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Biomedical subjects

Shiro Nozawa

Publications and source records attributed to Shiro Nozawa.

At least 19 recordsLinked to original sources
PubMed2005

Frequent immune responses to a cancer/testis antigen, CAGE, in patients with microsatellite instability-positive endometrial cancer.

PURPOSE: Identification of cancer/testis antigens useful for diagnosis or immunotherapy of cancers was attempted by cDNA expression cloning with patients' sera (SEREX). EXPERIMENTAL DESIGN: cDNA expression libraries made from testis or endometrial cancer cell lines were screened using sera from patients with endometrial cancer or melanoma patients immunized with dendritic cells pulsed with autologous tum or lysates. Tissue-specific expression by RT-PCR and immunogenicity by Western blotting of the bacterial recombinant antigen with sera from cancer patients were evaluated. RESULTS: A cancer/testis antigen, CAGE, was isolated by two independently performed SEREX. CAGE was expressed in various cancer cell lines including endometrial cancer, colon cancer, and melanoma in 7 of 10 endometrial cancer tissues and in 1 of 3 atypical endometrial hyperplasia, but not in normal tissues including the endometrium and testis. The protein expression on cancer cells was confirmed by Western blot analysis with the recombinant CAGE protein, anti-CAGE IgG antibody was detected in sera from 5 of 45 endometrial cancer, 2 of 24 melanoma, and 2 of 33 colon cancer patients, but not in sera from healthy individuals. By ELISA analysis, anti-CAGE antibody was detected in 12 of 45 endometrial cancer, 2 of 20 melanoma, and 4 of 33 colon cancer patients. Intriguingly, anti-CAGE antibody was highly positive in 7 of the 13 (53.8%) microsatellite instability (MSI)-H patients with endometrial cancer, but negative in 20 non-MSI-H patients (P = 0.001). CONCLUSION: CAGE may be useful for immunotherapy and diagnosis of various cancers particularly MSI-positive endometrial cancer.

Antibodies, Neoplasm↗
PubMed2005

Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation.

Angiopoietin (Ang) signaling plays a role in angiogenesis and remodeling of blood vessels through the receptor tyrosine kinase Tie2, which is expressed on blood vessel endothelial cells (BECs). Recently it has been shown that Ang-2 is crucial for the formation of lymphatic vasculature and that defects in lymphangiogenesis seen in Ang-2 mutant mice are rescued by Ang-1. These findings suggest important roles for Ang signaling in the lymphatic vessel system; however, Ang function in lymphangiogenesis has not been characterized. In this study, we reveal that lymphatic vascular endothelial hyaluronan receptor 1-positive (LYVE-1(+)) lymphatic endothelial cells (LECs) express Tie2 in both embryonic and adult settings, indicating that Ang signaling occurs in lymphatic vessels. Therefore, we examined whether Ang-1 acts on in vivo lymphatic angiogenesis and in vitro growth of LECs. A chimeric form of Ang-1, cartilage oligomeric matrix protein (COMP)-Ang-1, promotes in vivo lymphatic angiogenesis in mouse cornea. Moreover, we found that COMP-Ang-1 stimulates in vitro colony formation of LECs. These Ang-1-induced in vivo and in vitro effects on LECs were suppressed by soluble Tie2-Fc fusion protein, which acts as an inhibitor by sequestering Ang-1. On the basis of these observations, we propose that Ang signaling regulates lymphatic vessel formation through Tie2.

Angiopoietin-1↗
PubMed2005

Long-term effects on bone mineral density and bone metabolism of 6 months' treatment with gonadotropin-releasing hormone analogues in Japanese women: comparison of buserelin acetate with leuprolide acetate.

Our objective was to assess the effects of 6 months' treatment with two types of gonadotropin-releasing hormone (GnRH) analogues on lumbar bone mineral density (BMD) and bone metabolism. We studied 27 women who had been given a diagnosis of endometriosis or uterine myoma. The subjects received drug therapy for 6 months and were subsequently followed up for 1 year. The BMD of the lumbar spine (L2, L3, L4) was measured by dual energy X-ray absorptiometry four times: at baseline, after 6 months, after 12 months, and after 18 months. The serum concentrations of sex steroids and bone metabolic markers were measured at the same times as BMD. Compared with the baseline value, the mean decrease in the buserelin group L2-4 BMD was 3.7% at 6 months, 1.7% at 12 months, and 0.4% at 18 months. In the leuprolide group, L2-4 BMD decreased respectively by 5.1%, 6.2%, and 4.3%. Serum concentrations of calcium increased significantly after 6 months of treatment (P < 0.05) and returned to the baseline level at 12 months in both groups. In the leuprolide group, the intact osteocalcin concentration after 6 months was significantly higher than the baseline value, and after 12 months, it decreased to the baseline level. Our results indicate that the effect on BMD of 6 months' treatment with GnRH analogues virtually resolves by 1 year after treatment, provided that drugs affecting bone metabolism are not given during this period.

Absorptiometry, Photon↗
PubMed2005

Clinical characteristics of prognostic factors in poorly differentiated (G3) endometrioid adenocarcinoma in Japan.

BACKGROUND: It has been reported that prognosis is less favorable in poorly (G3) differentiated endometrioid adenocarcinoma than in well (G1) or moderately (G2) differentiated endometrioid adenocarcinoma. The goal of this study is therefore to analyze the prognosis of G3 endometrioid adenocarcinoma and various factors that may predict a favorable prognosis. METHOD: This study included 699 Japanese cases of endometrioid adenocarcinoma at the International Federation of Gynaecology and Obstetrics (FIGO) surgical stages I-IV (including 74 G3 cases). We investigated the G1-G3 survival rates of endometrioid adenocarcinoma cases and the G2 and G3 disease-free periods. We also examined the clinicopathological characteristics of G3 endometrioid adenocarcinoma. RESULT: The prognosis was poor in stages III and IV in G3 and in G2 cases, but recurrence was observed more frequently in G3 cases than in G2 cases. Adnexal metastasis and high pre-surgery CA602 values showed significantly low P-values for survival. CONCLUSIONS: We suggest that the risk of late recurrence is higher in G3 than in G2 cases. The absence of adnexal metastasis and low pre-surgery CA19-9 values may suggest a relatively favorable prognosis in G3 endometrioid adenocarcinoma.

Adult↗
PubMed2005

Comparison between in situ hybridization and real-time PCR technique as a means of detecting the integrated form of human papillomavirus 16 in cervical neoplasia.

Integration of the human papillomavirus (HPV) genome is thought to be one of the causes of cancer progression. However, there is controversy concerning the physical status of HPV 16 in premalignant cervical lesions, and there have been no reports on the concordance between detection of the integrated form of HPV16 by real-time PCR and by in situ hybridization. We investigated specimens of cervical intraepithelial neoplasia (CIN) and invasive carcinomas for the physical status of HPV 16 by real-time PCR and in situ hybridization. The presence of the integrated form was detected by both real-time PCR and in situ hybridization in zero of four cases of CIN1, three of six cases of CIN2, nine of 27 cases of CIN3, and two of six cases of invasive carcinomas. Integrated HPV 16 was present in some premalignant lesions but was not always present in carcinomas. The concordance rate between the two methods for the detection of the presence of the integrated form was 37 of 43 (86%) cases. Real-time PCR and in situ hybridization were found to be complementary and convenient techniques for determining the physical status of the HPV genome. We conclude that a combination of both methods is a more reliable means of assessing the physical status of the HPV genome in cervical neoplasia.

Carcinoma↗
PubMed2005

Status of climacteric symptoms among middle-aged to elderly Japanese women: comparison of general healthy women with women presenting at a menopausal clinic.

AIM: To examine the status and characteristics of climacteric symptoms reported by generally healthy middle-aged to elderly women in Japan, those living in Saitama Prefecture were surveyed . METHODS: The subjects comprised 398 women ranging in age from 40 to <60 years (mean age, 50.5 years). Climacteric symptoms were objectively assessed using the Keio questionnaire. The total scores obtained for the 40 symptoms were used to calculate symptom prevalence and severity. RESULTS: (i) The most frequent symptom was poor memory, reported by 88.7% of the women. (ii) Lumbar-sacral back pain was rated as a severe symptom by the highest percentage of women (15.3%). (iii) The prevalence and severity of poor memory and lumbar-sacral back pain did not differ with menopausal status. (iv) Hot flashes and sweats were slightly higher in peri- and early postmenopausal women than in premenopausal women. CONCLUSIONS: The present study showed that healthy women who do not consult physicians because of climacteric symptoms are primarily concerned with age-related symptoms, such as poor memory, loss of hair, and forgetfulness.

Adult↗
PubMed2005

Alterations in the glycolipid composition and cellular properties of ovarian carcinoma-derived RMG-1 cells on transfection of the alpha1,2-fucosyltransferase gene.

Transfection of the mouse Fut1 and Fut2, and human FUT1 genes into human ovarian carcinoma-derived RMG-1 cells resulted in 20-30-fold increases in cellular alpha1,2-fucosyltransferase activity, and in alteration of the glycolipid composition, including not only fucosylated products, but also precursor glycolipids. Although globo-series glycolipids were not significantly affected by the transfection, the major glycolipids belonging to the lacto-series type 1 chain family in RMG-1 cells and the transfectants were the Lc4Cer, Lewis a (Le)a and Leb, and H-1 glycolipids, respectively, suggesting that fucosylation of Lc4Cer to the H-1 glycolipid prevents the further modification of Lc4Cer to Lea and Leb in the transfectants. Also, the lacto-series type 2 chains in RMG-1 cells were LeX, NeuAc-nLc4Cer and NeuAc-LeX, and those in the transfectants were LeX and LeY, indicating that the sialylation of nLc4Cer and LeX is restricted by increased fucosylation of LeX. As a result, the amount of sialic acid released by sialidase from the transfectants decreased to 70% of that from RMG-1 cells, and several membrane-mediated phenomena, such as the cell-to-cell interaction between cancer cells and mesothelial cells, and the cell viability in the presence of an anticancer drug, 5-fluorouracil, for the transfectants was found to be increased in comparison to that for RMG-1 cells. These findings indicate that cell surface carbohydrates are involved in the biological properties, including cell-to-cell adhesion and drug resistance, of cancer cells.

Animals↗
PubMed2005

Is laser conization adequate for therapeutic excision of adenocarcinoma in situ of the uterine cervix?

AIMS: To determine the safety of uterine-preserving operations for adenocarcinoma in situ of the cervix. METHODS: Fifteen cases of adenocarcinoma in situ (AIS) were diagnosed using neodymium:yttrium aluminum garnet (Nd:YAG) laser conization. The accuracy of preconization histology or cytology was evaluated in 15 AIS cases. In these AIS cases, we investigated how far the tumor was located from the squamocolumnar junction (SCJ) and the endocervix. Fourteen cases of the 15 AIS-affected patients were treated using laser conization alone. These patients were closely followed up. RESULTS: Precise agreement between preconization diagnosis and conization histology was seen in 46.7% (7/15) of the AIS cases. In 14 of the 15 cases of AIS (93.3%), the tumor was adjacent to the transitional zone, within 3 mm of the SCJ, and in the other case (6.7%), the tumor was between 0 and 5 mm away from the SCJ. In all subjects, cone height was 8-18 mm (mean 13.1 mm). None of the 15 patients showed any recurrence of AIS during follow up ranging from 15 to 75 months (43.1 months on average). CONCLUSIONS: Women with AIS who want to preserve their fecundity might be treated with laser conization alone.

Adenocarcinoma↗
PubMed2005

Clinicopathologic manifestations of early-onset endometrial cancer in Japanese women with a familial predisposition to cancer.

AIM: The number of patients under 40 years of age with early-onset endometrial cancer is on the rise in Japan. Preservation of fertility in younger patients is a critical issue. In order to examine the clinical and pathological characteristics of these patients, cases of early-onset endometrial cancer at a single hospital were analyzed. METHODS: Seventy-four patients were diagnosed with endometrial cancer before age 40 and included in this study after obtaining informed consent. RESULTS: The clinical characteristics included a significantly higher prevalence of complications such as nulligravidity and nulliparity (P < 0.001). Pathologically, well-differentiated endometrial carcinoma was significantly more frequent (P = 0.011). The 5-year survival rate was high (98.7%). In regards to the relationship between clinicopathological features and grade of differentiation, the prevalence of G2 and G3 carcinoma was not significantly lower (P = 0.24) in patients with obesity. Although the frequency of G2 and G3 carcinoma was significantly higher in patients with a family history of cancer (P = 0.02), their 5-year survival rate was not significantly lower (100%). CONCLUSION: This study found that these two types of early-onset endometrial cancer are clinicopathologically different. In patients with a family history of cancer, their body mass index was lower, and the frequency of G2 and G3 carcinoma was significantly higher, but their 5-year disease-free survival rate was not significantly lower.

Adenocarcinoma↗
PubMed2005

Histoculture drug response assay to monitor chemoresponse.

We provide a detailed explanation of the procedure of the histoculture drug response assay (HDRA) with 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) end point among several modified HDRA procedures. Fresh surgical specimens are cut into approx 1- to 2-mm3 pieces and put on a gelatin sponge infiltrated with culture medium containing a test drug. After incubation for 7 d, cell viability is assessed by the MTT assay. HDRA uses cancer tissue fragments with cells growing in three dimensions, with maintenance of intercellular contact and interactions with stromal cells. Therefore, it seems that HDRA can assess the sensitivity of tumor cells to anticancer drugs in conditions similar to those in vivo and, consequently, shows high prediction rate.

Antineoplastic Agents↗
PubMed2005

Analysis of fatty acid composition in human bone marrow aspirates.

In the present study, the fatty acid composition of bone marrow aspirates and serum phospholipids in nine patients with hematologic diseases was investigated, and the effect of fatty acids on osteoblast differentiation in ST2 cells was examined. The concentrations of oleic acid and palmitic acid were significantly higher in bone marrow aspirates than in serum phospholipids, but the concentrations of other fatty acids did not differ. The rate of alkaline phosphatase positive ST2 cells induced by BMP2 was significantly increased by oleic acid, but was unaffected by the presence or absence of palmitic acid. We conclude that the fatty acid composition of bone marrow aspirates differs from that of serum phospholipids. This difference may affect osteoblast differentiation in the bone marrow microenvironment.

Adipocytes↗
PubMed2005

[CA546, CA602].

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Antigens, Tumor-Associated, Carbohydrate↗
PubMed2004

HMMC-1: a humanized monoclonal antibody with therapeutic potential against Müllerian duct-related carcinomas.

PURPOSE: The purpose of this research was to generate a human monoclonal antibody specific to gynecological cancers and to evaluate such an antibody as therapy for gynecological cancers. EXPERIMENTAL DESIGN: Transchromosomal KM mice were immunized with the human uterine endometrial cancer cell line SNG-S. Hybridomas were constructed between spleen cells from KM mice and mouse myeloma cells. Reactivity of the antibody was evaluated by immunohistochemistry of pathological specimens of gynecological cancers. Cytotoxicity of HMMC-1 against SNG-S cells was tested by in vitro cytotoxicity assays. The epitope of HMMC-1 was determined by transfection with a panel of glycosyltransferase cDNAs and by inhibition assays with chemically synthesized oligosaccharides. RESULTS: HMMC-1 is a human IgM monoclonal antibody that reacts positively with mullerian duct-related carcinomas with positive rates of 54.6% against uterine endometrial adenocarcinoma, 76.9% against uterine cervical adenocarcinoma, and 75.0% against epithelial ovarian cancer. HMMC-1 does not react with normal endometrium at proliferative or secretory phases, normal uterine cervix, or normal and malignant tissue from other organs, whereas it reacts weakly with the epithelium of the gall bladder and the collecting duct of the kidney. HMMC-1 exhibits antigen-dependent and complement-mediated cytotoxicity. Upon cotransfection with cDNAs encoding two glycosyltransferases required for fucosylated extended core 1 O-glycan, mammalian cells express HMMC-1 antigen. Finally, binding of HMMC-1 to SNG-S cells is inhibited by synthetic Fucalpha1-->2Galbeta1-->4GlcNAcbeta1-->3Galbeta1-->3GalNAcalpha1-octyl. CONCLUSIONS: These results indicate that HMMC-1 specifically recognizes a novel O-glycan structure. The unique specificity and cytotoxicity of HMMC-1 strongly suggest a therapeutic potential of this antibody.

Animals↗
PubMed2004

Association of HNPCC and endometrial cancers.

Hereditary nonpolyposis colorectal cancer (HNPCC) is among the representative familial cancers that are autosomally dominant inherited disorders. Because endometrial cancers develop at high rates in women with HNPCC, it is suggested that some endometrial cancers are familial cancers that are induced by mutations of the DNA mismatch repair (MMR) genes, as in HNPCC. To understand the clinical pathology of familial endometrial cancers that are associated with HNPCC, we surveyed the family histories of 385 patients with endometrial cancer and found that 0.5% of endometrial cancers met the new diagnostic criteria of HNPCC. From molecular and biological analyses, we found microsatellite instability in 30.8% of endometrial cancers and germline mutations of MMR genes in 8.3%. These results suggest a close relationship of MMR gene mutations to the development of endometrial cancers. For a better understanding of the clinical pathology of HNPCC-associated familial endometrial cancers, it is critical for gynecologists to perform a large multicenter study, including detailed family histories.

Chromosomal Instability↗
PubMed2004

Dominant human papillomavirus 16 infection in cervical neoplasia in young Japanese women; study of 881 outpatients.

OBJECTIVE: Human papillomavirus (HPV) infection is reported to be related to carcinogenesis in the uterine cervix. In Japan, screening for cervical cancer by cytology is performed in women over 30 years old. The purpose of this study was to determine whether there is an association between patient age and cervical neoplasia or HPV infection in Japanese women. METHODS: Specimens from 881 randomly selected patients who came to our clinic were tested for HPV DNA by using Hybrid Capture II, whereas specimens from a 204-patient randomly selected subset diagnosed with cervical neoplasia were tested for HPV DNA by using polymerase chain reaction (PCR). HPV typing was performed in all the PCR-positive cases. RESULTS: The HPV-positive rate in the 20- to 29-year-old patients (29.0% in the normal cytology/histology group and 85.5% in the abnormal group) was higher than in the 30- to 59-year-old patients, and the rate declined until age 60 when age increased. While HPV 18, HPV 52, other HPV types, and HPV types as a whole were frequently detected in 30- to 49-year-old patients, HPV 16 was detected more frequently in the younger group than the other HPV types (P = 0.03). Among the HPV 16-positive patients with cervical neoplasia, the proportion of cervical intraepithelial neoplasia (CIN) 3 cases was high (44%) in the 20- to 29-year-old group. CONCLUSIONS: Screening for cervical neoplasia by cytology should also be performed in women under 30 years old in Japan. The HPV typing could be a tool to strictly follow-up younger women who were diagnosed with CIN.

Adult↗
PubMed2004

Phase II trial of 3-h infusion of paclitaxel in patients with adenocarcinoma of endometrium: Japanese Multicenter Study Group.

OBJECTIVE: We assessed the antineoplastic effect and adverse reactions of paclitaxel monotherapy with paclitaxel 210 mg/m(2) given every 3 weeks by 3-h infusion on patients with endometrial cancer given as a 3-h infusion. METHODS: This study was a multi-center, open-label phase II clinical trial of paclitaxel 210 mg/m(2) given every 3 weeks by 3-h infusion. Patients with advanced or recurrent endometrial cancer were enrolled. The primary endpoint for efficacy was tumor response rate. The secondary endpoints were duration of response and adverse drug reactions. RESULTS: Among 23 patients evaluated for efficacy, partial remission (PR) was achieved in 7, no change (NC) in 10, progressive disease (PD) in 5, and not estimable (NE) in 1. The overall response rate was 30.4% (7/23 cases). In seven PR cases, median duration of response was 130 days (100-245 days). Subjective or objective symptoms > or =grade 3 included febrile neutropenia and constipation in 8.7% (2/23 cases) each; and nausea, vomiting, fatigue, pain, urinary tract infection, lowered oxygen saturation, anorexia, arthralgia, myalgia, neuropathy, weight loss, dyspnea, and need for red cell transfusion in 4.3% (1/23) each. Laboratory test abnormalities > or =grade 3 included neutropenia (78.3%, 18/23), leucopenia (47.8%, 11/23), lowered hemoglobin (13.0%, 3/23), decreased potassium (8.7%, 2/23), and decreased sodium (4.3%, 1/23). All adverse reactions were successfully managed by prolonging treatment interval, dose reduction, interrupting administration, discontinuation, and administration of G-CSF. CONCLUSION: Three-hour intravenous infusion of paclitaxel 210 mg/m(2) is useful for endometrial cancer. Antineoplastic effect was achieved and adverse reactions were clinically manageable.

Adenocarcinoma↗