Naoto Furukawa

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.

Redox-active iron-induced oxidative stress in the pathogenesis of clear cell carcinoma of the ovary.

Objective: Epithelial ovarian cancer (EOC) is the most lethal pelvic gynecologic cancer. Clear cell carcinoma (CCC) and endometrioid adenocarcinoma (EAC) of the ovary have been associated with endometriosis, thus indicating that endometriosis has been believed to increase the risk of developing EOC. The aim of our review was to identify and synthesize the most current information on CCC with regard to molecular and pathophysiological distinctions. Method: This article reviews the English-language literature for molecular, pathogenetic, and pathophysiological studies on endometriosis and endometriosis-associated ovarian cancer (EAOC). In this review, we focus on the functions and roles of redox-active iron in CCC carcinogenesis. Results: The iron-induced reactive oxygen species signals can contribute to carcinogenesis via 3 major processes: step 1, by increasing oxidative stress, which promotes DNA mutagenesis, histone modification, chromatin remodeling, and gene products activation/inactivation thus contributing to EAOC initiation; step 2, by activating detoxification and antiapoptotic pathways via the transcription factor hepatocyte nuclear factor 1&bgr; overexpression, thereby contributing to CCC promotion; and step 3, by creating an environment that supports sustained growth, angiogenesis, migration, and invasion of cancer cells via estrogen-dependent (EAC) or estrogen-independent (CCC) mechanisms, thus supporting tumor progression and metastasis. Conclusions: These aspects of reactive oxygen species biology will be discussed in the context of its relationship to EAOC carcinogenesis.

Molecular Mechanisms Linking Endometriosis Under Oxidative Stress With Ovarian Tumorigenesis and Therapeutic Modalities

Inflammation plays a role in the pathogenesis of endometriosis. Endometriosis-associated ovarian carcinogenesis might be promoted through oxidative stress-induced increased genomic instability, aberrant methylation, and aberrant chromatin remodeling, as well as mutations of tumor suppressor genes. Aberrant expression of ARID1A, PIK3CA, and NF-kB genes has been recognized as the major target genes involved in oxidative stress-induced carcinogenesis. HNF-1beta appears to play a key role in anti-oxidative defense mechanisms. We discuss the pathophysiologic roles of oxidative stress as somatic mutations as well as highly specific agents that effectively modulate these targets.

CA-125 cut-off value as a predictor for complete interval debulking surgery after neoadjuvant chemotherapy in patients with advanced ovarian cancer

Objective In the present study, we evaluated changes in CA-125 cut-off values predictive of complete interval debulking surgery (IDS) after neoadjuvant chemotherapy (NAC) using receiver operating characteristic (ROC) analysis. Methods This retrospective single-institution study included patients with International Federation of Gynecology and Obstetrics (FIGO) stage III epithelial ovarian cancer and a pre-NAC serum CA-125 level of greater than 40 U/mL who were treated with neoadjuvant platinum-based chemotherapy followed by IDS between 1994 and 2009. Logistic regression analysis was used to evaluate univariate and independent multivariate associations with the effect of clinical, pathological, and CA-125 parameters on complete IDS, and ROC analysis was used to determine potential cut-off values of CA-125 for prediction of the possibility of complete IDS. Results Seventy-five patients were identified. Complete IDS was achieved in 46 (61.3%) patients and non-complete IDS was observed 29 (38.7%). Median pre-NAC CA-125 level was 639 U/mL (range, 57 to 6,539 U/mL) in the complete IDS group and 1,427 U/mL (range, 45 to 10,989 U/mL) in the non-complete IDS group. Median pre-IDS CA-125 level was 15 U/mL (range, 2 to 60 U/mL) in the complete IDS group and 53 U/mL (range, 5 to 980 U/mL) in the non-complete IDS group (p<0.001). Multivariate analyses performed with complete IDS as the endpoint revealed only pre-IDS CA-125 as an independent predictor. The odds ratio of non-complete IDS was 10.861 when the pre-IDS CA-125 level was greater than 20 U/mL. Conclusion The present data suggest that in the setting of IDS after platinum-based NAC for advanced ovarian cancer, a pre-IDS CA-125 level less than 20 U/mL is an independent predictor of complete IDS.

Endometrial Cancer Diagnosed by the Presence of Bone Metastasis and Treated with Zoledronic Acid: A Case Report and Review of the Literature

Bone metastasis from endometrial cancer is rare. We report a case of endometrial cancer which was diagnosed by the presence of bone metastasis and treated with zoledronic acid. A 57-year-old woman complaining of progressive right hip pain consulted an orthopedist. She had no gynecologic complaints. X-rays revealed an osteolytic lesion of the right ischium. Bone scintigraphy was subsequently carried out and showed isotope accumulation in the right ischium. Computed tomography revealed an enlarged uterus; the patient consequently consulted a gynecologist. Histological sections of an endometrial biopsy showed endometrioid adenocarcinoma. Hysterectomy and bilateral salpingo-oophorectomy, as well as bone biopsy of the right ischium, were therefore carried out. A moderately differentiated endometrioid adenocarcinoma was expressed in the corpus. Histopathological examination of the bone biopsy also revealed adenocarcinoma. The final diagnosis was stage IVB endometrial cancer with bone and lung metastasis. Good pain relief was achieved due to chemotherapy. However, 2 months after completion of the chemotherapy, the patient was administered zoledronic acid because her hip pain had gradually increased. Following zoledronic acid administration, the hip pain reduced. Radiotherapy was then given for the right ischial metastasis after the ninth course of zoledronic acid therapy because the metastasis site had increased and the possibility of a pathological fracture had risen. However, the patient died 21 months after the initial treatment because of disease progression.

Phase II trial of paclitaxel and nedaplatin in patients with advanced/recurrent uterine cervical cancer: A Kansai Clinical Oncology Group study

OBJECTIVE A multicenter phase II trial was conducted to evaluate the activity and toxicity of paclitaxel and nedaplatin (cis-diammineglycolatoplatonum) in patients with advanced/recurrent uterine cervical cancer. METHODS Patients were required to have measurable disease. Histologic confirmation of the primary diagnosis as uterine cervical cancer was mandatory. The treatment consisted of paclitaxel 175 mg/m(2) over 3 hours and nedaplatin 80 mg/m(2) intravenously over 1 hour on day 1 every 28 days until progressive disease or adverse effects prohibited further therapy. RESULTS Fifty patients were enrolled into the study protocol from October 2007 to February 2010. 45 patients(90%) were eligible for assessment of response (RECIST version 1.0) to treatment; 31 patients (62%) received prior radiotherapy and 23 patients (46%) received prior chemotherapy. The overall response rate was 44.4% (11 complete responses and 8 partial responses) with 22.2% of patients having stable disease. Grades 3 or 4 adverse events (NCI-CTCAE ver 3) included neutropenia (n=16, 32.7%), febrile neutropenia (n=1, 2.0%), anemia (n=9, 18.4%), but there was no significant thrombocytopenia. Non-hematologic toxicity was generally not serious and without a dominant pattern. The median progression-free survival was 7.5 months (95% C.I., 5.7, 9.4) and overall survival was 15.7 months (95% C.I., 9.4, 21.9). CONCLUSIONS Paclitaxel 175 mg/m(2) and nedaplatin 80 mg/m(2) intravenously on day 1 every 28 days in patients with advanced/recurrence uterine cervical cancer demonstrated easy administration, favorable antitumor activity, and the toxicity profile of this regimen would be decreased compared with cisplatin-containing combinations. Evaluation of this regimen in phase III trials is warranted.

Cut-off value of D-dimer for prediction of deep venous thrombosis before treatment in ovarian cancer

Objective The purpose of the present study was to elucidate the incidence of deep venous thrombosis (DVT) before treatment in ovarian cancer and the appropriate cut-off value of D-dimer (DD) for the diagnosis of DVT. Methods Between July 2007 and October 2008, eighty seven patients with presumed ovarian cancer (final diagnosis: ovarian cancer, n=59; borderline malignancy, n=28) were enrolled. Measurement of DD levels and subsequent venous ultrasonography were performed before treatment. Results The mean DD level was 4.1 µg/mL. Subsequent venous ultrasonography revealed DVT in 14 of 87 (16.1%) patients (ovarian cancer, 12 cases; borderline malignancy, 2 cases). None were found to have developed DVT if they had a DD level of <1.5 µg/mL. If 1.5 µg/mL was used as a cut-off value for DD levels to diagnose DVT, sensitivity, specificity, positive predictive value, and negative predictive value were 100%, 61.6%, 33.3%, and 100%. There was noclinical onset of postoperative pulmonary thromboembolism. Conclusion Our data suggest that presumed ovarian cancer patients with at least more than 1.5 µg/mL should be examined using venous ultrasonogaphy to detect DVT.

Signaling pathway involved in cyclooxygenase-2 up-regulation by hepatocyte growth factor in endometrial cancer cells

Hepatocyte growth factor (HGF) is up-regulated in tissue repair and has been implicated in playing a role in this process through its anti-apoptotic and proliferative activities. Cyclooxygenase-2 (COX-2) is an inducible enzyme in the biosynthetic pathway of prostaglandins, and its activation has been shown to play an important role in cell growth. We previously reported that HGF significantly inhibited anoikis, possibly through the up-regulation of COX-2 expression in the endometrial RL95-2 cancer cell line. Here, we report that i) treatment of RL95-2 cells with HGF resulted in phosphorylation of the HGF receptor c-Met, activation of Akt and IκB, translocation of NF-κB into the nucleus, and up-regulation of COX-2 mRNA; ii) the IκB-α phosphorylation inhibitor BAY11-7082 and the selective COX-2 inhibitor CAY10452 blocked HGF-mediated anoikis resistance in RL95-2 cells; and iii) HGF induced migration and invasion in RL95-2 cells, while the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and CAY10452 blocked these effects of HGF stimulation. Our data suggest that HGF possesses chemotactic ability, has anti-apoptosis action, and induces cellular infiltration via the PI3K/Akt pathway; it also triggers NF-κB activation and up-regulates COX-2 gene expression in endometrial cancer cells.

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.

Use of high‐dose cisplatin with aprepitant in an outpatient setting

Chemotherapy-induced nausea and vomiting (CINV) and nephrotoxicity are adverse events induced by cisplatin administration. These effects can be reduced by treatment regimens with low-dose cisplatin, but high-dose cisplatin is still used. In Japan, high-dose cisplatin is usually administered in an inpatient setting to permit management of CINV. However, with use of new-generation antiemetic agents such as aprepitant, CINV and nephrotoxicity are controllable in an outpatient setting. Here, we discuss issues related to the management of high-dose cisplatin administration in outpatients. Grade 2 or worse CINV induced by high-dose cisplatin occurs in more than 40% of patients without treatment with aprepitant, but is controllable by administration of a 5-HT3 receptor antagonist, steroids and aprepitant. Moreover, prevention of CINV using these drugs is cost-effective, since outpatient settings have advantages with regard to health economics and patient quality of life. These findings suggest that shifting high-dose cisplatin administration to the outpatient setting may be achieved with co-administration of aprepitant. Available facilities and the status of the patient should be considered when selecting whether an outpatient setting is suitable for administration of cisplatin, but the use of aprepitant and adequate oral hydration should allow use of cisplatin in this setting.