Biomedical subjects

T Kamura

Publications and source records attributed to T Kamura.

At least 37 records · Page 2Linked to original sources

PubMed2000

Identification of a new endoplasmic reticulum-resident protein recognized by HLA-A24-restricted tumor-infiltrating lymphocytes of lung cancer.

To help clarify the molecular basis of tumor immunology in lung cancer, we have investigated antigens recognized by HLA-A24-restricted CTLs established from T cells infiltrating into lung adenocarcinoma and report a new gene encoding tumor epitopes recognized by the CTLs. This gene was located on chromosome 4q31.22 and encoded an unreported endoplasmic reticulum-resident protein with 412 deduced amino acids. This protein had a molecular mass of 46 kDa and was expressed in the majority of malignant cells and tissues tested, with the exception of T-cell leukemia cells, but was not expressed in a panel of normal cells and tissues, except in those of the testis, placenta, and fetal liver. Two peptides at positions 13-20 and 75-84 were recognized by the CTLs and had an ability to induce HLA-A24-restricted and tumor-specific CTLs in peripheral blood mononuclear cells of lung cancer patients. Thus, these peptides might be appropriate molecules for use in the specific immunotherapy of HLA-A24+ patients with lung and other cancers.

Adenocarcinoma↗

PubMed2000

Clinical characteristics of clear cell carcinoma of the ovary: a distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy.

BACKGROUND: A retrospective review of treatment results comparing women with clear cell carcinoma of the ovary (CCC) with a group with serous adenocarcinoma of the ovary (SAC) was conducted. METHODS: Between 1988-1998, 662 patients with epithelial ovarian carcinoma were identified through the medical records department and the tumor registry at 4 institutions. After the central pathologic review, 101 patients with pure or dominant (>/= 90%) CCC (15.3%) were entered into the current study. Two hundred thirty five patients with pure SAC were selected as a group for comparison. All patients underwent staging laparotomy followed by platinum-based chemotherapy. Distribution of the International Federation of Gynecology and Obstetrics (FIGO) disease stage, response to chemotherapy, and prognosis for patients with CCC were compared with the same values in patients with SAC. RESULTS: Patients with CCC were significantly more likely to have FIGO Stage I disease than were patients with SAC (48.5% vs. 16.6%). A high recurrence rate was noted in those patients with Stage IC CCC (37%). In those patients with Stage IC disease, the survival rates for patients with CCC were lower than those for patients with SAC. The 3-year and 5-year survival rates for Stage III CCC patients were significantly lower compared with Stage III SAC patients. The response rate to platinum-based chemotherapy in patients with CCC was significantly lower than that in patients with SAC. CONCLUSIONS: CCC is an intriguing histologic type of epithelial ovarian cancer that demonstrates a clinical behavior distinctly different from that of SAC.

Adenocarcinoma, Clear Cell↗

PubMed2000

Ovarian endometriosis associated with ovarian carcinoma: a clinicopathological and immunohistochemical study.

OBJECTIVE: The purpose of this study was to demonstrate the incidence, the histopathological characteristics, and the proliferation activity of endometriosis and atypical endometriosis associated with ovarian carcinoma. METHODS: Microscopic slides of primary lesions from 127 patients with primary ovarian carcinoma were reviewed. The presence or absence of endometriosis and the transitions from typical endometriosis to atypical endometriosis and from atypical endometriosis to carcinoma were also histologically evaluated. Ki-67 immunoreactivity of typical and atypical endometriosis and carcinoma was examined. In addition, endometrial metaplasias were also evaluated. RESULTS: Of the 127 patients, 37 had endometriosis: 70% (30/43) had clear cell adenocarcinoma, 43% (3/7) had endometrioid adenocarcinoma, 7% (4/60) had serous adenocarcinoma, and none (0/17) had mucinous adenocarcinoma. Thirty-three cases showed typical endometriosis and 29 cases had atypical endometriosis (25 cases had both). Tufting and the stratification of the lining epithelium were observed in 25 and 23 cases, respectively. The transition from typical endometriosis to atypical endometriosis was observed in 22 cases, and the transition from atypical endometriosis to carcinoma, in 23 cases. Only one case showed a direct transition from typical endometriosis to carcinoma. The mean Ki-67 indices were as follows: ovarian carcinoma, 23.1; atypical endometriosis, 9.9; typical endometriosis, 2.7. In 18 cases with metaplasia in endometriosis, eosinophilic metaplasia and ciliated metaplasia were the most common types. Five cases had two types of metaplasia. CONCLUSIONS: Ovarian carcinomas, especially clear cell and endometrioid adenocarcinomas, are highly associated with endometriosis. Atypical endometriosis shows proliferation activity intermediate to those of typical endometriosis and ovarian carcinoma, suggesting it is a precancerous status.

Adenocarcinoma, Clear Cell↗

PubMed2000

Expression of tumor-rejection antigens in gynecologic cancers.

We recently reported the four tumor-rejection antigens (SART1(259), SART2, SART3, and ART4) that possess tumor epitopes capable of inducing HLA-A2402-restricted cytotoxic T lymphocytes (CTLs) in cancer patients. This study investigated the expression of these tumor antigens in gynecologic cancers, including 33 ovarian cancers, 38 cervical cancers, and 40 endometrial cancers. SART1(259) antigen was detected in 56%, 35%, and 30% of ovarian, cervical and endometrial cancers, while SART2 antigen was detected in 46%, 66%, and 30% of these cancers, respectively. Both SART3 and ART4 antigens were detectable in the majority of these gynecologic cancers tested. In contrast, none of these antigens was detectable in any of the normal ovarian and uterine tissues tested. Peripheral blood mononuclear cells (PBMCs) of HLA-A24(+) patients with gynecologic cancers were found to produce significant levels of interferon-gamma in response to HLA-A24(+) SART3(+) gynecologic cancer cells after having been stimulated three times in vitro with either SART3(109 - 118) or SART3(315 - 323) peptide. These PBMCs lysed HLA-A24(+) SART3(+) gynecologic cancer cells, but not HLA-A24(-) SART3(+) gynecologic cancer cells or HLA-A24(+) normal cells. Therefore, these four antigens and their peptides, including SART3 peptides, would be appropriate molecules for use in specific immunotherapy of HLA-A24(+) gynecologic cancer patients.

Antigens, Neoplasm↗

PubMed2000

[New regimens for the treatment of gynecologic cancers].

Until the late-1980s, combination CDDP (or CBDCA)/cyclophosphamide (CPA) and CDDP (or CBDCA)/CPA/adriamycin (ADM) were the two most common choices for treating patients with ovarian cancer. In the last several years, the identification of paclitaxel (TXL) activity in previously treated ovarian cancer patients has led to its incorporation into primary chemotherapy regimens for newly diagnosed patients. Based on prospective trials by the Gynecologic Oncology Group (GOG) and European-Canadian investigators, CDDP/TXL became the new standard regimen in 1998. Now, three randomized trials by the GOG (158), AGO, and a Dutch group comparing CDDP/TXL and carboplatin (CBDCA)/TXL are also in progress. These study groups recommended that CBDCA/TXL be used as the standard regimen in 1999 because CBDCA/TXL is less toxic, allows a better quality of life during treatment, and results in an equivalent response rate and progression-free survival. In patients with high-risk corpus cancer, clinical trials comparing platinum/TXL or platinum/ADM/TXL versus platinum/ADM are in progress. In Japan, CPT-11/CDDP has been shown to be an effective and safe regimen in patients with advanced ovarian cancer, especially clear cell carcinoma and cervical cancer.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2000

[Neoadjuvant chemotherapy with cisplatin and CPT-11 for advanced cervical cancer].

Neoadjuvant chemotherapy (NAC) is currently used for the treatment of advanced cervical cancer by many institutions. We investigated the value of NAC followed by radical surgery and/or radiotherapy for patients with locally advanced cervical cancer. Sixteen patients with stage Ib2-IIIb cervical cancer were enrolled in this study. CPT-11 (60 mg/m2) in 500 m/5% glucose was given intravenously on Days 1, 8, and 15, before cisplatin (60 mg/m2) in 500 ml normal saline. The treatment was repeated every 4 weeks for 2 or 3 cycles. All patients were evaluable for response and toxicity. Two achieved a clinical complete response (CR), 11 had a partial response (PR), 2 had no change (NC) and 1 had progressive disease (PD), for an overall response of 81.3%. Neutropenia was observed in 100% (> grade 3: 70.6%) and diarrhea was recorded in 55.9% (> grade 3: 5.9%). The combination of CPT-11 and cisplatin in locally advanced cervical cancer is thus an active regimen with a manageable toxicity as a neoadjuvant chemotherapy.

Adult↗

PubMed2000

DNA polymorphism analysis of a pure non-gestational choriocarcinoma of the ovary: case report.

A 45-year-old nulligravida woman died from carcinoma peritonitis with choriocarcinoma arising in the ovary. This tumor was resistant to chemotherapy after debulking surgery. DNA polymorphism analysis was useful in proving the choriocarcinoma to be non-gestational carcinoma. In this paper, the clinical course and DNA polymorphism findings are mainly discussed.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1999

The Rbx1 subunit of SCF and VHL E3 ubiquitin ligase activates Rub1 modification of cullins Cdc53 and Cul2.

The RING-H2 finger protein Rbx1 is a subunit of the related SCF (Skp1-Cdc53/Cul1-F-box protein) and von Hippel-Lindau (VHL) tumor suppressor (elongin BC-Cul2-VHL) E3 ubiquitin ligase complexes, where it functions as a component of Cdc53/Rbx1 and Cul2/Rbx1 modules that activate ubiquitination of target proteins by the E2 ubiquitin-conjugating enzymes Cdc34 and Ubc5. Here we demonstrate that the Cdc53/Rbx1 and Cul2/Rbx1 modules also activate conjugation of the ubiquitin-like protein Rub1 to Cdc53 and Cul2 by the dedicated E2 Rub1 conjugating enzyme Ubc12. Our findings identify Rbx1 as a common component of enzyme systems responsible for ubiquitin and Rub1 modification of target proteins.

Amino Acid Sequence↗

PubMed1999

The grading of lymphovascular space invasion in endometrial carcinoma.

BACKGROUND: This study was conducted to elucidate the prognostic significance of a three-grade system for lymphovascular space invasion (LVSI). METHODS: The prognostic significance of the grading of LVSI as compared with other pathologic variables was evaluated in a study of 303 Japanese women with endometrial carcinoma. The criteria for determining the grade of LVSI were as follows: none (no LVSI), mild (a focus of LVSI was recognized around a tumor), and severe (diffuse or multifocal LVSI were recognized around the tumor or in the myometrium regardless of the degree of myometrial invasion). Both univariate and multivariate regression analyses were performed. The effects of different surgical methods and adjuvant therapies on survival were also examined. RESULTS: A univariate survival analysis showed that survival significantly correlated with surgical stage, histologic grade, depth of myometrial invasion, LVSI, cervical invasion, ovarian metastasis, and tubal metastasis. Of the three grades of LVSI, survival showed the most difference between the mild and severe groups. In multivariate analysis, the highest correlation with survival was observed for LVSI (P = 0.0008). Lymph node metastasis was also significantly associated with LVSI (P = 0. 0001). The correlation between histologic variables and survival was only slightly influenced by the differences in surgical methods and adjuvant therapies. CONCLUSIONS: The grading of LVSI was found to be an important histologic prognostic variable. The severe degree of LVSI also was found to be a good indicator of lymph node metastasis. It is therefore important to evaluate the grade of LVSI based on a histologic examination of at least one cut surface of the hysterectomy specimen that macroscopically shows the deepest myometrial invasion.

Endometrial Neoplasms↗

PubMed1999

Identification of the von Hippel-lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex.

Mutations of von Hippel-Lindau disease (VHL) tumor-suppressor gene product (pVHL) are found in patients with dominant inherited VHL syndrome and in the vast majority of sporadic clear cell renal carcinomas. The function of the pVHL protein has not been clarified. pVHL has been shown to form a complex with elongin B and elongin C (VBC) and with cullin (CUL)-2. In light of the structural analogy of VBC-CUL-2 to SKP1-CUL-1-F-box ubiquitin ligases, the ubiquitin ligase activity of VBC-CUL-2 was examined in this study. We show that VBC-CUL-2 exhibits ubiquitin ligase activity, and we identified UbcH5a, b, and c, but not CDC34, as the ubiquitin-conjugating enzymes of the VBC-CUL-2 ubiquitin ligase. The protein Rbx1/ROC1 enhances ligase activity of VBC-CUL-2 as it does in the SKP1-CUL-1-F-box protein ligase complex. We also found that pVHL associates with two proteins, p100 and p220, which migrate at a similar molecular weight as two major bands in the ubiquitination assay. Furthermore, naturally occurring pVHL missense mutations, including mutants capable of forming a complex with elongin B-elongin C-CUL-2, fail to associate with p100 and p220 and cannot exhibit the E3 ligase activity. These results suggest that pVHL might be the substrate recognition subunit of the VBC-CUL-2 E3 ligase. This is also, to our knowledge, the first example of a human tumor-suppressor protein being directly involved in the ubiquitin conjugation system which leads to the targeted degradation of substrate proteins.

Carrier Proteins↗

PubMed1999

Is nuclear expression of Y box-binding protein-1 a new prognostic factor in ovarian serous adenocarcinoma?

BACKGROUND: Nuclear expression of Y box-binding protein (YB-1), a member of the DNA binding protein family, has been reported to be much more highly concentrated in cisplatin-resistant cell lines than in their parental counterparts, suggesting an ability to limit cisplatin sensitivity. Moreover, YB-1 plays a key role in P-glycoprotein expression. Because ovarian carcinoma traditionally has been treated with cisplatin-based chemotherapy, the sensitivity of the tumors to chemotherapy could reflect a particular prognosis in patients with ovarian carcinoma. The aim of the current study was to determine whether YB-1 expression correlated with prognosis in ovarian serous adenocarcinoma patients. METHODS: The expression of YB-1 in the nucleus was examined immunohistochemically in 42 paraffin embedded primary Stage III (International Federation of Gynecology and Obstetrics) serous ovarian carcinoma tumors extirpated by primary surgery at Kyushu University Hospital between 1985-1995. RESULTS: Of the 40 primary ovarian tumors examined, 12 (30%) were positive for YB-1 expression in the nucleus. There was no significant difference in intraperitoneal stage, histologic grade, or residual tumor size after primary surgery between patients with tumors with positive and those with negative nuclear expression of YB-1 protein. The disease free survival curve for patients whose tumors were positive for nuclear expression of YB-1 protein was significantly worse than that for patients whose tumors were negative (P = 0.0025). P-glycoprotein was overexpressed in 4 of 12 tumors with nuclear YB-1 expression (33%) but there was no statistical significance between the expression of nuclear YB-1 and P-glycoprotein. CONCLUSIONS: The expression of YB- 1 protein in the nucleus may be considered a useful prognostic marker and also may reflect the sensitivity of ovarian serous adenocarcinoma to chemotherapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1999

The elongin B ubiquitin homology domain. Identification of Elongin B sequences important for interaction with Elongin C.

Mammalian Elongin B is a 118-amino acid protein composed of an 84-amino acid amino-terminal ubiquitin-like domain and a 34-amino acid carboxyl-terminal tail. Elongin B is found in cells as a subunit of the heterodimeric Elongin BC complex, which was originally identified as a positive regulator of RNA polymerase II elongation factor Elongin A and subsequently as a component of the multiprotein von Hippel-Lindau tumor suppressor and suppressor of cytokine signaling complexes. As part of our effort to understand how the Elongin BC complex regulates the activity of Elongin A, we are characterizing Elongin B functional domains. In this report, we show that the Elongin B ubiquitin-like domain is necessary and sufficient for interaction with Elongin C and for positive regulation of Elongin A transcriptional activity. In addition, by site-directed mutagenesis of the Elongin B ubiquitin-like domain, we identify a short Elongin B region that is important for its interaction with Elongin C. Finally, we observe that both the ubiquitin-like domain and carboxyl-terminal tail are conserved in Drosophila melanogaster and Caenorhabditis elegans Elongin B homologs that efficiently substitute for mammalian Elongin B in reconstitution of the transcriptionally active Elongin ABC complex, suggesting that the carboxyl-terminal tail performs an additional function not detected in our assays.

Amino Acid Sequence↗

PubMed1999

Rbx1, a component of the VHL tumor suppressor complex and SCF ubiquitin ligase.

The von Hippel-Lindau (VHL) tumor suppressor gene is mutated in most human kidney cancers. The VHL protein is part of a complex that includes Elongin B, Elongin C, and Cullin-2, proteins associated with transcriptional elongation and ubiquitination. Here it is shown that the endogenous VHL complex in rat liver also includes Rbx1, an evolutionarily conserved protein that contains a RING-H2 fingerlike motif and that interacts with Cullins. The yeast homolog of Rbx1 is a subunit and potent activator of the Cdc53-containing SCFCdc4 ubiquitin ligase required for ubiquitination of the cyclin-dependent kinase inhibitor Sic1 and for the G1 to S cell cycle transition. These findings provide a further link between VHL and the cellular ubiquitination machinery.

Amino Acid Sequence↗

PubMed1999

Reconstitution of G1 cyclin ubiquitination with complexes containing SCFGrr1 and Rbx1.

Control of cyclin levels is critical for proper cell cycle regulation. In yeast, the stability of the G1 cyclin Cln1 is controlled by phosphorylation-dependent ubiquitination. Here it is shown that this reaction can be reconstituted in vitro with an SCF E3 ubiquitin ligase complex. Phosphorylated Cln1 was ubiquitinated by SCF (Skp1-Cdc53-F-box protein) complexes containing the F-box protein Grr1, Rbx1, and the E2 Cdc34. Rbx1 promotes association of Cdc34 with Cdc53 and stimulates Cdc34 auto-ubiquitination in the context of Cdc53 or SCF complexes. Rbx1, which is also a component of the von Hippel-Lindau tumor suppressor complex, may define a previously unrecognized class of E3-associated proteins.

Amino Acid Sequence↗

PubMed1999

Endometrial carcinoma associated with hyperplasia--immunohistochemical study of angiogenesis and p53 expression.

OBJECTIVE: To clarify the hypothesis that there are two pathways of endometrial carcinogenesis we compared the frequency of abnormal p53 protein expression and angiogenesis in endometrial carcinomas with and without hyperplasia. METHODS: Specimens obtained from 70 patients with stage I-IV endometrial carcinomas were available for this immunohistochemical study. Immunohistochemical staining for factor VIII-related and p53 antigens was performed using a standard immunoperoxidase technique (Histofine SAB-PO Kit, Nichirei Co., Tokyo, Japan). Microvessels were highlighted by staining endothelial cells for factor VIII-related antigen, and microvessel density (MVD) was counted in a x200 field (0.785 mm2 per field) in the area of most active neovascularization. p53 protein was detected with monoclonal anti-p53 antibodies (clone DO-7, Dako, Santa Barbara, CA). RESULTS: Twenty-six of 73 (37%) patients had hyperplasia in the endometrium adjacent to the carcinoma. Significantly more patients with low MVD (less than 60) had carcinoma with hyperplasia than those with carcinoma without hyperplasia (P = 0.0053). p53 expression was noted in a carcinomatous area in 8 of 26 patients (30. 8%) with hyperplasia compared to 26 of 44 (59.1%) without hyperplasia, and the difference was statistically significant (P = 0. 0220). CONCLUSION: The presence or absence of hyperplasia is a different pathogenesis and important in assessing the biological behavior of endometrial carcinoma, especially concerning angiogenesis and p53 expression.

Adenocarcinoma↗

PubMed1999

Comparison of p53, Ki-67, and CD44v6 expression between primary and matched metastatic lesions in ovarian cancer.

OBJECTIVE: Many studies have demonstrated that clinically evident tumor cells already carry multiple genetic alterations and further accumulation of genetic alteration causes tumor progression which plays a role in metastasis. Therefore, it could be expected that malignant potential in the metastatic site is more aggressive than that in the primary site. Using several immunohistochemical markers (p53, Ki-67, and CD44v6), we investigated an alteration of malignant potential. METHODS: We immunohistochemically examined expression of p53, Ki-67, and CD44 in primary and metastatic lesions of ovarian cancer. Fifty-six samples of primary lesions and matched metastatic sites from 56 patients with primary epithelial ovarian cancers were included in this study. RESULTS: In 16 cases (28%), the histological grade of the metastatic lesion increased. This difference was statistically significant (P = 0.0232). In 16 cases (28%), the expression of p53 increased in the metastatic lesions, in 5 pairs from negative to positive, whereas the case decrease in the metastatic lesions was only 1. This difference was statistically significant (P = 0.0046). There was no significant difference in Ki-67 labeling indices and expression of CD44v6 between the primary and matched metastatic lesions. The degree of p53 expression in the metastatic lesions significantly correlated with disease-free survival (P = 0.0482), whereas that in the primary lesions did not. Moreover, high p53 expression in the metastatic lesions significantly correlated with disease-free survival in multivariate analysis. CONCLUSIONS: The p53 expression in metastatic lesions may reflect an aggressive biologic behavior in ovarian cancer.

Adenocarcinoma↗

PubMed1999

Predicting pelvic lymph node metastasis in endometrial carcinoma.

BACKGROUND: To determine the possibility of individualizing the pelvic lymph node dissection in patients with endometrial cancer, the relationship between pelvic lymph node (PLN) metastasis and various prognostic factors was retrospectively investigated. METHODS: From 1979 to 1994, 175 patients with endometrial carcinoma were treated with either total or radical hysterectomy combined with a PLN dissection as initial therapy. The prognostic factors examined included clinical stage, patient age, histological grade, the microscopic degree of myometrial invasion (DMI), cervical invasion, adnexal metastasis, and macroscopic tumor diameter (TD). RESULTS: Of the 175 patients undergoing PLN dissection, 24 (14%) had PLN metastasis. An endometrial cancer with PLN metastasis had a significantly longer diameter than those without PLN metastasis. The frequency of PLN metastasis increased along with increases in tumor diameter. A logistic regression analysis revealed DMI and TD to be independently correlated with PLN metastasis. The formula based on the coefficients of TD and DMI obtained from the analysis also showed a good correlation, which allowed us to estimate the probability of patients having PLN metastasis. CONCLUSIONS: DMI and TD could accurately estimate the status of PLN in endometrial carcinoma patients.

Adenocarcinoma↗

PubMed1999

Prognostic significance of epithelial-stromal vascular cuffing and microvessel density in squamous cell carcinoma of the uterine cervix.

OBJECTIVE: Tumor angiogenesis has been shown to play an important role in tumor growth and metastasis. This study examines the prognostic significance of two histological markers of angiogenesis, i.e., vascular cuffing (VC), a bead-like arrangement of microvessels closely surrounding microscopic tumor nests, and microvessel density (MVD), the number of microvessels in a unit area, in cervical squamous cell carcinoma. METHODS: One hundred twenty-two specimens from surgically resected uteri with cervical squamous cell carcinoma were histologically reviewed and immunostained for CD34. VC was graded into "none," "incomplete," and "complete." The MVD was determined by counting the microvessels with a light microscope within a x200 field area where neovascularization occurred most actively. Stromal inflammation was also split into three grades. The relationship of VC or MVD to clinicopathological prognostic factors such as FIGO stage, cervical stromal invasion, lymph-vascular space invasion, pelvic lymph node metastasis, and parametrial invasion was evaluated using univariate and multivariate analyses. RESULTS: The patients with a complete VC pattern showed a significantly worse prognosis compared to those with a pattern graded as either none or incomplete (P<0.011 and P<0.0001, respectively). The Cox regression analysis revealed the complete VC pattern, together with parametrial invasion, to be an independent prognostic indicator for overall survival. MVD and the grading of stromal inflammation showed no significant relationship with VC or overall survival. CONCLUSIONS: The complete VC pattern may therefore be a useful prognostic indicator in cervical squamous cell carcinoma.

Adult↗