Biomedical subjects

M Saegusa

Publications and source records attributed to M Saegusa.

At least 37 records · Page 2Linked to original sources

PubMed1999

CD44 expression in benign, premalignant, and malignant ovarian neoplasms: relation to tumour development and progression.

To clarify the possible role of CD44 expression in ovarian tumour development and progression, an immunohistochemical investigation was undertaken of a series of 115 carcinomas, 32 tumours with low malignant potential (LMP), and 53 cystadenomas. A combination of the reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot hybridization (SBH) assays was also performed for 17 malignant, four LMP, six cystadenoma, and seven normal ovarian samples. Immunoreactivity scores for CD44s, CD44v3, and CD44v6 were significantly higher in LMP and malignant tumours than in the benign or normal cases, in line with the results of gross mRNA-based assays. Exon-specific RT-PCR/SBH assays revealed that the expression of large CD44 transcripts containing v6 to v8 exons and small isoforms containing v2 and v3 was common among normal and neoplastic tissues, while a simultaneous increase of large isoforms containing v2 to v5 was also revealed in LMP and malignant tumours. In ovarian carcinomas, the scores for CD44s, CD44v3, and CD44v6 were inversely related to the FIGO stage, but there was no association with lymph node status or expression of hormone receptors. Multivariate analysis revealed loss of CD44v3 expression to be an independent factor for poor survival. The findings indicate that CD44 is up-regulated during the development of ovarian carcinomas but is subsequently down-regulated during their progression, resulting in aggressive behaviour and an unfavourable prognosis.

Adult↗

PubMed1999

The role of the Epstein-Barr virus in the oncogenesis of EBV(+) gastric carcinomas.

Five hundred and thirteen cases of gastric carcinoma were investigated for the presence of viral RNA, and the clinico-pathological data, geno-type, BamHIF restriction fragment polymorphism (RFLP) and specific LMP-1 30 bp gene deletion were also examined. EBVs detected in lymphocytes in 20 normal gastric mucosa, 7 lymphoma cell lines (LCLs) maintained in severe combined immunodeficiency (SCID) mice and 18 non-Hodgkin's lymphomas were compared with those in the gastric carcinoma cases. Thirty-three cases (6.4%) were demonstrated to be positive for EBV by means of EBER-1 RNA in situ hybridization. Clinico-pathological data showed no statistically significant difference in histological grading, location of cancer and status of vessel and lymphatic invasion between the EBV-positive and -negative groups, although the former significantly predominated in the submucosal invasion group (submucosal vs mucosal P=0.021; submucosal vs advanced cancer P=0.033). Some of these data were different from corresponding data in earlier reports. In cases that were evaluated by molecular biology, type A, wild-type F and LMP-1 gene deletion predominated except one in 21 informative cases, one in 24 and two in 16, respectively. EBVs detected in lymphocytes in normal gastric mucosa, LCLs in SCID mice and non-Hodgkin's lymphoma were also predominantly affected by type A, wild-type F and LMP-1 gene deletion with few exceptions. The results indicate a lack of genetic differences among EBVs in gastric carcinoma, normal population, LCLs of SCID mice and non-Hodgkin lymphomas. Some EBV infections in gastric carcinomas may be transient, especially in the submucosal invasion group.

Animals↗

PubMed1999

DCC expression is related to mucinous differentiation but not changes in expression of p21(WAF1/Cip1) and p27Kip1, apoptosis, cell proliferation and human papillomavirus infection in uterine cervical adenocarcinomas.

To clarify possible roles of DCC expression in tumour differentiation and cell kinetics, we immunohistochemically investigated 80 uterine cervical adenocarcinomas (C-ACs), including 31 mucinous (M) and 31 endometrioid (E) lesions, and 18 adenocarcinomas in situ (AIS), along with 39 normal cervical samples. The results were compared with findings for p21(WAF1/Cip1) and p27Kip1 expression, apoptosis, cell proliferation and human papillomavirus (HPV) infection. Nine C-AC cases were also examined using a combination of the reverse transcription-polymerase chain reaction and Southern blot hybridization, as well as Western blot assays. Significantly decreased DCC scores were observed in E-ACs but not M-ACs, as compared to normal cervical glandular epithelia and AIS. Average p21(WAF1/Cip1) and p27Kip1 scores were significantly higher in E-ACs than M-ACs, in line with high apoptotic, mitotic and Ki-67 labelling indices. A concordance of the results for DCC and p21(WAF1/Cip1) expression between mRNA- and protein-based assays was also noted. Change of DCC expression, however, was not related to any of the cell kinetic markers or clinicopathological features in ACs of either type. There was also no association with the HPV status, although infection was significantly linked with high values for cell kinetics. These results suggest that DCC expression in C-ACs is closely associated with mucinous differentiation.

Adenocarcinoma↗

PubMed1999

Down-regulation of p27Kip1 expression is correlated with increased cell proliferation but not expression of p21waf1 and p53, and human papillomavirus infection in benign and malignant tumours of sinonasal regions.

AIMS: Although p27Kip1(p27) is a cyclin-dependent kinase inhibitor and a contribution to tumorigenesis has been hypothesized, the possible role in tumours arising in the nasal and paranasal sinus regions is still unknown. METHODS AND RESULTS: Seventy-six sinonasal tumours, including 28 inverted papillomas (IPs) and 48 squamous cell carcinomas (SCCs), were immunohistochemically investigated, along with 46 exophytic papillomas (EPs) of upper respiratory tract and 34 samples of normal paranasal sinus epithelium. The results were also compared with expression of p21WAF1 (p21) and p53, cell proliferation assessed in terms of Ki67 labelling indices (LIs), and human papillomavirus (HPV) infection. The average p27 scores decreased from normal through to malignant lesions, while Ki67 LI scores showed a stepwise increase, the inverse correlation between scores for all categories being significant (r = - 0.639, P < 0. 0001). In the SCCs, p27 expression was significantly higher in keratinizing than nonkeratinizing type tumours (P < 0.05), while there was no association with p21 and p53 expression. Although HPV DNAs for type 16 and 18 were detected in two (7.4%) of 27 EPs, six (35.8%) of 28 IPs, and nine (28.1%) of 32 SCCs, no relation with p27 scores was evident. CONCLUSION: Loss of p27 expression correlates with increased cell proliferation in sinonasal tumours. Moreover, the expression appears to be associated with keratinization in SCCs of the paranasal sinus. These findings indicate that p27 expression may be a useful marker for the dysregulation of cell kinetics in these tumours.

Blotting, Southern↗

PubMed1998

Progesterone therapy for endometrial carcinoma reduces cell proliferation but does not alter apoptosis.

BACKGROUND: Although the anticancer effects of progesterone therapy for patients with endometrial carcinoma are widely acknowledged, a detailed assessment of the resultant morphologic alterations in tumor tissue kinetics has hitherto been lacking. METHODS: Biopsy and hysterectomy specimens of 14 endometrial carcinomas (endometrioid-type) before and during progesterone therapy were studied to clarify changes in apoptosis and cell proliferation and their relation to morphologic alterations. The extent of squamous differentiation within tumor lesions was also examined. RESULTS: In the good-response group, tumor cells took on characteristics of normal endometrial gland cells in the secretory phase. A positive correlation between reduction in the mitotic index and the degree of morphologic alterations during hormone therapy was observed, but the frequency of apoptotic cells did not vary. In both the good-response and poor-response groups, development or enlargement of squamous areas was observed, in comparison with the initial biopsy specimens. CONCLUSIONS: These results suggest that prolonged progesterone administration can suppress cell proliferation in endometrial carcinomas through tumor cell differentiation without altering apoptosis, resulting in a shift in tissue kinetics toward a relative predominance of cell deletion. In addition, increases in the occurrence of squamous areas within tumors do not always appear to be related to treatment efficacy.

Adult↗

PubMed1998

CD44 expression in normal, hyperplastic, and malignant endometrium.

A total of 140 endometrial carcinomas (endometrioid type), as well as 72 hyperplasias (41 of simple or complex and 31 of atypical type) and 141 normal endometria (35 in the proliferative and 106 in the secretory phase), were immunohistochemically investigated for expression of the standard and variant-3 and -6 isoforms of CD44, and the results compared with several known prognostic factors. A combination of the reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot hybridization (SBH) for CD44 mRNA levels was also carried out on 27 endometrial carcinomas. In normal endometrium, the expression of standard and variant CD44 forms was remarkably higher in the secretory than in the proliferative phase, with immunoreactivity scores being inversely correlated with numbers of oestrogen and progesterone receptors. Significantly elevated levels of CD44 expression in endometrial carcinomas compared with the proliferative phase and hyperplasia were also revealed by both the immunohistochemical and the RT-PCR/SBH assays, while no association was noted with any prognostic factors. The results indicate that CD44 expression in the normal menstrual cycle is closely related to the secretory differentiation of the glandular epithelium. Moreover, detection of aberrant expression may be useful for the early diagnosis of endometrial carcinoma, but not as an indicator of tumour progression.

Antigens, Neoplasm↗

PubMed1998

Up-regulation of CD44 variant exon expression in endometrial carcinomas: analysis of mRNA and protein isoforms, and relation to clinicopathological factors.

In order to clarify the relation between expression of individual CD44 variant exons and tumor progression, 34 endometrial carcinomas (endometrioid type) were investigated, as well as 27 samples of normal endometrium, using a combination of reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot hybridization (SBH). Western blotting was also performed for comparison of protein levels with the results of the RT-PCR/SBH methods. Analysis of gross CD44 splicing patterns demonstrated high-level expression of variant isoforms in endometrial carcinomas as compared with normal endometrium. Exon-specific RT-PCR/SBH assays revealed large, abundant transcripts of individual variant exons in particular v3, v4, and v5, in tumors, but these isoforms were also expressed in normal endometria, suggesting a lack of tumor-specificity. No individual CD44 variant transcripts were associated with any of the prognostic factors investigated. Parallel observations showed variant CD44 transcripts to be more readily detectable than protein isoforms in the same samples. These findings indicate that in endometrial carcinomas, expression of individual variant CD44 exons is markedly up-regulated, but this molecule may not be useful as a consistent indicator of tumor progression.

Endometrial Neoplasms↗

PubMed1998

[Combination chemotherapy with cis-platinum and ifosfamide for hormone unresponsive prostate cancer].

PURPOSE: There is no effective therapy against hormone refractory prostate cancer. This led us to evaluate the effectiveness and toxicity of cis-platinum (CDDP) and ifosfamide (IFM) combination chemotherapy in the patients with hormone-unresponsive carcinoma of the prostate. METHODS: Patients with hormone-unresponsive prostate cancer were scheduled to receive CDDP 70 mg/m2 intravenously on day 1 and IFM 1.2 g/m2/day intravenously on day 1 through day 5 of 28-day cycle. RESULTS: Twenty seven patients with hormone unresponsive prostate cancer were enrolled onto this trial. Of these patients, seven (26%) demonstrated a partial objective response (PR), and ten (37%) a stable disease (ST). The response duration of PR cases lasted from 6 to 49 months with a median of 16 months and the response duration of PR + ST cases lasted from 3 to 36 months with a median of 10 months. Subjective improvement was obtained in 11 patients (41%). Survival duration of all cases were 4 to 89 months with a median of 23 months and probabilities of survival at 3 years and 5 years were 36% and 24%, respectively. The toxicity of this treatment was mostly mild to moderate, anemia (96%), leukocytopenia (89%), anorexia (81%), alopecia (67%), thrombocytopenia (44%), hematuria (38%), renal dysfunction (19%) and liver dysfunction (7%) were noticed. Severe toxicity was observed in two cases, one acute renal failure and one endotoxin shock. CONCLUSION: We conclude that CDDP and IFM combination chemotherapy was active regimen for hormone unresponsive prostate cancer.

Aged↗

PubMed1997

Expression of bcl-2 protein in esophageal squamous cell carcinomas and its association with lymph node metastasis.

BACKGROUND: Recent studies on the role of bcl-2 in malignant tumors have suggested its prognostic significance. The goals of the current study were to determine any correlation between bcl-2 expression in esophageal squamous cell carcinoma and histopathology, lymph node metastasis, and clinical variables, and to assess its applicability as a parameter for prognosis. METHODS: Immunohistochemical staining for bcl-2 (clone 124) was performed on archival material from 105 esophageal squamous cell carcinomas. The results were compared among patient subgroups. RESULTS: bcl-2 was expressed in 58% of esophageal carcinomas, demonstrating positive correlations with a lack of keratinization and an early stage of disease. Lymph node metastasis was significantly less frequently observed in the subset of early stage carcinomas with bcl-2 staining. Univariate analysis revealed significantly longer disease free survival in patients with bcl-2 positive carcinomas than in those bcl-2 negative. bcl-2 expression did not have independent prognostic value in a multivariate survival analysis. CONCLUSIONS: bcl-2 is frequently expressed in esophageal carcinomas, and this expression is positively associated with nonkeratinization and an early stage, whereas it is negatively linked with lymph node metastasis and may indicate a favorable prognosis.

Carcinoma, Squamous Cell↗

PubMed1997

Down-regulation of bcl-2 expression is closely related to squamous differentiation and progesterone therapy in endometrial carcinomas.

To clarify whether changes in bcl-2 protein (bcl-2) expression are directly linked to differentiation, an immunohistochemical investigation was carried out on areas of squamous differentiation within 38 endometrial carcinomas (25 grade 1 and 13 grade 2 cases) as well as eight grade 1 carcinomas after progesterone therapy. Such areas of altered differentiation were subdivided into foci of squamous metaplasia (Sq-M) and morules. Expression of oestrogen and progesterone receptors (ER and PR) and cell proliferation were also examined. Immunoreactivity scores for bcl-2 in Sq-M foci were significantly lower than in the surrounding tumour regions, in line with reduced staining for ER and PR and Ki-67 labelling indices (LIs), while morule values were intermediate. After progesterone therapy, a marked decrease in bcl-2 immunoreactivity was found in the response group, along with low Ki-67 LIs and tumour cell maturation. These results indicate that in endometrial carcinoma, down-regulation of bcl-2 expression may be closely linked with squamous differentiation, in line with changes in ER and PR expression, as well as in cell proliferation. In addition, bcl-2 expression appears to be down-regulated by progesterone therapy through tumour cell maturation, indicating that bcl-2 may be a clinically useful marker of hormone therapy effects.

Biomarkers, Tumor↗

PubMed1997

Apoptosis, proliferative activity and Bcl-2 expression in Epstein-Barr-virus-positive non-Hodgkin's lymphomas.

In order to clarify the effects of Epstein-Barr virus (EBV) infection on apoptosis and proliferative activity of non-Hodgkin's lymphoma, 135 Japanese lymphoma cases were investigated for the presence of viral RNA and its correlation with bcl-2 protein (Bcl-2) expression. In addition, the role of EBV in lymphoma-genesis was also studied in terms of EBV genotyping and specific deletion in the gene for the latent membrane protein 1 (LMP-1). EBER-1 RNA in situ hybridization revealed EBV in 18 cases (13.3%), comprising 12 of 44 T cell (27.3%) and 6 of 91 B cell (6.6%) lymphomas. Type A EBV was found in all 18 cases (100%), and 17 of the 17 (100%) evaluable cases showed a 30-bp deletion within the 3' end of LMP-1. Comparison of apoptotic indices (AI), assessed by DNA nick-end labelling, and proliferative activity, estimated in terms of Ki-67 labelling and mitotic indices (KI and MI), demonstrated an overall correlation among AI, KI and MI increases in association with Bcl-2 negativity, indicating a close relation between apoptosis and proliferation. EBV-positive cases showed significantly elevated AI values, independent of Bcl-2 positivity, with no change in KI and MI. These results indicate that EBV in Japanese non-Hodgkin's lymphomas is exclusively of type A with a specific deletion in LMP-1 and that it tends to be present in T cell lymphomas. Moreover, EBV up-regulates apoptosis without any relation to Bcl-2 expression and exerts only minor effects on proliferation.

Apoptosis↗

PubMed1997

Bcl-2 is closely correlated with favorable prognostic factors and inversely associated with p53 protein accumulation in endometrial carcinomas: immunohistochemical and polymerase chain reaction/loss of heterozygosity findings.

To clarify the relation between bcl-2 protein (Bcl-2) expression and p53 alteration during progression of endometrial carcinomas (endometrioid type), 92 consecutive hysterectomy specimens were examined by immunohistochemistry. Loss of heterozygosity (LOH) for the p53 gene was also examined using the polymerase chain reaction(PCR)-LOH assay. Moderate to strong Bcl-2 immunointensity in more than 30% of cells was found in 32 (34.8%) of 92 carcinomas, with a clear link to favorable clinicopathological features, such as a high differentiation grade (P = 0.0084), an early stage (P = 0.0432) and limited invasion into the myometrium (P = 0.0084). In contrast, positive results for p53 immunohistochemistry (more than 30% positive cells) or PCR-LOH analysis were revealed in 16 (17.4%) of 92 and 18 (22.5%) of 80 tumors respectively. Although there was no apparent association between the nuclear p53 staining and the presence of LOH, the lack of correlation being observed in 23 (28.7%) of the tumors, both alterations were significantly linked with several unfavorable prognostic factors. In addition, an inverse correlation was observed between Bcl-2 expression and p53 protein accumulation (P = 0.0084). These data suggest that, in endometrial carcinomas, Bcl-2 and p53 alterations may play important roles in determining whether tumor progression from early to advanced stages will occur.

Disease Progression↗

PubMed1997

Apoptosis, cell proliferation and expression of Bcl-2 and Bax in gastric carcinomas: immunohistochemical and clinicopathological study.

To clarify the relation between bcl-2 and bax protein (Bcl-2 and Bax) expression with regard to apoptosis and cell proliferation, 82 gastric carcinomas were immunohistochemically investigated. The significance of apoptosis for biological behaviour of the tumours was also examined. The apoptotic indices (AIs) were significantly lower in early-stage than in advanced-stage lesions (P<0.05), being positively correlated with the mitotic indices (MIs) (r=0.447, P<0.001). No association between either AIs or MIs and tumour size (diameter of intramural spreading) was noted. The AIs in the high Bcl-2-immunoreactive score group were significantly smaller than in either the low or the negative categories, whereas they were relatively elevated in the high Bax score group. In addition, an inverse correlation between Bcl-2 and Bax expression was revealed for both AIs and MIs. Although depth of tumour invasion and lymph node status were clearly associated with favourable outcome, no relation between survival rates and average values of either AIs or MIs, or immunoreactive scores for Bcl-2 and Bax was observed. These results indicate that in gastric carcinomas, apoptosis is closely associated with cell proliferation and expression of Bcl-2 and Bax, but appears likely to have no particular biological significance as a prognostic factor.

Adenocarcinoma↗

PubMed1997

Detection of the Epstein-Barr virus genome in cervical neoplasia is closely related to the degree of infiltrating lymphoid cells: a polymerase chain reaction and in situ hybridization approach.

To cast light on the significance of Epstein-Barr virus (EBV) infection in cervical tumorigenesis, 44 cervical intraepithelial neoplasia (CIN) types I/II, and 70 CIN III lesions, 60 invasive squamous cell carcinomas (ISCC), and 20 normal cervical samples were investigated by polymerase chain reaction (PCR) and RNA in situ hybridization (RISH) assays. The EBV genome was detected by PCR using primers targeting the IR region in three (6.8%) of the CIN I/II, 15 (21.4%) of the CIN III and 13 (21.7%) of the ISCC lesions, while using an EBER oligonucleotide probe RISH revealed positive signals in infiltrating lymphocytes located in the cervical stroma, but not in dysplastic or tumor cells. There was a significant correlation between the presence of EBV DNA and the degree of lymphoid cell infiltration (P = 0.0223). In contrast, none of the normal cervical samples that were without inflammation demonstrated any EBV infection. Thus, the results indicated that a positive result for EBV on PCR may be simply dependent on the amount of lymphocytes in cervical stroma, suggesting that this virus does not play a major role in the etiology of cervical neoplasia.

Carcinoma, Squamous Cell↗

PubMed1997

Absence of human papillomavirus genomic sequences detected by the polymerase chain reaction in oesophageal and gastric carcinomas in Japan.

AIMS: To estimate the occurrence of human papillomavirus (HPV) infection in oesophageal or gastric carcinomas in patients in Japan. METHODS: 103 oesophageal and 99 gastric carcinomas were investigated by polymerase chain reaction (PCR) assays using two consensus (targeting either the L1 or the E6-E7 regions) and two type specific (type 16 and 18) primer sets. A beta globin gene specific primer set was also applied to examine the quality of the extracted DNA. RESULTS: Amplification of beta globin gene was clearly visible in 92 (89.3%) of the 103 oesophageal, and 89 (89.8%) of the 99 gastric carcinoma specimens. However, the entire series of tumour DNA was negative for HPV sequences by PCR assay using all four primer sets. CONCLUSION: HPV is not likely to be involved in oesophageal or gastric tumorigenesis in Japanese patients.

Adenocarcinoma↗

PubMed1996

Bcl-2 expression is correlated with a low apoptotic index and associated with progesterone receptor immunoreactivity in endometrial carcinomas.

A total of 103 endometrial carcinomas (endometrioid type), as well as 15 samples of normal (atrophic or proliferative phase) and 26 of hyperplastic endometrium, were immunohistochemically investigated for expression of Bcl-2, and oestrogen and progesterone receptors (ER and PR), and the results compared with findings for apoptosis and cell proliferation. Carcinoma cases were subdivided into tubular and solid components on the basis of tumour growth patterns. Immunopositivity for Bcl-2, ER, and PR in tubular components was significantly higher than in the solid category, being negatively associated with histological grading. Immunoreactivity scores revealed that Bcl-2 in the tubular group was positively correlated with PR but not ER, while its expression in normal and hyperplastic endometrium was closely linked with both. Apoptotic and mitotic indices (AI and MI) were both significantly lower in tubular than in solid areas. In the tubular areas, AI, values were significantly lower in the subgroup with a high level of Bcl-2 expression than in either low-level or negative groups. These results indicate that Bcl-2 expression may play a central role in the inhibition of apoptosis in endometrial carcinoma, in particular those cases with tubular components, possibly being associated with PR rather than ER. Changes in the propensity for apoptosis may be related to alterations of tumour growth pattern and of features of differentiation.

Apoptosis↗

PubMed1996

Bcl-2 expression and allelic loss of the p53 gene in gastric carcinomas.

In order to clarify the association between bcl-2 protein (Bcl-2) expression and genetic alteration, we investigated p53 and DCC (deleted in the colon carcinoma gene locus) gene abnormalities in Bcl-2-positive and -negative gastric carcinomas using a polymerase chain reaction/loss of heterozygosity (LOH) assay. Bcl-2 immunoreactivity was found in 25 of 178 (14%) gastric carcinoma cases. With these 25 positive cases, the proportion 18/87 (20.6%) of the total in early stages demonstrating invasion of the mucosa and/or submucosa was significantly greater (P = 0.013) than the 7/91 (7.7%) found for advanced tumors exhibiting invasion into or through the muscularis propria. However, there was no statistically significant variation between the proportions for differentiated (17/98 cases, 17.3%) and undifferentiated (8/80 cases, 10%) lesions. Sixteen Bcl-2-positive cases (9 cases were not studied because of insufficient specimen material to allow extraction of DNA) and 31 cases randomly selected from a Bcl-2-negative group were analyzed for the presence of p53-LOH or DCC-LOH and for p53 by immuno-histochemistry. The minority of the Bcl-2-positive group had p53-LOH and were immunopositive for p53 (P = 0.033, P = 0.028 respectively), while no association was found in the Bcl-2-negative category. In contrast, there was no correlation at all between Bcl-2 expression and DCC-LOH although the number of informative cases analyzed was too small to allow definite conclusions. These results indicate that Bcl-2 may be predominantly expressed at an early stage in gastric carcinomas, possibly in negative association with p53 gene abnormalities.

Alleles↗

PubMed1996

Apoptosis of colon cancer: comparison with Ki-67 proliferative activity and expression of p53.

The role of apoptosis in colon cancer was investigated in terms of control of growth and expression on p53, using the nick-ended-DNA labelling method and immunohistochemistry. The apoptotic labeling index was highest in the T1 stage (24 cases), as was the proliferative activity, assessed in terms of the Ki-67 labeling index. Both labeling indices demonstrated similar overall incidence curves for the total 95 colon cancer cases, and examination of individual cases revealed a statistically significant correlation (P=0.01). However, neither index had any relation to p53. The results thus suggest that apoptosis in colon cancers has a linkage with proliferative activity that can be assessed by Ki-67 labeling, but is not regulated by the p53 system. This might contribute to the diversity of colon cancer growth.

Apoptosis↗