IMPORTANCE Randomized clinical trials of vitamin D supplementation for secondary prevention in patients with cancer are needed, given positive results of observational studies. OBJECTIVE To determine whether postoperative vitamin D 3 supplementation can improve survival of patients with digestive tract cancers overall and in subgroups stratified by 25-hydroxyvitamin D (25[OH]D) levels. DESIGN, SETTING, AND PARTICIPANTS The AMATERASU trial, a randomized, double-blind, placebo-controlled trial conducted at a single university hospital in Japan. Enrollment began in January 2010 and follow-up was completed in February 2018. Patients aged 30 to 90 years with cancers of the digestive tract from the esophagus to the rectum, stages I to III, were recruited. Of 439 eligible patients, 15 declined and 7 were excluded after operation. INTERVENTIONS Patients were randomized to receive oral supplemental capsules of vitamin D (2000 IU/d; n = 251) or placebo (n = 166) from the first postoperative outpatient visit to until the end of the trial. MAIN OUTCOMES AND MEASURES The primary outcome was relapse-free survival time to relapse or death. The secondary outcome was overall survival time to death due to any cause. Subgroups analyzed had baseline serum 25(OH)D levels of 0 to less than 20 ng/mL, 20 to 40 ng/mL, and greater than 40 ng/mL; because of small sample size for the highest-baselinelevel group, interactions were tested only between the low-and middle-baseline-level groups. RESULTS All 417 randomized patients (mean age, 66 years; male, 66%; esophageal cancer, 10%; gastric cancer, 42%; colorectal cancer, 48%) were included in the analyses. There was 99.8% follow-up over a median 3.5 (interquartile range, 2.3-5.3) years, with maximal follow-up of 7.6 years. Relapse or death occurred in 50 patients (20%) randomized to vitamin D and 43 patients (26%) randomized to placebo. Death occurred in 37 (15%) in the vitamin D group and 25 (15%) in the placebo group. The 5-year relapse-free survival was 77% with vitamin D vs 69% with placebo (hazard ratio [HR] for relapse or death, 0.76; 95% CI, 0.50-1.14; P = .18). The 5-year overall survival in the vitamin D vs placebo groups was 82% vs 81% (HR for death, 0.95; 95% CI, 0.57-1.57; P = .83). In the subgroup of patients with baseline serum 25(OH)D levels between 20 and 40 ng/mL, the 5-year relapse-free survival was 85% with vitamin D vs 71% with placebo (HR for relapse or death, 0.46; 95% CI, 0.24-0.86; P = .02; P = .04 for interaction). Fractures occurred in 3 patients (1.3%) in the vitamin D group and 5 (3.4%) in the placebo group. Urinary stones occurred in 2 patients (0.9%) in the vitamin D group and 0 in the placebo group. CONCLUSIONS AND RELEVANCE Among patients with digestive tract cancer, vitamin D supplementation, compared with placebo, did not result in significant improvement in relapse-free survival at 5 years.

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BACKGROUND The authors investigated whether the presence of matrix metalloproteinase‐2 (MMP‐2) and its inducer, CD147, in cancerous esophageal lesions and surrounding tissue might help to predict patient prognosis. METHODS Tissue samples from 101 patients with esophageal squamous cell carcinoma were stained with anti‐CD147 and anti–MMP‐2 antibodies for immunohistochemical analysis. RESULTS CD147 was expressed in cancerous and dysplastic lesions, but not in normal tissue. In contrast, MMP‐2 was detected mainly in normal interstitial tissue adjacent to cancerous lesions, but it was detected also in cancerous lesions in some patients. Pathologic findings demonstrated that the intensity of MMP‐2 staining in normal tissue was associated positively with the depth of tumor infiltration and the stage of disease, whereas MMP‐2 staining in cancerous tissue was associated positively with vascular and lymphatic vessel invasion as well as with immature differentiation of cancer cells. Using a proportional hazard model, including information on CD147 staining patterns within cancerous lesions along with clinical cancer staging, improved the accuracy of predicting patient prognosis. CONCLUSIONS These results suggested that measurement of CD147 and MMP‐2 expression with simple immunohistochemical staining may enhance further the understanding of the pathophysiology of invading tumor cells and, when used in combination with cancer staging, may increase the ability of investigators to predict prognosis in patients with esophageal squamous cell carcinoma. Cancer 2004. © 2004 American Cancer Society.

The altered form of the high-mobility group A2 (HMGA2) gene is somehow related to the generation of human benign and malignant tumours of mesenchymal origin. However, only a few data on the expression of HMGA2 in malignant tumour originating from epithelial tissue are available. In this study, we examined the HMGA2 expression level in pancreatic carcinoma, and investigated whether alterations in the HMGA2 expression level are associated with a malignant phenotype in pancreatic tissue. High-mobility group A2 mRNA and protein expression was determined in eight surgically resected specimens of non-neoplastic tissue (six specimens of normal pancreatic tissue and two of chronic pancreatitis tissue) and 27 pancreatic carcinomas by highly sensitive reverse transcriptase -polymerase chain reaction (RT -PCR) techniques and immunohistochemical staining, respectively. Reverse transcriptase -polymerase chain reaction analysis revealed the expression of the HMGA2 gene in non-neoplastic pancreatic tissue, although its expression level was significantly lower than that in carcinoma. Immunohistochemical analysis indicated that the presence of the HMGA2 gene in non-neoplastic pancreatic tissue observed in RT -PCR reflects its abundant expression in islet cells, together with its focal expression in duct epithelial cells. Intense and multifocal or diffuse HMGA2 immunoreactivity was noted in all the pancreatic carcinoma examined. A strong correlation between HMGA2 overexpression and the diagnosis of carcinoma was statistically verified. Based on these findings, we propose that an increased expression level of the HMGA2 protein is closely associated with the malignant phenotype in the pancreatic exocrine system, and accordingly, HMGA2 could serve as a potential diagnostic molecular marker for distinguishing pancreatic malignant cells from non-neoplastic pancreatic exocrine cells.

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