Yasuhiro Udagawa

Kouji Banno, Nobuyuki Susumu, Takeshi Hirao, Megumi Yanokura, Akira Hirasawa, Daisuke Aoki, Yasuhiro Udagawa, Kokichi Sugano and Shiro Nozawa: Two Japanese kindreds occurring endometrial cancer meeting new clinical criteria for hereditary non-polyposis colorectal cancer (HNPCC), Amsterdam Criteria Ⅱ<br />

Kouji Banno, Nobuyuki Susumu, Takeshi Hirao, Megumi Yanokura, Akira Hirasawa, Daisuke Aoki, Yasuhiro Udagawa, Kokichi Sugano and Shiro Nozawa: Two Japanese kindreds occurring endometrial cancer meeting new clinical criteria for hereditary non-polyposis colorectal cancer (HNPCC), Amsterdam Criteria Ⅱ<br />

Endometrial cancer is the second most common malignancy in patients with hereditary nonpolyposis colorectal cancer (HNPCC). This cancer is caused by germline mutations in one of the DNA mismatch repair (MMR) genes. The present study was undertaken to analyze the relation between microsatellite instability (MSI) and germline mutations of MMR genes. We analyzed MSI in 38 cases of endometrial cancer. MSI was present in one or more (out of 5 examined) regions in 11 (29%) cases. Furthermore, alterations in MLH1 and MSH2, two culprit genes representative of HNPCC, were examined in the 11 MSI-positive patients using polymerase chain reaction-single-strand conformation polymorphism and sequencing. Germline mutations, namely, 1) a missense mutation at codon 688 (ATG--&gt;ATA, Met--&gt;Ile) and 2) a missense mutation at codon 390 (CTT--&gt;TTT, Leu--&gt;Phe) of the MSH2 gene, were found in 2 of the 11 patients (18%). Although these two cases do not fulfill the new Amsterdam criteria, they had strong family histories of colorectal and endometrial carcinoma. Our results show that genetic testing is important in cases of endometrial cancer with a history suggestive of HNPCC even if the new Amsterdam criteria are not fulfilled. (C) 2003 Elsevier Inc. All rights reserved.

Endometrial cancer is the second most common malignancy in patients with hereditary nonpolyposis colorectal cancer (HNPCC). This cancer is caused by germline mutations in one of the DNA mismatch repair (MMR) genes. The present study was undertaken to analyze the relation between microsatellite instability (MSI) and germline mutations of MMR genes. We analyzed MSI in 38 cases of endometrial cancer. MSI was present in one or more (out of 5 examined) regions in 11 (29%) cases. Furthermore, alterations in MLH1 and MSH2, two culprit genes representative of HNPCC, were examined in the 11 MSI-positive patients using polymerase chain reaction-single-strand conformation polymorphism and sequencing. Germline mutations, namely, 1) a missense mutation at codon 688 (ATG--&gt;ATA, Met--&gt;Ile) and 2) a missense mutation at codon 390 (CTT--&gt;TTT, Leu--&gt;Phe) of the MSH2 gene, were found in 2 of the 11 patients (18%). Although these two cases do not fulfill the new Amsterdam criteria, they had strong family histories of colorectal and endometrial carcinoma. Our results show that genetic testing is important in cases of endometrial cancer with a history suggestive of HNPCC even if the new Amsterdam criteria are not fulfilled. (C) 2003 Elsevier Inc. All rights reserved.

The serum level of beta1,4-galactosyltransferase (beta1,4-GalT) is increased in both malignancy and benign diseases. Galactosyltransferase associated with tumor (GAT) is one of the soluble forms of beta1,4-GalT, and is a marker of ovarian cancer with a high specificity. GAT and normal soluble beta1,4-GalT are both derived from the same membrane-bound form of the enzyme. This study investigated the mechanism of GAT elevation in patients with ovarian cancer. The serum levels of GAT and normal beta1,4-GalT were measured using specific monoclonal antibodies. In addition, nude mice bearing human ovarian cancer were used to assess the kinetics of tumor-derived enzymes. GAT and normal beta1,4-GalT were both detected in ovarian cancer patients, but only GAT reflected the tumor status. In tumor-bearing nude mice, both soluble forms of beta1,4-GalT were released from tumor cells, but the half-life of GAT was far shorter than that of normal beta1,4GalT. Addition of serum from healthy women to colostrum (which has a high GAT content) reduced the GAT level, while adding patient serum caused a significantly smaller reduction of GAT. Addition of the serum from mouse which includes no human beta1,4-GalT to colostrum also reduced the GAT level with no significant chance of total soluble beta1,4-GalT. These findings indicate that human serum contains certain factors that decrease the GAT level, but these factors are inhibited in ovarian cancer patients so that a high GAT level persists. It seems that the decrease of GAT occurs as a result of conversion into normal beta1A-GalT.

The serum level of beta1,4-galactosyltransferase (beta1,4-GalT) is increased in both malignancy and benign diseases. Galactosyltransferase associated with tumor (GAT) is one of the soluble forms of beta1,4-GalT, and is a marker of ovarian cancer with a high specificity. GAT and normal soluble beta1,4-GalT are both derived from the same membrane-bound form of the enzyme. This study investigated the mechanism of GAT elevation in patients with ovarian cancer. The serum levels of GAT and normal beta1,4-GalT were measured using specific monoclonal antibodies. In addition, nude mice bearing human ovarian cancer were used to assess the kinetics of tumor-derived enzymes. GAT and normal beta1,4-GalT were both detected in ovarian cancer patients, but only GAT reflected the tumor status. In tumor-bearing nude mice, both soluble forms of beta1,4-GalT were released from tumor cells, but the half-life of GAT was far shorter than that of normal beta1,4GalT. Addition of serum from healthy women to colostrum (which has a high GAT content) reduced the GAT level, while adding patient serum caused a significantly smaller reduction of GAT. Addition of the serum from mouse which includes no human beta1,4-GalT to colostrum also reduced the GAT level with no significant chance of total soluble beta1,4-GalT. These findings indicate that human serum contains certain factors that decrease the GAT level, but these factors are inhibited in ovarian cancer patients so that a high GAT level persists. It seems that the decrease of GAT occurs as a result of conversion into normal beta1A-GalT.

Hiroaki Shiraishi, Taiya Kato, Koji Atsuta, Chiho Sumi-Ichinose, Masatsugu Ohtsuki, Mitsuyasu Itoh, Hitoshi Hishida, Shin Tada, Yasuhiro Udagawa: Toshiharu Nagatsu, Yasumichi Hagino, Hiroshi Ichinose, and Takahide Nomura: cGMP Inhibits GPT Cyclohydrolase I Activity and Biosynthesis of Tetrahydrobiopterin in Human Umbilical Vein Endothelial Cells<br />

The objective of this research is whether the classification of vascular invasion severity can be used as a prognostic factor in cases of uterine endometrial cancer. Sixty-five patients with stage I to III uterine endometrial cancer were included in the study. All patients were seen between 1987 and 1997, and the types of their cancers were histologically confirmed. The degree of vascular invasion was classified according to three different systems: (1) positive or negative; (2) negative, mild, or severe; and (3) negative, mild, moderate, or severe. For each classification, the disease-free survival rate was calculated according to various pathologic factors using the Wilcoxon test; multivariate analyses were performed using the Cox proportional hazard model. Patients with severe vascular invasion showed a significantly lower disease-free survival rate than did patients with moderate or less severe invasion. In the multivariate analysis, severe vascular invasion was shown to be an independent prognostic factor indicating a high relative risk. We conclude that the severity of vascular invasion is an important histopathologic factor in determining the prognosis of uterine endometrial cancer. Vascular invasion classification systems employing three subjective or four objective categories may be more appropriate than a positive/negative classification system for judging the prognosis in cases of uterine endometrial cancer.

Hiroaki Shiraishi, Taiya Kato, Koji Atsuta, Chiho Sumi-Ichinose, Masatsugu Ohtsuki, Mitsuyasu Itoh, Hitoshi Hishida, Shin Tada, Yasuhiro Udagawa: Toshiharu Nagatsu, Yasumichi Hagino, Hiroshi Ichinose, and Takahide Nomura: cGMP Inhibits GPT Cyclohydrolase I Activity and Biosynthesis of Tetrahydrobiopterin in Human Umbilical Vein Endothelial Cells<br />

The objective of this research is whether the classification of vascular invasion severity can be used as a prognostic factor in cases of uterine endometrial cancer. Sixty-five patients with stage I to III uterine endometrial cancer were included in the study. All patients were seen between 1987 and 1997, and the types of their cancers were histologically confirmed. The degree of vascular invasion was classified according to three different systems: (1) positive or negative; (2) negative, mild, or severe; and (3) negative, mild, moderate, or severe. For each classification, the disease-free survival rate was calculated according to various pathologic factors using the Wilcoxon test; multivariate analyses were performed using the Cox proportional hazard model. Patients with severe vascular invasion showed a significantly lower disease-free survival rate than did patients with moderate or less severe invasion. In the multivariate analysis, severe vascular invasion was shown to be an independent prognostic factor indicating a high relative risk. We conclude that the severity of vascular invasion is an important histopathologic factor in determining the prognosis of uterine endometrial cancer. Vascular invasion classification systems employing three subjective or four objective categories may be more appropriate than a positive/negative classification system for judging the prognosis in cases of uterine endometrial cancer.