A retrospective analysis of secondary cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy in patients with recurrent ovarian cancer.

AIM: To evaluate the effect of secondary cytoreductive surgery (SeCRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) in recurrent epithelial ovarian cancer patients. METHODS: This retrospective study analyzed a prospective database. We collected information of 389 patients who were diagnosed with recurrent epithelial ovarian cancer. All patients underwent SeCRS with or without HIPEC. Overall survival and progression-free survival (PFS) were used to evaluate the treatment effectiveness. RESULTS: Of the 389 patients collected, 123 underwent primary or interval cytoreductive surgery at initial treatment and SeCRS at recurrence (Group A), 130 underwent primary or interval cytoreductive surgery at initial and SeCRS plus HIPEC at recurrence (Group B), and 136 underwent primary or interval cytoreductive surgery plus HIPEC at initial and SeCRS plus HIPEC at recurrence (Group C). The median overall survival for Groups A, B, and C were 49.1 months (95% confidence interval [CI]: 47.6-50.5), 56.0 months (95% CI: 54.2-57.7), and 64.4 months (95% CI: 63.1-65.6), respectively. The median PFS for Groups A, B, and C were 13.1 months (95% CI: 12.6-13.5), 15.0 months (95% CI: 14.2-15.7), and 16.8 months (95% CI: 16.1-17.4), respectively. There were no significant difference in incidence and grade of adverse events among groups. CONCLUSIONS: This study suggested that SeCRS plus HIPEC followed by chemotherapy resulted in longer overall survival and PFS than only SeCRS followed by chemotherapy in patients with recurrent ovarian cancer, especially in patients who were treated with repeat HIPEC.

Adjuvant Chemotherapy May Not Be Necessary for Women with Stage IC1 Epithelial Ovarian Cancer.

OBJECTIVE: To determine whether adjuvant chemotherapy improves the prognoses in women with stage IC1 epithelial ovarian cancer (EOC). METHODS: All eligible women diagnosed with stage IC1 EOC from 2003 to 2019 in Tongji Hospital were included. Patient characteristics, tumor features, surgical types, and chemotherapeutic treatments were collected. Kaplan-Meier analysis and Cox regression analysis were performed to evaluate progression-free survival (PFS) and overall survival (OS). RESULTS: Of the 140 patients (median age: 47 years old), 13 patients did not receive chemotherapy, and 127 received adjuvant chemotherapy. Kaplan-Meier analysis indicated that adjuvant chemotherapy offered no obvious improvements in PFS or OS. Subgroup analysis was conducted to adjust for the significant difference in incomplete staging surgery between the two groups, and chemotherapy still showed no benefit for survival. Cox regression analysis indicated that incomplete staging surgery was a risk factor for a worse PFS and that adjuvant chemotherapy remained unrelated to the prognosis. The patients were further divided based on the National Comprehensive Cancer Network recommendations: patients for whom observation is optional and chemotherapy would not improve the prognosis; and patients for whom chemotherapy is recommended. The results showed that postoperative chemotherapy had little correlation with survival. CONCLUSION: Our study suggests that postoperative chemotherapy may be unnecessary for patients with stage IC1 EOC. According to our results, incomplete staging surgery is a significant risk factor for PFS.

Impact of Surgeon Type and Rurality on Treatment and Survival of Ovarian Cancer Patients.

BACKGROUND: National Comprehensive Cancer Network guidelines recommend ovarian cancer patients receive cancer-directed surgery from a gynecologic oncologist surgeon. We aimed to determine if rurality impacts type of surgeon and estimate if the interaction between rurality and type of surgeon impacts cytoreductive surgery, chemotherapy initiation, and survival. METHODS: Our population-based cohort of Iowan (N=675) ovarian cancer patients included women diagnosed with histologically confirmed stages IB-IV cancer in 2010 to 2016 at the ages of 18 to 89 years old and who received cancer-directed surgery in Iowa. Multivariable logistic regression analysis and Cox proportional hazards models were used. RESULTS: Rural (vs. urban) patients were less likely to receive surgery from a gynecologic oncologist (adjusted odds ratio [OR]: 0.48; 95% confidence interval [CI]: 0.30-0.78). Rural patients with a gynecologic oncologist (vs. nongynecologic oncologist) surgeon were more likely to receive cytoreduction (OR: 2.84; 95% CI: 1.31-6.14) and chemotherapy (OR: 4.22; 95% CI: 1.82-9.78). Gynecologic oncologist-provided surgery conferred a 3-year cause-specific survival advantage among rural patients (adjusted hazard ratio: 0.57; 95% CI: 0.33-0.97) and disadvantage among urban patients (hazard ratio: 1.77; 95% CI: 1.02-3.06) in the model without treatment covariates. Significance dissipated in models with treatment variables. DISCUSSION: The variation in the gynecologic oncologist survival advantage may be because of treatment, referral, volume, or nongynecologic oncologist surgeons' specialty difference by rurality. This is the first study to investigate the ovarian cancer survival advantage of having a gynecologic oncologist surgeon by rurality.

Disparities in ovarian cancer treatment and overall survival according to race: An update.

OBJECTIVE: To determine whether guideline non-adherence is associated with Black race. METHODS: A retrospective review of National Cancer Database records of women diagnosed with epithelial ovarian cancer from 2012 to 2016 who identified as "White" or "Black" was performed. Exposure was adherence or non-adherence to National Comprehensive Cancer Network guidelines for treatment. Outcomes were differences in disease characteristics and overall survival in months. RESULTS: Of the 29,948 eligible patients, 93% (n = 27,744) were White and 7% (n = 2204) were Black. Having stage IV disease (OR 1.45, 95% CI 1.23-1.70; P < 0.001) and treatment in a comprehensive (OR 1.58, 95% CI 1.16-2.15; P = 0.0039) or academic (OR 2.30, 95% CI 1.70-3.12; P < 0.001) treatment facility were associated with Black race. Adherence to guidelines did not predict Black race (OR for adherence 1.0021, 95% CI 0.89-1.13; P = 0.97). Median survival for White patients with adherent care was 63.4 months and 51.4 months for Black patients (P = 0.0001). Median survival for White patients with non-adherent care was 60.5 months and 47.2 months for Black patients (P < 0.0001). Median overall survival was 61.1 months in White patients and 49.3 months in Black patients (P < 0.0001). CONCLUSIONS: Our data suggest that while Black patients and patients who receive non-NCCN guideline directed care have worse survival outcomes, guideline adherence is not independently associated with Black race. We must consider other socioeconomic, environmental and system factors that are contributing to the survival discrepancy in Black patients with ovarian cancer.

The impact of expanding gynecologic oncology care to ovarian cancer patients in small cities and rural communities.

OBJECTIVE: Patients with ovarian cancer from smaller cities and rural communities face unique challenges in accessing comprehensive care. This study compares management strategies, outcomes, and access to care for patients in a small city and surrounding rural communities before and after establishing a full-time gynecologic oncology (GO) office. METHODS: A local tumor registry was used to identify patients diagnosed with ovarian cancer before and after a full-time GO office was established. Quantitative analyses were used to compare disease characteristics, management strategies, overall survival, and distance traveled for care between cohorts. RESULTS: Out of 381 patients, 171 women were diagnosed prior to establishing a full-time GO office (pre-GO) and 210 after (post-GO). Post-GO patients were more likely to undergo surgery by a GO specialist (97.1% versus 53.2%, p < 0.01), receive surgery locally (79.0% versus 43.3%, p < 0.01), and undergo complete lymph node dissection (63.3% versus 38.6%, p < 0.01). Patients treated with chemotherapy by GO increased from 10.3% pre-GO to 76.9% post-GO. 5-year survival rates were 33.8% versus 49.5% in the pre-GO and post-GO groups, respectively (p < 0.01). Median survival time increased from 30.8 months to 52.5 months from pre-GO to post-GO time periods. Distance patients traveled for surgery decreased from a mean of 47.9 miles pre-GO to 26.8 miles post-GO. CONCLUSION: After establishing a full-time GO office within a small city, local patients had significantly improved overall survival and access to care. These results highlight the benefit of expanding GO care into small cities with surrounding rural communities and may be used to address public health discrepancies for women across the country.

Role of hsa­miR­105 during the pathogenesis of paclitaxel resistance and its clinical implication in ovarian cancer.

More than 70% of patients with epithelial ovarian cancer (EOC), one of the leading cause of gynecological cancer­related deaths worldwide, are diagnosed at an advanced stage of the disease. Currently, the mainstay for treatment of advanced EOC is tumor debulking surgery followed by combined platinum­ and paclitaxel (PTX)­based chemotherapy. However, most patients eventually develop chemoresistance, which remains a major obstacle to successful treatment. Herein, by using clinical specimens and experimentally induced cell models, we found that the expression levels of hsa­miR­105 were significantly decreased in PTX­resistant EOC tissues and cell lines. Follow­up functional experiments demonstrated that repression of hsa­miR­105 conferred resistance to paclitaxel in EOC cells, whereas restoration of hsa­miR­105 expression in situ via intratumoral injection of hsa­miR­105 micrON™ agomir potentiated in vivo sensitivity to PTX and thereafter significantly inhibited tumor growth in a PTX­challenged xenograft model. Mechanistically, hsa­miR­105 exerted its tumor suppressor function by directly inhibiting the zinc and ring finger 2 (ZNRF2) signaling pathway. Importantly, aberrant expression of hsa­miR­105 in both tumor and circulating samples predicted a poor post­chemotherapy prognosis in EOC patients. These findings collectively suggest that hsa­miR­105 may act as a potent tumor suppressor miRNA during the progression of EOC, likely affecting cell proliferation, invasiveness and chemosensitivity to PTX, and functioning at least in part via inhibition of ZNRF2 signaling. The stability and availability and ease in measurement of circulating hsa­miR­105 make it a valuable diagnostic/prognostic biomarker candidate for chemotherapy of EOC.

Malignant struma ovarii: surgical, histopathological and survival outcomes for thyroid-type carcinoma of struma ovarii with recommendations for standardising multi-modal management. A retrospective case series sharing the experience of a single institution over 10 years.

PURPOSE: Struma ovarii is rare, accounting for 0.3-1% of ovarian tumours. Malignant transformation may occur, most often into papillary thyroid carcinoma. There is a paucity of data pertaining to malignant struma ovarii. This paper shares a decade of experience of a single institution in the management of this rare ovarian cancer, exploring the characteristics of this tumour and suggesting a standardised approach to treatment and follow-up. METHODS: All patients treated for malignant struma ovarii within a large cancer centre over one decade were identified and data collected retrospectively on presentation, diagnosis, management, follow-up and survival outcomes. A literature review was also undertaken. RESULTS: Eleven cases of malignant struma ovarii were managed in the Oxford Cancer Centre between 2010 and 2019, 6 of which were of papillary thyroid carcinoma sub-type. No cases were correctly diagnosed pre-operatively. All patients had stage I disease and were managed surgically-but with variation in radicality. Patients identified as high-risk based on final histopathology underwent additional thyroidectomy and radio-active iodine ablation therapy. One case of synchronous malignancy of the thyroid gland proper was identified. No disease recurrence occurred. CONCLUSION: Malignant struma ovarii present a diagnostic challenge. Multi-disciplinary team (MDT) input is essential. Unilateral salpingo-oophrectomy may be adequate if stage I; reserving more radical surgery for advanced disease. Histopathological risk-stratification should be used to identify those most likely to benefit from adjuvant thyroid-targeting therapies. Patients require follow-up, anticipating an overall good prognosis.

Effect of traditional Chinese medicine (TCM) on survival, quality of life, and immune function in patients with ovarian carcinoma: A protocol for systematic review and meta analysis.

BACKGROUND: Traditional Chinese medicine (TCM) has been widely applied as promising adjunctive drugs for ovarian carcinoma (OC) in China and other Asian countries. However, its exact clinical efficacy and safety is still not well investigated. In this study, we aimed to summarize the efficacy of TCM on survival, quality of life (QoL), and immune function in patients with OC through the meta-analysis. METHODS: Relevant clinical trials of TCM for the treatment OC patients will be searched in Cochrane Library, Web of Science, Google Scholar, PubMed, Medline, Embase, China Scientific Journal Database, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, and Wanfang Database from their inception to November 2020. Two researchers will perform data extraction and risk of bias assessment independently. The clinical outcomes, including overall survival (OS), QoL, immune function, tumor markers, and adverse events, were systematically evaluated by using Review Manager 5.3 and Stata 14.0 statistical software. RESULTS: The results of this study will provide high-quality evidence for the effect of TCM on survival, QoL and immune function in patients with OC. CONCLUSION: The conclusions of this meta-analysis will be published in a peer-reviewed journal, and draw an objective conclusion of the efficacy of TCM on survival, QoL, and immune function in patients with OC. TRIAL REGISTRATION NUMBER: INPLASY2020110104.

Correlation between an integrative oncology treatment program and survival in patients with advanced gynecological cancer.

OBJECTIVE: Integrative oncology (IO) is increasingly becoming part of palliative cancer care. This study examined the correlation between an IO treatment program and rates of survival among patients with advanced gynecological cancer. METHODS: Patients were referred by their oncology healthcare professionals to an integrative physician (IP) for consultation and IO treatments. Those undergoing at least 4 treatments during the 6 weeks following the consultation were considered adherence to the integrative care program (AIC), versus non-adherent (non-AIC). Survival was monitored for a period of 3 years, comparing the AIC vs. non-AIC groups, as well as controls who did not attend the IP consultation. RESULTS: A total of 189 patients were included: 71 in the AIC group, 44 non-AIC, and 74 controls. Overall 3-year survival was greater in the AIC group (vs. non-AIC, p = 0.012; vs. controls, p = 0.003), with no difference found between non-AIC and controls (p = 0.954). Multimodal IO programs (≥ 3 modalities) were correlated in the AIC group with greater overall 3-year survival (p = 0.027). Greater rates of survival were also found in the AIC group at 12 (p = 0.004) and 18 months (p = 0.001). When compared with the AIC group, a multivariate analysis found higher crude and adjusted hazard ratios for 3-year mortality in the non-AIC group (HR 95% CI 2.18 (1.2-3.9), p = 0.010) and controls (2.23 (1.35-3.7), p = 0.002). CONCLUSION: Adherence to an IO treatment program was associated with higher survival rates among patients with advanced gynecological cancer. Larger prospective trials are needed to explore whether the IO setting enhances patients' resilience, coping, and adherence to oncology treatment.

Adherence to treatment guidelines as a major determinant of survival disparities between black and white patients with ovarian cancer.

OBJECTIVE: To evaluate whether non-adherence to National Comprehensive Cancer Network (NCCN) treatment guidelines and other factors related to treatment access contribute to racial disparities in ovarian cancer survival. METHODS: This large cohort study included patients from the National Cancer Database who were diagnosed with ovarian cancer between 2004 and 2014, with follow-up data up to 2017. The multivariable Cox regression was used to assess the effect of study variables on five-year overall survival. The proportion contributions of prognostic factors to the survival disparities were estimated using individual and sequential adjustment of these factors based on the Cox proportional hazards models. RESULTS: Of the 120,712 patients eligible for this study, 110,032 (91.1%) were whites and 10,680 (8.9%) were blacks. Black patients, compared with their white counterparts, had a lower adherence to NCCN guidelines (60.8% vs. 70.4%, respectively, P < 0.001), and a higher five-year mortality after cancer diagnosis (age- and tumor characteristics- adjusted hazard ratio: 1.22, 95% confidence interval: 1.19-1.25). Non-adherence to NCCN treatment guidelines was the most significant contributor to racial disparity in ovarian cancer survival, followed by access to care and comorbidity, each explaining 36.4%, 22.7%, and 18.2% of the racial differences in five-year overall survival, respectively. These factors combined explain 59.1% of racial survival disparities. Risk factors identified for non-adherence to treatment guidelines among blacks include insurance status, treatment facility type, educational attainment, age, and comorbidity. CONCLUSIONS: Adherence status to NCCN treatment guidelines is the most important contributor to the survival disparities between black and white patients with ovarian cancer. Our findings call for measures to promote equitable access to guideline-adherence care to improve the survival of black women with ovarian cancer.

Network Pharmacology-Based and Clinically Relevant Prediction of the Potential Targets of Chinese Herbs in Ovarian Cancer Patients.

Reports increasingly suggest that Chinese herbal medicine (CHM) has been used to treat ovarian cancer (OvCa) with a good curative effect; however, the molecular mechanisms underlying CHM are still unclear. In this retrospective study, we explored CHM's molecular targets for the treatment of OvCa based on clinical data and network pharmacology. We used the Kaplan-Meier method and Cox regression analysis to verify the survival rate of 202 patients with CHM-treated OvCa. The association between CHM and survival time was analyzed by bivariate correlation. A target network of CHM active ingredients against OvCa was established via network pharmacology. Cox regression analysis showed that CHM is an independent favorable prognostic factor. The median survival time was 91 months in the CHM group and 65 months in the non-CHM group. The survival time of FIGO stage III patients in the two groups was 91 months and 52 months, and the median survival period of FIOG stage IV patients was 60 months and 22 months, respectively (p < 0.001). Correlation analysis demonstrated that 12 herbs were closely associated with prognosis, especially in regard to the long-term benefits. Bioinformatics analysis indicated that the anti-OvCa activity of these 12 herbs occurs mainly through the regulation of apoptosis-related protein expression, which promotes OvCa cell apoptosis and inhibits OvCa development. They also regulate the progress of OvCa treatment by promoting or inhibiting protein expression on the p53 signaling pathway and by inhibiting the NF-κB signaling pathway by directly inhibiting NF-κB.

Ovarian cancer in California: Guideline adherence, survival, and the impact of geographic location, 1996-2014.

BACKGROUND: Evidence suggests that geographic location may independently contribute to ovarian cancer survival. We aimed to investigate how the association between residential location and ovarian cancer-specific survival in California varies by race/ethnicity and socioeconomic status. METHODS: Additive Cox proportional hazard models were used to predict hazard ratios (HRs) and 95% confidence intervals (CI) for the association between geographic location throughout California and survival among 29,844 women diagnosed with epithelial ovarian cancer between 1996 and 2014. We conducted permutation tests to determine a global P-value for significance of location. Adjusted analyses considered distance traveled for care, distance to closest high-quality-of-care hospital, and receipt of National Comprehensive Cancer Network guideline care. Models were also stratified by stage, race/ethnicity, and socioeconomic status. RESULTS: Location was significant in unadjusted models (P = 0.009 among all stages) but not in adjusted models (P = 0.20). HRs ranged from 0.81 (95% CI: 0.70, 0.93) in Southern Central Valley to 1.41 (95% CI: 1.15, 1.73) in Northern California but were attenuated after adjustment (maximum HR = 1.17, 95% CI: 1.08, 1.27). Better survival was generally observed for patients traveling longer distances for care. Associations between survival and proximity to closest high-quality-of-care hospitals were null except for women of lowest socioeconomic status living furthest away (HR = 1.22, 95% CI: 1.03, 1.43). CONCLUSIONS: Overall, geographic variations observed in ovarian cancer-specific survival were due to important predictors such as receiving guideline-adherent care. Improving access to expert care and ensuring receipt of guideline-adherent treatment should be priorities in optimizing ovarian cancer survival.

Combination therapy with B7H3-redirected bispecific antibody and Sorafenib elicits enhanced synergistic antitumor efficacy.

Rationale: Current traditional treatment options are frequently ineffective to fight against ovarian cancer due to late diagnosis and high recurrence. Therefore, there is a vital need for the development of novel therapeutic agents. B7H3, an immune checkpoint protein, is highly expressed in various cancers, representing it a promising target for cancer immunotherapy. Although targeting B7H3 by bispecific T cell-engaging antibodies (BiTE) has achieved successes in hematological malignancies during recent years, attempts to use them for the treatment of solid cancers are less favorable, in part due to the heterogeneity of tumors. Sorafenib is an unselective inhibitor of multiple kinases currently being tested in clinical trials for several tumors, including ovarian cancer which showed limited activity and inevitable side effect for ovarian cancer treatment. However, it is able to enhance antitumor immune response, which indicates sorafenib may improve the efficiency of immunotherapy. Methods: We evaluated the expression of B7H3 in ovarian cancer using online database and validated its expression of tumor tissues by immunohistochemistry staining. Then, B7H3 expression and the effects of sorafenib on ovarian cancer cell lines were determined by flow cytometry. In addition, 2D and 3D ovarian cancer models were established to test the combined therapeutic effect in vitro. Finally, the efficiency of B7H3×CD3 BiTE alone and its combination with sorafenib were evaluated both in vitro and in vivo. Results: Our data showed that B7H3 was highly expressed in ovarian cancer compared with normal samples. Treatment with sorafenib inhibited ovarian cancer cell proliferation and induced a noticeable upregulation of B7H3 expression level. Further study suggested that B7H3×CD3 BiTE was effective in mediating T cell killing to cancer cells. Combined treatment of sorafenib and B7H3×CD3 BiTE had synergistic anti-tumor effects in ovarian cancer models. Conclusions: Overall, our study indicates that combination therapy with sorafenib and B7H3×CD3 BiTE may be a new therapeutic option for the further study of preclinical treatment of OC.

Phase II trial of bevacizumab and sorafenib in recurrent ovarian cancer patients with or without prior-bevacizumab treatment.

OBJECTIVE: To examine whether blocking multiple points of the angiogenesis pathway by addition of sorafenib, a multi-kinase inhibitor against VEGFR2/3, Raf, c-Kit, and PDGFR, to bevacizumab would yield clinical activity in ovarian cancer (OvCa). METHODS: This phase II study tested bevacizumab plus sorafenib in two cohorts; bevacizumab-naïve and bevacizumab-exposed patients. Bevacizumab (5 mg/kg IV every 2 weeks) was given with sorafenib 200 mg bid 5 days-on/2 days-off. The primary objective was response rate using a Simon two-stage optimal design. Progression-free survival (PFS) and toxicity were the secondary endpoints. Exploratory correlative studies included plasma cytokine concentrations, tissue proteomics and dynamic contrast-enhanced-magnetic resonance imaging (DCE-MRI). RESULTS: Between March 2007 and August 2012, 54 women were enrolled, 41 bevacizumab-naive and 13 bevacizumab-prior, with median 5 (2-9) and 6 (5-9) prior systemic therapies, respectively. Nine of 35 (26%) evaluable bevacizumab-naive patients attained partial responses (PR), and 18 had stable disease (SD) ≥ 4 months. No responses were seen in the bevacizumab-prior group and 7 (54%) patients had SD ≥ 4 months, including one exceptional responder with SD of 27 months. The overall median PFS was 5.5 months (95%CI: 4.0-6.8 months). Treatment-related grade 3/4 adverse events (≥5%) included hypertension (17/54 [31%]; grade 3 in 16 patients and grade 4 in one patient) and venous thrombosis or pulmonary embolism (5/54 [9%]; grade 3 in 4 patients and grade 4 in one patient). Pretreatment low IL8 concentration was associated with PFS ≥ 4 months (p = .031). CONCLUSIONS: The bevacizumab and sorafenib combination did not meet the pre-specified primary endpoint although some clinical activity was seen in heavily-pretreated bevacizumab-naive OvCa patients with platinum-resistant disease. Anticipated class toxicities required close monitoring and dose modifications.

Cross­validation of genes potentially associated with neoadjuvant chemotherapy and platinum­based chemoresistance in epithelial ovarian carcinoma.

Ovarian carcinomas have the poorest prognosis and the highest mortality among gynecological malignancies. Neoadjuvant chemotherapy (NACT) is considered as a novel therapeutic strategy and an alternative treatment for advanced epithelial ovarian cancer (AEOC). The aim of the present study was to identify the core genes related to platinum­based NACT resistance in AEOC and to allow screening at the molecular level for the most appropriate ovarian cancer patients for NACT. We obtained three drug­resistant microarrays GSE114206, GSE41499 and GSE33482 from the Gene Expression Omnibus (GEO) database as well as a microarray representing NACT, GSE109934. Bioinformatics analysis revealed the nature of the four potential candidate genes for using in functional enrichment analyses and interaction network construction. The potential associations and possible genetic alterations among the DEGs were summarized using the STRING database in Cytoscape and the cBioPortal visualization tool, respectively. A total of 63 genes were identified as DEGs from GSE109934 representing NACT. From the drug­resistant GSE114206 and GSE41499 datasets, 106 DEGs containing 36 upregulated genes and 70 downregulated genes were selected, and from the drug­resistant GSE114206 and GSE33482 datasets, 406 DEGs with 157 upregulated genes and 249 downregulated genes were selected. The 36 upregulated DEGs and the 70 downregulated genes were notably abundant in the different categories. In KEGG pathway analysis, the 157 upregulated genes and the 249 downregulated genes were concentrated in distinctive signaling pathways. Four potential genes associated with NACT and platinum­based chemoresistance were screened, including nuclear factor of activated T­cells, cytoplasmic 1 (NAFTc1), Kruppel­like factor 4 (KLF4), nuclear receptor subfamily 4 group A member 3 (NR4A3) and hepatocyte growth factor (HGF). Our study showed that the mRNA expression levels of NAFTc1, NR4A3 and HGF were increased in drug­resistant OC cell lines (all P<0.01), whereas the mRNA expression levels of KLF4 were notably lower in the SKOV3­CDDP and HeyA8­CDDP cell line (all P<0.01) but higher in the A2780­CBP cell line. The NAFTc1, KLF4, NR4A3 and HGF genes may be potential therapeutic targets for NACT and platinum­based chemoresistance factors as well as candidate biomarkers in AEOC. Determination of the expression levels of these four genes in tumor tissues before planning NACT treatment or initial surgery would be beneficial for AEOC patients.

Cost-Effectiveness and Net Monetary Benefit of Olaparib Maintenance Therapy Versus No Maintenance Therapy After First-line Platinum-based Chemotherapy in Newly Diagnosed Advanced BRCA1/2-mutated Ovarian Cancer in the Italian National Health Service.

PURPOSE: The aim of this study was to evaluate the cost-effectiveness and net monetary benefit of olaparib maintenance therapy compared with no maintenance therapy after first-line platinum-based chemotherapy in newly diagnosed advanced BRCA1/2-mutated ovarian cancer from the Italian National Health Service (NHS) perspective. METHODS: We developed a lifetime Markov model in which a cohort of patients with newly diagnosed advanced BRCA1/2-mutated ovarian cancer was assigned to receive either olaparib maintenance therapy or active surveillance (Italian standard of care) after first-line platinum-based chemotherapy to compare cost-effectiveness and net monetary benefit of the 2 strategies. Data on clinical outcomes were obtained from related clinical trial literature and extrapolated using parametric survival analyses. Data on costs were derived from Italian official sources and relevant real-world studies. The incremental cost-effectiveness ratio (ICER), incremental cost-utility ratio (ICUR), and incremental net monetary benefit (INMB) were computed and compared against an incremental cost per quality-adjusted life-year (QALY) gained of €16,372 willingness-to-pay (WTP) threshold. We used deterministic sensitivity analysis (DSA) and probabilistic sensitivity analysis (PSA) to assess how uncertainty affects results; we also performed scenario analyses to compare results under different pricing settings. FINDINGS: In the base-case scenario, during a 50-year time horizon, the total costs for patients treated with olaparib therapy and active surveillance were €124,359 and €97,043, respectively, and QALYs gained were 7.29 and 4.88, respectively, with an ICER of €9,515 per life-year gained, an ICUR of €11,345 per QALY gained, and an INMB of €12,104. In scenario analyses, considering maximum selling prices for all other drugs, ICUR decreased to €11,311 per QALY and €7,498 per QALY when a 10% and 20% discount, respectively, was applied to the olaparib official price, and the INMB increased to €12,186 and €21,366, respectively. DSA found that the model results were most sensitive to the proportion of patients with relapsing disease in response to platinum-based chemotherapy, time receiving olaparib first-line maintenance treatment, and subsequent treatments price. According to PSAresults, olaparib was associated with a probability of being cost-effective at a €16,372 per QALY WTP threshold ranging from 70% to 100% in the scenarios examined. IMPLICATIONS: Our analysis indicates that olaparib maintenance therapy may deliver a significant health benefit with a contained upfront cost during a 50-year time horizon, from the Italian NHS perspective, providing value in a setting with curative intent.

Importance of Standard Treatment in Prognosis of Patients with Ovarian Cancer and Associated Cerebral Infarction.

OBJECTIVE: Data on the treatment of patients with ovarian cancer (OC) and associated cerebral infarction (CI) are extremely limited. The objectives were to investigate the risk factors for prognosis in patients with OC and associated CI. METHODS: We retrospectively reviewed the electronic medical records of patients with OC from January 2013 to November 2018 in Peking Union Medical Hospital. RESULTS: In total, 2632 inpatients were diagnosed with malignant ovarian cancer in our institution, and 30 patients (1.1%) were diagnosed with OC-associated CI. The median age was 60 years (range, 37-83). The standard treatment, according to National Comprehensive Cancer Network (NCCN) guidelines, was administered to 19 patients. The median follow-up time was 19.5 months (range, 1-59 months). In total, 17 patients experienced tumor progression, and 16 of them died. In univariate analysis, overall survival was significantly associated with the D-dimer level (P=0.017), FIGO stage (P=0.014), complete cytoreduction (P<0.000) and standard treatment (P<0.000). In multivariate analysis, the standard treatment remained an independent protective factor for death (hazard ratio=0.061, 95% confidence interval=0.007-0.537, P=0.012). CONCLUSION: Although the prognosis of patients with OC and associated CI was poor, those who underwent the standard treatment still benefited.

Patterns and predictors of genetic referral among ovarian cancer patients at a National Cancer Institute-Comprehensive Cancer Center.

Germline mutations (eg, BRCA1/2) have prognostic and treatment implications for ovarian cancer (OVCA) patients. Thus, national guidelines recommend genetic testing for OVCA patients. The present study examines patterns and predictors of genetics referral in OVCA patients. Electronic medical record data were abstracted retrospectively from 557 OVCA patients treated from 1 January 2001 to 31 December 2015. Logistic regression models identified sociodemographic characteristics, disease/treatment characteristics, family history data, provider characteristics, and survival data that predicted genetics referral. Overall, 27.5% of patients received referral. Eleven variables predicting referral were selected during stepwise regression: younger age, White race, not having private insurance, professional school education, year of OVCA diagnosis, platinum sensitivity, female gynecologic oncologist, chemotherapy administered by a gynecologic oncologist, clinical trial enrollment, longer overall survival, and family history of OVCA. Genetics referral among OVCA patients was similar to rates reported nationwide. Unique predictive factors will contribute to quality improvement and should be validated at a multi-institutional level to ensure guideline concordant care is provided to all OVCA patients. Future research should identify both patient-level and provider-level factors associated with genetics referral.

A retrospective study comparing the efficacy of dose-dense chemotherapy, intraperitoneal chemotherapy and dose-dense chemotherapy with hyperthermic intraperitoneal chemotherapy in the treatment of advanced stage ovarian carcinoma.

OBJECTIVES: Hyperthermic intraperitoneal chemotherapy (HIPEC), intraperitoneal chemotherapy (IP) and dose-dense (DD) chemotherapy have been employed with varying success in the treatment of advanced stage ovarian carcinoma. Despite the clinical benefits associated with these specific forms of chemotherapy administration, they have not been comparatively analyzed, vis-à-vis their efficacy. STUDY DESIGN: Advanced stage ovarian cancer patients who were treated with platinum/taxane chemotherapy via a DD regimen (n = 100), IP approach (n = 81) or a DD regimen in conjunction with HIPEC (n = 64) were retrospectively evaluated. The clinical variables of interest were patient age, body mass index, surgery and pathology data, chemotherapy regimen, inclusion of maintenance therapy, and progression free/overall survival. RESULTS: Progression free survival (PFS) was significantly more pronounced in the HIPEC (34.9 months) and IP (34.0 months) patients, compared to the DD group (27.6 months) (P = 0.005). A cox-proportional hazards regression model indicated that there was a decreased risk of disease progression accorded to the patients who were treated with IP chemo or HIPEC and DD chemotherapy (HR, 0.43; 95 % CI: 0.21-0.88; P = 0.022) and the subjects who underwent optimal cytoreductive surgery (HR, 2.42; 95 % CI: 1.22-4.80; P = 0.011). Positive BRCA status (HR, 0.434; 95 % CI: 1.59-3.44; P = 0.001) and number of chemotherapy regimens (HR, 1.36; 95 % CI: 1.159-1.61; P = 0.001) were significantly correlated with improved OS although we did not discern a survival benefit associated with any of the chemotherapy treatments (P = 0.136). CONCLUSION: We observed PFS advantages conferred to the ovarian cancer patients treated with HIPEC and IP chemotherapy compared to DD chemotherapy. However, an overall survival advantage related to the chemotherapy regimens was not borne out, possibly due to the retrospective nature of the study or differing time periods wherein the specific patient cohorts underwent treatment.

High RIG-I expression in ovarian cancer associates with an immune-escape signature and poor clinical outcome.

Ovarian cancer (OC) is the most lethal gynecological malignancy, with platinum-based chemotherapy remaining the mainstay for adjuvant treatment after surgery. The lack of indication for immunotherapy may at least in part result from the lack of suitable biomarkers allowing stratification of potentially responding patients. In this monocentric study of 141 cases with OC, we used real-time quantitative PCR to assess the expression of retinoic acid-inducible gene-I (RIG-I) in primary tumor and healthy ovarian control tissues. RIG-I expression was correlated to various clinicopathological characteristics as well as to a set of molecular and immunological markers. The prognostic significance of RIG-I expression was queried in univariate and multivariate analyses and validated in an independent cohort. RIG-I was overexpressed in the cancerous ovary and correlated with a higher tumor grade. The more aggressive Type-II cancers and cancers with inactivating p53 mutations exhibited higher RIG-I expression. RIG-I levels were also elevated in cancers that recurred after remission or were platinum-refractory. Survival analyses disclosed RIG-I as an independent marker of poor outcome in OC. Continuative analyses revealed the molecular and immunological correlates of RIG-I expression in the tumor microenvironment, including interferon production and a distinct immune-regulatory signature involving checkpoint molecules (PD-L1/PD-1), the RNA-editing enzyme ADAR1 and the regulatory T cell-specific transcription factor FoxP3. We conclude that high RIG-I expression associates with poor outcome in OC, which is explainable by local immunosuppression in the tumor bed. RIG-I expression may inform checkpoint blockade and/or RIG-I agonistic targeting in a subset of high-risk OC patients.