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Background: Understanding the prognostic factors of advanced gastric cancer before starting chemotherapy is important to determine personalized treatment strategies. However, the details of chemotherapy and the prognosis of advanced gastric cancer patients have changed with the time and environment. The aim of this study was to understand the current reality of chemotherapy and to estimate the prognostic factors of advanced gastric cancer patients before starting chemotherapy at multiple centers. This includes specialized cancer hospitals and community hospitals, with the latest data under the Japanese insurance system., Methods: We evaluated the clinical parameters and treatment details of 1025 patients who received systemic chemotherapy for unresectable advanced gastric cancer from 2012 to 2018 at 12 institutions in Japan. Prognostic factors were analyzed using the Cox proportional hazards regression model., Results: As of April 2021, 953 (93%) patients had died, while 72 (7%) patients survived. The median overall survival and progression-free survival of first-line chemotherapy was 11.8 months (95% confidence interval, 10.8-12.3 months) and 6.3 months (95% confidence interval, 5.9-6.9 months), respectively. Multivariate analysis revealed eight prognostic factors: age < 40 years, performance status ≥2, no gastrectomy, diffuse histological type, albumin <3.6, alkaline phosphatase ≥300, creatinine ≥1.0 and neutrophil-to-lymphocyte ratio > 3.0. Patients using trastuzumab showed better survival than patients without (16.1 months vs. 11.1 months; P = 0.0005)., Conclusions: We identified eight prognostic factors for patients with advanced gastric cancer undergoing Japanese standard chemotherapy. Our results will help clinicians develop treatment strategies for every patient., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Objective: Owing to the risks of serious and sustained toxicity, anticancer drugs such as cisplatin and irinotecan cannot be readily administered to patients with gastric cancer and severe peritoneal metastasis. Therefore, a standard chemotherapy regimen has yet to be established for these types of patients. This randomized study investigated the utility of sequential methotrexate and 5-fluorouracil therapy vs. 5-fluorouracil continuous infusion for gastric cancer with peritoneal metastasis., Methods: Eligible patients had radiologically confirmed peritoneal metastasis with intestinal stenosis, peritoneal tumor or ascites. Treatment with 5-fluorouracil continuous infusion (800 mg/m(2)/day, ci, d1-5, q4w) or methotrexate and 5-fluorouracil therapy (methotrexate, 100 mg/m(2), bolus infusion, followed 3 h later by 5-fluorouracil, 600 mg/m(2), bolus infusion, with leucovorin rescue, q1w) was continued until disease progression or unacceptable toxicity. The projected sample size was 236, providing 80% power to detect a 40% increase in median overall survival in methotrexate and 5-fluorouracil therapy with a one-sided α of 0.05., Results: All 237 randomized patients were included in the primary analysis. The methotrexate and 5-fluorouracil therapy arm was not superior to the 5-fluorouracil continuous infusion arm (median survival time, 9.4 months in the 5-fluorouracil continuous infusion arm, 10.6 months in the methotrexate and 5-fluorouracil therapy arm; hazard ratio, 0.94; 95% confidence interval, 0.72-1.22; one-sided P = 0.31). Frequencies of Grade 3 or higher neutropenia, Grade 3 or higher anorexia and treatment-related deaths were 0.9, 27.4 and 1.7%, respectively, in the 5-fluorouracil continuous infusion arm, and 31.9, 33.6 and 0.9%, respectively, in the methotrexate and 5-fluorouracil therapy arm., Conclusions: Methotrexate and 5-fluorouracil therapy is not suitable for use as standard therapy for advanced gastric cancer with peritoneal metastasis.

Expression of DAF (CD55) is enhanced on colonic epithelial cells of patients with ulcerative colitis (UC), and stool DAF concentrations are increased in patients with active disease. Cytokines are known to modulate DAF expression in various human cells, and lesions of UC reveal altered profiles of cytokine production. In this study, we evaluate the effects of various cytokines, IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, and interferon-gamma (IFN-gamma), on the synthesis and kinetics of DAF protein in HT-29 human intestinal epithelial cells. Using flow cytometry and an ELISA, we found that HT-29 cells constitutively express DAF on the cell surface and spontaneously release DAF into the culture supernatant under standard culture conditions. When the culture supernatant was centrifuged at 100000g, nearly a half of DAF was precipitated, indicating that one half of the released DAF was present as a membrane-bound form and the other half as a soluble form. Analysis of the culture supernatant of biotin surface-labelled HT-29 cells suggested that the soluble form DAF was derived by secretion from within the cell or by cleavage from the cell surface. Among the cytokines, IL-4 markedly, and IL-1beta moderately, enhanced the expression and the release of DAF. Actinomycin D, cycloheximide, and brefeldin A inhibited the increase in DAF release induced by IL-4 and IL-1beta stimulation. These results suggest that DAF is released from intestinal epithelial cells in response to cytokine stimulation and that IL-4 and IL-1beta are possible cytokines involved in DAF release into the colonic lumen of patients with UC.

Colonic epithelial cells of patients with UC express DAF in relation to the severity of mucosal inflammation. The aim of this study was to determine whether this factor in stool could be used as a marker of disease activity in UC patients. Stool DAF was measured by use of an immunoassay in 181 stool specimens obtained from 55 patients with UC of various levels of disease activity. Stool DAF concentrations in patients whose UC was active (0.0-785.6 ng/g stool; median 47.1 ng/g; n = 115) were significantly higher than concentrations in patients whose disease was inactive (0.0-48.6 ng/g; median 0.0 ng/g; n = 66) (P < 0.0001). Values in active UC patients also were higher than those in control patients with diarrhoea (0.0-30.0 ng/g; median 0.0 ng/g; n = 26) (P < 0.0001) and in control subjects without apparent colorectal disease (0-20.4 ng/g; median 0.0 ng/g; n = 44) (P < 0.0001). The elevated levels of stool DAF obtained from UC patients in relapse declined markedly in specimens collected after the disease went into remission following medical therapy. Stool DAF levels correlated with the severity of endoscopic and histological findings and the degree of DAF expression on the colonic epithelia. Our results suggest that the measurement of stool DAF is useful as a non-invasive means of monitoring intestinal disease activity in patients with UC.

The third component of complement (C3) is central to both the classical and alternative pathways in complement activation. In this study, involvement of C3 activation in the mucosal injury of UC was investigated. We examined the distribution of activated (C3b) and degraded fragments (iC3b/C3dg) of C3, terminal complement complex (TCC), and complement regulatory proteins in normal and diseased colonic mucosa including UC and other types of colitis using immunohistochemical techniques at the level of light and electron microscopy. While C3b and iC3b/C3dg staining was negligible in the normal mucosa, iC3b/C3dg and, to a lesser extent, C3b were deposited in UC mucosa along the epithelial basement membrane. The deposition was enhanced in relation to the severity of mucosal inflammation (C3b, P less than 0.05; iC3b/C3dg, P less than 0.01). Epithelial deposition of TCC was not observed in most UC mucosa. Immunoelectron microscopy showed that C3b and iC3b/C3dg were distributed mainly along the epithelial basement membrane and the underlying connective tissue in a granular, studded manner, and weakly present along the basolateral surface of epithelial cells. These C3 fragments were also deposited in inflammatory control mucosa such as ischaemic and infectious colitis. Our findings suggest that deposition of the C3 fragments occurs in inflamed colonic mucosa of diverse etiologies, including UC, but to define a role of the deposition in the development of mucosal injury in UC awaits direct study.

The relation of a family history of cancer and environmental factors to colorectal cancer was investigated in a case-control study conducted from 1992 to 1994 at 10 medical institutions in Japan using a self-administered questionnaire, and 363 cases of colorectal cancer were compared with 363 controls matched for sex and age. A family history of colorectal cancer was positively associated with colon cancer (odds ratio (OR) = 2.0, 95% confidence interval (CI) 1.03-3.87) and rectal cancer (OR = 2.1 CI 0.94-4.48), but a family history of other cancers did not increase the risk. The proportion of patients with a family history of colorectal cancer within first-degree relatives was 12.4%--appreciably higher than figures previously reported in Japan. On the other hand, the incidence of hereditary non-polyposis colorectal cancer was 1.4%, and lower than previous estimates. Among dietary factors, a western-style diet significantly increased the risk of both colon and and rectal cancer (OR = 2.3 CI 1.30-3.88 and OR = 2.1 CI 1.26-3.63, respectively). Consumption of rice was protective against both colon and rectal cancer (OR = 0.5 CI 0.31-0.82 and OR = 0.3 CI 18-0.65, respectively). Animal meat, oily food, fish, vegetables and fruit were shown to affect the risk, but no statistically significant correlation was found. Among other factors, constipation increased the risk of colon cancer (OR = 2.0 CI 1.02-3.76) and consumption of coffee raised the risk of rectal cancer (OR = 1.7 CI 1.07-2.82). Our findings suggest that a family history of colorectal cancer is an important risk factor for this disease, and does not contradict the hypothesis that the risk of colorectal cancer in Japan may be influenced by westernization of lifestyle. However, we were unable to find conclusive evidence that familial clustering of this disease is strongly affected by environmental factors or genetic diseases such as hereditary non-polyposis colorectal cancer.