Suboptimal Debulking Research Articles

Recurrence Rate and Associated Factors of Primary Fallopian Tube Carcinoma in the South of Vietnam

Abstract Objectives: This study aimed to determine the recurrence rate and related risk factors of primary fallopian tube cancer (PFTC). Materials and Methods: We conducted a retrospective study of 47 patients with histopathological diagnosis of PFTC treated at Tu Du Hospital between January 1, 2015, and July 31, 2022. The cumulative recurrence rate was estimated using the life table method, and recurrence-associated factors were determined using the Log–rank test and Cox proportional hazard model. Results: The median follow-up period was 40 months (range, 7–96 months). Eight patients (17.0%) experienced recurrence. The cumulative recurrence rate of PFTC patients at 12 months was 4.4% (95% confidence interval [95% CI]: 1.12–16.45), at 24 months was 9.1% (95% CI:3.52–22.5), at 36 months was 14.9% (95% CI: 6.92–30.41), at 48 months was 19.3% (95% CI: 9.35–37.24), and at 60 months was 25.7% (95% CI: 12.68–47.88). A higher recurrence rate was significantly associated with elevated pretreatment CA 125 level (<35 U/mL vs. ≥35 U/mL, hazards ratio [HR] = 36.9, 95% CI: 1.47–921.37), advanced FIGO stages (Stage I-II vs. stages III, HR = 6.61, 95% CI: 1.18–36.93), and suboptimal debulking surgery (residual disease ≤1 cm vs. residual disease >1 cm, HR = 7.52, 95% CI: 1.47–38.49). Conclusion: The overall recurrence rate of PFTC patients in Southern Vietnam was 17.0%. Appropriate follow-up strategies for patients with high-risk factors are needed for early detection and management of recurrence.

Radiomics combined with clinical and MRI features may provide preoperative evaluation of suboptimal debulking surgery for serous ovarian carcinoma.

To develop and validate a model for predicting suboptimal debulking surgery (SDS) of serous ovarian carcinoma (SOC) using radiomics method, clinical and MRI features. 228 patients eligible from institution A (randomly divided into the training and internal validation cohorts) and 45 patients from institution B (external validation cohort) were collected and retrospectively analyzed. All patients underwent abdominal pelvic enhanced MRI scan, including T2-weighted imaging fat-suppressed fast spin-echo (T2FSE), T1-weighteddual-echomagnetic resonanceimaging (T1DEI), diffusion weighted imaging (DWI), and T1 with contrast enhancement (T1CE). We extracted, selected and eliminated highly correlated radiomic features for each sequence. Then, Radiomic models were made by each single sequence, dual-sequence (T1CE + T2FSE), and all-sequence, respectively. Univariate and multivariate analyses were performed to screen the clinical and MRI independent predictors. The radiomic model with the highest area under the curve (AUC) was used to combine the independent predictors as a combined model. The optimal radiomic model was based on dual sequences (T2FSE + T1CE) among the five radiomic models (AUC = 0.720, P < 0.05). Serum carbohydrate antigen 125, the relationship between sigmoid colon/rectum and ovarian mass or mass implanted in Douglas' pouch, diaphragm nodules, and peritoneum/mesentery nodules were considered independent predictors. The AUC of the radiomic-clinical-radiological model was higher than either the optimal radiomic model or the clinical-radiological model in the training cohort (AUC = 0.908 vs. 0.720/0.854). The radiomic-clinical-radiological model has an overall algorithm reproducibility and may help create individualized treatment programs and improve the prognosis of patients with SOC.

Outcome and prognostic factors of low‑grade serous ovarian cancer: An observational retrospective study.

Low-grade serous ovarian cancer (LGSOC) is a very rare histological subtype of serous ovarian cancer, representing ~2% of all epithelial ovarian cancer cases. LGSOC has a better prognosis but a lower response rate to chemotherapy in comparison to high-grade serous ovarian carcinoma (HGSOC). The present study is a retrospective review of the medical records of all patients with histologically proven LGSOC diagnosed and treated in a single institute between January 2003 and December 2019. A total of 23 patients diagnosed with LGSOC and treated at King Faisal Specialist Hospital and Research Center (Riyadh, Saudi Arabia) were identified. The median age at diagnosis was 45.5 years (range, 26-66 years) and the median body mass index was 26.1 (range, 18-43). A total of 21 patients (91.3%) had de novo LGSOC, whereas only 2 patients (8.7%) had LGSOC that had transformed from serous borderline ovarian tumors and recurred. A total of 8 patients (34.8%) were diagnosed with International Federation of Gynecology and Obstetrics stage IV, whereas 3 (13.0%), 3 (13.0%) and 9 (39.1%) were diagnosed with stages I, II and III, respectively. In addition, 10 (43.5%), 5 (21.7%), and 3 (13.0%) patients had complete response, stable disease and partial response statuses after first-line therapy, respectively. At a median follow-up time of 34 months [95% confidence interval (CI), 25.32-42.69], the median progression-free survival (PFS) time was 75.2 months (95% CI, 17.35-133.05) and the median overall survival (OS) time was not reached. In conclusion, LGSOC exhibited better PFS and OS times than HGSOC as compared with data from the literature, and there is the option for systemic treatment (chemotherapy or hormonal therapy). Optimal cytoreduction showed numerically higher, but non-significant, PFS and OS times compared with suboptimal debulking; however, the optimal systemic chemotherapy or hormonal treatment remains controversial.

Chemotherapy response score as a predictor of survival in ovarian cancer patients

ObjectiveThe chemotherapy response score (CRS) has been widely adopted as a predictive tool for ovarian cancer survival. In the present study, we seek to define differences in survival rates among patients grouped in the traditionally established three-tiered system and those who have not been offered debulking surgery. Study designWe designed a retrospective cohort study involving women treated with chemotherapy and offered interval or late debulking surgery for ovarian cancer. Twenty-eight women were not considered for a debulking procedure for various reasons. Of the 89 women who were finally offered interval debulking or late debulking surgery, 28 had a CRS 1 score, 34 had a CRS 2 score and 27 had a CRS 3 score. ResultsSignificant differences were noted in the progression-free survival (PFS) and overall survival (OS) of patients based on the CRS stratification, although survival rates were considerably longer for all three groups compared to those of patients who were not offered surgery. Cox regression univariate analysis revealed that suboptimal debulking and CRS 1 or no surgery had a significant negative impact on PFS and OS rates. The binary stratification of CRS (CRS 1–2 vs CRS 3) revealed comparable differences in the PFS and OS to those in the groups that were stratified as platinum resistant and platinum sensitive. ConclusionThe chemotherapy response score is a significant determinant of ovarian cancer survival that helps evaluate the risk of early disease relapse and death and may soon be useful in guiding patient-tailored treatment.

Developing a novel image marker to predict the clinical outcome of neoadjuvant chemotherapy (NACT) for ovarian cancer patients

ObjectiveNeoadjuvant chemotherapy (NACT) is one kind of treatment for advanced stage ovarian cancer patients. However, due to the nature of tumor heterogeneity, the clinical outcomes to NACT vary significantly among different subgroups. Partial responses to NACT may lead to suboptimal debulking surgery, which will result in adverse prognosis. To address this clinical challenge, the purpose of this study is to develop a novel image marker to achieve high accuracy prognosis prediction of NACT at an early stage. MethodsFor this purpose, we first computed a total of 1373 radiomics features to quantify the tumor characteristics, which can be grouped into three categories: geometric, intensity, and texture features. Second, all these features were optimized by principal component analysis algorithm to generate a compact and informative feature cluster. This cluster was used as input for developing and optimizing support vector machine (SVM) based classifiers, which indicated the likelihood of receiving suboptimal cytoreduction after the NACT treatment. Two different kernels for SVM algorithm were explored and compared. A total of 42 ovarian cancer cases were retrospectively collected to validate the scheme. A nested leave-one-out cross-validation framework was adopted for model performance assessment. ResultsThe results demonstrated that the model with a Gaussian radial basis function kernel SVM yielded an AUC (area under the ROC [receiver characteristic operation] curve) of 0.806 ± 0.078. Meanwhile, this model achieved overall accuracy (ACC) of 83.3%, positive predictive value (PPV) of 81.8%, and negative predictive value (NPV) of 83.9%. ConclusionThis study provides meaningful information for the development of radiomics based image markers in NACT treatment outcome prediction.

Preoperative serum level of CA153 and a new model to predict the sub-optimal primary debulking surgery in patients with advanced epithelial ovarian cancer

ObjectiveThe aim of this study was to establish a preoperative model to predict the outcome of primary debulking surgery (PDS) for advanced ovarian cancer (AOC) patients by combing Suidan predictive model with HE4, CA125, CA153 and ROMA index.Methods76 AOC Patients in revised 2014 International Federation of Gynecology and Obstetrics (FIGO) stage III-IV who underwent PDS between 2017 and 2019 from Yunnan Cancer Hospital were included. Clinical data including the levels of preoperative serum HE4, CA125, CA153 and mid-lower abdominal CT-enhanced scan results were collected. The logistics regression analysis was performed to find factors associated with sub-optimal debulking surgery (SDS). The receiver operating characteristic curve was used to evaluate the predictive performances of selected variables in the outcome of primary debulking surgery. The predictive index value (PIV) model was constructed to predict the outcome of SDS.ResultsOptimal surgical cytoreduction was achieved in 61.84% (47/76) patients. The value for CA125, HE4, CA153, ROMA index and Suidan score was lower in optimal debulking surgery (ODS) group than SDS group. Based on the Youden index, which is widely used for evaluating the performance of predictive models, the best cutoff point for the preoperative serum HE4, CA125, CA153, ROMA index and Suidan score to distinguish SDS were 431.55 pmol/l, 2277 KU/L, 57.19 KU/L, 97.525% and 2.5, respectively. Patients with PIV≥5 may not be able to achieve optimal surgical cytoreduction. The diagnostic accuracy, NPV, PPV and specificity for diagnosing SDS were 73.7%, 82.9%, 62.9% and 72.3%, respectively. In the constructed model, the AUC of the SDS prediction was 0.770 (95% confidence interval: 0.654-0.887), P<0.001.ConclusionPreoperative serum CA153 level is an important non-invasive predictor of primary SDS in advanced AOC, which has not been reported before. The constructed PIV model based on Suidan's predictive model plus HE4, CA125, CA153 and ROMA index can noninvasively predict SDS in AOC patients, the accuracy of this prediction model still needs to be validated in future studies.

Survival outcomes of epithelial ovarian cancer treated at a tertiary-level hospital in India.

One needs to choose wisely between primary neoadjuvant chemotherapy and primary cytoreductive surgery in ovarian cancer. The aim was to determine the recurrence free survival and overall survival after surgery for epithelial ovarian cancer and also the risk factors for recurrence and death. Electronic medical records of 322 women operated for ovarian, fallopian or primary peritoneal cancer between 2011 and 2015table were reviewed. Descriptive statistics were used to describe patients and their clinical outcomes. Cox proportional hazard models were used for risk factor analysis. Adjusted hazard ratios were obtained for recurrence and death, adjusted for stage, primary treatment modality, residual disease and histology. Kaplan-Meier curves were drawn for probability of recurrence-free survival and overall survival. The log rank test was used to compare survival probabilities. The majority were stage III or stage IV (78%), serous histology (71%) and high grade (64%). Primary cytoreduction was done in 48% and interval cytoreduction in 52%. The median duration of follow up (survival) was 77 months (95% CI 72-82). There were 179 known recurrences (55.6 %). The estimated median time to recurrence was 22 (95% CI 14.5- 29.5) months. The independent risk factors for recurrence were neoadjuvant chemotherapy [HR 2.14, 95% CI 1.48-3.09], stage III/IV [HR 2.75; 95% CI 1.40-5.41], high grade serous histology [HR 1.69; 95% CI 1.12-2.54] and sub-optimal debulking [HR 3.15, 95% CI 2.19-4.55]. There were 78 known deaths (24.2 %) with a mean time to death of 24.3 (SD 16.1) months. The independent risk factors for death were sub-optimal debulking [HR 3.07; 95% CI 1.78-5.29] and stages III and IV cancer [HR 3.07; 95% CI 1.14-8.27]. Most ovarian cancers recur within 2 years. Risk factors for mortality are advanced stage and sub-optimal debulking. Maximal efforts at down staging and surgical resection will increase survival.

Role of Serine arginine protein kinase 1 and Minichromosome maintenance protein 2 in predicting epithelial ovarian cancer response to treatment and prognosis.

Serine-Arginine (SR) proteins are a conserved family of proteins involved in RNA splicing and are reported to be over-expressed in multiple cancers. The aim of the study is evaluation of the expression of Serine arginine protein kinase 1 (SRPK1) and Minichromosome maintenance protein 2 (MCM2) in epithelial ovarian cancer (EOC) and their correlation with clinicopathological features, response to therapy, progression-free survival (PFS), and cancer-specific survival (CSS). This study was carried out on surgical specimens of 65 patients diagnosed with EOC which were submitted to immunohistochemical staining by SRPK1 and MCM2 antibodies. About 89.2% of cases showed SRPK1 expression and its high expression was significantly associated with type II tumors and advanced stage. All cases showed nuclear immunoreaction for MCM2 with high expression in 49.2% of cases. There was a significant relationship between high values of SRPK1 H-score and percentage of MCM2. Postmenopause, type II pathology, advanced stage, absence of complete response to the treatment, resistance to platinum-based chemotherapy, and surgery done by a general surgeon were the factors affecting PFS. Response to treatment and platinum sensitivity were the most independent factors affecting patients' PFS. The factors associated with shorter CSS were suboptimal debulking, advanced stage, absence of complete response to the treatment, platinum resistance, and high SRPK1. High SRPK1 expression and platinum sensitivity were the independent factors affecting patients' CSS. SRPK1 is an unfavorable biomarker in EOC patients because of its association with aggressive histologic type, advanced International Federation of Gynecology and Obstetrics (FIGO) stage, and worse survival. SRPK1 could promote the proliferation of EOC by up-regulation of MCM2.

Impact of supradiaphragmatic lymphadenectomy on the survival of patients in stage IVB ovarian cancer with thoracic lymph node metastasis.

To evaluate the survival impact of supradiaphragmatic lymphadenectomy as part of debulking surgery in stage IVB ovarian cancer with thoracic lymph node metastasis (LNM). We retrospectively enrolled patients diagnosed with stage IVB ovarian, fallopian or primary peritoneal cancer between 2010 and 2020, carrying cardiophrenic, parasternal, anterior mediastinal or supraclavicular lymph nodes ≥5 mm on axial chest computed tomography. All tumors were classified into the abdominal (abdominal tumors and cardiophrenic lymph nodes) and supradiaphragmatic (parasternal, anterior mediastinal or supraclavicular lymph nodes) categories depending on the area involved. Residual tumors were classified into <5 vs ≥5 mm in the abdominal and supradiaphragmatic areas. Based on the site of recurrence, they were divided into abdominal, supradiaphragmatic and other areas. A total of 120 patients underwent primary debulking surgery (PDS, n=68) and interval debulking surgery after neoadjuvant chemotherapy (IDS/NAC, n=53). Residual tumors in the supradiaphragmatic area ≥5 mm adversely affected progression-free survival (PFS) and overall survival (OS) with marginal significance after PDS despite the lack of effect on survival after IDS/NAC (adjusted hazard ratios [HRs], 6.478 and 6.370; 95% confidence intervals [CIs], 2.224-18.864 and 0.953-42.598). Further, the size of residual tumors in the abdominal area measuring ≥5 mm diminished OS after IDS/NAC (adjusted HR, 9.330; 95% CIs, 1.386-62.800). Supradiaphragmatic lymphadenectomy during PDS may improve survival in patients diagnosed with stage IVB ovarian cancer manifesting thoracic LNM. Further, suboptimal debulking surgery in the abdominal area may be associated with poor OS after IDS/NAC. ClinicalTrials.gov (NCT05005650; https://clinicaltrials.gov/ct2/show/NCT05005650; first registration, 13/08/2021).Research Registry (Research Registry UIN, researchregistry7366; https://www.researchregistry.com/browse-the-registry#home/?view_2_search=researchregistry7366&view_2_page=1).

ACCURACY OF CANCER ANTIGEN 125 AND ALBUMIN BEFORE OPERATION TO PREDICT THE OPERATION OUTCOME IN PATIENTS WITH ADVANCED STAGE EPITHELIAL TYPE OVARIAN CANCER

Ovarian cancer is a malignancy that grows and develops in the ovaries with a high mortality rate. Primary debulking surgery (P.D.S.) is diagnostic and therapeutic and has become the standard option. CA-125 levels were increasing with the worsening disease conditions in ovarian cancer. In addition, preoperative albumin levels were strongly associated with worse ovarian cancer outcomes. This study assessed the prediction of CA-125 markers and albumin levels on P.D.S. outcomes. This research is a diagnostic test conducted at Prof. Dr I.G.N.G. Ngoerah Hospital. The study sample consisted of 50 women aged 18 and over who underwent P.D.S. from 2018 to 2020 with P.A. results of advanced stage (III-IV) epithelial-type ovarian cancer. CA-125 and albumin levels were assessed before surgery and compared with the findings of P.D.S., which were grouped into suboptimal debulking and optimal debulking. There were no significant differences in the characteristics of the two groups. The accuracy of CA-125 levels on the outcome of P.D.S. surgery with a sensitivity of 75.6%, specificity of 55.6%, PPV of 88.6%, N.P.V. of 35.3% and accuracy of 72%. While the accuracy of albumin levels on the outcome of P.D.S. surgery with a sensitivity of 55.6%, specificity of 51.2%, PPV of 20%, N.P.V. of 84% and accuracy of 52%. CA-125 levels were higher in the suboptimal group but not statistically significant, but the sensitivity (70%) and specificity (80%) were still high, so they still have diagnostic value for ovarian cancer. The relationship between albumin levels and ovarian cancer is multifactorial, so it cannot be used to predict surgical outcomes

The Prognostic Value of Cancer Stem Cell Markers (CSCs) Expression-ALDH1A1, CD133, CD44-For Survival and Long-Term Follow-Up of Ovarian Cancer Patients.

Recurrent disease and treatment-associated chemoresistance are the two main factors accounting for poor clinical outcomes of ovarian cancer (OC) patients. Both can be associated with cancer stem cells (CSCs), which contribute to cancer formation, progression, chemoresistance, and recurrence. Hence, this study investigated whether the expression of known CSC-associated markers ALDH1A, CD44, and CD133 may predict OC patient prognosis. We analyzed their expression in primary epithelial ovarian cancer (EOC) patients using immunohistochemistry and related them to clinicopathological data, including overall survival (OS) and progression-free survival (PFS). Expression of ALDH1A1 was detected in 32%, CD133 in 28%, and CD44 in 33% of cases. While Kaplan-Meier analysis revealed no association of the expression of CD133 and CD44 with PFS and OS, ALDH1A1-positive patients were characterized with both significantly shorter OS (p = 0.00022) and PFS (p = 0.027). Multivariate analysis demonstrated that the expression of ALDH1A1, FIGO stage III-IV, and residual disease after suboptimal debulking or neoadjuvant chemotherapy correlated with shorter OS. The results of this study identify ALDH1A1 as a potential independent prognostic factor of shorter OS and PFS in EOC patients. Therefore, targeting ALDH1A1-positive cancer cells may be a promising therapeutic strategy to influence the disease course and treatment response.

A prediction nomogram for suboptimal debulking surgery in patients with serous ovarian carcinoma based on MRI T1 dual-echo imaging and diffusion-weighted imaging

BackgroundSerous ovarian carcinoma (SOC) has the highest morbidity and mortality among ovarian carcinoma. Accurate identification of the probability of suboptimal debulking surgery (SDS) is critical. This study aimed to develop a preoperative prediction nomogram of SDS for patients with SOC.MethodsA prediction model was established including 205 patients of SOC from institution A, and 45 patients from institution B were enrolled for external validation. Multivariate logistic regression was used to screen independent predictors and establish a nomogram to predict the occurrence of SDS.ResultsMultivariate logistic regression demonstrated that the CA-125 level (odds ratio [OR] 8.260, 95% confidence interval [CI] 2.003–43.372), relationship between the sigmoid colon/rectum and ovarian mass (OR 28.701, 95% CI 4.561–286.070), diaphragmatic metastasis (OR 12.369, 95% CI 1.675–274.063), and FIGO stage (OR 32.990, 95% CI 6.623–274.509) were independent predictors for SDS. The area under the curve, concordance index, and 95% CI of the nomogram constructed from the above four factors were 0.951, 0.934, and 0.919–0.982, respectively. The model showed a good fit by the Hosmer–Lemeshow test (training set, p = 0.2475; internal validation set, p = 0.2355; external validation set, p = 0.2707). The external validation proved the reliability of the prediction nomogram. The calibration curve was close to the ideal diagonal line. The decision curve analysis demonstrated a significantly better net benefit. The clinical impact curve indicated good effectiveness in clinical application.ConclusionA prediction nomogram for SDS in patients with SOC provides gynecologists with an accurate and effective tool for appropriate management.

Overall Survival and Related Factors of Advanced-stage Epithelial Ovarian Cancer Patients Underwent Debulking Surgery in Jakarta, Indonesia: A Single-center Experience

AIM: The worrisome prognosis of advanced-stage epithelial ovarian cancer (EOC) needs a new perspective from developing countries. Thus, we attempted to study the 5-year overall survival (OS) of advanced-stage EOC patients who underwent debulking surgery in an Indonesian tertiary hospital. METHODS: A retrospective study recruited forty-eight subjects between 2013 and 2015. We conducted multiple logistic regression analyses to predict risk factors leading to unwanted disease outcomes. The OS was evaluated through the Kaplan–Meier curve and Log-rank test. Cox proportional hazards regression examined prognostic factors of patients. RESULTS: Prominent characteristics of our patients were middle age (mean: 51.9 ± 8.9 years), obese, with normal menarche onset, multiparous, not using contraception, premenopausal, with serous EOC, and FIGO stage IIIC. The subjects mainly underwent primary debulking surgery (66.8%), with 47.9% of all individuals acquiring optimal results, 77.1% of patients treated had the residual disease (RD), and 52.1% got adjuvant chemotherapy. The risk factor for serous EOC was menopause (odds ratio [OR] = 4.82). The predictors of suboptimal surgery were serous EOC (OR = 8.25) and FIGO stage IV (OR = 11.13). The different OS and median survival were observed exclusively in RD, making it an independent prognostic factor (hazard ratio = 3.50). 5-year A five year OS and median survival for patients with advanced-stage EOC who underwent debulking surgery was 37.5% and 32 months, respectively. Optimal versus suboptimal debulking surgery yielded OS 43.5% versus 32% and median survival of 39 versus 29 months. Both optimal and suboptimal debulking surgery followed with chemotherapy demonstrated an OS 40% lower than those not administered (46.2% and 20%, respectively). The highest 5-year OS was in serous EOC (50%). Meanwhile, the most extended median survival was with mucinous EOC (45 months). CONCLUSION: Chemotherapy following optimal and suboptimal debulking surgery has the best OS among approaches researched in this study. RD is a significant prognostic factor among advanced-stage EOC. Suboptimal surgery outcomes can be predicted by stage and histological subtype.

TRNAGlyGCC-Derived Internal Fragment (i-tRF-GlyGCC) in Ovarian Cancer Treatment Outcome and Progression.

Simple SummaryIn the precision medicine era, epithelial ovarian cancer (EOC) is characterized by a high death-to-incidence rate and poor 5-year survival. The identification of novel molecular markers is of utmost importance to guide personalized prognosis. The objective of the present study has been to evaluate, for the first time, the prognostic utility of tRNA-derived fragments (tRFs) in ovarian carcinomas. In this context, we have performed in silico analysis and expression profiling, utilizing a TCGA-OV database, GEO datasets and our two institutionally-independent cohorts. The analysis highlighted the internal tRF derived from tRNAGlyGCC (i-tRF-GlyGCC) as a novel molecular predictor of EOC prognosis. More precisely, elevated i-tRF-GlyGCC levels were correlated with an aggressive phenotype of ovarian tumor and linked to adverse survival outcomes and early progression following debulking surgery and platinum-based chemotherapy. Interestingly, i-tRF-GlyGCC integration in multivariate strategies benefits prognostication and achieves superior patient risk-stratification, supporting precision medicine decisions.Epithelial ovarian cancer (EOC) remains a highly-lethal gynecological malignancy, characterized by frequent recurrence, chemotherapy resistance and poor 5-year survival. Identifying novel predictive molecular markers remains an overdue challenge in the disease’s clinical management. Herein, in silico analysis of TCGA-OV highlighted the tRNA-derived internal fragment (i-tRF-GlyGCC) among the most abundant tRFs in ovarian tumors, while target prediction and gene ontology (GO) enrichment analysis predicted its implication in key biological processes. Thereafter, i-tRF-GlyGCC levels were quantified in a screening EOC (n = 98) and an institutionally-independent serous ovarian cancer (SOC) validation cohort (n = 100, OVCAD multicenter study). Disease progression and patient death were used as clinical endpoints for the survival analysis. Internal validation was performed by bootstrap analysis and the clinical net benefit was estimated by decision curve analysis. The analysis highlighted the significant association of i-tRF-GlyGCC with advanced FIGO stages, suboptimal debulking and most importantly, with early progression and poor overall survival of EOC patients. The OVCAD validation cohort corroborated the unfavorable predictive value of i-tRF-GlyGCC in EOC. Ultimately, evaluation of i-tRF-GlyGCC with the established/clinically used prognostic markers offered superior patient risk-stratification and enhanced clinical benefit in EOC prognosis. In conclusion, i-tRF-GlyGCC assessment could aid towards personalized prognosis and support precision medicine decisions in EOC.

Evaluation of circulating Dickkopf-1 as a prognostic biomarker in ovarian cancer patients.

Dickkopf-1 (DKK1) is a secreted protein, known for suppressing the differentiation and activity of bone-building osteoblasts by acting as an inhibitor of Wnt-signalling. Soluble DKK1 (sDKK1) has been proposed as prognostic biomarker for a wide range of malignancies, however, clinical relevance of sDKK1 as potential blood-based marker for ovarian cancer is unknown. sDKK1 levels were quantified in a cohort of 150 clinically documented ovarian cancer patients by a commercially available DKK1 ELISA (Biomedica, Vienna, Austria). Median sDKK1 level was significantly elevated at primary diagnosis of ovarian cancer compared to healthy controls (estimated difference (ED) of 7.75ng/mL (95% CI: 3.01-12.30ng/mL, p=0.001)). Higher levels of sDKK1 at diagnosis indicated an increased volume of intraoperative malignant ascites (ED 7.08pmol/L, 95% CI: 1.46-13.05, p=0.02) and predicted suboptimal debulking surgery (ED 6.88pmol/L, 95% CI: 1.73-11.87, p=0.01). sDKK1 did not correlate with CA125 and higher sDKK1 levels predicted a higher risk of recurrence and poor survival (PFS: HR=0.507, 95% CI: 0.317-0.809; p=0.004; OS: HR=0.561, 95% CI: 0.320-0.986; p=0.044). Prognostic relevance of sDKK1 was partly sustained in wtBRCA patients (PFS: HR=0.507, 95% CI: 0.317-0.809; p=0.004). This is the first study demonstrating the prognostic relevance of sDKK1 in ovarian cancer patients, including those with wtBRCA1/2 status. Our data encourage further evaluation of sDKK1 in ovarian cancer patients, possibly in terms of a therapy monitoring marker or a response predictor for sDKK1-directed targeted therapies.

The Impact of Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios in Epithelial Ovarian Cancer

OBJECTIVE: This study aims to investigate the prognostic value of the preoperative neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in patients with epithelial ovarian cancer. STUDY DESIGN: Between January 2012 and December 2018, the data and preoperative levels of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio of 116 epithelial ovarian cancer patients were retrospectively collected. The association of these relevant markers with outcomes was analyzed. RESULTS: The difference was observed concerning optimal and suboptimal debulking in platelet-to-lymphocyte ratio ratios (p=0.04). Lymphovascular space involvement was significantly associated with higher platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio ratios (p&lt;0.0001). Patients with ascites and lymph node involvement had a higher platelet-to-lymphocyte ratio ratio (p=0.007 and p=0.004). In recurrences, higher ratios of platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio were observed (p=0.03 and p=0.02). The analysis revealed that platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio were not independent prognostic factors for recurrence (p=0.783 and p=0.391). Regarding mortality, platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio were not independently prognostic (p=0.621 and p=0.830). It was determined that neutrophil-to-lymphocyte ratio &gt;2.45 (HR 0.714, CI 0.622-0.794, p&lt;0.0001) and platelet-to-lymphocyte ratio &gt;179.4 (HR 0.736, CI 0.646-0.814, p&lt;0.0001) could predict the presence of recurrence with a certain sensitivity and specificity, and for predicting the death, a neutrophil-to-lymphocyte ratio of &gt;2.45 had a sensitivity of 78.26% (95% CI: 56.3 to 92.5%) and a specificity of 54.84% (95%CI: 44.2 - 65.2) (p=0.03). CONCLUSION: The evaluation of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio is important in obtaining prognostic information before surgery. However, no significant association between the neutrophil-to-lymphocyte ratio or platelet-to-lymphocyte ratio with survival was identified.

Intrinsic STING expression inversely associates with survival in ovarian cancer patients

<h3>Objectives:</h3> The DNA sensing cGAS-STING signaling pathway plays a dual role of anti-tumor immunity and tumorigenesis. Chemoradiotherapy and PARPi induce DNA damage leading to activation of the cGAS-STING pathway, robust anti-tumor responses and improved clinical outcomes. Chronic activation of STING signaling creates an immunosuppressive TME and promotes metastases. Studies show that ovarian cancer cells have defective STING signaling. Current therapeutic strategies are focused on harnessing the beneficial effects of PARPi, IC blockade and STING agonists. However, the role for intrinsic ovarian tumor cGAS-STING levels in treatment responses and patient survival is unknown. The goal of this study is to determine the effect of tumor-specific cGAS-STING expression on survival in ovarian cancer patients. <h3>Methods:</h3> Using the Roswell Park Cancer Registry (RPCR), TMAs were generated from 488 patients treated for ovarian, fallopian tube or primary peritoneal cancer from 1991-2012. TMAs were stained for cGAS, STING and CD8 by IHC. cGAS and STING were scored based on the staining intensity (0-3) and the percent of positive cells (0-3) with a maximum combined score of 6 (0=no expression, 6=strong staining in >50% of cells). Additionally, the OS, PFS and cGAS-STING expression in 558 ovarian cancer patients from TCGA were analyzed. Clinico-pathologic data (age, demographics, histopathology, stage, tumor grade, treatment response, recurrence and survival) were retrieved from the electronic health records. <h3>Results:</h3> TCGA ovarian cancer patients with tumors expressing cGAShighSTINGhigh compared to cGASlowSTINGlow had OS of 38.4 months vs. 31.18 months (p=0.05). There was a significant positive correlation between gene and protein expression for cGAS (r=0.39, p=0.01) and STING (r=0.62, p<0.0001). Of the 488 patients in the RPCR, 95.3% were Caucasian with a median age at diagnosis of 63 years (range 20-93) and a median follow up of 44 months (range 0-279). The majority were diagnosed at an advanced surgical stage (68% and 14% at stage III and IV respectively), serous histology in 72% and high grade in 90.6% of cases. 72% received optimal and 27% had suboptimal debulking surgery. All patients received adjuvant platinum and taxane chemotherapy and the initial recurrence rate was 52%. In addition, 42.2% were platinum sensitive, 30% were refractory and 18% were platinum resistant. During the first 60 months of follow up, there was a trend toward improved OS and PFS in patients with cGASlowSTINGlow compared to cGAShighSTINGhigh tumors. Independently, cGAS did not associate with OS or PFS. Interestingly, STING high tumors correlated positively with CD8+ TILs (r=0.05, p=0.0002) but associated with decreased PFS (p=0.016). <h3>Conclusions:</h3> TCGA dataset revealed cGAShighSTINGhigh expressing tumors correlated with improved OS. By contrast, high grade ovarian tumors with intrinsically high levels of STING correlate with increased CD8+ TILs and decreased PFS.

Cytoreduction status and platinum sensitivity in women with recurrent ovarian cancer

<h3>Objectives:</h3> Neoadjuvant chemotherapy (NACT) and interval cytoreduction (IDS) is an increasingly used treatment modality for women with advanced ovarian cancer not amenable to primary cytoreduction. Clinical trials have demonstrated decreased perioperative morbidity and mortality with similar overall survival (OS) with NACT-IDS. However, controversy regarding initial management is ongoing. This study aims to determine the association between cytoreduction status and time to second recurrence (TTSR) in women with ovarian cancer treated with NACT-IDS; and explore associations between platinum sensitivity, <i>BRCA1/2</i> status, homologous recombination deficiency (HRD), and TTSR. <h3>Methods:</h3> Women diagnosed with advanced ovarian, tubal, and peritoneal cancer who received NACT-IDS from 2000-2020 were included. Patients were enrolled in a prospective NACT database from 9/2013. Demographics and cancer-specific data, including germline/somatic <i>BRCA1/2</i> status; HRD status defined based on genomic instability scoring; platinum sensitivity (sensitive [PS]/resistant [PR]) at first and second recurrences; TTSR, and survival were abstracted from medical records. Residual disease after cytoreduction was classified as optimal (<1cm residual) or suboptimal (>1 cm) as R0 was not consistently reported. Kaplan Meier (KM) curves and log-rank tests were used to estimate TTSR based on cytoreduction status and platinum sensitivity. Patients achieving complete remission were included in the PS cohort. <h3>Results:</h3> 187 women were included in the study, the majority had optimal cytoreductive surgery (81.8%). Overall, 39.6% (74/187) of patients did not have germline/somatic testing. Of those tested, 30.9% (35/113) had ≥1 positive test (18 germline <i>BRCA,</i> 8 somatic <i>BRCA,</i> 9 HRD). Women with optimal cytoreduction experienced a longer median TTSR or death compared to those who underwent suboptimal debulking (24.2 vs 15.6 months; p<0.001). Though not statistically significant, median TTSR or death in women with suboptimal cytoreduction and PS disease at first recurrence was 26.7 months vs 16.5 months for those with optimal cytoreduction and PR disease at first recurrence (p=0.055). Women with <i>BRCA1/2</i> mutation or HRD had no difference in odds of optimal debulking (p=0.34) or TTSR (p=0.07) compared to those without <i>BRCA</i> mutations or HRD, though sample size was limited by patients with incomplete or no <i>BRCA</i> testing. There was a significant difference in survival and TTSR by cytoreductive status and platinum sensitivity (p<0.001). In pairwise tests, the difference between OC+PS vs OC+PR (p<0.0001), OC+PS vs SC+PR (p<0.0001), SC+PS vs SC+PR (p=0.02) were significant. <h3>Conclusions:</h3> Platinum sensitivity at first recurrence may have a greater association with survival than cytoreductive status for women receiving NACT for advanced ovarian cancer. Cytoreductive status is associated with TTSR. Genetic evaluation has evolved into critical knowledge in the care of these patients; further analysis is warranted to define the association between genetic mutational burden, TTSR, and OS to individualize adjuvant therapy.

Treatment-resistant Hypercalcemia from Ectopic PTH Hypersecretion Suspected Secondary to Disseminated Ovarian Cancer

Hypercalcemia of malignancy (HCM) can present secondary to hypersecretion of parathyroid hormone (PTH)-related protein (PTHrP) from malignant tumors, but rare cases of HCM have also been documented due to inappropriate PTH secretion from ectopic neoplasms. Here, we report an unusual case of HCM due to hypersecretion of PTH suspected secondary to a disseminated mucinous ovarian adenocarcinoma. A 45-year-old female presented with severe hypercalcemia and significant elevations in both PTH and PTHrP two weeks after total abdominal hysterectomy with bilateral salpingo-oophorectomy and suboptimal debulking of a newly discovered left ovarian mucinous adenocarcinoma with numerous metastases. Ectopic PTH secretion was highly suspected after a negative parathyroid ultrasound. Pamidronate, calcitonin, and fluid resuscitation were unable to normalize her serum calcium, resulting in the need for dialysis and subsequent continuous renal replacement therapy. Further intervention with denosumab, etelcalcetide, and cinacalcet was attempted. Serum calcium began to decline, but repeat PTH resulted greater than 2,500 pg/mL. Unfortunately, the patient died just one week into her hospital course from septic shock and multi-organ system failure. While patients with localized PTH-secreting tumors carry a good prognosis, disseminated malignancies can result in significant morbidity and mortality due to severe treatment-resistant hypercalcemia.

Treatment-Resistant Hypercalcemia Secondary to Ectopic PTH Hypersecretion From Disseminated Ovarian Cancer

Background: Hypercalcemia of malignancy (HCM) can present secondary to hypersecretion of parathyroid hormone (PTH)-related protein (PTHrP) from malignant tumors, but rare cases of HCM have also been documented due to inappropriate PTH secretion from ectopic neoplasms. Here, we report an unusual case of HCM due to hypersecretion of PTH from a disseminated mucinous ovarian adenocarcinoma. Case Presentation: A 45-year-old female presented with confusion, constipation, fatigue, and abdominal pain two weeks after total abdominal hysterectomy with bilateral salpingo-oophorectomy and suboptimal debulking of a newly discovered left ovarian mucinous adenocarcinoma with metastasis to the bladder, parametrium, vagina, right ovary, and rectosigmoid. Subsequent CT revealed numerous bilateral pulmonary nodules, hilar adenopathy, liver lesions, and abdominal adenopathy. On exam, she was tachycardic and hypertensive with diaphoresis, dry mucous membranes, respiratory distress, guarded abdominal tenderness, and altered mental status. Her labs were significant for a serum calcium of 21.7 mg/dL, creatinine of 1.93 mg/dL, ferritin of 2,379 ng/mL, leukocytosis of 21.9 bil/L, PTH of 1,061 pg/mL, and PTHrP of 29 pmol/L. Ectopic PTH secretion was highly suspected after negative parathyroid ultrasound. Pamidronate (60 mg IV), calcitonin (200 U IM), and fluid resuscitation were unable to normalize her serum calcium, resulting in the need for dialysis and subsequent continuous renal replacement therapy. Further intervention with denosumab (120 mg SQ), etelcalcetide (5 mg IV), and cinacalcet (60 mg PO) was also attempted. Serum calcium began to decline, but repeat PTH resulted greater than 2,500 pg/mL. Unfortunately, the patient died just one week into her hospital course from septic shock and multi-organ system failure. Discussion: Hypercalcemia of malignancy typically arises from tumor secretion of PTHrP, cytokine release from osteolytic metastases, or tumor production of calcitriol. In cases of hypercalcemia due to excess PTH secretion, primary parathyroid etiologies are typically considered while ectopic PTH-secreting tumors are rare. PTH staining of biopsy specimens and total body sestamibi scan may prove useful in the early detection and treatment of these tumors, but HCM offers a poor prognosis with mean survival of 2 to 3 months and in-hospital mortality of 6.8%. Currently, there are only three cases in the reported literature of ectopic PTH-induced hypercalcemia related to ovarian cancer. To our knowledge, this is the fourth reported case. Conclusion: Ectopic PTH-secreting tumors carry a poor prognosis and should be considered in cancer patients presenting with PTH-associated hypercalcemia. Biopsy staining for PTH and total body sestamibi scan may assist in the early detection of these tumors, but current treatment strategies offer suboptimal outcomes.