Ovarian Clear Cell Adenocarcinoma Research Articles

Abstract PR-006: A novel bispecific NK cell engager targeting FSHR and Siglec-7 displays potent anti-tumor immunity against ovarian cancer

Abstract Ovarian cancer (OC) is the deadliest gynecologic malignancy, with the highest mortality among cancers of the female reproductive system. Because of the close interaction between the OC cells and tumor microenvironment (TME), development of approaches which not only target tumor cells but also can maintain their anti-tumor function in this TME is of high importance. Uniquely, Follicle stimulating hormone receptor (FSHR) represents such an important target with specificity for OC and ovarian granulosa cells. We have recently developed monoclonal antibodies (mAbs) that specifically recognize human FSHR on the surface of multiple OC. We characterized them, selected potent anti-FSHR mAb: D2AP11 for detailed investigation and immune engineering in the form of a bispecific T cell engager (D2AP11-TCE) (Bordoloi et al., JCI Insight, 2022). Since most OCs are extremely aggressive and have restricted treatment choices, engaging additional immune effector components may further help. We have developed mAbs against PAN NK marker; Siglec 7 in humanized mice. We identified several Siglec-7 mAbs through high throughput screening and down-selected the pertinent clones. By using a highly potent anti-Siglec-7 clone DB7.2, we have developed a novel NK cell engager (NKCE): DB7.2xD2AP11 NKCE, by linking two antibody binding fragments (scFVs) arranged to bind FSHR, the OC antigen and hman Siglec-7, the NK marker. The NKCE was efficiently expressed in vitro and showed potent binding to both FSHR overexpressing K562 cells as well as Siglec-7 overexpressed HEK293T cells. This novel NKCE resulted in robust and specific killing of multiple OC targets in vitro in the presence of human PBMCs or NK cells, from multiple donors. The OC targets evaluated for killing by the NKCE include high grade serous adenocarcinoma, ovarian clear cell adenocarcinoma and ovarian cystadenocarcinoma lines which carry different mutations; BRCA1&2, AKT, TP53, PIK3CA, BRAF etc. and exhibit resistance against a wide array of cancer drug targets; PARP, HSP90, HDAC, MTORC, DNA alkylating agents, EGFR, PI3K, and WEE1, among others. DB7.2xD2AP11 NKCE displayed killing with EC50-142.87 pM and 236.6 pM against target OVISE-FSHR and OVCAR3 cells respectively, indicating its potency. Further, DNA encoded DB7.2xD2AP11 NKCE significantly attenuated the tumor burden in OVCAR3-FSHR and OVISE challenged humanized mice model. Additionally, this novel NKCE significantly enhanced the median survival of OVCAR3-FSHR challenged mice, suggesting in vivo potency. These data support further research on this novel NKCE as crucial tools for treating OC as well as targeted therapies for other malignancies. Of note, it is the first study of the development of Siglec-7 or any Siglec family member as a bispecific immune engager for targeted immunotherapy. Citation Format: Devivasha Bordoloi, Abhijeet J. Kulkarni, Opeyemi S. Adeniji, Pratik S. Bhojnagarwala, Shushu Zhao, Candice Ionescu, Mohamed bdel-Mohsen, David B. Weiner. A novel bispecific NK cell engager targeting FSHR and Siglec-7 displays potent anti-tumor immunity against ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr PR-006.

An algorithm for the pre-operative differentiation of benign ovarian tumours based on magnetic resonance imaging interpretation in a regional core hospital: a retrospective study

ObjectiveFor selecting minimally invasive surgery (i.e. laparoscopic ovarian cystectomy) for treating ovarian tumours (OTs) in premenopausal patients, the pre-operative differentiation of benign ovarian tumours (Be-OTs) based on magnetic resonance imaging (MRI) interpretation is important. This paper describes the authors’ 8-year experience of approximately 1000 OT cases, and provides information about a diagnostic algorithm to help other hospitals. Study designThe medical records of 901 patients aged < 50 years with OTs from 1 January 2015–31 March 31 2023 were reviewed. First, the accuracy of pre-operative differentiation between Be-OTs and borderline/malignant ovarian tumours (Bo/Ma-OTs) was compared in each type of OT. Second, to identify the factors influencing differentiation between Be-OTs and Bo/Ma-OTs in 164 serous/mucinous ovarian tumours (SM-OTs), a multi-variate logistic regression analysis was performed to assess the effect of 13 factors, including MRI findings, OT size and tumour markers. ResultsIn the comparison of diagnostic accuracy of pre-operative MRI for each OT type, accuracy was found to be notably high for ovarian endometrial cyst (OEC) (n = 409), ovarian mature cystic teratoma (OMCT) (n = 308), ovarian endometrioid adenocarcinoma (OEA) (n = 6) and ovarian clear cell adenocarcinoma (OCCA) (n = 14). On the other hand, discrepancies between MRI and pathological findings often occurred in SM-OTs, including ovarian serous cystadenoma (n = 86), ovarian mucinous adenocarcinoma (n = 61), ovarian serous adenocarcinoma (n = 12) and ovarian mucinous adenocarcinoma (n = 5). In the multi-variate logistic regression analysis of the latter 164 patients, in addition to MRI findings, OT size and carbohydrate antigen 125 also had an effect to some extent. The combination of MRI interpretation and OT size may enhance differentiation of Be-OTs and Bo/Ma-OTs. ConclusionsAmong four types of OTs (OEC, OMCT, OEA and OCCA), MRI interpretation was able to differentiate between Be-OTs and Bo/Ma-OTs almost perfectly. Additionally, to mitigate the difficulty in differentiating SM-OTs, OT size may be useful in combination with MRI findings, although further accumulation and analysis of OT cases is needed.

Preclinical testing of farletuzumab ecteribulin (FZEC [MORAb-202]) and MORAb-109, folate receptor α and mesothelin targeting antibody-drug conjugates (ADCs), in rare gynecologic cancers.

e17634 Background: Rare gynecologic cancers, such as ovarian carcinosarcoma (OCS), uterine serous carcinoma (USC) and ovarian clear cell adenocarcinoma (OCCA), have limited treatment options and molecular alterations that drive cell proliferation and drug resistance, resulting in poor overall survival. The anti-microtubule agent (AMA) paclitaxel is used in first-line treatment of most gynecologic cancers; however, the AMA eribulin is known to have additional anticancer properties (Goto et al. Anticancer Res 38:2929, 2018; Ho et al. Cancer Res 82:4457, 2022). Eribulin ADCs have been developed for targeted delivery to limit toxicity and maximize response. FZEC is an anti-folate receptor α (FRA)-eribulin ADC (Shimizu et al. Clin Cancer Res 27:3905, 2021) and MORAb-109 targets eribulin to mesothelin (MSLN; Albone et al. Annals Oncol 31:S491, 2020). Here we provide preclinical data to support clinical trials of FZEC and MORAb-109 in rare gynecologic cancers. Methods: Fresh tumor tissue from patients consented to the WEHI Stafford Fox Rare Cancer Program was used to establish a cohort of patient-derived xenograft (PDX) models of high-grade serous ovarian carcinoma (HGSOC), OCS, USC and OCCA. PDX models were screened for FRA and MSLN expression by IHC and quantified by HALO software, and 15 models were selected for in vivo testing. Tumor-bearing mice were treated with eribulin (1 mg/kg TIW 3 wks), FZEC (12.5 mg/kg Q14Dx3) or MORAb-109 (25 mg/kg Q14Dx3) and compared to standard of care treatments. Results: About 80% of HGSOC PDX models were FRA positive with no difference between models from chemonaïve samples vs multiple lines of prior treatment. FRA expression was frequent in USC and OCCA models, with MSLN seen in a smaller subset. Despite most (80%) models being cisplatin refractory, 11/15 responded to eribulin with the 4 non-responders having high MDR1 expression and being from previously treated patients. Overall, responses to FZEC and MORAb-109 appeared to correlate with FRA and MSLN expression; importantly, some models with moderate to high target antigen expression showed deeper and more durable responses to FZEC and MORAb-109 compared to eribulin. Conclusions: Responses to FZEC and MORAb-109 correlated with FRA and MSLN expression, with equivalent or better activity compared to eribulin in target-positive PDX models of HGSOC, USC and OCCA. [Table: see text]

Abstract 4262: Immunotherapy of ovarian cancer targeting FSHR by innate and adaptive immunity

Abstract Ovarian cancer (OC) represents the deadliest gynecologic malignancy. Despite important advances in the field of OC therapy, recurrent OC still has very poor prognosis with a median survival of 1 year. Due to the close interaction between the ovarian cancer cells and tumor microenvironment, development of treatment strategies which not only target the tumor cells but also the components of the tumor microenvironment hold significance. Notably, a prime obstacle in the development of therapies is to identify targets with specific expression limited to the tumor surface and not the healthy tissues. The follicle-stimulating hormone receptor (FSHR) is one such target with selective expression in ovarian granulosa cells and thus, a potentially important therapeutic target in OC. Therefore, we developed monoclonal antibodies against FSHR and focused on studies of the most potent of these reagents. Anti-FSHR antibody bound to diverse FSHR expressing ovarian serous and clear cell adenocarcinoma cells suggesting these antibodies could be used to specifically target OC. We then designed a novel DNA encoded bispecific T cell engager targeting FSHR (FSHRxCD3) and evaluated this bispecific in therapeutic models for the treatment of OC. FSHRxCD3 bispecific in the presence of human PBMCs was highly specific in killing FSHR positive ovarian tumor lines. However, T cell approaches alone may not be fully effective in treating OC, referred as Immunologically “Cold” Tumors. Hence, we hypothesized that engaging the other components of immune system, would provide better tumor control. Increasing lines of evidence suggest that OC is receptive to Natural killer (NK) cell attack. We designed antibodies against human Siglec-7, an inhibitory receptor present on human NK cells and showed they could bind to NK cells. We then used these to create a novel class of bispecific NK engager (NKE) that simultaneously targets both Siglec-7 and FSHR (Siglec-7xFSHR). This NKE was potent at killing FSHR positive OC targets in both in vitro and in vivo assays. Multiple Ovarian tumors including BRCA mutated and PARPi resistant ovarian cancer cells could be targeted by this immune therapy. Our data demonstrate the therapeutic potential of these two novel bispecific molecules and initial studies suggest that their combination may be valuable in patients with OC. Citation Format: Devivasha Bordoloi, Pratik Bhojnagarwala, Abhijeet J. Kulkarni, Opeyemi S. Adeniji, Alfredo Perales-Puchalt, Ryan P. O’Connell, Xizhou Zhu, Elizabeth M. Parzych, Rugang Zhang, Mohamed Abdel-Mohsen, David B. Weiner. Immunotherapy of ovarian cancer targeting FSHR by innate and adaptive immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4262.

A multicenter phase II randomized trial of durvalumab (D) versus physician’s choice chemotherapy (PCC) in patients (pts) with recurrent ovarian clear cell adenocarcinoma (MOCCA/APGOT-OV2/GCGS-OV3).

5565 Background: The optimal treatment of recurrent ovarian clear cell carcinoma (rOCCC) remains unknown. Prior data suggests rOCCC is a chemo-resistant disease that may respond to programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint inhibition (ICI). We aimed to determine the efficacy of D versus PCC in pts with rOCCC. Methods: In this multicentre, open-label, randomised phase 2 trial, 9 academic centres across Singapore, South Korea and Australia, enrolled rOCCC (determined histologically) and Eastern Cooperative Oncology Group performance status (PS) 0-2 pts, who had recurred after prior platinum-based chemotherapy and had not received more than 4 prior lines of systemic therapy, nor prior ICI therapy. Eligible pts were randomly assigned (2:1), using dynamic block randomization with block size of 6, and stratification by ECOG PS, to receive D (1500mg on day 1, in 28-day cycles) or PCC until disease progression (PD), intolerable toxicity or withdrawal of consent. Pts with PD on PCC were allowed to crossover to D. The primary endpoint was investigator-assessed progression-free survival (PFS) by RECIST version 1.1 and analyses included pts who had commenced at least 1 cycle of study treatment. Results: Between 7 Nov 2017 and 17 Feb 2020, 57 pts were assessed for eligibility, of whom 47 (PS 0-1) were randomly assigned to treatment with D (31 pts) or PCC (16 pts). At the data cut-off date (10 Jan 2022), the median follow-up was 83.0 weeks (IQR: 54.1—97.0) in the PCC group and 107.0 weeks (IQR: 82.7—116.4) in the D group. Median PFS was 7.4 weeks (IQR: 6.0—16.0) in the D group and 14.0 (IQR: 7.0—28.6) in the PCC group (HR 1.5 [95% CI 0.8-2.8], log-rank p = 0.89). The objective response rate (ORR) was 10.7% in pts randomised to D and 18.8% in the PCC group (p = 0.884). Clinical benefit rate (CR/PR/SD for ≥16weeks) was similar for PCC (37.5%) and D (32.1%) (p = 0.756). 9 pts on PCC crossed over to receive D, with 2 of the 8 evaluable pts achieving partial response (PR). When crossover D pts were included, ORR to D was 13.9% (5/36) with a clinical benefit rate of 30.6% (11/36). Median duration of response was 44 weeks for the 3 PCC responders (PR to gemcitabine 24.9wks, PR to liposomal doxorubicin 65.7wks, CR to carboplatin/liposomal doxorubicin 44wks), and 18 weeks (range 2.1-45.3) for the 5 responders to D. Frequency of adverse events (AEs) across all grades was 68.8% for PCC and 38.7% for D. Grade 3/4 AEs were observed in 37.5% of PCC pts and 9.7% of D pts. Conclusions: No significant differences in PFS, ORR or clinical benefit rate were observed between D and PCC treatment in rOCCC. Treatment with D was associated with less grade 3-4 adverse events. Correlative translational analyses to elucidate predictive biomarkers of response and resistance are ongoing. Clinical trial information: NCT03405454.

Clinical analysis of 23 cases with simultaneous double primary gynecological malignant tumors

Objective: To investigate the clinicopathological features, diagnosis, treatment and prognosis of simultaneous double primary gynecological malignant tumors. Methods: A total of 23 patients with simultaneous double primary malignant tumors of female reproductive system primarily treated in Beijing Obstetrics and Gynecology Hospital, Capital Medical University from January 1, 2010 to December 31, 2020 were retrospectively collected. The age, symptoms, tumor stage, tumor type, treatment and prognosis of patients were collected and followed up. Results: (1) The number of patients with gynecological tumors in our hospital increased year by year in the past 11 years. A total of 8 987 patients with gynecological malignant tumors were firstly diagnosed and cured in our hospital, including 3 474 cases of cervical cancer, 3 484 cases of endometrial cancer, 1 329 cases of ovarian malignancies, 171 cases of fallopian tube cancer, 182 cases of uterine sarcoma, 42 cases of vaginal cancer, 192 cases of vulvar cancer, 110 cases of trophoblastic tumor and 3 cases of other gynecological malignancies. The top three cancers were endometrial cancer, cervical cancer and ovarian malignancies. (2) There were 23 patients identified with simultaneous double primary gynecological tumors in the past 11 years, accounting for 0.26% (23/8 987) of female malignant tumors. There were 3 cases of cervical cancer complicated with endometrial cancer, 3 cases of cervical cancer complicated with ovarian cancer, 16 cases of endometrial cancer combined with ovarian cancer, and 1 patient with endometrial cancer combined with fallopian tube cancer. (3) All 23 patients underwent surgical treatment. According to the first diagnosis of the tumor, the surgical methods included cervical cancer radical surgery, endometrial cancer staging surgery and ovarian cancer cytoreductive surgery. After operation, radiotherapy and chemotherapy were supplemented according to the results of pathological examination and tumor staging. (4) The age of 23 patients ranged from 28 to 66 years, with an average age of (49.4±9.7) years. All patients had vaginal bleeding or conscious pelvic mass as their main clinical manifestation. The clinical stage was found in 7 patients (30%, 7/23) with advanced gynecological cancer (stage Ⅲ-Ⅳ), and 16 patients (70%, 16/23) with early stage gynecological cancer (stage Ⅰ-Ⅱ). According to the nonspecific tumor markers, 13 patients (57%, 13/23) had elevated CA125 and CA199. (5) Among the 23 patients, 1 case was uncontrolled and 3 cases recurred during the follow-up period, and the sites of uncontrolled or recurred were all located in the abdominopelvic cavity. Three cases died. Among the 3 patients who died, 1 patient was an uncontrolled patient, whose tumor type was cervical adenosquamous cell carcinoma combined with ovarian clear cell adenocarcinoma. The overall survival time was 19 months with postoperative supplementary radiotherapy and chemotherapy. There were 2 recurrent patients, and the tumor types were endometrioid carcinoma complicated with high-grade serous ovarian carcinoma and ovarian endometrioid carcinoma, respectively. After surgery, all patients received supplementary chemotherapy and recurred 60 and 21 months after surgery, respectively, and the overall survival time was 78 and 28 months, respectively. Another patient recurred 43 months after surgery, and survived with tumor for 14 months after recurrence. The remaining 19 patients were tumor-free and were still being followed up. Conclusions: There are no specific markers for simultaneous double primary gynecological malignant tumors. The most common clinical symptoms are vaginal bleeding or pelvic mass. The treatment principle of simultaneous double primary gynecological malignant tumor is the same as that of single gynecological malignant tumor, but need to be taken into account the characteristics of two tumors. Surgery is the main treatment method, and radiotherapy and chemotherapy play an important auxiliary role. The prognosis of simultaneous double primary gynecological malignancies is related to the late stage of the two malignancies.

Immunochemical analysis of iron transporters and M2 macrophages in ovarian endometrioma and clear cell adenocarcinoma.

The association between iron ions and endometriosis-associated ovarian cancer (EAOC) has been previously investigated to elucidate EAOC carcinogenesis; however, the dynamics of iron deposition in the endometrial epithelium and endometrial stroma of ovarian endometrioma (OE) remains unknown. The present study aimed to determine the expression of iron transporters on the cell surface and the distribution of tumor-associated macrophages (TAMs) englobed with iron in the endometrial stroma. The current retrospective study investigated 20 OE and 18 ovarian clear cell adenocarcinoma (CCC) samples, using Perls Prussian blue staining and immunohistochemistry of iron transporters, including divalent metal transporter 1 (DMT1), transferrin receptor (TfR) and ferroportin (FPN). Additionally, samples were stained for CD68, CD11c, CD163 and CD206, and double-immunostained for iron and CD163 to define the distribution of macrophages. Iron transporters were identified on the endometrial epithelium of OE and CCC tumor cells, and TAMs were englobed with iron in the endometrial stroma of OE and CCC. Histological findings revealed DMT1 upregulation in OE and CCC, whereas lower TfR and FPN expression was observed in OE than in CCC. M2 macrophages were englobed with iron ions in the deep layers of the OE and CCC stroma. The endometrial epithelium located in the endometrial stroma of one patient with OE and the endometrial epithelium adjacent to CCC in two patients with CCC stained positive for the tumor proliferation marker Ki67. Epithelium infiltrating the stroma of OE may become the origin of cancer under the influence of M2 macrophages englobed with iron. These findings provide new perspectives on the malignant transformation of OE into EAOC and its possibility as a precancerous index.

Noncanonical IL6 Signaling-Mediated Activation of YAP Regulates Cell Migration and Invasion in Ovarian Clear Cell Cancer.

Ovarian clear cell adenocarcinoma (OCCA) is characterized by a particularly poor response to conventional chemotherapy and a short overall survival time in women with established disease. The development of targeted treatments for OCCA relies on a better understanding of its molecular characteristics. IL6 is strongly expressed in OCCA and may therefore provide a novel therapeutic target. Here we use CRISPR/Cas9 and conditional short hairpin interfering RNA to perform loss-of-function studies in human OCCA cell lines to explore the requirement for IL6 in vitro and in vivo. While reduction of IL6 expression exerted limited effects in vitro, its attenuation significantly impaired tumor growth and neovascularization in vivo. In contrast to typical signaling via STAT3, IL6 in OCCA signaled via a noncanonical pathway involving gp130, Src, and the Hippo pathway protein YAP. A high-throughput combination drug screen identified agents that enhanced cell killing following reduction of IL6 signaling. Intersection of screen hits obtained from two cell lines and orthogonal approaches to attenuation of IL6 yielded AKT and EGFR inhibitors as enhancers of the inhibitory monoclonal IL6 receptor antibody tocilizumab. This study defines for the first time the requirements for, and mechanisms of, signaling by IL6 in human OCCA cell lines and identifies potential combinatory therapeutic approaches. Given the molecular diversity of OCCA, further in vitro and in vivo studies are warranted to determine whether such approaches will overcome the limited efficacy of tocilizumab observed in ovarian cancer to date. SIGNIFICANCE: This study defines the requirements for and mechanisms of noncanonical signaling by IL6 in human ovarian clear cell adenocarcinoma cell lines and identifies combinatory therapeutic approaches to be explored clinically.

Identification of Candidate Genes Associated with Susceptibility to Ovarian Clear Cell Adenocarcinoma Using cis-eQTL Analysis.

Ovarian clear cell adenocarcinoma (Ov-CCA) has a higher prevalence in the Japanese ancestry than other populations. The ancestral disparities in Ov-CCA prevalence suggests the presence of Ov-CCA-specific genetic alterations and may provide an opportunity to identify the novel genes associated with Ov-CCA tumorigenesis. Using 94 previously reported genes as the phenotypic trait, we conducted multistep expression quantitative trait loci (eQTL) analysis with the HapMap3 project datasets. Four single-nucleotide polymorphisms (SNPs) (rs4873815, rs12976454, rs11136002, and rs13259097) that had different allele frequencies in the Japanese ancestry and seven genes associated in cis (APBA3, C8orf58, KIAA1967, NAPRT1, RHOBTB2, TNFRSF10B, and ZNF707) were identified. In silico functional annotation analysis and in vitro promoter assay validated the regulatory effect of rs4873815-TT on ZNF707 and rs11136002-TT on TNFRSF10B. Furthermore, ZNF707 was highly expressed in Ov-CCA and had a negative prognostic value in disease recurrence in our sample cohort. This prognostic power was consistently observed in The Cancer Genome Atlas (TCGA) clear cell renal cell carcinoma dataset, suggesting that ZNF707 may have prognostic value in clear cell histology regardless of tissue origin. In conclusion, rs4873815-TT/ZNF707 may have clinical significance in the prognosis and tumorigenesis of Ov-CCA, which may be more relevant to clear cell histology. Besides, this study may underpin the evidence that cis-eQTL analysis based on ancestral disparities can facilitate the discovery of causal genetic alterations in complex diseases, such as cancer.

Alpha-fetoprotein-producing ovarian clear cell adenocarcinoma with fetal gut differentiation: a rare case report and literature review

BackgroundAlpha-fetoprotein (AFP) is a useful tumor marker for ovarian germ cell tumors, particularly yolk sac tumor (YST). It is valuable for both diagnosis and further follow-up. Epithelial ovarian carcinoma (EOC) rarely secretes AFP, especially for clear cell type and in the postmenopausal women. Based on the limited knowledge about AFP-producing clear cell type EOC, a case and literature review on this topic is extensively reviewed.Case presentationWe report a 55-year-old postmenopausal woman experienced vaginal spotting for one month, and serum level of AFP was 60,721 ng/ml initially. Histological examination was clear cell type EOC. Tumor cells revealed strong immunoreactivity for glypican-3 (GPC3) and AFP and weak for hepatocyte nuclear factor-1 beta (HNF-1 beta), but negative for CD30, making the diagnosis of AFP-producing clear cell type EOC with fetal gut differentiation in focal areas, FIGO (International Federation of Gynecology and Obstetrics) IIIc. Although the patient underwent an intensive treatment, including optimal debulking surgery and multi-agent chemotherapy, the patient died of disease. To provide a better understanding of clinical and molecular characteristics of the AFP-producing clear cell type EOC, we conducted a systematic literature review.ConclusionsA total of three papers described the AFP-producing clear cell type EOC are available. The overall survival rate of these cases, including the current case is 50%. Although immunohistochemical examination is not always needed in routine for the diagnosis of clear cell type EOC, to distinguish from other tumors, especially germ cell tumors, or to provide the better way to monitor therapeutic response or to evaluate the disease status, immunostaining, including GPC3, HNF-1 beta, CD30, cytokeratin 7 or 20, and AFP is taken into account. Due to rarity, the appropriate chemotherapy regimen and the biological behavior of AFP-producing clear cell type EOC are still unclear.

Single nucleotide polymorphism and associated gene expression related with Japanese ovarian clear cell adenocarcinoma: eQTL analysis using HapMap3 and survival analysis with TCGA data

Single nucleotide polymorphism and associated gene expression related with Japanese ovarian clear cell adenocarcinoma: eQTL analysis using HapMap3 and survival analysis with TCGA data

Demographic, Clinical, and Prognostic Factors of Ovarian Clear Cell Adenocarcinomas According to Endometriosis Status.

Women with endometriosis carry an increased risk for ovarian clear cell adenocarcinomas (CCCs). Clear cell adenocarcinoma may develop from endometriosis lesions. Few studies have compared clinical and prognostic factors and overall survival in patients diagnosed as having CCC according to endometriosis status. Population-based prospectively collected data on CCC with coexisting pelvic (including ovarian; n = 80) and ovarian (n = 46) endometriosis or without endometriosis (n = 95) were obtained through the Danish Gynecological Cancer Database. χ Test, independent-samples t test, logistic regression, Kaplan-Meier test, and Cox regression were used. Statistical tests were 2 sided. P values less than 0.05 were considered statistically significant. Patients with CCC and pelvic or ovarian endometriosis were significantly younger than CCC patients without endometriosis, and a higher proportion of them were nulliparous (28% and 31% vs 17% (P = 0.07 and P = 0.09). Accordingly, a significantly higher proportion of women without endometriosis had given birth to more than 1 child. Interestingly, a significantly higher proportion of patients with ovarian endometriosis had pure CCCs (97.8% vs 82.1%; P = 0.001) as compared with patients without endometriosis. Overall survival was poorer among CCC patients with concomitant ovarian endometriosis (hazard ratio, 2.56 [95% confidence interval, 1.29-5.02], in the multivariate analysis. Age at CCC diagnosis and parity as well as histology differ between CCC patients with and without concomitant endometriosis. Furthermore, CCC patients with concomitant ovarian endometriosis have a poorer prognosis compared with endometriosis-negative CCC patients. These differences warrant further research to determine whether CCCs with and without concomitant endometriosis develop through distinct pathogenic pathways.

Ovarian clear cell adenocarcinoma revealed in a young patient during hormone therapy: a case report

Ovarian clear cell adenocarcinoma revealed in a young patient during hormone therapy: a case report

Prognostic significance of apoptotic activity and its relationship with morphological characteristics in clear cell ovarian adenocarcinoma.

Objective: Clear cell adenocarcinoma of the ovary is more resistant to chemotherapy and has a worse prognosis than other ovarian carcinomas. In order to clarify the factors that contribute to the poor prognosis of clear cell adenocarcinomas, we examined the expression of proliferation- and apoptosis-related factors. In addition, we attempted to discover correlations between the structure of clear cell adenocarcinomas and prognosis. Material and Methods: We evaluated clinicopathological data on 39 patients with ovarian clear cell adenocarcinoma who underwent resection at the Tokyo Medical and Dental University Hospital. The tumors were examined for the expression of proliferation-related factors (mitotic index, Ki-67 labeling index) and apoptosis-related factors (apoptotic index, bcl-2 and p53). In addition, we investigated correlations between the expression of these factors and the cell types and structure of the tumors. Results: High bcl-2 expression and low apoptotic index were associated with a reduced survival rate. The survival rate of patients with tumors of the hobnail cell type was shorter than that of patients with clear cell type, and expression of bcl-2 was significantly associated with the hobnail cell type. Tumors with a papillary structure showed lower apoptotic index and the patients had a lower survival rate than those with a tubulocystic structure. Conclusion: The results of the current study suggest that a low apoptotic activity controlled by bcl-2 correlated with shorter survival in patients with ovarian clear cell adenocarcinoma. The cases with poorer prognosis, associated with higher expression of bcl-2 and lower expression of apoptosis-related factors, may be discerned by morphological characteristics of routinely sampled specimens.

Effect of ARID1A/BAF250a expression on carcinogenesis and clinicopathological factors in pure-type clear cell adenocarcinoma of the ovary.

Frequent mutation of the ARID1A gene has been recently identified in ovarian clear-cell adenocarcinoma (CCA); however, the clinical significance of BAF250a expression encoded by the ARID1A gene remains to be determined. The aim of the present study was to assess whether BAF250a expression had an impact on the clinical features of CCA. A total of 97 cases of CCA treated at a single institution were enrolled in the present study. The tissue samples were evaluated by immunohistochemical staining. BAF250a-deficient expression was observed in 30% (29/97) of all CCA cases. Of this, 19% of non-atypical endometriosis, 26% of atypical endometriosis, 39% of endometriosis-related CCA, 5% of benign clear-cell adenofibroma (CCAF), 5% of borderline CCAF and 10% of CCAF-related CCA. BAF250a-deficient expression was significantly more frequent in endometriosis-related CCA compared with that in CCAF-related CCA (P=0.02). No significant difference was observed in the response rate of primary chemotherapy according to BAF250a expression status (P=0.48). Additionally, BAF250a expression status was not significantly correlated with progression-free and overall survival in patients with CCA. Although loss of BAF250a expression was associated with early tumorigenesis in endometriosis-related CCA, this alteration was not significantly correlated with chemosensitivity and prognoses of CCA. Further biomarker analyses, including BAF250a expression, are required to improve the prognoses of CCA.

A case of bevacizumab has responded to platinum-resistance of young ovarian clear cell adenocarcinoma

A case of bevacizumab has responded to platinum-resistance of young ovarian clear cell adenocarcinoma

ARID1A gene mutation in ovarian and endometrial cancers (Review).

The AT-rich interacting domain-containing protein 1A gene (ARID1A) encodes ARID1A, a member of the SWI/SNF chromatin remodeling complex. Mutation of ARID1A induces changes in expression of multiple genes (CDKN1A, SMAD3, MLH1 and PIK3IP1) via chromatin remodeling dysfunction, contributes to carcinogenesis, and has been shown to cause transformation of cells in association with the PI3K/AKT pathway. Information on ARID1A has emerged from comprehensive genome-wide analyses with next-generation sequencers. ARID1A mutations have been found in various types of cancer and occur at high frequency in endometriosis-associated ovarian cancer, including clear cell adenocarcinoma and endometrioid adenocarcinoma, and also occur at endometrial cancer especially in endometrioid adenocarcinoma. It has also been suggested that ARID1A mutation occurs at the early stage of canceration from endometriosis to endometriosis-associated carcinoma in ovarian cancer and also from atypical endo-metrial hyperplasia to endometrioid adenocarcinoma in endometrial cancer. Therefore, development of a screening method that can detect mutations of ARID1A and activation of the PI3K/AKT pathway might enable early diagnosis of endometriosis-associated ovarian cancers and endometrial cancers. Important results may also emerge from a current clinical trial examining a multidrug regimen of temsirolimus, a small molecule inhibitor of the PI3K/AKT pathway, for treatment of advanced ovarian clear cell adenocarcinoma with ARID1A mutation and PI3K/AKT pathway activation. Also administration of sorafenib, a multikinase inhibitor, can inhibit cancer proliferation with PIK3CA mutation and resistance to mTOR inhibitors and GSK126, a molecular-targeted drug can inhibit proliferation of ARID1A-mutated ovarian clear cell adenocarcinoma cells by targeting and inhibiting EZH2. Further studies are needed to determine the mechanism of chromatin remodeling dysregulation initiated by ARID1A mutation, to develop methods for early diagnosis, to investigate new cancer therapy targeting ARID1A, and to examine the involvement of ARID1A mutations in development, survival and progression of cancer cells.

Low Expression of S100P Is Associated With Poor Prognosis in Patients With Clear Cell Adenocarcinoma of the Ovary.

The S100P protein stimulates cell proliferation and survival, thereby contributing to cancer progression. The purposes of this study were to evaluate S100P expression in ovarian clear cell adenocarcinoma and to determine whether S100P expression was correlated with the clinicopathological features or prognoses of patients with clear cell adenocarcinoma. We examined S100P expression in 30 ovarian clear cell adenocarcinoma specimens using immunohistochemistry analysis. The Kaplan-Meier method was used for analysis of overall survival, and comparisons were made based on the log-rank test. Negative staining for nuclear S100P was associated with a poor prognosis as compared with that of positive staining for nuclear S100P in specimens from patients with clear cell adenocarcinoma. These data suggested that S100P may serve as an independent prognostic factor and marker for acquired resistance to chemotherapeutic drugs in clear cell adenocarcinoma.

Clear Cell Adenocarcinoma Arising from Adenofibroma in a Patient with Endometriosis of the Ovary.

Ovarian clear cell adenocarcinomas (CCACs) are frequently associated with endometriosis and, less often with clear cell adenofibromas (CCAFs). We encountered a case of ovarian CCAC arising from benign and borderline adenofibromas of the clear cell and endometrioid types with endometriosis in a 53-year-old woman. Regions of the adenofibromas showed transformation to CCAC and regions of the endometriosis showed atypical endometriotic cysts. This case demonstrates that CCAC can arise from CCAF or endometriosis.

Optimal cytoreductive surgery for underlying ovarian cancer associated with deep venous thrombosis without placement of inferior vena cava filter: A case report and literature review.

Ovarian cancer associated with deep venous thrombosis (DVT) is an uncommon, potentially life-threatening condition. The primary therapeutic strategy for the treatment of this condition is up-front primary cytoreductive surgery, with placement of an inferior vena cava (IVC) filter prior to surgery to prevent fatal pulmonary embolism. The present study describes the case of a 49-year-old female, who presented with DVT unresponsive to anticoagulant therapy in the lower extremities prior to the diagnosis of ovarian cancer. During the search for the underlying malignancy, transvaginal sonography (TVS) revealed a cystic solid mass in the pelvic cavity. Subsequently, the patient underwent up-front primary cytoreductive surgery without placement of a preoperative IVC filter, followed by six cycles of chemotherapy. The patient was diagnosed with ovarian clear cell adenocarcinoma stage IIIC, complicated by DVT, and had survived >3 years without relapse at the time of completion of the present study. The successful outcome of the present case demonstrated that occult primary cancer should be suspected in patients with DVT unresponsive to anticoagulant therapy. The present study also indicated that up-front primary cytoreductive surgery without placement of an IVC filter represents an effective potential strategy for the treatment of advanced ovarian cancer associated with DVT, as the thrombus strongly adheres to the vessel wall following organization.