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Gestational choriocarcinoma accounts for 5% of gestational trophoblastic neoplasms. Approximately 50%, 25%, and 25% of gestational choriocarcinoma occur after molar pregnancies, term pregnancies, and other gestational events, respectively. The FIGO scoring system categorizes patients into low (score 0 to 6) and high risk (score 7 or more) choriocarcinoma. Single-agent and multi-agent chemotherapy are used in low- and high-risk patients, respectively. Chemotherapy for localized disease has a goal of eradication of disease without surgery and is associated with favorable prognosis and fertility preservation. Most patients with gestational choriocarcinoma are cured with chemotherapy; however, some (<5.0%) will die as a result of multi-drug resistance, underscoring the need for novel approaches in this group of patients. Although there are limited data due to its rarity, the treatment response with immunotherapy is high, ranging between 50-70%. Novel combinations of immune checkpoint inhibitors with targeted therapies (including VEGFR-2 inhibitors) are under evaluation. PD-L1 inhibitors are considered a potential important opportunity for chemo-resistant patients, and to replace or de-escalate chemotherapy to avoid or minimize chemotherapy toxicity. In this review, the Rare Tumor Working Group and the European Organization for Research and Treatment of Cancer evaluated the current landscape and further perspective in the management of patients diagnosed with gestational choriocarcinoma., Competing Interests: Competing interests: Competing interests not related to the topic of this investigation: GB: Novartis AG Pharma (C/A, H), Italian Ministry of Health (RG); NC: AstraZeneca (C/A, SH), Seattle Genetics (C/A, SH), MSD (SAB), Mersana (C/A, SH), eTheRNA immunotherapies NV (C/A, SH), Roche (travel expenses), Genmab (travel expenses), Amgen (travel expenses). IR-C: honoraria from AstraZeneca, Clovis, GSK/Tesaro, and PharmaMar; consulting/advisory board fees from AstraZeneca, Roche, Clovis, GSK/Tesaro, Genmab, PharmaMar, MSD, Mersana, Deciphera, OncXea, Esai, BMS, Novartis, and Pfizer; research funding from MSD; travel expenses from AstraZeneca, GSK, and Roche. YS: AstraZeneca (CA), GSK (CA). PW: Amgen (SH, RF, SAB), AstraZeneca (SH, RF, H, SAB), Clovis (SH, RF, SAB), Eisai (SH, SAB), GSK (SH, SAB), Lilly (SH, SAB), MSD (SH, RF, SAB), Novartis (SH, RF, SAB), Pfizer (SH, RF, SAB), Roche (SH, RF, H, SAB), TEVA (SH, SAB). NYLN: AstraZeneca (SH), Janssen (SH). KT: AstraZeneca (SH), Chugai (SH, RF), Eisai (SH), MSD (SH), Mochida (SH), Takeda (SH). RLC: Leadership: Onxeo; Stock and Other Ownership Interests: McKesson; Consulting or Advisory Role: Clovis Oncology, Genentech/Roche, AstraZeneca/MedImmune, Genmab, Tesaro, OncoMed, Sotio, Oncolytics, AbbVie/Stemcentrx, ImmunoGen, AbbVie, Agenus, Novocure, Merck, OncXerna Therapeutics, Alkermes, Gradalis, Regeneron; Research Funding: AstraZeneca/MedImmune, Esperance Pharmaceuticals, Array BioPharma, Clovis Oncology, Johnson & Johnson, Merck, Roche/Genentech, Abbott/AbbVie, ImmunoGen (Inst), Mirati Therapeutics (Inst), Amgen (Inst), Pfizer (Inst), Lilly (Inst), Regeneron (Inst); Travel, Accommodations, Expenses: Merck, AstraZeneca/MedImmune, Array BioPharma, Clovis Oncology, Roche/Genentech, Research to Practice, GOG Foundation, Sotio, Vaniam GroupTE: Takeda (SH), Astra Zeneca (SH), Eisai (SH), Chugai Pharma (SH, RF), MSD (SH), Mochida (SH). DL: AstraZeneca (H, CA), Clovis (H, CA, RF), GSK/Tesaro (H, CA), Roche (CA), Genmab (CA), PharmaMar (CA, RF), MSD (CA, RF), Esai (CA), Merck Serono (CA), Novartis (CA), and PharmaMar (H); consulting/advisory board fees from AstraZeneca, Roche, Clovis, GSK/Tesaro. NC, advisory board membership for AstraZeneca, Clovis Oncology, Eisai, GSK, Immunogen, Mersana, MSD/Merck, Nuvation Bio, Onxerna, Pfizer, Pieris, Roche; fees as an invited speaker for AstraZeneca, Novartis, Clovis Oncology, GSK, MSD/Merck; institutional research grants from AstraZeneca, and Roche. BJM: AstraZeneca (SH, SAB), GSK (SH, SAB), Incyte (SAB), Merck (SH, SAB), Roche/Genentech (SH, SAB), Eisai (SAB), GOG-Foundation (E), US Oncology (E)., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Since the National Cancer Institute (NCI) alert of concurrent chemoradiotherapy, radiotherapy has been changed from external beam radiotherapy plus brachytherapy to platinum-based concurrent chemoradiotherapy. Therefore, concurrent chemoradiotherapy plus brachytherapy has become a standard treatment for locally advanced cervical cancer. Simultaneously, definitive radiotherapy has been changed gradually from external beam radiotherapy plus low-dose-rate intracavitary brachytherapy to external beam radiotherapy plus high-dose-rate intracavitary brachytherapy. Cervix cancer is uncommon in developed countries; hence, international collaborations have been critical in large-scale clinical trials. The Cervical Cancer Research Network (CCRN), created from the Gynecologic Cancer InterGroup (GCIG), has investigated various concurrent chemotherapy regimens and sequential methods of radiation and chemotherapy. Most recently, many clinical trials of combining immune checkpoint inhibitors with radiotherapy have been ongoing for sequential or concurrent settings. During the last decade, the method of standard radiation therapy has changed from three-dimensional conformal radiation therapy to intensity-modulated radiation therapy for external beam radiotherapy and from two-dimensional to three-dimensional image-guided approaches for brachytherapy. Recent improvements include stereotactic ablative body radiotherapy and MRI-guided linear accelerator (MRI-LINAC) using adaptive radiotherapy. Here we review the current progress of radiation therapy during the last two decades., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2023. Re-use permitted under CC BY. Published by BMJ.)

Endometrial carcinosarcoma is a rare and aggressive high-grade endometrial carcinoma with secondary sarcomatous trans-differentiation (conversion theory). The clinical presentation and diagnostic work-up roughly align with those of the more common endometrioid counterpart, although endometrial carcinosarcoma is more frequently diagnosed at an advanced stage. Endometrial carcinosarcoma is not a single entity but encompasses different histological subtypes, depending on the type of carcinomatous and sarcomatous elements. The majority of endometrial carcinosarcomas are characterized by p53 abnormalities. The proportion of POLE and microsatellite instablity-high (MSI-H) is directly related to the epithelial component, being approximately 25% and 3% in endometrioid and non-endometrioid components.The management of non-metastatic disease is based on a multimodal approach with optimal surgery followed by (concomitant or sequential) chemotherapy and radiotherapy, even for early stages. Palliative chemotherapy is recommended in the metastatic or recurrent setting, with carboplatin/paclitaxel doublet being the first-line regimen. Although the introduction of immunotherapy plus/minus a tyrosine kinase inhibitor shifted the paradigm of treatment of patients with recurrent endometrial cancer, patients with endometrial carcinosarcoma were excluded from most studies evaluating single-agent immunotherapy or the combination. However, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved the use of pembrolizumab and lenvatinib in endometrial cancer (all histotypes) after progression on chemotherapy and single-agent immunotherapy in MSI-H cancers. In the era of precision medicine, emerging knowledge on molecular endometrial carcinosarcoma is opening new promising therapeutic options for more personalized treatment. The present review outlines state-of-the-art knowledge and future directions for patients with endometrial carcinosarcoma., Competing Interests: Competing interests: GB: Novartis AG Pharma (C/A, H), Italian Ministry of Health (RG); NC: AstraZeneca (C/A, SH), Seattle Genetics (C/A, SH), MSD (SAB), Mersana (C/A, SH), eTheRNA immunotherapies NV (C/A, SH), Roche (travel expenses), Genmab (travel expenses), Amgen (travel expenses). IR-C: honoraria from AstraZeneca, Clovis, GSK/Tesaro, and PharmaMar; consulting/advisory board fees from AstraZeneca, Roche, Clovis, GSK/Tesaro, Genmab, PharmaMar, MSD, Mersana, Deciphera, OncXea, Esai, BMS, Novartis, and Pfizer; research funding from MSD; travel expenses from AstraZeneca, GSK, and Roche. YS: AstraZeneca (CA), GSK (CA). PW: Amgen (SH, RF, SAB), AstraZeneca (SH, RF, H, SAB), Clovis (SH, RF, SAB), Eisai (SH, SAB), GSK (SH, SAB), Lilly (SH, SAB), MSD (SH, RF, SAB), Novartis (SH, RF, SAB), Pfizer (SH, RF, SAB), Roche (SH, RF, H, SAB), TEVA (SH, SAB). NYLN: AstraZeneca (SH), Janssen (SH). KT: AstraZeneca (SH), Chugai (SH, RF), Eisai (SH), MSD (SH), Mochida (SH), Takeda (SH). TE: Takeda (SH), Astra Zeneca (SH), Eisai (SH), Chugai Pharma (SH, RF), MSD (SH), Mochida (SH). DL: AstraZeneca (H, CA), Clovis (H, CA, RF), GSK/Tesaro (H, CA), Roche (CA), Genmab (CA), PharmaMar (CA, RF), MSD (CA, RF), Esai (CA), Merck Serono (CA), Novartis (CA), and PharmaMar (H); consulting/advisory board fees from AstraZeneca, Roche, Clovis, GSK/Tesaro. DMP: AstraZeneca (CA, SH, SAB), GSK (CA, SH, SAB). NRA-R: NIH/NCI Cancer Center support grant P30 CA008748 (F). HD: Roche (CA, SH, SAB), Pfizer (CA, SH, SAB), AstraZeneca (SH, SAB), Lily (SAB), GSK (SAB), Novartis (SH), Pharmamar (SH); BJM: AstraZeneca (SH, SAB), GSK (SH, SAB), Incyte (SAB), Merck (SH, SAB), Roche/Genentech (SH, SAB), Eisai (SAB), GOG-Foundation (E), US Oncology (E)., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Clear cell endometrial carcinoma represents an uncommon and poorly understood entity. Data from molecular/genomic profiling highlighted the importance of various signatures in assessing the prognosis of endometrial cancer according to four classes of risk (POLE mutated, MMRd, NSMP, and p53 abnormal). Unfortunately, data specific to clear cell histological subtype endometrial cancer are lacking. More recently, data has emerged to suggest that most of the patients (more than 80%) with clear cell endometrial carcinoma are characterized by p53 abnormality or NSMP type. This classification has important therapeutic implications. Although it is an uncommon entity, clear cell endometrial cancer patients with POLE mutation seem characterized by a good prognosis. Chemotherapy is effective in patients with NSMP (especially in stage III and IV) and patients with p53 abnormal disease (all stages). While, preliminary data suggested that patients with MMRd are less likely to benefit from chemotherapy. The latter group appears to benefit much more from immune checkpoint inhibitors: recent data from clinical trials on pembrolizumab plus lenvatinib and nivolumab plus cabozantinib supported that immunotherapy plus tyrosine kinase inhibitors (TKI) would be the most appropriate treatment for recurrent non-endometrioid endometrial cancer (including clear cell carcinoma) after the failure of platinum-based chemotherapy. Moreover, ongoing clinical trials testing the anti-tumor activity of innovative products will clarify the better strategies for advanced/recurrent clear cell endometrial carcinoma. Further prospective evidence is urgently needed to better characterize clear cell endometrial carcinoma., Competing Interests: Declaration of Competing Interest Giorgio Bogani: Novartis AG Pharma (C/A, H), Italian Ministry of Health (RG). Nicole Concin: AstraZeneca (C/A, SH), Seattle Genetics (C/A, SH), MSD (SAB), Mersana (C/A, SH), eTheRNA immunotherapies NV (C/A, SH), Roche (travel expenses), Genmab (travel expenses), Amgen (travel expenses). Isabelle Ray-Coquard: Honoraria from AstraZeneca, Clovis, GSK/Tesaro and PharmaMar; Consulting/advisory board fees from AstraZeneca, Roche, Clovis, GSK/Tesaro, Genmab, PharmaMar, MSD, Mersana, Deciphera, OncXea, Esai, BMS, Novartis and Pfizer; Research funding from MSD;Travel expenses from AstraZeneca, GSK and Roche. Yakir Segev: AstraZeneca (CA), GSK (CA). Pauline Wimberger: Amgen (SH, RF, SAB), AstraZeneca (SH, RF, H, SAB), Clovis (SH, RF, SAB), Eisai (SH, SAB), GSK (SH, SAB), Lilly (SH, SAB), MSD (SH, RF, SAB), Novartis (SH, RF, SAB), Pfizer (SH, RF, SAB), Roche (SH, RF, H, SAB), TEVA (SH, SAB). Natalie YL Ngoi: AstraZeneca (SH), Janssen (SH). Kazuhiro Takehara: AstraZeneca (SH), Chugai (SH, RF), Eisai (SH), MSD (SH), Mochida (SH), Takeda (SH). Takayuki Enomoto: Takeda (SH), Astra Zeneca (SH), Eisai (SH), Chugai Pharma (SH, RF), MSD (SH), Mochida (SH). Domenica Lorusso: AstraZeneca (H, CA), Clovis (H, CA, RF), GSK/Tesaro (H, CA), Roche (CA), Genmab (CA), PharmaMar (CA, RF), MSD (CA, RF), Esai (CA), Merck Serono (CA), Novartis (CA) and PharmaMar (H); Consulting/advisory board fees from AstraZeneca, Roche, Clovis, GSK/Tesaro. Diane Provencher: AstraZeneca (CA, SH, SAB), GSK (CA, SH, SAB). Nadeem Abu-Rustum: NIH/NCI Cancer Center Support Grant P30 CA008748 (F). Hannelore Denys: Roche (CA, SH, SAB), Pfizer (CA, SH, SAB), AstraZeneca (SH, SAB), Lily (SAB), GSK (SAB), Novartis (SH), Pharmamar (SH). Bradley J Monk: AstraZeneca (SH, SAB), GSK (SH, SAB), Incyte (SAB), Merck (SH, SAB), Roche/Genentech (SH, SAB), Eisai (SAB), GOG-Foundation (E), US Oncology (E). The other authors indicated no financial relationship. Legend: consulting/advisory relationship (CA); speaker honoraria (SH); honoraria (H); research funding (RF); ownership interest (OI); intellectual propriety/patent holder (IP); scientific advisory board (SAB)., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives　We investigated the participation and detection rates of cervical lesions in cervical screening non-attenders offered HPV (human papillomavirus) self-sampling with cytology triage.Methods　From 2016 to 2018, HPV self-sampling was routinely offered as an option, along with cytology, to all non-attenders in Ebetsu City, Japan. The primary endpoints were ≥CIN2 and ≥CIN3 detection rates, and secondary endpoints were abnormal cytology rates and follow-up compliance.Results　Overall, recall invitations were mailed to 6,116 non-attenders, with a response rate of 15.9% (cytology: 6.5%, HPV testing: 9.4%). Of the responders to undergo HPV self-sampling, 11.7% had a positive result and were referred to cytology triage. Moreover, ≥CIN2 and ≥CIN3 detection rates were 1.7% and 0.9%, respectively, in the HPV self-sampling group, and 1.0% and 0.8%, respectively, in the cytology group, showing no statistically significant differences. In those who underwent cytology triage following an HPV positive test, ≥CIN2 and ≥CIN3 detection rates were 23.8% and 11.9%, respectively, which was significantly higher than those who only underwent cytology alone.Conclusion　HPV self-sampling followed by cytology triage is highly effective at detecting high grade disease in non-attenders. Thus, multi-municipality-based studies to standardize processes involving this method are warranted. Furthermore, HPV self-sampling could be a promising method for inviting non-attenders who have difficulty undergoing cervical screening in the COVID-19 pandemic era.

Serous endometrial cancer represents a relative rare entity accounting for about 10% of all diagnosed endometrial cancer, but it is responsible for 40% of endometrial cancer-related deaths. Patients with serous endometrial cancer are often diagnosed at earlier disease stage, but remain at higher risk of recurrence and poorer prognosis when compared stage-for-stage with endometrioid subtype endometrial cancer. Serous endometrial cancers are characterized by marked nuclear atypia and abnormal p53 staining in immunohistochemistry. The mainstay of treatment for newly diagnosed serous endometrial cancer includes a multi-modal therapy with surgery, chemotherapy and/or radiotherapy. Unfortunately, despite these efforts, survival outcomes still remain poor. Recently, The Cancer Genome Atlas (TCGA) Research Network classified all endometrial cancer types into four categories, of which, serous endometrial cancer mostly is found within the "copy number high" group. This group is characterized by the increased cell cycle deregulation (e.g., CCNE1, MYC, PPP2R1A, PIKCA, ERBB2 and CDKN2A) and TP53 mutations (90%). To date, the combination of pembrolizumab and lenvatinib is an effective treatment modality in second-line therapy, with a response rate of 50% in advanced/recurrent serous endometrial cancer. Owing to the unfavorable outcomes of serous endometrial cancer, clinical trials are a priority. At present, ongoing studies are testing novel combinations of various targeted and immunotherapeutic agents in newly diagnosed and advanced/recurrent endometrial cancer - an important strategy for serous endometrial cancer, whereby tumors are usually p53+ and pMMR, making response to PD-1 inhibitor monotherapy unlikely. Here, the rare tumor working group (including members from the European Society of Gynecologic Oncology (ESGO), Gynecologic Cancer Intergroup (GCIG), and Japanese Gynecologic Oncology Group (JGOG)), performed a narrative review reporting on the current landscape of serous endometrial cancer and focusing on standard and emerging therapeutic options for patients affected by this difficult disease., (Copyright © 2021. Published by Elsevier Inc.)

Objective: The objective of this study was to calculate the positive rate and overall concordance rate of high-risk human papillomavirus (hrHPV) test and cytology using self-sampled and physician-sampled cervicovaginal tests and to compare both specimens., Methods: In collaboration with 3 private hospitals in Sapporo city, 300 women visiting these organizations were enrolled in the study by previously signing an informed consent. From these women, both types of samples (self-obtained and physician-sampled) were obtained at the same time. HrHPV test and cytology were performed on both specimens, and the positive rate and overall concordance rate were calculated to compare both specimens., Results: HrHPV-positive women were 13.7% in physician-sampled specimens and 14.7% in self-sampled specimens, with an overall concordance rate of 96.3% (95% confidence interval [CI]: 94-98%). On the other hand, the positive rate of the cases higher than or equal to atypical squamous cells of undetermined significance (ASCUS) on cytology was different between both groups, that is, 12.3% in physician-obtained and 5.3% in self-sampled specimens; the overall concordance rate was 90.7% (95% CI: 87-94%), indicating an apparent decrease in the positive rate of cytology in self-obtained specimens., Conclusion: HrHPV test and cytology were performed on parallel samples obtained by the patients with a self-sampling tool and by the physician. The positive rate of cytology was considerably different between these specimens, while almost equivalent results were obtained for hrHPV test in both specimens. It was concluded that hrHPV test may be safely and accurately performed on self-obtained cervicovaginal samples by the help of a self-sampling device in the Japanese population as a first screening tool, with equivalent results to physician-obtained specimens., (© 2020 S. Karger AG, Basel.)

The Japanese Gynecologic Oncology Group (JGOG) is leading Japan in the treatment of gynecological malignancies. The JGOG consists of three treatment committees focusing on uterine cervical cancer, endometrial cancer, and ovarian cancer. Each committee makes efforts to improve treatment and diagnosis. In addition, the Supportive and Palliative Care Committee was established in 2015. Novel studies of supportive care and palliative care have been initiated by this committee. Furthermore, surveys about not only treatment results such as overall survival rates but also quality of life (QOL) and cost-effectiveness assessments are performed by the ovarian cancer committee. Improvements of patients' QOL in the treatment of gynecological malignancies were divided into three concepts as follows: QOL associated with cancer treatment, health care after cancer therapy, and progression of cancer. In this review, we report the contributions and future plans for the improvement of QOL in patients with gynecological malignancies.

Objective: Cervical cancer is responsible for more than a quarter of a million deaths globally each year, mostly in developing countries, making therapeutic advances in all health care settings a top priority. The Gynecologic Cancer InterGroup (GCIG) is a worldwide collaboration of leading national research groups that develops and promotes multinational trials in gynecologic cancer. In recognition of the pressing need for action, the GCIG convened an international meeting with expert representation from the GCIG groups and selected large sites in low- and middle-income countries., Methods: The focus was to develop a consensus on several concepts for future clinical trials, which would be developed and promoted by the GCIG and launched with major international participation. The first half of the meeting was devoted to a resume of the current state of the knowledge and identifying the gaps in need of new evidence, validating control arms for present and future clinical trials and identifying national and international barriers for studies of cervix cancers. The second half of the meeting was concerned with achieving consensus on a path forward., Results and Conclusions: There were 5 principal outcomes as follows: first, a proposal to expand fertility-preserving options with neoadjuvant chemotherapy; second, validation of the assessment of sentinel lymph nodes using minimally invasive surgery with an emphasis on identification and management of low-volume metastasis, such as isolated tumor cells and micrometastasis; third, evaluation of hypofractionation for palliative and curative radiation under the umbrella of the GCIG Cervix Cancer Research Network; fourth, adding to the advances in antiangiogenesis therapy in the setting of metastatic disease; and fifth, developing a maintenance study among women at high risk of relapse. The latter 2 systemic interventions could study PI3K (phosphatidylinositol-3-kinase) inhibitors, immunotherapy, anti-human papillomavirus approaches, or novel antiangiogenic agents/combinations.

Objectives: Uterine serous carcinoma (USC) represents a rare and aggressive histologic subtype of endometrial cancer, associated with a poor prognosis. This article critically reviews the literature pertinent to the epidemiology, pathology, molecular biology, diagnosis, management, and perspectives of patients with USC., Methods: As one of a series of The Gynecologic Cancer InterGroup (GCIG) Rare Tumor Working Group in London, November 2013, we discussed about USC many times with various experts among international GCIG groups., Results: Both USC and approximately 25% of high-grade endometrioid tumors represent extensive copy number alterations, few DNA methylation changes, low estrogen and progesterone levels, and frequent P53 mutations. Uterine serous carcinoma shares molecular characteristics with ovarian serous and basal-like breast carcinomas. In addition to optimal surgery, platinum- and taxane-based chemotherapy should be considered in the treatment of both early- and advanced-stage disease. The combination of radiation and chemotherapy appears to be associated with the highest survival rates. The role of radiation therapy in the management of this disease, with a high propensity for distant failures, remains elusive., Conclusions: Uterine serous carcinoma is a unique and biologically aggressive subtype of endometrial cancer and should be studied as a distinct entity. Futures studies should identify the optimized chemotherapy and radiation regimens, sequence of therapy and schedule, and the role of targeted biologic therapy.

The Gynecological Cancer Intergroup (GCIG) has previously reached consensus regarding the criteria that should be used in clinical trial protocols to define progression-free survival after first-line therapy as well as the criteria to define response to treatment in recurrent disease using the serum marker CA 125 and has specified the situations where these criteria should be used. However, the publications did not include detailed definitions, nor were they written to accommodate the new version of Response Evaluation Criteria In Solid Tumors (RECIST) criteria (version 1.1) now available. Thus, we recommend that the definitions described later in detail are incorporated into clinical trial protocols to maintain consistency. The criteria for defining progression are now acceptable in clinical trials of recurrent disease as they have since been validated (Pujade-Lauraine, personal communication, 2010). The GCIG requests that data from all clinical trials using these definitions are made available to GCIG trial centers so that continual validation and improvement can be accomplished. These definitions were developed from analyzing patients receiving cytotoxic chemotherapy and have not yet been validated in patients receiving molecular targeting agents.

Endometrial carcinoma is one of the most common gynecologic malignancies in Japan and its incidence has increased recently. Although surgery is the cornerstone of the management of patients with endometrial cancer, there is significant variation in Japan with regard to the type of hysterectomy employed. Additionally, it remains controversial whether full nodal staging is required in all patients. Furthermore, adjuvant therapy differs between Japan and Western countries. To delineate clearly the standard of care for endometrial cancer treatment in Japan, the guidelines for the treatment of endometrial cancer were published in 2006 and revised in 2009. The 2009 edition included topics not addressed in the previous edition including the treatment of mesenchymal tumors, for example leiomyosarcoma, and sections covering the treatment of serous and clear-cell adenocarcinoma. These guidelines are composed of nine chapters and include nine algorithms. The guidelines also contain fifty-one clinical questions (CQs) and each CQ consists of recommendations, background, explanations, and references. The treatment recommendations herein are tailored to reflect current Japanese clinical practice and ensure equitable care for all Japanese women diagnosed with endometrial cancer.

Introduction: Ovarian clear cell carcinoma (CCC) is regarded as grade 3 tumor, and the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines recommend adjuvant chemotherapy for the tumor even at stage IA. However, CCC often showed chemo-resistant phenotype, and the effect of adjuvant chemotherapy still remained uncertain., Methods: Clear cell carcinoma cases treated at collaborating institutions during the period 1992-2005 were retrospectively identified. After a central pathological review, survival analysis was estimated by the Kaplan-Meier method, and prognostic factors were evaluated using a Cox regression model., Results: Among 219 patients with stage I CCC, 195 patients received adjuvant chemotherapy (C+) and 24 patients (C-) did not. The C+ group had 77 pT1a and 118 pT1c cases, and the C- group included 18 pT1a and 6 pT1c tumors (P < 0.001). The median age was 52 years in the C+ group and 57 years in C- group (P = 0.04). During the median follow-up period of 48 months (range, 7-160 years), relapse was observed in one patient (4%) in the C- group and in 35 patients (18%) in the C+ group. There were no statistical differences of progression-free survival and overall survival between the C+ and the C- groups. Multivariate analysis revealed that peritoneal cytology status (P = 0.02) and pT status (P = 0.04) were independent prognostic factors for progression-free survival; however, adjuvant chemotherapy was not a prognostic factor (P = 0.80)., Conclusions: Although the present study was a limited retrospective investigation, it suggested that adjuvant chemotherapy had little impact on the survival of stage I CCC patients. Further strategy, such as a molecular targeting agent, is needed to improve survival of CCC, especially in cases with positive peritoneal washing.

Disease burden of cervical cancer in Asia was summarized. Human papillomavirus 16 is the most oncogenic human papillomavirus type. Korea's national cervical cancer screening program targets women aged 30 or over, with coverage of almost 80%. Japan has a long history (50 years) of cervical cancer screening, and cytological screening programs have reduced the incidence/mortality of cervical cancer by 70%. But, recent cervical cancer screening coverage is ∼24%. Modeling suggested that vaccination of all 12-year-old girls would reduce cervical cancer cases by 73% in Japan. India has no cervical cancer screening program, as well as a serious lack of awareness in the general population, medical professionals and policy-makers. A realistic, affordable approach would be a low-volume, once-in-a-lifetime human papillomavirus-based screening program. In Australia, the national cervical cancer program has been very successful in reducing the incidence and mortality of cervical cancer. Australia was the first country to implement free, national human papillomavirus immunization (April 2007), expected to reduce human papillomavirus 16 infections by 56% in 2010 and 92% in 2050. A comparison of the UK and Japan was demonstrated that in the UK, cervical cancer screening and human papillomavirus vaccination uptakes are high because the government provides adequate education/funding. The Japanese government needs to put more emphasis on women's health and preventative medicine. Our conclusion and recommendations are that heightened public awareness of cervical cancer prevention, focusing on screening and vaccination will lead to improved survival and a better quality of life.

Objective: To determine the current status of postoperative management of endometrial cancer in Japan by surveying members of the Japanese Gynecologic Oncology Group (JGOG)., Method: We conducted an original mail survey regarding the status of postoperative treatment including indication criteria, treatment procedures, and chemotherapeutic regimen among all 226 active member institutions of the JGOG., Results: A total of 199 institutions (88.1%) responded to the survey. A total of 4063 patients with endometrial cancer were treated at the member institutions of the JGOG over a year. As adjuvant therapy, chemotherapy (79.9%) was significantly (p<0.01) preferred over radiotherapy (13.0%) or hormonal therapy (7.1%). Furthermore, more than 50% of respondent institutions performed adjuvant therapy when patients exhibited International Federation of Gynecology and Obstetrics (FIGO) stage IB/G3/positive lymph-vascular space invasion (LVSI)/endometrioid adenocarcinoma or FIGO IB/G3/non-endometrioid histology, and more than 90% institutions administered adjuvant therapy when patients exhibited FIGO IC/G3/positive LVSI/endometrioid adenocarcinoma or FIGO stage IC/G3/regardless of LVSI/non-endometrioid histology. A combination of paclitaxel and carboplatin was the most preferred first-line regimen for adjuvant chemotherapy followed by combination regimens consisting of anthracycline and platinum., Conclusion: The present survey provides relevant information regarding the current status of adjuvant therapy in Japanese patients with endometrial cancer.

Pure-type clear cell carcinoma (CCC) has been recognized as a distinct subtype of ovarian cancer, showing resistance to conventional platinum-based chemotherapy and resulting in poor prognosis. The aim of the study was to evaluate the effects of complete surgical staging procedures for early-stage CCC patients in a retrospective multi-institutional analysis. During the period 1992 to 2002, a total of 199 patients with pT1 M0 CCC were identified. Survival analysis was estimated by Kaplan-Meier methods, and prognostic factors were evaluated using a Cox regression model. Among pT1 M0 tumors, retroperitoneal lymph node status was negative in 125 cases (pN0, 63%), positive in 10 cases (pN1, 5%), and unknown in 64 cases (pNx, 32%). Progression-free survival of pN1 was significantly worse than that of pN0 (P < 0.05), whereas there was no significant difference between pN1 and pNx. There was no significant difference of overall survival (OS) among the 3 groups. Multivariate analysis revealed that peritoneal cytology status was the only independent prognostic factor for progression-free survival (P = 0.04), but completion of surgical staging procedures was not a prognostic factor. There was no significant prognostic factor for OS. Our study implied that complete surgical staging enabled us to distinguish a high-risk group of recurrence in pT1 M0 CCC; however, the procedure could not improve OS. Although the study was a limited retrospective study, the impact of peritoneal cytology status was more important than complete surgical staging procedure in CCC patients. More effective treatment modality was warranted, especially for CCC cases positive for malignant peritoneal cytology.

Background: The long-term efficacy and safety of docetaxel/cisplatin as first-line chemotherapy in Japanese patients was evaluated in order to find an optional regimen for ovarian cancer., Patients and Methods: Women with surgically resected stage Ic-IV epithelial ovarian cancer were treated with docetaxel 70 mg/m2 and cisplatin 60 mg/m2 every 4 weeks., Results: Ninety women were enrolled of whom 89 (median age, 54 years) received a median of 6 cycles (range 1 to 9). With a median 38 months'follow-up, median progression-free survival was 28 months (95% lower confidence interval, 24 months) in 60 patients with stage III-IV disease. The overall response rate for 20 patients was 45%. Neutropenia was the most common (67%) grade 3/4 toxicity. Major grade 3/4 nonhaematological toxicities were gastrointestinal toxicities (< or = 11%) and fatigue (8%). No grade 3/4 neurotoxicity was observed., Conclusion: The combination of docetaxel/cisplatin is a regimen with favourable progression-free survival for ovarian cancer.

Objective: To establish an optimal adjuvant therapy for intermediate- and high-risk endometrial cancer patients, we conducted a multi-center randomized phase III trial of adjuvant pelvic radiation therapy (PRT) versus cyclophosphamide-doxorubicin-cisplatin (CAP) chemotherapy in women with endometrioid adenocarcinoma with deeper than 50% myometrial invasion., Methods: Among 385 evaluated patients, 193 patients received PRT and 192 received CAP. The PRT group received at least 40 Gy. The CAP group received cyclophosphamide (333 mg/m2), doxorubicin (40 mg/m2) and cisplatin (50 mg/m2) every 4 weeks for 3 or more courses., Results: No statistically significant differences in progression-free survival (PFS) and overall survival (OS) were observed. The 5-year PFS rates in the PRT and CAP groups were 83.5% and 81.8% respectively, while the 5-year OS rates were 85.3% and 86.7% respectively. These rates were also not significantly different in a low- to intermediate-risk group defined as stage IC patients under 70 years old with G1/2 endometrioid adenocarcinoma. However, among 120 patients in a high- to intermediate-risk group defined as (1) stage IC in patients over 70 years old or with G3 endometrioid adenocarcinoma or (2) stage II or IIIA (positive cytology), the CAP group had a significantly higher PFS rate (83.8% vs. 66.2%, log-rank test P=0.024, hazard ratio 0.44) and higher OS rate (89.7% vs. 73.6%, log-rank test P=0.006, hazard ratio 0.24). Adverse effects were not significantly increased in the CAP group versus the PRT group., Conclusion: Adjuvant chemotherapy may be a useful alternative to radiotherapy for intermediate-risk endometrial cancer.

Background: Irinotecan hydrochloride, a topoisomerase I inhibitor, has been preliminarily recognized as an effective agent against clear cell carcinoma of the ovary (CCC), but there are few clinical data. Our aim was to compare progression-free survival (PFS) between patients treated with irinotecan hydrochloride and cisplatin (CPT-P) and those with treated with paclitaxel and carboplatin (TC)., Methods: One hundred and seventeen patients at International Federation of Gynecology and Obstetrics (FIGO) stages Ic (ascites/malignant washing) - IV were identified by scanning the medical records of ten Japanese hospitals. After complete surgical staging procedures including lymphadenectomy, 35 patients received CPT-P and 82 patients received TC. The PFS and overall survival of the two groups were compared using the Kaplan-Meier method., Results: There was no significant difference in median age, performance status, FIGO stage, rate of optimal cytoreduction, or follow-up period between the CPT-P and TC groups. Two-year and 5-year PFS was 48% and 40%, respectively, in the TC group and 55% and 55%, respectively, in the CPT-P group (P = 0.31). Multiple regression analysis revealed that only residual tumor was an independent prognostic factor for PFS (P < 0.01)., Conclusion: CPT-P showed a potential therapeutic effect, at least no less than that of TC therapy. Although there was no significant survival benefit in the present retrospective analysis, we recommend that the CPT-P regimen be evaluated in a larger, prospective, clinical trial.

Objective: We investigated the current status of surgical procedures for endometrial carcinoma in Japan by surveying members of the Japan Gynecologic Oncology Group (JGOG)., Methods: A mail survey focusing on hysterectomy procedures, indications for radical hysterectomy, methods for detecting pelvic (PEN) and para-aortic lymph node (PAN) status, and indications for PAN dissection/biopsy, was sent to all 215 authorized JGOG member institutions., Results: A total of 139 (57.2%) members responded to the survey. Abdominal total hysterectomy (TAH) was utilized by 35.3% of institutions and Piver class II extended hysterectomy by 30.2%. In 35.5% of institutions, hysterectomy procedures were selectively employed based on tumor-related factors. Radical hysterectomy (RH) was utilized by 29.5% of institutions; TAH was used significantly more frequently by specialist hospitals while RH was significantly less commonly utilized by specialist hospitals compared with university hospitals and general hospitals. PEN dissection was routinely utilized by 97.8% of institutions. In 93.5% of institutions, PAN dissection/biopsy was used either routinely (12.2%) or selectively based on tumor-related factors (81.2%). In 6.5% of institutions, PAN dissection/biopsy has never been employed., Conclusion: The status of surgical procedures for the treatment of endometrial cancer is still not standardized. However, TAH, bilateral salpingo-oophorectomy, PEN dissection, and PAN dissection/biopsy in selected cases are recent surgical procedures used for the treatment of endometrial cancer in Japan. Clinical trials to determine the survival benefit of the different surgical procedures should be developed to determine the standard surgical procedures to be used for the treatment of endometrial cancer.

Clear cell carcinoma (CCC) of the ovary has distinct characteristics showing resistance to conventional platinum-based regimen. Our aim was to evaluate the effects of combination therapy with irinotecan hydrochloride and cisplatin (CPT-P), comparing to regimen with paclitaxel and platinum (TP). We retrospective reviewed 172 patients with complete surgical staging procedures including lymphadenenctomy. Forty-six patients received CPT-P and 126 patients were treated with TP. Survival of the two groups was compared. Between CPT-P group and TP group, there was no significant difference in median age, performance status, FIGO stage, rate of optimal cytoreduction, and follow-up period. There was no significant difference in progression-free survival of patients with stage I tumors (p=0.95) and suboptimally debulked stage II-IV tumors (p=0.92). Although there was no significant difference of overall survival, progression-free survival of CPT-P group was significantly better than that of TP group in optimally debulked stage II-IV (p=0.03). Multiple regression survival analysis revealed CPT-P regimen (p=0.02) and residual tumor diameter (p<0.01) were both independent prognostic factors in stage II-IV tumors. The combination of CPT-P was shown to have a potential therapeutic benefit for advanced CCC of the ovary, especially for cases with optimal debulking surgery. However, this is a limited retrospective study, therefore we recommend that the CPT-P regimen be evaluated in a larger prospective study.

A 32-year-old Japanese woman was diagnosed as having stage Ib1 adenocarcinoma by diagnostic laser conization at a local hospital. She was admitted to our hospital for fertility-sparing treatment. A radical trachelectomy (RT) was performed using the laparoscopic vaginal procedure. The procedure was started with a laparoscopic pelvic lymphadenectomy. As the lymph nodes were tumor free, RT was carried out transvaginally. The excised uterine cervix and lymph nodes were pathologically negative for cancer. Eight months after the operation, the patient became pregnant without any artificial reproduction techniques. At 17 weeks of gestation, she was admitted to our hospital again for a threatened abortion. Continuous tocolytic treatment with ritodrine and daily administration of a granulocyte elastase inhibitor vaginal suppository were given. At 32 weeks of gestation, she underwent emergency cesarean section because of sudden premature rupture of the membranes. A girl weighing 1991 g was delivered, with Apgar scores of 7 and 8 at 1 and 5 min, respectively. Both the mother and the baby were discharged without trouble. This is the first successful case in Japan of delivery after vaginal RT for invasive uterine cervical cancer.

A pilot trial of combined chemotherapy with paclitaxel, doxorubicin and cisplatin was conducted in patients with advanced endometrial cancer. Between June 2000 and March 2002 8 patients were treated with combined chemotherapy, consisting of paclitaxel, 135 mg/m2; doxorubicin, 30 mg/m2; and cisplatin, 50 mg/m2 (TAP therapy). Patients received 3 to 5 courses of TAP therapy every 4 weeks. The major adverse effect was myelosuppression. All patients had grade 3 or 4 neutropenia, but did not have any severe infection with uncontrollable fever. Only 1 patient discontinued additional therapy due to grade 3 thrombocytopenia after 3 cycles. Grade 2 neurotoxicity occurred in 5 patients, but grade 3 was not observed. Among 5 patients with measurable tumors, 4 achieved partial response and 1 had no change of tumor size, indicating a response rate of 80.0%. We found that TAP therapy was feasible with G-CSF support and shows potential for high efficacy in advanced endometrial cancer.

Purpose: The purpose of this work was to explore the role of epigenetic inactivation of apoptotic pathways in ovarian cancer by examining the DNA methylation and expression status of four proapoptotic genes in primary ovarian cancers and cancer cell lines and to correlate those findings with the clinicopathological features of ovarian cancer patients., Experimental Design: Genomic DNA was isolated from 15 ovarian cancer cell lines, 80 primary ovarian cancer specimens, and 4 normal ovary specimens using phenol-chloroform extraction. The methylation status of the DNA was evaluated using combined bisulfite restriction analysis, gene expression was evaluated using reverse transcription-PCR, and histone acetylation was evaluated using chromatin immunoprecipitation., Results: Of the four proapoptotic genes studied, expression of TMS1/ASC was absent in six ovarian cancer cell lines. Dense methylation of the 5' region of TMS1/ASC was detected in cells not expressing TMS1/ASC. Treating methylated cells with 5-aza-deoxycytidine restored gene expression, confirming the role of methylation in silencing the gene. Chromatin immunoprecipitation revealed histone to be deacetylated in cells not expressing TMS1/ASC, indicating that histone deacetylation is also involved in silencing TMS1/ASC. Aberrant methylation of TMS1/ASC was detected in 15 of 80 ovarian cancer tissues (19%) but in none of the normal ovary specimens. Aberrant methylation of TMS1/ASC was observed significantly more often in clear cell-type ovarian cancers than in other tumor types (P < 0.0001)., Conclusions: Methylation-mediated silencing of TMS1/ASC confers a survival advantage to tumor cells by enabling them to escape apoptosis. The role for aberrant methylation in human ovarian tumorigenesis may be particularly important for ovarian cancers with the clear cell phenotype.

Ultrastructural characteristics of benign, low-malignant potential (LMP), and malignant ovarian tumors were investigated, considering the aspects of histologic subtypes and histologic grading. In addition, the histogenesis of ovarian cancer was histologically investigated in an attempt to elucidate whether malignant tumor was generated from benign or LMP tumor, or whether it was generated de novo from normal tissues. Although all the benign, LMP, and malignant tumors appeared to be derived from Mullerian duct in serous tumors, the origin of endometrioid or mucinous tumor could not be ultrastructurally clarified. However, there was ultrastructural similarity between benign and malignant tumors among serous, endometrioid, and mucinous tumors, and it was suggested that benign adenoma may be the developmental origin of malignant tumors regardless of the histologic subtype. In addition, the investigation of endometrioid tumors revealed that the differences of histologic grading in malignant tumors reflected the ultrastructural differences, and that G1 tumor had an ultrastructure that was more similar to that of benign and LMP tumors than to that of G2 tumor.

Objective: The aim of this study was to evaluate the clinicopathological features of uterine sarcoma in Hokkaido, Japan, between 1990 and 1999, and to identify prognostic factors of patients with such malignancies in this area and period., Methods: One hundred and six patients with histologically proven uterine sarcoma were evaluated retrospectively., Results: 93.5% of the patients with carcinosarcoma (CS) were diagnosed as having malignant disease preoperatively, while 65% of those with leiomyosarcoma (LMS) and 75% of those with endometrial stromal sarcoma (ESS) were preoperatively diagnosed as benign leiomyoma. When patients had no residual disease postoperatively, 5-year survival rates in patients with CS and LMS were 78.8 and 73.0%, respectively. ESS cases had a better prognosis (94.7% for stage I cases). In patients with early-stage sarcoma, pelvic lymphadenectomy and adjuvant chemotherapy, with or without cis-diamminedichloroplatinum, failed to show a survival benefit in both CS and LMS cases. Distant metastasis, myometrial invasion, and no residual disease at surgery were significantly associated with risk of death or recurrence in CS and LMS cases., Conclusion: Accurate preoperative diagnosis of uterine sarcoma was difficult, and no residual disease at surgery was the most important prognostic factor in patients with this disease. Postoperative adjuvant therapy had little effect on survival, especially in early-stage disease., (Copyright 2004 S. Karger AG, Basel)

Objective: A binary grading system has been proposed to assess the amount of solid growth, the pattern of invasion, and the presence of necrosis, and thereby divide endometrial endometrioid carcinomas into low- and high-grade tumors. We analyzed this system for predicting the prognosis, with respect to inter- and intraobserver reproducibility and treatment modalities., Methods: A total of 200 endometrial carcinomas, based on hysterectomy specimens, were graded according to the binary grading system, for comparison against The International Federation of Gynecology and Obstetrics (FIGO) system and nuclear grading., Results: Both inter- and intraobserver agreement using the binary grading system (kappa = 0.57; percent agreement: 82% and kappa = 0.62; 84%) were superior compared with the FIGO system (0.50; 60% and 0.62; 73%) and the nuclear grading (0.23; 49% and 0.43; 65%). Patients with early-stage low-grade tumors had a 98% rate for 5-year survival (5YS). Patients with early-stage high-grade tumors, and those with advanced-stage low-grade tumors, had respectively 86% to 87% rates for 5YS. But patients with advanced-stage high-grade tumors had a 49% rate for 5YS. In binary low-grade early-stage tumors, the patient outcome was better with no adjuvant therapy and chemotherapy, compared with other therapies., Conclusion: A binary grading system was superior to others in permitting greater reproducibility and predicting the prognosis of endometrial cancer patients., (Copyright (c) 2004 S. Karger AG, Basel)

Background: To understand the complicated network of paclitaxel (PTX)-induced apoptosis pathways and to elucidate mechanisms of drug resistance in ovarian cancer, we looked at PTX-induced apoptosis by using cDNA microarray. We also quantitated the changes in apoptosis-related proteins in the process of apoptosis., Methods: An ovarian cancer cell line KF, and its PTX-resistant clone KFTX, were treated with PTX or carboplatin (CBDCA). After exposure to PTX or CBDCA, the induction of apoptosis was examined by internucleosomal DNA fragmentation. Changes in mRNA expression after 12 h of exposure to PTX were studied using cDNA microarray and RT-PCR. Changes in P53 and Bcl-2 levels were also measured over 24 h by ELISA., Results: With increased doses of PTX or CBDCA, an increase in apoptosis was noted in both cell lines. cDNA microarray revealed that PTX treatment upregulated expression of caspase 1, 2, 3, 4, 6, 9, 10, their activator apaf-1, and stress reaction-related genes, gadd34, gadd153 in KF, although most of them were unchanged or downregulated in KFTX. bag-1 and hsc70 were markedly upregulated in KFTX. p53 and bcl-2 were not upregulated in either cell line. Results from protein studies also supported the cDNA microarray data., Conclusions: p53-independent mitochondrial pathways and stress-reaction-induced pathways play critical roles in PTX-induced apoptosis in ovarian cancer cells. Suppression of those pathways and upregulation of bag-1 and hsp-70 played an important role in acquiring resistance to PTX., (Copyright 2004 S. Karger AG, Basel)

Single nucleotide polymorphism (SNP) of the promoter region of MMP-1 (at -1607 bp) creates Ets binding sites, and correlations between this SNP and cancer susceptibility have been reported for various cancers. In this study, we genotyped the SNP in 23 cervical intraepithelial neoplasias (CIN) and 86 cervical cancer specimens. We found a correlation between promoter polymorphism and MMP-1 expression, and that this SNP was correlated with the clinical stage of cervical cancer. These findings suggested that SNP of MMP-1 promoter might influence the ability in cervical cancer invasion via transcriptional activity of this gene.

Objective: The aim of this study was to compare the usefulness of a new universal grading system for ovarian cancer proposed by Shimizu et al. (Cancer 82 (1998), 893; Gynecol. Oncol. 70 (1998), 2) with that of the FIGO grading system as a prognostic factor of ovarian cancer., Methods: We reviewed all paraffin-embedded tissues of epithelial ovarian cancer obtained from 130 women who underwent initial treatment including primary surgery in our hospital between January 1990 and December 2000. The scores of the specimens were obtained according to both the universal grading system and the FIGO grading system., Results: Both the FIGO grading system and the universal grading system worked as significant prognostic indicators. Patients with Grades 1 and 3 of the universal grading system had high and low 5-year survival rates, respectively, compared to those of the FIGO grading system. Inconsistencies in histologic grade between the FIGO and universal grading systems were observed in 22 patients. The positive rate of lymph node metastasis in patients with Grade 3 of the universal grading system was significantly high compared to those of the FIGO grading system (P = 0.03). Patients with Grade 3 of the universal grading system with residual tumor of not less than 2 cm in diameter were observed more frequently than those of the FIGO grading system. C4ONCLUSION: The universal grading system was superior to the FIGO grading system in terms of the prediction of malignancies such as the potential of lymph node metastasis and invasion and the adaptability to clear cell cancer.

The outcome and reproductive function were examined among patients with malignant ovarian germ cell tumors treated since 1980. Between 1980 and 2001, fertility-sparing surgery was performed in 26 women, 23 of whom received adjuvant chemotherapy. With a median follow-up of 66.6 months, all patients have been alive, with histological types of 6 immature teratomas, 8 dysgerminomas, 6 yolk sac tumors, and 6 mixed types. Clinical stages were involved of 17 early stage and 9 advanced stage patients. After treatment, 20 women out of 26 recovered menstruation within 6 months. During follow-up, two chemotherapy-untreated and one treated patients experienced 4 conceptions in total. A treated patient conceived but selected artificial termination by affection of chemotherapy. Conservative surgery with adjuvant chemotherapy is the standard approach to treat patients with malignant ovarian germ cell tumors. In these 20 years, we experienced no delivery, so that fertility seems to be seriously affected by treatments.

The differential diagnosis of endocervical glandular lesions can be very difficult, and the interobserver agreement on borderline cases can be low. We are proposing a new scoring system to aid in the reproducibility of the diagnosis of noninvasive endocervical glandular lesions. The total of 67 diagnostically difficult cases were independently reviewed by five pathologists. After the completion of the first round review, a consensus diagnosis was reached for each lesion by all participants. This consensus diagnosis was used as the reference diagnosis. According to the consensus, the lesions included 21 benign/reactive conditions, 7 endocervical glandular dysplasias, and 39 adenocarcinomas in situ. During the second round review, all cases were assessed using the new scoring scheme, according to which separate scores from 0 to 3 were given to each lesion for: 1) nuclear atypia, 2) stratification, and 3) sum of mitoses/apoptoses (counted in the two most active glands, and the average number used). These three scores were then added to result in the total score (0-3 = benign; 4-5 = endocervical glandular dysplasia; 6-9 = adenocarcinoma in situ). Complete agreement between all observers in the first round review was seen in 35 of 67 cases (52.2%), kappa = 0.565. This agreement improved in the second round with the use of the scoring scheme: 52 of 67 cases (77.6%), kappa = 0.705. If the benign and endocervical glandular dysplasia diagnostic categories were combined, the overall agreement in the second round review would be 63 of 67 cases (94%), meaning that the scheme affords accurate distinction between adenocarcinoma in situ and lesser lesions. We propose applying this new scoring scheme to the diagnosis of noninvasive endocervical glandular lesions to improve interobserver agreement. The use of this scheme will result in more consistency of data in series from different institutions and will allow uniformity on the issue of adenocarcinoma in situ precursor lesions.

The insufficient state of knowledge concerning the biology of endocervical glandular lesions is compounded by the lack of universal diagnostic criteria for recognizing endocervical glandular dysplasia. This study addressed the issue of diagnostic reproducibility of noninvasive endocervical glandular lesions and tested the proposed new scoring scheme designed to improve this reproducibility. We have shown that the application of this scheme has significantly improved interobserver agreement in all diagnostic categories. Moreover, the results of this study lend support to the recommendation not to diagnose endocervical glandular dysplasia in the clinical setting, although this category can be still reliably separated out for research purposes. Application of our scoring scheme will bring uniformity to the diagnosis of noninvasive endocervical glandular lesions and allow the study of a precursor to endocervical adenocarcinoma

Objective: To better control both acute and delayed emesis resulting from cisplatin(CDDP)-based chemotherapy for gynecological malignancies, we designed a 'cocktail therapy' (CCT) using granisetron (GRN) in combination with methylprednisolone (MPD) plus droperidol (DRP)., Methods: Two crossover clinical trials were carried out to compare the efficacy and safety of (a) GRN alone (3 mg/patient) with that of GRN, MPD (250 mg/patient) and DRP (0.5 ml/patient) in 42 patients (CCT group) and (b) GRN and MPD (CMB group) with that of the CCT group in 27 patients during the first 7 days of chemotherapy, independent of the weight/body surface of the patients. One of these regimens was administered intravenously for the first 3 days of chemotherapy, in case of failure for a maximum of 5 days., Results: For acute emesis, complete protection from nausea and vomiting by the end of the 1st day was achieved in 64.3% receiving GRN and in 92.9% receiving CCT (p < 0.01). For delayed emesis, complete protection was best achieved in CCT on days 2-3, showing statistical significance compared to GRN treatment (p < 0.01). Comparing the three kinds of treatment during 7 days, the lowest protection was 38.1% in the GRN group, 51.9% in the CMB group and 72.5% in the CCT group, especially on days 2 or 3., Conclusions: The CCT combination is useful for the control of delayed and/or anticipatory emesis resulting from CDDP-based chemotherapy for women with gynecological malignancies., (Copyright 2003 S. Karger AG, Basel)

Purpose: To examine the incidence of radiation-induced late rectal complications by analyzing the data of measured rectal doses in patients with cancer of the uterine cervix treated with high-dose-rate intracavitary brachytherapy., Methods and Materials: We measured doses to the rectum in 105 patients with cancer of the cervix during high-dose-rate intracavitary brachytherapy with a semiconductor dosimeter that can measure five points in the rectum simultaneously. On the basis of these measurements, equivalent doses, to which the biologically equivalent doses were converted as if given as fractionated irradiation at 2 Gy/fraction, were calculated as components of the cumulative dose at five rectal points in intracavitary brachytherapy combined with the external whole pelvic dose., Results: The calculated values of equivalent doses for late effects at the rectum ranged from 15 to 100 Gy (median 60 Gy for patients who did not develop complications and 76 Gy for patients who subsequently developed Grade II or III complications). When converted to a graph of absolute rectal complication probability, the data could be fitted to a sigmoid curve. The data showed a very definite dose-response relationship, with a threshold for complications at approximately 50 Gy and the curve starting to rise more steeply at approximately 60 Gy. The steepest part of the curve had a slope equivalent to approximately 4% incidence/1 Gy increase in equivalent doses., Conclusion: The radiation tolerance dose, 5% and 50% complication probability, was about 64 and 79 Gy, respectively. Our data almost agree with the prescribed dose for the rectum for the radiation tolerance doses on the basis of the recorded human and animal data. The probability of rectal complications increased drastically after the maximal rectal dose was >60 Gy.

To evaluate the significance of mitotic activity and apoptosis in the differential diagnosis of endocervical glandular lesions, we examined the frequency of mitoses and apoptosis in 89 endocervical glandular lesions from 78 patients, which consisted of benign reactive changes (7 cases), lobular or diffuse laminar endocervical glandular hyperplasia (4), microglandular hyperplasia (3), tunnel clusters (7), nabothian cysts (2), mesonephric remnants (3), tubal metaplasia (3), endocervical glandular dysplasias (including atypical tubal metaplasia) (EGD) (7), adenocarcinoma in situ (AIS) (31), microinvasive adenocarcinoma (7), frankly invasive adenocarcinoma (12), and minimal deviation adenocarcinoma (3). Mitotic index (MI; mitotic figures per 1000 cells) was significantly higher in AIS, microinvasive adenocarcinoma, and frankly invasive adenocarcinoma than any other lesions examined. Microinvasive adenocarcinoma showed the highest MI. Apoptosis was detected consistently and frequently in AIS, microinvasive adenocarcinoma, and frankly invasive adenocarcinoma. AIS showed the highest apoptotic index (AI; apoptoses per 1000 cells). Frequent apoptotic bodies and mitotic figures are a common feature of endocervical glandular malignancies (except for minimal deviation adenocarcinoma) and are an important feature that can facilitate their differentiation from benign and borderline lesions. High MI in microinvasive adenocarcinoma might aid the distinction of microinvasive adenocarcinoma from AIS. Although both MI and AI of EGD were between those of benign reactive changes and of AIS, MI and AI alone are not sufficient to differentiate EGD from benign reactive changes. MI and AI are not helpful in the differential diagnosis between minimal deviation adenocarcinoma and its benign mimics.

We select surgical treatment for cases for which severe dysmenorrhea persists following medical treatment. Many reports have described the use of neurectomies by cutting off pain conducting nerve pathways using laparoscopic surgery. Laparoscopic uterosacral nerve ablation (LUNA) has been associated with a high success rate for pain control, but there are few reports of anatomical studies in the uterosacral ligament. Using an immunohistochemical method, we examined the number and types of nerve fiber bundles in the uterosacral ligaments and its surrounding tissue in cadavers. The greatest number of nerve fiber bundles was found at a distance of 16.5-33 mm and at a depth of 3-15 mm distal to the site of attachment of the uterosacral ligament to the uterine cervix. Furthermore, there were many more sympathetic and parasympathetic nerve fiber bundles than sensory ones in the uterosacral ligament and its surrounding tissue. These results show the appropriate site of transection of uterosacral ligaments when performing LUNA., (Copyright 2002 S. Karger AG, Basel)

Epidemiological studies of cancer of the ovaries, among the leading sites for cancer incidence and mortality in women in very many countries of the world, have pointed to high saturated fat and carbohydrate intake, postmenopausal hormone replacement therapy and use of cosmetic talc as risk factors. Conversely, vegetable consumption, parity, lactation and generally appear to confer protection. Genetic influence also clearly plays a role, women with mutations in the BRCA1 or BRCA2 genes having an elevated risk, for example. Overall there appear to be shared risk factors for breast cancer. However, there are many types of epithelial ovarian cancer and cross-country comparisons of incidence data from various cancer registries in Europe and North America published in the IARC Cancer Incidence in Five Continents Vol VII suggest that only the serous type is linked to mammary tumour development. Thus future studies should concentrate more attention on the individual subtypes of ovarian cancer in order to better establish preventive measures.