Introduction: Some patients are more susceptible to multiple primary malignancies (MPMs). However, understanding of the effects of this susceptibility on the benefits and detriments to patient survival are poorly understood.

Introduction: Whether good baseline quality of life (QOL) is linked to improved QOL: improved overall survival (OS) which is relevant to HLA-restricted peptides has not been evaluated, and the causal nature of this correlation is not known.

Introduction: Whether human leukocyte antigens (HLAs) and human endogenous retroviruses (HERVs) affect therapeutic outcomes is unknown. Here, we focused on the similarity between HERV and human immunodeficiency virus (HIV) genes.

It is not well known that the correlation between HLA antigens and response to cancer therapy. To evaluate the correlation among patients' outcome, HLA antigens and therapies, we used the hierarchical clustering analysis (Ward method). We examined HLA antigens as biomarkers as well as models of gene polymorphism in 1753 gastric cancer patients followed over 25 years after treatment. Among these patients, we identified that HLA haplotypes; HLA-B54-Cw1-DQ4-DR4, might be restricting to Fluoropyrimidine drugs plus PSK therapy in gastric cancer. HLA haplotypes including HLA-B54 were candidate predictors for response to FPSK therapy in gastric cancer. HLAs will be useful biomarkers for response to therapy in Japanese patients.

There are no strategies to predict a patient's response to therapy. In a previous report, we classified Japanese patients into four groups according to the incidence of HLA antigens, by using the quantification method III. We examined the HLA antigens of patients before surgery and evaluated their outcome according to the HLA classification by this quantification method. We also reported that HLA-oriented therapy was better than old fashioned therapy. The aim of the present study was to evaluate whether HLA classification is useful in the treatment of individual cancer patients, by using a consecutive retrospective study series of 1932 patients from Jan 1977 to May 1996 and a consecutive prospective study series of 582 patients from Jun 1996 to Aug 2005, all of whom received gastrectomies.There were significant differences between male patients who agreed to get the recommended therapy (the patients in agreement) and those who did not (the patients in disagreement), those with lymph node metastasis, those with undifferentiated adenocarcinoma, and those in stage 3A. Moreover, stage 2 and 3A patients benefitted from HLA-oriented therapy in a prospective study.In conclusion, our results showed that it is beneficial to examine HLA antigens preoperatively, that HLA-oriented therapy is promising, and that we must determine predictive factors for response to therapy in the future. We concluded that HLA antigens are promising predictive markers for cancer treatment.

Extensive lymphadenectomy, including upper mediastinum, for thoracic esophageal carcinoma was introduced at the beginning of 1980s. However, the efficacy has not been analyzed in large series at a single institute. We evaluated factors potentially related to improved surgical results in patients with thoracic esophageal squamous cell carcinoma (SCC). From 1959 to 1998, a total of 792 patients with thoracic esophageal SCC underwent R0 surgery. A variety of clinicopathological factors were compared among patients treated from 1990 to 1998 (recent group, n = 164) and 1959 to 1989 (former group, n = 628). The recent group showed significantly better survival than the former group (5-year survival rates: 51 versus 17%, P < 0.01), partly because earlier stage disease was included in the recent group than in the former group. Multivariable analysis, using the Cox regression analysis, indicated the time period of surgery, age, tumor location, the number of positive nodes (>5), venous invasion, and tumor–node–metastasis stage. Upper mediastinum lymphadenectomy was also an independent factor to improve survival of patients with thoracic esophageal SCC.

BACKGROUND: Because invasion to an adjacent organ (T4) indicates highly advanced disease, and most surgeons avoid esophagectomy, the prognostic impact of clinicopathologic factors for survival of these patients after esophagectomy has rarely been analyzed. STUDY DESIGN: From 1960 to 2005, a total of 268 patients with esophageal squamous cell carcinoma underwent esophagectomy for pathologic T4 disease (pT4). The impact of clinicopathologic factors on survival was evaluated by univariate and multivariate analysis. Changes in surgical outcomes and longterm survival between the earlier period (1960 to 1989) and the later period (1990 to 2005) were analyzed. RESULTS: Overall survival rates of all patients were 25% at 1 year, 10% at 3 years, and 5% at 5 years. The survival curve of the later group was significantly better than that of the earlier group (p < 0.01). Multivariate analysis indicated that venous invasion (hazards ratio, 1.76; 95% CI, 1.33 to 2.33, p < 0.01) and presence of a postoperative complication (hazards ratio, 2.62; 95% CI, 1.96 to 3.51, p < 0.01) were independent risk factors for poor overall survival. Presence of residual cancer was also an independent risk factor for poor cause-specific survival (hazards ratio, 2.40; 95% CI, 1.23 to 4.69, p = 0.01). Venous invasion and intramural metastasis were risk factors for residual cancer. A total of 38 (14%) patients, 15 in the early period and 23 in the later period, underwent complete resection (R0). Although overall survival after R0 resection in the later period improved slightly, cancer-related survival rates were similar in both periods. CONCLUSIONS: Although overall survival of patients with pT4 improved after 1990, this improvement might be mainly dependent on curability of the resection.

Background Although thoracic lymph node metastasis in patients with thoracic esophageal squamous cell carcinoma (SCC) has been reported to be a negative risk factor for long-term survival, only a few studies have evaluated the clinicopathologic difference between the impact of metastasis to the paraesophageal lymph nodes and to the nonparaesophageal lymph nodes. The purpose of this study was to evaluate surgical outcome after the clearance of metastatic thoracic lymph nodes. Methods Retrospectively reviewed were 164 consecutive patients with thoracic esophageal SCC who had not had preoperative treatment and underwent surgery from 1980 to 2005 and were found to have thoracic lymph node metastases. Of these patients, 83 underwent surgery from 1980 to 1994 and 81 from 1995 to 2005. Univariate and multivariate analyses were performed to evaluate the impact of nonparaesophageal lymph node metastasis on survival. Results Univariate analysis revealed that T3/T4 tumors and the presence of nonparaesophageal node metastases were associated with only a 20% overall five-year survival rate. The overall five-year survival for the most recent period was significantly better than for the former period (42% vs. 13%, p < 0.01). Based on a multivariate analysis of prognostic impact of each nonparaesophageal node, the presence of metastatic subcarinal and/or posterior mediastinal nodes was an independent risk factor for reduced survival. Conclusion Surgical outcome for patients with thoracic esophageal cancer and metastatic thoracic lymph nodes has improved during the last 25 years. Although postoperative chemotherapy might improve survival, the presence of T3/T4 tumors and/or metastatic nonparaesophageal nodes were unfavorable factors for survival.

Background/Purpose: Ncx (Enx, Hox11L.1)-deficient (Ncx-/-) mice develop mega-ileo-ceco-colon with a larger number of neuronal cells in the enteric ganglia. We investigated mechanisms related to this abnormality and directed our attention to the effects on gastrointestinal tract functions.Methods: The number of NADPH diaphorase or cuprolinic blue positive neuronal cells in the enteric ganglia was examined during growth of the mice. Neuronal cell death of enteric ganglia was assayed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling. Function of the gastrointestinal tract was determined by measuring excretion time of the barium chloride given into the stomach.Results: The number of neuronal cells decreased in control mice older than 2 weeks, and neuronal cell death was evident in the ganglia. However, the number of neuronal cells did not decrease in Ncx-/- mice, and cell death was rare. Excretion time of barium chloride was prolonged in all Ncx-/- mice examined and was improved by the administration of an inhibitor of nitric oxide synthase.Conclusions: Ncx participates in cell death of enteric neurons. Motor abnormality of the gastrointestinal tract in Ncx-/- mice may be attributed to the large number of neuronal cells. (c) 2007 Elsevier Inc. All rights reserved.

Between 1987 and 2005 we performed serological HLA typing in 4,094 Japanese people to evaluate the frequencies of HLA antigens among cancer patients, non-cancer patients and normal subjects. Among these cancer patients compared with non-cancer and normal patients, there were significantly lower frequencies for HLA-24, -A33, -B35, -B44, -DR8, and -DR9, but there was only one significantly lower frequency for HLA-DR8, even after the Bonferroni correction. In cases of gastric cancer, there was a significantly lower frequency for HLA-A33 and -B44 than among non-cancer subjects, even after the Bonferroni correction. In cases of esophageal cancer, significantly lower frequencies for HLA-A33, -B44, -DR6, -DR8, and -DQ4 were found. In cases of hepatoma, the frequency of HLA-DQ3 was significantly lower. In lung cancer, HLA-DR8 and DQ4, and in breast cancer, HLA-Cw3, -DR8, and -DR9 were also significantly lower after the Bonferroni correction. The data demonstrated here shows that there may be an association between different cancers and different antigens. The frequencies of HLA-A33, -B44, -Cw3, -DR6, -DR8, -DR9 and -DQ4 antigens were lower in total; therefore, these antigens may act as defensive factors of carcinogenesis.

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To investigate the biological significance of a longevity mutation found in daf-2 of Caenorhabditis elegans, we generated a homologous murine model by replacing Pro-1195 of insulin receptors with Leu using a targeted knock-in strategy. Homozygous mice died in the neonatal stage from diabetic ketoacidosis, whereas heterozygous mice showed the suppressed kinase activity of the insulin receptor but grew normally without spontaneously developing diabetes during adulthood. We examined heterozygous insulin receptor mutant mice for longevity phenotypes. Under 80% oxygen, mutant female mice survived 33.3% longer than wild-type female mice, whereas mutant male mice survived 18.2% longer than wild-type male mice. These results suggested that mutant mice acquired more resistance to oxidative stress, but the benefit of the longevity mutation was more pronounced in females than males. Manganese superoxide dismutase activity in mutant mice was significantly upregulated, suggesting that the suppressed insulin signaling leads to an enhanced antioxidant defense. To analyze the molecular basis of the gender difference, we administered estrogen to mutant mice. It was found that the survival of mice under 80% oxygen was extended when they were administered estradiol. In contrast, mutant and wild-type female mice showed shortened survivals when their ovaries were removed. The influence of estrogen is remarkable in mutant mice compared with wild-type mice, suggesting that estrogen modulates insulin signaling in mutant mice. Furthermore, we showed additional extension of survival under oxidative conditions when their diet was restricted. Collectively, we show that three distinct signals; insulin, estrogen, and dietary signals work in independent and cooperative ways to enhance the resistance to oxidative stress in mice.

Background: The influence of lower body mass index on the survival in cancer patients has not been fully estimated. While, many studies suggest that body mass index were positively associated with an increased risk of cancers of the esophagus, colon, gallbladder, pancreas, breast, endometrium, kidney, and ovary, so the rapid growth in the prevalence of obesity as new threats foretells health problems in years to come.Methods: We assessed preoperative body mass index (BMI) of 2677 patients with malignant and benign diseases who enrolled in the data base for The Japanese Society of strategies of Cancer research and Therapy from May 1975 to February 2004, for evaluating how BMI effect on the outcomes of patients, with examining some parameters.Results: During the period of this study from 1975-, the median BMI increased from 21.6 kg/m2, 21.9 kg/m2, 21.9 kg/m2, and 22.2 kg/m2, to 22.4 kg/m2. Serum gastrrin levels, T-IGR, SA, IAP, and CEA were increased significantly than those in both normal and obesity patients. The 10-year-survival rates (disease specific death) of patients of underweight, normal, overweight, and obese were 38.0 (52.0) %, 58.7 (69.5) %, 68.5 (77.4) %, and 54.3 (62.6) %, respectively. (Fig. 3 left) There were significant differences among these groups. (Underweight vs. normal, overweight, and obese, p<0.001, p<0.001, and p=0.042. normal vs. overweight, p<0.001)Conclusions: We found that underweight as well as obese not but overweight patients were shown poor survival rates, and that underweight group showed older persons with lower acid output, higher gastrinemia, higher serum levels of IAP, sialic acid, and CEA than normal weight and overweight group. These findings of this study suggest that underweight group also alterations in growth factors and acute phase reactants. This needs to be investigated in other samples and populations.

Purpose: Previous studies showed that HLA-B40 and -B51 antigens were associated with the response to immunotherapy using protein-bound polysaccharide (PSK) and chemotherapy, respectively, in gastric cancer. We evaluated whether a putative HLA antigen correlated with the response to therapy, and associated with secondary malignancies. Patients and Methods: 413 patients with 302 gastric, 57 colon and 52 rectal cancers, and 2 synchronous gastric and colon cancers who underwent resection of the tumors from DEC-1990 to AUG-1993. They were examined 53 HLA antigens by using the micro-cytotoxicity assay and were randomized to immunotherapy or chemotherapy according to status of the positive or negative HLA -B40 and -B51 antigen and followed for secondary malignancy. Results: Three hundred two gastric cancers followed to be 12 secondary malignancies and 109 colorectal cancers 3. HLA-B40 and -B51 antigens were not significantly associated with the response to therapy. Patients in stage 1A gastric cancer without HLA-40 antigen who received chemotherapy and those with this antigen who received immunotherapy all lived. HLA-Cw3 positive patients with gastric cancer showed significantly higher incidence of secondary malignancies. Patients with heterozygous at HLA-A and -C, and those with homozygous at HLA-DQ also showed significantly higher incidence of secondary malignancies than those with homozygous at HLA-A and -C, and those with heterozygous at HLA-DQ. Conclusion: This study failed to confirm that HLA-B40 and -B51 antigens significantly associated with response to therapy, but we have discovered that HLA-Cw3 antigen was susceptible to subsequent malignancies in gastric cancer.

Reported differences in clinicopathological patterns of gastric carcinoma between the West and Japan suggest the presence of differences in cancer biology. The aim of the present study was to analyze clinopathological changing patterns of gastric cancer biology in a large series of patients from Japan, where mortality rates for GC are relatively high. Based on the registered data of 2569 patients diagnosed between January 1980 and December 2000, we analyzed the differences in clinicopathological patterns for two consecutive periods: 1980-1990 (A group) and 1991-2000 (B group). Patient age ranged from 21-92 years (median: 61 years), with 70.9% of the study participants being men. Analysis revealed that there were no significant differences in the conditions of lymph node metastasis, and also no significant differences in the frequencies of tumor depth, gender, and double cancer between A and B groups. With regard to differences in age (less than 49 years vs. 50 years and over), there was a significant increase in the incidence of cancer in the patients 50 years and over. The pattern of tumor location of the lower third of the stomach increased over the period of the study, while that of the upper third of the stomach decreased. With regard to histological type, there was a significant increase in the incidence of a moderately differentiated type of tubular adenocarcinoma and poorly differentiated adenocarcinoma (por), but a significant decrease in that of signet ring cell carcinoma. Taking every factor into consideration, the incidence of early-localized cancers appears to have increased and that of advanced invasive cancers appears to have decreased in Japan during the past 20 years.In conclusion, adenocarcinomas of the stomach with intestinal types, which related with the HP infection, decreased and those of diffuse types, which did not relate with the HP infection increased during the past 20 years.

Mammalian Polycomb group (PcG) proteins are known to function during the maintenance of spatially restricted expression of Hox cluster genes and cellular proliferation. To understand the molecular basis of PcG functions, it is important to identify the components of mammalian PcG complexes. We isolated mouse YAF2 as a protein that interacts with Ring1B, a known constituent of mammalian PcG complexes. We show that the murine YAF2 locus generates two different transcripts, mYAF2-a and mYAF2-b by alternative splicing of the third exons which encode two YAF2 isoforms of 179 and conceptual 60 amino acids, respectively. At least five exons encoding mYAF2 transcripts are mapped on chromosome 15E3 region. Expression of mYAF2 mRNA was observed in both pre- and postimplantation embryos. In mid-gestation embryos, mYAF2 expression is strongly seen in the region close to the surface ectoderm. Finally, biochemical evidence and colocalization studies in tissue culture cells suggest that the product of the mYAF2 gene is involved in PcG complexes together with Ring1B and/or Ring1A.

Last June, I undertook the responsibility of dissolving the Japanese Society for Esophageal Diseases (JSED), which was founded by Prof. Kohmei Nakayama of Chiba University about 40 years ago and was served by four presidents, Hiroshi Sato, Teruo Kakegawa and myself. In place of this we developed a new organization, the Japan Esophageal Society (JES), composed of individual academic members, rather than an institution. The JSED took a step forward to hold an academic meeting (JES) this June, after a one-year period of preparation. In retrospect, the JSED was started in 1965 to study and research surgical therapy for esophageal cancer as its main theme, then subsequently developed markedly, and 72 institutions had already joined it by 1972. If we consider 1932, when Prof. Sadanobu Seo (Chiba University) submitted the assignment report of the Japan Surgical Society, to be the dawn of surgical therapy for esophageal cancer in Japan, Japanese esophageal surgical history could be approximately divided into three periods: the initial period from 1930 to 1960 (the period of improvement of direct operative mortality), the middle period from 1960 to 1980 (the period of improvement of postoperative complaints and introduction of modern diagnostic techniques), and the latter period from 1980 to 2000 [the period of improvement in survival rate and quality of life (QOL) of patients]. The JSED was, therefore, organized in the beginning of the middle period. At that time, direct operative mortality was 40% to 50%, and, whilst various reports were actively discussed among the various institutions of the JSED, it was very difficult to reach a conclusion from various opinions with no single specific set of rules. Therefore, in view of the need for discussing under a standard, “Guidelines for Clinical and Pathologic Studies on Carcinoma of the Esophagus” was made with much effort and time, and the JSED developed rapidly after that. In the latter period, direct operative mortality of esophAt the Inauguration of the Japan Esophageal Society

The vertebrate Polycomb Group (PcG) genes encode proteins that form large multimeric and chromatin-associated complexes implicated in the stable repression of developmentally essential genes. Here we have isolated a 2.5-kb cDNA for Edr2, a mouse homolog of the Drosophila PcG gene Ph, although it was originally identified as a 3.8-kb cDNA. However, little is known about molecular basis of the 3.8-kb cDNA. Genomic and RNA analyses have shown that Edr2 locates on Chromosome 4 as a single copy gene and is transcribed into at least two transcript isoforms about 3.0 and 4.4 kb in length, most likely corresponding to the 2.5- and 3.8-kb cDNAs, respectively. The largest open reading frames in the 2.5- and 3.8-kb cDNAs encode 36- and 90-kDa polypeptides, respectively. The 36-kDa protein is a truncated form lacking of the N-terminal region of the 90-kDa protein. Interestingly, it has been demonstrated that the 3.0-kb mRNA accumulates at a much higher level than the 3.8-kb mRNA in mouse embryos and mature tissues. Immunostaining assay of mammalian cells has shown that the 36-kDa form tagged with HA colocalizes with the other PcG protein Mel18 in nuclei, suggesting that the smaller protein is capable of forming maltimeric complex with other PcG proteins. Therefore, the 36-kDa protein might function generally as a PcG protein.

The products of the Polycomb group of genes form complexes that maintain the state of transcriptional repression of several genes with relevance to development and in cell proliferation. We have identified Ring1B, the product of the Ring1B gene (Rnf2 - Mouse Genome Informatics), by means of its interaction with the Polycomb group protein Mel18. We describe biochemical and genetic studies directed to understand the biological role of Ring1B. Immunoprecipitation studies indicate that Ring1B form part of protein complexes containing the products of other Polycomb group genes, such as Rae28/Mph1 and M33, and that this complexes associate to chromosomal DNA. We have generated a mouse line bearing a hypomorphic Ring1B allele, which shows posterior homeotic transformations of the axial skeleton and a mild derepression of some Hox genes (Hoxb4, Hoxb6 and Hoxb8) in cells anterior to their normal boundaries of expression in the mesodermal compartment. By contrast, the overexpression of Ring1B in chick embryos results in the repression of Hoxb9 expression in the neural tube. These results, together with the genetic interactions observed in compound Ring1B/Mel18 mutant mice, are consistent with a role for Ring1B in the regulation of Hox gene expression by Polycomb group complexes.

Manganese superoxide dismutase (MnSOD) is the enzyme that converts toxic O(2)(-) to H(2)O(2) in mitochondria. Previous reports showed that a deficiency of MnSOD in mice was neonatal lethal. Therefore, a model mouse was not available for the analysis of the pathological role of O(2)(-) injuries in adult tissues. To explore an adult-type model mouse, we designed tissue-specific MnSOD conditional knockout mice using a Cre-loxp system. First, we crossbred MnSOD flox mice with transgenic mice expressing Cre recombinase under the control of the chicken actin promoter (CAG). We confirmed that CAG MnSOD knockout mice were completely deficient in MnSOD and died as neonates, validating the use of the Cre-loxp system. Next, we generated liver-specific MnSOD-deficient mice by crossbreeding with Alb-Cre transgenic mice. MnSOD activity and protein were both significantly downregulated in the liver of liver-specific MnSOD knockout mice. However, no obvious morphological abnormality was observed in the liver when biochemical alterations such as lipid peroxidation were not detectable, suggesting a redundant or less important physiological role for MnSOD in the liver than previously thought. In the present study, we successfully generated tissue-specific MnSOD conditional knockout mice that would provide a useful tool for the analysis of various age-associated diseases such as diabetes mellitus, Parkinson's disease, stroke, and heart disease, when crossbred with tissue-specific transgenic Cre mice.