Mariko Sakata

A randomized study of screening for ovarian cancer: a multicenter study in Japan.

Ovarian cancer is common in women from developed countries. We designed a prospective randomized controlled trial of ovarian cancer screening to establish an improved strategy for the early detection of cancers. Asymptomatic postmenopausal women were randomly assigned between 1985 and 1999 to either an intervention group (n= 41,688) or a control group (n= 40,799) in a ratio of 1:1, with follow-up of mean 9.2 years, in Shizuoka district, Japan. The original intention was to offer women in the intervention group annual screens by gynecological examination (sequential pelvic ultrasound [US] and serum CA125 test). Women with abnormal US findings and/or raised CA125 values were referred for surgical investigation by a gynecological oncologist. In December 2002, the code was broken and the Shizuoka Cohort Study of Ovarian Cancer Screening and Shizuoka Cancer Registry were searched to determine both malignant and nonmalignant diagnoses. Twenty-seven cancers were detected in the 41,688-screened women. Eight more cancers were diagnosed outside the screening program. Detection rates of ovarian cancer were 0.31 per 1000 at the prevalent screen and 0.38–0.74 per 1000 at subsequent screens; they increased with successive screening rounds. Among the 40,779 control women, 32 women developed ovarian cancer. The proportion of stage I ovarian cancer was higher in the screened group (63%) than in the control group (38%), which did not reach statistical significance (P= 0.2285). This is to our knowledge the first prospective randomized report of the ovarian cancer screening. The rise in the detection of early-stage ovarian cancer in asymptomatic postmenopausal women is not significant, but future decisions on screening policy should be informed by further follow-up from this trial.

The role of iron in the pathogenesis of endometriosis

Background. Endometriosis may cause symptoms including chronic pelvic pain and infertility, and increases susceptibility to the development of ovarian cancer. Genomic studies have started to delineate the wide array of mediators involved in the development of endometriosis. Understanding the mechanisms of endometriosis development and elucidating its pathogenesis and pathophysiology are intrinsic to prevention and the search for effective therapies. Method of study. The present article reviews the English language literature for biological, pathogenetic and pathophysiological studies on endometriosis. Several recent genomic studies are discussed in the context of endometriosis biology. Results. Severe hemolysis occurring during the development of endometriosis results in high levels of free heme and iron. These compounds oxidatively modify lipids and proteins, leading to cell and DNA damage, and subsequently fibrosis development. Recent studies based on genome-wide expression analysis technology have noted specific expression of heme/iron-dependent mediators in endometriosis. The heme/iron-dependent signaling pathway of endometriosis, which is providing new insights into the regulation of inflammation, detoxification and survival, is discussed. Conclusion. Several important endometriosis-specific genes overlap with those known to be regulated by iron. Other genes are involved in oxidative stress. Iron has a significant impact on endometriotic-cell gene expression. This review summarizes recent advances in the heme/iron-mediated signaling and its target genes, outlines the potential challenges to understanding of the pathogenesis and pathophysiology of endometriosis, and proposes a possible novel model.

The role of hepatocyte nuclear factor-1beta in the pathogenesis of clear cell carcinoma of the ovary.

Problem: Clear cell carcinoma (CCC) of the ovary has a number of features distinguishing it from other epithelial ovarian carcinomas (EOC) because of its characteristic histology and biology, frequent concurrence with endometriotic lesion, and highly chemoresistant nature resulting in an extremely poor prognosis. The incidence of CCC has been steadily increasing in Japan. They comprise approximately 20% of all EOC. Understanding the mechanisms of CCC development and elucidating pathogenesis and pathophysiology are intrinsic to prevention and effective therapies for CCC. Method of study: This article reviews the English language literature for biology, pathogenesis, and pathophysiological studies on endometriosis-associated EOC. Several data are discussed in the context of endometriosis and CCC biology. Results: Recent studies based on genome-wide expression analysis technology have noted specific expression of hepatocyte nuclear factor-1β (HNF-1β) in endometriosis and CCC, suggesting that early differentiation into the clear cell lineage takes place in the endometriosis. The HNF-1β-dependent pathway of CCC will be discussed, which are providing new insights into regulation of apoptosis and glycogen synthesis and resistance of CCC to anticancer agents. Conclusions: This review summarizes recent advances in the HNF-1β and its target genes; the potential challenges to the understanding of carcinogenesis, pathogenesis, and pathophysiology of CCC; and a possible novel model is proposed.

Clinicopathologic features of ovarian cancer in patients with ovarian endometrioma

Objective:  The purpose of this study was to describe the clinicopathologic features of malignant transformation in patients with ovarian endometrioma, their treatment and outcome in the Kinki region, Japan.

Theoretical model of treatment strategies for clear cell carcinoma of the ovary: focus on perspectives.

OBJECTIVES Among epithelial ovarian cancer (EOC), clear cell carcinomas (CCC) differ from the other histologic types with respect to their clinical characteristics, carcinogenesis and prognosis. The aim of this review is to summarize the current knowledge and future perspective on the new therapeutic targets and treatment strategies for CCC. MATERIALS AND METHODS The present article reviews the English language literature for preclinical and clinical trials and promising molecular targets on CCC of the ovary, based on the gene expression profiling studies. RESULTS Here, we show that (1) the expression of the genes involved in transcription, signaling, cell cycle, adhesion, matrix, proteinase, and detoxification was greatly increased in the CCC carcinogenesis; (2) upregulation of hepatocyte nuclear factor-1beta (HNF-1beta) and Polo-like kinase (PLK)-Early mitotic inhibitor-1 (Emi1) as well as their downstream targets are specifically found in most CCC. The promising molecular targeting approach will emerge in the context of HNF-1beta and PLK-Emi1 biology; and 3) several significant common pathways observed in CCC of the ovary overlap the datasets identified in CCC of the kidney. To improve the outcome in CCC therapy, we must learn various adaptive treatment strategies for renal CCC, although it is not supported by any preliminary clinical data. CONCLUSION The inhibitors that target HNF-1beta and PLK-Emi1 and their downstream signaling molecules would be evaluated. In addition, the therapy currently used in renal CCC should be considered as an alternative for the present treatments or an attractive therapeutic option for ovarian CCC. The challenges accompanying the recent advance are described in this review article.

Iron-dependent oxidative stress as a pathogenesis for preterm birth.

Problem: Preterm birth (PTB) is an oxidative stress-related disease that lacks effective therapies partly because of the poor understanding of disease pathogenesis. The aim of this manuscript was to review molecular pathways that could be responsible for the pathogenesis of PTB. Genomic and proteomic studies have started to delineate the wide array of mediators involved in this disorder. Understanding the mechanisms of the development of PTB and elucidating pathogenesis and pathophysiology are intrinsic to prevention and effective therapies for this disorder. Method of Study. This article reviews the English language literature for pathogenesis and pathophysiological studies on PTB. Several recent genomic and proteomic studies are discussed in the context of PTB biology. Results: Decidual hemorrhage has been identified histologically in the placentas of patients with PTB, which may result in high levels of free heme and iron. Several important PTB-specific genes and proteins overlap with those known to be regulated by iron. Others were genes involved in oxidative stress and detoxification. Free iron oxidatively modifies lipid and protein, leading to DNA and cell damage. This signaling pathway of PTB will be discussed as it provides new insights into regulation of inflammation, oxidative stress, and detoxification. Conclusion: This review summarizes recent advances in heme/iron-mediated signaling, the target genes thereof, and the potential challenges to the understanding of pathogenesis and pathophysiology of PTB. A novel model is proposed. Collectively, decidual hemorrhage and inflammation are considered to be major contributors to the pathogenesis of PTB. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader should be able to paraphrase the role of oxidative stress in pathogenesis of preterm birth, explain the idea of preterm birth as a “syndrome,” and summarize the potential role of early uterine bleeding in pathophysiology of preterm birth.

Serum CA125 level before the development of ovarian cancer

Little is known about the natural history of ovarian cancer with respect to the change of serum CA125 level.

Giant abdominal tumor of the ovary

A giant abdominal tumor can exert a mass effect on surrounding structures. We report here a 34‐year‐old single female who presented with an increased abdominal girth and was subsequently found to have a giant abdominal mass. Large volume aspiration (85 L) at a slow rate (1 L/min) was initially performed before surgical resection to prevent the development of severe clinical hypotension after large volume aspiration. The patient underwent left salpingo‐oophorectomy. Histology revealed a serous cystadenoma of the ovary. Systemic hemodynamics were sequentially measured during the perioperative period. The patient is now well.

Ryudocan expression by luteinized granulosa cells is associated with the process of follicle atresia

OBJECTIVE To evaluate the presence of ryudocan in follicular fluid (FF) and its possible correlation with FF E(2) and P, and to study the levels of ryudocan in granulosa-lutein cells stimulated with hCG. DESIGN Controlled clinical study and in vitro experiment. SETTING University teaching hospital. PATIENT(S) One hundred seven patients undergoing IVF. INTERVENTION(S) The FF and granulosa-lutein cells were aspirated from follicles 34 hours after an ovulatory gonadotropin bolus. MAIN OUTCOME MEASURE(S) FF ryudocan, E(2), and P levels as well as hCG-mediated induction of ryudocan. RESULT(S) Ryudocan was abundant in the FF; the concentration of ryudocan in human FF was estimated to be 305.5 +/- 200.8 ng/mL (mean +/- SD). Atretic follicles had higher concentrations of ryudocan (559.1 +/- 156.5 ng/mL). FF ryudocan levels were inversely correlated with FF E(2) (r = -0.5023) and P concentrations (r = -0.4459). A detectable amount of ryudocan was found in pooled granulosa-lutein cells. Ryudocan production was augmented by surge levels of hCG. CONCLUSION(S) Ryudocan is expressed in luteinized granulosa cells in vitro. The higher concentrations of ryudocan in FF of atretic follicles suggest an involvement of ryudocan in the process of atresia.

Two cases of pregnant women with ovarian endometrioma mimicking a malignant ovarian tumor

The detection of an ovarian mass during pregnancy is often a diagnostic challenge. We describe 2 cases of ovarian endometrioma during pregnancy with marked mural nodules on the cyst wall. The sonographic and MR imaging findings mimicked ovarian cancer. Surgical intervention may still be inevitable to exclude the possibility of malignancy.