Mikio Mikami

High-Risk Ovarian Cancer Based on 126-Gene Expression Signature Is Uniquely Characterized by Downregulation of Antigen Presentation Pathway

Purpose: High-grade serous ovarian cancers are heterogeneous not only in terms of clinical outcome but also at the molecular level. Our aim was to establish a novel risk classification system based on a gene expression signature for predicting overall survival, leading to suggesting novel therapeutic strategies for high-risk patients. Experimental Design: In this large-scale cross-platform study of six microarray data sets consisting of 1,054 ovarian cancer patients, we developed a gene expression signature for predicting overall survival by applying elastic net and 10-fold cross-validation to a Japanese data set A (n = 260) and evaluated the signature in five other data sets. Subsequently, we investigated differences in the biological characteristics between high- and low-risk ovarian cancer groups. Results: An elastic net analysis identified a 126-gene expression signature for predicting overall survival in patients with ovarian cancer using the Japanese data set A (multivariate analysis, P = 4 × 10−20). We validated its predictive ability with five other data sets using multivariate analysis (Tothills data set, P = 1 × 10−5; Bonomes data set, P = 0.0033; Dressmans data set, P = 0.0016; TCGA data set, P = 0.0027; Japanese data set B, P = 0.021). Through gene ontology and pathway analyses, we identified a significant reduction in expression of immune-response–related genes, especially on the antigen presentation pathway, in high-risk ovarian cancer patients. Conclusions: This risk classification based on the 126-gene expression signature is an accurate predictor of clinical outcome in patients with advanced stage high-grade serous ovarian cancer and has the potential to develop new therapeutic strategies for high-grade serous ovarian cancer patients. Clin Cancer Res; 18(5); 1374–85. ©2012 AACR.

Therapeutic strategy targeting the mTOR-HIF-1α-VEGF pathway in ovarian clear cell adenocarcinoma

Malignant tumors usually involve a relatively hypoxic state, which induces overexpression of hypoxia‐inducible factor‐1α (HIF‐1α) to satisfactorily enable the tumor to survive. Thus, inhibition of the mammalian target of rapamycin (mTOR) pathway including HIF‐1α is expected to play a major role in suppression of tumor cell growth, having recently drawn much attention as an anti‐cancer therapeutic strategy for various malignant tumors. In the present study, which compared clear cell adenocarcinoma (CLA) of the ovary with serous adenocarcinoma (SEA), the immunohistochemical expression of mTOR, phosphorylated‐mTOR (p‐mTOR), HIF‐1α, and vascular endothelial growth factor (VEGF) was examined in surgically resected specimens of 29 SEA and 47 CLA. There were no significant differences in expression of mTOR, HIF‐1α and VEGF between SEA and CLA, but it was noted that p‐mTOR expression was more prominent in CLA than SEA. Then, using the cell lines of CLA (RMG‐1 and W3uF), an experimental study was designed to clarify whether tumor suppression due to downregulation of mTOR activity could represent a promising therapeutic strategy for CLA. After treatment of an analogue of rapamycin (everolimus), expression of mTOR, p‐mTOR, HIF‐1α and VEGF was examined on western blot. As a result, although mTOR expression remained unchangeable, expression of p‐mTOR, HIF‐1α and VEGF was shown to be sharply depressed. The same expression alterations were demonstrated in the xenograft model treated with everolimus. In conclusion, mTOR‐targeted therapy through usage of drugs such as everolimus may be more effective for CLA of the ovary because of its significant expression of p‐mTOR.

Phase II study of concurrent chemoradiotherapy with high-dose-rate intracavitary brachytherapy in patients with locally advanced uterine cervical cancer: Efficacy and toxicity of a low cumulative radiation dose schedule ☆

OBJECTIVE A multicenter phase II trial was conducted to assess the efficacy and toxicity of concurrent chemoradiotherapy (CCRT) with high-dose-rate intracavitary brachytherapy (HDR-ICBT) using a low cumulative prescribed dose schedule in patients with locally advanced uterine cervical cancer. METHODS The Japanese Gynecologic Oncology Group (JGOG) study JGOG1066 enrolled patients with FIGO stages III-IVA uterine cervical cancer who had no para-aortic lymphadenopathy (>10 mm) assessed by CT. Patients received definitive radiotherapy (RT) consisting of external beam whole pelvic RT and HDR-ICBT. The cumulative linear quadratic equivalent dose (EQD2) was 62-65 Gy prescribed at point A. Cisplatin 40 mg/m(2) weekly was administered concurrently with RT for 5 courses. RESULTS Of the 72 patients registered, 71 were eligible. With a median follow-up of 28 months, the 2-year progression-free survival rate and pelvic disease progression-free rate were 66% (95% CI, 54% to 76%) and 73% (95% CI, 61% to 82%), respectively. Progression-free survival decreased significantly with increased central tumor size (P=0.036). The 2-year cumulative late complication rates were 24% for all grades, 9% for grade 1, 12% for grade 2, 3% for grade 3, and 0 for grades 4/5. CONCLUSIONS The JGOG1066 demonstrated that CCRT using HDR-ICBT with a low cumulative RT dose schedule achieved comparable outcome as those achieved with global dose schedules (EQD2=85 Gy) with a lower incidence of late toxicity for locally advanced uterine cervical cancer in a Japanese population.

Menstrual cycle-associated alteration of sulfogalactosylceramide in human uterine endometrium: Possible induction of glycolipid sulfation by sex steroid hormones

The human uterine endometrium is a tissue in which cell proliferation and differentiation are strictly controlled by sex steroid hormones, and these hormone-controlled cellular events occurring in association with the menstrual cycle of the uterine endometrium should be accompanied by characteristic molecular and metabolic changes. To characterize the menstrual cycle at the molecular level, we analyzed the glycolipids of human uterine endometrium in the proliferative and secretory phases of the menstrual cycle. Neutral glycosphingolipids from uterine endometrium comprised globo-series glycosphingolipids, such as GlcCer, LacCer, Gb3Cer, and Gb4Cer, and the relative concentrations remained constant in the two phases. However, in the case of acidic glycosphingolipids, although the concentrations of sialoglycosphingolipids remained at constant levels in the two phases, sulfatide, I3-SulfoGalCer, dramatically increased from the proliferative to the secretory phase, amounting to 7-17 nmol/g dry weight in the proliferative phase and 115-245 nmol/g dry weight in the secretory phase. Since sulfatide was the only glycolipid that changed in association with the menstrual cycle, it is likely that the sulfotransferase responsible for the synthesis of sulfatide might be induced by sex steroid hormones, estrogen and progesterone, and that sulfatide might play an essential biological role in the secretory phase of the menstrual cycle in the uterine endometrium.

Reduced expression of αvβ3 integrin in the endometrium of unexplained infertility patients with recurrent IVF-ET failures: Improvement by danazol treatment

AbstractPurpose: To determine whether there is any association between the expression of endometrial integrin α v β3 and repeated IVF-ET failure and to examine the effect of danazol treatment on α v β3 expression. Methods: This prospective study was performed using a semiquantitative immunohistochemical analysis on the staining intensity of α v β3 in the mid-secretory endometria derived from 10 fertile women and 57 infertile patients with a history of repeated IVF-ET failures. Nine patients randomly selected from these 22 patients with unexplained infertility were then treated with oral danazol administration for 12 weeks and reexamined at the first mid-secretory phase after the danazol treatment. Result(s): The levels of endometrial α v β3 expression were lower in 22 patients with unexplained infertility than in the fertile control and 35 patients with explained infertility. The 9 patients treated with danazol showed a significant increase in the α v β3 staining. Conclusion(s): The significantly decreased expression of endometrial integrin α v β3 suggested that functional, but not morphological, endometrial defect may be one of the causes for the patients with unexplained infertility. Danazol may have a therapeutic potential in improving endometrial function together with up-regulation of α v β3.

Randomized phase III trial of irinotecan plus cisplatin compared with paclitaxel plus carboplatin as first-line chemotherapy for ovarian clear cell carcinoma: JGOG3017/GCIG trial

PURPOSE Clear cell carcinoma (CCC) is a rare histologic subtype that demonstrates poor outcomes in epithelial ovarian cancer. The Japanese Gynecologic Oncology Group conducted the first randomized phase III, CCC-specific clinical trial that compared irinotecan and cisplatin (CPT-P) with paclitaxel plus carboplatin (TC) in patients with CCC. PATIENTS AND METHODS Six hundred sixty-seven patients with stage I to IV CCC of the ovary were randomly assigned to receive irinotecan 60 mg/m(2) on days 1, 8, and 15 plus cisplatin 60 mg/m(2) on day 1 (CPT-P group) every 4 weeks for six cycles or paclitaxel 175 mg/m(2) plus carboplatin area under the curve 6.0 mg/mL/min on day 1 every 3 weeks for six cycles (TC group). The primary end point was progression-free survival. Secondary end points were overall survival, overall response rate, and adverse events. RESULTS Six hundred nineteen patients were clinically and pathologically eligible for evaluation. With a median follow-up of 44.3 months, 2-year progression-free survival rates were 73.0% in the CPT-P group and 77.6% in TC group (hazard ratio, 1.17; 95% CI, 0.87 to 1.58; P = .85). Two-year overall survival rates were 85.5% with CPT-P and 87.4% with TC (hazard ratio, 1.13; 95% CI, 0.80 to 1.61; one-sided P = .76). Grade 3/4 anorexia, diarrhea, nausea, vomiting, and febrile neutropenia occurred more frequently with CPT-P, whereas grade 3/4 leukopenia, neutropenia, thrombocytopenia, peripheral sensory neuropathy, and joint pain occurred more frequently with TC. CONCLUSION No significant survival benefit was found for CPT-P. Both regimens were well tolerated, but the toxicity profiles differed significantly. Treatment with existing anticancer agents has limitations to improving the prognosis of CCC.

RETROPERITONEAL PRIMARY MUCINOUS ADENOCARCINOMA WITH A MURAL NODULE OF ANAPLASTIC TUMOR: A CASE REPORT AND LITERATURE REVIEW

A 38-year-old female presented with a lower abdominal mass. During the operation the mass was found to be retroperitoneal and was excised. Gross examination revealed a mucin-containing cystic lesion with a mural nodule. On microscopic examination, the cystic areas were lined by an invasive mucinous adenocarcinoma and the nodule was composed of an anaplastic sarcomatoid tumor that was immunoreactive for cytokeratin. This present case is the 21st example of a retroperitoneal primary mucinous cystadenocarcinoma and the fourth with a mural nodule. Three of four cases with a mural nodule, including our case, had a rapidly fatal outcome.

Japan Society of Gynecologic Oncology guidelines 2011 for the treatment of uterine cervical cancer.

The second edition of the Japan Society of Gynecologic Oncology guidelines for the treatment of uterine cervical cancer was published in 2011. The guidelines comprise eight chapters and five algorithms. They were prepared by consensus among the members of the Japan Society of Gynecologic Oncology Guidelines Formulation Committee and Evaluation Committee and are based on a careful review of the evidence obtained from the literature, health insurance system, and actual clinical settings in Japan. The highlights of the 2011 revision are (1) the recommended grades have been changed to five stages—A, B, C1, C2, and D; (2) the revisions are consistent with the new International Federation of Gynecology and Obstetrics staging system; (3) the roles are shared between the ‘Japanese classification of cervical cancer’ and the new guidelines; (4) clinical questions related to adenocarcinoma have been revised; and (5) a clinical question regarding cervical cancer in pregnant patients has been added. Each chapter includes a clinical question, recommendations, background, objectives, explanations, and references. Each recommendation is accompanied by a classification of recommendation categories. The objective of these guidelines is to update the standard treatment strategies for cervical cancer, thus eliminating unnecessary and insufficient treatment.

Evidence-based guidelines for treatment of uterine body neoplasm in Japan: Japan Society of Gynecologic Oncology (JSGO) 2009 edition

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.

Novel Glycobiomarker for Ovarian Cancer That Detects Clear Cell Carcinoma

Epithelial ovarian cancer (EOC) is often asymptomatic and thus diagnosed at advanced stages with a poor prognosis. False-negative results for the conventional marker CA125 frequently occur in cases of clear cell carcinoma (CCC), a type of EOC; therefore, it is necessary to develop biomarkers with greater sensitivity. We previously reported a strategy to discover glycobiomarker candidates by combined lectin microarray and IGOT-LC/MS analysis. We have now optimized this strategy for discovering EOC biomarkers. Glycopeptides possessing cancerous glycans were enriched from the ascites fluids and culture supernatants of cancer cell lines with a fucose-binding lectin, AAL. IGOT-LC/MS analysis of CCC samples yielded 144 candidate glycoproteins. We selected WFA by lectin microarray as the optimal lectin to distinguish EOC from gastric and colon cancer. The candidates were narrowed by Western analysis of the WFA-bound fraction of ascites fluids. One of the final candidates, WFA-reactive ceruloplasmin, produced higher signals in the ascites fluids of EOC patients, including CCC, in comparison with the benign samples, while CA125 levels were comparable in the sandwich ELISA. Thus, our glycoproteomic strategy featuring efficient enrichment of glycans with disease-related alterations is applicable to various diseases.