Significance of nuclear p-Akt in endometrial carcinogenesis: rapid translocation of p-Akt into the nucleus by estrogen, possibly resulting in inhibition of apoptosis.

INTRODUCTION: Endometrial endometrioid adenocarcinoma (endometrial cancer) develops through endometrial hyperplasia caused by estrogenic hyperstimulation. Estrogen is known to activate growth factor signaling pathways, resulting in cellular proliferation, but precisely how has not been clarified. The aim of this study was to investigate the significance of estrogen and downstream factors such as the MAPK (MEK, ERK) and Akt pathways in endometrial carcinogenesis. METHODS: The expression of p-MEK, p-ERK, and p-Akt was analyzed immunohistochemically in normal, hyperplastic, and neoplastic endometria. The estrogenic effect on p-Akt was examined using an endometrial cancer cell line (Ishikawa cells). The estrogenic effect on the apoptosis of Ishikawa cells was assessed by the TUNEL method. RESULTS: Phospho-MEK (p-MEK) and p-ERK expression levels were similar among histological types but correlated with each other. The nuclear p-Akt labeling index (LI) was higher in cancer than in normal endometrium and hyperplasia. The nuclear p-Akt LI of well-differentiated cancer (G1) was higher than that of moderately (G2) or poorly (G3) differentiated cancers. The nuclear expression of p-Akt was correlated with that of estrogen receptor α (ER-α). The nuclear p-Akt level was significantly correlated with prognosis in cases of G1. In Ishikawa cells transfected with ERα, p-Akt was translocated into the nucleus from the cytoplasm in 1 to 3 hours after estrogenic stimulation. Further, apoptosis induced by H2O2 was inhibited by estrogen in the ER-α-positive cells. CONCLUSIONS: The translocation of p-Akt into the nucleus by estrogen may be related to the suppression of apoptosis by estrogen and consequently to endometrial carcinogenesis and prognosis in G1 endometrial cancer.

Clinical significance of human papillomavirus genotype by linear array assay in Japanese women with uterine cervical lesions and type 16 physical status by in situ hybridization.

The aim of this study was to clarify the relation of human papillomavirus (HPV) genotypes and physical status in the cervical neoplasm of Japanese patients with the grade of the disease. Human papillomavirus genotype was detected using a linear array genotyping assay. Human papillomavirus status, diffuse or punctate signal pattern, was studied by biotynyl-tyramide-based in situ hybridization for positive cases of HPV-16. Human papillomavirus types 16, 52, 58, and 31, in descending order of frequency, were prevalent. The rates of HPV infection in patients with cervical intraepithelial neoplasia (CIN) or squamous cell carcinoma (SCC) were significantly higher than those in patients without cervical lesions. The frequency of HPV single infection in SCC was higher than that in CIN1 or CIN2. In an unspecified-risk HPV, types 66 and 70 were found in SCC and 62, 71, and 82 were detected in CIN3. The diffuse pattern was more frequent in CIN, and the punctate pattern was more frequent in SCC. Human papillomavirus types 16, 52, 58, and 31 were frequently detected in Japanese women with cervical neoplasias, and several unspecified-risk HPVs might be high-risk types. A single infection of HPV and a punctate signal pattern seemed to be closely correlated with cervical carcinogenesis.

Abscopal effect of radiation on toruliform para-aortic lymph node metastases of advanced uterine cervical carcinoma--a case report.

The case of a 69-year-old woman with advanced uterine cervical carcinoma with toruliform para-aortic lymph node metastases that showed an abscopal effect of radiation therapy (effect out of irradiated field) is reported. The patient was admitted to our University Hospital in March 2005, and treated with radiation therapy only for the primary pelvic lesions without chemotherapy because of her severe economic status. After the treatment, not only did the cervical tumor in the irradiated field disappear, but the toruliform para-aortic lymph node swelling outside the irradiated field also spontaneously disappeared. The patient is still alive and well without relapse. This case is the first clinical demonstration of an abscopal effect in advanced uterine cervical carcinoma.

Phase II study of radiation therapy combined with weekly nedaplatin in locally advanced uterine cervical carcinoma: Kitasato Gynecologic Radiation Oncology Group (KGROG 0501).

In order to evaluate the safety and efficacy of chemoradiotherapy using nedaplatin for locally advanced uterine cervical carcinoma in Japanese patients, we have started a single-institute phase II trial. Eligibility criteria include: (i) pathologically proven squamous cell carcinoma or adenocarcinoma, (ii) clinical FIGO stage Ib, IIa, or IIb with bulky tumor (> 40 mm) or pelvic lymph node swelling, or (iii) clinical FIGO stage IIIa, IIIb and IVa, (iv) no para-aortic lymph node swelling. A combination of external beam radiation and high dose rate intracavitary irradiation is given. Nedaplatin (30 mg/m2) is intravenously infused on a weekly basis for five times. The primary endpoint is 3-year overall survival, and the secondary endpoints are tumor response, 2-year overall survival, 3-year progression-free survival, acute adverse events, protocol treatment compliance, and late adverse events. We plan to recruit 45 patients within 3 years.

Comparative image analysis of conventional and thin-layer preparations in endometrial cytology.

We evaluated the differences in cytologic findings between conventional and thin-layer preparations in endometrial cytology to introduce the thin-layer method into routine cytology. Eighty patients who had undergone endometrial cytology and biopsy on the same day were selected and we compared the cytological findings between conventional- and thin-layer preparations (TLP) in endometrial cytology. The numbers of neutrophils and cell clusters in the thin-layer method were lower than those in the conventional smear (CSS) method. The average number of neutrophils in endometrioid adenocarcinoma was significantly higher than that in normal morphology endometrium and endometrial hyperplasia. Regarding the shape of the cell clusters, ball-like patterns and round-edged cell clusters were not identified in CSS. The average number of clusters in CSS was significantly greater than that using the TLP. The average of the nuclear area in CSS was significantly larger than that using the TLP, indicating that the nuclear areas in CSS were more uneven than that using the TLP. In the future, it is expected that liquid-based cytology will be applied to the cytological diagnosis of a variety of lesions. The influence on cells due to fixation is considerable in liquid-based preparations. Therefore, if we strive to pick up the differences between CSS and TLP of endometrial samples, the diagnostic accuracy of the latter could be improved.

Objective evaluation of the alleviating effects of Goshajinkigan on peripheral neuropathy induced by paclitaxel/carboplatin therapy: A multicenter collaborative study.

Paclitaxel/carboplatin chemotherapy for cancer (TC therapy) exhibits neurotoxicity and causes peripheral neuropathy at a high frequency, which is difficult to cope with. In this study, we investigated the efficacy of Goshajinkigan, a traditional Japanese herbal medicine, for TC therapy-induced peripheral neuropathy. The subjects included in our study were patients with ovarian or endometrial cancer who underwent TC therapy and developed peripheral neuropathy. The patients were randomly divided into Group A, comprising of 14 patients (vitamin B12 treatment), and Group B, comprising of 15 patients (vitamin B12 + Goshajinkigan treatment). The observation period was 6 weeks following treatment initiation, and the evaluation items were as follows: i) the current perception threshold (CPT value) of the peripheral nerve, ii) visual analogue scale for numbness, iii) National Cancer Institute Common Terminology Criteria for Adverse Events v3.0 grade of neurotoxicity, and iv) a questionnaire on the subjective symptoms of peripheral neuropathy (functional assessment of cancer therapy-taxane). These were compared between the groups and no significant differences were noted in any item. However, CTCAE grade 3 neurotoxicity developed in 2 patients (14.3%) after 6 weeks of administration in Group A, whereas no neurotoxicity was observed in Group B. When the change in the frequency of abnormal CPT ratio at 6 weeks of administration from that before treatment was compared between the groups, the frequency of abnormal value was significantly lower in Group B than in Group A (p<0.05). This suggests that Goshajinkigan inhibits the progression of peripheral neuropathy.

Liquid-based preparation for endometrial cytology--usefulness for predicting the prognosis of endometrial carcinoma preoperatively.

BACKGROUND: The authors evaluated the applicability and usefulness of immunocytochemical staining for cyclin A, p53, estrogen receptor alpha (ER-alpha), and progesterone receptor B (PR-B) as a preoperative prognostic indicators for endometrial carcinoma using endometrial cytology with the liquid-based cytology (LBC) method. METHODS: Cytologic specimens from 44 patients who had endometrial carcinoma were prepared with the LBC method. The results of immunocytochemical and immunohistochemical staining for cyclin A, p53, ER-alpha, and PR-B were compared with clinicopathologic parameters and prognosis. RESULTS: Patients who had positive results for cyclin A and p53 and negative results for ER-alpha and PR-B appeared to have unfavorable clinicopathologic characteristics, such as high-grade histology, advanced clinical stage, lymphovascular space involvement (LVSI), and deeper myometrial invasion (MI), and had a poor prognosis. In contrast, patients who had positive results for ER-alpha and PR-B, and negative results for cyclin A and p53 had favorable characteristics, such well differentiated tumor, early clinical stage, negative LVSI, and less MI, and had a good prognosis. Immunostaining results from cytologic specimens obtained in the clinic and at surgery and from histologic specimens obtained at surgery were correlated positively. CONCLUSIONS: Consistent specimens that were prepared using the LBC method facilitated multiple immunocytochemical analyses. Endometrial cytology with the LBC method was useful for predicting the prognosis of patients with endometrial carcinoma before therapy.