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Background and Aim Endoscopy‐based Kyoto classification predicts the risk of Helicobacter pylori infection and gastric cancer; however, the change in score following H. pylori eradication remains unknown. We retrospectively compared the Kyoto score before and after H. pylori eradication. Methods H. pylori‐positive patients who underwent baseline esophagogastroduodenoscopy (EGD), successful H. pylori eradication, and surveillance EGD were enrolled. The Kyoto score is a sum of scores for atrophy (Kimura‐Takemoto atrophic‐border classification none or C1: 0, C‐II or C‐III: 1, O‐I to O‐III: 2), intestinal metaplasia (none: 0, antrum: 1, corpus and antrum: 2), enlarged folds (absence: 0, presence: 1), nodularity (absence: 0, presence: 1), and diffuse redness (none: 0, mild: 1, severe: 2) and ranges from 0 to 8. Results Eighty‐three patients (mean age: 54.9 years; 65.1% women) were enrolled. The mean duration from successful eradication to surveillance EGD was 256 days. The Kyoto score significantly decreased from 3.90 to 2.78 following H. pylori eradication (P, The Kyoto classification score on endoscopic gastritis (sum of scores for atrophy, intestinal metaplasia, enlarged folds, nodularity, and diffuse redness with or without regular arrangement of collecting venules) is associated with Helicobacter pylori infection status and gastric cancer risk. We found that the Kyoto classification score improved with H. pylori eradication. Improvement in the scores for enlarged folds, nodularity, and diffuse redness might be predictors for successful H. pylori eradication.

Background Despite advances in chemotherapy, curing multiple liver metastases is quite rare. Even when response is obtained, regrowth of the tumors is almost inevitable. We aimed to evaluate the efficacy and adverse events of helical tomotherapy for chemo‐refractory multiple liver metastases. Methods Forty‐five patients with chemo‐refractory multiple (3‐10) liver metastases after standard systemic chemotherapy entered the single‐institutional prospective study. Liver metastases were the major disease; however, 31 also had uncontrolled primary lesions and/or other metastases. The prescribed dose was 55 Gy in 25 fractions. The median planning target volume (PTV) and normal liver volume (NLV) of first treatment were 128 cm3 and 1175 cm3, respectively. The median of V15Gy, V30Gy, and mean dose to NLV were 45%, 23%, and 19.4 Gy, respectively. Results Forty‐two patients (93%) completed the planned treatment. Median survival time (MST) for all patients was 8 months, and the 1‐year survival rate was 29%. The median local control (LC) period was 5 months and the 6‐month control rate of irradiated tumors was 33%. A ≥30% decrease in tumor markers was observed in 31%. The most common grade 3 toxicity was lymphocytopenia (40%), followed by fatigue (6%). Radiation‐induced liver disease (RILD) was not observed. Pancreatic cancer as the primary tumor, distant metastases outside the liver, low pretreatment neutrophil‐to‐lymphocyte ratio (NLR), and low pretreatment monocyte‐to‐lymphocyte ratio (MLR) were associated with poorer prognoses. Conclusions Helical tomotherapy for chemo‐refractory multiple liver metastases is a feasible and potentially effective treatment. Incorporating tomotherapy into the first‐line treatment in combination with systemic chemotherapy should be considered. Trial registration number CROG 12005., Despite the remarkable advances of systemic chemotherapy for multiple liver metastases, the efficacy is still limited and cure of the multiple lesions is difficult. Helical tomotherapy for chemo‐refractory multiple liver metastases was suggested to be a feasible and potentially effective treatment with acceptable adverse events.

Background and aim The risk of developing colorectal cancer is higher in patients with ulcerative colitis (UC) than in the general population. Guidelines recommend surveillance colonoscopy (SCS) to reduce mortality; however, few studies have assessed physicians’ adherence to guidelines. This study was aimed to clarify the current status of SCS and adherence to guidelines through the characteristics of cancer/dysplasia surveillance for UC patients in Japan. Methods A questionnaire was mailed to 541 physicians who attended meetings on inflammatory bowel disease. Results The respondents encountered a median of 100 UC cases. Thirty percent of the respondents had never managed a UC patient with cancer. Fifty-one percent of the respondents had never diagnosed colorectal cancer with UC. Forty-seven percent of the respondents considered total colitis and left-sided colitis as indications for SCS, and 38% performed SCS regardless of the disease extent. Sixty-three percent of the respondents started SCS at 7–10 years after UC onset, whereas 20% started SCS at 3 years or less. Fifty-two percent of the respondents obtained targeted biopsies only, and chromoendoscopy was employed by 49% of the respondents as a special technique for surveillance. The median number of biopsies at SCS was 5 per patient; it was 3 among patients performed by physicians who obtained targeted biopsies only and 7 among those performed by physicians who obtained step biopsies and targeted biopsies (p < 0.0001). Conclusion A considerable proportion of the respondents did not follow the guidelines when selecting patients for surveillance and performing SCS. This article is protected by copyright. All rights reserved.

The gold standard for breast cancer treatment is surgery, but many women may desire to avoid surgery if possible. The purpose of this study was to evaluate whether breast cancer could be cured with modern sophisticated radiation techniques with good cosmetic outcome. We have treated 18 patients with operable breast cancer by conventional whole-breast irradiation followed by stereotactic body radiotherapy (primary tumor only) or intensity-modulated radiotherapy (tumor plus axillary nodes) boost. The planned doses were 50 Gy in 25 fractions, 18 to 25.5 Gy in 3 fractions, and 20 Gy in 8 fractions, respectively, for the 3 modalities. Stereotactic body radiotherapy was delivered with 7 to 9 coplanar and noncoplanar fixed beams, and intensity-modulated radiotherapy was given by tomotherapy. Chemotherapy and/or hormone therapy was used depending on the stage and receptor status. In 9 recent patients, hydrogen peroxide was intratumorally injected twice a week before whole-breast irradiation. All treatments were well tolerable and there were no grade ≥3 toxicities. With a median follow-up period of 35 months (range, 8-120 months), only 1 patient developed local recurrence and 2 patients developed distant metastasis. Overall survival, progression-free survival, and local control rates were 93%, 85%, and 92%, respectively, at 3 years. In 50% of the patients, the irradiated breast became better rounded, and the position of the nipple of the irradiated breast became ≥1 cm higher compared to that of the unirradiated breast. Thus, the treated breasts may be more aesthetically favorable than before irradiation in these patients. This may become a treatment option for patients with operable breast cancer.

Background and Goals: The prevalence of irritable bowel syndrome (IBS) among Japanese patients who visit hospitals departments of internal medicine is thought to be high. However, no clear statistical evidence has been provided to support such a claim. We tested the hypotheses that the prevalence of IBS in medical outpatients clinics in Japan is high, and that IBS patients feel more psychosocial stress than patients without IBS. Study: The subjects in this study were 633 patients who visited participating physicians. Patients were asked to fill in the Japanese version of the Rome II Modular Questionnaire (RIIMQ) for IBS diagnosis, the Self-reported Irritable Bowel Syndrome Questionnaire (SIBSQ) for severity of the disease and the demographic questionnaire for perceived stress and life style. Results: Rome II-defined IBS was diagnosed in 196 patients (31%). Analysis of variance revealed significant difference in the IBS scores of SIBSQ among IBS subjects (39.0 ± 11.1, mean ± SD), functional bowel disorder subjects (27.1 ± 10.2), and normal subjects (24.0 ± 10.0, P < 0.01). The prevalence of IBS depending on age formed 2 peaks, one among adolescents and the other among the elderly. IBS patients had significantly more perceived stress (P < 0.0001), irregular sleep habit (P < 0.0001), and irregular meal habit (P < 0.0001) than those without IBS. Conclusions: The prevalence of IBS among medical outpatients in Japan is high (31%). IBS subjects among medically ill patients are thought to have more perceived stress and less regular life styles.

Interleukin-18 (IL-18) is believed to be one of the most important cytokines in the pathogenesis of inflammatory bowel disease (IBD). The aim of the study was to clarify the significance of single-nucleotide polymorphisms (SNPs) at the 5′-end of the IL-18 gene in the development of IBD. DNA was obtained from peripheral blood of 99 patients with ulcerative colitis (UC), 79 patients with Crohn's disease (CD), and 102 healthy controls. All participants were Japanese. SNPs at −656G/T, −607C/A, −137G/C, +113T/G, and +127C/T were determined by means of direct sequencing, and a genetic association with IBD was examined. The frequencies of the G allele at +113 and the T allele at +127 were significantly higher in patients with CD and UC compared with controls. The differences in allelic frequencies were more striking in patients with CD than in patients with UC, and at position +127 than at position +113. The haplotype estimation, according to the E-M algorithm, suggested that TACGT is closely associated with IBD, especially with CD. It was concluded that SNPs at the 5′-end of IL-18 gene might be closely related to the etiology of IBD.

Vascular smooth muscle cells and pericytes express MMP-1, MMP-9, TIMP-1 and type I procollagen in inflammatory bowel disease Aims: Matrix metalloproteinases (MMPs) are involved in tissue remodelling, which is one of the important aspects of inflammatory disease. To assess the balance between the matrix degradation and production, we analysed the in situ expression of MMP-1, -3, -8 and -9, tissue inhibitor of metalloproteinases (TIMP)-1 and -2, and type I procollagen (PC-I) in inflammatory bowel disease. Methods and results: Immunohistochemistry using frozen sections was performed in 17 patients with ulcerative colitis (UC) and 16 with Crohn’s disease (CD). In both UC and CD, MMPs and TIMPs were expressed by inflammatory cells as well as by fibroblastic cells most prominently in actively inflamed areas in ulcer bases, but sparsely in intact inflamed mucosa in both UC and CD. In UC, inflamed mucosa with erosions expressed these substances focally. Fibroblasts also expressed PC-I. We identified that vascular smooth muscle cells of venules in ulcer bases expressed MMP-1 and -9, TIMP-1 and PC-I. These venules also expressed E-selectin, a cell adhesion molecule to facilitate the leucocyte extravasation, and vascular endothelial growth factor (VEGF) receptor 2, consistent with their property of newly formed vessels. Conclusions: Our results suggest that MMPs are involved in the tissue remodelling, angiogenesis and promotion of leucocyte extravasation in the actively inflamed area in the ulcer base in both UC and CD. MMP-1 expression in the mucosa may be related to the initial step of ulceration in UC. Therapeutic manipulation of extracellular matrix turnover would be an effective therapy to alleviate active inflammation and accelerate ulcer healing.

Myofibroblasts in the periacinar area of the pancreas have been demonstrated to mediate fibrogenesis in pancreatic fibrosis. However, only a few reports have described myofibroblasts in the pancreatic duct. To elucidate the presence of myofibroblasts in the pancreatic ductal wall, we performed an immunohistochemical study, using immunostains for both alpha-smooth muscle actin (alphaSMA) and desmin, and an electron microscopic study on surgically resected pancreatic specimens from 10, 23, 23, and 56 cases of focal pancreatitis (FP), chronic pancreatitis (CP), pancreatic carcinoma (PCa), and carcinoma of the papilla of Vater (VPCa), respectively. All cases showed localized stenosis of the main pancreatic duct by means of preoperative pancreatography. As controls, 20 autopsy cases were studied. alphaSMA-positive and desmin-negative cells existed in the ductal walls of controls and were revealed as myofibroblasts by means of electron microscopy. In six FPs, proliferation of myofibroblasts was observed at the stenotic portion. In VPCas, myofibroblasts mainly proliferated in the pancreatic ductal wall. In CPs and PCas, no myofibroblast proliferation was observed at the stenotic portion. The proliferation of myofibroblasts might occur as a wound healing process in FP, while acting against elevation of intraductal pressure in VPCa. In conclusion, proliferation of myofibroblasts plays an important role in ductal changes in various pathological situations.

The aim of this study was to elucidate the pathogenetic backgrounds of early-onset gastric cancers. Mutations of the E-cadherin and beta-catenin genes were analyzed by subjecting microdissected cancer cells and corresponding non-cancerous epithelial cells obtained from 9 gastric cancer patients under 35 years old to polymerase chain reaction-single strand conformation polymorphism analysis. Somatic, but no germline, E-cadherin gene mutations were detected in 6 (67%) of the patients. The cancer cells of 2 patients were exon 9-deleted E-cadherin molecule-immunoreactive. Neither somatic nor germline mutations in exon 3 of the beta-catenin gene were observed in any patient. One patient lacked beta-catenin immunoreactivity and the cancer cells of 6 others showed cytoplasmic beta-catenin immunoreactivity. The E-cadherin-mediated cell adhesion system in the cancer cells of all the patients examined appeared to be disrupted, indicating that somatically acquired dysfunction of this system plays an important role in early-onset diffuse-type gastric cancers. Helicobacter pylori infection was observed in 6 (67%) of our 9 patients, an incidence higher than the average in young Japanese individuals. Thus, early-onset gastric cancers may be attributable to environmental factors such as Helicobacter pylori infection.

Ulcerative colitis (UC) is characterized by a long-standing chronic inflammation of the bowel with intermittent periods of exacerbation and remission. Its acute exacerbation appears to be related to various stresses. Urocortin 1 (Ucn1) may play important roles in integrated local responses to stress. We therefore examined local production of Ucn1 in patients with UC by immunohistochemistry and mRNA in situ hybridization. Ucn1 immunoreactivity was predominantly detected in lamina propria plasma cells and enterochromaffin cells. In UC patients without glucocorticoid treatment, Ucn1-positive cells and plasma cells increased in proportion to the severity of inflammation (P0.0001). Ucn1-positive cells significantly increased in UC patients with advanced inflammatory grades, compared with a control group (P0.0001) and nonspecific colitis group (P0.0001). In glucocorticoid-treated patients, Ucn1-positive cells were significantly lower in number, compared with the nonglucocorticoid-treated group. Ucn1 mRNA was expressed in lamina propria plasma cells, and both corticotropin-releasing factor(1) and corticotropin-releasing factor(2(a)) mRNAs were also partially coexpressed in these cells and macrophages. The present study showed that Ucn1-positive cells were correlated with the severity of inflammation in colonic mucosa with UC, and glucocorticoid treatment decreased these cells. Ucn1 therefore may act as a possible local immune-inflammatory mediator in UC.

Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders. The prevalence rate is 10-20% and women have a higher prevalence. IBS adversely affects quality of life and is associated with health care use and costs. IBS comprises a group of functional bowel disorders in which abdominal discomfort or pain is associated with defecation or a change in bowel habit, and with features of disordered defecation. The consensus definition and criteria for IBS have been formalized in the “Rome II criteria”. Food, psychiatric disorders, and gastroenteritis are risk factors for developing IBS. The mechanism in IBS involves biopsychosocial disorders; psychosocial factors, altered motility, and heightened sensory function. Brain-gut interaction is the most important in understanding the pathophysiology of IBS. Effective management requires an effective physician-patient relationship. Dietary treatment, lifestyle therapy, behavioral therapy, and pharmacologic therapy play a major role in treating IBS. Calcium polycarbophil can benefit IBS patients with constipation or alternating diarrhea and constipation.

Helicobacter species can induce carcinoma in the liver of certain mice. Furthermore, Helicobacter pylori (H. pylori) exhibits hepatotoxicity in vitro. These reports indicate that H. pylori may play a role in hepatocarcinogenesis. The aim of this study was to assess the presence of H. pylori in human hepatocellular carcinoma (HCC) to determine if H. pylori may affect the development of this disease. Liver specimens from 15 HCC patients dissected into tumor and non-tumor tissues were examined for H. pylori by PCR using two sets of primers for 16S rRNA and urease B. DNA sequencing analysis was performed to confirm that PCR products with 16S rRNA primers were derived from H. pylori DNA. The specimens were also examined for H. pylori by immunohistochemistry using anti-H. pylori antibody. H. pylori was found in 13 of 15 tumor tissues, not in the non-tumor tissues. By contrast, Escherichia coli and Bacteroides fragilis, frequent colonizers of gut, were not detected by PCR in the HCC tumors. Ten cirrhotic liver tissue specimens and seven normal liver tissue specimens were also negative for H. pylori DNA by PCR. The nucleotide sequence of the amplified fragment shared 100% identity with the 16S rRNA gene of H. pylori. H. pylori was also detected in HCC tissue by immunohistochemical analysis. The presence of H. pylori in human HCC tissue was demonstrated by PCR and immunohistochemical analysis. These findings suggest that H. pylori might contribute to the development of HCC. Further study is needed to prove the pathogenetic role of H. pylori in the development of human HCC.

Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is selectively expressed in the endothelial cells of intestinal mucosa and gut-associated lymphoid tissue (GALT). Engagement of MAdCAM-1 to its ligand, integrin alpha4beta7, on lymphocytes is associated with the homing of gut-associated lymphocytes to normal gastrointestinal tract and inflammation sites. The present study was designed to elucidate differences between Crohn's disease (CrD) and ulcerative colitis (UC) from the expression patterns of MAdCAM-1. Samples were taken from 40 patients with CrD and 24 patients with UC at surgical resection. Using frozen sections, immunohistochemistry was performed for MAdCAM-1, E-selectin and CD34. MAdCAM-1+ venules were abundant in inflamed mucosa in both UC and CrD. In contrast, clear differences were noted between UC and CrD in the inflammatory area in the ulcer base, that is, MAdCAM-1+ venules were more abundant in CrD than in UC (P < 0.001), while E-selectin was expressed equally in these venules in both diseases. Furthermore, CrD was characterized by the occurrence of MAdCAM-1+ venules in deeper layers of the intestinal tissue, mainly in lymphoid aggregates. Our data indicated more extensive expression of MAdCAM-1 in CrD, which could contribute not only to mucosal inflammation, but also to transmural inflammation in CrD.

OBJECTIVES: Studies in the US and Europe have shown that appendectomy may prevent the development of ulcerative colitis, but no detailed study has been conducted in Japan, where ulcerative colitis is uncommon and the population is racially homogeneous. In addition, there has been no detailed analysis of the relationship between appendectomy and the clinical course of ulcerative colitis. In this multicenter clinical study, we evaluated the effects of appendectomy on ulcerative colitis in Japan. METHODS: A case-control study was undertaken in seven medical institutions comparing the incidence of appendectomy and tonsillectomy in 325 patients with ulcerative colitis and 325 controls matched for age (10-yr intervals) and sex. Disease duration, extent, and prognosis were determined in 21 patients with ulcerative colitis who underwent appendectomies and 304 patients with ulcerative colitis who did not undergo appendectomies. RESULTS: Appendectomy was performed in a significantly lower percentage of patients in the ulcerative colitis group (21/325, 6.5%) than in the control group (53/325, 16.3%) (p < 0.001) (odds ratios = 0.355, 95% CI = 0.208–0.603). In contrast, no significant difference was observed between the groups with respect to tonsillectomy. The mean age (25.7 ± 10.9 yr) of patients with ulcerative colitis at the time of appendectomy was significantly higher than the mean age (20.1 ± 8.7 yr) of patients in the control group at the time of appendectomy (p < 0.05). The incidence of proctitis was higher in the appendectomy group than in the group that did not undergo appendectomies (38.1% vs 18.1%). In addition, the recurrence rates were significantly lower in the appendectomy group than in the group that did not undergo appendectomies (57.1% vs 78.6%, p < 0.05), although both groups were similar in composition as to sex, age, duration of disease, smoking status, and previous medical treatment. CONCLUSIONS: Our results indicate that appendectomy has a negative association with and perhaps a preventive effect on the development of ulcerative colitis in the Japanese population. Furthermore, appendectomy also appears to reduce the extent and recurrence of ulcerative colitis.