Hisaya Fujiwara

Gene expression profile for predicting survival in advanced-stage serous ovarian cancer across two independent datasets.

Background Advanced-stage ovarian cancer patients are generally treated with platinum/taxane-based chemotherapy after primary debulking surgery. However, there is a wide range of outcomes for individual patients. Therefore, the clinicopathological factors alone are insufficient for predicting prognosis. Our aim is to identify a progression-free survival (PFS)-related molecular profile for predicting survival of patients with advanced-stage serous ovarian cancer. Methodology/Principal Findings Advanced-stage serous ovarian cancer tissues from 110 Japanese patients who underwent primary surgery and platinum/taxane-based chemotherapy were profiled using oligonucleotide microarrays. We selected 88 PFS-related genes by a univariate Cox model (p<0.01) and generated the prognostic index based on 88 PFS-related genes after adjustment of regression coefficients of the respective genes by ridge regression Cox model using 10-fold cross-validation. The prognostic index was independently associated with PFS time compared to other clinical factors in multivariate analysis [hazard ratio (HR), 3.72; 95% confidence interval (CI), 2.66–5.43; p<0.0001]. In an external dataset, multivariate analysis revealed that this prognostic index was significantly correlated with PFS time (HR, 1.54; 95% CI, 1.20–1.98; p = 0.0008). Furthermore, the correlation between the prognostic index and overall survival time was confirmed in the two independent external datasets (log rank test, p = 0.0010 and 0.0008). Conclusions/Significance The prognostic ability of our index based on the 88-gene expression profile in ridge regression Cox hazard model was shown to be independent of other clinical factors in predicting cancer prognosis across two distinct datasets. Further study will be necessary to improve predictive accuracy of the prognostic index toward clinical application for evaluation of the risk of recurrence in patients with advanced-stage serous ovarian cancer.

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.

Gene expression profiling of advanced-stage serous ovarian cancers distinguishes novel subclasses and implicates ZEB2 in tumor progression and prognosis

To elucidate the mechanisms of rapid progression of serous ovarian cancer, gene expression profiles from 43 ovarian cancer tissues comprising eight early stage and 35 advanced stage tissues were carried out using oligonucleotide microarrays of 18 716 genes. By non‐negative matrix factorization analysis using 178 genes, which were extracted as stage‐specific genes, 35 advanced stage cases were classified into two subclasses with superior (n = 17) and poor (n = 18) outcome evaluated by progression‐free survival (log rank test, P = 0.03). Of the 178 stage‐specific genes, 112 genes were identified as showing different expression between the two subclasses. Of the 48 genes selected for biological function by gene ontology analysis or Ingenuity Pathway Analysis, five genes (ZEB2, CDH1, LTBP2, COL16A1, and ACTA2) were extracted as candidates for prognostic factors associated with progression‐free survival. The relationship between high ZEB2 or low CDH1 expression and shorter progression‐free survival was validated by real‐time RT‐PCR experiments of 37 independent advanced stage cancer samples. ZEB2 expression was negatively correlated with CDH1 expression in advanced stage samples, whereas ZEB2 knockdown in ovarian adenocarcinoma SKOV3 cells resulted in an increase in CDH1 expression. Multivariate analysis showed that high ZEB2 expression was independently associated with poor prognosis. Furthermore, the prognostic effect of E‐cadherin encoded by CDH1 was verified using immunohistochemical analysis of an independent advanced stage cancer samples set (n = 74). These findings suggest that the expression of epithelial–mesenchymal transition‐related genes such as ZEB2 and CDH1 may play important roles in the invasion process of advanced stage serous ovarian cancer. (Cancer Sci 2009)

Intergender differences in histological architecture of the fascia pelvis parietalis: a cadaveric study.

The fascia pelvis parietalis (FPP) or endopelvic fascia is a well‐known structure, but few studies described the detailed histological architecture, including the composite fiber directions. We hypothesized a gender‐specific fiber architecture corresponding to the functional demand. For the first step to examine this hypothesis, we investigated specimens from 27 adult cadavers (10 males and 17 females) and 11 midterm fetuses (five males and six females) using immunohistochemistry and aldehyde‐fuchsin staining. The adult female FPP was a solid, thick monolayered structure that was reinforced by abundant elastic fibers running across the striated muscle fibers, but it contained little or no smooth muscles (SM). In contrast, the male FPP was multilayered with abundant SM. In midterm fetuses, SM originated from the inferior part of the bladder and extended inferiorly along the gender‐specific courses. Thus, we found a clear intergender difference in FPP architecture. However, the functional significance remained unknown because the basic architecture was common between nulliparous and multiparous women. Rather than for meeting the likely mechanical demands of pregnancy and vaginal delivery, the intergender difference of the FPP seemed to result from differences in the amount and migration course of bladder‐derived SM as well as in hormonal background. Clin. Anat. 24:469–477, 2011.

Epithelioid trophoblastic tumor of the lung

Epithelioid trophoblastic tumor (ETT) is a rare type of gestational trophoblastic disease and only 25 cases have been reported so far. It was first proposed by Mazur and Kurman in 1994 as an unusual type of trophoblastic tumor that is distinct from placental site trophoblastic tumor and choriocarcinoma and has features resembling carcinoma. A case of ETT of the lung in a 38‐year‐old Japanese woman is reported. The patient had suffered from a hydatidiform mole at the age of 27 years, and had four normal deliveries at the ages of 24, 31, 35 and 37 years. Because no tumor lesions were detected in the uterus, the patient was suspected of having metastatic choriocarcinoma with multiple lesions in the lung accompanied by an elevated level of human chorionic gonadotropin (hCG). In order to make an exact diagnosis, a partial resection of metastatic foci in the lung was performed. Microscopically, the tumor showed hemorrhagic necrotic foci and was composed of mainly mononuclear tumor cells and some giant tumor cells resembling trophoblastic cells. Immunohistochemical examination showed that a few large cells were stained positively for hCG, and that other cells were positive for human placental lactogen, pregnancy‐specific β1‐glycoprotein, cytokeratin 7 and inhibin‐α. In the ultrastructure, the tumor cells contained large nuclei and rich organella with desmosomes and well‐formed filaments. The diagnosis of ETT was confirmed from the findings as described above.

Comparative histological study of levels 1–3 supportive tissues using pelvic floor semiserial sections from elderly nulliparous and multiparous women

Aim:  The connective tissue located between the uterine cervix and sacrospinous ligament (the uterospinous connective tissue; USCT) has recently been noted as the level 1 supportive tissue instead of the classical uterosacral ligament. We examined whether or not the USCT changes its histological architecture by vaginal delivery in correlation with the levels 2 and 3 supportive tissues.

Enhanced Expression of P2X4 and P2X7 Purinergic Receptors in the Myometrium of Pregnant Rats in Preterm Delivery Models

The expression levels of P2X purinergic receptors were determined in the myometrium of pregnant rats using the quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR). The messenger RNAs (mRNAs) of P2X4 and P2X7 were expressed most strongly. The expression levels of these receptors increased during the late stages of pregnancy; at the time of delivery, the mRNA levels of P2X4 and P2X7 had increased to 1.9 and 3.2 times the day 19 values, respectively. We also explored the roles of P2X receptors in hormone-induced and inflammation-induced preterm delivery models. In the former, mifepristone caused the P2X4 and P2X7 mRNA levels to increase to 2.1 and 4.1 times the control values, respectively. In the latter, lipopolysaccharide (LPS) caused the mRNA levels of P2X4 and P2X7 to increase dramatically to 7.4 and 18.6 times the control values, respectively. These findings suggest that increased P2X4 and P2X7 receptor expression in pregnant rats is related to uterine contraction leading to term and preterm delivery.

Surgical principles for managing stage IB2, IIA2, and IIB uterine cervical cancer (Bulky Tumors) in Japan: a survey of the Japanese Gynecologic Oncology Group.

Objective The aim of this study was to determine the current operative management of International Federation of Gynecology and Obstetrics (FIGO) stage IB2, IIA2, and IIB uterine cervical cancer (bulky tumors) in Japan by surveying the member institutions of the Japanese Gynecologic Oncology Group. Methods We conducted a survey to assess current operative management, including indications and treatment, at all 199 active member institutions of the Japanese Gynecologic Oncology Group. Results A total of 166 institutions (83.4%) responded to the survey. For patients with stage IIB squamous cell carcinoma, 35.5% (59/166) of the institutions performed surgery. For stage IIB nonsquamous cell carcinoma, surgery was performed at 88 (53.7%) of 164 institutions. Neoadjuvant chemotherapy was provided by 75 (45.5%) of 165 institutions (actively in 44 and reluctantly in 31). At 101 (61.2%) of 165 institutions, para-aortic node dissection was performed as part of radical surgery in patients with any indications. At 96 (57.9%) of 166 institutions, high-risk patients underwent chemoradiotherapy after surgery. On the other hand, adjuvant chemotherapy was given to high-risk and intermediate-risk patients at 19.9% and 33.1% institutions, respectively. More than half of the 166 institutions considered the number of metastatic nodes (91/166, 54.8%) and tumor histology (116/166, 69.9%) when selecting adjuvant therapy. Conclusions This survey provided information regarding the current surgical management of uterine cervical cancer (stages IB2, IIA2, and IIA) in Japan.

CD133(+) cells from human umbilical cord blood reduce cortical damage and promote axonal growth in neonatal rat organ co-cultures exposed to hypoxia

To evaluate the effect of CD133+ cells (endothelial progenitor cells) on the hypoxia‐induced suppression of axonal growth of cortical neurons and the destruction of blood vessels (endothelial cells), we used anterograde axonal tracing and immunofluorescence in organ co‐cultures of the cortex and the spinal cord from 3‐day‐old neonatal rats. CD133+ cells prepared from human umbilical cord blood were added to the organ co‐cultures after hypoxic insult, and axonal growth, vascular damage and apoptosis were evaluated. Anterograde axonal tracing with 1,1′‐dioctadecyl‐3,3,3′,3′‐tetramethylindocarbocyanine perchlorate was used to analyze axonal projections from the cortex to the spinal cord. Immunolabeling co‐cultured tissues of the cortex and the spinal cord were used to investigate the effect of CD133+ cells on the survival of blood vessels and apoptosis in the brain cortex. Hypoxia remarkably suppressed axonal growth in organ co‐cultures of the cortex and the spinal cord, and this suppression was significantly restored by the addition of CD133+ cells. CD133+ cells also reduced the hypoxia‐induced destruction of the cortical blood vessels and apoptosis. CD133+ cells had protective effects on hypoxia‐induced injury of neurons and blood vessels of the brain cortex in vitro. These results suggest that CD133+ cell transplantation may be a possible therapeutic intervention for perinatal hypoxia‐induced brain injury.

Current surgical principle for uterine cervical cancer of stages Ia2, Ib1, and IIa1 in Japan: a survey of the Japanese Gynecologic Oncology Group.

Objective The objective of this study was to determine the current operative principle of uterine cervical cancer of stages Ia2, Ib1, and IIa1 (International Federation of Gynecology and Obstetrics) in Japan by surveying member institutions of the Japanese Gynecologic Oncology Group (JGOG). Methods We conducted a survey to assess the current operative principle, including indications and treatment, at all 199 active member institutions of the JGOG. Results A total of 166 institutions (83.4%) responded to the survey. For Ia2 squamous cell carcinoma without the need to preserve fertility, modified radical hysterectomy was performed, and lymph node dissection was done in about 85%. At 60% of JGOG institutions, it was considered that less invasive procedures might be suitable. At the majority of JGOG institutions, radical surgery and lymph node dissection were considered necessary for stages Ib1 and IIa1 squamous cell carcinoma, with 70% considering that less invasive procedures might not be suitable. Conclusions This survey provides information regarding the current status of surgical principle for uterine cervical cancer (stages Ia2, Ib1, and IIa1) in Japan.