bluuebunny/crossref_metadata_2025_split huggingface dataset:
Homologous recombination deficiency associated with response to poly (ADP-ribose) polymerase inhibitors in ovarian cancer patients: The first real-word data from China.
Authors: Chen Xiaoxiang , Ni Jing , Xu Xia , Guo Wenwen , Cheng Xianzhong , Zhao Qian , Zhou Rui , Gu Hongyuan , Chen Chen 
Published: June 2021

e17543 Background: Homologous recombination deficiency (HRD) is the first phenotypically defined predictive biomarker for Poly (ADP-ribose) polymerase inhibitors (PARPi) in ovarian cancer. However, the proportion of HRD positive in real world and the relationship of HRD status with PARPi in Chinese ovarian cancer patients remains unknown. Methods: A total of sixty-four ovarian cancer patients underwent PARPi, both Olaparib and Niraparib, were enrolled from August 2018 to January 2021 in Jiangsu Institute of Cancer Hospital. HRD score which was the sum of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI) and large-scale state transitions (LST) events were calculated using tumor DNA-based next generation sequencing (NGS) assays. HRD-positive was defined by either BRCA1/2 pathogenic or likely pathogenic mutation or HRD score ≥42. Progression-free survival (PFS) was analyzed with a log-rank test using HRD status and summarized using Kaplan-Meier methodology. Univariate and multiple cox-regression analysis were conducted to investigate all possible clinical factors. Results: 71.9% (46/64) patients were HRD positive and the rest 28.1% (18/64) were HRD negative, which was higher than the HRD positive proportion reported in Western countries. The PFS among HRD positive patients was significantly longer than those HRD negative patients (medium PFS 8.9 m vs 3.6 m, hazard ratio [HR]: 0.22, p < 0.001). Among them, 23 patients who were BRCA wild type but HRD positive had longer PFS than those with BRCA wild type and HRD negative (medium PFS 9.2 m vs 3.6 m, HR: 0.20, p < 0.001). Univariate cox-regression analysis found that HRD status, previous treatment lines, secondary cytoreductive surgery (SCS) were significantly associated with PFS after PARPi treatment. After multiple regression correction, HRD status (HR: 0.39, 95% CI: [0.20-0.76], p = 0.006), ECOG score (HR: 2.53, 95% CI: [1.24-5.17], p = 0.011) and SCS (HR: 2.21, 95% CI: [1.09-4.48], p = 0.028) were the independent factors. Subgroup analysis in ECOG = 0 subgroup (N = 36), HRD positive patients had significant longer PFS than HRD negative patients (medium PFS 10.3 m vs 5.8 m, HR: 0.14, p < 0.001). Also in the subgroup of patients without SCS, PFS in patients with HRD was longer than patients without HRD (medium PFS 10.2 m vs 5.7 m, HR: 0.29, p = 0.003). Conclusions: This is the first real-world data of HRD status in ovarian cancer patients from China and demonstrate that HRD is a valid biomarker for PARP inhibitors in Chinese ovarian cancer patients.
Is age-related worsening in ovarian cancer prognosis linked to changes in body composition and pharmacokinetics?
Authors: Extermann Martine , Walko Christine Marie , Mishra Asmita , Thomas Kerry , Cao Biwei , Chon Hye Sook , Cristea Mihaela C. , Shahzad Mian M. , Chern Jing-Yi , Hoffman Mitchell S , Kim Jongphil , Marchion Douglas C. , Sansil Samer , Sehovic Marina 
Published: June 2021

e17553 Background: The prognosis of ovarian cancer worsens markedly with age. Yet few data are available to explain this phenomenon. Two hypotheses can be made. Changes in pharmacokinetics and treatment tolerance limit the dosing of chemotherapy. And/or changes in tumor and host-tumor biology limit treatment efficacy. Methods: We conducted a prospective cohort study of women with stage III/IV high-grade serous ovarian cancers treated with neoadjuvant intravenous carboplatin(C) AUC 5 every 3 weeks and paclitaxel(P) dosed either weekly at 80 mg/m2 or every 3 weeks at 175 mg/m2. Body composition was assessed using baseline CT scans at the L3 level. Total muscle mass, total fat mass, skeletal muscle index (SMI) and fat index were computed. Plasma concentrations were collected at pre-established time points for both C1D1 of C and P and concentration-time data was analyzed by non-compartmental methods. Area under the curve (AUC)0-INF, volume of distribution(Vd), clearance (Cl), half-life, and mean residence time were calculated. Free C concentrations were determined in plasma ultrafiltrate and assayed, along with P plasma concentrations, by liquid chromatography-tandem mass spectrometry. Toxicity was assessed as first cycle nadir ANC and G4 hematologic(H) or grade 3-4 non-hematologic(NH) toxicity by CTCAE 4.0 criteria over a 3 cycles follow-up. The correlation between continuous measures was assessed by Spearman correlation coefficient, and the association with toxicity was evaluated by Wilcoxon rank sum test. Results: Seventeen patients, ages 38 to 86 (median 61) were eligible. All patients but one received 3 cycles of chemotherapy and median dose intensity was 100% (range 33.3-100%). Mean 1st cycle nadir ANC was 1.29 (range 0.06-9.0). 10/17 (59%) patients experienced G4 H and/or G3-4 NH toxicity. SMI was associated with C AUC (r -0.50, p < 0.05), and both total muscle (r = 0.61) and total fat (r = 0.53) were associated with C Vd. We did not find a correlation of P pharmacokinetics with body composition. A lower SMI was associated with 1st cycle G4H toxicity (p = 0.02), while C AUC had a borderline trend only (p = 0.15). Age was associated with a lower Vd (r -0.63, p = 0.009) and Cl (r -0.67, p = 0.004) of C. There was no significant age trend in the body composition parameters. Conclusions: Neoadjuvant treatment delivery was high in an academic setting. Toxicity appeared driven by low skeletal muscle index, in part via affecting carboplatin pharmacokinetics, and showed no significant age trend. The explanation for age-related changes in prognosis is more likely to lay with changes in tumor and host-tumor biology, which are being analyzed.
Retrospective analysis of ovarian cancer patients treated with PARP inhibitors.
Authors: Liang Connie , Leung Ashley , Lee Chung-Shien , Hernandez Jennifer , Cheng Kit , Stefanov Dimitre C. , John Veena S. 
Published: June 2021

e17555 Background: Over the last few years, targeted therapy has become the mainstay maintenance treatment of patients with ovarian cancer including patients with BRCA1 or BRCA2 mutations. Poly ADP ribose polymerase (PARP) inhibitors are effective in the treatment of patients who are in complete or partial remission. PARP inhibitors are known to cause hematological adverse events (AEs), but have not been compared directly to each other. Methods: We conducted a single institution, IRB approved, retrospective study on patients who were treated with PARP inhibitors from December 2016 to October 2020. Patients were stratified according to which PARP inhibitor they received. Our primary objective was to assess the incidence of hematological and non-hematological adverse events associated with the use of PARP inhibitor therapy used in patients with ovarian cancer. Data from absolute neutrophil count, hemoglobin and platelet count during the first 2 cycles were graded for hematologic toxicity according to CTCAE v 5.0. Results: A total of 126 patients received a PARP inhibitor during the study time frame. 34 were excluded and 92 patients were included for analysis. Median age of patients were 64.3 (range, 33.8 to 92.3) years, 66 (71.7%) white, and 84 (91.3%) had an ECOG PS of 0/1. Thirty-one (33.7%) of patients received niraparib and 61 (66.3%) of patients received olaparib. Patients in the niraparib group experienced more hematologic AEs, with 11 (35.5%) (95% CI 19.2-54.6), 20 (64.5%) (95% CI 45.4-80.8), and 18 (58.1%) (95% CI 39.1-75.5) experiencing neutropenia, anemia, thrombocytopenia, respectively. Eight (13.1%) (95% CI 5.8-24.2), 24 (39.3%) (95% CI 27.1-52.7), 16 (26.2%) (95% CI 15.8-39.1) patients in the olaparib group experienced neutropenia, anemia, thrombocytopenia, respectively. Conclusions: This single institution retrospective study outlines the hematological toxicities observed between two PARP inhibitors. Although there are four PARP inhibitors approved by FDA, our data compared only two of the four (as they were the most commonly prescribed PARP inhibitors in our institution). Our results suggested that niraparib tended to be associated with a higher risk for hematologic toxicities than olaparib. Our data showed anemia as the most common hematologic toxicity which was consistent with what has been widely documented in the literature.
Using 3D perfusion bioreactor system to studying cell biology of ovarian cancer.
Authors: Martínez Alba , Buckley Molly , Berry Joel , Arend Rebecca Christian 
Published: June 2021

e17558 Background: Epithelial Ovarian Cancer (EOC) is the most common cause of death among gynecological malignancies. This is a result of the high rate of recurrence and chemo-resistance in EOC patients. Therefore, the development of new therapeutics is crucial. A major factor contributing to this is the lack of therapeutic candidates is lack of translational accuracy in preclinical models. Recently, 3-dimensional (3-D) models have aided in accurately recreating tumor biology. We have developed an EOC 3-D perfused bioreactor system that recapitulates EOC tumor biology and incorporates tumor biomechanical regulation. This model allows for us to more accurately predict the clinical response of new drug candidates, which aids in elimination of ineffective candidates prior to clinical trials. Methods: EOC cell lines (luciferase-taggedSKOV-3 and OVCAR-8) were embedded in a relevant extracellular matrix (ECM) and injected into a perfused, polydimethylsiloxane (PDMS) bioreactor. Microchannels were embedded in matrigel so that the cell culture media with or without chemotherapy could flow through the perfused PDMS to provide nutrient delivery and gas exchange enhancing viability and function of surrounding cells. The bioreactors were connected to a peristaltic pump that allowed for the cell culture media to perfuse over a 7-day period. We monitored cell viability using bioluminescence imaging (BLI), immunohistochemistry (IHC), and lactate dehydrogenase (LDH) release in media. Results: BLI showed a linear increase in SKOV-3 and OVCAR-8 cell growth over 7 days. These results were confirmed by IHC measuring the number of nucleated cells per micron2. Graphical representation of the region of interest (ROI) showed a high correlation between IHC staining of nucleated cells and BLI score. IHC analysis of PAX8 staining was positive and proved that the perfusion bioreactor system maintains EOC biology over time. In addition, our results suggest that the bioreactor is a suitable model for drug preclinical testing in both cell lines as well as in patients’ samples. Conclusions: Our preliminary results using the 3D EOC perfused, PDMS bioreactor model showed increased EOC cell growth overtime, while maintaining original EOC histology. Moreover, our results suggest that this model could provide a novel platform to study therapeutic interventions in EOC. Our ultimate goal is to implement ovarian cancer microenvironment components (e.g. immune cells) into bioreactor system to study different drug treatments to better determine drug candidate’s translational efficacy.
Clinicopathologic characteristics of distinct molecular subtypes of endometrial carcinoma in Chinese population.
Authors: Zhang Qing , Ma Xinyue , Cao Wenyu , Wu Huan , Dong Xiaomeng , Sun Chenggong , Song Kun , Kong Beihua 
Published: June 2021

e17568 Background: Stratifying endometrial carcinoma (EC) based on molecular profiling is of importance. While, spectrum of molecular subtypes of EC in Chinese population needs to be elucidated. Conventional approaches involve methodologies including Sanger sequencing as well as immunohistochemistry which is highly dependent on experience of pathologists. This study is of first time to display clinical and pathological characters of molecular subtypes of EC which were defined by a simplified NGS panel in Chinese population. Methods: Paraffin-embedded tissues of 135 consented EC patients were retrospectively collected from Qilu Hospital, Shandong Province, China. Genomic DNA was extracted and subjected to a simplified panel covering POLE, TP53 as well as 55 MSI loci for massive parallel sequencing. Mutations annotated as Tier I, II were applied for subtyping. MSI was defined as instability in 22 or more microsatellite loci. Subtypes were stratified as POLE, MSI, TP53-wt or TP53-mut group. Correlations of clinicopathological characters as well as prognosis were further conducted. Results: Histology of collected samples were mostly Endometrioid EC (EEC, 93.33%). Most of samples were at stage I (80%). The fractions of POLE (n=10), MSI (n=29), TP53-wt (n=84) and TP53-mut (n=12) group were 7.41%, 21.48%, 62.22%, and 8.89%, respectively. POLE group was associated with earlier stage (Stage I, 90%), EEC (80%) and less lympho-vascular space invasion (LVSI) (10%). TP53-mutant subtype was correlated to later stage (Stage II-IV, 41.67%), higher grade (G2+G3, 83.33%), serous histology (25%) and higher rate of LVSI (25%). The median follow-up was 74 (1.5-122) months. The 8-year overall (OS) and disease-specific survival (DSS) rate were 100% in POLE group, while only 58.3% and 75% in TP53 mutant cases (P<0.001 for OS, P=0.01 for DSS). Conclusions: Molecular subtypes of EC significantly correlated with clinicopathologic characters, especially with patients’ prognosis. This simplified NGS-panel could accurately delineate different EC subgroups.[Table: see text]
A longitudinal study of the adherence to PORTEC-2 based adjuvant radiotherapy in high-intermediate-risk endometrial adenocarcinoma and associated oncologic outcomes.
Authors: Erfani Hadi , Rezaei Atefeh , Costales Anthony 
Published: June 2021

e17570 Background: In 2010, Nout et al. reported on PORTEC-2, which randomized patients with high intermediate risk (HIR) endometrial cancer to adjuvant vaginal brachytherapy or pelvic radiotherapy or observation, and showed that vaginal brachytherapy was non-inferior in terms of locoregional control and was deemed the adjuvant treatment of choice for these patients. We sought to evaluate the adherence to and the oncologic outcomes of the PORTEC-2 regimen. Methods: We utilized the SEER database to identify patients who met PORTEC-2 inclusion criteria. All patients underwent surgery followed by either vaginal brachytherapy (VBT) or whole pelvic radiotherapy (WPRT). Inclusion criteria were patients with the following characteristics: grade 1 with ≥ 50% myometrial invasion (MI), grade 2 with any invasion, and grade 3 with < 50% MI. Patients were excluded if any lymph nodes were examined or involved, if they received any chemotherapy, or had any missing values for any of the variables. HIR endometrial adenocarcinoma was defined as the presence of 2 of the following: age > 60, grade 3, and ≥50% myometrial invasion. Radiation status was extracted from the SEER Radiation/Chemotherapy database. Outcomes were overall death, cancer specific death and total survival months per SEER’s standard definitions. Variables are reported as median and interquartile range (IQR) or number (%). Mean survival was calculated using Kaplan Meier analysis and Mantel-Cox rank test was done to test for statistical significance between the study groups. Cox regression analysis was performed, and hazard ratios (HR) were calculated. Statistical analysis was performed using SPSS v. 22.0. Results: Between 2005- 2015, 571 patients met PORTEC-2 inclusion criteria of whom 349 (61.1%) and 222 (38.9%) received WPRT and VBT, respectively. We showed that the rate of VBT was significantly increased from 85 (27.4%) between 2005-2010 to 137 (52.5%) between 2011-2015 (p < 0.001). There was no difference in grade and myometrial invasion between the study groups. Kaplan Meier analysis showed a 22.5 and 16.3 month improvement in overall and cancer specific survival in subjects who underwent VBT as compared to WPRT, respectively (p < 0.001 for both). Cox regression analysis revealed a 36% and 66% decrease in the hazard of overall and cancer specific death, respectively, in the VBT group as compared to WPRT group (Overall death: HR = 0.64, 95% CI: 0.45-0.91, p = 0.012; Cancer specific death: HR = 0.34, 95% CI: 0.16-0.73, p = 0.006). Conclusions: Administration of vaginal brachytherapy following surgery has become significantly more popular after publication of the PORTEC-2 results in 2010. Our study shows a significant decrease in both overall and cancer related death and an increase in survival with VBT over WPRT in patients with HIR endometrial cancer.
Disparities in adjuvant treatment of high-grade endometrial cancer.
Authors: Corey Logan , Cote Michele L. , Ruterbusch Julie J. , Winer Ira Seth 
Published: June 2021

e17572 Background: To examine surgical outcomes, patterns of adjuvant therapy, and survival for non-Hispanic Black (NHB) women compared to non-Hispanic White (NHW) and Hispanic (HS) women who have undergone surgery for high grade endometrial cancer in the Medicare population. Methods: We utilized the SEER-Medicare linked database to identify women who underwent surgery as a primary treatment for uterine grade 3 endometrioid adenocarcinoma, carcinosarcoma, clear cell carcinoma, or serous carcinoma between the years 2000 and 2015. Multinomial logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for receiving a treatment delay or not receiving adjuvant treatment (compared to those who received adjuvant treatment within 12 weeks) adjusted for clinical and demographic characteristics. Overall survival (OS) stratified by race/ethnicity, route of surgery, operative complications, and type and timing of adjuvant therapy were analyzed using the Kaplan-Meier method. Cox Proportional hazards regression was used to estimate hazard of death by race/ethnicity adjusted for known predictors, as well as surgical outcomes and adjuvant therapy patterns. Results: 12, 201 women met study inclusion criteria. NHB patients had a significantly worse five-year overall survival (OS) than HS and NHW patients (30.9 months vs 51.0 months vs 53.6 months, respectively). Approximately 8.6% of patients who received adjuvant treatment experienced a treatment delay (632/7, 282). Delay in treatment of greater than or equal to 12 weeks was significantly different by race/ethnicity (p=0.034), with 12% of HS, 9% of NHB, and 8% of NHW women experiencing a delay. After adjustment for number of complications, age, histology (endometrioid v. non-endometroid), FIGO stage, marital status, comorbidity count, surgical approach, lymph node dissection, and urban-rural code, HS had a 71% increased risk of treatment delay (OR 1.71, CI 1.23-2.38) for all stages of disease. In the same model, NHB race was independently predictive of decreased use of adjuvant treatment for FIGO stage II and higher (OR 1.32, CI 1.04-1.68). NHB race, number of perioperative complications, and non-endometrioid histology were predictive of worse OS in univariate models. Treatment delay was not independently predictive of worse 1- or 5-year survival at any stage. Conclusions: NHB race is predictive of worse 5-year survival across all stages and is also associated with omission of adjuvant treatment in ≥FIGO Stage II high grade endometrial cancers. HS ethnicity was associated with treatment delay across all stages. In unadjusted analyses, patients who experience treatment omission or delay experienced poorer OS, but these factors were not independently associated in multivariate analyses.
ALDH1 expression in primary and recurrent vulvar carcinoma.
Authors: Abdullaeva Nina M. , Verenikina Ekaterina V. , Zlatnik Elena Yu. , Ulianova Elena P. , Novikova Inna A. , Sagakyants Aleksandr B. , Menshenina Anna P. , Adamyan Meri L. 
Published: June 2021

e17573 Background: Our aim was to evaluate ALDH1 expression as a stem cell marker in primary and recurrence vulvar squamous cell carcinoma. Methods: 27 patients aged 27-80 years with vulvar squamous cell carcinomas, together with their verified histopathological and clinical data were included in the study. All of them underwent treatment the first stage of which was surgery in National Research Centre for Oncology in 2015-2020. In 10 of them I stage of vulvar squamous cell carcinomas was diagnosed, in 13 – II stage, 4 had relapses after complex treatment and 2-10 years` remission. All paraffin-embedded samples of the primary and recurrent vulvar carcinoma were recruited. The presence of ALDH1 was detected by immunohistochemistry using murine monoclonal antibodies to ALDH1 (clone B-5 Santa Cruz Biotechnology) diluted 1:800 and Reveal Polyvalent HRP-DB Detection System. Positively stained cells were counted among all the tumor cells as well as a part of tumors positive for ALDH1 ( > 10% of cells). Statistics analysis was performed by program STATISTICA 13.0 (StatSoftInc., the USА). Results: By immunohistochemical staining, the expression of ALDH1 was observed in 5 patients with I stage of vulvar squamous cell carcinomas, in 5 patients with II stage and in all the patients with recurrence. Mean values of ALDH1 expression in patients with I stage were 14.1±4.3%, in patients with II stage – 16.0±3.6%, in patients with recurrence – 29.6±3.6%. Maximal ALDH1 accumulation was observed in tumor cells of patients with recurrence, it was 1.9 times higher than in the II stage (p = 0.03) and 2.1 times exceeded ones of the I stage (p = 0.027). All the differences were statistically significant according to Student`s t-test (p < 0.05). The was no statistically significant difference between values of the patients with I and II stages (p = 0.738), but it is noteworthy that ALDH1-expressing cells prevailed in tumor stroma especially in II stage. Conclusions: There is some discrepancy in the assessment of ALDH1 prognostic value in vulvar carcinoma patients as well as in understanding if it is related predominantly to cancer stem cells or to normal stem cells either. Our results though obtained on a few cases of vulvar squamous cell carcinomas show that ALDH1 expression in recurrent carcinomas markedly exceeds that in primary tumors and is related to tumor cells while in primary tumors is related rather to stromal cells.