Search

Aim: Tissue factor pathway inhibitor 2 (TFPI2) is a structural homolog of tissue factor pathway inhibitor 1 (TFPI1). Since TFPI2 is a placenta-derived protein, dynamic changes in TFPI2 levels may be related to pregnancy-related diseases. Furthermore, TFPI2 has been reported to be a novel serum biomarker for detecting ovarian cancer, especially clear cell carcinoma (CCC). This review aims to summarize the current knowledge on the biological function of TFPI2, highlight the major challenges that remain to be addressed, and discuss future research directions., Methods: Papers published up to March 31, 2023 in the PubMed and Google Scholar databases were included in this review. We also provide novel complementary information to what is known about the action of TFPI2., Results: Since TFPI2 concentrations in the blood of pregnant women, preeclampsia patients, and cancer patients vary greatly, its pathophysiological functions have attracted attention. Downregulation of TFPI2, a tumor-suppressor gene, by hypermethylation may contribute to the progression of several cancers. On the other hand, TFPI2 overexpressed in CCC is a risk factor for the development of thrombosis, possibly through inhibition of plasmin activity. However, agreement on the biological function of TFPI2 is still lacking and there are many scientific questions to be addressed. In particular, the lack of international standardization for the quantification of TFPI2 concentrations makes it difficult for researchers and clinicians to evaluate, pool, and compare data from different studies across countries., Discussion: This review summarizes current understandings and challenges in TFPI2 research and discusses future perspectives., (© 2023 Japan Society of Obstetrics and Gynecology.)

Objectives: Carbohydrate antigen 125 (CA125), CA19-9, carcinoembryonic antigen (CEA), human epididymis protein 4 (HE4), and the Risk of Ovarian Malignancy Algorithm (ROMA) are widely used as tumor markers and algorithms for the diagnosis of ovarian cancer (OC). Tissue factor pathway inhibitor 2 (TFPI2) has been developed as a potential serodiagnostic marker for OC in Japan. The aim of this study is to evaluate the diagnostic accuracy of the six markers alone and in combination to find the best marker for discriminating between benign and malignant ovarian tumors., Methods: Frozen serum samples collected from 484 patients were divided into three groups based on histopathological results: OC (n = 119), borderline ovarian tumors (BR) (n = 48), and benign ovarian tumors (BN) (n = 317). Diagnostic accuracy was calculated with an area under a receiver operating characteristic (AUC) curve., Results: TFPI2 achieved the highest discrimination between the OC + BR group versus the BN group (AUC 0.8076). ROMA values best discriminated patients with OC from those with BN (AUC, 0.8966), which was equivalent to TFPI2 (AUC, 0.8937). For discriminating the OC group from the BR + BN group, the highest AUC value was achieved by ROMA values (AUC, 0.8884), and TFPI2 also showed comparable diagnostic accuracy (AUC, 0.8845). Combining TFPI2 with ROMA had the highest AUC (0.8420-0.9357)., Conclusion: TFPI2 may be a clinically useful single marker comparable to conventional ROMA values for discriminating between benign and malignant ovarian tumors., (© 2022 Japan Society of Obstetrics and Gynecology.)

Context: Metastatic intradural extramedullary spinal cord tumors are extremely rare. Findings: A 76-year-old woman presented with intractable neck pain. Three years earlier, she had been treated for ovarian cancer with bilateral salpingo-oophorectomy. A year later, she underwent resection of a brain metastasis. Magnetic resonance imaging (MRI) showed an encapsulated intradural extramedullary mass at C4-C5. C4-C5 hemilaminectomy, tumor resection, and biopsy were performed. Histological examination of the resection revealed an adenocarcinoma. After surgery, her intolerable neck-shoulder pain was fully resolved, and she had no difficulties with daily living activities. However, two months later, she underwent gamma knife radiosurgery for the recurrent metastatic brain tumor, and four months later, she died from cachexia. Conclusion: Although cases of metastatic intradural extramedullary spinal tumors from ovarian cancer are extremely rare, their possibility should be considered in the differential diagnosis. A history of brain metastases and enhancement on T1-weighted MRI were helpful for making an accurate diagnosis.

Objectives: Patients with asymptomatic venous thromboembolism (VTE) are associated with an increased risk of pulmonary thromboembolism events. However, due to low specificity and high false-positive rates, D-dimer testing cannot be used alone to diagnose VTE. Tissue factor pathway inhibitor 2 (TFPI2), a new serodiagnostic marker for ovarian cancer, plays a role in blood coagulation system regulation. We hypothesized that combining D-dimer and TFPI2 would improve its utility in diagnosing VTE. This study aimed to look into the clinical utility of serum D-dimer and TFPI2 levels in detecting asymptomatic VTE in patients with epithelial ovarian cancer (EOC)., Design: From January 2008 to December 2015, researchers at Nara Medical University Hospital's Department of Gynecology conducted a single-center retrospective study. The receiver operating characteristic (ROC) curve analysis was used to determine the diagnostic value of preoperative D-dimer, TFPI2, and D-dimer combined with TFPI2 in distinguishing VTE patients from those who did not have VTE., Participants: This study included 122 patients with EOC who met the inclusion and exclusion criteria out of 223 admitted to the hospital with EOC. The patients were divided into two groups: VTE (n = 25) and non-VTE (n = 97)., Results: There were significant differences in D-dimer, TFPI2, and CA125 levels and residual tumor between the VTE and non-VTE groups. The D-dimer level was found to be significantly related to age, body mass index, VTE, massive ascites, residual tumor, histology, and Federation of Gynecology and Obstetrics stage, whereas the TFPI2 level was only related to VTE. Multivariate analysis revealed that D-dimer (the optimal cutoff value, 3.5 μg/mL) and TFPI2 (the optimal cutoff value, 400 pg/mL) are independent risk factors for preoperative VTE. ROC analysis revealed that the area under the curve was 0.8266 for D-dimer, 0.7963 for TFPI2, and 0.8495 for the combination of D-dimer and TFPI2. When compared to the D-dimer test alone, the combination of D-dimer and TFPI2 had higher specificity (77.3-96.9%) and positive predictive value (48.8-81.2%) for the diagnosis of VTE., Limitations: This is a single-center retrospective study., Conclusion: The combination of D-dimer and TFPI2 may be useful to safely exclude VTE and select patients at high risk of VTE., (© 2022 S. Karger AG, Basel.)

Objectives: The balance between oxidative stress and antioxidant defense has been reported to differ between women with endometriosis and patients with its malignant transformation. The aim of this study is to investigate changes in redox balance in endometriosis and endometriosis-related ovarian cancer (EAOC) by simultaneously measuring iron-related compounds and bilirubin., Methods: This study included 235 patients with a histopathologically confirmed diagnosis of endometriosis (n=178) and EAOC (n=57). Cyst fluid samples were collected in Nara Medical University hospital from January 2013 to May 2019. The levels of iron-related compounds (total iron, heme iron, free iron, oxyhemoglobin [oxyHb], methemoglobin [metHb], and metHb/oxyHb ratio) and bilirubin were measured., Results: Total iron, heme iron, free iron, metHb/oxyHb ratio, and bilirubin were significantly elevated in endometriosis compared to EAOC. In both endometriosis and EAOC, iron-related compounds in the cyst were correlated with each other. There was no statistically significant difference in oxyHb and metHb levels between the two groups, but the metHb/oxyHb ratio was significantly higher in endometriosis than in EAOC. Bilirubin was positively correlated with total iron and free iron in EAOC, but there was no correlation between bilirubin and iron-related compounds in endometriosis., Conclusions: Iron-induced oxidative stress in endometriosis may exceed bilirubin-dependent antioxidant capability, while redox homeostasis in EAOC can be maintained by at least bilirubin., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Purpose: This phase III, multicenter, randomized, open-label study investigated the efficacy and safety of nivolumab versus chemotherapy (gemcitabine [GEM] or pegylated liposomal doxorubicin [PLD]) in patients with platinum-resistant ovarian cancer., Materials and Methods: Eligible patients had platinum-resistant epithelial ovarian cancer, received ≤ 1 regimen after diagnosis of resistance, and had an Eastern Cooperative Oncology Group performance score of ≤ 1. Patients were randomly assigned 1:1 to nivolumab (240 mg once every 2 weeks [as one cycle]) or chemotherapy (GEM 1000 mg/m 2 for 30 minutes [once on days 1, 8, and 15] followed by a week's rest [as one cycle], or PLD 50 mg/m 2 once every 4 weeks [as one cycle]). The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), overall response rate, duration of response, and safety., Results: Patients (n = 316) were randomly assigned to nivolumab (n = 157) or GEM or PLD (n = 159) between October 2015 and December 2017. Median OS was 10.1 (95% CI, 8.3 to 14.1) and 12.1 (95% CI, 9.3 to 15.3) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.0; 95% CI, 0.8 to 1.3; P = .808). Median PFS was 2.0 (95% CI, 1.9 to 2.2) and 3.8 (95% CI, 3.6 to 4.2) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.5; 95% CI, 1.2 to 1.9; P = .002). There was no statistical difference in overall response rate between groups (7.6% v 13.2%; odds ratio, 0.6; 95% CI, 0.2 to 1.3; P = .191). Median duration of response was numerically longer with nivolumab than GEM or PLD (18.7 v 7.4 months). Fewer treatment-related adverse events were observed with nivolumab versus GEM or PLD (61.5% v 98.1%), with no additional or new safety risks., Conclusion: Although well-tolerated, nivolumab did not improve OS and showed worse PFS compared with GEM or PLD in patients with platinum-resistant ovarian cancer., Competing Interests: Junzo HamanishiResearch Funding: MSD, Ono Pharmaceutical, Sumitomo Dainippon Pharma Noriyuki KatsumataConsulting or Advisory Role: Nippon Zoki Pharmaceutical Co, Ltd Kimio UshijimaHonoraria: AstraZeneca, Chugai Pharmaceutical, Takeda, Nippon Kayaku, MSD, Kaken Pharmaceutical, Kyowa Kirin InternationalResearch Funding: AstraZeneca, Chugai Pharmaceutical, Takeda, Kaken Pharmaceutical, Nippon Kayaku, Mochida Pharmaceutical Co, Ltd, Taiho Pharmaceutical, Eisai, Ono Pharmaceutical, AbbVie, MSD Tadashi KimuraHonoraria: Nobelpharma Co, Ltd, GE Healthcare Japan, Mochida Pharmaceutical Co, Ltd, Chugai Pharmaceutical Co, Ltd, Bayer Pharmaceuticals, Aska PharmaceuticalConsulting or Advisory Role: Fermata Pharma, Rohto PharmaceuticalResearch Funding: Fuji Pharma, Nippon Shinyaku, Takeda Yakuhin, Taihou Yakuhin, Mochida Pharmaceutical Co, Ltd, Nihon Seiyaku, Zeria Pharmaceutical Koji MatsumotoHonoraria: Chugai Pharmaceutical, AstraZeneca, Kyowa Hakko Kirin, Eisai, MSD K.K., Eli Lilly Japan K.K., Taiho Oncology, AbbVie, PfizerResearch Funding: Ono Pharmaceutical, MSD, AstraZeneca, Novartis, Chugai Pharmaceutical, Eisai Kimihiko ItoHonoraria: AstraZenecaConsulting or Advisory Role: AstraZeneca, AbbVie, Nippon Shinyaku, TerumoUncompensated Relationships: Kansai Clinical Oncology Group Hidemichi WatariHonoraria: MSD K.K., Tsumura & Co, AstraZeneca, Aska Pharmaceutical Co, Ltd, Terumo, Bayer Yakuhin, Kaken Pharmaceutical, Mochida Pharmaceutical Co, Ltd, Daiichi Sankyo/UCB Japan, Chugai Pharmaceutical, TakedaConsulting or Advisory Role: Decision Resources Group Japan, Kaken Pharmaceutical, Chugai PharmaceuticalResearch Funding: Hokkaido Welfare Federation of Agricultural Cooperatives, Kaken Pharmaceutical, Mochida Pharmaceutical Co, Ltd, Taiho Pharmaceutical, Chugai Pharmaceutical, Hokkaido Cancer Society, TakedaOther Relationship: T-PEC Nobutaka TakahashiHonoraria: Olympus, Ethicon/Johnson & Johnson, Intuitive Surgical, Kaken Pharmaceutical Kosei HasegawaHonoraria: MSD K.K., Daiichi Sankyo, Bayer Yakuhin, Bristol-Myers Squibb K.K., Chugai Pharmaceutical, AstraZeneca, EisaiConsulting or Advisory Role: MSD K.K., Kaken PharmaceuticalResearch Funding: Ono Pharmaceutical, Daiichi Sankyo, Takeda Kan YonemoriHonoraria: Eisai, Pfizer, AstraZeneca, Novartis, Taiho PharmaceuticalConsulting or Advisory Role: Chugai Pharmaceutical, Ono Pharmaceutical, Novartis, EisaiResearch Funding: Ono Pharmaceutical Kazuhiro TakeharaHonoraria: Takeda Pharmaceutical Company, AstraZeneca, Eisai, Chugai Pharmaceutical, MSD, Mochida Pharmaceutical Co, LtdResearch Funding: Chugai Pharmaceutical Hitoshi NiikuraHonoraria: Takeda Sari NakaoUncompensated Relationships: Japanese Gynecologic Oncology Group Toshiaki SaitoHonoraria: Nippon Kayaku, Kyowa Hakko Kirin, Eisai, Kaken Pharmaceutical CompanyResearch Funding: Chugai Pharmaceutical, Taiho Pharmaceutical Takayuki EnomotoHonoraria: AstraZeneca, MSD, Chugai Pharmaceutical Satoru NagaseHonoraria: Chugai Pharmaceutical, AstraZeneca Aikou OkamotoHonoraria: AstraZeneca K.K., MSD, Chugai Pharmaceutical, TakedaConsulting or Advisory Role: AstraZeneca K.K., Chugai PharmaceuticalSpeakers' Bureau: AstraZeneca K.K.Research Funding: Kissei Pharmaceutical, Meiji Holdings, Pfizer, Fuji Pharma, Taiho Pharmaceutical, Kaken Pharmaceutical, Chugai Pharmaceutical, Tsumura & Co, Daiichi Sankyo Company, Ltd, Shinnihonseiyaku, Mochida Pharmaceutical Co, Ltd, Aska Pharmaceutical Co, Ltd, Takeda, Terumo Yoshito TeraiResearch Funding: Ethicon/Johnson & Johnson, MSD, Covidien, Terumo, Daiichi Sankyo/UCB Japan, Chugai Pharmaceutical, Taiho Pharmaceutical Akira TakazawaEmployment: Ono Pharmaceutical Yusuke TakahashiEmployment: Ono PharmaceuticalStock and Other Ownership Interests: Ono Pharmaceutical Yoshinobu NambaEmployment: Ono PharmaceuticalHonoraria: Boehringer Ingelheim Daisuke AokiHonoraria: AstraZeneca K.K., MSD K.K., Takeda, Chugai Pharmaceutical, Myriad GeneticsConsulting or Advisory Role: Takeda, MSD K.K., AstraZeneca K.K.Speakers' Bureau: AstraZeneca K.K., Takeda Keiichi FujiwaraHonoraria: Kyowa Hakko Kirin, Zeria Pharmaceutical, Nippon Kayaku, Chugai Pharmaceutical, Eisai, Taiho Pharmaceutical, Daiichi Sankyo, Ono Pharmaceutical, TakedaConsulting or Advisory Role: AstraZeneca, MSD, Taiho Pharmaceutical, Eisai, Takeda, Genmab, AbbVie, Pfizer, NanoCarrierResearch Funding: Eisai, Kaken Pharmaceutical, Chugai Pharmaceutical, Shionogi, ImmunoGen, ONCOtherapeutics, AstraZeneca, Eli Lilly, Zeria Pharmaceutical, Ono Pharmaceutical, MSD, Genmab, Regeneron, Merck KGaA, Ono PharmaceuticalTravel, Accommodations, Expenses: Pfizer, AbbVie, MSDNo other potential conflicts of interest were reported.

Objective: The addition of maintenance olaparib to bevacizumab demonstrated a significant progression-free survival (PFS) benefit in patients with newly diagnosed, advanced ovarian cancer in the PAOLA-1/ENGOT-ov25 trial (NCT02477644). We evaluated maintenance olaparib plus bevacizumab in the Japan subset of PAOLA-1., Methods: PAOLA-1 was a randomized, double-blind, phase III trial. Patients received maintenance olaparib tablets 300 mg twice daily or placebo twice daily for up to 24 months, plus bevacizumab 15 mg/kg every 3 weeks for up to 15 months in total. This prespecified subgroup analysis evaluated investigator-assessed PFS (primary endpoint)., Results: Of 24 randomized Japanese patients, 15 were assigned to olaparib and 9 to placebo. After a median follow-up for PFS of 27.7 months for olaparib plus bevacizumab and 24.0 months for placebo plus bevacizumab, median PFS was 27.4 versus 19.4 months, respectively (hazard ratio [HR]=0.34; 95% confidence interval [CI]=0.11-1.00). In patients with tumors positive for homologous recombination deficiency, the HR for PFS was 0.57 (95% CI=0.16-2.09). Adverse events in the Japan subset were generally consistent with those of the PAOLA-1 overall population and with the established safety and tolerability profiles of olaparib and bevacizumab., Conclusion: Results in the Japan subset of PAOLA-1 support the overall conclusion of the PAOLA-1 trial demonstrating that the addition of maintenance olaparib to bevacizumab provides a PFS benefit in patients with newly diagnosed, advanced ovarian cancer., Trial Registration: ClinicalTrials.gov Identifier: NCT02477644., Competing Interests: Professor Keiichi Fujiwara reports receiving consulting fees and grant support from Pfizer, Eisai, Merck Sharp & Dohme, Taiho, Zeria, Chugai Pharmaceutical, Genmab, and Takeda Pharmaceutical Company, receiving grant support from Immunogen, Oncotherapy, and Regeneron, and receiving consulting fees from Novartis, Kyowa Hakko Kirin, Daiichi Sankyo, Mochida Pharmaceutical, and NanoCarrier; Dr Toyomi Satoh reports receiving consulting fees from AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo, Kyowa Kirin, Eisai, Tsumura, Nippon Kayaku, Mochida Pharmaceutical, Bayer Yakuhin, ASKA Pharmaceutical, Bristol-Myers Squibb, Taiho Pharmaceutical, Takeda Pharmaceutical Company, Kaken Pharmaceutical, Nobelpharma, and Ono Pharmaceutical; Dr Kan Yonemori reports receiving lecture fees and advisory fees from Takeda Pharmaceutical Company and Esai, receiving lecture fees from AstraZeneca, Pfizer, and Daiichi Sankyo, and advisory fees from Chugai Pharmaceutical, Ono Pharmaceutical, and Novartis; Dr Shogi Nagao reports receiving consulting fees and grant support from Takeda Pharmaceutical Company, consulting fees from Chugai Pharmaceutical, AstraZeneca, Asahi Kasei Medical, and Mochida Pharmaceutical, and grant support from AbbVie, Clovis Oncology, Pfizer, Toray, Tosoh, and Preferred Networks; Dr Philipp Harter reports receiving consulting fees and grant support AstraZeneca, Roche, Tesaro, and GlaxoSmithKline, consulting fees from Sotio, Zai Lab, Merck Sharp & Dohme, Clovis Oncology, and Immunogen, and grant support from Boehringer Ingelheim, Medac, Genmab, the European Union, Deutsche Krebshilfe, and Deutsche Forschungsgemeinschaft; Dr Isabel Palacio Vazquez reports receiving payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Novartis, GlaxoSmithKline, and Bristol-Myers Squibb, travel fees from Novartis, GlaxoSmithKline, and Roche, and advisory board fees from AstraZeneca, Bristol, GSK, and Clovis Oncology; Tomoko Fujita reports being employed by AstraZeneca and being a shareholder of AstraZeneca; Philip Rowe reports being employed by AstraZeneca; Professor Eric Pujade-Lauraine reports receiving consulting and other non-financial support from AstraZeneca, Roche, and Tesaro, consulting fees from Clovis Oncology, Incyte, and Pfizer, and holds the role as chairperson in ARCAGY Research; Professor Isabelle Ray-Coquard reports receiving consulting fees, grant and travel support from AstraZeneca and Roche, consulting fees and travel support from GlaxoSmithKline, consulting fees from Clovis Oncology, PharmaMar, Mersana Therapeutics, Deciphera Pharmaceutical, Amgen, and Chugai Pharmaceutical, grant support from Bristol Myers Squibb, and consulting fees and grant support from Merck Sharp & Dohme; Dr Hiroyuki Fujiwara, Dr Hiroyuki Yoshida, Dr Takashi Matsumoto, Dr Hiroaki Kobayashi, Dr Hugues Bourgeois, Dr Anna Maria Mosconi, and Dr Alexander Reinthaller report no potential conflict of interest relevant to this article., (Copyright © 2021. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Aims: Tissue factor pathway inhibitor (TFPI)-2 has recently emerged as a serodiagnostic marker for patients with epithelial ovarian cancer (EOC), especially clear cell carcinoma (CCC). This review discusses the biological properties of TFPI-2 and why serum levels are elevated in CCC patients., Methods: A comprehensive literature search was conducted in PubMed up until March, 2021., Results: TFPI-2 is a Kunitz-type protease inhibitor and negatively regulates the enzymatic activities, such as plasmin. TFPI-2 has been characterized as a tumor suppressor gene and was frequently downregulated through promoter hypermethylation in various human cancers. In contrast, TFPI-2 was overexpressed only in CCC. TFPI-2 may be involved in the pathophysiology of CCC, possibly through regulation of coagulation system, stabilization of extracellular matrix (ECM), and induction of intracellular signal transduction. TFPI-2 suppresses tissue factor-induced hypercoagulation in a hypoxic environment. TFPI-2, secreted by CCC cells, platelets, and adjacent vascular endothelial cells, may suppress tumor growth and invasion through ECM remodeling. Nuclear TFPI-2 may suppress matrix metalloproteinase production via transcription factors and modulate caspase-mediated cell apoptosis. CCC cells may upregulate the TFPI-2 expression to adapt to survival in the demanding environment. TFPI-2 is secreted by CCC cells and enters the systemic circulation, resulting in elevated blood levels., Discussion: Serum TFPI-2 reflects the overexpression of TFPI-2 in CCC tissues and is a potential serodiagnostic marker. Further research is needed to explore the expression, clinical significance, biological function, and potential mechanism of TFPI-2 in CCC., (© 2021 Japan Society of Obstetrics and Gynecology.)

Background: The recent improvements in anti-cancer therapy following first-line treatment can potentially impact post-progression survival. We evaluated the factors that influence post-progression survival in advanced recurrent ovarian cancer., Methods: Eighty-nine patients who underwent first-line treatment between June 2005 and December 2017 were included. The post-progression survival was defined as the difference between overall survival and initial progression-free survival. The effects of age, histology, stage, optimal surgery, secondary debulking surgery, bevacizumab administration, platinum sensitivity, and olaparib maintenance in recurrence were compared and independent risk factors were determined., Results: The median follow-up duration was 60.0 months (range: 2-181). Platinum-sensitive recurrence had longer post-progression survival than platinum-resistant (P < 0.001). Inclusion of bevacizumab in first-line treatment did not produce a significant difference in post-progression survival (P = 0.462). Secondary debulking surgery (P = 0.013), bevacizumab administration (P < 0.001), and olaparib maintenance (P = 0.001) during recurrence increased post-progression survival. In multivariate analysis, histologies other than serous or endometrioid (hazard ratio = 2.389; 95% confidence interval = 1.200-4.754; P = 0.013) and non-bevacizumab usage in recurrence (hazard ratio = 4.484; 95% confidence interval = 1.939-10.370; P < 0.001) were independently correlated with poorer prognosis. Bevacizumab administration beyond progressive disease elicited improved post-progression survival (P < 0.001). In patients receiving bevacizumab in first-line treatment, exclusion of bevacizumab in the recurrent therapy (hazard ratio = 5.507; 95% confidence interval = 2.301-12.124; P < 0.001) was independently correlated with poorer prognosis., Conclusions: The continuous use of bevacizumab beyond progressive disease improves post-progression survival suggesting its important role in first-line and recurrence treatment for ovarian cancer., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Tissue factor pathway inhibitor 2 (TFPI2) is a novel serum biomarker that discriminates ovarian clear cell carcinoma (CCC) from borderline ovarian tumors (BOTs) and non-clear cell epithelial ovarian cancers (EOCs). Here, we examined the performance of TFPI2 for preoperative diagnosis of CCC., Methods: Serum samples were obtained preoperatively from patients with ovarian masses, who needed surgical treatment at five hospitals in Japan. The diagnostic powers of TFPI2 and cancer antigen 125 (CA125) serum levels to discriminate CCC from BOTs, other EOCs, and benign lesions were compared., Results: A total of 351 patients including 69 CCCs were analyzed. Serum TFPI2 levels were significantly higher in CCC patients (mean ± SD, 508.2 ± 812.0 pg/mL) than in patients with benign lesions (154.7 ± 46.5), BOTs (181 ± 95.5) and other EOCs (265.4 ± 289.1). TFPI2 had a high diagnostic specificity for CCC (79.5%). In patients with benign ovarian endometriosis, no patient was positive for TFPI2, but 71.4% (15/21) were CA125 positive. TFPI2 showed good performance in discriminating stage II-IV CCC from BOTs and other EOCs (AUC 0.815 for TFPI2 versus 0.505 for CA125) or endometriosis (AUC 0.957 for TFPI2 versus 0.748 for CA125). The diagnostic sensitivity of TFPI2 to discriminate CCC from BOTs and other EOCs was improved from 43.5 to 71.0% when combined with CA125., Conclusions: High specificity of TFPI2 for preoperative detection of CCC was verified with the defined cutoff level of TFPI2 in clinical practice. TFPI2 and CA125 may contribute substantially to precise prediction of intractable CCC.

Background: Ovarian clear cell carcinoma (OCCC) is resistant to platinum chemotherapy and is characterized by poor prognosis. Today, the use of poly (ADP-ribose) polymerase (PARP) inhibitor, which is based on synthetic lethality strategy and characterized by cancer selectivity, is widely used for new types of molecular-targeted treatment of relapsed platinum-sensitive ovarian cancer. However, it is less effective against OCCC., Methods: We conducted siRNA screening to identify synthetic lethal candidates for the ARID1A mutation; as a result, we identified Cyclin-E1 ( CCNE1 ) as a potential target that affects cell viability. To further clarify the effects of CCNE1 , human OCCC cell lines, namely TOV-21G and KOC7c ( ARID1A mutant lines), and RMG-I and ES2 ( ARID1A wild type lines) were transfected with siRNA targeting CCNE1 or a control vector., Results: Loss of CCNE1 reduced proliferation of the TOV-21G and KOC7c cells but not of the RMG-I and ES2 cells. Furthermore, in vivo interference of CCNE1 effectively inhibited tumor cell proliferation in a xenograft mouse model., Conclusion: This study showed for the first time that CCNE1 is a synthetic lethal target gene to ARID1A -mutated OCCC. Targeting this gene may represent a putative, novel, anticancer strategy in OCCC treatment.

A high pre-treatment plasma D-dimer level was recently identified as a poor prognostic factor in several malignancies. The aim of this study was to evaluate the prognostic significance of plasma D-dimer levels in epithelial ovarian cancer (EOC). Data of 199 patients were retrospectively analysed. The relationships between pre-treatment D-dimer levels and other clinical parameters and prognosis were evaluated. Univariate analysis identified age, pre-treatment plasma D-dimer level, massive ascites, residual tumours, pre-treatment CA125 level, histological type, and FIGO stage as predictors of overall survival. The multivariate analysis showed that a high pre-treatment plasma D-dimer level ( p =.017), residual tumours ( p  < .001), and FIGO stage ( p  = .036) were independent risk factors of overall survival. Venous thromboembolism (VTE) did not influence overall survival ( p =.091). High pre-treatment D-dimer levels are associated with a poor prognosis independent of VTE status in EOC patients, and might be a useful prognostic biomarker.Impact statement What is already known on this subject? In recent years, a high pre-treatment plasma D-dimer level has been identified as a prognostic factor in several malignancies, but only a handful of studies have assessed the role of pre-treatment plasma D-dimer levels in patients with EOC patients. Thus, the clinical significance and prognostic value of the plasma D-dimer level in EOC remain controversial, and there is also debate related to the association of the higher mortality rate among cancer patients with elevated D-dimer levels with VTE. What do the results of this study add? In our study, high pre-treatment D-dimer levels are associated with a poor prognosis independently of VTE in EOC patients. What are the implications of these findings for clinical practice and/or further research? The D-dimer level might emerge as a valuable prognostic biomarker, which will help doctors in the choice of initiating a more aggressive therapy, the combination of chemotherapy with anticoagulation therapy.

Aim: Expression of CD44 variant isoforms (CD44v) promotes the synthesis of reduced glutathione and contributes to reactive oxygen species defense through up-regulation of the intracellular antioxidant. The aim of the study was to investigate the expression of CD44v9 and oxidative DNA damage marker, 8-OHdG, in benign ovarian endometrioma (OE) and OE harboring clear cell carcinomas (CCC)., Methods: A retrospective study was performed at the Department of Gynecology, Nara Medical University hospital from January 2006 to December 2012. Patients with histologically confirmed benign OE (n = 27) and OE harboring areas of CCC (n = 8) were selected. Tissue samples were immunohistochemically analyzed for the presence of CD44v9 and 8-OHdG using avidin-biotin complex method., Results: CD44v9 was located on the cell membrane of endometriotic epithelial cells and expressed in 88.9% (24/27) of benign OE tissues. Only 25.0% (2/8) of benign endometriotic lesions adjacent to CCC was found to stain weakly for CD44v9. Percentage of CD44v9 positive cells was 68.5 ± 20.2% (mean ± standard deviation) of benign OE, 16.7 ± 16.5% of CCC endometriotic tissue (P < 0.001). Compared to benign OE, CCC endometriotic tissue showed a significant increase in the proportion of 8-OHdG expression (77.3 ± 22.5% vs 94.9 ± 3.0%, P = 0.049). A significant negative correlation was observed between CD44v9 status and 8-OHdG nuclear expression (r = -0.458, P  =  0.006)., Conclusion: Alterations in CD44v9 and 8-OHdG may be associated with malignant transformation of benign OE., (© 2019 Japan Society of Obstetrics and Gynecology.)

Introduction: Magnetic resonance (MR) relaxometry provides a noninvasive predictive tool to discriminate between benign ovarian endometrioma (OE) and endometriosis-associated ovarian cancer (EAOC). Transverse relaxation rate R2 value was determined using a single-voxel, multi-echo MR sequence (HISTO) by a 3T-MR system. R2 with cutoff value of 12.1 s was established to discriminate between benign and malignant tumors., Patient Concerns: We present a case of a 39-year-old woman who was initially thought to be malignant transformation of endometriosis by diagnostic MR imaging of the vascularized solid components., Diagnosis: A R2 value of 42.62 s on MR relaxometry demonstrated that this case is non-malignant., Interventions: To confirm the diagnose, left salpingo-oophorectomy by laparoscopic surgery was performed., Outcomes: Histopathological results revealed seromucinous borderline tumor (SMBT). Our experience suggests that preoperative MR relaxometry may be useful for discriminating "borderline (SMBT)" from "malignancy (EAOC)." Furthermore, immunohistochemical studies of this case demonstrated ovarian SMBT cells were positive for estrogen receptor, progesterone receptor, and hepatocyte nuclear factor-1beta. A similar expression pattern was also observed in patients with benign OE., Lessons: In many respects, SMBT characteristics differ from those of EAOC but resemble those of benign OE. MR relaxometry unveils a new clinical approach as an adjunctive modality for discriminating SMBT from EAOC.

Malignant transformation of endometriosis is a rare and still poorly understood event, but is associated with the distortion of the pro-oxidant and anti-oxidant balance. The aim of the present study was to quantify the numbers of macrophages polarized as M1 or M2 phenotypes and the expression of heme oxygenase (HO)-1 in tissue sections from patients with benign ovarian endometrioma (OE) and its malignant transformation (endometriosis-associated ovarian cancer, EAOC). We performed a retrospective study at the Department of Gynecology, Nara Medical University hospital from December 2012 to March 2015. This study included 53 patients with OE (n = 33) and EAOC (n = 20), and we evaluated polarized functional status of macrophages by immunohistochemical staining of CD68, CD11c, CD163 and HO-1. The number of the M1 phenotype (CD11c + , p = 0.001) and the M2 phenotype (CD163 + , p = 0.009) was significantly lower in EAOC patients than in OE patients. Analyzing the correlations between the studied markers, the expression of CD68, CD11c, and CD163 proteins significantly correlated with each other (p < 0.001). The number of M2 phenotypes expressing HO-1 was significantly decreased in the EAOC group, compared with the OE group (P < 0.001), demonstrating sustained downregulation of an antioxidant marker, HO-1, in EAOC. In conclusion, reduced number of M2 macrophages expressing HO-1 may have an important role in promoting malignant transformation of OE., (Copyright © 2018. Published by Elsevier GmbH.)

In the present study, we summarize the role of the shared and independent (epi)genetic background between endometrioid carcinoma (EC) and clear cell carcinoma (CCC), two histological subtypes of endometriosis-associated ovarian cancer (EAOC). Using the PubMed database, we conducted a literature review of various studies related to the malignant transformation of endometriosis. Both endometriosis and EAOC face potential environmental hazards, including hemoglobin (Hb), heme and free iron, which induces DNA damage and mutations. Although EC is distinguished from CCC due to different morphologies, both represent common environmental profiles and maintain the similar (epi)genomic abnormalities with multiple overlaps and share similar molecular signatures. By contrast, EAOC also has disease-specific gene signatures corresponding with each histological subtype: Estrogen receptor promotes EC cell proliferation ('go') and hepatocyte nuclear factor-1β (HNF-1β) induces CCC cell cycle arrest ('stop') under oxidative stress conditions. This model underscores a subtype-dependent 'go or stop' dichotomy, possibly through better ability to adapt in a changing environment. It was found that cyst fluid Hb and iron concentrations were significantly lower in EAOC when compared to benign ovarian endometrioma (OE), supporting the hypothesis that the redox imbalance plays a key role in the pathogenesis of EAOC. There are at least two phases of iron carcinogenesis and tumor progression: The initial wave of iron-induced oxidative stress and DNA mutations would be followed by the second big wave of subsequent synthesis of the antioxidants, which diminishes cellular oxidative stress capacity, increases apoptosis resistance and promotes tumor initiation and progression. Special emphasis is given to novel pathophysiological concepts of malignant transformation of endometriosis.

Background: Common cancerous histological types associated with endometriosis are clear cell carcinoma (CCC) and endometrioid carcinoma (EC). CCC is regarded as an aggressive, chemoresistant histological subtype. Magnetic resonance imaging (MRI) offers some potential advantages to diagnose ovarian tumors compared with ultrasonography or computed tomography. This study aimed to identify MRI features that can be used to differentiate between CCC and EC., Methods: We searched medical records of patients with ovarian cancers who underwent surgical treatment at Nara Medical University Hospital between January 2008 and September 2018; we identified 98 patients with CCC or EC who had undergone preoperative MRI. Contrasted MRI scans were performed less than 2 months before surgery. Patients were excluded from the study if they had no pathology, other pathological subtype of epithelial ovarian cancer, and/or salvage treatment for recurrence and metastatic ovarian cancer at the time of study initiation. Clinically relevant variables that were statistically significant by univariate analysis were selected for subsequent multivariate regression analysis to identify independent factors to distinguish CCC from EC., Results: MRI of CCC and EC showed a large cystic heterogeneous mixed mass with mural nodules protruding into the cystic space. Univariate logistic regression analysis revealed that the growth pattern (broad-based nodular structures [multifocal/concentric sign] or polypoid structures [focal/eccentric sign]), surface irregularity (a smooth/regular surface or a rough/irregular/lobulated surface), "Width" of mural nodule, "Height-to-Width" ratio (HWR), and presence of preoperative ascites were factors that significantly differed between CCC and EC. In the multivariate logistic regression analysis, the growth pattern of the mural nodule (odds ratio [OR] = 0.69, 95% confidence interval [CI]: 0.013-0.273, p = 0.0004) and the HWR (OR = 3.71, 95% CI: 1.128-13.438, p = 0.036) were independent predictors to distinguish CCC from EC., Conclusions: In conclusion, MRI data showed that the growth pattern of mural nodules and the HWR were independent factors that could allow differentiation between CCC and EC. This finding may be helpful to predict patient prognosis before operation.

Background: The purpose of this study was to clarify the clinicopathological characteristics of, and the clinical approach used to identify, atypical glandular cells (AGCs) in Japan based on cervical cytology screening., Objectives: This study included 1,254 patients with AGCs who underwent cervical cytology., Method: Data from patients with AGCs were used to examine the practical management of AGCs and the histological results., Results: The incidence of AGCs was 0.20% (1,254/614,791). The 1,254 AGC cases included 859 endocervical cells not otherwise specified (NOS), 3 glandular cells NOS, 91 endocervical cells favor neoplasia (FN), and 301 atypical endometrial cells (AEMCs). Among the 1,254 AGC patients, the histological diagnosis was benign in 666 (53.1%), cervical intraepithelial neoplasia (CIN) 1 in 60 (4.8%), CIN2 in 31 (2.5%), CIN3 in 52 (4.1%), squamous cell carcinoma in 19 (1.5%), adenocarcinoma in situ in 39 (3.1%), cervical adenocarcinoma in 106 (8.5%), endometrial carcinoma in 209 (16.7%), ovarian cancer in 26 (2.1%), other malignancy in 4 (0.3%), and other under follow-up in 42 (3.3%). When the 1,254 AGC patients were divided into three medical intervention degrees according to histology, AGC-NOS, AGC-FN, and AEMC required no medical intervention in 78.7, 13.2, and 25.9% (678, 12, and 78) of the patients, cervical cone resection in 13.0, 9.9, and 0.3% (112, 9, and 1) of the patients, and radical laparotomy for invasive cancer in 8.3, 76.9, and 73.8% (72, 70, and 222) of the patients, respectively., Conclusions: Our histological results supported the medical interventions applied for AGC diagnosis and treatment. AGC cases require careful histological evaluation., (© 2019 S. Karger AG, Basel.)

Purpose: Mural nodules and papillary projections can be seen in benign ovarian endometriosis (OE) and malignant transformation of OE (endometriosis-associated ovarian cancer [EAOC]), which can pose a challenging diagnostic dilemma to clinicians. We identify the preoperative imaging characteristics helpful to the differential diagnosis between benign OE with mural nodules and EAOC., Materials and Methods: This was a retrospective study of 82 patients who were diagnosed pathologically to have OE with mural nodules (n = 42) and malignant transformations of these tumors (n = 40) at the Nara Medical University Hospital from January 2008 to January 2015. All patients were assessed with contrast-enhanced MRI before surgery. Patient demographics, and clinical and pathologic features were analyzed to detect the significant differences between the two groups., Results: Histological examinations of resected OE tissue specimens revealed that a majority (78.6%) of the mural nodular lesions were retracted blood clots. We found that the patients with malignant mural nodules, when compared to those with benign nodules, were older, had larger cyst diameters and larger mural nodule sizes, and were more likely to exhibit a taller than wider lesion. They were also more likely to present with various signal intensities on T 1 -weighted images (T 1 WI), high-signal intensity on T 2 -weighted images (T 2 WI), a lower proportion of shading on T 2 WI, and were more likely to show an anterior location of the cyst. In the multivariate logistic regression analysis, "Height" (>1.5 cm) and "Height-Width ratio (HWR)" (>0.9) of mural nodules, maximum diameter of the cyst (>7.9 cm), and age at diagnosis (>43 years) were independent predictors to distinguish EAOC from OE with mural nodules., Conclusion: The "Height" and "HWR" of the mural nodules in the cyst may yield a novel potential diagnostic factor for differentiating EAOC from benign OE with mural nodules.

The mechanism of high-grade serous ovarian cancer (HGSC) development remains elusive. This review outlines recent advances in the understanding of sequential molecular changes associated with the development of HGSC, as well as describes oxidative stress-induced genomic instability and carcinogenesis. This article reviews the English language literature between 2005 and 2017. Clinicopathological features analysis provides a sequential progression of fallopian tubal epithelium to precursor lesions to type 2 HGSC. HGSC may develop over a long time after incessant ovulation and repeated retrograde menstruation via stepwise accumulation of genetic alterations, including PAX2, ALDH1A1, STMN1, EZH2 and CCNE1, which confer positive selection of cells with growth advantages through acquiring driver mutations such as BRCA1/2, p53 or PTEN/PIK3CA. Haemoglobin and iron-induced oxidative stress leads to the emergence of genetic alterations in fallopian tubal epithelium via increased DNA damage and impaired DNA repair. Serous tubal intraepithelial carcinoma (STIC), the likely precursor of HGSC, may be susceptible to DNA double-strand breaks, exhibit DNA replication stress and increase genomic instability. The induction of genomic instability is considered to be a driving mechanism of reactive oxygen species (ROS)-induced carcinogenesis. HGSC exemplifies the view of stepwise cancer development. We describe how genetic alterations emerge during HGSC carcinogenesis related to oxidative stress.

Aim: Hand-foot syndrome (HFS) induced by chemotherapy and molecule-targeting drugs is correlated with treatment efficacy. We conducted a retrospective analysis to evaluate the relationship between HFS and efficacy of pegylated liposomal doxorubicin (PLD) for recurrent ovarian cancer., Methods: Patients were treated with PLD between July 2009 and May 2014. We evaluated patient characteristics, incidence of adverse events, clinical benefit (rate of complete response, partial response, and stable disease), progression-free survival, and overall survival., Results: Twenty-seven patients were included in the study. Median age was 63 years (range, 41-77 years). The median number of cycles of PLD was 3 (range, 1-6). The clinical benefit rate was 33.3%, and progressive disease was noted in 18 patients (66.7%). Median overall survival was 6.7 months (range, 1.1-41 months). Compared with patients with grade 0/1 HFS and oral mucositis, patients with grade 2-4 toxicity (n = 9, 33.3%) had a significantly higher rate of clinical benefit (11.1% vs 77.7%; P < 0.001) and a longer median overall survival (3.7 months vs 20.8 months; P < 0.001)., Conclusions: Severity of HFS and mucositis may be a predictive marker of PLD efficacy. The prevention and management of HFS and mucositis are important for continued treatment., (© 2017 Japan Society of Obstetrics and Gynecology.)

Purpose: We proposed to detect the in vivo enzyme activity of γ-glutamyl transferase (GGT) within mouse models of human ovarian cancers using catalyCEST MRI with a diamagnetic CEST agent., Methods: A CEST-FISP MRI protocol and a diamagnetic CEST agent were developed to detect GGT enzyme activity in biochemical solution. A quantitative Michaelis-Menten enzyme kinetics study was performed to confirm that catalyCEST MRI can measure enzyme activity. In vivo catalyCEST MRI studies generated pixel-wise activity maps of GGT activities. Ex vivo fluorescence imaging was performed for validation., Results: CatalyCEST MRI selectively detected two CEST signals from a single CEST agent, whereby one CEST signal was responsive to GGT enzyme activity and the other CEST signal was an unresponsive control signal. The comparison of these CEST signals facilitated in vivo catalyCEST MRI studies that detected high GGT activity in OVCAR-8 tumors, low GGT activity in OVCAR-3 tumors, and low or no GGT activity in muscle tissues., Conclusion: CatalyCEST MRI with a diamagnetic CEST agent can detect the level of GGT enzyme activity within in vivo tumor models of human ovarian cancers. Magn Reson Med 77:2005-2014, 2017. © 2016 International Society for Magnetic Resonance in Medicine., (© 2016 International Society for Magnetic Resonance in Medicine.)

Fast, selective, and noninvasive reporting of intracellular cancer-associated events and species will lead to a better understanding of tumorigenesis at the molecular level and development of precision medicine approaches in oncology. Overexpressed reductase presence in solid tumor cells is key to cancer progression and protection of those diseased cells from the oxidative effects of therapeutics meant to kill them. Human NAD(P)H:quinone oxidoreductase isozyme I (hNQO1), a cytoprotective 2-electron-specific reductase found at unusually high activity levels in cancer cells of multiple origins, has attracted significant attention due to its major role in metastatic pathways and its link to low survival rates in patients, as well as its ability to effectively activate quinone-based, anticancer drugs. Accurate assessment of hNQO1 activities in living tumor models and ready differentiation of metastases from healthy tissue by fluorescent light-based protocols requires creation of hNQO1-responsive, near-infrared probes that offer deep tissue penetration and low background fluorescence. Herein, we disclose a quinone-trigger-based, near-infrared probe whose fluorescence is effectively turned on several hundred-fold through highly selective reduction of the quinone trigger group by hNQO1, with unprecedented, catalytically efficient formation of a fluorescent reporter. hNQO1 activity-specific production of a fluorescence signal in two-dimensional cultures of respiring human cancer cells that harbor the reductase enzyme allows for their quick (30 min) high-integrity recognition. The characteristics of the near-infrared probe make possible the imaging of clinically relevant three-dimensional colorectal tumor models possessing spatially heterogeneous hNQO1 activities and provide for fluorescence-assisted identification of submillimeter dimension metastases in a preclinical mouse model of human ovarian serous adenocarcinoma.

Purpose: Heme and iron accumulation due to repeated hemorrhage in endometriosis may contribute to a pivotal role in carcinogenesis. We evaluate the clinical application of MR relaxometry in a series of ovarian endometriosis (OE) and endometriosis-associated ovarian cancer (EAOC)., Materials and Methods: A prospective study of diagnostic accuracy was conducted among 82 patients (67 OE and 15 EAOC) to compare MR relaxometry and biochemical measurement of cyst fluid total iron concentration. Transverse relaxation rate R2 value was determined using a single-voxel, multi-echo MR sequence (HISTO) by a 3T-MR system. Phantom experiments were also performed to assess the correlation between the ex vivo R2 values and total iron concentrations., Results: Both the results of phantom experiments and in vivo human data confirmed that in vivo R2 values were highly correlated with total iron concentrations. Compared to OE, EAOC exhibit decreased in vivo R2 values and total iron levels, regardless of their age, menopausal status and cyst size. The use of in vivo R2 values retained excellent accuracy in distinguishing EAOC versus OE (sensitivity and specificity: 86% and 94%)., Conclusions: We have demonstrated that MR relaxometry provides a noninvasive predictive tool to discriminate between EAOC and OE.

Near-infrared photoimmunotherapy (NIR-PIT) is a highly cell-selective cancer therapy based on an armed antibody conjugated with a phthalocyanine-based photo-absorber, IRDye700DX (IR700). NIR-PIT can quickly kill target cells that express specific proteins on the cellular membrane but only when the antibody-IR700 conjugate binds to the cell membrane and is then exposed to NIR light. NIR-PIT is highly selective based on the specificity of the antibody. Galactosyl serum albumin (GSA) is composed of albumin decorated with galactose molecules conjugated to the carboxyl groups of albumin. GSA binds to beta-D-galactose receptors, a surface lectin, which are overexpressed on the cell surface of many cancers, including ovarian cancers and is quickly internalized after binding. Here, we demonstrate the feasibility of NIR-PIT in a model of disseminated peritoneal ovarian cancer (SHIN3 cells) using GSA-IR700 that binds to beta-D-galactose receptors. GSA-IR700 bound quickly to SHIN3 cells, then accumulated in the endo-lysosomes. Cell-specific killing was observed in vitro, yet a relatively large dose of NIR light exposure was required for cell killing compared to antibody-IR700 conjugates. To evaluate in vivo therapeutic effects of GSA-IR700 NIR-PIT, peritoneal disseminated SHIN3 tumor-bearing mice were separated into four groups: no treatment; NIR light only; GSA-IR700 only; and GSA-IR700 NIR-PIT. Repeated NIR-PIT showed significant suppression of tumor based on bioluminescence compared to the other groups (p < 0.05). Thus, repeated NIR-PIT using GSA-IR700 can achieve efficient antitumor effects, although GSA-IR700 NIR-PIT was less effective than antibody-IR700 NIR-PIT conjugates likely due to the rapid internalization of GSA-IR700.

Background: In clinical practice, 40mg/m 2 of pegylated liposomal doxorubicin (PLD40) has been used as an initial dosage for treating recurrent epithelial ovarian cancer (OC) instead of the recommended dose of 50mg/m 2 (PLD50). However, no robust evidence is available to support the use of PLD40. This post-hoc study aimed to compare the efficacy and safety of initial PLD dosages in propensity score (P-score)-matched dataset., Methods: The data source was a PLD postmarketing surveillance dataset (n=2189) conducted in Japan. Eligibility criteria for the present study were as follows: recurrent OC, history of chemotherapy, and treatment with PLD monotherapy at a dosage between 35.5 and 54.4mg/m 2 . Overall survival (OS) was compared between PLD50- and PLD40-treated groups using the log-rank test. Incidences of palmar-plantar erythrodysesthesia (PPE) and stomatitis were also compared between the groups., Results: Overall, 503 matched pairs were generated using P-score analysis. The median survival time with PLD50 and PLD40 was 383 and 350days, respectively, with a hazard ratio of 1.10 (95% confidence interval, 0.98-1.26; p=0.211), although the difference was not statistically significant in the P-score-matched dataset. However, the incidence and severity of PPE and stomatitis were significantly lower with PLD40., Conclusions: Our study showed that the efficacy of PLD did not differ based on initial dosages, but the risk of adverse events was reduced with PLD40. Considering the balance between patient benefits and risks, our results support the use of PLD40 in clinical practice., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: There is currently no reliable serum biomarker for ovarian clear cell carcinoma (CCC), a highly lethal histological subtype of epithelial ovarian cancer (EOC). Previously, using a proteome-based approach, we identified tissue factor pathway inhibitor 2 (TFPI2) as a candidate serum biomarker for CCC. In this study, we sought to evaluate the clinical diagnostic performance of TFPI2 in preoperative prediction of CCC., Methods: Serum TFPI2 levels were measured in serum samples from a retrospective training set consisting of patients with benign and borderline ovarian tumors, EOC subtypes, and uterine diseases. Via receiver operating characteristic (ROC) analyses, we compared the diagnostic performance of TFPI2 with that of CA125 in discrimination of patients with ovarian CCC from other patient groups. The observed diagnostic performances were examined in a prospective validation set., Results: The 268-patient training set included 29 patients with ovarian CCC. Unlike CA125, which was also elevated in patients with endometriosis and several EOC subtypes, serum TFPI2 levels were specifically elevated only in ovarian CCC patients, consistent with the mRNA expression pattern in tumor tissues. The area under the ROC curve (AUC) of serum TFPI2 was obviously higher than that of CA125 for discrimination of CCC from other ovarian diseases (AUC = 0.891 versus 0.595). Applying a cut-off value of 280 pg/mL, TFPI2 could distinguish early-stage (FIGO I and II) CCC from endometriosis with 72.2% sensitivity, 93.3% specificity, and 88.8% accuracy. Similar results were confirmed in an independent 156-patient prospective validation set., Conclusions: TFPI2 is a useful serum biomarker for preoperative clinical diagnosis of CCC., Competing Interests: NA had previously received a research funding from Tosoh Co., Ltd. for another research project. NA, Y. Masuishi, FH, HH and EM are inventors of patents on ovarian CCC biomarkers filed by and issued to Yokohama City University. Also, NA, NO, HH, and EM are inventors of patents related to TFPI2 in ovarian CCC diagnosis which are jointly filed by Yokohama City University and Tosoh Co., Ltd. These facts do not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

FBXW7 is a ubiquitin ligase that mediates ubiquitylation of oncoproteins, such as c-Myc, cyclin E, Notch and c-Jun. FBXW7 is a known tumor-suppressor gene, and mutations in FBXW7 have been reported in various human malignancies. In this study, we examined the sequences of the FBXW7 and p53 genes in 57 ovarian cancer clinical samples. Interestingly, we found no FBXW7 mutations associated with amino acid changes. We also investigated FBXW7 expression levels in 126 epithelial ovarian tumors. FBXW7 expression was negatively correlated with the malignant potential of ovarian tumors. That is to say, FBXW7 expression levels in ovarian cancer samples were significantly lower than those in borderline and benign tumors (P < 0.01). FBXW7 expression levels in serous carcinoma samples were the lowest among four major histological subtypes. In addition, p53-mutated ovarian cancer samples showed significantly lower levels of FBXW7 expression compared with p53 wild-type cancer samples (P < 0.001). DNA methylation arrays and bisulfite PCR sequencing experiments revealed that 5'-upstream regions of FBXW7 gene in p53-mutated samples were significantly higher methylated compared with those in p53 wild-type samples (P < 0.01). This data indicates that p53 mutations might suppress FBXW7 expression through DNA hypermethylation of FBXW7 5'-upstream regions. Thus, FBXW7 expression was downregulated in ovarian cancers, and was associated with p53 mutations and the DNA methylation status of the 5'-upstream regions of FBXW7., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: We conducted a phase III, non-inferiority trial comparing upfront primary debulking surgery (PDS) and interval debulking surgery (IDS) following neoadjuvant chemotherapy (NAC) for stage III/IV ovarian, tubal, and peritoneal cancers (JCOG0602). Two earlier studies, EORTC55971 and CHORUS, demonstrated non-inferior survival of patients treated with NAC. However, they could not evaluate true treatment invasiveness because of adding diagnostic laparotomy or laparoscopy before treatment in over 30% of both arms of EORTC55971 and in 16% of NAC arm of CHORUS., Methods: Patients were randomised into the standard arm (PDS followed by eight cycles of paclitaxel and carboplatin [TC]) and NAC arm (four cycles of TC, IDS, and four cycles of TC). In the standard arm, IDS was optional for patients who had undergone suboptimal or incomplete PDS. Treatment invasiveness was compared between arms (UMIN000000523)., Results: Between November 2006 and October 2011, 301 patients were randomised. In the standard arm, 147/149 underwent PDS and 49 underwent IDS. In the NAC arm, 130/152 underwent IDS. The NAC arm required fewer surgeries (mean 0.86 versus 1.32, p < 0.001) and shorter total operation time (median 273 min versus 341 min, p < 0.001) than the standard arm and required a lower frequency of abdominal organ resection (23.7% versus 37.6%, p = 0.012) or distant metastases resection (3.9% versus 10.7%, p = 0.027). In the NAC arm IDS, blood/ascites loss was smaller (median 787 ml versus 3235 ml, p < 0.001) and albumin transfusion and G3/4 adverse events after surgery in total were less frequent (26.2% versus 58.5%, p < 0.001; 4.6% versus 15.0%, p = 0.005, respectively)., Conclusion: Our findings demonstrated that NAC treatment is less invasive than standard treatment. NAC treatment may become the new standard treatment for advanced ovarian cancer when non-inferior survival is confirmed in the planned primary analysis in 2017., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objectives: The aim of this review was to highlight recent advances in our understanding of the pathogenesis of malignant transformation of endometriosis., Methods: This study reviewed the English-language literature concerning basic science studies of the potential promotion of carcinogenesis., Results: Repeated episodes of hemorrhage occur in endometriosis at the onset of menstruation. Extracellular hemoglobin, heme, and iron derivatives in endometriosis cause DNA damage and mutations, which create increased cellular susceptibility to oxidant-mediated cell killing. Excess DNA damage and mutations are linked to cell death, but not carcinogenesis. In response to an oxidative and inflammatory microenvironment, endometriotic cells and macrophages secrete antioxidants that control excess oxidative stress in the surrounding environment. Exposure of endometriotic cells to a sublethal level of oxidative stress may lead to carcinogenesis. Macrophages also secrete immunosuppressive factors that lead to promotion of malignant transformation., Discussion: At least two potential scenarios could result in ovarian cancer arising from endometriosis. The first step: extracellular hemoglobin, heme, and iron cause cellular oxidative damage by promoting reactive oxygen species formation, which results in DNA damage and mutations (ovarian cancer initiation from endometriosis). The second step: cancer progression may be associated with persistent antioxidant production favoring a protumoral microenvironment.

We report an incidental case of intravascular large B-cell lymphoma (IVLBCL) coexisting with an ovarian carcinoma in a 76-year-old woman. She visited our hospital with difficulty in defecation. Magnetic resonance imaging and computerized tomography scan revealed a solid and cystic mass probably arising from the left ovary. Gross examination of the tumor obtained by an exploratory surgery showed a solid area in a simple cyst. The ovarian tumor was diagnosed as a high-grade serous carcinoma (HGSC). Early in the post-operative course, this patient developed fever of unknown origin with central nervous system manifestations. Magnetic resonance imaging of the brain showed multiple space-occupying lesions. When we reviewed the histological sections, atypical lymphocytes were found in the lumina of small vessels of almost the entire ovary. These cells were positive for CD20 and CD79a by immunohistochemistry. A diagnosis of IVLBCL coexisting with HGSC was finally made. Although radiation therapy for brain lesions was performed and rituximab was administered, she died two months after the operation. To the best of our knowledge, this is the first case of IVLBCL incidentally identified in HGSC through microscopic examination. This case serves to create awareness of the rare event where IVLBCL may involve the ovary of patients who also have carcinoma in the organ.

Background: Although several studies have demonstrated the tumor suppressive function of CNN1 (calponin 1), no studies have performed a site-specific analysis of CNN1 on tumor cell activities., Materials and Methods: We herein studied the site-specific effects of CNN1 in ovarian cancer cells using full-length CNN1 (fCNN1), three CNN1 repeats (3CNRs), or the first CNN1 repeat (CNR1) expression vectors. Ovarian cancer cells stably expressing each construct were analyzed for in vitro proliferation, cell motility, invasion, and soft agar assays. An in vitro model of pleural dissemination was also established., Results: Cell proliferation, anchorage-independent colony formation, cell motility, and cell invasion were all suppressed in fCNN1, 3CNRs, and CNR1-stably-expressing cells. CNN1 expression in mesothelial cells suppressed cancer cell invasion into a monolayer of mesothelial cells., Conclusion: CNR1 showed similar suppressive effects as fCNN1. Results suggest CNR1 as a potential small synthetic peptide candidate for therapeutic strategies against ovarian cancer., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Fluorescence-guided diagnostics is one of the most promising approaches for facile detection of cancer in situ. Here we focus on β-galactosidase, which is overexpressed in primary ovarian cancers, as a molecular target for visualizing peritoneal metastases from ovarian cancers. As existing fluorescence probes are unsuitable, we have designed membrane-permeable HMRef-βGal, in which the optimized intramolecular spirocyclic function affords >1,400-fold fluorescence enhancement on activation. We confirm that HMRef-βGal sensitively detects intracellular β-galactosidase activity in several ovarian cancer lines. In vivo, this probe visualizes metastases as small as <1 mm in diameter in seven mouse models of disseminated human peritoneal ovarian cancer (SHIN3, SKOV3, OVK18, OVCAR3, OVCAR4, OVCAR5 and OVCAR8). Because of its high brightness, real-time detection of metastases with the naked eye is possible. Endoscopic fluorescence detection of metastases is also demonstrated. The results clearly indicate preclinical potential value of the probe for fluorescence-guided diagnosis of peritoneal metastases from ovarian cancers.

Aim: The aim of this study was to investigate prognostic factors, including postoperative chemotherapy regimen, for the treatment of ovarian yolk sac tumour (YST), and resulting fertility outcome., Methods: A multi-institutional retrospective investigation was undertaken to identify patients with ovarian pure or mixed YST who were treated between 1980 and 2007. Postoperative chemotherapy regimen and other variables were assessed in univariate and multivariate analyses. Additionally, the reproductive safety of the BEP (bleomycin, etoposide and cisplatin) regimen was evaluated., Results: There were 211 patients enrolled from 43 institutions. The BEP regimen and a non-BEP regimen were administered to 112 and 99 patients as postoperative chemotherapy, respectively. In univariate and multivariate analyses, age⩾22, alpha-fetoprotein⩾33,000 ng/ml, residual tumours after surgery and non-BEP regimen were independently and significantly associated with poor overall survival (OS). BEP was significantly superior to non-BEP in 5-year OS (93.6% versus 74.6%, P=0.0004). Reduced-dose BEP (<75% standard-dose bleomycin and<50% etoposide dose) was significantly associated with poorer 5-year OS compared with standard-dose BEP (89.4% versus 100%, P=0.02 and 62.5% versus 96.9%, P=0.0002). All patients who underwent fertility-sparing surgery recovered their menstrual cycles. Sixteen of 23 patients receiving BEP (70.0%) and 13 of 17 patients receiving non-BEP (76.5%) who were nulliparous at fertility-sparing surgery and married at the time of investigation gave birth to 21 and 19 healthy children, respectively., Conclusions: The results of the present study suggest that standard-dose BEP should be administered for ovarian YST. BEP is as safe as non-BEP for preserving reproductive function., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Near infrared photoimmunotherapy (NIR-PIT) is a new cancer treatment that combines the specificity of intravenously injected antibodies for targeting tumors with the toxicity induced by photosensitizers after exposure to near infrared (NIR) light. Herein, we evaluate the efficacy of NIR-PIT in a mouse model of disseminated peritoneal ovarian cancer. In vitro and in vivo experiments were conducted with a HER2-expressing, luciferase-expressing, ovarian cancer cell line (SKOV-luc). An antibody-photosensitizer conjugate (APC) consisting of trastuzumab and a phthalocyanine dye, IRDye-700DX, was synthesized (tra-IR700) and cells or tumors were exposed to NIR light. In vitro PIT cytotoxicity was assessed with dead staining and luciferase activity in freely growing cells and in a three-dimensional (3D) spheroid model. In vivo NIR-PIT was performed in mice with tumors implanted in the peritoneum and in the flank and these were assessed by tumor volume and/or bioluminescence. In vitro NIR-PIT-induced cytotoxicity was light dose dependent. Repeated light exposures induced complete tumor cell killing in the 3D spheroid model. In vivo the antitumor effects of NIR-PIT were confirmed by significant reductions in both tumor volume and luciferase activity in the flank model (NIR-PIT vs. control in tumor volume changes at day 10, P = 0.0001; NIR-PIT vs. control in luciferase activity at day 4, P = 0.0237), and the peritoneal model (NIR-PIT vs. control in luciferase activity at day 7, P = 0.0037). NIR-PIT provided effective cell killing in this HER2-positive model of disseminated peritoneal ovarian cancer. Thus, NIR-PIT is a promising new therapy for the treatment of disseminated peritoneal tumors., (©2014 American Association for Cancer Research.)

Objective: The purpose of this study was to investigate cyst fluid levels of total iron, heme iron and free iron in benign endometriotic cysts and endometriosis-associated ovarian cancer (EAOC) and to demonstrate the significance of these biomarkers in differential diagnosis between EAOC and endometriotic cysts., Methods: Cyst fluid samples were obtained from eleven patients with EAOC and thirty-six women with benign endometriotic cysts at the time of surgery., Results: The median (± SD) total iron levels for endometriotic cysts and EAOC cysts were 244.4 ± 204.9 mg/L and 14.2 ± 36.6 mg/L, respectively. EAOC patients had much lower levels of iron-related compounds compared with endometriotic cyst samples (p< 0.001). When the total iron results were analyzed using the receiver operating characteristics (ROC) curve method, the optimum diagnostic cut-off point was 64.8 mg/L, sensitivity was 90.9%, specificity was 100%, positive predictive value (PPV) was 100%, and negative predictive value (NPV) was 97.3%. Patient demographic characteristics such as tumor size, age at operation, parity and menopause were not correlated with cyst fluid iron levels., Conclusions: We conclude for the first time that iron-related compounds are important biomarkers that can predict malignant transformation with high sensitivity and specificity for women with endometriosis.

Objective: Appropriate cell cycle checkpoints are essential for the maintenance of normal cells and chemosensitivity of cancer cells. Clear cell adenocarcinoma (CCA) of the ovary is highly resistant to chemotherapy. Hepatocyte nuclear factor-1β (HNF-1β) is known to be overexpressed in CCA, but its role and clinical significance is unclear. We investigated the role of HNF-1β in regulation of the cell cycle in CCA., Methods: To clarify the effects of HNF-1β on cell cycle checkpoints, we compared the cell cycle distribution and the expression of key proteins involved in CCA cells in which HNF-1β had been stably knocked down and in vector-control cell lines after treatment with bleomycin. HNF-1β (+) cells were arrested in G2 phase because of DNA damage., Results: HNF-1β (-) cells died because of a checkpoint mechanism. G2 arrest of HNF-1β (+) cells resulted from sustained CHK1 activation, a protein that plays a major role in the checkpoint mechanism. HNF-1β (+) cells were treated with a CHK1 inhibitor after bleomycin treatment. Flow cytometric analysis of the cell cycle demonstrated that DNA damage-induced G2-arrested cells were released from the checkpoint and killed by a CHK1 inhibitor., Conclusions: The chemoresistance of CCA may be due to aberrant retention of the G2 checkpoint through overexpression of HNF-1β. This is the first study demonstrating cell cycle regulation and chemosensitization by a CHK1 inhibitor in CCA.

Blood contamination, such as bloody ascites or hemorrhages during surgery, is a potential hazard for clinical application of fluorescence imaging. In order to overcome this problem, we investigate if fluorescence-lifetime imaging helps to overcome this problem. Samples were prepared at concentrations ranging 0.3-2.4 μm and mixed with 0-10% of blood. Fluorescence intensities and lifetimes of samples were measured using a time-domain fluorescence imager. Ovarian cancer SHIN3 cells overexpressing the D-galactose receptor were injected into the peritoneal cavity 2.5 weeks before the experiments. Galactosyl serum albumin-rhodamine green (GSA-RhodG), which bound to the D-galactose receptor and was internalized thereafter, was administered intraperitoneally to peritoneal ovarian cancer-bearing mice with various degrees of bloody ascites. In vitro study showed a linear correlation between fluorescence intensity and probe concentration (r(2) > 0.99), whereas the fluorescence lifetime was consistent (range, 3.33 ± 0.15-3.75 ± 0.04 ns). By adding 10% of blood to samples, fluorescence intensities decreased to <1%, while fluorescence lifetimes were consistent. In vivo fluorescence lifetime of GSA-RhodG stained tumors was longer than the autofluorescence lifetime (threshold, 2.87 ns). Tumor lesions under hemorrhagic peritonitis were not depicted using fluorescence intensity imaging; however, fluorescence-lifetime imaging clearly detected tumor lesions by prolonged lifetimes. In conclusion, fluorescence-lifetime imaging with GSA-RhodG depicted ovarian cancer lesions, which were invisible in intensity images, in hemorrhagic ascites., (Published 2013. This article is a U.S. Government work and is in the public domain in the USA. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)

Objective: To investigate the clinical features of patients in Japan with malignant transformation of ovarian endometrioma., Patients: Thirty-three patients diagnosed with ovarian cancer presumably arising from endometrioma were recruited retrospectively. These patients had been followed for at least 2 years after the ovarian endometrioma diagnosis, then continued to be followed after they had been found to have malignant transformation., Results: The average age of the patients was 47.7 ± 9.3 years; 75.7% were premenopausal at the time of diagnosis of ovarian cancer. Among the 33 patients, ovarian cancer developed in the ipsilateral ovary of 6 patients with endometrioma after cystectomy. Twenty-eight patients were diagnosed with stage I ovarian cancer, and major histotypes were clear cell in 23 cases and endometrioid in 8. Before surgery for cancer, mural nodules within the endometriomas were detected in 32 patients, and 1 patient had a small 3-mm nodule. In 30 patients, the diameter of the tumor doubled in size 6 months prior to the diagnosis of malignant transformation. The diameter of the endometrioma and the preoperative CA125 value did not significantly correlate., Conclusions: To detect malignant transformation of ovarian endometrioma early and precisely, the clinician should determine the existence of a mural nodule and assess the rapid growth of the endometrioma., (© 2014 S. Karger AG, Basel.)

We describe the case of a 75-year-old woman who underwent bilateral oophorectomy for bleeding due to right ovarian metastasis after hepatectomy for metachronous liver metastasis from sigmoid colon cancer. She underwent curative resection for sigmoid colon cancer( T4a, N2, M0, Stage IIIC). She received adjuvant chemotherapy of tegafur/uracil(UFT) plus leucovorin for 6 months. The patient underwent hepatectomy for liver metastasis 13 months after the primary resection for sigmoid colon cancer. One year after liver resection, the patient underwent emergency surgery for the treatment of bleeding due to ovarian metastasis. She received adjuvant capecitabine chemotherapy for 6 months after oophorectomy. The patient was alive with no evidence of disease 36 months after her oophorectomy. In the present report, we describe the case of a patient who underwent repeated resection for distant metastases after sigmoidectomy. These findings suggest that therapeutic strategies including surgical resection will be very important in the future.

Objectives: Ovarian cancer is the most lethal gynecological malignancy in North America. Although survival rates are high when the disease is diagnosed at an early stage, this decreases exponentially in late-stage diagnoses. As such, there is a need for novel early detection biomarkers. Through an integrated approach to ovarian cancer biomarker discovery that combines proteomics with transcriptomics and bioinformatics, our laboratory has identified folate-receptor 1 (FOLR1) and Dickkopf-related protein 3 (Dkk-3) as putative biomarkers. The objective of this study was to measure the levels of FOLR1 and Dkk-3 in the serum of patients with ovarian cancer, benign gynecological conditions and healthy women., Design and Methods: FOLR1 and Dkk-3 were analyzed in serum of 100 ovarian cancer patients, 100 patients with benign gynecological conditions, and 100 healthy women using enzyme-linked immunosorbent assays (ELISAs). All specimens were analyzed in triplicate., Results: FOLR1 was significantly elevated in the serum of ovarian cancer patients compared to serum of both healthy controls (P<0.0001) and patients with benign gynecological conditions (P<0.0001). Furthermore, FOLR1 was strongly correlated with CA125 as both were elevated in the serous histotype and in late-stage disease. FOLR1 did not outperform CA125 in receiver operating characteristic curve analysis and there was no significant complementarity between the two markers. Dkk-3 was not significantly different between the three serum cohorts and was not correlated with CA125., Conclusions: FOLR1 is a new biomarker for ovarian cancer which correlates closely with CA125. The role of FOLR1 in the pathogenesis of ovarian cancer warrants further investigation., (Copyright © 2013 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Women with hereditary breast and ovarian cancer (HBOC) syndrome represent a unique group who are diagnosed at a younger age and result in an increased lifetime risk for developing breast, ovarian and other cancers. This review integrates recent progress and insights into the molecular basis that underlie the HBOC syndrome. A review of English language literature was performed by searching MEDLINE published between January 1994 and October 2012. Mutations and common sequence variants in the BRCA1 and BRCA2 (BRCA) genes are responsible for the majority of HBOC syndrome. Lifetime cancer risks in BRCA mutation carriers are 60-80% for breast cancer and 20-40% for ovarian cancer. Mutations in BRCA genes cannot account for all cases of HBOC, indicating that the remaining cases can be attributed to the involvement of constitutive epimutations or other cancer susceptibility genes, which include Fanconi anemia (FA) cluster (FANCD2, FANCA and FANCC), mismatch repair (MMR) cluster (MLH1, MSH2, PMS1, PMS2 and MSH6), DNA repair cluster (ATM, ATR and CHK1/2), and tumor suppressor cluster (TP53, SKT11 and PTEN). Sporadic breast cancers with TP53 mutations or epigenetic silencing (hypermethylation), ER- and PgR-negative status, an earlier age of onset and high tumor grade resemble phenotypically BRCA1 mutated cancers termed 'BRCAness', those with no BRCA mutations but with a dysfunction of the DNA repair system. In conclusion, genetic or epigenetic loss-of-function mutations of genes that are known to be involved in the repair of DNA damage may lead to increased risk of developing a broad spectrum of breast and ovarian cancers.

Ovarian transitional cell tumors include Brenner tumors (BTs) and transitional cell carcinoma (TCC; non-BTs) according to the most recent World Health Organization classification. However, it remains a matter of debate whether TCC represents a distinct entity or a morphologic variant of high-grade serous adenocarcinoma (HG-SC). The purpose of this study was to resolve the above question by clarifying the morphologic, immunohistochemical, and molecular features of TCC. We reviewed 488 cases of epithelial ovarian carcinomas and reclassified them on the basis of the most recent World Health Organization classification with the modifications proposed by Köbel and colleagues, and 35 cases of TCC were identified; 25 and 6 TCCs were admixed with HG-SC and endometrioid adenocarcinoma (EC), respectively, and the remaining 4 cases were pure TCC. TCC components were not observed in any clear cell carcinomas or mucinous adenocarcinomas. Only 2 cases of malignant BT were identified. In addition to TCCs, malignant BTs, and related adenocarcinomas, benign and borderline BTs were included in the following immunohistochemical and molecular analyses. Immunohistochemically, pure TCCs, TCCs admixed with HG-SC, and pure HG-SCs were characterized by frequent aberrant p53 expression (diffuse or null pattern) and WT1+/ER+/PR+/IMP2+ immunophenotype, whereas BTs, including benign, borderline, and malignant BTs, were characterized by lack of aberrant p53 expression and WT1-/ER-/PR-/IMP2- immunophenotype. In contrast to the BTs, pure ECs and TCCs admixed with EC showed an ER+/PR+ immunophenotype. Nearly all the tumors with a TP53 gene mutation by molecular analysis showed aberrant p53 staining patterns. In conclusion, TCC is not a distinct entity but a poorly differentiated form of serous or EC, as (1) most TCCs coexist with HG-SC (mostly) or EC (occasionally), and (2) the immunophenotype and molecular features are similar to those of HG-SC or EC but different from those of BTs.

Clear cell adenocarcinoma of the ovary (OCC) is a chemo-resistant tumor with a relatively poor prognosis and is frequently associated with endometriosis. Although it is assumed that oxidative stress plays some role in the malignant transformation of this tumor, the characteristic molecular events leading to carcinogenesis remain unknown. In this study, an array-based comparative genomic hybridization (CGH) analysis revealed Met gene amplification in 4/13 OCC primary tumors and 2/8 OCC cell lines. Amplification of the AKT2 gene, which is a downstream component of the Met/PI3K signaling pathway, was also observed in 5/21 samples by array-based CGH analysis. In one patient, both the Met and AKT2 genes were amplified. These findings were confirmed using fluorescence in situ hybridization, real-time quantitative PCR, immunoblotting, and immunohistochemistry. In total, 73 OCC cases were evaluated using real-time quantitative PCR; 37.0% demonstrated Met gene amplification (>4 copies), and 8.2% had AKT2 amplification. Furthermore, stage 1 and 2 patients with Met gene amplification had significantly worse survival than patients without Met gene amplification (p<0.05). Met knockdown by shRNA resulted in reduced viability of OCC cells with Met amplification due to increased apoptosis and cellular senescence, suggesting that the Met signaling pathway plays an important role in OCC carcinogenesis. Thus, we believe that targeted inhibition of the Met pathway may be a promising treatment for OCC.

The nature of "piling up" proliferation of clear cells in müllerian mucinous/mixed borderline tumor has not been well characterized. The purpose of this study was to clarify whether or not such clear cells represent concomitant clear cell neoplasms. First, we carefully reviewed hematoxylin and eosin slides taken from 139 ovarian tumors diagnosed as clear cell carcinoma (112 cases) and müllerian mucinous/mixed borderline tumor (27 cases) to clarify (1) the frequency of piling-up clear cells in müllerian mucinous/mixed borderline tumor and (2) the frequency of the coexistence of typical clear cell carcinoma and müllerian mucinous/mixed borderline tumor. Second, we investigated the immunohistochemical expression of estrogen receptor, hepatocyte nuclear factor-1β, and glypican-3 in proliferating clear cells in both tumors. We identified piling-up clear cells in 56% of müllerian mucinous/mixed borderline tumors. Such clear cells lacked the severe nuclear atypia, complex branching, and dense hyalinized cores of typical clear cell carcinoma. We did not find coexistence of typical clear cell carcinoma and müllerian mucinous/mixed borderline tumor in any tumors. Piling-up clear cells and endocervical-like mucinous cells were positive for estrogen receptor but negative for hepatocyte nuclear factor-1β and glypican-3. Most clear cell carcinomas showed a hepatocyte nuclear factor-1β-positive/estrogen receptor-negative immunophenotype, and about half of them were glypican-3 positive. In conclusion, piling-up clear cells in müllerian mucinous/mixed borderline tumor do not represent concomitant clear cell neoplasms because clear cell carcinoma and müllerian mucinous/mixed borderline tumor hardly ever coexist and because such clear cells in both tumors are immunophenotypically distinct., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Patient survival depends on the completeness of resection of peritoneal ovarian cancer metastases (POCM), and therefore, it is important to develop methods to enhance detection. Previous probe designs based on activatable galactosyl human serum albumin (hGSA)-fluorophore pairs, which target lectin receptors expressed on POCM, have used only visible range dyes conjugated to hGSA. However, imaging probes emitting fluorescence in the NIR range are advantageous because NIR photons have deeper in vivo tissue penetration and result in lower background autofluorescence than those emitting in the visible range. A NIR-activatable hGSA fluorophore was synthesized using a bacteriochlorin-based dye, NMP1. NMP1 has two unique absorption peaks, one in the green range and the other in the NIR range, but emits at a NIR peak of 780 nm. NMP1, thus, has two different Stokes shifts that have the potential to allow imaging of POCM both at the peritoneal surface and just below it. hGSA was conjugated with 2 NMP1 molecules to create a self-quenching complex (hGSA-NMP1). The activation ratio of hGSA-NMP1 was measured by the fluorescence intensity before and after exposure to 10% SDS. The activation ratio of hGSA-NMP1 was ~100-fold in vitro. Flow cytometry, fluorescence microscopy, and in vivo spectral fluorescence imaging were carried out to compare hGSA-NMP1 with hGSA-IR800 and hGSA-ICG (two always-on control agents with similar emission to NMP1) in terms of comparative fluorescence signal and the ability to detect POCM in mice models. The sensitivity and specificity of hGSA-NMP1 for POCM implant detection were determined by colocalizing NMP1 emission spectra with red fluorescent protein (RFP) expressed constitutively in SHIN3 tumor implants at different depths below the peritoneal surface. In vitro, SHIN3 cells were easily detectable after 3 h of incubation with hGSA-NMP1. In vivo submillimeter POCM foci were clearly detectable with spectral fluorescence imaging using hGSA-NMP1. Among 555 peritoneal lesions, hGSA-NMP, using NIR and green excitation light, respectively, detect 75% of all lesions and 91% of lesions ~0.8 mm or greater in diameter. Few false positives were encountered. Nodules located at a depth below the small bowel surface were only depicted with hGSA-NMP1. We conclude that hGSA-NMP1 is useful in imaging peritoneal ovarian cancer metastases, located both superficially and deep in the abdominal cavity.

Identification of the potential gene expression profiles of epithelial ovarian cancer and the arrival of newly targeted therapies have advanced the strategies used for treatment of this disease. This review focuses on the design of ongoing and planned clinical trials and offers a synopsis of the English-language literature for preclinical and clinical targeted therapies for epithelial ovarian cancer. Among many targeted agents, a promising, novel class of targeted drugs for special patient populations expected to improve the effectiveness of current therapy include inhibitors of angiogenesis, poly (ADP ribose) polymerase (PARP) and DNA repair mechanisms. Inhibition of PARP or homologous recombination (HR) repair mediated by Chk1 (checkpoint kinase 1) would selectively sensitize p53 mutation, BRCAness phenotype (serous type ovarian cancer) or HNF (hepatocyte nuclear factor)-1β-overexpressing tumor cells (clear cell type ovarian cancer) to chemotherapeutic agents. The therapeutic response is likely to be limited to a targeted patient, but not to the broad population. This review discusses some of the key current developments and existing challenges.