PFS time compared to other clinical factors in multivariate analysis [hazard ratio (HR), 3.72; 95% confidence interval (CI), 2.66-5.43; p<0.0001]. In an external dataset, multivariate analysis revealed that this prognostic index was significantly correlated with PFS time (HR, 1.54; 95% CI, 1.20-1.98; p = 0.0008). Furthermore, the correlation between the prognostic index and overall survival time was confirmed in the two independent external datasets (log rank test, p = 0.0010 and 0.0008). CONCLUSIONS/SIGNIFICANCE: The prognostic ability of our index based on the 88-gene expression profile in ridge regression Cox hazard model was shown to be independent of other clinical factors in predicting cancer prognosis across two distinct datasets. Further study will be necessary to improve predictive accuracy of the prognostic index toward clinical application for evaluation of the risk of recurrence in patients with advanced-stage serous ovarian cancer.

Epstein-Barr virus (EBV) involvement in gastric carcinoma has been demonstrated by the presence of EBV genomes and EBV-encoded small RNA (EBER) in the carcinoma cells, monoclonal proliferation of EBV-infected carcinoma cells and elevated antibody titers. The present study was conducted to investigate the prevalence of EBV involvement among gastric carcinomas observed in nine Japanese cities with varying gastric cancer rates. In situ hybridization of EBER-1 was applied to paraffin sections from 1848 carcinomas observed in 1795 cases and EBV involvement was detected based on uniform hybridization in carcinoma cells. Epstein-Barr virus was detected in 6.6% of lesions and 6.7% of cases. The rate of EBV involvement did not vary significantly for each city and there was no correlation with underlying gastric cancer mortality rates. Thus, geographic variation of gastric cancer rates within Japan cannot be explained in terms of EBV involvement. Epstein-Barr virus-related gastric carcinoma is one of the most common EBV-related tumors in Japan. The involvement of EBV was significantly more frequent among males than among females, mainly for cancers occurring in the upper and middle part of the stomach, and exhibited more variation by cell type among males. These observations suggest that other factors yet to be discovered may modulate the causal role of EBV in gastric carcinogenesis.

Epstein-Barr virus (EBV) is known to be related to lymphoid tumors and some types of epithelial tumors, including lymphoepithelioma-like gastric carcinoma with marked lymphocytic stroma. In this study, prevalence of EBV involvement in gastric cancer, and characteristics of tumors with such involvement, were investigated by EBV-encoded RNA 1 in situ hybridization applied to paraffin sections, including the tumor and adjacent gastric tissue, from 999 gastric carcinomas observed in 970 consecutive cases from a large Japanese hospital. EBV involvement occurred in 6.9 percent of lesions, a significantly lower proportion than has been observed in a North American series. Involvement was significantly more frequent among males, in tumors in the upper part of the stomach, and in adenocarcinomas of the moderately differentiated tubular and poorly differentiated solid or medullary types. Almost all carcinomas with marked lymphoid stroma were EBV-positive. Positive lesions were characterized by the presence of uniform hybridized signals in almost all carcinoma cells and by their absence from adjacent non-neoplastic tissue.