Biography:

In the past Tsuyoshi Iwasaka has collaborated on articles with Toru Hachisuga and Peng-Sheng Zheng. One of their most recent publications is Immunohistochemical demonstration of histiocytes in normal ectocervical epithelium and epithelial lesions of the uterine cervix. Which was published in journal Gynecologic Oncology.

More information about Tsuyoshi Iwasaka research including statistics on their citations can be found on their Copernicus Academic profile page.

Tsuyoshi Iwasaka's Articles: (11)

Immunohistochemical demonstration of histiocytes in normal ectocervical epithelium and epithelial lesions of the uterine cervix

AbstractThe numbers of Langerhans cells and lysozyme-positive macrophages were assessed quantitatively in normal ectocervical epithelium, cervical intraepithelial neoplasia (CIN), microinvasive squamous cell carcinoma (MICA), clinical invasive squamous cell carcinoma (CICA), and koilocytotic atypia using the avidin-biotin-peroxidase complex (ABC) method. The distribution of Langerhans cells was different from that of lysozyme-positive macrophages in that the former were intermingled with the cervical lesion, while the latter were present mainly surrounding the cervical lesion and/or on the edge of the cervical lesion. The numbers of Langerhans cells and lysozyme-positive macrophages in CIN were significantly larger than those in normal ectocervical epithelium and significantly smaller than those in invasive squamous cell carcinoma (MICA + CICA). Langerhans cell number significantly increased as the grade of CIN advanced. In contrast, the number of lysozyme-positive macrophages did not differ significantly between progressive grades of CIN. As for koilocytotic atypia, the numbers of Langerhans cells and lysozyme-positive macrophages in koilocytotic atypia were significantly greater than those in normal ectocervical epithelium but did not differ significantly from those in CIN 1 and CIN 2. With respect to stromal lymphoid infiltration, invasive squamous cell carcinoma with moderate or dense stromal lymphoid infiltration showed significantly greater numbers of Langerhans cells and lysozyme-positive macrophages than that with no or scattered stromal lymphoid infiltration, but such a correlation was not found in CIN.

Regular articleAntitumor effects of human recombinant interferon-γ and tumor necrosis factor on five cervical adenocarcinoma cell lines, in vivo and in vitro

AbstractWe examined the antitumor effects of recombinant interferonγ (IFN-γ) and tumor necrosis factor (TNF) on cervical adenocarcinoma cell lines, in vitro and in vivo. Four of five cell lines showed a high sensitivity to IFN-γ, in vitro. One of five cell lines showed a remarkable sensitivity to TNF, in vitro. Only one cell line resistant to both IFN and TNF was derived from a welldifferentiated adenocarcinoma of endocervical type. Experiments using nude mice bearing transplanted tumors revealed that these cytokines were also effective against tumors in vivo. All these observations suggest that IFN-γ or TNF can have positive effects in the treatment of patients with adenocarcinoma of the uterine cervix.

Regular articleDetection of Epstein-Barr virus DNA from a lymphoma-like lesion of the uterine cervix

AbstractThe case of a 60-year-old woman in whom a lymphoma-like lesion of the cervix was found during an episode of silent Epstein-Barr virus (EBV) infection is presented. Fractional curettage was performed because of abnormal endometrial smear. The endocervical curettage specimens were diagnosed as highly suggestive of malignant lymphoma, but microscopic examination of a subsequent hysterectomy specimen revealed a benign lymphoid hyperplasia. Those were retrospectively interpreted as a lymphomalike lesion of the cervix. In the absence of clinical symptoms of infectious mononucleosis, the results of serologic tests for EBV revealed an active EBV infection. EBV DNA was demonstrated in nuclei of large lymphoid cells in endocervical curettage specimens by in situ hybridization. She is alive and well 32 months postoperatively. When female patients with lymphoma-like lesions of the lower genital tract are encountered, examinations for EBV are recommended.

Regular ArticleTelomerase Activity in Papanicolaou Smear-Negative Exfoliated Cervical Cells and Its Association with Lesions and Oncogenic Human Papillomaviruses

AbstractObjective. The goal of this study was to evaluate telomerase activity in exfoliated cervical cells and its association with cytology, pathology, and human papillomavirus (HPV).Methods. Telomerase activity and HPV DNA sequences were examined in the exfoliated cervical cells from a general population of 245 women aged more than 30 years undergoing routine cervical screening by Papanicolaou smear. The women who were found to have telomerase activity or abnormal cytology in their exfoliated cervical cells were examined for cervical lesions by colposcopy and biopsy.Results. Cytology for our population (mean, 56 years) revealed only one abnormal smear (1/245, 0.4%), in which a cervical intraepithelial neoplasia grade I (CIN I) lesion was found. The exfoliated cervical cells used to prepare the smear were negative for telomerase and contained low-risk HPV DNA. Telomerase activity was found in 16 exfoliated cell samples (16/245, 6.5%); high-risk HPV DNA was found in 9 of these samples (9/16, 56%) and 9 of the biopsy specimens that could be evaluated from patients testing positive for telomerase revealed CIN I lesions (9/11, 82%).Conclusions. Telomerase activity is often associated with high-risk HPV infection and it is suggested that telomerase assay can help to detect occult cervical lesions.

The tea polyphenol, (−)-epigallocatechin gallate effects on growth, apoptosis, and telomerase activity in cervical cell lines

AbstractObjective. To investigate the effect of the major tea polyphenol, (−)-epigallocatechin gallate (EGCG) in cervical carcinogenesis.Methods. Cell growth rate was examined after treatment for 4, 7, and 10 days with 0–100 μM EGCG in primary human endocervical cells (HEN), human papillomavirus type 18 (HPV 18)-immortalized endocervical cell (HEN-18), ectocervical cell (HEC-18), serum-adapted HEN-18 (HEN-18S), transformed HEC-18 (HEN-18T), and four cervical cancer cell lines. The effect of EGCG treatment was examined on dysplastic epithelium formation in organotypic culture, induction of apoptosis by DNA ladder assay and telomerase activity by PCR telomere extension assay.Results. EGCG inhibited growth more than 90% in HEN-18 and HEC-18, whereas growth inhibition was less in ME180, TMCC-1, HeLa, SiHa, HEC-18T, and HEN-18S. In organotypic culture, thickness of epithelial multilayers was decreased in all EGCG-treated cells. EGCG resulted in apoptosis of HEN-18 or HEC-18, but not HEN-18S nor HEC-18T and inhibited telomerase activity in HEN-18 and HEC-18, as well as HEN-18S and HEC-18T.Conclusion. Our data suggest that EGCG prevents the carcinogenesis of cervical cancer, induces apoptosis and inhibited telomerase activity. The effect by EGCG treatment may be associated with the induction of apoptosis and telomerase inhibition in early cervical lesions.

Regular ArticleCorrelation between Human Papillomavirus Positivity and p53 Gene Overexpression in Adenocarcinoma of the Uterine Cervix☆

AbstractIn the pathogenesis of cervical squamous cell carcinoma, an inverse correlation between human papillomavirus (HPV) infection and mutation of the p53 anti-oncogene has been suggested. Much less is known of a possible correlation in the case of adenocarcinoma of cervix. Twenty-five cervical adenocarcinomas and 7 adenosquamous carcinomas were analyzed for presence of HPV DNA sequences and overexpression of the p53 gene. Polymerase chain reaction revealed that 11 were positive for HPV DNA (34%). Seven were positive for HPV 16 and 5 for HPV 18. A mixed infection with HPV 16 and 18 was observed in 1 case. Patients with HPV-positive carcinoma were significantly younger than those with HPV-negative carcinoma (43 ± 13.3 years versus 57 ± 17.4 years,P= 0.01). Immunohistochemical staining showed that p53 was overexpressed in 11 of 32 cases (34%). Overexpression of the p53 gene was found in only 1 of 11 HPV-positive cases (9%) yet was evident in 10 of 21 HPV-negative cases (48%). This inverse association was statistically significant (P< 0.05). Prognostic analysis revealed that HPV-negative adenocarcinomas had a poorer prognosis than HPV-positive cases (P< 0.01) and that tumors with p53 overexpression also had a poorer prognosis than those without such overexpression (P< 0.01). Our observations suggest that HPV-negative or p53-positive adenocarcinomas may be a biologically distinct subset with a poorer prognosis.

Regular ArticleNeoadjuvant Chemotherapy with Mitomycin C, Etoposide, and Cisplatin for Adenocarcinoma of the Cervix☆

AbstractBetween May 1990 and February 1995, 16 patients with adenocarcinoma or adenosquamous carcinoma of the uterine cervix were prescribed neoadjuvant chemotherapy consisting of cisplatin (50 mg/m2) on day 1, mitomycin C (10 mg/m2) on day 1, and etoposide (100 mg/m2) on days 1, 3, and 5 (MEP). In 2 patients stage was IB1, 5 were in stage IB2, 1 was in stage IIA, 5 were in stage IIB, 2 were in stage IIIB, and one was in stage IVB. A median of three courses of chemotherapy was given (range two to five). Of the 16 patients, 3 had a complete response and 5 had a partial response (response rate, 50%). Following termination of this chemotherapy, 12 patients with stage I or stage II carcinoma underwent radical hysterectomy. Three were given adjuvant radiotherapy because of positive pelvic nodes. One stage IIB patient, 1 stage IIIB patient and 1 stage IVB patient underwent standard radiotherapy and 1 stage IIIB patient underwent chemotherapy with another regimen because MEP therapy was without effect. Histopathological examinations revealed that changes as a result of the chemotherapy correlated well with clinical responses. Moderate or marked pathological changes occurred in 3 with a clinically complete response. The mean survival period of responders was 47.5 months while that of nonresponders was 28.3 months. Side effects of chemotherapy with MEP were within acceptable limits. The dose-limiting toxicity was myelosuppression and for only 1 patient the dose was reduced because of thrombocytopenia. Our preliminary study indicates that this chemotherapy regimen is effective for subjects with adenocarcinoma of the cervix. A prospective cooperative group trial on this regimen is ongoing.

Regular ArticlePreoperative Cervical Cytology in Endometrial Carcinoma and Its Clinicopathologic Relevance

AbstractObjective.The aim of this study was to assess the significance of malignant or suspicious cervical cytology in preoperative identification of poor prognostic factors in endometrial carcinoma and to determine whether preoperative abnormal cervical cytology is an independent prognostic factor for endometrial carcinoma.Methods.We evaluated the correlation between preoperative cervical cytology and postoperative clinicopathologic findings, sites of metastasis, and receptor status from 99 surgically staged patients with endometrial carcinoma.Results.Sixty-eight patients (68.7%) had normal cervical cytology, 1 (1.0%) had atypical cytology suspicious for malignancy, and 30 (30.3%) had malignant cytology on preoperative cervical cytology. Malignant and suspicious cervical smears were statistically correlated with surgical stage (P= 0.001), histopathology (P= 0.010), tumor grade (P= 0.012), depth of myometrial tumor invasion (P= 0.001), cervical involvement (P= 0.01), lymph node metastases (P= 0.002), adnexal metastases (P= 0.012), progesterone receptor (P= 0.007), and estrogen receptor (P= 0.031). No association was found between preoperative cervical cytology and patients' age or peritoneal cytology. Univariate analysis showed that cervical cytology was related to survival (P= 0.018). However, multivariate analysis of cervical cytology, stage, grade, and myometrial invasion showed that preoperative cervical cytology was not a significant prognosticator for survival.Conclusion.Patients with endometrial carcinoma who have malignant or suspicious cytology detected by preoperative cervical cytology are at increased risk of having known poor prognostic factors. However, positive preoperative cervical cytology itself does not appear to be an independent prognostic factor and probably should not influence treatment decisions in endometrial cancer.

Regular ArticlePrognostic Significance of Progesterone Receptor Immunohistochemistry for Lymph Node Metastases in Endometrial Carcinoma

AbstractObjective.The aim of this study was to determine whether progesterone receptor (PR), estrogen receptor (ER), p53 protein, and proliferating cell nuclear antigen (PCNA) expression constitute independent prognostic factors for lymph node metastases in endometrial carcinoma using immunohistochemical techniques on hysterectomy and biopsy specimens.Methods.We evaluated the correlation between lymph node metastases and PR/ER immunohistochemistry, p53/PCNA expression, age, tumor grade, myometrial tumor invasion, cervical involvement, and ovarian metastases in a series of 99 cases of primary endometrial carcinoma surgically staged with systemic pelvic lymphadenectomy and para-aortic lymph node biopsy.Results.Lymph node metastases from endometrial carcinoma were statistically correlated with negative PR immunohistochemistry (P= 0.001), intense p53 expression (66% or more of the tumor cells stained,P= 0.003), deep myometrial tumor invasion (greater than one-half,P= 0.001), and cervical involvement (P= 0.001). Tumor grade showed borderline statistical significance for lymph node metastases (P= 0.058). On multivariate analysis, negative PR, intense p53 expression, and cervical involvement were significant prognostic variables for lymph node metastases (P= 0.0001, 0.0023, and 0.002, respectively). Immunohistochemical study indicated that the PR status on preoperative biopsy specimens and hysterectomy specimens was in good agreement, but p53 status was not. Age, ovarian metastases, ER immunohistochemistry, and PCNA expression were not significantly related to lymph node metastases.Conclusion.PR immunohistochemistry appeared to be the most powerful prognostic factor associated with lymph node metastases in endometrial carcinoma, independent of other clinicopathological parameters.

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

AbstractThirty-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.

Retinoic acid receptor β2 is epigenetically silenced either by DNA methylation or repressive histone modifications at the promoter in cervical cancer cells

AbstractTo elucidate the silencing mechanism of retinoic acid receptor β2 (RARβ2) in cervical carcinogenesis, we investigated RARβ2 expression and the status of both DNA methylation and histone modifications at the promoter in cervical cancer cell lines. RARβ2 was frequently repressed in cancer cell lines and in primary cancers of the cervix. Although the majority of RARβ2-negative cancers had methylated promoter, RARβ2 was repressed with hypomethylated promoter in a substantial fraction of the cancers. The RARβ2-negative cells with hypomethylated promoters showed a repressive histone modification pattern at the promoter. RARβ2 was reactivated by a histone deacetylase inhibitor, accompanied by formation of active histone modifications. The repressive modification was also observed in cells repressed with hypermethylated promoter, but RARβ2 was reactivated only by DNA demethylating agent and not by histone deacetylase inhibitor. Our results suggest that RARβ2 is silenced by either of the two key epigenetic pathways, DNA methylation or repressive histone modifications, depending on the individual cancer cells.

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