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    Fertility-sparing surgery in patients with clear-cell carcinoma of the ovary: is it possible? Kajiyama Hiroaki,Shibata Kiyosumi,Mizuno Mika,Hosono Satoyo,Kawai Michiyasu,Nagasaka Tetsuro,Kikkawa Fumitaka Human reproduction (Oxford, England) BACKGROUND:Clear-cell carcinoma of the ovary (CCC) is often diagnosed at childbearing age, or sometimes during treatment for infertility. Therefore, most young women with early-stage CCC wish to preserve their reproductive and endocrine functions if possible. METHODS:Clinicopathologic data collected under the central pathological review system were subjected to survival analyses. We analyzed patients with stage I CCC who underwent fertility-sparing surgery (FSS, n = 16) and compared their long-term survival with those receiving radical surgery (n = 205), or patients with non-CCC undergoing FSS (n = 64). RESULTS:There was no difference in both the overall survival (OS) and disease-free survival (DFS) between patients with CCC who underwent FSS and those who received radical surgery [CCC/FSS (n = 16) versus CCC/radical (n = 205); OS: P= 0.519, DFS: P= 0.265]. Moreover, patients with CCC who underwent FSS did not show a poorer OS and DFS than non-CCC patients who underwent FSS (CCC/FSS versus non-CCC/FSS; OS: P= 0.584, DFS: P= 0.401), or those at the corresponding stage with no CCC. Furthermore, according to the series of patients with CCC in both the current study and four studies in the literature, there was no difference in the recurrence rate between patients with or without CCC who were treated conservatively (CCC/FSS: 13.2% versus non-CCC/FSS: 10.9%, P= 0.614). CONCLUSIONS:Although our study did not have sufficient power to yield a definite conclusion, our data suggests that at least patients with stage IA CCC may be treated with FSS. 10.1093/humrep/der342
    Randomized phase II trial of paclitaxel plus carboplatin therapy versus irinotecan plus cisplatin therapy as first-line chemotherapy for clear cell adenocarcinoma of the ovary: a JGOG study. Takakura Satoshi,Takano Masashi,Takahashi Fumiaki,Saito Toshiaki,Aoki Daisuke,Inaba Noriyuki,Noda Kiichiro,Sugiyama Toru,Ochiai Kazunori, International journal of gynecological cancer : official journal of the International Gynecological Cancer Society INTRODUCTION:Paclitaxel plus carboplatin (TC) is generally considered to be the "gold standard" regimen for treatment of epithelial ovarian carcinomas. Little data are available, however, on the use of this regimen in patients with clear cell adenocarcinoma of the ovary (CCC). Combination chemotherapy with irinotecan hydrochloride plus cisplatin has been reported to be effective for primary and recurrent or resistant CCC. We compared these 2 combinations in patients with CCC. METHODS:Patients (n = 99) with CCC were randomly assigned to receive either 180 mg/m2 paclitaxel on day 1 plus AUC 6 mg/mL x minute carboplatin on day 1 every 21 days (TC arm) or 60 mg/m2 irinotecan hydrochloride on days 1, 8, 15 plus 60 mg/m2 cisplatin on day 1 every 28 days (CPT-P arm). RESULTS:Percentages of patients receiving the scheduled 6 cycles of chemotherapy in the TC and CPT-P arms were 70.8% and 72.0%, respectively. Although toxicity was well tolerated in both arms, the toxicity profile of each arm differed. Progression-free survival (PFS) showed no significant difference between the 2 treatment groups. Because there were more patients with large residual disease in the CPT-P arm, we performed a subset analysis by removing those patients, and then compared the PFS with that of patients without residual disease or with residual disease less than 2 cm. The PFS tended to be longer in the CPT-P group, although the difference was not statistically significant. CONCLUSIONS:A phase III randomized trial is required to elucidate the effectiveness of CPT-P combination chemotherapy for CCC. 10.1111/igc.0b013e3181cafb47
    Cabozantinib in ovarian clear cell cancers: UnMET expectations. Secord Angeles Alvarez,Previs Rebecca A,Nixon Andrew B Gynecologic oncology 10.1016/j.ygyno.2018.06.006
    Clear cell carcinoma of the ovary: a review of the literature. del Carmen Marcela G,Birrer Michael,Schorge John O Gynecologic oncology OBJECTIVE:Different histologic types of epithelial ovarian cancer may represent different diseases with unique clinical and molecular characteristics. Clear cell carcinoma (CCC) of the ovary has been reported as having a worse prognosis than high grade serous epithelial ovarian cancer (EOC). This article critically reviews the literature pertinent to the pathology, pathogenesis, diagnosis, management, and outcome of patients with ovarian CCC. METHODS:MEDLINE was searched for all research articles published in English between January 01, 1977 and January 30, 2012 which reported on patients diagnosed with ovarian CCC. Given the rarity of this tumor, studies were not limited by design or number of reported patients. RESULTS:Ovarian CCC tumors represent 5-25% of ovarian cancers. Its histologic diagnosis can be challenging, resulting often times in misclassification of these tumors. Ovarian CCC tends to present at earlier stages and has been associated with endometriosis, ARID1A and PIK3CA mutations. When compared to stage-matched controls, patients with early-stage ovarian CCCs may have a better prognosis than patients with high-grade serous tumors. For those with advanced stage disease, high-grade serous histology confers a better prognosis than ovarian CCC. Patients with Stage IC-IV have a relatively poor prognosis and efforts should center in discovery of more effective treatment strategies. CONCLUSIONS:Ovarian CCC is a biologically distinct entity, different from high-grade serous EOC. Future studies should explore the role of targeted therapies in the management of ovarian CCC. 10.1016/j.ygyno.2012.04.021
    Postoperative whole abdominal radiotherapy in clear cell adenocarcinoma of the ovary. Nagai Yutaka,Inamine Morihiko,Hirakawa Makoto,Kamiyama Kazuya,Ogawa Kazuhiko,Toita Takafumi,Murayama Sadayuki,Aoki Yoichi Gynecologic oncology OBJECTIVES:The aim of this study was to clarify the efficacy of postoperative whole abdominal radiotherapy (WAR) for ovarian clear cell adenocarcinoma (OCCA). METHODS:Between 1996 and 2004, 16 patients with OCCA underwent initial debulking surgery and received postoperative WAR. Indications for WAR were as follows: OCCA, International Federation of Gynaecology and Obstetrics (FIGO) stage Ic-III, no macroscopic residual disease in the upper abdomen and residual disease in the pelvic cavity < or = 2 cm. The planned WAR comprised external beam radiotherapy (EBRT) to the entire abdominal cavity with 22.0-24.0 Gy/22-24 fractions followed by EBRT to the pelvis with 23.4-21.6 Gy/12-13 fractions. Overall survival (OS) and disease-free survival (DFS) were compared with 12 historical control (HC) patients treated with initial debulking surgery followed by platinum-based chemotherapy. RESULTS:The FIGO stage in the WAR group was stage Ic in 11 patients, stage II in 3, and stage III in 2. Fifteen of the 16 patients (94%) completed the planned WAR. Two patients developed radiation enterocolitis and required bowel surgery. Five-year OS and DFS in the WAR/HC group were 81.8%/33.3% and 81.2%/25.0% (p=0.031 and p=0.006), respectively. CONCLUSIONS:This study suggests that postoperative WAR may be effective in selected patients with OCCA. Prospective randomized trials should be considered to assess postoperative WAR for OCCA. 10.1016/j.ygyno.2007.07.079
    Chemotherapy alone for patients 75 years and older with epithelial ovarian cancer-is interval cytoreductive surgery still needed? Klein David A,Mann Amandeep K,Freeman Alexandra H,Liao Cheng-I,Kapp Daniel S,Chan John K American journal of obstetrics and gynecology BACKGROUND:Patients ≥75 years old with ovarian cancer experience high perioperative morbidity, but recruitment into prospective trials to assess the role of surgery continues to be challenging. OBJECTIVE:To compare overall survival for patients ≥75 years old with ovarian cancer after chemotherapy alone vs neoadjuvant chemotherapy with interval cytoreductive surgery. STUDY DESIGN:Data were extracted from the National Cancer Data Base from 2004 to 2014. Kaplan-Meier and Cox proportional hazards models were used for statistical analyses. RESULTS:Of 1661 patients (median age: 79 years), most were white (88%) and had stage III-IV disease (95%), and 51% had serous histology. Of those who did not receive primary surgery, 58% had chemotherapy alone and the remainder had neoadjuvant chemotherapy with interval cytoreductive surgery. The use of neoadjuvant chemotherapy with interval cytoreductive surgery increased from 28% to 50% in years 2004-2007 to 2012-2014 (P<.001). Compared with neoadjuvant chemotherapy with interval cytoreductive surgery, chemotherapy-only patients were older (80 vs 78 years; P<.001) and had more advanced stage disease (98% vs 91%; P<.001). The 5-year overall survival of the entire study group was 14%; those who underwent neoadjuvant chemotherapy with interval cytoreductive surgery had overall survival of 25% compared with only 7% in chemotherapy alone group (P<.001). In multivariable analysis, neoadjuvant chemotherapy with interval cytoreductive surgery (hazard ratio, 0.44; 95% confidence interval, 0.36-0.54; P<.001) was an independent predictor for improved survival. Older (80-84 years) age (hazard ratio, 1.35; 95% confidence interval, 1.12-1.63; P=.002), advanced (stage III-IV) disease (hazard ratio; 2.06, 95% confidence interval, 1.37-3.09; P=.001), and clear cell histology (hazard ratio; 2.17, 95% confidence interval, 1.10-4.28; P=.03) portended for worse outcome. CONCLUSION:Patients ≥75 years with ovarian cancer old have an overall poor prognosis. Receiving neoadjuvant chemotherapy followed by interval cytoreductive surgery is associated with greater overall survival compared to chemotherapy alone. 10.1016/j.ajog.2019.07.050
    Role of adjuvant chemotherapy in early-stage endometrioid and clear-cell ovarian cancer. Lorusso D,Pignata S Annals of oncology : official journal of the European Society for Medical Oncology 10.1093/annonc/mdx539
    Hormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study. Sieh Weiva,Köbel Martin,Longacre Teri A,Bowtell David D,deFazio Anna,Goodman Marc T,Høgdall Estrid,Deen Suha,Wentzensen Nicolas,Moysich Kirsten B,Brenton James D,Clarke Blaise A,Menon Usha,Gilks C Blake,Kim Andre,Madore Jason,Fereday Sian,George Joshy,Galletta Laura,Lurie Galina,Wilkens Lynne R,Carney Michael E,Thompson Pamela J,Matsuno Rayna K,Kjær Susanne Krüger,Jensen Allan,Høgdall Claus,Kalli Kimberly R,Fridley Brooke L,Keeney Gary L,Vierkant Robert A,Cunningham Julie M,Brinton Louise A,Yang Hannah P,Sherman Mark E,García-Closas Montserrat,Lissowska Jolanta,Odunsi Kunle,Morrison Carl,Lele Shashikant,Bshara Wiam,Sucheston Lara,Jimenez-Linan Mercedes,Driver Kristy,Alsop Jennifer,Mack Marie,McGuire Valerie,Rothstein Joseph H,Rosen Barry P,Bernardini Marcus Q,Mackay Helen,Oza Amit,Wozniak Eva L,Benjamin Elizabeth,Gentry-Maharaj Aleksandra,Gayther Simon A,Tinker Anna V,Prentice Leah M,Chow Christine,Anglesio Michael S,Johnatty Sharon E,Chenevix-Trench Georgia,Whittemore Alice S,Pharoah Paul D P,Goode Ellen L,Huntsman David G,Ramus Susan J The Lancet. Oncology BACKGROUND:Few biomarkers of ovarian cancer prognosis have been established, partly because subtype-specific associations might be obscured in studies combining all histopathological subtypes. We examined whether tumour expression of the progesterone receptor (PR) and oestrogen receptor (ER) was associated with subtype-specific survival. METHODS:12 studies participating in the Ovarian Tumor Tissue Analysis consortium contributed tissue microarray sections and clinical data to our study. Participants included in our analysis had been diagnosed with invasive serous, mucinous, endometrioid, or clear-cell carcinomas of the ovary. For a patient to be eligible, tissue microarrays, clinical follow-up data, age at diagnosis, and tumour grade and stage had to be available. Clinical data were obtained from medical records, cancer registries, death certificates, pathology reports, and review of histological slides. PR and ER statuses were assessed by central immunohistochemistry analysis done by masked pathologists. PR and ER staining was defined as negative (<1% tumour cell nuclei), weak (1 to <50%), or strong (≥50%). Associations with disease-specific survival were assessed. FINDINGS:2933 women with invasive epithelial ovarian cancer were included: 1742 with high-grade serous carcinoma, 110 with low-grade serous carcinoma, 207 with mucinous carcinoma, 484 with endometrioid carcinoma, and 390 with clear-cell carcinoma. PR expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001) and high-grade serous carcinoma (log-rank p=0·0006), and ER expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001). We recorded no significant associations for mucinous, clear-cell, or low-grade serous carcinoma. Positive hormone-receptor expression (weak or strong staining for PR or ER, or both) was associated with significantly improved disease-specific survival in endometrioid carcinoma compared with negative hormone-receptor expression, independent of study site, age, stage, and grade (hazard ratio 0·33, 95% CI 0·21-0·51; p<0·0001). Strong PR expression was independently associated with improved disease-specific survival in high-grade serous carcinoma (0·71, 0·55-0·91; p=0·0080), but weak PR expression was not (1·02, 0·89-1·18; p=0·74). INTERPRETATION:PR and ER are prognostic biomarkers for endometrioid and high-grade serous ovarian cancers. Clinical trials, stratified by subtype and biomarker status, are needed to establish whether hormone-receptor status predicts response to endocrine treatment, and whether it could guide personalised treatment for ovarian cancer. FUNDING:Carraresi Foundation and others. 10.1016/S1470-2045(13)70253-5
    Progression-free survival and overall survival of patients with clear cell carcinoma of the ovary treated with paclitaxel-carboplatin or irinotecan-cisplatin: retrospective analysis. Takano Masashi,Sugiyama Toru,Yaegashi Nobuo,Suzuki Mitsuaki,Tsuda Hiroshi,Sagae Satoru,Udagawa Yasuhiro,Kuzuya Kazuo,Kigawa Junzo,Takeuchi Satoshi,Tsuda Hitoshi,Moriya Takuya,Kikuchi Yoshihiro International journal of clinical oncology BACKGROUND:Irinotecan hydrochloride, a topoisomerase I inhibitor, has been preliminarily recognized as an effective agent against clear cell carcinoma of the ovary (CCC), but there are few clinical data. Our aim was to compare progression-free survival (PFS) between patients treated with irinotecan hydrochloride and cisplatin (CPT-P) and those with treated with paclitaxel and carboplatin (TC). METHODS:One hundred and seventeen patients at International Federation of Gynecology and Obstetrics (FIGO) stages Ic (ascites/malignant washing) - IV were identified by scanning the medical records of ten Japanese hospitals. After complete surgical staging procedures including lymphadenectomy, 35 patients received CPT-P and 82 patients received TC. The PFS and overall survival of the two groups were compared using the Kaplan-Meier method. RESULTS:There was no significant difference in median age, performance status, FIGO stage, rate of optimal cytoreduction, or follow-up period between the CPT-P and TC groups. Two-year and 5-year PFS was 48% and 40%, respectively, in the TC group and 55% and 55%, respectively, in the CPT-P group (P = 0.31). Multiple regression analysis revealed that only residual tumor was an independent prognostic factor for PFS (P < 0.01). CONCLUSION:CPT-P showed a potential therapeutic effect, at least no less than that of TC therapy. Although there was no significant survival benefit in the present retrospective analysis, we recommend that the CPT-P regimen be evaluated in a larger, prospective, clinical trial. 10.1007/s10147-007-0670-1
    Radiation Therapy for Recurrent Clear-Cell Cancer of the Ovary. Westhoff Gina L,Fuh Katherine C,Longacre Terry A,McNally Jennifer Leah,Hsu I-Chow,Kapp Daniel S,Teng Nelson,Chen Lee-May International journal of gynecological cancer : official journal of the International Gynecological Cancer Society OBJECTIVE:Given the relative chemo-resistant nature of clear-cell gynecologic cancers, we investigated the utility of radiation therapy (RT) to treat recurrent clear-cell carcinoma (CCC) of the ovary. METHODS:A retrospective chart review of patients with recurrent CCC managed from 1994-2012 was conducted at 2 academic medical centers. Demographic and clinicopathologic factors were abstracted and evaluated using Pearson χ or t tests, Kaplan-Meier and Cox regression analyses. RESULTS:Fifty-three patients had recurrent CCC, and 24 (45.3%) of these patients received RT. There were no significant differences in age, stage, optimal cytoreduction, platinum response, or the percentage of patients that received more than 3 regimens of chemotherapy between the 2 groups. Patients who received RT for recurrent CCC were more likely to have had a focal recurrence (62.5% vs 10.3%, P ≤ 0.001) and to have undergone secondary cytoreduction (70.8% vs 10.3%, P ≤ 0.001). Of patients who received RT, 73.9% underwent surgery with or before their treatment. Five-year survival after recurrence was significantly higher in the group that received RT, 62.9% versus 18.8% (P = 0.002). In a multivariate analysis, platinum-sensitive disease and RT were associated with improved survival from recurrence, (hazard ratio, 0.26; 95% confidence interval, 0.08-0.81; P = 0.02 and hazard ratio, 0.28; 95% confidence interval, 0.09-0.90, P = 0.03, respectively). CONCLUSIONS:In this cohort of patients with recurrent CCC, platinum-sensitive disease and RT are associated with improved survival. However, it is important to note that the majority of these patients underwent surgery along with RT, and it may be that the benefit of RT is limited to those who undergo secondary cytoreduction. 10.1097/IGC.0000000000000810
    Significant clinical response of progressive recurrent ovarian clear cell carcinoma to glypican-3-derived peptide vaccine therapy: two case reports. Suzuki Shiro,Shibata Kiyosumi,Kikkawa Fumitaka,Nakatsura Tetsuya Human vaccines & immunotherapeutics Carcinoembryonic antigen glypican-3 (GPC3) is expressed by>40% of ovarian clear cell carcinoma (CCC) and is a promising immunotherapeutic target. We previously reported the safety of and immunological and clinical responses to a GPC3-derived peptide vaccine in a phase I clinical trial of patients with advanced hepatocellular carcinoma (HCC). Although the efficacy of the GPC3-derived peptide vaccine against HCC patients was evaluated, other GPC3-positive cancer patients have not yet been investigated. Therefore, we conducted a phase II trial to evaluate the clinical outcome of ovarian CCC patients treated with a GPC3-derived peptide vaccine. The GPC3 peptide was administered at a dose of 3 mg per body. Patients received an intradermal injection of the GPC3 peptide emulsified with incomplete Freund's adjuvant. Vaccinations were performed biweekly from the first until the 6th injection and were then repeated at 6-week intervals after the 7th injection. Treatment continued until disease progression. We herein present two patients with chemotherapy-refractory ovarian CCC who achieved a significant clinical response in an ongoing trial of a GPC3 peptide vaccine. Case 1, a 42-year-old patient with advanced recurrent ovarian CCC with liver and retroperitoneal lymph node metastases, received the HLA-A24-restricted GPC3 peptide vaccine. Contrast-enhanced CT at week 10 revealed a partial response (PR) using RECIST criteria. Case 2 was a 67-year-old female with multiple lymph node metastases. She was injected with the HLA-A2-restricted GPC3 peptide vaccine. According to RECIST, PR was achieved at week 37. The stabilization of their diseases over one year provided us with the first clinical evidence to demonstrate that GPC3 peptide-based immunotherapy may significantly prolong the overall survival of patients with refractory ovarian CCC. 10.4161/hv.27217
    A phase II study of combination chemotherapy using docetaxel and irinotecan for TC-refractory or TC-resistant ovarian carcinomas (GOGO-OV2 study) and for primary clear or mucinous ovarian carcinomas (GOGO-OV3 Study). Ueda Yutaka,Miyatake Takashi,Nagamatsu Masaaki,Yamasaki Masato,Nishio Yukihiro,Yoshino Kiyoshi,Fujita Masami,Tsutsui Tateki,Enomoto Takayuki,Kimura Tadashi European journal of obstetrics, gynecology, and reproductive biology OBJECTIVE:To analyze the efficacy and safety of combination chemotherapy of docetaxel and irinotecan for paclitaxel and carboplatin (TC) -refractory or -resistant ovarian carcinomas and for first treatment of primary clear cell and mucinous ovarian carcinomas. STUDY DESIGN:Between 2002 and 2009, we conducted a prospective Phase II study of the efficacy and safety of combination chemotherapy using docetaxel and irinotecan in 62 patients with TC-refractory or -resistant ovarian carcinoma cases (GOGO-OV2) and 15 patients with primary clear cell and mucinous ovarian carcinoma cases (GOGO-OV3). The dose of docetaxel and irinotecan was determined during our previous Phase I study. RESULTS:A docetaxel plus irinotecan regimen provided a 53% response rate, 6 months progression-free survival (PFS), and 12 months overall survival (OS) for primary clear cell and mucinous ovarian carcinomas (similar to TC therapy). The differences of anti-tumor and survival effects between refractory and resistant cases were not statistically significant. The regimen also provided a 15% response rate, 5 months PFS, and 15 months OS for TC-refractory or TC-resistant cases, when used as a second-line chemotherapy. These data are similar to previous reports, however, our study provides the first data exclusively for the cases refractory or resistant to a gold standard TC therapy as a second-line chemotherapy. The regimen was demonstrated to be well tolerable. CONCLUSION:Combination chemotherapy of docetaxel and irinotecan may be a useful option to treat TC-refractory/resistant cases and primary clear cell and mucinous adenocarcinoma cases of ovarian carcinoma. 10.1016/j.ejogrb.2013.06.035
    Current Position of the Molecular Therapeutic Targets for Ovarian Clear Cell Carcinoma: A Literature Review. Amano Tsukuru,Chano Tokuhiro,Yoshino Fumi,Kimura Fuminori,Murakami Takashi Healthcare (Basel, Switzerland) Ovarian clear cell carcinoma (OCCC) shows low sensitivity to conventional chemotherapy and has a poor prognosis, especially in advanced stages. Therefore, the development of innovative therapeutic strategies and precision medicine for the treatment of OCCC are important. Recently, several new molecular targets have been identified for OCCC, which can be broadly divided into four categories: a) downstream pathways of receptor tyrosine kinases, b) anti-oxidative stress molecules, c) AT-rich interactive domain 1A-related chromatin remodeling errors, and d) anti-programmed death ligand 1/programmed cell death 1 agents. Several inhibitors have been discovered for these targets, and the suppression of OCCC cells has been demonstrated both in vitro and in vivo. However, no single inhibitor has shown a sufficient effectiveness in clinical pilot studies. This review outlines recent progress regarding the molecular biological characteristics of OCCC to identify future directions for the development of precision medicine and combinatorial therapies to treat OCCC. 10.3390/healthcare7030094
    Prognostic significance of histological grade in clear-cell carcinoma of the ovary: a retrospective study of Korean Gynecologic Oncology Group. Ryu S-Y,Park S-I,Nam B-H,Kim I,Yoo C W,Nam J-H,Lee K H,Cho C-H,Kim J-H,Park S Y,Kim B-G,Kang S-B Annals of oncology : official journal of the European Society for Medical Oncology BACKGROUND:This study was to investigate the prognostic significance of clinicopathologic characteristics in patients with clear-cell carcinoma (CCC) of the ovary. MATERIALS AND METHODS:Two hundred and one patients with CCC of the ovary were registered in the Korean Gynecologic Oncology Group. The Korean Gynecologic Pathology Study Group reviewed the pathological slides centrally, using a universal grading system. The prognostic significances of clinicopathologic factors were evaluated by multivariate analysis. RESULTS:Most of the patients were diagnosed at an early stage (stage I, 61.3%), and the overall 5-year survival rate was 57%. Early-stage disease showed a favorable prognosis, but advanced diseases showed poor prognosis. Stage of disease was the only significant prognostic factor on multivariate analysis (P < 0.001). However, universal grade and residual tumor also showed prognostic significance on the forward stepwise likelihood ratio test. There was no survival difference observed between patients treated with paclitaxel-based and those treated with platinum-based combination chemotherapy. CONCLUSIONS:The stage, residual tumor, and universal grade were significant prognostic factors in patients with CCC of the ovary. The universal grading system is applicable in determining prognosis of CCC of the ovary. Further clinical trials for optimal chemotherapy are in need. 10.1093/annonc/mdn764
    Achievement of 10-year survival: a case of pubic bone recurrence as the primary failure site of chemo-refractory ovarian clear cell carcinoma. Akashi Daisuke,Todo Yukiharu,Okamoto Kazuhira,Minobe Shinichiro,Kato Hidenori The journal of obstetrics and gynaecology research Clear cell carcinoma of the ovary tends to have a poor response to conventional platinum-based chemotherapy. Bone recurrence from ovarian cancer is rare and prognosis of patients with such a condition is poor. We report a patient with chemo-refractory ovarian clear cell carcinoma who developed pubic bone recurrence and subsequent para-aortic node recurrence. The patient achieved long-term survival after salvage surgery twice in spite of these inauspicious conditions. Surgical treatment should be taken into consideration for skeletal recurrence from ovarian clear cell carcinoma. 10.1111/jog.12060
    Salvage chemotherapy for recurrent or persistent clear cell carcinoma of the ovary: a single-institution experience for a series of 20 patients. Yoshino Kiyoshi,Enomoto Takayuki,Fujita Masami,Ueda Yutaka,Kimura Toshihiro,Kobayashi Eiji,Tsutsui Tateki,Kimura Tadashi International journal of clinical oncology BACKGROUND:Recurrent or persistent clear cell carcinoma (CCC) of the ovary is particularly chemotherapy resistant. The purpose of this study was to review our extensive institutional experiences with recurrent or persistent CCC with the aim of finding a more effective chemotherapy regimen. METHODS:The medical records of 67 patients treated for CCC of the ovary were retrospectively reviewed to select patients subsequently treated for recurrence or persistence of the disease. RESULTS:The review identified 20 patients treated for recurrent or persistent CCC. For these 20 patients, 9 chemotherapeutic regimens, with 125 cycles, were administered. Gemcitabine monotherapy showed the best response rate [1 partial response (20%) and 2 stable diseases out of 5 patients so treated]. A partial response was observed with a combination of docetaxel plus irinotecan in 1 of 11 patients (9%). Stable disease was observed in 1 of 9 cases on a paclitaxel/carboplatin doublet and in 1 case on a docetaxel/carboplatin doublet. The median overall survival time was 8 months (range, 2-52). One group of patients who received gemcitabine therapy showed significantly better survival (n = 5, median 18 months) compared with a group who did not (n = 15, median 7 months) (P = 0.0108, by univariate analysis). In addition, multivariate Cox proportional hazards analysis revealed that gemcitabine administration was a significant factor for survival (hazard ratio: 13.0, 95% CI: 1.4727-115.2255, P = 0.02). CONCLUSION:Although most chemotherapeutic regimens for recurrent or persistent CCC have little or no effect, gemcitabine showed modest activity and is the most effective agent we have tested to date. 10.1007/s10147-011-0357-5
    Recurrence Patterns and Survival Outcomes in Chinese Patients with Surgically Treated Recurrent Ovarian Clear Cell Carcinoma: A Single Institutional Analysis of 45 Cases. Ye Shuang,Zhou Shuling,Chen Wei,Xiang Libing,Wu Xiaohua,Yang Huijuan Cancer management and research Background:To evaluate the recurrence patterns and survival outcomes of surgically treated relapsed ovarian clear cell carcinoma (OCCC) patients. Methods:We performed a comprehensive retrospective analysis of all the patients who underwent secondary debulking from 2004/10 to 2019/04. Results:In total, 45 eligible patients were included. 75.6% of the patients had early-stage disease and platinum-sensitive recurrence accounted for 70.5%. The median progression-free survival after primary surgery (PFS 1) was 20 months (range, 2-137). Of all, 64.4% patients had solitary recurrence and 86.7% patients had no residual disease after secondary surgery. Regarding tumor distribution, the most common site was pelvis (47.5%), followed by lymph node metastases (18.0%) and abdominal wall lesions (8.2%). For the entire population, the median disease-free survival after recurrence (PFS 2) and post-relapse survival (PRS) was 15 months (range, 0-96), and 24 months (range, 3-159), respectively. Eight patients (17.8%) had a prolonged PFS2 more than 30 months. Patients with localized relapse had better survival including PFS 2 (=0.023), PRS (=0.004), and overall survival (OS) (=0.029). Patients who achieved complete resection tended to have longer PFS 2 (=0.017). After multivariate analysis, complete resection at recurrence remained as an independent positive predictor for PFS 2 (=0.022). The median OS was 50 months and was significantly associated with platinum response (=0.003) and number of relapsed lesions (=0.002). Conclusion:A high rate of pelvic recurrence was noted in this population. Patients with focal recurrence had a favorable prognosis. Complete resection at secondary debulking proved to be an independent predictor for disease-free survival. 10.2147/CMAR.S242129
    Ovarian clear cell carcinoma: high risk of venous thromboembolism. Lim Myong Cheol,Park Sae Hyun,Park Sang-Yoon Gynecologic oncology 10.1016/j.ygyno.2010.04.006
    Venous thromboembolism, interleukin-6 and survival outcomes in patients with advanced ovarian clear cell carcinoma. Matsuo Koji,Hasegawa Kosei,Yoshino Kiyoshi,Murakami Ryusuke,Hisamatsu Takeshi,Stone Rebecca L,Previs Rebecca A,Hansen Jean M,Ikeda Yuji,Miyara Akiko,Hiramatsu Kosuke,Enomoto Takayuki,Fujiwara Keiichi,Matsumura Noriomi,Konishi Ikuo,Roman Lynda D,Gabra Hani,Fotopoulou Christina,Sood Anil K European journal of cancer (Oxford, England : 1990) BACKGROUND:We compared survival outcomes and risk of venous thromboembolism (VTE) among patients with advanced and early-stage ovarian clear cell carcinoma (OCCC) and serous ovarian carcinoma (SOC), as well as potential links with interleukin-6 (IL-6) levels. METHODS:A multicenter case-control study was conducted in 370 patients with OCCC and 938 with SOC. In a subset of 200 cases, pretreatment plasma IL-6 levels were examined. FINDINGS:Patients with advanced OCCC had the highest 2-year cumulative VTE rates (advanced OCCC 43.1%, advanced SOC 16.2%, early-stage OCCC 11.9% and early-stage SOC 6.4%, P<0.0001) and the highest median levels of IL-6 (advanced OCCC 17.8 pg/mL, advanced SOC 9.0 pg/mL, early-stage OCCC 4.2 pg/mL and early-stage SOC 5.0 pg/mL, P=0.006). Advanced OCCC (hazard ratio [HR] 3.38, P<0.0001), thrombocytosis (HR 1.42, P=0.032) and elevated IL-6 (HR 8.90, P=0.046) were independent predictors of VTE. In multivariate analysis, patients with advanced OCCC had significantly poorer 5-year progression-free and overall survival rates than those with advanced SOC (P<0.01), and thrombocytosis was an independent predictor of decreased survival outcomes (P<0.01). Elevated IL-6 levels led to poorer 2-year progression-free survival rates in patients with OCCC (50% versus 87.5%, HR 4.89, P=0.016) than in those with SOC (24.9% versus 40.8%, HR 1.40, P=0.07). INTERPRETATION:Advanced OCCC is associated with an increased incidence of VTE and decreased survival outcomes, which has major implications for clinical management of OCCC. 10.1016/j.ejca.2015.07.012
    Prognostic value of preoperative lymphocyte-monocyte ratio in patients with ovarian clear cell carcinoma. Kwon Byung Su,Jeong Dae Hoon,Byun Jung Mi,Lee Tae Hwa,Choi Kyung Un,Song Yong Jung,Suh Dong Soo,Kim Ki Hyung Journal of Cancer The aim of the present study was to determine the prognostic significances of markers of preoperative systemic inflammatory response (SIR) in patients with ovarian clear cell carcinoma (OCCC). A total of 109 patients diagnosed with OCCC that underwent primary cytoreductive surgery and adjuvant platinum-based chemotherapy from 2009 to 2012 were enrolled in this retrospective study. SIR markers were calculated from complete blood cell counts determined before surgery. Receiver operating characteristic (ROC) curve analysis was used to determine optimal cut-off values for neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR). Prognostic significances with respect to overall survival (OS) and progression-free survival (PFS) were determined by Kaplan-Meier curve and multivariate Cox regression analysis. The optimized NLR, LMR and PLR cut-off values as determined by ROC curve analysis for PFS and OS were 2.3, 4.2, and 123.6, respectively. When the cohort was divided using these optimized cut-offs, NLR and LMR were found to be significantly associated with clinicopathologic factors, NLR with FIGO stage, the presence of malignant ascites, and platinum response, and LMR with FIGO stage, lymph node metastasis, malignant ascites, and platinum response. Kaplan-Meier analysis revealed a high NLR (> 2.3) was significantly associated with low 5-year PFS and OS rates and that a high LMR was significantly associated with high 5-year PFS and OS rates. Multivariate analysis identified FIGO stage, residual mass, and platinum response as independent prognostic factors of PFS, and FIGO stage, residual mass, platinum response, and LMR as independent prognostic factors of OS. Markers of systemic inflammatory response provide useful prognostic information and lymphocyte-to-monocyte ratio is the most reliable independent prognostic factor of overall survival in patients with ovarian clear cell carcinoma. 10.7150/jca.24057
    The activity of trabectedin as a single agent or in combination with everolimus for clear cell carcinoma of the ovary. Mabuchi Seiji,Hisamatsu Takeshi,Kawase Chiaki,Hayashi Masami,Sawada Kenjiro,Mimura Kazuya,Takahashi Kazuhiro,Takahashi Toshifumi,Kurachi Hirohisa,Kimura Tadashi Clinical cancer research : an official journal of the American Association for Cancer Research PURPOSE:The objective of this study was to evaluate the antitumor efficacy of trabectedin in clear cell carcinoma (CCC) of the ovary, which is regarded as an aggressive, chemoresistant, histologic subtype. EXPERIMENTAL DESIGN:Using 6 human ovarian cancer cell lines (3 CCC and 3 serous adenocarcinomas), the antitumor effects of trabectedin were examined in vitro, and we compared its activity according to histology. We next examined the antitumor activity of trabectedin in both cisplatin-resistant and paclitaxel-resistant CCC cells in vitro. Then, the in vivo effects of trabectedin were evaluated using mice inoculated with CCC cell lines. Using 2 pairs of trabectedin-sensitive parental and trabectedin-resistant CCC sublines, we investigated the role of mTOR in the mechanism of acquired resistance to trabectedin. Finally, we determined the effect of mTOR inhibition by everolimus on the antitumor efficacy of trabectedin in vitro and in vivo. RESULTS:Trabectedin showed significant antitumor activity toward chemosensitive and chemoresistant CCC cells in vitro. Mouse xenografts of CCC cells revealed that trabectedin significantly inhibits tumor growth. Greater activation of mTOR was observed in trabectedin-resistant CCC cells than in their respective parental cells. The continuous inhibition of mTOR significantly enhanced the therapeutic efficacy of trabectedin and prevented CCC cells from acquiring resistance to trabectedin. CONCLUSION:Trabectedin is a promising agent for CCC as a first-line chemotherapy and as a second-line treatment of recurrent CCC that had previously been treated with cisplatin or paclitaxel. Moreover, trabectedin combined with everolimus may be more efficacious for the management of CCC. 10.1158/1078-0432.CCR-10-2987
    Lack of effective systemic therapy for recurrent clear cell carcinoma of the ovary. Crotzer David R,Sun Charlotte C,Coleman Robert L,Wolf Judith K,Levenback Charles F,Gershenson David M Gynecologic oncology OBJECTIVE:Clear cell carcinoma of the ovary is an aggressive tumor characterized by relative chemoresistance and a poor prognosis. The purpose of this study was to review our experience with recurrent clear cell carcinoma of the ovary to evaluate its responsiveness to systemic cytotoxic and hormonal agents. METHODS:All patients diagnosed with clear cell carcinoma of the ovary seen at our institution between 1990 and 2002 were identified and their medical records reviewed. Eligibility criteria were: 1) primary diagnosis of clear cell carcinoma of the ovary, 2) measurable recurrent disease, 3) treatment of recurrent disease with 1 or more systemic regimens, and 4) adequate clinical information. End points were clinical response, progression-free survival, and overall survival. RESULTS:Fifty-one patients treated for recurrent clear cell carcinoma were identified. The patients received a total of 105 regimens (344 cycles of therapy). Among patients with platinum-sensitive disease (n=22 regimens), 2 patients (9%) had partial responses to retreatment with carboplatin plus paclitaxel, and 4 (18%) had stable disease. Among patients with platinum-resistant disease (n=83 regimens), only 1 patient (1%) had a partial response - to gemcitabine - and 1 patient had stable disease in response to 2 different regimens-paclitaxel and gemcitabine. The median progression-free survival was 8 months, and the median overall survival was 18 months. CONCLUSION:Our findings suggest that recurrent clear cell carcinoma of the ovary is particularly chemoresistant. A continued search for more active, targeted agents is warranted. 10.1016/j.ygyno.2006.12.024
    Exploring palliative treatment outcomes in women with advanced or recurrent ovarian clear cell carcinoma. Al-Barrak J,Santos J L,Tinker A,Hoskins P,Gilks C B,Lau H,Swenerton K D Gynecologic oncology OBJECTIVE:Clear cell carcinoma (CCC) of the ovary is increasingly recognized as responding poorly to chemotherapy (CT). This review examines the outcomes achieved with a variety of CT regimens, looking for evidence of activity that might guide the development of more effective treatments. METHODS:A retrospective chart review of all cases of CCC referred to the BC Cancer Agency (BCCA) between 2000 and 2008 was conducted. Data were collected from those with primarily advanced disease and from those who recurred after adjuvant treatment. Outcomes were measured using broad definitions of treatment benefit (any objective or subjective evidence of disease control) in order to reflect the real-life use of palliative therapy. RESULTS:There were 158 women with pure CCC. First-line therapy for advanced disease was delivered to 33 patients. Second- and third-line treatment was delivered to 47 and 25 patients, respectively. The total number of treatment courses was 105: 88 CT-alone courses, 14 radiation therapy (RT)-alone and 3 combined modality. Treatment benefit was recorded in 24% of patients receiving CT, 64% of patients receiving RT, and each who received combined modality treatment. There was no CT drug class identified as obviously efficacious. CONCLUSION:Most patients with advanced or recurrent CCC have a low benefit-to-failure ratio from palliative CT. The role of RT and targeted agents must be explored to improve clinical outcomes for such patients. 10.1016/j.ygyno.2011.03.011
    The Potential Role of Complement System in the Progression of Ovarian Clear Cell Carcinoma Inferred from the Gene Ontology-Based Immunofunctionome Analysis. Su Kuo-Min,Lin Tzu-Wei,Liu Li-Chun,Yang Yi-Pin,Wang Mong-Lien,Tsai Ping-Hsing,Wang Peng-Hui,Yu Mu-Hsien,Chang Chia-Ming,Chang Cheng-Chang International journal of molecular sciences Ovarian clear cell carcinoma (OCCC) is the second most common epithelial ovarian carcinoma (EOC). It is refractory to chemotherapy with a worse prognosis after the preliminary optimal debulking operation, such that the treatment of OCCC remains a challenge. OCCC is believed to evolve from endometriosis, a chronic immune/inflammation-related disease, so that immunotherapy may be a potential alternative treatment. Here, gene set-based analysis was used to investigate the immunofunctionomes of OCCC in early and advanced stages. Quantified biological functions defined by 5917 Gene Ontology (GO) terms downloaded from the Gene Expression Omnibus (GEO) database were used. DNA microarray gene expression profiles were used to convert 85 OCCCs and 136 normal controls into to the functionome. Relevant offspring were as extracted and the immunofunctionomes were rebuilt at different stages by machine learning. Several dysregulated pathogenic functions were found to coexist in the immunopathogenesis of early and advanced OCCC, wherein the complement-activation-alternative-pathway may be the headmost dysfunctional immunological pathway in duality for carcinogenesis at all OCCC stages. Several immunological genes involved in the complement system had dual influences on patients' survival, and immunohistochemistrical analysis implied the higher expression of C3a receptor (C3aR) and C5a receptor (C5aR) levels in OCCC than in controls. 10.3390/ijms21082824
    Is there any association between retroperitoneal lymphadenectomy and survival benefit in ovarian clear cell carcinoma patients? Suzuki S,Kajiyama H,Shibata K,Ino K,Nawa A,Sakakibara K,Matsuzawa K,Takeda A,Kinoshita Y,Kawai M,Nagasaka T,Kikkawa F Annals of oncology : official journal of the European Society for Medical Oncology BACKGROUND:To estimate the survival impact of systemic retroperitoneal lymphadenectomy in patients diagnosed with International Federation of Gynecology and Obstetrics pTI-IIb clear cell carcinoma of the ovary (CCC). PATIENTS AND METHODS:Demographic and clinicopathologic data were obtained from the Tokai Ovarian Tumor Study Group between 1986 and 2006. Survival curves were calculated using the Kaplan-Meier method. Differences in survival rates were analyzed using the log-rank test. RESULTS:A total of 205 patients had clinical pTI-IIb CCC (median age: 52 years, range: 30-75). One hundred and four (50.7%) patients underwent systemic retroperitoneal lymphadenectomy. Lymphadenectomy was not associated with improved disease-free and overall survival in all patients (P = 0.353 and P = 0.645, respectively). Moreover, lymphadenectomy did not improve the overall survival in those with pTIc CCC (P = 0.433). Similarly, on univariate analysis, age, volume of ascites, preoperative CA 125 values, and regimen of chemotherapy were not significant factors. In addition, there was no significant difference in the ratio of positive lymph node metastases regardless of the completion of lymphadenectomy (P = 0.955). CONCLUSION:Our data suggest that patients with pTI-IIb CCC who underwent lymphadenectomy did not show a significant improvement in survival. There was no significant difference in the overall and disease-free survival rates in pTI-IIb CCC patients regardless of the completion of surgical staging lymphadenectomy. 10.1093/annonc/mdn059
    Precision medicine for ovarian clear cell carcinoma based on gene alterations. Kuroda Takafumi,Kohno Takashi International journal of clinical oncology Ovarian clear cell carcinoma (OCCC) is a histological subtype of epithelial ovarian carcinoma prevalent in Asians. No clear therapeutic selection based on molecular profile has been implemented for this disease. Oncogenic PIK3CA mutation, which activates the PIK3CA/AKT/mTOR signaling pathway, is a promising druggable alteration in OCCC. Recent studies by our group and others have identified the ARID1A mutation as another alteration linked to therapeutic selection based on synthetic lethality: deleterious ARID1A mutations, resulting in ARID1A deficiency, make OCCC cells sensitive to drugs targeting poly (ADP-ribose) polymerase and EZH2, as well as to glutathione inhibitors. In addition, we recently obtained evidence that ARID1A-deficient OCCC could benefit from gemcitabine treatment. Precision medicine based on gene alteration profiling might improve the prognosis of OCCC patients. 10.1007/s10147-020-01622-z
    Mechanisms of chemoresistance and poor prognosis in ovarian clear cell carcinoma. Itamochi Hiroaki,Kigawa Junzo,Terakawa Naoki Cancer science Clear cell carcinoma (CCC) accounts for 4% to 12% of epithelial ovarian cancer in Western countries and, for some unknown reasons, it comprises more than 20% of such cancers in Japan. CCC shows unique clinical features such as a high incidence of stage I disease, a large pelvic mass, an increased incidence of vascular thromboembolic complications, and hypercalcemia. It is frequently associated with endometriosis. Compared to serous adenocarcinoma (SAC), CCC is relatively resistant to conventional platinum, or taxane-based chemotherapy which is associated with its poor prognosis. However, the mechanisms underlying CCC's resistance to chemotherapy have not been understood. Although several mechanisms involved in drug resistance exist in CCC, including decreased drug accumulation, increased drug detoxification, and an increased DNA repair activity; however, no particular chemoresistance system has been identified. On the other hand, an in vitro study revealed that low cell proliferation may cause the insensitivity of CCC to cisplatin. The Ki-67 labeling index in CCC tumors was significantly lower than SAC. The Ki-67 labeling index for responders was significantly higher than that for non-responders in both tumor types. A multivariable analysis revealed that Ki-67 labeling index and residual tumor size were independent prognostic factors in CCC. Therefore, lower proliferation of the tumor cells may contribute to their resistance to chemotherapy. However, further investigation into the molecular biology and genetics of CCC is warranted. This review discusses the current state of knowledge of the chemoresistance mechanism in CCC and novel treatment strategies for CCC. 10.1111/j.1349-7006.2008.00747.x
    The target therapy of ovarian clear cell carcinoma. Jin Ying,Li Yan,Pan Lingya OncoTargets and therapy Clear cell adenocarcinoma (CCC) of the ovary accounts for 10% of epithelial ovarian cancer and is a distinct entity from other epithelial ovarian carcinomas. It arises from the endometriosis. CCC has specific biological and clinical behavior. Compared with other histological types, CCC shows a chemoresistant phenotype, which leads to poorer prognosis. Thus, development of new target-based therapies remains an unmet need for these patients. Mutations in the gene ARID1A have been found to occur in high frequency in CCC. The majority of these mutations lead to a loss of expression of the ARID1A protein, which is a subunit of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex and considered as a bona fide tumor suppressor. Upregulation of the PIK3/AKT/mTOR pathway, particularly through mutations of PIK3CA and inactivation of PTEN, is involved in tumorigenesis of CCC. Targeting angiogenesis, the Met protooncogene pathway, and HER2 are also discussed in this review. 10.2147/OTT.S49993
    Ovarian clear cell carcinoma--bad endometriosis or bad endometrium? Gounaris Ioannis,Charnock-Jones D Stephen,Brenton James D The Journal of pathology It has become increasingly clear that the four main histological subtypes of epithelial ovarian cancer (EOC), high-grade serous, endometrioid, clear cell and mucinous, are entities with different epidemiologies, clinical presentations, responses to treatment, and ultimate outcomes. In fact, for all intents and purposes, they can be considered different diseases, their only common denominator being that they frequently involve the ovary and pelvic organs. However, clinical practice has not caught up with these insights and the treatment of EOC is that of a single disease entity. In part, this is because we lack detailed knowledge of the molecular mechanisms driving the pathogenesis of each disease, which is vital in order to develop therapeutic approaches against common driver events. In the last few years, mutations in ARID1A and PIK3CA have been described in a substantial fraction of cases of ovarian clear cell carcinoma, yet the paper by Yamamoto et al in this issue of The Journal of Pathology reveals that PIK3CA mutations can be detected in precursor endometriosis tissues. These and other recent observations underscore the importance of investigating whether mutations in the eutopic endometrium actually predispose to endometriosis and eventually to malignancy. 10.1002/path.2970
    Gynecologic Cancer InterGroup (GCIG) consensus review for clear cell carcinoma of the ovary. Okamoto Aikou,Glasspool Rosalind M,Mabuchi Seiji,Matsumura Noriomi,Nomura Hiroyuki,Itamochi Hiroaki,Takano Masashi,Takano Tadao,Susumu Nobuyuki,Aoki Daisuke,Konishi Ikuo,Covens Alan,Ledermann Jonathan,Mezzanzanica Delia,Mezzazanica Delia,Steer Christopher,Millan David,McNeish Iain A,Pfisterer Jacobus,Kang Sokbom,Gladieff Laurence,Bryce Jane,Oza Amit International journal of gynecological cancer : official journal of the International Gynecological Cancer Society Clear cell carcinoma of the ovary (CCC) is a histologic subtype of epithelial ovarian cancer with a distinct clinical behavior. There are marked geographic differences in the prevalence of CCC. The CCC is more likely to be detected at an early stage than high-grade serous cancers, and when confined within the ovary, the prognosis is good. However, advanced disease is associated with a very poor prognosis and resistance to standard treatment. Cytoreductive surgery should be performed for patients with stage II, III, or IV disease. An international phase III study to compare irinotecan/cisplatin and paclitaxel/carboplatin as adjuvant chemotherapy for stage IIV CCC has completed enrollment (GCIG/JGOG3017). Considering the frequent PIK3CA mutation in CCC, dual inhibitors targeting PI3K, AKT in the mTOR pathway, are promising. Performing these trials and generating the evidence will require considerable international collaboration. 10.1097/IGC.0000000000000289
    Mismatch repair status and PD-L1 expression in clear cell carcinomas of the ovary and endometrium. Willis Brian C,Sloan Emily A,Atkins Kristen A,Stoler Mark H,Mills Anne M Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Clear cell carcinoma represents a distinct histologic type of müllerian carcinoma that is resistant to conventional chemotherapy. Expression of programmed cell death ligand (PD-L1) has been associated with immune evasion in numerous tumor types and may be used to identify patients who will benefit from targeted immunotherapy, particularly in the setting of mismatch repair defects. We evaluated PD-L1 expression in 23 ovarian clear cell carcinomas and 21 endometrial clear cell carcinomas, and correlated expression with mismatch repair status. Tumor PD-L1 staining was seen in 43% of ovarian tumors and 76% of endometrial tumors, including 71% of cases (67% of ovarian and 75% of endometrial) with mismatch repair defects. Extensive tumoral staining (>50%) was seen in only one case (an endometrial case with MSH6 loss). However, tumoral PD-L1 expression remained common in mismatch repair-intact tumors and mismatch repair status was not significantly correlated with PD-L1 expression. The increased incidence of PD-L1 positivity in tumor cells (P=0.04) in endometrial vs ovarian clear cell carcinomas suggests differences in the tumor microenvironment of these histologically and molecularly similar tumors that may inform treatment options. These results suggest that clear cell histology may be a useful susceptibility marker for immunotherapy targeting the PD-1/PD-L1 axis irrespective of mismatch repair status, particularly in endometrial carcinomas. 10.1038/modpathol.2017.67
    Phase II study of single-agent cabozantinib in patients with recurrent clear cell ovarian, primary peritoneal or fallopian tube cancer (NRG-GY001). Konstantinopoulos Panagiotis A,Brady William E,Farley John,Armstrong Amy,Uyar Denise S,Gershenson David M Gynecologic oncology OBJECTIVE:To evaluate the efficacy and tolerability of cabozantinib in recurrent clear cell ovarian, primary peritoneal or fallopian tube cancer. METHODS:Patients with recurrent ovarian, fallopian or primary peritoneal tumors with at least 50% clear cell histomorphology, measurable disease, one or two prior regimens and ECOG performance status 0-2 received cabozantinib 60 mg orally once daily continuously, in 4-week cycles until disease progression or unacceptable toxicity. Primary endpoints were progression-free survival (PFS) at six months and complete or partial tumor response (as assessed by RECIST 1.1). Secondary endpoints included toxicity, PFS, and overall survival (OS). RESULTS:Over 19 months, 13 patients were accrued. Fifty-four percent of patients were ≥60 years of age. Performance statuses of 0 and 1 comprised 8 and 5 patients. No objective tumor responses were seen. Three (23% [95% CI: 5%, 54%]) of 13 patients had PFS ≥6 months, including one patient who received cabozantinib for 23 cycles and was still on treatment as of the data cut-off date. Median PFS and OS were 3.6 and 8.1 months, respectively. There was one patient with a grade 5 event: a thromboembolic event considered possibly related to study therapy; patient's cause of death was determined to be due to disease and protocol treatment. Four other patients had thromboembolic events (two grade 3 and one each grade 1 and grade 2). Other grade 3 or higher events reported in two or more patients were nausea, vomiting, fatigue, dyspnea, and dehydration. CONCLUSIONS:Cabozantinib demonstrated minimal activity in the second- and third-line treatments of clear cell ovarian, fallopian tube or primary peritoneal carcinoma. 10.1016/j.ygyno.2018.04.572
    Potential benefit of Sunitinib in recurrent and refractory ovarian clear cell adenocarcinoma. Rauh-Hain J A,Penson R T International journal of gynecological cancer : official journal of the International Gynecological Cancer Society Ovarian clear cell adenocarcinoma (OCCA) is a unique biological subtype of epithelial ovarian cancer, with a similar gene profile to renal cell carcinoma (RCC). Sunitinib is a vascular endothelial growth factor receptor tyrosine kinase inhibitor with proven antitumor activity in RCC and a rational biological option for treatment of OCCA. A 60-year-old woman presented with recurrent and refractory stage IA OCCA, after 9 years of remission. Sunitinib was initiated as fifth-line chemotherapy, associated with cystic degeneration of liver metastasis and a short downward trend in her CA125 level. Recurrent and refractory OCCA may respond to Sunitinib. Clinical trials are needed to objectively confirm these findings, as benefit may be limited in patients with extensively pretreated tumors. 10.1111/j.1525-1438.2007.01156.x
    Sorafenib efficacy in ovarian clear cell carcinoma revealed by transcriptome profiling. Matsumura Noriomi,Mandai Masaki,Okamoto Takako,Yamaguchi Ken,Yamamura Shogo,Oura Tomonori,Baba Tsukasa,Hamanishi Junzo,Kang Hyun S,Matsui Shigeyuki,Mori Seiichi,Murphy Susan K,Konishi Ikuo Cancer science The purpose of this study was to investigate a new modality of therapy against ovarian clear cell carcinoma (OCCC), a chemoresistant subtype of ovarian cancer. Microarray datasets of ovarian cancer cell lines and cancer tissues were analyzed using bioinformatic tools. The gene expression profile of OCCC was similar to that of renal cell carcinoma (RCC). This similarity was at least partially due to hepatocyte nuclear factor 1 pathway activation common to both malignancies. In addition, oncogenic pathway alterations were characteristic of OCCC including hypoxia inducible factor 1 alpha subunit and relatively high Ras activities. Therefore, we predicted that the multi-kinase inhibitor sorafenib, which is approved for RCC and suppresses Ras activity, would also be effective against OCCC. Orally administered sorafenib (40 mg/kg per day) significantly inhibited tumor growth in nude mice when it was given after inoculation with the OCCC cell line RMG-2 (P = 0.002). Furthermore, sorafenib significantly reduced tumor size when it was administered to established RMG-2 tumors (P = 0.0002), while intraperitoneal injection of cisplatin (5 mg/kg per week) did not. In conclusion, the prominent anti-tumor effect of sorafenib against OCCC indicates that sorafenib is a promising candidate drug and supports the need for clinical trials using sorafenib against OCCC. This report demonstrates a method to utilize genome-wide information to facilitate translational research for treatments against less common subtypes of cancers. 10.1111/j.1349-7006.2010.01736.x
    Adjuvant chemotherapy in patients with stage I endometrioid or clear cell ovarian cancer in the platinum era: a Surveillance, Epidemiology, and End Results Cohort Study, 2000-2013. Oseledchyk A,Leitao M M,Konner J,O'Cearbhaill R E,Zamarin D,Sonoda Y,Gardner G J,Long Roche K,Aghajanian C A,Grisham R N,Brown C L,Snyder A,Chi D S,Soslow R A,Abu-Rustum N R,Zivanovic O Annals of oncology : official journal of the European Society for Medical Oncology Background:We sought to evaluate the impact of adjuvant chemotherapy on overall survival (OS) in patients with stage I endometrioid epithelial ovarian cancer (EEOC) or ovarian clear cell cancer (OCCC) using a national database. Patients and methods:The Surveillance, Epidemiology, and End Results database was used to identify patients diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage I EEOC or OCCC from 2000 to 2013. We sought to identify predictors of chemotherapy use and to assess the impact of chemotherapy on OS in these patients. OS was compared using the log-rank test and the Cox proportional hazards model. Results:In all, 3552 patients with FIGO stage I EEOC and 1995 patients with stage I OCCC were identified. Of the 1600 patients (45%) with EEOC who underwent adjuvant chemotherapy, the 5-year OS rate was 90%, compared with 89% for those who did not undergo adjuvant chemotherapy (P = 0.807). Of the 1374 (69%) patients with OCCC who underwent adjuvant chemotherapy, the 5-year OS rate was 85%, compared with 83% (P = 0.439) for those who did not undergo adjuvant chemotherapy. Chemotherapy use was associated with younger age, higher substage, and more recent year of diagnosis for both the EEOC and OCCC groups. Only in the subgroup of patients with FIGO substage IC, grade 3 EEOC (n = 282) was chemotherapy associated with an improved 5-year OS-81% compared with 62% (P = 0.003) in untreated patients (HR: 0.583; 95% CI: 0.359-0.949; P = 0.030). In patients with OCCC, there was no significant effect of adjuvant chemotherapy on OS in any substage. Conclusions:Adjuvant chemotherapy was associated with improved OS only in patients with substage IC, grade 3 EEOC. In stage I OCCC, adjuvant chemotherapy was not associated with improved OS. 10.1093/annonc/mdx525
    Randomized Phase III Trial of Irinotecan Plus Cisplatin Compared With Paclitaxel Plus Carboplatin As First-Line Chemotherapy for Ovarian Clear Cell Carcinoma: JGOG3017/GCIG Trial. Sugiyama Toru,Okamoto Aikou,Enomoto Takayuki,Hamano Tetsutaro,Aotani Eriko,Terao Yasuhisa,Suzuki Nao,Mikami Mikio,Yaegashi Nobuo,Kato Kiyoko,Yoshikawa Hiroyuki,Yokoyama Yoshihito,Tanabe Hiroshi,Nishino Koji,Nomura Hiroyuki,Kim Jae-Weon,Kim Byoung-Gie,Pignata Sandro,Alexandre Jerome,Green John,Isonishi Seiji,Terauchi Fumitoshi,Fujiwara Keiichi,Aoki Daisuke Journal of clinical oncology : official journal of the American Society of Clinical Oncology PURPOSE:Clear cell carcinoma (CCC) is a rare histologic subtype that demonstrates poor outcomes in epithelial ovarian cancer. The Japanese Gynecologic Oncology Group conducted the first randomized phase III, CCC-specific clinical trial that compared irinotecan and cisplatin (CPT-P) with paclitaxel plus carboplatin (TC) in patients with CCC. PATIENTS AND METHODS:Six hundred sixty-seven patients with stage I to IV CCC of the ovary were randomly assigned to receive irinotecan 60 mg/m(2) on days 1, 8, and 15 plus cisplatin 60 mg/m(2) on day 1 (CPT-P group) every 4 weeks for six cycles or paclitaxel 175 mg/m(2) plus carboplatin area under the curve 6.0 mg/mL/min on day 1 every 3 weeks for six cycles (TC group). The primary end point was progression-free survival. Secondary end points were overall survival, overall response rate, and adverse events. RESULTS:Six hundred nineteen patients were clinically and pathologically eligible for evaluation. With a median follow-up of 44.3 months, 2-year progression-free survival rates were 73.0% in the CPT-P group and 77.6% in TC group (hazard ratio, 1.17; 95% CI, 0.87 to 1.58; P = .85). Two-year overall survival rates were 85.5% with CPT-P and 87.4% with TC (hazard ratio, 1.13; 95% CI, 0.80 to 1.61; one-sided P = .76). Grade 3/4 anorexia, diarrhea, nausea, vomiting, and febrile neutropenia occurred more frequently with CPT-P, whereas grade 3/4 leukopenia, neutropenia, thrombocytopenia, peripheral sensory neuropathy, and joint pain occurred more frequently with TC. CONCLUSION:No significant survival benefit was found for CPT-P. Both regimens were well tolerated, but the toxicity profiles differed significantly. Treatment with existing anticancer agents has limitations to improving the prognosis of CCC. 10.1200/JCO.2016.66.9010
    A phase II evaluation of sunitinib in the treatment of persistent or recurrent clear cell ovarian carcinoma: An NRG Oncology/Gynecologic Oncology Group Study (GOG-254). Chan John K,Brady William,Monk Bradley J,Brown Jubilee,Shahin Mark S,Rose Peter G,Kim Jae-Hoon,Secord Angeles Alvarez,Walker Joan L,Gershenson David M Gynecologic oncology OBJECTIVES:To determine the efficacy and tolerability of sunitinib in recurrent or persistent clear cell ovarian cancer patients. METHODS:All patients had one or two prior regimens with measurable disease. Tumors were at least 50% clear cell histomorphology and negative for WT-1 antigen and estrogen receptor expression by immunohistochemistry. Sunitinib 50 mg per day for 4 weeks was administered in repeated 6-week cycles until disease progression or prohibitive toxicity. Primary end points were progression-free survival (PFS) at 6 months and clinical response. The study was designed to determine if the drug had a response rate of at least 20% or 6-month PFS of at least 25%. RESULTS:Of 35 patients enrolled, 30 were treated and eligible (median age: 51, range: 27-73). Twenty-five (83%) were White, 4 (13%) Asian, and 1 (3%) unknown. The majority 28 (83%) patients, underwent ≤3 but 2 (7%) had 16 courses of study therapy. Five (16.7%) patients had PFS ≥6 months (90% CI: 6.8%-31.9%). Two (6.7%) patients had a partial or complete response (90% CI: 1.2%-19.5%). The median PFS was 2.7 months. The median overall survival was 12.8 months. The most common grade 3 adverse events were fatigue (4), hypertension (4), neutropenia (4), anemia (3), abdominal pain (3), and leukopenia (3). Grade 4-5 adverse events included: thrombocytopenia (5), anemia (2), acute kidney Injury (1), stroke (1), and allergic reaction (1). CONCLUSION:Sunitinib demonstrated minimal activity in the second- and third-line treatment of persistent or recurrent clear cell ovarian carcinoma. ClinicalTrials.gov number, NCT00979992. 10.1016/j.ygyno.2018.05.029
    Low-stage ovarian clear cell carcinoma: population-based outcomes in British Columbia, Canada, with evidence for a survival benefit as a result of irradiation. Hoskins Paul J,Le Nhu,Gilks Blake,Tinker Anna,Santos Jennifer,Wong Frances,Swenerton Kenneth D Journal of clinical oncology : official journal of the American Society of Clinical Oncology PURPOSE:To evaluate the population-based outcomes of stage I and II ovarian clear cell carcinoma (OCCC) in a North American population treated with carboplatin/paclitaxel and abdominopelvic irradiation. PATIENTS AND METHODS:Retrospective analysis was performed of 241 patients referred in the carboplatin/paclitaxel era. Irradiation was to be used with a few defined exceptions. However, because of differing beliefs as to its effectiveness, its use was consistently avoided by specific oncologists, allowing the opportunity to study its possible effect on disease-free survival (DFS) in these concurrent cohorts. RESULTS:Five- and 10-year DFS rates were 84% and 70% for stage IA/B; 67% and 57% for stage IC; and 49% and 44% for stage II, respectively. Five- and 10-year DFS rates for those with stage IC disease based purely on rupture were similar to rates for patients with stage IA/B, at 92% and 71%, respectively. The remaining patients with stage IC had 48% 5- and 10-year DFS. Multivariate analysis using a decision tree identified positive cytology as the most important factor (72% relapse rate if positive and 27% if negative or unknown). If, in addition, the capsule surface was involved, then the relapse rate was 93%. Irradiation had no discernible survival benefit for patients with stage IA and IC (rupture alone), whereas for the remainder of patients with stage IC and stage II, it improved DFS by 20% at 5 years (relative risk, 0.5); the benefit was most evident in the cytologically negative/unknown group. CONCLUSION:DFS is similar in this North American population with early OCCC to the DFS reported in Asia. A potential benefit from irradiation was evident in a subset. 10.1200/JCO.2011.40.1646
    Ovarian clear cell carcinoma as a stress-responsive cancer: influence of the microenvironment on the carcinogenesis and cancer phenotype. Mandai Masaki,Matsumura Noriomi,Baba Tsukasa,Yamaguchi Ken,Hamanishi Junzo,Konishi Ikuo Cancer letters Although it is well known that ovarian endometriosis occasionally gives rise to ovarian cancers with specific histology such as endometrioid and clear cell carcinomas, its etiology is not fully understood. We have shown that a stressful microenvironment within the endometriotic cyst may lead to cancer development by inducing unique gene expressions, which potentially serves as a molecular marker for treatment modality. In this review, by referring to other articles in this field, we explore how the carcinogenic microenvironment affects the phenotype and gene expression of a cancer, and how we can develop new treatment based on this concept. 10.1016/j.canlet.2011.06.039
    Clear-cell carcinoma of the ovary. Fujiwara K,Shintani D,Nishikawa T Annals of oncology : official journal of the European Society for Medical Oncology Clear-cell carcinoma of the ovary (CCCO) is a distinct entity of epithelial ovarian cancer in terms of clinical, histopathological, or genetic features. The incidence of CCCO is different by ethnicity but the reason is not clear yet. Overall prognosis of CCCO is good because most CCCO is found in stage I. However, advanced disease is associated with a very poor prognosis and resistance to standard treatment. The same is true for recurrent disease. Therefore, genetic analysis of CCCO is important to find the right target(s) and better therapeutic approaches. Because of its rarity, international collaboration is necessary to conduct randomized clinical trials for CCCO. 10.1093/annonc/mdw086
    Prognostic factors and effects of fertility-sparing surgery in women of reproductive age with ovarian clear-cell carcinoma: a propensity score analysis. Yoshihara Masato,Kajiyama Hiroaki,Tamauchi Satoshi,Suzuki Shiro,Takahashi Kunihiko,Matsui Shigeyuki,Kikkawa Fumitaka Journal of gynecologic oncology OBJECTIVE:The aim of this study was to investigate the clinical characteristics of young patients with stage I clear-cell carcinoma (CCC) and evaluate the prognostic factors and effects of fertility-sparing surgery (FSS) using propensity score (PS) adjustment. METHODS:We conducted a regional multi-institutional study between 1986 and 2017. Among 4,277 patients with ovarian tumor, clinical and pathological data of 103 fertile women with stage I unilateral CCC were collected. We evaluated survival and reproductive outcomes in these patients. Additionally, to analyze the effects of FSS, baseline imbalance between patients with and those without FSS was adjusted with an inverse probability of treatment weighting using PSs involving independent clinical variables. RESULTS:The mean patient age was 39.4 years, and the median follow-up period for surviving patients was 55.6 months. In multivariate analysis, stage IC2/IC3 (vs. IA/IC1) was the only independent prognostic factor for recurrence-free survival (RFS) and overall survival (OS). FSS was not associated with poorer prognosis when compared to the prognosis with non-preserving surgery with regard to both RFS and OS. No statistical difference in survival outcomes between FSS and other approaches was confirmed after PS adjustment. Among patients who underwent FSS, four deliveries with healthy neonates were noted without any gestational complications. CONCLUSION:FSS can be considered in stage I CCC, specifically in stage IA and IC1 patients who strongly desire to have children in the future. Further clinical research is needed to clarify the optimal application of FSS for CCC. 10.3802/jgo.2019.30.e102
    The impact of systematic retroperitoneal lymphadenectomy on long-term oncologic outcome of women with advanced ovarian clear-cell carcinoma. Kajiyama Hiroaki,Suzuki Shiro,Yoshikawa Nobuhisa,Tamauchi Satoshi,Shibata Kiyosumi,Kikkawa Fumitaka Journal of gynecologic oncology OBJECTIVE:The impact of systematic retroperitoneal lymphadenectomy (SRL) remains controversial in patients with advanced ovarian clear-cell carcinoma (CCC) who are optimally debulked. METHODS:Between 1986 and 2017, a total of 3,227 women with epithelial ovarian carcinoma were analyzed in a multi-institutional study. Among them, 166 optimally debulked women with stage IIB-IV CCC were collected (residual tumor of <1 cm). All patients were divided into 2 groups: 1) Group I (n=112): underwent standard radical surgery with SRL, 2) Group II (n=54): underwent non-staging limited surgery. The pathological slides were assessed based on central pathological review. Oncologic outcomes were compared between the two groups using a propensity score (PS)-matching technique to adjust for various clinicopathologic factors. RESULTS:The median follow-up duration of all surviving women was 52.8 (1.6-184.2) months. Overall, 88 patients (53.0%) experienced recurrence and 68 patients (41.0%) died of the disease. In the original cohort, the 5-year overall survival (OS) rates of groups I and II were 57.9 and 64.9%, respectively (log-rank p=0.415). In the PS-adjusted cohort, the 5-year OS rates were 64.9 and 58.8% in women in groups I and II, respectively (p=0.453). Furthermore, in the PS-matched cohort after adjustment for multiple clinicopathologic factors, there was no significant difference in OS between the 2 groups (group I vs. group II; hazard ratio=1.170; 95% confidence interval=0.633-2.187; p=0.615). CONCLUSIONS:This study suggests that the performance of SRL including radical surgery may not lead to a significant improvement in the oncologic outcome of advanced CCC patients with optimal cytoreduction. 10.3802/jgo.2020.31.e47
    Prevalence and prognostic impact of lymphadenectomy and lymph node metastasis in clinically early-stage ovarian clear cell carcinoma. Mahdi Haider,Moslemi-Kebria Mehdi,Levinson Kimberly L,Gojayev Anar,Lockhart David,Ali-Fehmi Rouba,Munkarah Adnan R International journal of gynecological cancer : official journal of the International Gynecological Cancer Society OBJECTIVES:The objective of this study was to estimate the prevalence and prognostic impact of lymphadenectomy and lymph node involvement in patients with ovarian clear cell carcinoma (OCCC) grossly confined to the ovary. METHODS:Patients with a diagnosis of OCCC grossly confined to the ovary were identified from Surveillance, Epidemiology, and End Results program from 1988 to 2007. Only surgically treated patients were included. Statistical analysis using Student t test, Kaplan-Meier survival methods, and Cox proportional hazards regression were performed. RESULTS:One thousand eight hundred ninety-seven patients with OCCC who have undergone surgical treatment and deemed at time of the surgery to have disease grossly confined to the ovary were included: 538 (28.3%) had no lymphadenectomy (LND -1), and 1359 (71.7%) had lymphadenectomy. Of the 1359 patients who had lymphadenectomy, 1298 (95.5%) were International Federation of Gynecology and Obstetrics (FIGO) surgical stage I (LND +1), and 61 (4.5%) were upstaged to FIGO stage IIIC due to nodal metastasis (LND +3C). The 5-year disease-specific survival was 84.9% for LND -1, 88.0% for LND +1, and 65.0% for LND +3C (P < 0.001). Among those with histologically negative lymph nodes, the 5-year disease-specific survival was 85% for patients with 1 to 10 nodes removed, and 91% for those with more than 10 nodes removed (P = 0.054). On multivariate analysis after controlling for stage, age, and race, lymph node metastasis was an independent predictor of poor disease-specific survival (hazard ratio, 3.1; 95% confidence interval, 1.86-5.28; P < 0.001). On other hand, there was a trend toward an improved survival when more extensive lymphadenectomy is performed in patients with histologically negative nodes (1-10 vs >10 nodes), but it did not reach statistical significance (hazard ratio, 0.71; 95% confidence interval, 0.49-1.02; P = 0.064). CONCLUSIONS:Lymph node metastasis was uncommon in patients diagnosed with OCCC grossly confined to the ovary; however, patients with positive nodes were more likely to die compared to those with negative nodes. More extensive lymphadenectomy plays an important role in providing accurate staging and prognostic information. 10.1097/IGC.0b013e3182856736
    Survival outcome of stage I ovarian clear cell carcinoma with lympho-vascular space invasion. Matsuo Koji,Yoshino Kiyoshi,Hasegawa Kosei,Murakami Ryusuke,Ikeda Yuji,Adachi Sosuke,Hiramatsu Kosuke,Yokoyama Takuhei,Nishimura Masato,Sheridan Todd B,Enomoto Takayuki,Fujiwara Keiichi,Matsumura Noriomi,Konishi Ikuo,Fotopoulou Christina,Roman Lynda D,Sood Anil K Gynecologic oncology BACKGROUND:The clinical impact of lympho-vascular space invasion (LVSI) in early-stage ovarian clear cell carcinoma (OCCC) is not well understood. Given the distinct tumor biology and survival patterns of OCCC, the significance of LVSI on survival outcome and treatment response was examined in OCCC. METHODS:A multicenter study was conducted to examine stage IA-IC3 OCCC cases that underwent primary surgical staging including lymphadenectomy. LVSI status was determined from archived histopathology slides, correlated with clinico-pathological results, chemotherapy patterns, and survival outcomes. RESULTS:LVSI was observed in 47 (20.3%) among 232 cases. In univariate analysis, LVSI was associated with older age (p=0.042), large tumor size (p=0.048), and stage IC (p=0.035). In survival analysis, LVSI was associated with decreased disease-free survival (DFS, 5-year rate, 70.6% versus 92.1%, p=0.0004) and overall survival (OS, 78.8% versus 93.3%, p=0.008) on univariate analysis. After controlling for age, tumor size, stage, and chemotherapy use, LVSI remained an independent prognostic factor for decreased survival outcomes (DFS, hazard ratio [HR] 4.35, 95% confidence interval [CI] 1.73-10.9, p=0.002; and OS, HR 4.73, 95%CI 1.60-14.0, p=0.015). Among 210 cases who received postoperative chemotherapy, while regimen type did not impact survival outcome regardless of LVSI status (DFS, p=0.63), the number of administered cycles showed a survival benefit towards ≥6cycles for patients with LVSI-positive tumors (DFS, p=0.009; and OS, p=0.016). CONCLUSION:LVSI is an important marker to predict survival outcome of stage I OCCC. Regardless of chemotherapy type, patients with stage I OCCC showing LVSI may benefit from receiving postoperative chemotherapy. 10.1016/j.ygyno.2014.12.006
    Prognostic value of neutrophil-to-lymphocyte ratio in early-stage ovarian clear-cell carcinoma. Yoshida Kosuke,Yoshikawa Nobuhisa,Shirakawa Akira,Niimi Kaoru,Suzuki Shiro,Kajiyama Hiroaki,Kikkawa Fumitaka Journal of gynecologic oncology OBJECTIVES:There is increasing evidence that systemic inflammatory response (SIR) markers are prognostic factors for various types of cancers. This is the first study to evaluate the usefulness of SIR markers for the prognosis of early-stage ovarian clear-cell carcinoma (OCCC). METHODS:We retrospectively investigated 83 patients diagnosed with stage I-II OCCC who underwent surgery between 2005 and 2017. Initially, receiver operating characteristic curve analysis for overall survival (OS) was used to determine optimal cut-off values for neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). Patients were stratified into 2 groups by the cut-off values (NLR=3.26, PLR=160). Univariate and multivariate analyses were performed to elucidate the significance of SIR markers as prognostic factors. RESULTS:In the median follow-up period of 64.1 months, 16 patients experienced recurrence, and nine patients died. The Kaplan-Meier curve showed that OS of the NLR-low group was significantly longer than the NLR-high group (p=0.021). There was no significant difference in progression-free survival between the 2 groups (p=0.668), but the post-recurrence survival of the NLR-low group was significantly longer than the NLR-high group (p=0.019). Furthermore, multivariate analysis showed that increase in NLR is a significant independent prognostic factor for poor prognosis (hazard ratio=7.437, p=0.017). There was no significant difference between PLR-low and PLR-high group. CONCLUSION:Results suggest that NLR can be a significant independent prognostic factor for early-stage OCCC. 10.3802/jgo.2019.30.e85
    Salvage Chemotherapy for Patients With Recurrent or Persistent Ovarian Clear Cell Carcinoma: A Retrospective Study of 164 Cases. Bai Huimin,Sha Guihua,Cao Dongyan,Yang Jiaxin,Chen Jie,Wang Yue,Lang Jinghe,Shen Keng,Zhang Zhenyu Medicine The purpose of this study was to evaluate the effects of salvage chemotherapy on recurrent or persistent ovarian clear cell carcinoma (CCC) with the goal of identifying a more rational treatment regimen for this lethal disease.The medical records of patients with CCC were retrospectively reviewed to select patients that were subsequently treated for recurrent or persistent disease.Of the 164 women with recurrent or persistent CCC, 485 chemotherapy courses with 1766 cycles were administered. Overall, the clinical benefit rate (CBR) was 39.4%, and the mean progression-free survival (PFS) was 4.5 months. Grade 3/4 toxicities occurred in 94 courses (19.4%). The CBR for TC was 45.1%, with a PFS of 3.7 months. Compared to that of TC, the CBRs for PC and CC were significantly lower (P = 0.020 and 0.021, respectively). The CBRs and PFS for PAF-C were slightly higher (P = 0.518 and 0.077, respectively), but showed a significantly higher adverse event rate (AER, P = 0.039). The CBR for bevacizumab was 50% with an extraordinarily long PFS (49.8 months). Gemcitabine and oxaliplatin had similar values for CBRs (44.4% and 44.1%) and PFS (2.5 and 3.4 months), respectively. Docetaxel (weekly) exhibited a notably low AER of 2.7%, and topotecan was associated with a relatively long PFS (7.7 months).For cis/carboplatin-pretreated patients, the existing active agents, such as oxaliplatin, gemcitabine, topotecan, and especially bevacizumab, are promising. Docetaxel (weekly) is well tolerated and might offer a particularly viable option for heavily pretreated patients. However, additional research to identify for a continued search for the optimal combination of chemotherapeutics or novel agents is still warranted. 10.1097/MD.0000000000001121
    Primary ovarian clear cell carcinoma of the abdominal wall--a systematic review of the literature to establish optimal surgical management. Ohler Aleksandra,Dudziak Mirosław,Sznurkowski Jacek Jan Ginekologia polska UNLABELLED:Primary ovarian clear cell carcinoma of the abdominal wall (AW-OCCC) is an extremely rare occurrence. Therefore, data on the prognosis and treatment regime remain limited. OBJECTIVES:The aim of the study was to provide an evidence-based review of the available case reports to establish optimal surgical management. MATERIAL AND METHODS:A literature search according to PRISMA guidelines was performed using PubMed database (from 01.01.1990 to 31.12.2013) with the terms: "clear cell carcinoma" and "abdominal wall". A total of 17 case reports on 18 patients with full text available were identified. RESULTS:All AW-OCCC's appeared after previous laparotomy for gynecological reasons, with cesarean section as the predominant intervention (15/18, 83%). Median age was 46 years (range 37-56) and median time elapsed between the initial laparotomy and the cancer was 19 years (range 9-30). Data on the course of the disease were available for 17 cases. The overall median follow-up was 11 months (range 1-60). No cases of metastatic spread to the ovaries or the intraperitoneal cavity were observed. Eight patients experienced recurrence (8/17, 47.1%). Metastatic lymph nodes appeared in 6 of the 8 relapsed women and local recurrence in the remaining 2 subjects. There were 4 fatal cases (4/17, 23.5%), including 3 with lymphatic cancer spread. The women with treatment failure (recurrence or death) more frequently developed lymph node metastases than the curable cases (p=0.002). CONCLUSIONS:Radical resection of the tumor with concomitant pelvic lymph nodes dissection seems to be the most suitable surgical approach. The need for comprehensive intraperitoneal surgical staging for ovarian cancer is questionable.
    Patterns of recurrence and role of pelvic radiotherapy in ovarian clear cell adenocarcinoma. Macrie Bryan D,Strauss Jonathan B,Helenowski Irene B,Rademaker Alfred,Schink Julian C,Lurain John R,Small William International journal of gynecological cancer : official journal of the International Gynecological Cancer Society OBJECTIVE(S):The aims of this study were to analyze patterns of recurrence in patients with ovarian clear cell adenocarcinoma (CCA) and to evaluate the role of pelvic radiotherapy (RT). METHODS AND MATERIALS:All patients with ovarian CCA treated at a single institution between 1989 and 2012 were identified, and their medical records were reviewed. Eligibility criteria included histologic diagnosis of pure CCA of the ovary, surgical staging for International Federation of Gynecology and Obstetrics stage I-to-IIIC disease, and adjuvant or neoadjuvant chemotherapy. Selected end points were 3-, 5-, and 8-year cumulative incidence of pelvic recurrence (CIPR). RESULTS:Fifty-six patients met eligibility criteria. Most received intravenous carboplatin and paclitaxel for a median of 6 cycles. Six patients (10.7%) received pelvic RT, and 50 (89.3%) did not. Pelvic RT patients had stage I-to-IIC disease. Median follow-up was 39 months (range, 1-69 months). For the group as a whole, 14 patients (25%) had initial disease recurrence involving the pelvis, whereas 6 (10.7%) had first recurrence outside the pelvis. Three-, 5- and 8-year CIPR were 28.2%, 38.5%, and 43.2%, respectively. There was no significant difference in 3-, 5-, or 8-year CIPR between the group of patients receiving RT (20%, 20%, and 20%) and a group of patients with stages I to IIC who did not receive RT (9.9%, 22.4%, and 30.2%), P = 0.22. During RT, patients developed mild grade 1-to-2 side effects. After RT, 1 patient developed lower extremity lymphedema with recurrent cellulitis. One patient who developed small bowel obstruction before RT developed small bowel radiation enteritis and obstruction after RT, ultimately requiring surgical intervention. CONCLUSIONS:These findings suggest that ovarian CCA exhibits a propensity for pelvic recurrence after surgery and chemotherapy. RT, a local treatment that can effectively sterilize microscopic tumor cells, may benefit patients with this disease. Prospective studies with sufficient statistical power are warranted to further evaluate the role of RT. 10.1097/IGC.0000000000000270
    The effect of adjuvant radiation on survival in early stage clear cell ovarian carcinoma. Hogen Liat,Thomas Gillian,Bernardini Marcus,Bassiouny Dina,Brar Harinder,Gien Lilian T,Rosen Barry,Le Lisa,Vicus Danielle Gynecologic oncology OBJECTIVE:To assess the impact of adjuvant radiotherapy (RT) on survival in patients with stage I and II ovarian clear cell carcinoma (OCCC). METHODS:Data collection and analysis of stage I and II OCCC patients treated at two tertiary centers in Toronto, between 1995 and 2014, was performed. Descriptive statistics and Kaplan-Meier survival probability estimates were completed. The log-rank test was used to compare survival curves. RESULTS:163 patients were eligible. 44 (27%) patients were treated with adjuvant RT: 37 of them received adjuvant chemotherapy (CT), and 7 had RT only. In the no-RT group, there were 119 patients: 83 patients received adjuvant CT and 36 had no adjuvant treatment. The 10year progression free survival (PFS) was 65% for patients treated with RT, and 59% no-RT patients. There were a total of 41 (25%) recurrences in the cohort: 12 (27.2%) patients in RT group and 29 (24.3%) in the no-RT group. On multivariable analysis, adjuvant RT was not significantly associated with an increased PFS (0.85 (0.44-1.63) p=0.63) or overall survival (OS) (0.84 (0.39-1.82) p=0.66). In the subset of 59 patients defined as high-risk: stage IC with positive cytology and/or surface involvement and stage II: RT was not found to be associated with a better PFS (HR 1.18 (95% CI: 0.55-2.54) or O S(HR 1.04 (95% CI: 0.40-2.69)). CONCLUSION:Adjuvant RT was not found to be associated with a survival benefit in patients with stage I and II ovarian clear cell carcinoma or in a high risk subset of patients including stage IC cytology positive/surface involvement and stage II patients. 10.1016/j.ygyno.2016.09.006
    Management and clinical outcomes of patients with recurrent/progressive ovarian clear cell carcinoma. Huang Huei-Jean,Yang Lan-Yan,Tung Hsiu-Jung,Ku Fei-Chun,Wu Ren-Chin,Tang Yun-Hsin,Chang Wei-Yang,Jung Shih-Ming,Wang Chun-Chieh,Lin Cheng-Tao,Liu Feng-Yuan,Lin Gigin,Chen Min-Yu,Chou Hung-Hsueh,Chang Ting-Chang,Chao Angel,Lai Chyong-Huey Journal of the Formosan Medical Association = Taiwan yi zhi BACKGROUND/PURPOSE:Ovarian clear cell carcinoma (OCCC) with recurrence/progression after treatment has dismal prognosis. We aimed to investigate the management and outcomes of such patients. METHODS:OCCC patients who were treated between 2000 and 2013 with cancer recurrence or progression after primary treatment were analyzed. Univariate and multivariate analyses were used to identify the independent predictors of survival after recurrence (SAR) and cancer-specific survival (CSS). RESULTS:A total of 64 patients experienced treatment failure (49 recurred after remission and 15 progressed without remission). The 5-year CSS rates of recurrent/progressive OCCC patients were 22.9% (progression group: median CSS 5.9 months [range, 0.8-25.2] vs recurrence group: 43.6 months [range, 7.1-217.8]; p < 0.001). Patients with solitary recurrence had significantly better SAR than those with disseminated relapse (median: not reached vs 10.4 months, p < 0.001). On multivariate analysis, six models each for SAR and CSS were formulated alternatively including highly correlated variables for the recurrence group. Of these models, solitary relapse pattern (HR: 0.07, p < 0.001), progression-free interval (PFI) > 12 months (HR: 0.22-0.40, p = 0.001 and p = 0.023), CA125 < 35 U/mL at initial recurrence (HR: 0.32, p = 0.007), and overall salvage treatment including radiotherapy (HR: 0.19, p = 0.001) were significant predictors of favorable SAR. The same significant predictors were selected for CSS. CONCLUSION:Recurrent OCCC can be treated with curative intent if the relapse is solitary and can be completely resected or encompassed with radiotherapy, whereas novel therapies are needed for disseminated relapse or progression during primary treatment. 10.1016/j.jfma.2019.11.018
    Antitumor effects of interleukin-6 (IL-6)/interleukin-6 receptor (IL-6R) signaling pathway inhibition in clear cell carcinoma of the ovary. Yanaihara Nozomu,Hirata Yukihiro,Yamaguchi Noriko,Noguchi Yukiko,Saito Misato,Nagata Chie,Takakura Satoshi,Yamada Kyosuke,Okamoto Aikou Molecular carcinogenesis Among epithelial ovarian cancers, clear cell carcinoma of the ovary (CCC) has unique clinical and molecular characteristics that include chemoresistance resulting in poor prognosis. It was shown that CCC recently was characterized by specific upregulation of the IL-6/IL-6R-signal transducer and activator of transcription 3 (Stat3) signaling pathway. In this study, we aim to clarify whether IL-6/IL-6R mediated signaling pathway could have clinical relations with CCC and to evaluate inhibitory effects of the pathway on CCC carcinogenesis. A total of 84 CCC cases collected from primary surgical specimens were evaluated by the immunohistochemical analysis for IL-6R and phosphorylated Stat3 (pStat3), and we found that high IL-6R expression correlated with poor patient survival both by the univariate and multivariate analyses, suggesting that IL-6/IL-6R signaling pathway could be implicated in the progression of CCC. We further investigated the effects of IL-6/IL-6R mediated signaling pathway inhibition either by IL-6R small interfering RNA (siRNA) approach or humanized anti-human IL-6R antibody (tocilizumab) in CCC. Inhibition of endogenous IL-6R including tocilizumab in CCC cells did reduce cell invasion ability and restored their response to cytotoxic reagent. These data suggest that IL-6/IL-6R signaling pathway could act on CCC cells to enhance invasion and chemoresistance and, therefore, targeting IL-6/IL-6R mediated signaling pathway could be a promising therapeutic strategy for CCC. 10.1002/mc.22325
    Impact of combination chemotherapy with itraconazole on survival for patients with recurrent or persistent ovarian clear cell carcinoma. Tsubamoto Hiroshi,Sonoda Takashi,Yamasaki Masaaki,Inoue Kayo Anticancer research BACKGROUND:Recurrent ovarian clear cell carcinoma (CCC) rarely responds to cytotoxic agents. Itraconazole is a potent inhibitor of the P-glycoprotein efflux pump, angiogenesis, and the Hedgehog pathway. We evaluated the efficacy of chemotherapy with itraconazole for CCC. PATIENTS AND METHODS:Medical charts of patients with CCC who had received chemotherapy with itraconazole were retrospectively reviewed. RESULTS:Among nine patients with CCC, five had a history of progression with paclitaxel and carboplatin, and none had received prior treatment with bevacizumab or other targeted therapy. Eight patients received docetaxel (35 mg/m(2), day 1) and carboplatin-based (area under the curve, 4 mg·min(-1)·mL(-1); day 1) chemotherapy with an oral itraconazole solution (400 mg, days -2 to 2), repeated every two weeks. The response rate, median progression-free survival and overall survival were 44% (95% confidence interval [(CI)=12-77%], 544 days (95% CI=82-544 days) and 1,047 days (95% CI=462-1332 days), respectively. CONCLUSION:Chemotherapy with itraconazole is promising for patients with CCC.
    Three versus six cycles of adjuvant platinum-based chemotherapy in early stage clear cell ovarian carcinoma - A multi-institutional cohort. Prendergast Emily N,Holzapfel Marie,Mueller Jennifer J,Leitao Mario M,Gunderson Camille C,Moore Kathleen N,Erickson Britt K,Leath Charles A,Diaz Moore Elena S,Cohen Joshua G,Walsh Christine S Gynecologic oncology OBJECTIVES:To determine if 6 versus 3cycles of adjuvant platinum-based chemotherapy with or without taxane impacts survival in early stage ovarian clear cell carcinoma (OCCC). METHODS:We retrospectively identified all cases of stage I and II OCCC treated at 5 institutions from January 1994 through December 2011. Patients were divided into 2 groups: those who received 3 versus 6cycles of adjuvant chemotherapy. Our cohort consisted of 210 patients with stage IA-II disease, 116 of whom underwent full surgical staging. Cox proportional hazards regression and Kaplan-Meier analyses were performed to evaluate progression-free (PFS) and overall survival (OS) between groups. RESULTS:Among 210 eligible patients, the median age was 53years (range 30-88). The majority of patients were Caucasian (83.8%). All patients received adjuvant chemotherapy with 90% receiving carboplatin and paclitaxel. Thirty-eight (18.1%) patients received 3cycles, and 172 (81.9%) patients received 6cycles of adjuvant treatment. Recurrence rate was comparable between groups (18.4% vs. 27.3% for 3 vs. 6cycles, p=0.4). There was no impact of 3 versus 6cycles of chemotherapy on PFS (hazard ratio [HR] 1.4; 95% confidence interval [CI] 0.63-3.12, p=0.4) or OS (HR 1.65; 95% CI 0.59-4.65, p=0.3) on univariate analysis. There was no benefit to more chemotherapy in stratified analysis by stage nor on multivariate analysis adjusting for the impact of stage. Subgroup analysis of surgically staged patients also showed no difference in survival between 3 versus 6cycles of chemotherapy. CONCLUSIONS:Three cycles of platinum with or without taxane adjuvant chemotherapy were comparable to 6cycles with respect to recurrence and survival in patients diagnosed with early stage ovarian clear cell carcinoma in this retrospective multi-institutional cohort. CONDENSATION:Three cycles of platinum with or without taxane adjuvant chemotherapy are comparable to 6 cycles with respect to recurrence and survival in patients diagnosed with early stage ovarian clear cell carcinoma in this retrospective multi-institutional cohort. 10.1016/j.ygyno.2016.12.004
    Epigenetic determinants of ovarian clear cell carcinoma biology. Yamaguchi Ken,Huang Zhiqing,Matsumura Noriomi,Mandai Masaki,Okamoto Takako,Baba Tsukasa,Konishi Ikuo,Berchuck Andrew,Murphy Susan K International journal of cancer Targeted approaches have revealed frequent epigenetic alterations in ovarian cancer, but the scope and relation of these changes to histologic subtype of disease is unclear. Genome-wide methylation and expression data for 14 clear cell carcinoma (CCC), 32 non-CCC and four corresponding normal cell lines were generated to determine how methylation profiles differ between cells of different histological derivations of ovarian cancer. Consensus clustering showed that CCC is epigenetically distinct. Inverse relationships between expression and methylation in CCC were identified, suggesting functional regulation by methylation, and included 22 hypomethylated (UM) genes and 276 hypermethylated (HM) genes. Categorical and pathway analyses indicated that the CCC-specific UM genes were involved in response to stress and many contain hepatocyte nuclear factor (HNF) 1-binding sites, while the CCC-specific HM genes included members of the estrogen receptor alpha (ERalpha) network and genes involved in tumor development. We independently validated the methylation status of 17 of these pathway-specific genes, and confirmed increased expression of HNF1 network genes and repression of ERalpha pathway genes in CCC cell lines and primary cancer tissues relative to non-CCC specimens. Treatment of three CCC cell lines with the demethylating agent Decitabine significantly induced expression for all five genes analyzed. Coordinate changes in pathway expression were confirmed using two primary ovarian cancer datasets (p < 0.0001 for both). Our results suggest that methylation regulates specific pathways and biological functions in CCC, with hypomethylation influencing the characteristic biology of the disease while hypermethylation contributes to the carcinogenic process. 10.1002/ijc.28701
    Clear cell carcinoma of ovary and uterus. Glasspool Rosalind M,McNeish Iain A Current oncology reports Clear cell carcinomas of the female genital tract are rare tumours with a fearsome reputation for having poor responses to conventional platinum-based chemotherapy and poor prognosis. However, it is now clear that early-stage ovarian clear cell carcinoma has an excellent prognosis and may not require any adjuvant therapy. In addition, radiotherapy may also have a key role to play in adjuvant management of clear cell tumours. Identification of patients who truly do not need adjuvant chemotherapy is important. The past 3 years has seen a significant improvement in our understanding of clear cell carcinoma biology-in particular, the role of mutations in the chromatin remodelling gene ARID1A as key drivers that are common to clear cell carcinomas of ovarian and endometrial origin. Moreover, gynaecological clear cell carcinomas appear to share many features with renal clear cell tumours, suggesting a common pathogenesis. This raises the possibility of clinical trials that include patients with clear cell tumours from different organs of origin. Dissecting the role of disordered chromatin organisation in clear cell carcinoma pathogenesis is a key priority. Finally, the role of endometriosis and the attendant chronic inflammation are recognised. The inflammatory cytokine interleukin-6 appears to play a key role in clear cell carcinoma biology and is an excellent potential therapeutic target. 10.1007/s11912-013-0346-0
    Prognostic significance and predictors of the system inflammation score in ovarian clear cell carcinoma. Zhang Hongwei,Lu Jiaqi,Lu Yingying,Zhou Jiayi,Wang Zehua,Liu Haiou,Xu Congjian PloS one Chronic inflammation is a well-known epidemiologic factor of ovarian clear cell carcinomas (OCCC), but has an uncertain role in prognosis. We developed a systemic inflammation score (SIS) based on preoperative serum albumin and neutrophil-to-lymphocyte ratio (NLR) for predicting progression-free survival (PFS) and overall survival (OS) in OCCC patients. A retrospective review was performed in 155 patients with OCCC undergoing primary debulking and chemotherapy at a single institute between 1995 and 2010. Cox regression models were fitted to analyze the effect of prognostic factors on PFS and OS. Harrell's concordance index was calculated to assess predictive accuracy. The SIS consisting of serum albumin and NLR was retained as an independent indicator adjusting for traditional clinicopathological features. A high SIS was significantly associated with aggressive tumor behavior, platinum resistance, and served as an independent predictor of reduced PFS (P = 0.006) and OS (P = 0.019). The SIS had a good discrimination ability for the predictive PFS (c-index = 0.712) and OS (c-index = 0.722). We have developed a system inflammation score for predicting prognosis of OCCC patients, which may help stratify patients for postsurgical management. 10.1371/journal.pone.0177520
    Prognostic value of programmed death-ligand 1 (PD-L1) expression in ovarian clear cell carcinoma. Zhu Jun,Wen Hao,Bi Rui,Wu Yong,Wu Xiaohua Journal of gynecologic oncology OBJECTIVE:Programmed death-ligand 1 (PD-L1) was expressed in various tumors and antibodies targeting its receptor programmed cell death-1 (PD-1) are emerging cancer therapeutics. This study was designed to evaluate the expression of PD-L1 and its correlation with clinicopathologic features and clinical outcomes in ovarian clear cell carcinoma (OCCC). METHODS:The PD-L1 expression was measured by tissue-microarray-based immunohistochemistry from 122 eligible patients diagnosed with OCCC. The associations of clinicopathologic features with progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier method and multivariate analysis was further performed by Cox regression model. RESULTS:Overall, high PD-L1 expression (PD-L1(high)) was observed in 44.7% (55/123) of OCCC patients, and was strongly associated with advanced stages (p=0.020), positive ascitic fluid (p=0.016), platinum-resistant (PR) disease (p=0.045), and recurrence (p=0.038). Moreover, patients with PD-L1(high) were associated with poorer OS (hazard ratio [HR]=2.877; p=0.001) and PFS (HR=1.843; p=0.021) than those with low PD-L1 expression (PD-L1(low)). In subgroup analysis, PD-L1(high) patients experienced a poorer PFS (HR=1.926; p=0.044) and OS (HR=2.492; p=0.021) than PD-L1(low) cases among advanced stages (III-IV), but this difference was not observed in stage I-II patients. Meanwhile, PD-L1(high) was associated with poorer prognosis than PD-L1(low) in PR patients (OS, HR=2.253; p=0.037; PFS, HR=1.448; p=0.233). Multivariate analysis revealed that PD-L1(high) and advanced stages (III-IV) were adverse independent prognosticators for both PFS (HR(PD-L1)=2.0; p(PD-L1)=0.038; HR(stage)=10.2; p(stage)<0.001) and OS (HR(PD-L1)=3.0; p(PD-L1)=0.011; HR(stage)=14.3; p(stage)<0.001). CONCLUSION:PD-L1(high) might serve as a risk factor for PFS and OS in patients with OCCC. It is possible that immunotherapy targeting PD-L1 pathway could be used in OCCC. 10.3802/jgo.2017.28.e77
    Ovarian clear cell carcinoma, outcomes by stage: the MSK experience. Shu Catherine A,Zhou Qin,Jotwani Anjali R,Iasonos Alexia,Leitao Mario M,Konner Jason A,Aghajanian Carol A Gynecologic oncology OBJECTIVE:Ovarian clear cell carcinomas (OCCCs) are rare, and uncertainty exists as to the optimal treatment paradigm and validity of the FIGO staging system, especially in early-stage disease. METHODS:We performed a retrospective cohort study of all OCCC patients diagnosed and treated at Memorial Sloan Kettering Cancer Center between January 1996 and December 2013. Progression-free survival (PFS) and overall survival (OS) were calculated by stage and race, and comparisons were made using the log-rank test. Statistical significance was set at p<0.05. Type and duration of treatment were also recorded. RESULTS:There were 177 evaluable patients. The majority of patients were stage I at diagnosis (110/177, 62.2%). Of these, 60/110 (54.6%) were stage IA, 31/110 (28.2%) were stage IC on the basis of rupture-only, and 19/110 (17.3%) were stage IC on the basis of surface involvement and/or positive cytology of ascites or washings. Patients with stage IA and IC based on rupture-only had similar PFS/OS outcomes. Patients with stage IC based on surface involvement and/or positive cytology had a statistically significant decrement in PFS/OS. Stage was an important indicator of PFS/OS, while race was not. CONCLUSIONS:OCCC often presents in early stage. Women with stage IA OCCC have excellent prognosis, and future studies should explore whether they benefit from adjuvant chemotherapy. Women with IC OCCC need further staging clarification, as surgical rupture alone affords better prognosis than surface involvement and/or positive cytology. Women with advanced OCCC have poor survival and are often chemotherapy resistant/refractory. New treatment paradigms are needed. 10.1016/j.ygyno.2015.09.016
    Outcomes of fertility-sparing surgery among young women with FIGO stage I clear cell carcinoma of the ovary. Park Jeong-Yeol,Suh Dae-Shik,Kim Jong-Hyeok,Kim Yong-Man,Kim Young-Tak,Nam Joo-Hyun International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics OBJECTIVES:To evaluate the outcome of fertility-sparing surgery among young women with early-stage clear cell carcinoma of the ovary. METHODS:In a retrospective study, data were reviewed for patients aged 45years or younger who had FIGO stage I clear cell carcinoma of the ovary and had attended one institution in South Korea between December 1999 and December 2009. Outcomes were compared between women undergoing fertility-sparing surgery, defined as preservation of the uterus and at least one adnexa, and those undergoing radical surgery. RESULTS:Overall, 47 patients were included (22 underwent fertility-sparing surgery, 25 radical surgery). After a median follow-up of 72months (range 8-175), 5 (23%) patients who underwent fertility-sparing surgery and 5 (20%) in the radical surgery group had recurrent disease (P=0.820). The mean time to recurrence was 19months after fertility-sparing surgery versus 20months after radical surgery (P=0.935). The anatomical location of recurrence did not differ. There was no difference in 5-year disease-free survival (77% vs 84%; P=0.849) or 5-year overall survival (91% vs 88%; P=0.480). CONCLUSION:Fertility-sparing surgery was found to be a safe alternative for young women with FIGO stage I clear cell carcinoma of the ovary who wish to preserve fertility. 10.1016/j.ijgo.2015.10.022
    Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma. Caumanns Joseph J,Berns Katrien,Wisman G Bea A,Fehrmann Rudolf S N,Tomar Tushar,Klip Harry,Meersma Gert J,Hijmans E Marielle,Gennissen Annemiek M C,Duiker Evelien W,Weening Desiree,Itamochi Hiroaki,Kluin Roelof J C,Reyners Anna K L,Birrer Michael J,Salvesen Helga B,Vergote Ignace,van Nieuwenhuysen Els,Brenton James,Braicu E Ioana,Kupryjanczyk Jolanta,Spiewankiewicz Beata,Mittempergher Lorenza,Bernards René,van der Zee Ate G J,de Jong Steven Clinical cancer research : an official journal of the American Association for Cancer Research Advanced-stage ovarian clear cell carcinoma (OCCC) is unresponsive to conventional platinum-based chemotherapy. Frequent alterations in OCCC include deleterious mutations in the tumor suppressor and activating mutations in the PI3K subunit In this study, we aimed to identify currently unknown mutated kinases in patients with OCCC and test druggability of downstream affected pathways in OCCC models. In a large set of patients with OCCC ( = 124), the human kinome (518 kinases) and additional cancer-related genes were sequenced, and copy-number alterations were determined. Genetically characterized OCCC cell lines ( = 17) and OCCC patient-derived xenografts ( = 3) were used for drug testing of ERBB tyrosine kinase inhibitors erlotinib and lapatinib, the PARP inhibitor olaparib, and the mTORC1/2 inhibitor AZD8055. We identified several putative driver mutations in kinases at low frequency that were not previously annotated in OCCC. Combining mutations and copy-number alterations, 91% of all tumors are affected in the PI3K/AKT/mTOR pathway, the MAPK pathway, or the ERBB family of receptor tyrosine kinases, and 82% in the DNA repair pathway. Strong p-S6 staining in patients with OCCC suggests high mTORC1/2 activity. We consistently found that the majority of OCCC cell lines are especially sensitive to mTORC1/2 inhibition by AZD8055 and not toward drugs targeting ERBB family of receptor tyrosine kinases or DNA repair signaling. We subsequently demonstrated the efficacy of mTORC1/2 inhibition in all our unique OCCC patient-derived xenograft models. These results propose mTORC1/2 inhibition as an effective treatment strategy in OCCC. . 10.1158/1078-0432.CCR-17-3060
    Is adjuvant chemotherapy beneficial for surgical stage I ovarian clear cell carcinoma? Hogen Liat,Brar Harry,Covens Allan,Bassiouny Dina,Bernardini Marcus Q,Gien Lilian T,Ferguson Sarah E,Vicus Danielle Gynecologic oncology Objective To assess the impact of adjuvant chemotherapy on survival in patients with surgical stage I ovarian clear cell carcinoma (OCCC). METHODS:Data collection and analysis of surgical stage I OCCC patients treated at two tertiary cancer centers was performed. Descriptive statistics, univariate and multivariable analyses and Kaplan-Meier survival probability estimates were completed. RESULTS:Sixty stage I OCCC patients who underwent comprehensive surgical staging were identified. 29 patients received adjuvant chemotherapy and 31 did not. Median follow-up was 4.96 (0.4-16.4) years. The 5-year disease specific survival (DSS) was 84.2%: 95% for stage IA and 76% for stage IB+IC (p=0.16). There were 11 disease specific deaths: 7 in the no adjuvant chemotherapy group (NACG) and 4 in the adjuvant chemotherapy group (ACG). 5-year DSS was 84.2%: 74% in NACG and 93% in ACG, (p=0.13). Seventeen patients recurred: 11 in NACG and 6 in ACG (p=0.2). None of the 21 patients with stage I known negative cytology recurred. 5-year PFS was 74%: 58% in NACG and 86% in ACG (p=0.035). On univariate analysis, no-adjuvant chemotherapy and positive cytology were poor prognostic factors for PFS: HR=2.36, p=0.04 and HR=3.1, p=0.027, respectively. After adjusting for positive cytology, no-adjuvant chemotherapy was still found to significantly correlate with a worse PFS (HR=4, p=0.01). CONCLUSION:Our data supports the use of adjuvant chemotherapy for surgical stage I OCCC. As no patients in our cohort with surgical stage I known negative cytology recurred, more research on the benefit of adjuvant chemotherapy in this group is warranted. 10.1016/j.ygyno.2017.07.128
    Origin of clear cell carcinoma: nature or nurture? Kolin David L,Dinulescu Daniela M,Crum Christopher P The Journal of pathology A rare but serious complication of endometriosis is the development of carcinoma, and clear cell and endometrioid carcinomas of the ovary are the two most common malignancies which arise from endometriosis. They are distinct diseases, characterized by unique morphologies, immunohistochemical profiles, and responses to treatment. However, both arise in endometriosis and can share common mutations. The overlapping mutational profiles of clear cell and endometrioid carcinomas suggest that their varied histologies may be due to a different cell of origin which gives rise to each type of cancer. Cochrane and colleagues address this question in a recent article in this journal. They show that a marker of ovarian clear cell carcinoma, cystathionine gamma lyase, is expressed in ciliated cells. Similarly, they show that markers of secretory cells (estrogen receptor and methylenetetrahydrofolate dehydrogenase 1) are expressed in ovarian endometrioid carcinoma. Taken together, they suggest that endometrioid and clear cell carcinomas arise from cells related to secretory and ciliated cells, respectively. We discuss Cochrane et al's work in the context of other efforts to determine the cell of origin of gynecological malignancies, with an emphasis on recent developments and challenges unique to the area. These limitations complicate our interpretation of tumor differentiation; does it reflect nature imposed by a specific cell of origin or nurture, by either mutation(s) or environment? Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. 10.1002/path.5009
    Could fertility-sparing surgery be considered for women with early stage ovarian clear cell carcinoma? Nasioudis Dimitrios,Chapman-Davis Eloise,Frey Melissa K,Witkin Steven S,Holcomb Kevin Journal of gynecologic oncology OBJECTIVE:The aim of the present retrospective population-based study was to investigate the oncologic impact of uterine and ovarian preservation (OP) in premenopausal women with stage IA or IC ovarian clear cell carcinoma (OCCC). METHODS:The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database was accessed and a cohort of surgically-staged premenopausal women (age <50 years) diagnosed with unilateral stage IA or IC OCCC was drawn. Based on site-specific surgery codes, women who did not undergo hysterectomy and/or bilateral salpingo-oophorectomy (BSO) were identified. Overall survival (OS) and cancer-specific survival (CSS) rates were calculated following generation of Kaplan-Meier curves; comparisons were made with the log-rank test. Multivariate Cox analysis was performed to control for possible confounders. RESULTS:A total of 741 premenopausal women who met the inclusion criteria were identified. Based on available information, rate of uterine preservation was 14.5% (96/663) while the rate of OP was 28.1% (71/253). Five-year CSS rates were 90.8% for women who did not undergo hysterectomy compared with 87.7% for those who did (p=0.290). Similarly, 5-year CSS rates in the OP and BSO groups were 92.6% and 85%, respectively (p=0.060). After controlling for disease sub-stage (IA vs. IC), uterine or OP was not associated with a worse overall or cancer-specific mortality. CONCLUSION:In the present cohort, uterine and OP did not have a negative impact on oncologic outcomes. Selection criteria for fertility-sparing surgery (FSS) could be expanded to include women with stage IA OCCC. 10.3802/jgo.2017.28.e71
    Expression and significance of CD44, CD47 and c-met in ovarian clear cell carcinoma. Wang Huimin,Tan Mingzi,Zhang Song,Li Xiao,Gao Jian,Zhang Danye,Hao Yingying,Gao Song,Liu Juanjuan,Lin Bei International journal of molecular sciences AIMS:The aim of the present study is to investigate the differential expression of CD44, CD47 and c-met in ovarian clear cell carcinoma (OCCC), the correlation in their expression and their relationship with the biological behavior of OCCC. METHODS:We used immunohistochemistry to examine the expression of CD44, CD47 and c-met in OCCC (86 cases) and investigated the effects of the expression and interaction of these molecules on the development of OCCC. RESULTS:CD44, CD47 and c-met expression was significantly high in OCCC. Expression of CD44 and CD47 correlated with patient surgical stage, chemotherapy resistance and prognosis (all p<0.05), and expression of c-met correlated with chemotherapy resistance and prognosis (all p<0.05), but did not correlate with lymph node metastasis (all p>0.05). The surgical stage, CD44, CD47 and c-met expression were independent risk factors for OCCC prognosis (all p<0.05). Patients with low levels of CD44, CD47 and c-met showed better survival than those with high levels (all p<0.05). There was a positive correlation between CD44 (or CD47) and c-met, as well as between CD44 and CD47 (the Spearman correlation coefficient rs was 0.783, 0.776 and 0.835, respectively, all p<0.01). Additionally, pairwise correlation analysis of these three markers shows that the high expression of CD44/CD47, CD44/c-met and CD47/c-met were correlated with patient surgical stage, chemotherapy resistance and prognosis (all p<0.05), but did not correlate with lymph node metastasis (all p>0.05). CONCLUSIONS:Expression of CD44, CD47 and c-met was upregulated in OCCC and pairwise correlation. CD44, CD47 and c-met may have synergistic effects on the development of OCCC and are prognostic factors for ovarian cancer. 10.3390/ijms16023391
    Molecular pathogenesis of ovarian clear cell carcinoma. Gounaris Ioannis,Brenton James D Future oncology (London, England) Ovarian clear cell carcinoma is a distinct subtype of epithelial ovarian cancer, characterized by an association with endometriosis, glycogen accumulation and resistance to chemotherapy. Key driver events, including ARID1A mutations and HNF1B overexpression, have been recently identified and their functional characterization is ongoing. Additionally, the role of glycogen in promoting the malignant phenotype is coming under scrutiny. Appreciation of the notion that ovarian clear cell carcinoma is essentially an ectopic uterine cancer will hopefully lead to improved animal models of the disease, in turn paving the way for effective treatments. 10.2217/fon.15.45
    Adjuvant chemotherapy for stage I ovarian clear cell carcinoma: Patterns of use and outcomes. Nasioudis Dimitrios,Mastroyannis Spyridon A,Albright Benjamin B,Haggerty Ashley F,Ko Emily M,Latif Nawar A Gynecologic oncology OBJECTIVE:The aim of this study was to investigate the patterns of use and outcomes of adjuvant chemotherapy for patients diagnosed with FIGO stage I ovarian clear cell carcinoma (OCCC). METHODS:A cohort of patients diagnosed between 2004 and 2015 with OCCC was drawn from the National Cancer Database. Those with stage I disease who had primary surgery and underwent systematic lymphadenectomy (defined as at least 10 lymph nodes removed) were selected for further analysis. Factors associated with the administration of adjuvant chemotherapy were investigated with multivariate logistic regression. Overall survival (OS) was evaluated using Kaplan-Meier curves for patients diagnosed between 2004 and 2014, while comparisons were made with the log-rank test. Multivariate Cox analysis was performed to control for possible confounders. RESULTS:A total of 2325 patients met the inclusion criteria. Median age was 55 years. The majority were White (86.6%). Adjuvant chemotherapy was administered to 1839 (79.1%) patients. Hospital type and location, patient age, disease sub-stage, and year of diagnosis were independently associated with the administration of chemotherapy. Patients who received adjuvant chemotherapy (n = 1629) had better OS than those who did not (n = 443), (5-year OS rates 89.2% vs 82.6%, p < 0.001). After controlling for disease sub-stage, age, race, hospital type and medical comorbidities, adjuvant chemotherapy was associated with better overall survival (HR: 0.59, 95% CI: 0.45, 0.78). CONCLUSIONS:Adjuvant chemotherapy could be associated with a survival benefit for patients with stage I OCCC. 10.1016/j.ygyno.2018.04.567
    Genomic landscape of ovarian clear cell carcinoma via whole exome sequencing. Kim Se Ik,Lee Ji Won,Lee Maria,Kim Hee Seung,Chung Hyun Hoon,Kim Jae-Weon,Park Noh Hyun,Song Yong-Sang,Seo Jeong-Sun Gynecologic oncology OBJECTIVE:To analyze whole exome sequencing (WES) data on ovarian clear cell carcinoma (OCCC) in Korean patients via the technique of next generation sequencing (NGS). Genomic profiles were compared between endometriosis-associated OCCC (EMS-OCCC) and Non-EMS-OCCC. METHODS:We used serum samples and cancer tissues, stored at the Seoul National University Hospital Human Biobank, that were initially collected from women diagnosed with OCCC between 2012 and 2016. In total, 15 patients were enrolled: 5 with pathologically confirmed EMS-OCCC and 10 with Non-EMS-OCCC. We performed NGS WES on 15 fresh frozen OCCC tissues and matched serum samples, enabling comprehensive genomic characterization of OCCC. RESULTS:OCCC was characterized by complex genomic alterations, with a median of 178 exonic mutations (range, 111-25,798) and a median of 343 somatic copy number variations (range, 43-1,820) per tumor sample. In all, 54 somatic mutations were discovered across 14 genes, including PIK3CA (40%), ARID1A (40%), and KRAS (20%) in the 15 Korean OCCCs. Copy number gains in NTRK1 (33%), MYC (40%), and GNAS (47%) and copy number losses in TET2 (73%), TSC1 (67%), BRCA2 (60%), and SMAD4 (47%) were frequent. The significantly altered pathways were associated with proliferation and survival (including the PI3K/AKT, TP53, and ERBB2 pathways) in 87% of OCCCs and with chromatin remodeling in 47% of OCCCs. No significant differences in frequencies of genetic alterations were detected between EMS-OCCC and Non-EMS-OCCC groups. CONCLUSION:We successfully characterized the genomic landscape of 15 Korean patients with OCCC. We identified potential therapeutic targets for the treatment of this malignancy. 10.1016/j.ygyno.2017.12.005
    Prognostic determinants in patients with uterine and ovarian clear cell carcinoma: a SEER analysis. Rauh-Hain J Alejandro,Davis Michelle,Clemmer Joel,Clark Rachel M,Growdon Whitfield B,Goodman A K,Boruta David M,Schorge John O,del Carmen Marcela G Gynecologic oncology INTRODUCTION:The purpose of this study is to analyze and compare the demographics, treatment, and survival rates in patients with uterine clear cell carcinoma (UCCC) and ovarian clear cell carcinoma (OCCC). METHODS:The Surveillance, Epidemiology and End Results (SEER) program data for all 18 registries from 1988 to 2010 was reviewed to identify women with OCCC and UCCC. Demographic and clinical data were compared, and the impact of tumor site on survival was analyzed using the Kaplan-Meier method. Factors predictive of outcome were compared using the Cox proportional hazards model. RESULTS:The final study group consisted of 5421 women with clear cell histopathology. 3631 (67%) had OCCC and 1790 (33%) had UCCC. The mean age at diagnosis was 56 (± 12) years for women with OCCC and 67.7 (± 12.0) years for UCCC (P<0.001). Patients with OCCC had a higher rate of late stage disease (38.9% vs. 21.2%; P<0.001). Over the entire study period, after adjusting for known variables, there was no significant difference in cancer specific mortality between UCCC and OCCC, HR 1.05 (0.92-1.19). In the subset analysis by staging, in women with localized disease there was an improved survival in UCCC compared to OCCC. In contrast, in women with distant disease there was an increased mortality in women with UCCC. CONCLUSION:In the entire population, there was no significant difference in cancer related mortality between the groups. However, in women with localized disease, UCCC had improved survival, but increased mortality in distant disease compared to OCCC. 10.1016/j.ygyno.2013.08.029
    Uncommon Human Telomerase Reverse Transcriptase Promoter Mutations Are Associated With Poor Survival in Ovarian Clear Cell Carcinoma. Nishikimi Kyoko,Nakagawa Kiyoshi,Tate Shinichi,Matsuoka Ayumu,Iwamoto Masami,Kiyokawa Takako,Shozu Makio American journal of clinical pathology Objectives:The present study assessed whether human telomerase reverse transcriptase (TERT) promoter mutations mediate the increased mortality risk observed in patients with ovarian clear cell carcinoma (CCC) and characterized the pathologic features of TERT promoter mutation-associated ovarian CCC. Methods:The TERT promoter region in genomic DNA extracted from paraffin-embedded ovarian CCC specimens (n = 93) was bidirectionally sequenced. Results:A total of 24 TERT promoter mutations were identified among the analyzed CCC cases, of which 11 were known "hotspot" mutations whose frequency was increased in CCC cases with compared to without coexistent adenofibroma (P < .05). In contrast, the 14 (including three novel) identified uncommon site mutations were shown to be associated with a poor progression-free survival rate (P < .01). Conclusions:The identified uncommon TERT promoter mutations exacerbate the poor prognosis characteristic of ovarian CCC cases, and the hotspot mutations appear to be a molecular feature of the adenofibroma-associated form of the disease. 10.1093/ajcp/aqx166
    Patterns of recurrence and impact on survival in patients with clear cell ovarian carcinoma. Hogen Liat,Vicus Danielle,Ferguson Sarah Elizabeth,Gien Lilian T,Nofech-Mozes Sharon,Lennox Genevieve K,Bernardini Marcus Q International journal of gynecological cancer : official journal of the International Gynecological Cancer Society BACKGROUND:Patients with recurrent clear cell ovarian cancer have poor prognosis and limited effective systemic treatment options. OBJECTIVES:To characterize patterns of recurrence and compare overall survival and post-recurrence survival parameters in patients with recurrent ovarian clear cell carcinoma. METHODS:Clinical data on patients with ovarian clear cell carcinoma between June 1995 and August 2014 were collected. Patients with clear cell ovarian cancer recurrence were included in this study. Patients with different histologic sub-type, persistent or progressive disease on completion of the initial treatment were excluded. Descriptive statistics, univariate and multivariable analyses, and Kaplan-Meier survival probability estimates were completed. The log-rank test was used to quantify survival differences on univariable analysis. To search for significant covariates related to the overall survival and post-recurrence survival, a univariable Cox proportional hazard model was performed. RESULTS:A total of 209 patients met inclusion criteria. Of these, 61 (29%) patients who were free of disease at completion of the initial treatment had recurrence. Patterns of recurrence were as follows: 38 (62%) patients had multiple-site recurrence, 12 (20%) had single-site recurrence, and 11 (18%) had nodal recurrence only. The median overall survival was 44.7 months (95% CI 33.4 to 64.2) and was significantly associated with pattern of recurrence (p=0.005). The median post-recurrence survival was 18.4 months (95% CI 12.5 to 26.7): 54.4 months (95% CI 11 to 125.5) in single-site recurrence, 13.7 months (95% CI 6.8 to 16.5) in multiple-site recurrence, and 30.1 (95% CI 7.2 to 89) months in nodal recurrence (p=0.0002). In the multivariable analysis, pattern of recurrence was a predictor of post-recurrence survival.Six patients (9.8%) had a prolonged disease-free interval after recurrence (disease-free for more than 30 months after completion of treatment for recurrence). Prolonged recurrences were noted in 4 (33%) of 12 patients with single-site recurrence, 1 (9%) of 11 patients with nodal recurrence, and in 1 (2.7%) of 38 patients with multiple-site recurrence. Three of the six patients with a prolonged disease-free interval after recurrence were treated surgically at the time of recurrence. CONCLUSION:Ovarian clear cell carcinoma predominantly recurs in multiple sites and it is associated with a high mortality rate and short post-recurrence survival. When recurrences are limited to a single site, or only to lymph nodes, the median post-recurrence survival is longer. Disease-free interval after recurrence is longer in patients with single-site recurrence who are treated surgically at the time of recurrence. 10.1136/ijgc-2019-000287
    Venous thromboembolism during primary treatment of ovarian clear cell carcinoma is associated with decreased survival. Diaz Elena S,Walts Ann E,Karlan Beth Y,Walsh Christine S Gynecologic oncology OBJECTIVES:To determine the impact of venous thromboembolism (VTE) during primary treatment of ovarian clear cell carcinoma (OCCC) on survival. METHODS:After Institutional Review Board approval, 74 cases of OCCC were retrieved from our pathology files. Clinical and pathological data were obtained by medical record and pathology review. Standard statistical analyses were performed. RESULTS:Among 74 patients with OCCC, VTE was diagnosed in 11 (15%) during primary treatment and 7 (9%) at time of cancer recurrence. 56 (76%) patients never developed VTE. Patients with VTE during OCCC primary treatment had shorter progression-free survival (PFS) and overall survival (OS) than OCCC patients without VTE (median PFS 11 vs. 76 months, p=0.01, median OS 19 vs. 90 months, p=0.001). Patients with VTE during OCCC primary treatment had a 3.9-fold increase in risk of recurrence (p=0.007) and a 6.3-fold increase in risk of death (p<0.001). After controlling for cancer stage, VTE during OCCC primary treatment remained an independent prognostic factor for death (HR=3.6, p=0.005). No patient died of VTE. CONCLUSIONS:VTE during OCCC primary treatment is associated with a significantly higher risk of cancer recurrence and death. This increased risk is not attributable to VTE-related mortality and raises the possibility that a paracrine circuit involving thrombosis might contribute to a more aggressive tumor biology. 10.1016/j.ygyno.2013.09.005
    Ovarian cancer: new developments in clear cell carcinoma and hopes for targeted therapy. Yamashita Yoriko Japanese journal of clinical oncology Until recently, ovarian clear cell carcinoma was recognized by its unique morphology and unfavorable patient outcome primarily due to tumor chemoresistance. Recently, specific molecular characteristics of ovarian clear cell carcinoma, such as PI3CA mutation, ARID1a mutation and MET amplification, have been elucidated. In addition, an association between endometriosis and the tumor has also been a focus of research in recent years. The aim of this review is to discuss the specificity and importance of molecular changes and various intriguing points that are not solved until today. Finally, future aspects, including hopes for the development of novel therapies, are discussed. 10.1093/jjco/hyu221
    Genomic and Molecular Abnormalities in Gynecologic Clear Cell Carcinoma. Marks Eric I,Brown Victoria S,Dizon Don S American journal of clinical oncology Gynecologic clear cell carcinoma is a rare histology, accounting for ~5% of all ovarian and endometrial cancers in the United States. Compared to other types of gynecologic cancer, they are generally less responsive to standard therapy and have an overall worse prognosis. In addition, mounting evidence suggests that the landscape of genetic and molecular abnormalities observed in these tumors is distinct from other cancers that arise from the same sites of origin. On a molecular level, these tumors characteristically display upregulation of the PI3K-AKT-mTOR and RAS-RAF-MAPK signaling axes, frequent loss of ARID1a, and overexpression of MDM2. Evidence also suggests that these tumors are more likely to express programmed death ligand 1 or demonstrate microsatellite instability than other gynecologic cancers. Despite these important differences, there has been relatively little investigation into histology-specific treatment of clear cell gynecologic cancers, representing an opportunity for new drug development. In this article, we review the unique genetic and molecular features of gynecologic clear cell cancers with an emphasis on potential therapeutic targets. The results of completed studies of treatment for clear cell carcinoma are also presented. We conclude with a discussion of ongoing clinical trials and potential avenues for future study. 10.1097/COC.0000000000000641
    A Clinical and Molecular Phase II Trial of Oral ENMD-2076 in Ovarian Clear Cell Carcinoma (OCCC): A Study of the Princess Margaret Phase II Consortium. Lheureux Stephanie,Tinker Anna,Clarke Blaise,Ghatage Prafull,Welch Stephen,Weberpals Johanne I,Dhani Neesha C,Butler Marcus O,Tonkin Katia,Tan Qian,Tan David S P,Brooks Kelly,Ramsahai Janelle,Wang Lisa,Pham Nhu-An,Shaw Patricia A,Tsao Ming S,Garg Swati,Stockley Tracey,Oza Amit M Clinical cancer research : an official journal of the American Association for Cancer Research PURPOSE:Patients with recurrent ovarian clear cell carcinoma (OCCC) have limited effective options due to chemoresistance. A phase II study was designed to assess the activity of ENMD-2076, an oral multitarget kinase selective against Aurora A and VEGFR. PATIENTS AND METHODS:This multicenter phase II study included patients with recurrent OCCC who received prior platinum-based chemotherapy. Primary endpoints were objective response and 6-month progression-free survival (PFS) rates. Correlative analyses include ARID1A and PTEN expression by IHC and gene sequencing with a targeted custom capture next-generation sequencing panel. RESULTS:Forty patients were enrolled with a median age of 54, of which 38 patients were evaluable. ENMD-2076 was well tolerated with main related grade 3 toxicities being hypertension (28%), proteinuria (10%), and diarrhea (10%). Best response was partial response for 3 patients (1 unconfirmed) and stable disease for 26 patients. The overall 6-month PFS rate was 22% and differed according to ARID1A expression (ARIDIA vs. ARID1A; 33% vs. 12%, = 0.023). PTEN-positive expression was observed in 20 of 36 patients, and there was no correlation with outcome. Median PFS in patients with wild-type versus -mutated group was 5 versus 3.7 months ( = 0.049). Molecular profiling showed variants in (27%), (26%), and (7%). The patient with the longest treatment duration (22 months) was wild-type, diploid PTEN with putative biallelic inactivation of . CONCLUSIONS:Single-agent ENMD-2076 did not meet the preset bar for efficacy. Loss of ARID1A correlated with better PFS on ENMD-2076 and warrants further investigation as a potential predictive biomarker. 10.1158/1078-0432.CCR-18-1244
    An evaluation of progression free survival and overall survival of ovarian cancer patients with clear cell carcinoma versus serous carcinoma treated with platinum therapy: An NRG Oncology/Gynecologic Oncology Group experience. Oliver Kate E,Brady William E,Birrer Michael,Gershenson David M,Fleming Gini,Copeland Larry J,Tewari Krishnansu,Argenta Peter A,Mannel Robert S,Secord Angeles Alvarez,Stephan Jean-Marie,Mutch David G,Stehman Frederick B,Muggia Franco M,Rose Peter G,Armstrong Deborah K,Bookman Michael A,Burger Robert A,Farley John H Gynecologic oncology PURPOSE:We examined disparities in prognosis between patients with ovarian clear cell carcinoma (OCCC) and serous epithelial ovarian cancer (SOC). METHODS:We reviewed data from FIGO stage I-IV epithelial ovarian cancer patients who participated in 12 prospective randomized GOG protocols. Proportional hazards models were used to compare progression-free survival (PFS) and overall survival (OS) by cell type (clear cell versus serous). RESULTS:There were 10,803 patients enrolled, 9531 were eligible, evaluable and treated with platinum, of whom 544 (6%) had OCCC, 7054 (74%) had SOC, and 1933 (20%) had other histologies and are not included further. In early stage (I-II) patients, PFS was significantly better in OCCC than in SOC patients. For late stage (III, IV) patients, OCCC had worse PFS and OS compared to SOC, OS HR=1.66 (1.43, 1.91; p<0.001). After adjusting for age and stratifying by protocol and treatment arm, stage, performance status, and race, OCCC had a significantly decreased OS, HR=1.53 (1.33, 1.76; p<0.001). In early stage cases, there was a significantly decreased treatment effect on PFS for consolidative therapy with weekly Paclitaxel versus observation in OCCC compared to SOC (p=0.048). CONCLUSIONS:This is one of the largest analyses to date of OCCC treated on multiple cooperative group trials. OCCC histology is more common than SOC in early stage disease. When adjusted for prognostic factors, in early stage patients, PFS was better for OCCC than for SOC; however, in late-stage patients, OCCC was significantly associated with decreased OS. Finally, treatment effect was influenced by histology. 10.1016/j.ygyno.2017.08.004
    Prognostic impact of interleukin-6 expression in stage I ovarian clear cell carcinoma. Kawabata Ayako,Yanaihara Nozomu,Nagata Chie,Saito Misato,Noguchi Daito,Takenaka Masataka,Iida Yasushi,Takano Hirokuni,Yamada Kyosuke,Iwamoto Masami,Kiyokawa Takako,Okamoto Aikou Gynecologic oncology OBJECTIVE:Ovarian clear cell carcinoma (OCCC) frequently presents at an early stage. In stage I OCCC, the prognosis differs according to substage. In particular, predictive biomarkers and new treatment strategies are needed for stage IC2/IC3 disease. We investigated tumor biology and prognostic factors for stage I OCCC from a clinicopathological perspective, including the expression of ARID1A and IL-6, which are considered critical for OCCC carcinogenesis. METHODS:A retrospective cohort study of 192 patients with stage I OCCC treated at a single institution was performed. We calculated overall survival (OS) with respect to 12 clinicopathological parameters that included the unique and diverse histological features of OCCC. RESULTS:The estimated 5-year OS rate in patients with all stage I OCCC was 88.9% during a median of 91months of follow-up. The multivariate analysis indicated that substage classification and IL-6 expression status were associated with poor OS (p=0.010 and p=0.027, respectively). Loss of ARID1A expression had no impact on survival; however, it was associated with substage (p=0.001), capsule rupture status (p=0.011), and ascites cytology (p=0.016). No clear association was found between ARID1A and IL-6 expressions. Histological findings, including the presence of endometriosis, adenofibroma, architectural pattern, and tumor cell type, showed no prognostic effects. CONCLUSIONS:Both substage classification and IL-6 expression status may be independent prognostic factors in stage I OCCC. Therefore, IL-6 molecular stratification may be crucial in optimizing therapeutic strategies for early stage OCCC to improve survival. 10.1016/j.ygyno.2017.06.027
    Frequent somatic mutations of the telomerase reverse transcriptase promoter in ovarian clear cell carcinoma but not in other major types of gynaecological malignancy. Wu Ren-Chin,Ayhan Ayse,Maeda Daichi,Kim Kyu-Rae,Clarke Blaise A,Shaw Patricia,Chui Michael Herman,Rosen Barry,Shih Ie-Ming,Wang Tian-Li The Journal of pathology Up-regulated expression of telomerase reverse transcriptase (TERT) and subsequent maintenance of telomere length are essential in tumour development. Recent studies have implicated somatic gain-of-function mutations at the TERT promoter as one of the mechanisms that promote transcriptional activation of TERT; however, it remains unclear whether this genetic abnormality is prevalent in gynaecological neoplasms. We performed mutational analysis in a total of 525 gynaecological cancers, and correlated TERT promoter mutations with clinicopathological features. With the exception of ovarian clear cell carcinomas, in which mutations were found in 37 (15.9%) of 233 cases, the majority of gynaecological malignancies were wild-type. TERT promoter mutation does not appear to be an early event during oncogenesis, as it was not detected in the contiguous endometriosis associated with ovarian clear cell carcinoma. Ovarian clear cell carcinoma cell lines with TERT promoter mutations exhibited higher TERT mRNA expression than those with wild-type sequences (p = 0.0238). TERT promoter mutation tended to be mutually exclusive with loss of ARID1A protein expression (p = 4.4 × 10(-9) ) and PIK3CA mutation (p = 0.0019) in ovarian clear cell carcinomas. No associations with disease-specific survival were observed for ovarian clear cell carcinoma. The above results, in conjunction with our previous report showing longer telomeres in ovarian clear cell carcinomas relative to other types of ovarian cancer, suggests that aberrations in telomere biology may play an important role in the pathogenesis of ovarian clear cell carcinoma. 10.1002/path.4315
    Oncologic outcomes after secondary surgery in recurrent clear-cell carcinoma of the ovary. Kajiyama Hiroaki,Suzuki Shiro,Yoshikawa Nobuhisa,Kawai Michiyasu,Shibata Kiyosumi,Nagasaka Tetsuro,Kikkawa Fumitaka International journal of gynecological cancer : official journal of the International Gynecological Cancer Society OBJECTIVE:Complete tumor resection is considered essential in the management of patients with ovarian clear-cell carcinoma. There is a debate regarding whether patients with recurrent ovarian clear-cell carcinoma benefit from secondary cytoreductive surgery. METHODS:Details of patients with clear-cell carcinoma were collected by the Tokai Ovarian Tumor Study Group (Nagoya University Hospital and 13 affiliated institutions) and evaluated between January 1990 and December 2015. Histology was confirmed after central pathological review. The primary endpoint of the study was disease-free survival after secondary cytoreductive surgery. Distributions of events were evaluated using the χ test. Survival analysis was based on the Kaplan-Meier method. Survival curves were compared using the log-rank test. A value of p<0.05 was considered significant. RESULTS:A total of 169 patients who underwent secondary cytoreductive surgery (N=25) or medical management (N=144) for recurrent clear-cell carcinoma were collected. The median age for patients undergoing secondary cytoreductive surgery was 50 years (range 35-66). Overall, 18 patients had complete resection. In patients who underwent secondary cytoreductive surgery, the median disease-free and post-recurrence survival periods were 10.9 months and 21.2 months, respectively. Moreover, among 18 patients who underwent complete resection, seven showed no evidence of disease during the observation periods. The median post-recurrence survival periods of patients with complete or incomplete resection were 30.1 months and 10.4 months, respectively (p=0.002). On stratification by the recurrence site, patients with intraperitoneal recurrence showed poorer post-recurrence survival than those with recurrence at other sites (p=0.016). However, comparison between the secondary cytoreductive surgery group versus the medical management group showed there was no difference in post-recurrence survival, even when considering complete tumor resection (p=0.114). CONCLUSION:Patients with intraperitoneal recurrence or incomplete tumor resection had the worst survival after secondary cytoreductive surgery. 10.1136/ijgc-2018-000142
    Genomics to immunotherapy of ovarian clear cell carcinoma: Unique opportunities for management. Oda Katsutoshi,Hamanishi Junzo,Matsuo Koji,Hasegawa Kosei Gynecologic oncology Ovarian clear cell carcinoma (OCCC) is distinctive from other histological types of epithelial ovarian cancer, with genetic/epigenetic alterations, a specific immune-related molecular profile, and epidemiologic associations with ethnicity and endometriosis. These findings allow for the exploration of unique and specific treatments for OCCC. Two major mutated genes in OCCC are PIK3CA and ARID1A, which are frequently coexistent with each other. Other genes' alterations also contribute to activation of the PI3K (e.g. PIK3R1 and PTEN) and dysregulation of the chromatin remodeling complex (e.g. ARID1B, and SMARKA4). Although the number of focal copy number variations is small in OCCC, amplification is recurrently detected at chromosome 20q13.2 (including ZNF217), 8q, and 17q. Both expression and methylation profiling highlight the significance of adjustments to oxidative stress and inflammation. In particular, up-regulation of HNF-1β resulting from hypomethylation contributes to the switch from anaerobic to aerobic glucose metabolism. Additionally, up-regulation of HNF-1β activates STAT3 and NF-κB signaling, and leads to immune suppression via production of IL-6 and IL-8. Immune suppression may also be induced by the increased expression of PD-1, Tim-3 and LAG3. Mismatch repair deficient (microsatellite instable) tumors as found in Lynch syndrome also induce immune suppression in some OCCC. In a recent phase II clinical trial in heavily-treated platinum-resistant ovarian cancer, two out of twenty cases with a complete response to the anti-PD-1 antibody, nivolumab, were OCCC subtypes. Thus, the immune-suppressive state resulting from both genetic alterations and the unique tumor microenvironment may be associated with sensitivity to immune checkpoint inhibitors in OCCC. In this review, we highlight recent update and progress in OCCC from both the genomic and immunologic points of view, addressing the future candidate therapeutic options. 10.1016/j.ygyno.2018.09.001
    CCNE1 copy-number gain and overexpression identify ovarian clear cell carcinoma with a poor prognosis. Ayhan Ayse,Kuhn Elisabetta,Wu Ren-Chin,Ogawa Hiroshi,Bahadirli-Talbott Asli,Mao Tsui-Lien,Sugimura Haruhiko,Shih Ie-Ming,Wang Tian-Li Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Ovarian clear cell carcinoma is a unique type of ovarian cancer, often derived from endometriosis, and advanced-stage disease has a dismal prognosis primarily due to the resistance to conventional chemotherapy. Previous studies have shown frequent somatic mutations in ARID1A, PIK3CA, hTERT promoter, and amplification of ZNF217; however, the molecular alterations that are associated with its aggressiveness remain largely unknown. This study examined and compared cyclin E1 expression in endometriosis-related ovarian tumors, with the aim of determining the relationship between hTERT mutations and ARID1A expression and evaluating the effects of these molecular alterations on patient survival. We performed immunohistochemistry on 207 tumors [clear cell carcinoma (n=120), endometrioid carcinoma (n=49), and seromucinous tumors (n=38)], followed by two-color fluorescence in situ hybridization (n=88) and compared with ARID1A expression and hTERT promoter mutations in the same samples. Cyclin E1 overexpression and CCNE1 copy-number gain occurred in 23.3% and 14.8% of ovarian clear cell carcinomas, respectively, but they were not detected in any of the other endometriosis-related tumors. All cases with CCNE1 copy-number gain demonstrated an intense cyclin E1 immunoreactivity (P<0.001). Cyclin E1 overexpression was positively correlated with hTERT promoter mutations (P=0.01), but not with the loss of ARID1A expression. A multivariate analysis revealed that CCNE1 overexpression predicts poor overall survival, even after adjusting for stage and age. Specifically, CCNE1 overexpression and copy-number gain were both correlated with a poor outcome in patients with stage I disease. Moreover, the subset with CCNE1 overexpression and ARID1A retention demonstrated the worst outcome. Our findings suggest that gene copy-number gain and upregulation of CCNE1 occur in ovarian clear cell carcinoma and are associated with a worse clinical outcome, dictating the survival of early-stage patients, and that these molecular alterations are unique to clear cell carcinoma among different types of endometriosis-related ovarian neoplasms. 10.1038/modpathol.2016.160
    Therapeutic preferability of gemcitabine for ARID1A-deficient ovarian clear cell carcinoma. Kuroda Takafumi,Ogiwara Hideaki,Sasaki Mariko,Takahashi Kazuaki,Yoshida Hiroshi,Kiyokawa Takako,Sudo Kazuki,Tamura Kenji,Kato Tomoyasu,Okamoto Aikou,Kohno Takashi Gynecologic oncology OBJECTIVE:Ovarian clear cell carcinoma (OCCC) is often resistant to conventional, standard chemotherapy using cytotoxic drugs. OCCC harbors a unique genomic feature of frequent (approximately 50%) ARID1A deficiency. The present study was performed to investigate standard chemotherapeutic options suitable for ARID1A-deficient OCCC patients. METHODS:Drugs with selective toxicity to ARID1A-deficient OCCC cells were identified among six cytotoxic drugs used in standard chemotherapy for OCCC by employing multiple ARID1A-knockout cell lines and an OCCC cell line panel. Anti-tumor effects of drug treatment were assessed using a xenograft model. To obtain proof of concept in patients, seven OCCC patients who received single-agent therapy with gemcitabine were identified in a retrospective cohort of 149 OCCC patients. Patient samples and cases were analyzed for association between therapeutic response and ARID1A deficiency. RESULTS:ARID1A-knockout and ARID1A-deficient OCCC cells had selective sensitivity to gemcitabine. IC50 values for gemcitabine of ARID1A-deficient cells were significantly lower than those of ARID1A-proficient cells (p = 0.0001). Growth of OCCC xenografts with ARID1A deficiency was inhibited by administration of gemcitabine, and gemcitabine treatment effectively induced apoptosis in ARID1A-deficient OCCC cells. Three ARID1A-deficient OCCC patients had significantly longer progression-free survival after gemcitabine treatment than four ARID1A-proficient OCCC patients (p = 0.02). An ARID1A-deficient case that was resistant to multiple cytotoxic drugs, including paclitaxel plus carboplatin in the adjuvant and etoposide plus irinotecan in the first-line treatment, exhibited a dramatic response to gemcitabine in the second-line treatment. CONCLUSION:ARID1A-deficient OCCC patients could benefit from gemcitabine treatment in clinical settings. 10.1016/j.ygyno.2019.10.002