bluuebunny/crossref_metadata_2025 huggingface dataset:
A cross-sectional study of 73,390 women without ovarian cancer and the effect of age and benign gynecological diseases on serum CA125 levels.
Authors: Zhu Chenchen , Jiang Shan , Yao Bei , Chen Liang , Liu Buyun , Liu Hanyuan , Qian Lili , Yan Qianqian , Liu Yi , Peng Cheng , Zhou Ying
Published: June 2023

e17500

Background: As an important tumor marker for follow-up and prognosis of ovarian cancer, CA125 is not suitable as a screening indicator due to its frequent elevation in many physiological or pathological condition, thus women are often puzzled by unaccountably elevated levels of CA125. While we have known that the CA125 level is differed by age and benign gynecological diseases, the specific trend of CA125 level changes is still not clear. We hope that this study will contribute to a more accurate and individual interpretation of CA125 by evaluating the baseline levels of CA125 in healthy women of different ages and analysis the association between benign gynecological diseases and CA125 level. Methods: This was a cross-sectional study enrolled 73390 women without ovarian cancer from January 2016 to December 2021 in three health examination centers. We have assessed the distribution of CA125 levels in different age groups and analyzed the variation trend of CA125 levels by age among women with normal ultrasonic results, as well as performed the correlation analysis between several benign gynecological diseases and CA125 levels. Results: 55422 women with normal ultrasonic results and CA125 level <200U/mL were included in the analysis of variations in CA125 depending on age. We observed CA125 levels were linearly associated with age (R2=0.0503, p<0.0001). Using the group <30 years as a baseline, average CA125 levels decreased by 3.4%, 10.1%, 42.6%, 40.5%, 31.8%, and 20.3% by every 10 years. With the increase of age, the downward trend of CA125 began to reverse at the age of 60, and it showed significantly difference between each adjacent subgroup (p<0.05). 8630 women were selected with abnormal ultrasonic results, we observed that CA125 was lower in women with uterine effusion, higher in endometrial hyperplasia, endometrial polyps, hydrosalpinx, ovarian cyst, adenomyosis and uterine fibroids. Age and all those diseases demonstrated possible associations (p<0.05) with CA125 levels ≥35U/ml in univariable logistic regressions. Multivariable analysis identified that ovarian cyst (p<0.001), adenomyosis (p<0.001) and uterine fibroids (p=0.018) were still significantly associated with abnormal CA125 level. Conclusions: With the increase of age, CA125 level generally showed a downward trend, but there is a slight increase in CA125 after age 60. Ovarian cyst, adenomyosis and uterine fibroids demonstrated significant associations with abnormal CA125 level. [Table: see text]
The combination of APR-246 and carboplatin in olaparib-resistant high grade serous ovarian cancer (HGSOC) and triple negative breast cancer (TNBC) cell lines.
Authors: Perez-Fidalgo Jose Alejandro , Martinez Pretel Juan Jose , Sanchez Serrano Paloma , Heredia Victoria , Mendiola Marta , Redondo Andres , Gonzalez Villena Lidia , Ruiz Linuesa Miriam , Pineda Begona
Published: June 2023

e17504

Background: PARP inhibitors (PARPi), as Olaparib (OLA), have changed the therapeutic landscape in HGSOC and TNBC. However, most patients will develop resistance to PARPi. Although resistance mechanisms are poorly understood, it is suggested that BRCA mutations reversions or cell cycle alterations could be involved. APR-246 is a new targeted agent that restores p53 in TP53-mutated cells. The aim of our study was to assess the potential synergism of the combination of carboplatin (carbo) plus APR-246 in both OLA-sensitive and OLA-resistant HGSOC and TNBC cell lines. Methods: We selected two HGSOC (PEO1-S and Kuramochi-S) and one TNBC TP53 mutant cell lines (MDA-MB-231-S). Resistance to OLA was generated by pulse doses with IC75 OLA for 24 hours and recovered for two weeks during a period of 6 months (PEO1-R) and to increased concentrations of OLA for 72 hours during a period of 1 year (Kuramochi-R, MDA-MB-231-R). Next-generation sequencing was performed in order to assess mutations. IC50 of APR-246 and Carbo and the combination of both (combo) were calculated for Kura-S/R, PEO1-S/R and 231-S/R cell lines. Synergism between both drugs was assessed with Chou-Talalay method for combination index (CI) at Fa50. DNA damage was assessed by gamma-H2AX expression by western-blot (WB). Results: 231-S harboured a TP53 mutation (mut) (missense R280K) and BRCA wildtype (wt), in PEO1-S BRCA2 mut p.Y1655* and TP53 mut was detectable. Kuramochi-S was TP53 mut (missense D816Y) and BRCA2 mut. BRCA and p53 mutation remained unchanged in the resistant lines generated.The mutation profile of each line and the IC50 of APR-246, carbo and combo are shown in the table. IC50 of carboplatin is superior in all 3 resistant cell lines when compared to their sensitive parental line, suggesting a potential cross-resistance to platinum in OLA-resistance. The combination of carbo and APR-246 is synergistic even in OLA-resistant cell lines, in fact in those cross-resistant lines values of synergism by Chou-Talalay are improved by the combo suggesting a potential role of this combination in PARPi resistant cell lines. WB showed an increased DNA damage with the combo when compared to either single agent, with an increase in H2AX in all lines either sensitive or resistant. Conclusions: The combination of APR246 and carboplatin is synergistic in all 3 studied cell lines but also in the OLA resistant ones. The combo increased its synergistic effect suggesting a potential role of combo in OLA-resistant tumors. [Table: see text]
Predictive molecular markers of chemoradiation resistance in cervical cancer.
Authors: Kumar Prashant , Chauhan Richa , George Irene A , Limaye Sewanti Atul , Sankaranarayanan Rengaswamy , Dhawale Ekta R , Kuriakose Moni , Venkataramanan R
Published: June 2023

e17505

Background: Cisplatin based concurrent chemoradiation therapy (CCRT) has been recognized as the standard treatment for locally advanced cervical cancer. Although patients treated with CCRT have better chances of survival and prognosis, over 30–40% of patients do not achieve a complete response and may develop locoregional recurrence. Hence predictive biomarkers-based treatment selection of right cohort could be a strong approach for personalized treatment. Therapy resistance occur due to multifactorial events and targeting key molecules involved in treatment resistance could combat treatment resistance. Herein, we profiled both the global proteomic and phosphoproteomic landscape of the concurrent chemotherapy resistant cervical cancer to identify potential predictive biomarkers as well as therapeutic targets. Methods: We employed mass spectrometry based global proteomic and phosphoproteomic strategies to identify proteomic signature and dysregulated kinase involved in CCRT resistance. The biopsy tissue samples were collected before the start of the therapy and the protein was extracted, digested from each sample and labelled with 10 plex TMT (Tandem Mass Tags). The pooled peptides were fractionated by basic pH liquid chromatography analyzed on Orbitrap-Fusion-Tribrid mass spectrometer (ThermoFisher Scientific). For the phosphoproteomic experiment, the peptides were enriched using IMAC based phosphopeptide enrichment method. Liquid chromatography-mass spectrometry/ experiments together with thorough bioinformatics analysis were carried out to characterize the global proteome and phosphoproteome. Results: Analysis of protein expression and phosphorylation led to the identification of dysregulated protein expression and phosphorylation between treatment sensitive and resistant patient cohorts. Further analysis and validation experiment revealed the potential of differentially expressed protein syntaxin 3 (STX3) as a predictive biomarker for treatment resistance. Phosphoproteomic analysis revealed the enrichment of DNA repair pathway in treatment-resistant cohort and the phosphorylation of the proteins involved in DNA repair such as SMC1A, HMGN1, MGMT, DDB2, MSH6 are dysregulated between the cohort suggesting role of DNA repair pathway in the treatment resistance. Kinase-substrate enrichment analysis revealed the activation of kinases such as CSNK2A1, PRKDC, PLK1, NEK2 and ATM in non-responders. Conclusions: We have identified an accurate and reliable biomarker STX3 to predict CCRT resistance in cervical cancer. Further, the phosphoproteomic profiling revealed dysregulation of DNA repair pathways which may be involved in treatment resistance. Targeting the activated kinases such as CSNK2A1, PRKDC, PLK1, NEK2 and ATM could combat treatment resistance in cervical cancer patients.
Identifying small non-coding RNAs as biomarkers for cervical cancer.
Authors: Peitz Josephine , Stockett Arica , Chawla Kiranpreet , Carvajal Diana N. , Plotkin Amy , Staats Paul , Adebamowo Clement Adebayo , Adebamowo Sally Nneoma
Published: June 2023

e17507

Background: Small non-coding RNAs (sncRNAs) that control post-transcriptional gene expression are attractive candidate molecular targets for cancer screening tests. We evaluated whether sncRNAs expression are markedly different in benign, precancerous, and cancerous cervical tissue. Methods: We examined the expression of six sncRNA species: circular RNAs (circRNAs) microRNAs (miRNAs), piwi-interacting RNA (piRNAs), small nuclear RNA (snRNAs), small nucleolar RNA (snoRNAs), and transfer RNA (tRNA), from archival formalin-fixed paraffin-embedded cervical specimen obtained from 172 women (74 benign, 58 high-grade squamous intraepithelial lesion (HSIL) and 40 invasive cervical cancer). We used DESeq2 to identify differentially expressed sncRNA molecules with adjusted p-value < 0.05 and at least 2-fold up- or down-regulation. Results: Comparing benign to HSIL samples, we foundseveral statistically significant, differentially expressed sncRNAs: 906 circRNAs (*circ_0066810, p=3.76x10-16), 87 miRNAs (*miR-149-5p, p=1.30x10-14), 11 piRNAs (*piR_016945, p=8.32x10-13), 32 snRNAs (*RNU1-17P, p=1.90x10-10), 5 snoRNAs (*SCARNA18, p=1.35x10-5), and 24 tRNA (*tRNA-Glu-TTC-8-1, p=6.45x10-17). Comparing benign to invasive cervical cancer samples, we also foundseveral statistically significant, differentially expressed sncRNAs: 3,192 circRNAs (*circ_0123115, p=7.46x10-50), 325 miRNAs (*miR-7-5p, p=6.72x10-36), 82 piRNAs (*piR-hsa-27513, p=1.44x10-15), 71 snRNAs (*RNU1-20P, p=1.37x10-45), 52 snoRNAs (*SNORD95, p=1.68x10-23), and 68 tRNA (*tRNA-Cys-GCA-9-3, p=1.01x10-21). * Indicates the sncRNA with the smallest p-value, for each specie. Conclusions: Our results identify sncRNAs with potential utility of as diagnostic and prognostic biomarkers, and therapeutic targets for cervical precancer and cancer.
Safety and survival in adult women with platinum sensitive relapsed BRCA mutant ovarian cancer: A study of patients in Olaparib Turkey Early Access Program—LynTurk study.
Authors: Esin Ece , Ahmed Melin Aydan , Yıldırım Hasan Çağrı , Mandel Nil Molinas , Erdemoglu Engin , Sari Murat , Aydiner Adnan , Arik Zafer , Gumus Mahmut , Basaran Mert , Er Ozlem , Gokyer Ali , Kose Fatih , On Sercan , Ozet Ahmet , Özer Leyla , Paksoy Nail , sütcüoğlu Osman , Uzunoglu Sernaz , Paydas Semra
Published: June 2023

e17509

Background: SOLO-2 trial results have proven the efficacy of Olaparib in BRCA-mutant platinum-sensitive relapsed ovarian cancer patients. LynTurk as an open label, multi-center study, designed to show the real world safety and efficacy results of Turkey Olaparib managed access program. Methods: Patients with BRCA mutated relapsed ovarian cancer who are in complete or partial response following platinum based chemotherapy were eligible for Olaparib maintenance in Turkish managed access program. The primary aim was safety. Progression free survival, overall survival were the secondary endpoints. Results: Between December 2014 and March 2021, 48 patients were accepted for program. Due to immaturity of data, in this report, a total of 26 patient results were analyzed. BRCA2 mutation was present in 5 patients, one patient have both BRCA1 and BRCA2 mutations; 20 cases were found to be BRCA1 mutated. The median age of patients was 51 (29-61) years. All patients have high grade serous adenocarcinoma of ovary or primary peritoneal carcinoma. The most common site of involvement are lymph nodes and peritoneal surfaces; in 11% of cases there are liver parenchyma metastasis. All of the patients received at least two lines of platinum-based chemotherapy; median 3 lines (2-4) of treatment were applied before Olaparib maintenance. Previous bevacizumab treatment was allowed in this program, 53.8% of cases were received at least 3 cycles, maintenance bevacizumab was given to 12 patients. Median treatment duration with Olaparib was 26,2 months (3-80m). In 30.7% of cases no adverse events were noted, at least one level dose reduction was needed for 50% of patients due to toxicity. Hematological adverse events were the mostly encountered followed by dyspepsia and fatigue. Anemia was the reason for permanent drug discontinuation in 2 patients (0.7%). No febrile neutropenia was reported. During the follow-up, no secondary malignancy and pneumonitis was noted. Median progression free survival from the end of last chemotherapy was 19.3 months. One-year PFS rate was 88.4% and 2-y PFS rate was 53.8%. One-year OS rate from the end of chemotherapy was 92.3% and 2-year was 61.5%. Conclusions: The real world data from Turkey managed access program has showed that Olaparib has a safety profile in paralel with clinical trials (SOLO). No new safety signals were reported. Although a heterogenous population including heavily pretreated patients, maintenance Olaparib was found effective. This report will be updated as the data of all intent to treat population will gather and will get mature.
Evaluation of the prevalence of HPV from environmentally unfavorable districts of the Republic of Karakalpakistan.
Authors: Zakhirova Nargiza Nematovna , Tillyashaykhov Mirzagaleb , Nishanov Daniyar , Saydakhmedova Viloyat , Osmanova Elnara , Islamov Khurshid
Published: June 2023

e17526

Background: Identification of HPV-positive women in the Aral regions of the Republic of Karakalpakstan and the city of Chirchik, Tashkent region. Methods: The study included 48,788 women aged 30-55 years.The project was approved by the Ministry of Health of the Republic, covering 10 districts, mainly near the Aral Sea: Khojeyli, Kanlykul, Shumanay, Chimbay, Karauzyak, Kungrad, Kegeili, Muynak, Buzatau, Nukus district. The Xpert HPV Assay is a qualitative in vitro diagnostic test for the detection of the E6/E7 region of high oncogenic risk human papillomavirus (HPV) genomic DNA in patient specimens. The analysis was performed on a Cepheid Gene Xpert system. The Xpert HPV test specifically identified HPV 16 and HPV 18/45 types in two separate detection channels and reported the presence of 11 other high risk virus types (31, 33, 35, 39, 51, 52, 56, 58, 59, 66 and 68) as a combined result. Results: Of these, HPV was detected in 3304 (6.8%) women, HPV-negative women were 45.484 (93.2%). Distribution by HPV types: among HPV-positive women HPV 16 - 28%; HPV 18.45-7.6%; HPV 31.33.35.52-23.9%; HPV 51-11.6%; HPV 39.56.66-18.4%; mixed forms - 10.2%. Erroneous tests were 2.9%. The age of HPV positive women was 35-45 years. Conclusions: In the studied regions, HPV types 16,31,33,35,52 were most often detected, which should be taken into account when developing the country's national screening program. Also, given the age-specific prevalence of HPV, may be considered for the target group of cervical cancer screening of women aged 35 and 45 years, which is more acceptable for a developing country.
Impact of hospital volume and margin status on survival following radical hysterectomy: An expanded NCDB study.
Authors: Jhaveri Vasanti , Tanner Jean Paul , Salemi Jason L. , Kamrava Mitchell , Rutherford Thomas , David John , Anderson Matthew L
Published: June 2023

e17527

Background: Use of a minimally invasive surgical (MIS) approach to manage early-stage cervical cancer has been previously associated with an elevated risk of disease recurrence and death. However, the reasons why MIS would lead to worse clinical outcomes remains unclear. Here, we sought to determine whether hospital surgical volume and surgical margin status contribute to worse outcomes previously reported for minimally invasive radical hysterectomy (RH-MIS). Methods: Demographic and outcome data for women diagnosed with an invasive carcinoma of the cervix (SCCa) between 2010 and 2015 were abstracted from the National Cancer Database (NCDB). Differences by surgery type were examined using chi-square test for categorical variables and independent samples t-test test for continuous variables. Surgical margin status was reported as either positive or negative according to the presence of malignancy. Overall survival was evaluated using the Kaplan-Meier method and multivariable Cox proportional hazards regression. Analyses were stratified by hospital volume. Low volume facilities were defined as institutions performing <10 surgeries per year. Results: We identified a total of 5,090 women who underwent radical hysterectomy by either minimally invasive (n=2181) or open (n=2909) approach. Between 2010 and 2015, the proportion of radical hysterectomies performed by RH-MIS increased from 42.7% to 70.3% of all cases. In contrast to prior reports, 5-year survival among RH-MIS patients was significantly better compared to RH-open patients (92.5% vs. 90.8%, p=0.02). However, women who underwent RH-MIS were significant younger (45.6±12.3 v. 46.8±12.3 years, p<0.001), more educated (p<0.001), more likely to be White Non-Hispanic (p<0.001) and diagnosed with earlier stage disease (p<0.008). Women who underwent RH-MIS were also less likely to have positive surgical margins (2.2% v 3.5%, p=0.006). After accounting for these differences, there was no statistically significant difference in survival for women undergoing RH-MIS vs. RH-open (HR, 1.18; 95% CI: (0.96-1.45). Positive margin status was associated with worse survival only at low-volume hospitals (HR, 2.30; 95% CI: 1.09-11.31). However, no other association between hospital volume, surgical route, margin status and survival was observed. Curiously, survival for women diagnosed in 2012 (HR, 1.51; 95% CI, 1.05 – 2.17) and 2013 (HR, 1.49; 95% CI, 1.03-2.15) not other years was significantly worse when compared to 2015, regardless of surgical route. Conclusions: Positive surgical margins following radical hysterectomy appear to be most effectively addressed at high volume centers caring for women with cervical cancer. These observations underscore a national need for equitable access to radiation care for women being treated for early stage cervical cancer.
Single cell analysis to study the longitudinal changes in systemic tumor immune environment in cervical cancer after radiochemotherapy.
Authors: Zhao Caining , Xu Zhiyuan , Zhang Yan , Ye Bin , Zheng Danyang , Yu Hao , Kong Feng-Ming Spring
Published: June 2023

e17530

Background: Chemoradiation is the mainstay treatment for cervical cancer, which affects not only tumor immune microenvironment (TIME) but may also the systemic tumor immune microenvironment (STIE). Improved understanding of STIE beyond the tumor may enhance improving treatment strategies for cervical cancer. With these motivations, we applied single-cell RNA-sequencing (SCRNA-seq) to investigate longitudinal dynamics of a comprehensive set of immune cells in cervical cancer patients receiving chemoradiation (RCT). Methods: Two patients diagnosed with cervical squamous cell carcinoma at a locally advanced stage and received 45Gy/25f, with concurrent cisplatin, were enrolled. Peripheral blood was collected for SCRNA-seq using the 10× Genomics. Fresh blood samples were obtained at baseline 1-week, 2-week, 3-week, 5-week (end of external beam radiotherapy) and after Chemoradiation. Seurat 4.0 was used to cluster and annotate cell clusters. Results: A total of 90862 cells were clustered into 3 main subsets, including NK&T, B, and myeloid subsets. Then NK&T subset was extracted and further annotated into 10 clusters, including CD8+T naive, CD8+T effector, CD8+T effector memory, mucosal-associated invariant T (MAIT), cycling CD8+T, CD4Tem, CD4+T naive/central memory, regulatory T (Treg), natural killer (NK), and NKT cells. After plotting the dynamic changes of different cell types, MAIT and cycling CD8+T cell steadily increased with time or RT dose accumulation, suggesting that RCT could induce their proliferation. MAIT highly expressed CD69 and CXCR4 much like CD8+T effector memory cell, and cycling CD8+T cell expressed CX3CR1 like CD8+T effector cell. Besides, pseudotime analysis revealed that the differentiation process started from naive CD8+T cell towards cycling CD8+T cell passing through effector memory CD8+T cell, and effector CD8+T cell. In this process, the transcriptionally distinct MAIT cell belong to a different branch of the Pseudotime trajectory compared to the rest of the T cells, albeit mapping close to effector memory CD8+T cell, in line with their shared phenotypic identity. Enrichment was employed to explore their function and MAIT was enriched with genes involving cytokine-cytokine receptor interaction. Moreover, MAIT cell with increased antigen process and presentation function was note, and PD-1 checkpoint pathway was up-regulated during RCT. Conclusions: Chemoradiation induced the accumulation of MAIT cell which has increased antigen process and presentation features and cycling CD8+T cell with a higher PD-1 checkpoint pathway gene expression signature. Taken together, we provide insight into the peripheral immune remodeling induced by RCT, which will help optimize and improve treatment strategies for cervical cancer. Clinical trial information: NCT05061342 .
Start so young? Defense of the primary HPV test as a screening test for cervical cancer in women aged 25 and over in Brazil.
Authors: Costa Jose Iran , Telles O. Lima Jurema , Sales Mozart J. T. , Katz Leticia
Published: June 2023

e17531

Background: Cervical cancer (CC) is the most frequent type of cancer on woman at reproductive age and on the puerperal pregnancy cycle in Brazil. It is a disease that can be prevented with the resources already available at Brazil’s public healthcare system.The most important risk factor for developing cervical cancer is infection with human papillomavirus (HPV). With the covid 19 pandemic, there was an advance in the possibility of carrying out an HPV test by PCR by through the government initiative "uterus is life" and we was asked what age should start the HPV test in the proposed screening organized. Methods: Descriptive, observational, cross sectional study Carried two cancer centers( using an adapted form, between 2020 2021 Sociodemographic data, cancer characteristics. Descriptive statistics were used to analyze the data and evaluation of secondary data from the ministry of health (DATASUS) This study was approved by the institution’s ethics committee. Recife, Brazil. Results: From 2021 -2022, 240 patients with CC mean age 50,48y (SD ± 13.8; range 24-87), 15, 8 % < 35 y, age of first sexual intercourse: mean age 16,7 (SD ± 3.2, range 11- 30) and 79,6 % < 18y. age of first pregnancy mean 18 (SD ± 6.54; range 12- 36) 77,4 % < 18 y.In the year 2019 of the number of patients undergoing treatment in the Brazilian public system (SUS), by age group, 14.076 patients <35 y (58%). $821,000 was spent in 2019 on anticancer chemotherapy for CC in women < 35 y. Conclusions: With a view to establishing an organized screening policy using the HPV test, considering the window of opportunity to diagnose the non-invasive cervical cancer stage, the onset of sexual activity and the age of first pregnancy among patients with invasive cervical cancer and the representativeness of patients with < 35 years undergoing treatment for advanced CC. The "Utero é Vida" initiative recommended starting the screening of the HPV test from the age of 25 y, in addition to intensifying vaccination coverage against HPV.
Homologous recombination deficiency (HRD) status and response to platinum-based chemotherapy and PARP inhibitors in Chinese patients with ovarian cancer.
Authors: Yuan Hua , Li Ning , Wu Lingying , Yao Hongwen
Published: June 2023

e17533

Background: The association between platinum-based chemotherapy and PARPis response and HRD status in Chinese epithelial ovarian cancer patients has not been fully elucidated. Methods: We assessed homologous recombination deficiency (HRD) score using genomic scar analysis (GSA) algorithm of Beijing Genomics Institute (BGI) assay. The definitive HRD status were determined by combining HRD score tested with the BGI assay and homologous recombination repair (HRR) gene mutation status. We then tested the association of HRD with response to platinum-based chemotherapy and PARP inhibitors in Chinese patients with ovarian cancer. Results: In total, 209 patients with definitive HRD status were included: 66.0% (138 of 209) for HRD and 34.0% (71 of 209) for non-HRD. Patients with HRD tumors were more likely to have a larger tumor (73.9% vs 59.2%, P = 0.029), and less likely to receive neoadjuvant chemotherapy (48.6% vs 67.6%, P = 0.009). No differences were found between patients with HRD and non-HRD tumors in age at diagnosis, histology, stage, postoperative residual disease status. In the entire cohort, patients with HRD tumors were more likely to be platinum sensitive with a platinum-free interval (PFI) of > 6 months than those with non-HRD (79.6% vs 65.7%, P=0.030). Patients with HRD had a significantly better PFS and OS than patients with non-HRD in the entire study population (PFS: unadjusted HR = 0.54, 95% CI: 0.38–0.77, P = 0.001; and OS: unadjusted HR = 0.44, 95% CI: 0.26–0.75, P = 0.002). Multivariate analysis showed that patients with HRD was an independent predictor of increased PFS and OS (PFS: HR = 0.56, 95% CI: 0.39-0.82, P = 0.002; OS: HR = 0.50, 95% CI: 0.29-0.86, P = 0.012). In patients who received PARPis as first-line maintenance (n=55), the median duration of PARPis was 23.3 months (1.2-40.0 months) and 11.0 months (1.4-39.1 months) in HRD and non-HRD subgroup, respectively. Patients with HRD had a significantly better PFS than non-HRD patients (median PFS: NR vs 22.5 months, unadjusted HR = 0.39, 95% CI: 0.16-0.97, P = 0.035). Multivariate analysis showed that patients with HRD was an independent predictor of increased PFS (HR = 0.22, 95% CI: 0.07-0.68, P = 0.008). Conclusions: Patients with HRD tumors are more likely to respond to platinum-based chemotherapy and PARPis when compared with those who are non-HRD. HRD tumors associate with a better survival in Chinese ovarian cancer patient.
Diagnostic model of low-grade serous ovarian cancer and borderline serous ovarian tumor: Model development and validation based on radiomics.
Authors: Song Kun , Chen Zhongshao , Wang Fang , Han Jiamin
Published: June 2023

e17534

Background: Evidence to date indicates that there is a close relationship between low-grade serous ovarian cancer (LGSOC) and serous borderline ovarian tumor, but there is a significant difference in prognosis. Preoperative imaging and clinical information to assess the nature of lesions as accurately as possible is beneficial to the surgical management of patients. Methods: A total of 104 patients who underwent CT examination and surgical treatment for pelvic masses in Qilu Hospital of Shandong University from 2013 to 2021 were included in the study, including 25 patients with low-grade serous ovarian cancer, 34 patients with serous borderline ovarian tumor, and 45 patients with serous cystadenoma. Quantitative image features were extracted from CT and combined with clinical information to construct a diagnostic model. The diagnostic performance was evaluated by ROC and AUC. Results: The diagnostic model was constructed by RFECV (recursive feature elimination and cross validation) together with SVM (support vector machine), random forest and XGBoost (eXtreme Gradient Boosting) algorithms, among which the RFECV combined random forest algorithm model showed the optimal accuracy (0.78) and AUC (0.92). Combined with clinical features, a new diagnostic model was constructed again by RFECV and random forest, and the accuracy (0.91) and AUC (0.96) were further improved. Conclusions: Through the combination of CT image-based radiomics and clinical features, the clinical diagnosis model was successfully constructed, which can accurately evaluate and predict the pathological types of patients, and is expected to be used in clinical practice and guide surgical decision-making.
Clinical remission rates in patients with epithelial ovarian cancer in the pandemic versus the pre-pandemic period.
Authors: Shammas Natalie , Mukherjee Amrita , Xu Lanfang , Cannavale Kimberly L. , Szamreta Elizabeth A. , Monberg Matthew , Hodeib Melissa , Chao Chun
Published: June 2023

e17541

Background: The COVID-19 pandemic presented challenges for patients with ovarian cancer (OC). The objectives of this study were to compare patient remission outcomes following first-line treatment before and after the onset of the pandemic, and to evaluate potential racial/ethnic disparities in remission outcomes during the pandemic. Methods: This retrospective cohort study was conducted at Kaiser Permanente Southern California (KPSC), a large, integrated healthcare delivery system. Patients diagnosed with Stage I-IV epithelial ovarian cancer 01/01/2017-06/30/2021 were included. Pre and post pandemic periods were designated using 03/04/2020 as the cut-off. Data on cancer characteristics and treatment were obtained from KPSC’s electronic medical records. Chart review was conducted to collect data on complete and clinical remission (complete + partial remission) after first course of treatment. Imaging showing no evidence of disease and normal CA 125 values were used to define complete remission. Partial remission was defined as an incomplete response to therapy documented by the treating physician. Other variables included age and stage at diagnosis, race/ethnicity, Charlson’s comorbidity index, neighborhood deprivation index and prior membership. Modified Poisson regression with robust error variance was used to evaluate the association for the pandemic period and race/ethnicity with the remission outcomes. Results: Of 728 patients included, 531 and 197 patients were diagnosed in the pre-pandemic and pandemic periods, respectively. The distributions of the patients’ age, race, and stage were similar between the pre-pandemic and pandemic period. The cohort was racially/ethnically diverse: 46.0% White, 33.5% Hispanic, 7.4% Black, and 13.1% Asian. Complete remission was observed in 406 (76.5%) patients in the pre-pandemic period compared to 149 (75.6%) patients in the pandemic period (p=0.82). Clinical remission was observed in 473 (89.1%) patients in per-pandemic and 176 (89.34%) patients in pandemic period (p=0.92). No statistically significant associations were found between the remission outcomes and the pandemic in the adjusted models. Black patients had lower complete remission rates (but not lower clinical remission rates) compared to White patients in the pandemic period (p=0.06). Of note, Black patients had 67.6% complete remission rate in the pre-pandemic period whereas only 35.3% achieved complete remission in the pandemic period (p=0.01). However, the number of Black patients in the pandemic period was small (N=17). Conclusions: Overall, patients diagnosed with ovarian cancer achieved similar complete and clinical remission rates between the pre-pandemic and pandemic period. Complete remission varies across subgroups of patients. This finding needs to be further investigated with a larger sample.
Spatial profiling of ovarian clear cell carcinoma (OCCC) and identification of immune-hot features.
Authors: Tai Ya-Ting , Lin Wei-Chou , Wang Duncan Yi-Te , Ye Jieru , Tan Tuan Zea , Wei Lin-Hung , Huang Ruby Yun-Ju
Published: June 2023

e17543

Background: OCCC is an ovarian cancer subtype with high incidence in Asia. Despite its frequent occurrence as an early-stage disease, optimal therapeutic options for high-risk patients are limited. Recently, immune-hot features have been proposed as an indicator for poor prognosis for early-stage OCCC. Specific patterns of intra-tumoral heterogeneity (ITH) associated with these immune-hot features have yet to be defined. Methods: Formalin-fixed paraffine embedded (FFPE) tumor sections from 10 early-stage primary OCCC patients were included. Digital Spatial Profiling (DSP) of 18 protein targets from the Human Protein Core Panel was conducted by using the nanoString GeoMx system to profile selected regions of interest (ROIs) based on the reference H&E staining morphology. Areas of illumination (AOIs) were defined according to ROI segmentation by the fluorescence signals of pan-cytokeratin (PanCK), CD45, or DNA. The digital signals were quantified by the nanoString nCounter system. Results: Unsupervised hierarchical clustering of 252 AOIs from 229 ROIs showed 5 distinct clusters. PanCK+ AOIs distributed in 5 clusters were found to express combinations of markers suggestive of immune mimicry: granzyme B (GZMB) high epithelial cells (C1-a), immune signal high epithelial cells (C1-b), immune-like cells (C1-c), fibronectin-high epithelial cells (C2-a), and signal-cold epithelial cells (C2-b). CD45+ AOIs were mostly clustered in C1-c. Tumor cells with C1-c and C2-a features were associated with recurrence while those in C1-a were associated with no recurrence (Chi-square p=2.8E-04). Tumor infiltrating immune cells (TIIs), which were found to be more enriched of the macrophage lineage (stronger CD68 expression, p=4.5E-03), were associated with recurrence (66.7% in recurrence vs 14.3% in no recurrence, Chi-Square p=0.098). TIIs appeared in PanCK segments of C1-b and C1-c with higher frequencies (45% in C1-b, 25% in C1-c, Chi-square p=0.046) and in PanCK segments of C1-a with extremely low frequency (0%). Correlating with morphology, tumors with recurrence showed higher frequency of papillary pattern (54.7%, Chi-Square p=1.01E-04) and lower frequency of tubulocystic pattern (18.9%, Chi-Square p=7.21E-03). Plus, TIIs were found with high frequency in ROIs with papillary pattern (65.2%, Chi-Square p=4.99E-04) and low frequency in ROIs with tubulocystic pattern (8.7%, Chi-Square p=6.43E-03). Papillary ROIs, which showed macrophage lineage immune mimicry, high CD68 intensity and low PanCK intensity, were found to have very low frequency of PanCK segments of C1-a (6.2%, Chi-Square p=1.26E-04), but extremely high frequency (100%) of PanCK segments of C1-c. Conclusions: Spatial profiling of early-stage OCCC tumors revealed immune-hot tumor features associated with recurrence. These features included immune mimicry of tumor cells, the presence of TIIs, and a papillary pattern in morphology.
A real-world study of US patients with metastatic ovarian, fallopian tube, and peritoneal cancer (mOFPC) using integrated electronic health records (EHR) and claims datasets.
Authors: P B Avinash , Funingana Gabriel , Singh Neeraj , George Rohini , Sowa Anna , Chakkrapani Sangavai , Priya Vandana , Vaidya Vivek Prabhakar , Vidal Laura , Saini Kamal S. , Agrawal Smita
Published: June 2023

e17548

Background: Ovarian cancer is the most lethal gynecologic cancer. Detailed epidemiologic descriptions from a real-world database of a large population of ovarian and related cancer patients can provide insights into the characteristics, treatment patterns, and outcomes of these patients, and could serve as a useful benchmark while developing new therapies. Methods: This retrospective analysis uses the ConcertAI RWD360 dataset which is a real-world de-identified dataset of more than 6 million patients from across the United States derived from various EHR systems and integrated with a large administrative open claims dataset (>90% overlap). 60429 patients in this dataset had OFPC out which 12406 patients had metastatic cancer. We present here the key characteristics of this mOFPC cohort including histology, biomarkers and top treatment patterns. We also performed overall survival (OS), time to treatment discontinuation (TTD) and time to next treatment (TTNT) analyses starting from initiation of 1st line of therapy (LoT) for all patients who received systemic treatment after metastatic diagnosis (8308 patients). Results: The top 5 histologies and biomarkers tested in this mOFPC cohort are presented in Table. The median OS from start of 1st LoT for this cohort was 2.45 years. The median TTD and TTNT across all 1st line therapies were 2.5 months and 5.5 months respectively. Top 2 treatments given as 1st LoT after metastatic diagnosis are also presented in Table. Chemotherapy (cis/carboplatin + pacli/docetaxel) and chemotherapy + bevacizumab were the most common 1st LoTs and there was no difference in the OS of patients treated with these two LoTs. Conclusions: This study describes the characteristics of a large US real-world cohort of mOFPC patients. Here we have presented data on the overall cohort, but further analysis of outcomes stratified by treatment arms, biomarkers and histology can be performed to better inform best treatments for specific sub-cohorts. [Table: see text]
Genetic counseling referral frequency and attrition for newly diagnosed epithelial ovarian cancer at Grady Memorial Hospital from 2012-2022.
Authors: Wood Sarah Jeanne , Cao Yichun , Canning Madison , Vemuru Shalini , Paysour Jamie , Murphy Danielle , Liu Yuan , Meisel Jane Lowe
Published: June 2023

e17549

Background: Ovarian cancer is the most lethal gynecologic cancer with roughly 20% of cases attributable to mutations in BRCA 1 or BRCA 2. In 2018, the SOLO-1 study, comparing PARPi to placebo in BRCA 1/2 mutated ovarian cancers following first-line chemotherapy showed an unprecedented 70% reduction in the hazard to progression or death. Consequently, in 2020, ASCO published a consensus statement recommending germline testing for all women with epithelial ovarian cancer. Currently, our understanding of the improvement, or lack thereof, in germline testing for ovarian cancers following these changes are not well described, and research is needed to determine the real-world frequency of and barriers to genetic testing. Methods: We retrospectively reviewed 115 patients’ charts with newly diagnosed ovarian cancer from 2012-2022 at Grady Memorial Hospital. An assessment of genetic testing was acquired, including genetic counseling referral frequency, attrition, somatic tumor testing, and mutated genes identified. Additional characteristics including age, race, histology, grade, and stage were obtained. Univariate association (Chi-square or Fisher’s exact test) was performed to correlate the above variables with germline testing. Results: Of 115 patients diagnosed with ovarian cancer from 2012–2022, 33% received a genetic counseling referral and 16.5% received an evaluation. Germline testing, in lieu of referral, was ordered by the physician in 20% of cases. Among patients who completed germline testing, a pathogenic mutation was found in 9.8% of patients. Patients who were ≤ 48 years old were more likely to be referred for genetic counseling (50% vs. 26.5%, p = 0.016), and those with earlier stage disease (stage 1 or 2 versus stage 3 or 4) were more likely to be referred for genetic counseling (46.5% vs. 25%, p = 0.018). There was a significant difference in those receiving genetic counseling referral pre and post October 2018 (when SOLO-1 was published) with 50% of patients being referred after October 2018 versus 18% of patient before referred prior (p = 0.005), and in 2021 (following the ASCO consensus statement), an impressive 63.6% of patients were referred with attrition rate of 54.5%. Conclusions: Our real-world data demonstrates improvement in germline testing for newly diagnosed ovarian cancers at our institution over the past decade, with significant increases in both genetic counseling referral and attrition since 2018. Despite these improvements, we continue to be deficient in testing patients who are older and with more advanced-stage disease, which may be due to the gravity of their presentation and prioritized focus of treatment initiation. System-wide changes, including the option of having genetic testing ordered by the oncologist in the clinic with genetic counseling performed after results are available, are being explored.
Screening mitophagy-related lncRNAs based on WGCNA to identify and validate a prognostic signature for patients with ovarian cancer.
Authors: Zheng Jianfeng , Sun Yang
Published: June 2023

e17554

Background: Mitophagy refers to the process by which cells selectively remove incomplete or damaged mitochondria through the autophagic mechanism. However, the value of mitophagy-related genes (MRGs) and mitophagy-related lncRNAs (MRLs) in ovarian cancer (OC) is still not clear. Methods: We explored the alterations of MRGs in four gynecological tumors using R packages. Based on weighted coexpression network analysis (WGCNA), MRLs were identified to carry out LASSO Cox regression analysis and then we established the prognostic MRL-signature. The prognosis and independent prognostic value of the MRL-signature was also validated by four independent datasets from GEO. The expression level of MRLs involved in the prognostic signature we established were detected by qPCR for the samples we collected. Analysis for characteristics of functional pathways, immunity status, and anti-tumor therapy were based on GSEA, ssGSEA, CIBERSORT, xCELL, MCPcounter, ESTIMATE, and TIDE. The ceRNA network was constructed applying miranda, miRWalk3.0, and Cytoscape. Results: Most MRGs were found at lower expression levels in four gynecological tumors. Among the four gynecological tumors, the levels of CNV and MRGs were positively correlated. Most MRGs were negatively correlated with methylation level. A total of 52 MRGs were differentially expressed in OC tissues. Nine MRLs were significantly associated with survival prognosis. Eight optimal lncRNA combinations were screened by LASSO Cox Regression algorithm. On the basis of Univariate Cox regression and Multivariate Cox regression analyses, the risk model based on MRLs was proved to be the independent prognostic factors. The qPCR assay showed that the differential expression trends of these MRLs in our collected OC samples were consistent with those in TCGA database. We found that TIDE score of OC patients with lower risk score was lower, suggesting that OC patients with low RSs are more sensitive to immune checkpoint blockade therapy. OC patients with higher risk score had higher immune cell scores and higher risk score correlated strongly with higher stromal and estimated scores, while lower risk score correlated with tumor purity. We found that the IC50 levels of paclitaxel and ABT.888 (Veliparib) in the high-risk group were observably higher than those in the low-risk group, suggesting a negative correlation between risk score and the drug susceptibility of OC. There were 539 miRNAs, 73 mRNAs and 8 lncRNAs in the ceRNA network. Conclusions: The integrative analysis of MRGs and MRLs revealed their roles in prognosis and therapeutic responsibility in chemotherapy and immunotherapy. Our findings demonstrate the important clinical significance of the signature based on MRLs, and will help improve clinical outcomes for patients with OC.
The peripheral TCR repertoire diversity indexes can be used as an independent indicator for long term survival rate of ovarian cancer patients.
Authors: Fu Kaiyu , Yang Xin , Li Kemin , Yin Rutie
Published: June 2023

e17558

Background: According to GLOBOCAN 2020 data, ovarian cancer (OC) ranks 19th in incidence and 15th in mortality with a rate of 1.6% and 2.1%, respectively, High-grade serous OC is the most common sub-type of malignant ovarian tumors, remains the leading cause of cancer-related death among all gynecological cancers in the developed parts of the world. In the United States in 2016, 5-year survival rate was only 10-25% in stage III or IV OC patients, and there was considerable variability in survival in an advanced stage. At present, there is no reliable molecular marker to identify patients with better or worse prognosis. As is known to all, the adaptive immune system defends the body against different foreign antigens, using two main types of antigen receptors: T-cell receptors (TCRs) and antibodies. Now we use high-throughput sequencing approach to analyze the expressed TCRβ repertoires in the peripheral blood of OC patients and healthy women donors. Methods: The experimental design and participant recruitment were approved by Medical Ethics Committee of West China Second University Hospital (Ethics Approval for Research: 2022). Total RNA was extracted from PBMC using TRIZOL reagent. High through put sequencing of the TCRβ gene, assignment of the Vβ, Dβ, and Jβ germline gene, and TCR diversity indexes analyses were conducted essentially following our previously published protocols. Statistical analysis and graph drawing were performed using R language (R 4.0.3). Results: Comparison of the TCR repertoires between the 232 OC patients (OC group) and the 250 healthy women donors (HD group) revealed significant differences. For examples, the VJ combinations of the OC group were distinct from those of the HD group. In addition, the TCR repertoire diversity indexes of the OC group were significantly lower than those of the HD group ( p < 0.001), including D50s, Simpson indexes, the number of highly expressed clones (HECs), and the frequencies of the largest TCR clones. As reported before, the TCR repertoire diversity indexes decreased gradually with increasing age in the HD group (all p < 0.001). Moreover, the TCR repertoire diversities in the survival group were significantly higher than those in the death group (D50: p = 0.0342; the number of HECs: p = 0.0414). Using as the cut off value, the OC patients with D50 < 0.032 had significantly higher mortality rates compared to the OC patients with D50 > 0.032 ( p = 0.0019). Similarly, using the numbers of HECs or the frequencies of the largest TCR clones can also distinguish OC patients in long term survival. Conclusions: Analyzing the peripheral TCR repertoires in the OC and HD revealed significant differences, and the peripheral TCR repertoire diversity indexes may be used as a potential predictor for long term survival for ovarian cancer.