Serous Epithelial Ovarian Cancer Research Articles

Differentiation of Serous and Non-serous Epithelial Ovarian Cancer by Radiological Imaging

Background: Ovarian cancer has a high incidence and fatality rate, with the most prevalent type is epithelial origin. The serous subtype of epithelial cancer predominates. For therapy selection, it is important to differentiate this subtype by histopathological examination as a gold standard method. Since some patients are not eligible for a biopsy, radiological modalities such as Magnetic Resonance Imaging (MRI) are superior in discriminating tissue compared to computed tomography (CT) or ultrasound. The use of the T1 weighted imaging (T1WI) and T2WI sequences can best differentiate between a cystic and a solid lesion. The goal of this study was to use radiological examination to assist in the identification of ovarian cancer.Methods: This cross-sectional study used secondary data from histopathology and MRI results from patients with ovarian cancer. Data was gathered utilizing electronic medical records in Dr. Sardjito Hospital between January 2017 and May 2022. The following MRI characteristics are evaluated including ascites, papillary projection, solid nodule, signal intensity of solid and cystic components, size, configuration, enhancement of contrast, and bilateral of the lesion.Results: Thirty-eight subjects made up the study’s sample, and 63% of them had serous subtypes. Bilateral lesion suggested a three times greater likelihood that it was serous ovarian cancer (p 0.02; binary logistic regression). Age 50 years old and strong enhancement on contrast was also relevant for separating the serous subtype from other subtypes (enhancement p 0.02; age p 0.044). Conclusions: A bilateral lesion with a significantly enhanced pattern can be seen on the MRI of a serous subtype of epithelial ovarian cancer. The elderly are also more likely to develop this cancer.

Abstract 6739: Efficacy and toxicity of microbial mimetic mesoporous silica nanoparticles in a mouse model of ovarian cancer

Abstract Ovarian cancer is predominately left undetected and untreated until the later stages of the disease where it becomes incredibly difficult to treat. Preclinical studies demonstrate that immunotherapy can be highly effective. Our lab has been working on an immunotherapy approach to treat women with ovarian cancer that utilizes mesoporous silica nanoparticles(MSN). MSN that present pathogen-associated molecular patterns (PAMPS) are able to significantly reduce tumor burden in mouse models of serous epithelial ovarian cancer when administered by intraperitoneal injection. These microbial mimetic particles are decorated with polyethyleneimine (PEI), CpG oligonucleotide, and monophosphoryl lipid A (MPLA). When in the presence of antigen presenting cells, they bind to Toll-like receptors (TLR) present on the cell surface and within the endosome. To better understand mechanisms underlying their efficacy, we injected fluorescent MSN-PEI-CpG-MPLA (100 or 500 nm) or unmodified MSN into mice with advanced ovarian cancer. The particles, regardless of the presence of TLR-agonists, were rapidly internalized by myeloid cells, with trafficking almost exclusively to immune clusters located in tumor-burdened adipose tissues when administered by intraperitoneal injection. Conversely, intravenous injection of MSN-PEI-CpG-MPLA led to predominate accumulation in liver, with no particles found in tertiary lymphoid clusters 24 hours post injection. Furthermore, unlike intraperitoneal injection, intravenous injection of MSN-PEI-CpG-MPLA was without therapeutic effect. Currently we are studying MSN safety and the impact of administration route and dose on efficacy and cytotoxicity. In summary, MSN, with and without TLR agonists, are trafficked by myeloid cells to tumor-burdened fat-associated lymphoid clusters when administered by intraperitoneal injection. Intraperitoneal injection of TLR-agonist modified MSN effectively reduces tumor burden in mice with ovarian cancer. Citation Format: Lorel Y. Medina, Rita E. Serda, Benjamin Marwedel, Melanie S. Jun, Josh Adogola. Efficacy and toxicity of microbial mimetic mesoporous silica nanoparticles in a mouse model of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6739.

Abstract 3403: Disentangling the obesity paradox in high-grade serous epithelial ovarian cancer

Abstract Background: Previously published evidence suggests an 'obesity paradox' in epithelial ovarian cancer, where excess adiposity is linked to better survival. However, prior studies did not jointly consider skeletal muscle, a key prognostic factor in cancer. Addressing this gap, our study examines the combined effects of adiposity and muscle phenotypes on mortality in high-grade serous epithelial ovarian cancer (HGSOC), offering novel insights into the role of body composition in patient outcomes. Methods: 343 HGSOC patients from the Body Composition and Epithelial Ovarian Cancer (BComES) Cohort at Roswell Park were included in this analysis. Body composition was derived from sliceOmatic software using computed tomography images obtained prior to chemotherapy. Body composition was quantified as surface area (cm2) at L3 for intermuscular adipose tissue (IMAT), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), total adipose tissue (TAT), and skeletal muscle index (SMI). SMI<38.5 cm2/m2 was defined as low SMI, a proxy for sarcopenia. For each adipose depot, phenotypes were categorized as: 1) low adiposity/high SMI (optimal/referent); 2) high adiposity/high SMI; 3) high adiposity/low SMI (e.g., sarcopenic obesity); and 4) low adiposity/low SMI (e.g., cancer cachexia). Multivariable Cox models adjusted for age, tumor stage, and surgical debulking status were used to estimate Hazard Ratios (HR) and 95% Confidence Intervals (CI) representing associations of each body composition phenotype with mortality. Results: High IMAT and VAT were associated with increased mortality in patients with high SMI (HR=1.80, 95% CI: 1.18-2.74 and HR=1.96, 95% CI: 1.27-3.04, respectively) and low SMI (HR=1.65, 95% CI: 1.05-2.61 and HR=1.70, 95% CI: 1.04-2.80). High SAT and TAT were also associated with increased mortality in patients with high SMI (HR=1.74, 95% CI: 1.14-2.67 and HR=2.04, 95% CI: 1.31-3.18), but associations were shy of significance for patients with low SMI (HR=1.37, 95% CI: 0.85-2.23 and HR=1.58, 95% CI: 0.95-2.61). Lastly, low SMI and low adiposity was associated with increased mortality for VAT (HR= 1.65, 95% CI: 1.01-2.70), SAT (HR=1.88, 95% CI: 1.14-3.10), TAT (HR=1.97, 95% CI:1.19-3.26) and IMAT (HR=1.46, 95% CI: 0.85-2.53). Conclusions: In this study, we observed no support for an obesity paradox. Rather, we observed compelling evidence linking high adiposity phenotypes with striking increases in HGSOC mortality, regardless of SMI. Notably, as the cachectic phenotype was also linked to substantial increases in mortality, unwittingly assigning patients with low adiposity and low muscle to a reference group in adiposity research could falsely induce an ‘obesity paradox’. Importantly, as body composition can be modified through diet and exercise, our data establishes it as a potential therapeutic target alongside chemotherapy to improve outcomes in this deadly disease. Citation Format: Evan W. Davis, Nancy Barone, Charles Roche, Gyorgy Paragh, André Klein, Rikki Cannioto. Disentangling the obesity paradox in high-grade serous epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3403.

Abstract 980: Plasma tumor fraction is an independent prognostic marker of response to front line chemotherapy in high-grade serous epithelial ovarian cancer: The MITO-16a/MANGO-OV2a/clinical trial experience

Abstract Background. Although 80% of high grade serous ovarian cancer (HGSOC) patients are initially responsive to platinum (Pt)-based chemotherapy, the majority of them experience relapse with a progressive Pt-resistant disease. One of the most challenging issue that hampers the possibility to effectively treat relapsed disease is the lack of biological information about tumor recurrence. To date, the Pt-free interval (PFI), an empirical measure of the time lagging between the end of front-line chemotherapy and relapse, is the only and widely accepted parameter to predict patient outcome and sensitivity to Pt second-line chemotherapy. We have previously demonstrated that analysis of circulating tumor DNA (ctDNA) by low pass whole genome sequencing (sWGS) is a suitable tool to predict patient outcome and to intercept early signs of relapsed disease (Paracchini et al. PMID:33323403). In the present study, we quantified the percentage of tumor fraction (TF) in plasma of patients enrolled within the frame of a phase III clinical trial (MITO-16A/MaNGO-OV2A-EUDRACT number: NCT01706120) to demonstrate, at baseline, the prognostic value of untargeted ctDNA analysis. Methods. 172 eligible patients enrolled with the frame of the MITO-16A/MaNGO-OV2A clinical trial, for whom plasma sample was collected at chemotherapy before chemotherapy, were selected for the study. For each plasma sample, circulating-free DNA (cfDNA) was purified and whole genome libraries (HyperPlus, Roche) sequenced (mean coverage 0.5X). ichorCN algorithm was used to infer the percentage of TF, as previously published (Paracchini et al. PMID:33323403). Results. In 168 out of 172 plasma samples analyzed, the TF was detectable and it ranged from 2.4% to 47%. Cox-model univariate analysis with patients’ overall survival (OS) and Progression-Free Survival (PFS), indicates association of TF levels with both OS and PFS (p<0.001). The prognostic relevance of TF was also confirmed in multivariate analysis, where, considering CA-125, residual tumor, stage of disease, histology and age as co-variables, TF maintained its statistical significance in PFS (HR = 2.1, CI 95%, p-value < 0.003). Conclusion. Retrospective analysis of baseline plasma samples collected within the frame of the MITO-16A/MaNGO-OV2A clinical trial, demonstrated that the percentage of TF is an independent prognostic marker of relapse. This finding confirms the importance of liquid biopsy analysis based on untargeted sWGS tool as an innovative approach to predict response to front line therapy and patient’s outcome Citation Format: Sergio Marchini, Lara Paracchini, Laura Arenare, Giovanni Scambia, Carmela Pisano, Riccardo Zadro, Laura Mannarino, Annamaria Ferrero, Paolo Chiodini, Daniela Califano, Sandro Pignata, Maurizio D'Incalci. Plasma tumor fraction is an independent prognostic marker of response to front line chemotherapy in high-grade serous epithelial ovarian cancer: The MITO-16a/MANGO-OV2a/clinical trial experience [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 980.

Abstract A062: Untargeted analysis of plasma tumor fraction is an independent prognostic marker of response to front line chemotherapy in high-grade serous epithelial ovarian cancer: the MITO-16A/MANGO-OV2A clinical trial experience

Abstract Background: Although 80% of high grade serous ovarian cancer (HGSOC) patients are initially responsive to platinum (Pt)-based chemotherapy, the majority of them experience relapse with a progressive Pt-resistant disease. One of the most challenging issues that hampers the possibility to effectively treat relapsed disease is the lack of biological information about tumor recurrence. To date, the Pt-free interval (PFI), an empirical measure of the time lagging between the end of front-line chemotherapy and relapse, is the only and widely accepted parameter to predict patient outcome and sensitivity to Pt second-line chemotherapy. We have previously demonstrated that analysis of circulating tumor DNA (ctDNA) by low pass whole genome sequencing (sWGS) is a suitable tool to predict patient outcome and to intercept early signs of relapsed disease (Paracchini et al. PMID:33323403). In the present study, we quantified the percentage of tumor fraction (TF) in plasma of patients enrolled within the frame of a phase III clinical trial (MITO-16A/MaNGO-OV2A-EUDRACT number: NCT01706120) to demonstrate, at baseline, the prognostic value of untargeted ctDNA analysis. Methods: 172 eligible patients enrolled with the frame of the MITO-16A/MaNGO-OV2A clinical trial, for whom plasma sample was collected at baseline before chemotherapy, were selected for the study. For each plasma sample, circulating-free DNA (cfDNA) was purified and whole genome libraries (HyperPlus, Roche) sequenced (mean coverage 0.5X). ichorCN algorithm was used to infer the percentage of TF, as previously published (Paracchini et al. PMID:33323403). Results: In 168 out of 172 plasma samples analyzed, the TF was detectable, and it ranged from 2.4% to 47%. Cox-model univariate analysis with patients’ overall survival (OS) and Progression-Free Survival (PFS), indicate association of TF levels with both OS and PFS (p<0.001). The prognostic relevance of TF was also confirmed in multivariate analysis, where, considering CA-125, residual tumor, stage of disease, histology and age as co-variables, TF maintained its statistical significance in PFS (HR = 2.1, CI 95%, p-value < 0.003). Conclusion: Retrospective analysis of baseline plasma samples collected within the frame of the MITO-16A/MaNGO-OVtrialnical trial, demonstrated that the percentage of TF is an independent prognostic marker of relapse. This finding confirms the importance of liquid biopsy analysis based on untargeted sWGS tool as an innovative approach to predict response to front line therapy and patient’s outcome. Citation Format: Sergio Marchini, Lara Paracchini, Laura Arenare, Giovanni Scambia, Carmela Pisano, Riccardo Zadro, Laura Mannarino, Annamaria Ferrero, Paolo Chiodini, Daniela Califano, Piergiacomo Di Gennaro, Sandro Pignata, Maurizio D'Incalci. Untargeted analysis of plasma tumor fraction is an independent prognostic marker of response to front line chemotherapy in high-grade serous epithelial ovarian cancer: the MITO-16A/MANGO-OV2A clinical trial experience [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 A062.

Prognostic value of HE4 in advanced-stage, high-grade serous ovarian cancer: Analysis of HE4 kinetics during NACT, predicting surgical outcome and recurrence in comparison to CA125

ObjectivesTo assess the prognostic value of human epididymis protein 4 (HE4) kinetics during and after neoadjuvant chemotherapy (NACT) cycles compared with cancer antigen 125 (CA-125), in predicting the surgical outcomes of interval debulking surgery (IDS) in patients with advanced-stage, high-grade serous ovarian cancer. MethodsThis retrospective cohort study was conducted at Severance Hospital in Seoul, South Korea and involved 123 women with high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who were diagnosed between April 2015 and July 2020. Three outcomes were considered: the chemotherapy response score (CRS) by omentum, residual disease after IDS, and recurrence. Other clinical, imaging, and biological parameters at baseline, during NACT cycles, and pre- and postoperative time were collected and analyzed. ResultsWe observed a substantial and gradual decrease in both CA-125 level (median from 1612 to 85.55 U/mL; p < 0.001) and HE4 level (514.7 to 87.7 pmol/L; p < 0.001) during NACT cycles, while pre-to-postoperative reduction was only significant for HE4 (median from 77.3 to 62.0 pmol/L (p < 0.001)). Of the total patients, 4.1% showed no response to NACT (chemoresistance) and 65.9% had a partial response. Residual disease was observed in 55 (44.7%) patients. Recurrence occurred in 90 patients (73.2%), with a median progression-free survival of 15.28 months. The percent reduction in CA-125 level– but not HE4 – during NACT was significantly associated with CRS (by omentum); the reduction in CA-125 during NACT cycles was higher when the CRS was found to be 3 and 2 (median = 96.4 [IQR = 8.3] and 93.7 [12.2] respectively) compared to score 1 (68.3 [34.1]), and the difference was statistically significant (p = 0.004). However, no significant association was observed between the percent reduction in CA-125 or HE4 levels during NACT and residual disease or recurrence. The normalization of HE4 – but not CA-125 – before surgery was predictive for surgery outcome; that is, an abnormal preop HE4 level was associated with a residual disease risk ratio of 2.72 (95% CI = 1.27–5.79). ConclusionMonitoring HE4 or CA-125 levels has low prognostic value in patients with advanced-stage, high-grade serous ovarian cancer who are treated with NACT followed by IDS. However, the preoperative level of the HE4 biomarker may be useful in identifying patients at higher risk for suboptimal cytoreductive surgery or who may require more extensive surgery. Further prospective studies are warranted to explore the prognostic utility of eventual combinations of clinical, radiological, and biological parameters, notably by using artificial intelligence-based models.

Real-world Study on the Effect of PARPi as Maintenance Therapy on Platinum Sensitivity after First- and Second-line Chemotherapy in Patients with Recurrent High-grade Serous Epithelial Ovarian Cancer.

This study investigated the effect of poly(ADP-ribose) polymerase inhibitors (PARPi) as maintenance therapy after first- and second-line chemotherapy on platinum sensitivity in patients with recurrent high-grade serous epithelial ovarian cancer (rHGSOC). This study retrospectively analyzed 172 patients with rHGSOC treated at Zhejiang Cancer Hospital and Jiaxing Maternity and Child Health Care Hospital between January 2017 and December 2021. The 1st-PARPi group comprised patients who received a PARPi as maintenance therapy after first-line chemotherapy (n=23), and the 1st-control group comprised those who did not (n = 105). Similarly, the 2nd-PARPi group comprised patients not given a PARPi in their first-line treatment (n = 30), and the 2nd-control group comprised those who were given a PARPi (n = 89). Among the 23 patients in the 1st-PARPi group and the 105 patients in the 1st-control group, nine and 99 were platinum-sensitive, and 14 and six were platinum-resistant, respectively (hazard ratio [HR]: 14.46, P < 0.0001). Among the 30 patients in the 2nd-PARPi group and 89 patients in the 2nd-control group, 10 and 71 were platinum-sensitive, and 20 and 18 were platinumresistant, respectively (HR: 4.37, P < 0.0001). Age, stage, residual tumor, the courses of platinumbased chemotherapy, and breast cancer susceptibility gene mutations were not associated with platinum sensitivity when using a PARPi as maintenance therapy after first- and second-line chemotherapy. Patients with rHGSOC using a PARPi were more likely to be platinum-sensitive and develop platinum resistance independent of PARPi duration. Care should be taken when using a PARPi as maintenance therapy after first- and second-line chemotherapy.

Prevalence of viral DNA in high-grade serous epithelial ovarian cancer and correlation with clinical outcomes.

Currently 11 infectious agents are classified as carcinogenic but the role of infectious agents on outcomes of epithelial ovarian cancer is largely unknown. To explore the association between infectious agents and ovarian cancer, we investigated the prevalence of viral DNA in primary ovarian cancer tumors and its association with clinical outcomes. Archived tumors from 98 patients diagnosed with high-grade serous epithelial ovarian cancer were collected between 1/1/1994 and 12/31/2010. After DNA extraction, Luminex technology was utilized to identify polymerase chain reaction-amplified viral DNA for 113 specific viruses. Demographic data and disease characteristics were summarized using descriptive statistics. We used logistic regression and Cox proportional hazards model to assess associations between tumor viral status and disease outcome and between tumor viral presence and overall survival (OS), respectively. Forty-six cases (45.9%) contained at least one virus. Six highly prevalent viruses were associated with clinical outcomes and considered viruses of interest (VOI; Epstein-Barr virus 1, Merkel cell polyomavirus, human herpes virus 6b, and human papillomaviruses 4, 16, and 23). Factors independently associated with OS were presence of VOI (HR 4.11, P = 0.0001) and platinum sensitivity (HR 0.21, P<0.0001). Median OS was significantly decreased when tumors showed VOI versus not having these viruses (22 vs 44 months, P<0.0001). Women <70 year old with VOI in tumors had significantly lower median OS versus age-matched women without VOI (20 vs 57 months, P = 0.0006); however, among women ≥70 years old, there was no difference in OS by tumor virus status. The presence of a VOI was significantly associated with a lower OS. These findings may have implications for clinical management of ovarian cancer but require additional studies.

The Prognostic Value of the Circulating-Tumor DNA in High-Grade Serous Epithelial Ovarian Cancer: Experience From MITO-16a/MANGO-OV2a/ Clinical Trial

The Prognostic Value of the Circulating-Tumor DNA in High-Grade Serous Epithelial Ovarian Cancer: Experience From MITO-16a/MANGO-OV2a/ Clinical Trial

Economic impact of olaparib on maintenance treatment of patients with BRCA-mutation positive, platinum-sensitive relapsing high-grade serous epithelial ovarian cancer in Spain

ObjectiveTo estimate the economic impact of the introduction of olapa- rib in the Spanish National Health System as maintenance monotherapy in patients with BRCA-mutation positive high-grade serous ovarian cancer. Method: A budget impact model was developed from the Spanish NHS perspective and a time horizon of 5 years for four treatment lines. The model included prevalent and incident patients estimated according to Spanish epidemiological data. Patients moved between treatment lines according to the progression-free survival and overall survival curves obtained from the respective clinical trials. Only direct costs (€2017) were considered: pharmacological, administration, adverse effects and genetic tests. The robustness of the model was verified by a univariate sensitivity analysis. ResultsThe use of olaparib meant that, after 5 years, 6% fewer patients progressed to later lines compared to scenario without olaparib, remaining longer in the second line and delaying the initiation of subsequent lines. The total estimated budgetary impact ranged between € 1.6 and € 5.4 million (1-5 years). The economic impact associated to the introduction of olaparib is partially offset by the lower cost of chemotherapy, related adverse events, and palliative care in patients with olaparib than in patients without it. ConclusionsOlaparib as maintenance treatment in patients with BR- CA-mutation positive high-grade serous ovarian cancer increases progression-free survival and delays the use of subsequent chemotherapy, with an budgetary impact for the Spanish National Health System of 5.4 million euros after 5 years.

High serum levels of inflammatory markers are associated with early recurrence in patients with high-grade serous ovarian cancer after platinum therapy

ObjectiveTo determine if inflammatory biomarkers can predict the long-term outcome of platinum therapy in patients with high-grade serous ovarian cancer. MethodsWomen diagnosed with high-grade serous epithelial ovarian cancer (n = 70) at a single institution were enrolled in a prospective serum collection study between 2005 and 2020. Seventeen markers of inflammation and oxidative stress were measured in serum samples on a chemistry analyzer. Association was tested for serum levels with progression-free survival (PFS), time to recurrence (TTR), overall survival (OS), and time to death (TTD) using Cox proportional hazards and Kaplan-Meier curves. Patient survival was censored at 10 years. ResultsHigher serum levels of LDH were associated with worse PFS (HR 2.57, p = 0.028). High serum levels of BAP (HR 0.38, p = 0.025), GSP (HR 0.40, p = 0.040), HDL-c (HR 0.27, p = 0.002), and MG (HR 0.36, p = 0.017) were associated with improved PFS. Higher expression of LDH was associated with worse OS (HR 2.16, p = 0.023). Higher levels of CK.nac (HR 0.39, p = 0.033) and HDL-c (HR 0.35, p = 0.029) were associated with improved OS. Similar outcomes were found with TTR and TTD analyses. ConclusionGeneral inflammatory biomarkers may serve as a guide for prognosis and treatment benefit. Future studies needed to further define their role in predicting prognosis or how these markers may affect response to therapy.

Pelvic inflammatory disease and risk of epithelial ovarian cancer: a national population-based case-control study in Sweden

Epithelial ovarian cancer is an insidious disease, and women are often diagnosed when the disease is beyond curative treatment. Accordingly, identifying modifiable risk factors is of paramount importance. Inflammation predisposes an individual to cancer in various organs, but whether pelvic inflammatory disease is associated with an increased risk of epithelial ovarian cancer has not been fully determined. The aim of the present study was to investigate a possible association between clinically verified pelvic inflammatory disease and risk of epithelial ovarian cancer. In this national population-based case-control study, we identified all women in Sweden diagnosed with epithelial ovarian cancer between 1999 and 2020 and ten controls for each, matched for age and residential district. Using several Swedish nationwide registers, we retrieved data on previous pelvic inflammatory disease and potential confounding factors (age, parity, educational level, and previous gynecological surgery). Adjusted odds ratios and 95% confidence intervals were estimated using conditional logistic regression. We performed histotype-specific analyzes for the subgroup of women diagnosed with epithelial ovarian cancer between 2015 and 2020. Hormonal contraceptives and menopausal hormone therapy were also adjusted for in addition to the aforementioned confounders. We included 15,072 women with epithelial ovarian cancer and 141,322 controls. A majority had serous carcinoma (n=9102, 60.4%). In a subgroup of cases diagnosed between 2015 and 2020 we identified high-grade serous carcinoma (n=2319, 60.0%). A total of 1.1% (n=168) of cases and 0.9% (n=1270) of controls were diagnosed with pelvic inflammatory disease. Previous pelvic inflammatory disease was associated with increased risk of epithelial ovarian cancer (adjusted odds ratio, 1.39; 95% confidence interval, 1.17-1.66) and serous carcinoma (adjusted odds ratio, 1.46; 95% confidence interval, 1.18-1.80) for the entire study population. For the subgroup of women diagnosed in 2015-2020, pelvic inflammatory disease was associated with high-grade serous carcinoma (adjusted odds ratio, 1.43; 95% confidence interval, 1.01-2.04). Odds ratios of the other histotypes were as follows: endometrioid (adjusted odds ratio, 0.13; 95% confidence interval, 0.02-1.06); mucinous (adjusted odds ratio, 1.55; 95% confidence interval, 0.56-4.29); and clear cell carcinoma (adjusted odds ratio, 2.30; 95% confidence interval, 0.90-5.86). A dose-response relationship was observed between the number of pelvic inflammatory disease episodes and risk of epithelial ovarian cancer (Ptrend<0.001). A history of pelvic inflammatory disease is associated with an increased risk of epithelial ovarian cancer and a dose-response relationship is evident. Histotype-specific analyzes show an association with increased risk of serous epithelial ovarian cancer and high-grade serous carcinoma, and potentially also with clear cell carcinoma, but no significant association with other histotypes. In conclusion, infection and inflammation of the upper reproductive tract might have serious long-term consequences, including epithelial ovarian cancer.

Specific Tumor Localization of Immunogenic Lipid-Coated Mesoporous Silica Nanoparticles following Intraperitoneal Administration in a Mouse Model of Serous Epithelial Ovarian Cancer.

Immunogenic lipid-coated mesoporous silica nanoparticles (ILM) present pathogen-associated molecular patterns (PAMPs) on the nanoparticle surface to engage pathogen-associated receptors on immune cells. The mesoporous core is capable of loading additional immunogens, antigens or drugs. In this study, the impact of lipid composition, surface potential and intercalation of lipophilic monophosphoryl lipid A (MPL-A) in the lipid coat on nanoparticle properties and cellular interactions is presented. Loading and retention of the model antigen ovalbumin into the mesoporous silica core were found to be similar for all nanoparticle formulations, with presentation of ova peptide (SIINFEKL) by major histocompatibility complex (MHC) evaluated to facilitate the selection of an anionic nanoparticle composition. ILM were able to induce lysosomal tubulation and streaming of lysosomes towards the cell surface in dendritic cells, leading to an enhanced surface presentation of MHC. Myeloid cells robustly internalized all ILM formulations; however, non-myeloid cells selectively internalized cationic ILM in vitro in the presence of 20% serum. Interestingly, ILM administration to the peritoneal cavity of mice with disseminated ovarian cancer resulted in selective accumulation of ILM in tumor-associated tissues (>80%), regardless of nanoparticle surface charge or the presence of MPL-A. Immunofluorescence analysis of the omental tumor showed that ILMs, regardless of surface charge, were localized within clusters of CD11b+ myeloid cells 24 h post administration. Selective uptake of ILMs by myeloid cells in vivo indicates that these cells outcompete other cell populations in the ovarian tumor microenvironment, making them a strong target for therapeutic interventions.

Recovery of the Decreased Phagocytic Function of Peripheral Monocytes and Neutrophil Granulocytes following Cytoreductive Surgery in Advanced Stage Epithelial Ovarian Cancer.

(1) Monocytes and neutrophil granulocytes are the phagocytic cells of the innate immune system, playing a crucial role in recognizing and eliminating tumor-transformed cells. Our objective was to assess the impact of advanced-stage epithelial ovarian cancer (EOC) and cytoreductive surgery on the phagocytic function of peripheral monocytes and neutrophil granulocytes. We aimed to compare the pre- and postoperative phagocytic function of these immune cells in EOC patients with healthy control women. Additionally, we aimed to examine the influence of surgery on phagocytic function by comparing pre- and postoperative samples from patients with benign gynecological tumors. (2) We examined peripheral blood samples from 20 patients with FIGO IIIC stage high-grade serous EOC and 16 patients with benign gynecological tumors as surgical controls, collected before and seven days after tumor removal surgery, and from 14 healthy women. After separation, the cells were incubated with Zymosan-A particles, and the phagocytic index (PI) was assessed using immunofluorescence microscopy. One-way ANOVA, the Kruskal-Wallis H-test, and the paired samples t-test were used for the statistical analysis of the data. A significance level of p < 0.05 was applied. (3) Peripheral monocytes and neutrophils from EOC patients exhibited significantly lower preoperative PI values compared to healthy controls (p < 0.001; p < 0.001, respectively). Following cytoreductive surgery, the PI values of immune cells in EOC patients significantly increased by the 7th postoperative day (p < 0.001; p < 0.001), reaching levels comparable to those of healthy controls (p = 0.700 and p = 0.991). In contrast, there was no significant disparity in the PI values of cells obtained from pre- and postoperative blood samples of surgical controls when compared to healthy women (monocytes: p = 0.361 and p = 0.303; neutrophils: p = 0.150 and p = 0.235). (4) EOC and/or its microenvironment may produce factors that reduce the phagocytic function of monocytes and neutrophils, and the production of these factors may be reduced or eliminated after tumor removal.

Bevacizumab Treatment for Low-Grade Serous Ovarian Cancer: A Systematic Review.

Serous epithelial ovarian cancer, classified as either high-grade (90%) or low-grade (10%), varies in molecular, histological, and clinicopathological presentation. Low-grade serous ovarian cancer (LGSOC) is a rare histologic subtype that lacks disease-specific evidence-based treatment regimens. However, LGSOC is relatively chemo-resistant and has a poor response to traditional treatments. Alternative treatments, including biologic therapies such as bevacizumab, have shown some activity in LGSOC. Thus, the objective of this systematic review is to determine the effect and safety of bevacizumab in the treatment of LGSOC. Following PRISMA guidelines, Medline ALL, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Embase all from the OvidSP platform, ClinicalTrials.gov, International Clinical Trials Registry Platform, International Standard Randomised Controlled Trial Number Registry were searched from inception to February 2022. Articles describing bevacizumab use in patients with LGSOC were included. Article screening, data extraction, and critical appraisal of included studies were completed by two independent reviewers. The effect of bevacizumab on the overall response rate, progression-free survival, overall survival, and adverse effects were summarized. The literature search identified 3064 articles, 6 of which were included in this study. A total of 153 patients were analyzed; the majority had stage IIIC cancer (56.2%). The overall median response rate reported in the studies was 47.5%. Overall, bevacizumab is a promising treatment for LGSOC, with response rates higher than traditional treatment modalities such as conventional chemotherapy, and is often overlooked as a treatment tool. A prospective clinical trial evaluating the use of bevacizumab in LGSOC is necessary to provide greater evidence and support these findings.

Critical Analysis of Advanced High-Grade Serous Epithelial Ovarian Cancer in Women: An Experience of 100 Cases from a Regional Cancer Center in Northeast India.

Debabrata BarmonOvarian cancer is the sixth most common cancer in women worldwide. Patients with ovarian carcinoma mostly present at an advanced stage with serous type of epithelial ovarian cancers, which is the most lethal of all pelvic malignancies. This study aims to critically analyze high-grade serous epithelial ovarian carcinomas in women from the Northeastern region of India and compare our data with Western literature to modify treatment strategies and improve survival outcomes. This hospital-based retrospective analysis involved data from the records of 100 women with high-grade epithelial ovarian cancer treated primarily with neoadjuvant chemotherapy followed by interval debulking surgery in the department of gynecologic oncology at a tertiary level regional cancer institute from January 2018 to December 2019. The demographic, clinical and pathological profile, and survival outcome were evaluated using descriptive statistics. The overall survival of the study population was calculated using Kaplan-Meier curves using SPSS software (version 24). The majority of women belonged to 41 to 55 years age group. At first presentation to the hospital, 89 and11% patients were in stage III and stage IV of disease, respectively. Clinically, 95% of women had ascites, and 18% had metastasis to lymph nodes. Distant metastasis to lungs and liver was present in 10 and 3% of cases, respectively. A substantial percentage (98%) of women had raised serum Ca125 > 1000 at baseline, ranging from 1,745 to 10,987 IU/mL. Almost two-thirds of the cases had partial-to-complete response to neoadjuvant chemotherapy (78%). In most of the women (72%), there was no residual disease at interval debulking surgery (R0), though 28% women had R1& R2 resection. The median overall survival time was 36 months. High-grade serous ovarian cancer is commonly seen in older age group, but its occurrence in younger population has also been observed. Early diagnosis is crucial in decreasing morbidity and mortality among these patients. Therefore, efforts should be made to identify risk factors for malignancy. Assessing each parameter of statistical information reflecting its own profile may be important for calculating the risk for the development of ovarian cancer, which can help in implementing preventive measures in the future.

Hormone Receptors and Epithelial Ovarian Cancer: Recent Advances in Biology and Treatment Options.

Epithelial ovarian cancer (EOC) is a significant cause of cancer-related mortality in women. Despite advances in diagnosis and treatment, EOC remains a challenging disease to manage, and the 5-year survival rate is still poor. The role of hormone receptors (HRs) in EOC carcinogenesis and prognosis has been actively explored; however, the role of hormone therapy (HT) in the treatment of these tumors is not well established. Most available data on HT mainly come from retrospective series and small early clinical trials. Several of these studies suggest that HT may have a role in adjuvant, maintenance therapy, or in the case of recurrent disease, especially for some subtypes of EOC (e.g., low-grade serous EOC). Furthermore, HT has recently been combined with targeted therapies, but most studies evaluating these combinations are still ongoing. The main aim of this review is to provide an overview of the progress made in the last decade to characterize the biological and prognostic role of HRs for EOC and the developments in their therapeutic targeting through HT.

Prognostic Significance of Preoperative NLR, MLR, and PLR Values in Predicting the Outcome of Primary Cytoreductive Surgery in Serous Epithelial Ovarian Cancer

(1) The degree of cytoreduction achieved during primary debulking surgery (PDS) is an important prognostic factor for the survival of patients with epithelial ovarian cancer (EOC). Our aim was to investigate the prognostic value of preoperative laboratory parameters for the outcome of PDS. (2) We analyzed the preoperative laboratory parameters of 150 serous EOC patients who underwent PDS between 2006 and 2013. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off values of the variables for predicting the PDS outcome. We used binary logistic regression to examine the independent predictive value of the factors for incomplete cytoreduction. (3) Among the parameters, we established optimal cut-off values for cancer antigen (Ca)-125, neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) to predict the outcome of PDS. The results of binary logistic regression showed that stage (FIGO III-IV), MLR (&gt;0.305), and Ca-125 (&gt;169.15 kU/L) were independent significant predictors of the degree of tumor reduction achieved during PDS. (4) In the future, MLR, especially in combination with other parameters, may be useful in determining prognosis and selecting the best treatment option (PDS or neoadjuvant chemotherapy + interval debulking surgery) for ovarian cancer patients.

Immune profile of primary and recurrent epithelial ovarian cancer cases indicates immune suppression, a major cause of progression and relapse of ovarian cancer

BackgroundOvarian cancer is the third most prevalent cancer in Indian women. Relative frequency of High grade serous epithelial ovarian cancer (HGSOC) and its associated deaths are highest in India which suggests the importance of understanding their immune profiles for better treatment modality. Hence, the present study investigated the NK cell receptor expression, their cognate ligands, serum cytokines, and soluble ligands in primary and recurrent HGSOC patients. We have used multicolor flow cytometry for immunophenotyping of tumor infiltrated and circulatory lymphocytes. Procartaplex, and ELISA were used to measure soluble ligands and cytokines of HGSOC patients.ResultsAmong the enrolled 51 EOC patients, 33 were primary high grade serous epithelial ovarian cancer (pEOC) and 18 were recurrent epithelial ovarian cancer (rEOC) patients. Blood samples from 46 age matched healthy controls (HC) were used for comparative analysis. Results revealed, frequency of circulatory CD56Bright NK, CD56Dim NK, NKT-like, and T cells was reduced with activating receptors while alterations in immune subsets with inhibitory receptors were observed in both groups. Study also highlights differential immune profile of primary and recurrent ovarian cancer patients. We have found increased soluble MICA which might have acted as “decoy” molecule and could be a reason of decrease in NKG2D positive subsets in both groups of patients. Furthermore, elevated level of serum cytokines IL-2, IL-5, IL-6, IL-10, and TNF-α in ovarian cancer patients, might be associated with ovarian cancer progression. Profiling of tumor infiltrated immune cells revealed the reduced level of DNAM-1 positive NK and T cells in both groups than their circulatory counterpart, which might have led to decrease in NK cell’s ability of synapse formation.ConclusionsThe study brings out differential receptor expression profile on CD56BrightNK, CD56DimNK, NKT-like, and T cells, cytokines levels and soluble ligands which may be exploited to develop alternate therapeutic approaches for HGSOC patients. Further, few differences in the circulatory immune profiles between pEOC and rEOC cases, indicates the immune signature of pEOC undergoes some changes in circulation that might facilitated the disease relapse. They also maintains some common immune signatures such as reduced expression of NKG2D, high level of MICA as well as IL-6, IL10 and TNF-α, which indicates irreversible immune suppression of ovarian cancer patients. It is also emphasized that a restoration of cytokines level, NKG2D and DNAM-1on tumor infiltrated immune cells may be targeted to develop specific therapeutic approaches for high-grade serous epithelial ovarian cancer.

Safety and efficacy of PIPAC in patients with ovarian cancer with peritoneal metastases: A first-in-US phase I study.

5554 Background: Epithelial ovarian cancer (EOC) is characterized by chemoresistant recurrences primarily confined to the intraperitoneal cavity, frequently leading to malignant small bowel obstructions. Intraperitoneal (IP) chemotherapy has been incorporated in EOC, but only in the first-line setting. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a novel IP drug delivery method that optimizes tissue penetration depth and drug distribution, to treat recurrent peritoneal malignancies. Recent trials outside the U.S. demonstrated partial to stable response following PIPAC in recurrent EOC. To date, no clinical trials have been completed investigating the role of PIPAC in EOC in the United States. Methods: We performed a multicenter prospective phase I trial using IP cisplatin 10.5 mg/m2 and doxorubicin 2.1 mg/m2 via PIPAC at 6-week intervals. Patients were eligible if they had recurrent disease with peritoneal metastasis; extraperitoneal metastasis was allowed. The primary endpoint was dose-limiting toxicity (DLT). Secondary endpoints included progression free survival, PCI scoring, RECIST measurements, and quality of life (QoL). The patients with gastric and uterine cancers’ toxicity data were used but given inherent prognostic differences the treatment efficacy for these patients were not used in this analysis. Adverse event (AE) monitoring was graded using CTCAE spanning 18 weeks. Following completion of treatment (³2 PIPACs) patients were followed up every 12 weeks. QoL was measured using patient-reported assessments at 0, 6, 12, and 18 weeks. Baseline demographics were summarized. Mean change in PCI was calculated between cycle (C) 1 and 2, and cycle 2 and 3. Toxicities attributed to the surgery or PIPAC were reported with highest grade for each patient. Results: Nine heavily pretreated, recurrent patients were enrolled in the trial: 7 with platinum-resistant recurrent EOC, 1 with uterine cancer, and 1 with gastric cancer. PIPAC completion rate was 71.4%. Median age of participants was 65 years. Median prior lines of chemotherapy were 4 (range 2 - 10). No surgical complications occurred in the cohort. Two patients came off study: one for G3 abdominal pain and the other for G3 anorexia. For the EOC cohort, the median PCI reduction was -1.4% (C1 to C2) and -2.8% (C1 to C3). One low-grade serous EOC patient demonstrated a partial response based on RECIST criteria and received 6 cycles. Two EOC patients showed an initial response based on PCI reduction, but progressed following Cycle 2. Overall, QoL was stable. Conclusions: PIPAC with cisplatin/doxorubicin in platinum-resistant ovarian cancer is well tolerated. Intraperitoneal responses were seen in a subset of low-grade serous ovarian cancer patients, which may warrant further study. Heavily pretreated, platinum-resistant high-grade EOC patients derived limited intraperitoneal control from PIPAC monotherapy. Clinical trial information: NCT04329494 .