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Biomedical subjects

H Tsuda

Publications and source records attributed to H Tsuda.

At least 19 recordsLinked to original sources
PubMed2002

The effectiveness of intravenous human immunoglobulin treatment after plasmapheresis in restoring serum immunoglobulin levels: a preliminary study.

This study was performed to examine the effects of intravenous human immunoglobulin (IVIG) on the level of serum immunoglobulin G (IgG) and its subclasses after plasmapheresis in patients with autoimmune disorders. Twenty-nine patients with predominantly rheumatoid arthritis were enrolled in this study. The plasmapheresis was performed by the use of double-filtration plasmapheresis (DFPP). Immediately after DFPP, IVIG (2.5 g, 50 ml) was intravenously administered. The treatment with IVIG had almost no effect on subjective and objective symptoms. Immediately after DFPP, the total of serum IgG was decreased by approximately 40%. After 24 h, the total of serum IgG recovered to 16% reduction in IVIG-treated patients whereas it remained at 32% reduction in nontreated patients. The beneficial effect of IVIG was significantly observed in patients who had shown 1,000-1,800 mg/dl IgG in their sera. After DFPP, IgG subclasses were decreased without change in the ratio of subclasses. Twenty percent to 30% of IgG subclasses were supplemented by the treatment with IVIG without change in the ratio of subclasses. These results suggested that the treatment with IVIG at minimal amount was safe and effective to supplement IgG for hypogammaglobulinemia after DFPP.

Adult↗
PubMed2001

Detection of HER-2/neu (c-erb B-2) DNA amplification in primary breast carcinoma. Interobserver reproducibility and correlation with immunohistochemical HER-2 overexpression.

BACKGROUND: Fluorescent in situ hybridization (FISH) has been shown to be one of the most reliable methods with which to estimate the status of the HER-2/neu (or c-erb B-2) oncogene at the DNA level. METHODS: To study interobserver reproducibility and to determine more clinically correlated criteria for HER-2/neu alterations, two observers independently estimated HER-2/neu DNA status. The correlation between the consensus HER-2/neu DNA status by FISH and HER-2/neu protein status detected by immunohistochemistry (IHC) using a polyclonal antibody was studied in 216 surgically resected breast carcinomas and 34 noncancerous tissues. RESULTS: According to the HER-2/CEP17 ratio and mean HER-2 copies per nucleus, agreement level of HER-2/neu amplification was shown to be nearly perfect between two observers (kappa statistic (kappa) = 0.94 and kappa = 0.84). Finally, 40 tumors (19%) were judged to have HER-2/neu DNA amplification, with 6 having low-level amplification (> or = 2 but < 3 folds) and 34 having high-level amplification (> or = 3 folds). One hundred seventy-six other tumors, including 3 tumors that only 1 of the observers determined to be low-level amplifiers, and 34 noncancerous tissues had no detected amplification. The DNA amplification status was concordant between invasive and intraductal components in 14 carcinomas. HER-2/neu protein overexpression of moderate (2+) or high (3+) intensity based on IHC was detected in 51 carcinomas (24%), and was 2+ in 20 carcinomas and 3+ in 31 carcinomas. The HER-2/CEP17 ratio of > or = 2 was concordant with IHC findings of 2+/3+ in 91% of carcinomas (195 of 215 carcinomas), with a sensitivity of 70% (35 of 50 carcinomas) and a specificity of 97% (160 of 165 carcinomas). High-level amplification was detected in 29 of 31 IHC 3+ cases (94%), but in only 5 of 20 IHC 2+ cases (25%) and 0 in 165 IHC 0/1+ cases. All 34 cases with high-level amplification showed an IHC score of 3+ (29 cases) or an IHC score of 2+ (5 cases), but only 1 case was found to have an IHC score of 3+ and the remainder were IHC 0/1+ in 6 low-amplification cases. The concordance rate of the high-level amplification with an IHC score of 3+ was 97% (208 of 215 cases), with a sensitivity of 94% (29 of 31 cases) and a specificity of 97% (179 of 184 cases). CONCLUSIONS: The results of the current study indicated that high-level HER-2/neu amplification and an IHC score of 3+ nearly optimally identified breast carcinomas with clinically and biologically significant HER-2/neu activation. Conversely, it was confirmed that careful interpretation of test results is required in the case of low-level amplification and/or an IHC score of 2+.

Breast Neoplasms↗
PubMed2001

Identification of cIAP1 as a candidate target gene within an amplicon at 11q22 in esophageal squamous cell carcinomas.

Amplification of chromosomal DNA is thought to be one of the mechanisms that activate cancer-related genes in tumors. In a recent study, we identified high copy-number amplification at 11q21-q23 in cell lines derived from esophageal squamous cell carcinomas (ESCs) using comparative genomic hybridization. Because 11q21-q23 amplification has been reported in tumors of various other types as well, gene(s) associated with tumor progression may lie within this chromosomal region. To identify the most likely target(s) for amplification at 11q21-q23, we determined the extent of the amplicon by fluorescence in situ hybridization and then analyzed ESC cell lines for expression levels of 11 known genes and one uncharacterized transcript present within the 1.8-Mb commonly amplified region. Only cIAP1, a member of the IAP (antiapoptotic) gene family, was consistently overexpressed in cell lines that showed amplification. Additionally, the cIAP1 protein was overexpressed in the primary tumors from which those cell lines had been established. The ESC cell lines with cIAP1 amplification were resistant to apoptosis induced by chemotherapeutic reagents. An increase in cIAP1 copy number was also detected in 4 of 42 (9.5%) primary ESC tumors that were not related to the cell lines examined. Because inhibition of apoptosis seems to be an important feature of carcinogenesis, cIAP1 is likely to be a target for 11q21-23 amplification and may be involved in the progression of ESC, as well as other malignancies.

Apoptosis↗
PubMed2001

Rat neuronal leucine-rich repeat protein-3: cloning and regulation of the gene expression.

Rat neuronal leucine-rich repeat protein-3 (rNLRR-3) gene was isolated and cloned from fibrosarcoma cells overexpressing c-Ha-ras. Stable expression of constitutively active forms of Ras (H-Ras(V12) or v-H-Ras) led to a two- to fourfold increase in rNLRR-3 mRNA in rat normal fibroblasts (3Y1). When cells expressing H-Ras(V12) were treated with mitogen activated protein kinase (MAPK) kinase inhibitors (U0126, PD98059), suppression of rNLRR-3 mRNA correlated well with a reduction in MAPK activity. Epidermal growth factor (EGF) led to elevation of rNLRR-3 gene expression about 4 h after stimulation of normal fibroblasts. U0126 completely suppressed the induction by EGF of rNLRR-3 mRNA with abrogation of MAPK phosphorylation. U0126 inhibited the basal transcription of rNLRR-3. LY294002, a PI3 kinase inhibitor, showed a lesser effect on expression of the gene. These results indicate that rNLRR-3 gene expression is regulated mainly through the Ras-MAPK signaling pathway in fibroblasts.

Amino Acid Sequence↗
PubMed2001

Conservative therapy for adenocarcinoma and atypical endometrial hyperplasia of the endometrium in young women: central pathologic review and treatment outcome.

Thirty-nine patients with endometrioid adenocarcinoma (EA) and atypical hyperplasia (AH) of the endometrium who received conservative treatment to preserve fertility were collected from member institutions of the Japan Gynecologic Oncology Study Group. Twenty-nine and ten were originally diagnosed with EA without myometrial invasion and AH, respectively. We performed a central pathological review to make definite diagnoses, and the diagnosis of EA in 29 cases was changed to AH in ten, complex hyperplasia in three and atypical polypoid adenomyoma in three, and AH in ten was changed to EA in one and simple hyperplasia in one. Nine of 12 women (75%) with EA and 15 of 18 women (83%) with AH had an initial response to medroxyprogesterone acetate (MPA) treatment. Two of nine responders with EA later developed relapse, and one of them had metastasis to the left obturator lymph node. Two became pregnant, and one delivered one full-term infant. One of the responders with AH had a relapse in the endometrium. Five became pregnant, and four delivered four normal infants. The young women with endometrial carcinoma localized in the endometrium who wish to preserve fertility may be treated as successfully with MPA as those with AH.

Adenocarcinoma↗
PubMed2001

High susceptibility of transgenic rats carrying the human c-Ha-ras proto-oncogene to chemically-induced mammary carcinogenesis.

A rat line carrying three copies of the human c-Ha-ras proto-oncogenes, including its own promoter region, was established and designated as Hras128. Expression of the transgene was detected in all organs by Northern blot analysis. To examine its influence on susceptibility to mammary carcinogenesis, female rats were treated with N-methyl-N-nitrosourea (MNU) or 7,12-dimethylbenz[a]anthracene (DMBA) at 50 days of age. With MNU, all the transgenic rats rapidly developed multiple mammary carcinomas within as short as 8 weeks (14.1 tumors/rat), in contrast to 0.46 tumors/rat in non-transgenic rats. PCR-RFLP analysis and direct sequencing for the transgene indicated that the large majority of carcinomas (38/44, 86.4%) contained cells with mutations at codon 12 in exon 1. However, comparison of the signal densities of the mutated band to dilution scale bands revealed that the cells with the mutated transgene were not in the majority. By PCR-SSCP analysis for codons 12 and 61 of the rat endogenous c-Ha-ras gene, no mutations were detected. Similarly, with DMBA, almost all (13/14, 92.9%) the transgenic rats developed multiple mammary carcinomas (9.39 tumors/rat) within 16 weeks, and 4 out of 12 (33.3%) non-transgenic rats had only small tumors (0.83 tumors/rat). A lower incidence of mutation of the transgene was found in codon 12 (5/25, 25%) than in MNU-induced tumors, but mutations were detected in codon 61 (7/20, 35%). No mutations were detected in the rat endogenous gene. No mutation was found in the rat endogenous c-Ha-ras gene in non-transgenic rats. As observed in both the MNU- and DMBA-induced tumor cases, the population of cells with the mutated transgene were in the minority. The results thus indicate that rats carrying the transduced human c-Ha-ras proto-oncogene are highly susceptible to MNU- and DMBA-induced mammary carcinogenesis and that this is not primarily due to mutations of the transgene or endogenous c-Ha-ras gene. Furthermore, irrespective of the mechanism of enhanced susceptibility, the Hras128 transgenic rats can be utilized for the screening of mammary carcinogens.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2001

Failure in the detection of aberrant mRNA from the heterozygotic splice site mutant allele for protein S in a patient with protein S deficiency.

A 29-year-old male patient with acute arterial obstruction and a medical history including thrombosis in the deep veins and pulmonary infarction presented with a reduced level of both protein S (PS) activity and free PS. Sequencing of the genomic PS gene in this patient revealed that the patient was heterozygous for the mutant PS allele, in which a nucleotide substitution occurred at the donor splice site in intron 12 (GT to GA). The patient was heterozygous for PS genes having dimorphic codons for Pro626 (CCA/CCG) and the aberrant allele in this patient was associated with the CCA form. Allelic exclusion of PS expression was demonstrated by use of Pro626 (CCA/CCG) dimorphism and only a normal mRNA sequence derived from the CCG-allele was identified in the patient. These findings suggested that the mutation at the splice site in the PS gene caused either defective production of mRNA or the gene may have produced extremely unstable RNA products, leading to reduced levels of PS activity and free PS in this patient.

Adult↗
PubMed2001

A novel splice acceptor site mutation of protein S gene in affected individuals with type I protein S deficiency: allelic exclusion of the mutant gene.

Sequencing studies of the protein S gene (PROS1) in a Japanese patient suffering from recurrent thrombosis revealed the following. The proband and his first daughter, but not the second daughter, were having the type I protein S (PS) deficiency due to a novel point mutation from A to G at the intronic acceptor splice site in intron 13 of the PROS1. In the affected daughter, exclusion of the aberrant allele was assessed by the BstX1 dimorphism of PROS1 at Pro626 (CCG/CCA). The reduced PS activities in the proband and his first daughter were apparently due to defective production of mRNA from the mutant allele.

Alleles↗
PubMed2001

Accuracy of contrast-enhanced computed tomography in the prediction of residual breast cancer after neoadjuvant chemotherapy.

Determination of the extent of residual disease after neoadjuvant chemotherapy is sometimes inaccurate by conventional diagnostic methods. The purpose of this study was to evaluate the accuracy of contrast-enhanced computed tomography (CE-CT) in depicting the extent of residual carcinomas. Fifty-seven patients with breast carcinomas of 3 cm diameter or more received neoadjuvant chemotherapy with four cycles of AT (doxorubicin and docetaxel). Before surgery, the patients underwent clinical examination, mammogram (MMG), ultrasonography (US), and CE-CT. Thirteen patients were not evaluated by CE-CT before surgery. Enhancement patterns on CE-CT were classified into multiple spots, tumor and spots, solid tumor type, and no enhancement. When all types of cancers were included in the analysis, clinical examination showed the best correlation with the pathology of the extent of residual carcinomas. However, except in invasive lobular carcinoma (ILC) and inflammatory breast carcinoma (IBC), CE-CT showed the best correlation (R insertion mark2 = 0.537). More than half of the residual microcalcifications on MMG after neoadjuvant chemotherapy suggested residual viable tumor. In conclusion, CE-CT is the most accurate noninvasive technique for identifying the extent of the residual carcinoma after neoadjuvant chemotherapy if cases of IBC and ILC are excluded.

Adult↗
PubMed2001

Global effects of anchorage on gene expression during mammary carcinoma cell growth reveal role of tumor necrosis factor-related apoptosis-inducing ligand in anoikis.

Anchorage-independent growth is a hallmark of tumor cells. We compared gene expression profiles of anchored and nonanchored human mammary carcinoma cells to study this phenomenon. In this study, we show that anchorage had striking effects on cell growth and morphology but altered transcript levels from a limited number of genes. Only about 1% of mRNA transcripts detected in these cells was altered by anchorage. These include genes related to amino acid and polyamine metabolism, apoptosis, ion channels, cytoskeletal and stress proteins, transcription factors, and growth factors. Some of these may be crucial for the survival of transformed cells. For example, clusterin and the tumor necrosis factor-related apoptosis inducing ligand (TRAIL) were suppressed by anchorage, which could help prevent programmed cell death of these tumor cells. In addition to suppressing TRAIL expression, anchorage also decreased the susceptibility of these tumor cells to TRAIL-induced apoptosis as determined by poly(ADP-ribose) phosphorylase cleavage, annexin-V binding (P < 0.01), and cell cycle analysis (P < 0.0001). These data may help explain mechanisms by which anchorage prevents apoptosis of cells that would otherwise experience anoikis. Thus, genes found to be altered by this analysis could serve as potential targets for anticancer therapy. These findings suggest that TRAIL may be used as a means to target circulating epithelial tumor cells before their attachment and colonization at new sites.

Anoikis↗
PubMed2001

Absence of endothelial cells, central necrosis, and fibrosis are associated with aggressive inflammatory breast cancer.

We recently established a new human inflammatory breast cancer (IBC) xenograft (WIBC-9) originating from a patient with IBC. The graft was transplantable in BALB/c nude and severe combined immunodeficient (SCID) mice. WIBC-9 was frequently accompanied by lung metastasis and exhibited erythema of the overlying skin, reflecting its human counterpart. Histological study of the original tumor and WIBC-9 revealed invasive ductal carcinoma with a hypervascular structure of solid nests and marked lymphatic permeation in the overlying dermis. In the central part of the solid nests, absence of endothelial cells, central necrosis, and fibrosis were observed. In vitro, WIBC-9 formed tube-like structures and loops, reflecting its in vivo feature and its human counterpart. WIBC-9 exhibited aneuploidy, ErbB-2 gene amplification, and an absence of estrogen receptor and progesterone receptor, which is consistent with IBC. Comparative studies of WIBC-9, three established non-IBC xenografts, and a human breast cancer cell line (SK-BR3) by reverse transcription-PCR, ELISA, and immunohistochemistry indicated that certain human genes (interleukin 8, vascular epidermal growth factor, basic fibroblast growth factor, angiopoietin 13, Flt-1, Tie-2, and Tie-1) and certain murine genes (integrin alpha(v)beta3, flt-1, tie-2, vascular epidermal growth factor, and CD31) were overexpressed in exposure to tumor cells. The molecular basis and these unique histological features may be associated with aggressive IBC on angiogenic and nonangiogenic pathways.

Angiogenesis Inducing Agents↗
PubMed2001

Differences in estrogen receptor status, HER2, and p53 comparing metachronous bilateral breast carcinoma.

BACKGROUND AND OBJECTIVES: We analyzed the clinicopathologic characteristics and tumor biology of metachronous bilateral breast carcinoma with regard to p53, HER2 and hormone receptor status. METHODS: A consecutive series of 54 female metachronous bilateral breast carcinoma patients treated at the National Cancer Center Hospital between 1980 and 1997 were the primary source of these retrospective data. Clinicopathologic background factors were analyzed, and immunohistochemical staining for p53, HER2, and hormone receptor status was carried out on paraffin-embedded specimens. RESULTS: There were no significant differences in clinical stage, p53 and HER2 expression levels between the first and second primary tumors. The positive rates for ER and PR were 48% (25 of 52) and 46% (25 of 54) for the first tumors, but only 19% (10 of 52) and 32% (17 of 54) for the second tumors (P = 0.004 for ER, P = 0.16 for PR), showing a significant loss of ER. CONCLUSIONS: Our findings indicate that p53 and HER2 expression levels in the second tumors might be the same as those of the first tumors in metachronous bilateral breast carcinoma; however, loss of ER was more frequently observed in the second primary tumors than in the first tumors.

Adult↗
PubMed2001

Contrast-enhanced computed tomography for diagnosing the intraductal component and small invasive foci of breast cancer.

It is important to eliminate local residual cancer to avoid local recurrence after breast conserving treatment. Many efforts have been made to detect extensive intraductal components (EICs) and small invasive foci of breast cancer by diagnostic imaging including MRI and contrast-enhanced computed tomography (CE-CT). The abilities and limitations of CE-CT are reviewed in this article. The sensitivity of EIC detection by CE-CT ranges from 76% to 88%, and specificity from 79% to 89%. The sensitivity for detecting EIC and cancerous lesions were significantly higher for CE-CT than for US or MMG. The enhanced patterns of CE-CT demonstrating EIC and small invasive foci were classified into diffuse, spotty, linear and multiple types. The differences of the size of cancerous extension by CE-CT from the pathological EIC were within 2 cm in almost all cases. CE-CT is useful for visualizing EIC and small invasive foci of breast cancer.

Breast Neoplasms↗
PubMed2001

A case of malignant phyllodes tumor of the breast with osteosarcomatous features.

A 64-year postmenopausal woman had noticed a left breast lump 5 months before presentation and was admitted due to increasing tumor size. Physical examination showed a well demarcated, movable mass 5 cm in diameter in the upper outer quadrant of the left breast. The lesion was not painful. She had no past history of malignancy or chest wall irradiation. She had no family history of malignancy. Mammography revealed an irregular tumorous lesion with coarse calcifications in the left breast. Intracystic papillary cancer was suspected by ultrasonography. Aspiration breast cytology yielded insufficient material for diagnosis. Laboratory findings were all within the normal limits including alkaline phosphatase and three tumor markers (CEA, CA 15-3, ST-439). An excisional biopsy of the left breast tumor was performed. Histopathological examination revealed malignant phyllodes tumor with osteosarcomatous features and negative tumor margins. Positive vimentin and negative cytokeratin staining was confirmed by immunohistochemistry, suggesting that the tumor did not originate from epithelial cells of the breast. The estrogen receptor (ER) status of the tumor was negative but progesterone receptor (PgR) was weakly positive. Positive p53 nuclear immunoreaction but negative c-erbB-2 overexpression by immunohistochemical staining was observed in this tumor. There was no evidence of generalized disease. She has been well 6 months after surgery without adjuvant therapy.

Breast Neoplasms↗
PubMed2001

Two special types of breast cancer presenting as progressive disease after neoadjuvant chemotherapy with docetaxel plus doxorubicin.

Seventy-eight patients with primary breast cancer over 3 cm in diameter in stages II A, II B, III A and III B according to the UICC classification received neoadjuvant chemotherapy from August 1, 1998 to June 30, 2000 at the Breast Division of the National Cancer Center Hospital. Neoadjuvant chemotherapy consisted of doxorubicin (Adriamycin: ADM) 50 mg/m(2) and docetaxel (Taxotere: DOC) 60 mg/m(2) every three weeks. The overall clinical response to this regimen was 88% (69/78). Although neoadjuvant chemotherapy with this regimen achieved good responses in patients with breast cancer, 2 patients presented with progressive disease (PD) after treatment. One patient had inflammatory breast cancer (IBC) and the other had primary squamous cell carcinoma (SCC) of the breast. There were 4 cases of IBC and one case of SCC of the breast who received neoadjuvant chemotherapy in this series. Our observations suggest that this regimen might not be effective for these types of breast cancer.

Adult↗
PubMed2001

Evaluation of HER2 status: for the treatment of metastatic breast cancers by humanized anti-HER2 Monoclonal antibody (trastuzumab) (Pathological committee for optimal use of trastuzumab).

For the treatment of patients with metastatic breast cancer by humanized anti- human epidermal growth factor receptor type 2 (HER2) antibody (trastuzumab), it is important to evaluate HER2 status adequately. "A guideline for HER2 testing" and "HER2 atlas" produced by the "Pathological committee for optimal use of trastuzumab" are introduced in this report. Appropriate evaluations of biological markers are essential for targeting therapy.

Antibodies, Monoclonal↗