bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic and transcriptomic characterization of ovarian cancer under neoadjuvant and adjuvant chemotherapy.
Authors: Jin Ying , Chen Jiayu , Zhao Yi , Gu Yu , Shan Ying , Li Yan , Wang Wei , Qin Meng , Dong Yu , Du Baochen , Pan Lingya , Liang Han 
Published: June 2023

e17571 Background: Neoadjuvant chemotherapy (NACT) has become a routine selection for late-staged ovarian cancer patients to reduce the tumor load before debulking surgery; and chemotherapy remains as the mainstream therapy for ovarian cancer. However, the effects of NACT on the cancer genome and the molecular determinates of tumor response to chemotherapy in ovarian cancer have not been characterized systematically. Methods: We obtained 121 clinical samples from 44 ovarian cancer patients (19 underwent NACT and 25 did not) and collected the key clinical features for these samples such as age, tumor stage, platinum-free interval, and platinum response. We then performed whole-exome sequencing for all the 121 samples and RNA-sequencing for 54 samples. We conducted a systematic comparative analysis between samples collected from the patients with and without NACT to characterize the effects of NACT on the cancer genome and transcriptomes. Focusing on the genomic and transcriptomic differences of treatment-naive samples between platinum sensitive and resistant patients, we also did a comparative analysis to identify molecular features that can predict the response to platinum. Results: We observed significantly elevated mutational signatures associated with platinum chemotherapy in the samples from patients who have undergone NACT. We also found increased microsatellite instability (MSI) in the post-NACT primary samples compared to treatment-naive ones. Interestingly, the prevalence of CCNE1 amplification significantly decreased in the post-NACT metastatic samples of patients. Consistently, the mRNA expression of CCNE1 appeared to down-regulated in such samples. Furthermore, the expression signature of cancer hallmarks related to this gene decreased in post-NACT metastatic samples, such as E2F targets, G2M checkpoint, and mitotic spindle. Remarkably, we found that homologous recombination deficiency (HRD) is a strong indicator for platinum sensitivity, which was also supported by HRD-associated mutational signatures. The expression signature of immune-related hallmarks was significantly upregulated in sensitive primary samples, including interferon alpha response, interferon gamma response, and IL6 JAK STAT3 signaling. Conclusions: Based on comprehensive profiling for genomic and transcriptomic characterization of a large cohort of ovarian cancer patients, we found that (i) NACT likely increased MSI and decreased prevalence of CCNE1 amplification; and (ii) a high HRD score and elevated immune-related expression signatures can strongly predict the sensitivity to platinum-based chemotherapy. These results lays a key foundation for develop novel, effective therapies for ovarian cancer.
The impact of homologous recombination deficiency on first-line adjuvant chemotherapy and first-line PARPi maintenance therapy in Chinese patients with epithelial ovarian cancer.
Authors: Li Lei , Gu Yu , Zhang Mengpei , Shi Xiaohua , Li Zhe , Xu Xinyun , Sun Tianqi , Dong Yu , Xue Chao , Zhu Xiaoru , Lv Ran , Jiao Kai , Ji Xuwo , Liang Zhiyong , Jin Ying , Yin Rutie , Wu Ming , Liang Han 
Published: June 2023

e17573 Background: Homologous recombination deficiency (HRD) testing has been approved by FDA for selecting epithelial ovarian cancer (EOC) patients who may benefit from the first-line poly (ADP-ribose) polymerase inhibitor (PARPi) maintenance therapy. However, the effects of HRD on the clinical outcomes of first-line chemotherapy and first-line PARPi maintenance therapy have not been rigorously evaluated in Chinese EOC patients. Methods: We developed a customized sequencing panel named “Precision Human HRD Assay”.This HRD assay contains two sets of probes, HRD-score probes (~50K) and DDR-gene probes, which were used to evaluate HRD score and genotype 36 DDR genes. Then we applied it to two large Chinese EOC patient cohorts and performed a retrospective analysis of progression-free survival (PFS) and overall survival (OS) estimated using the Kaplan-Meier method. Results: In the first-line adjuvant chemotherapy cohort (FACT, N = 380), HRD status significantly improved PFS (median, 15.6 months vs. 9.4 months; HR, 0.688; 95% CI, 0.526 to 0.899; P = 0.003) and OS (median, 89.5 months vs. 60.9 months; HR, 0.636; 95% CI, 0.423 to 0.955; P = 0.008). In the first-line PARPi maintenance therapy cohort (FPMT, N = 83), HRD status significantly improved PFS (median, NA vs 12 months; HR, 0.438; 95% CI, 0.201 to 0.957; P = 0.033) and OS (median, NA vs NA months; HR, 0.12; 95% CI, 0.029 to 0.505; P = 0.001). Conclusions: Our results demonstrate that HRD status is a significant predictor for PFS and OS in both first-line chemotherapy and first-line PARPi maintenance therapy, providing strong real-world evidence for conducting genetic testing and improving clinical recommendations for Chinese EOC patients.
Real world study on the effect of PARPi as maintenance therapy after first-line and second-line chemotherapy on platinum sensitivity in patients with recurrent high-grade serous epithelial ovarian cancer.
Authors: Guo Yanglong , Zhang Yingli 
Published: June 2023

e17574 Background: This study investigated the effect of PARPi as maintenance therapy after 1st-line and 2nd-line chemotherapy on platinum sensitivity in patients with recurrent high-grade serous epithelial ovarian cancer (rHGSOC). Methods: 172 patients with rHGSOC at Zhejiang Cancer Hospital and Jiaxing Maternity and Child Health Care Hospital from Jan 2017 to Dec 2021were retrospectively analyzed. Patients who received PARPi as maintenance therapy after first-line chemotherapy were enrolled to the 1st-PARPi group (n=23), and subjects who did not receive PARPi maintenance therapy were enrolled to the 1st control group (n=105). Similarly, 2nd- PARPi group (had not use PARPi in first-line treatment n=30), 2nd-control group (n=89) were divided. To evaluate progression-free survival (PFS), the first progression to second progression (TTSP), the second progression to third progressio (TTTP), PFS between the second progression and the end of the second-line chemotherapy (PFSs), PFS between the third progression and the end of the third-line chemotherapy (PFSt) and to compare whether PARPi as maintenance therapy affects the platinum sensitivity of these patients. Results: PFSs in 1st-PARPi vs.1st-control group (median 5 vs. 11 m; p=0.0037). PFSt in 2nd-PARPi vs. 2nd-control group(median 4.5 vs. 9.0 m; p=0.0009). TTSP in 1st-PARPi vs. 1st-control group (median 11 vs. 16 m; p=0.0045). TTTP in 2nd-PARPi vs. 2nd-control group (median 10 vs. 15 m; p=0.0007). Among the 23 patients in 1st-PARPi group and 105 patients in 1st-control group, 9 and 99 patients were platinum sensitive while 14 and 6 patients were platinum resistant respectively (HR 14.46, 95% CI =4.07-51.53, P < 0.0001). Among the 30 patients in 2nd-PARPi group and 89 patients in 2nd-control group, 10 and 71 patients were platinum sensitive while and 20 and 18 patients were platinum resistant respectively (HR 4.37 95% CI=1.98-9.64, P < 0.0001). Age, stage, residual tumor after initial surgery treatment and the courses of platinum-based chemotherapy before PARPi,BRCA gene mutation were not the related factors affecting the platinum sensitivity of next line chemotherapy. There was no statistical difference in the effect of duration of PARPi on the platinum sensitivity of next line chemotherapy (duration of PARPi≥ 18 months vs. <18 months in 1st-PARPi group, HR 0.60, 95% CI=0.18-2.04, P=0.41; duration of PARPi≥ 12 months vs. <12 months in 2nd-PARPi group, HR 0.62, 95% CI=0.26-1.48, P=0.24, respectively). Conclusions: Patients with rHGSOC using PARPi affected the platinum sensitivity and were more likely to lead to platinum resistance no matter how long the during of PARPi were.This conclusion was consistent with the cross resistance between PARPi and platinum. Care should be taken when using PARPi after 1st-line and 2nd-line chemotherapy as maintenance therapy.
Clinical features of long-term survivors with advanced high-grade serous ovarian cancer.
Authors: Barretina-Ginesta Maria-Pilar , Carbó Bagué Anna , Bujons Elisabet , Fortian Arola , Fina Claudia , Pardo Marta , Melendez-Muñoz Cristina , Cardenas Laura , Taltavull Anna , Sabaté Josep , Darder Esther , Feliubadalo Lidia , Barretina Jordi , Brunet Joan 
Published: June 2023

e17575 Background: Most patients diagnosed with high-grade serous ovarian cancer (HGSOC) at advanced stages (FIGO III&IV) have limited survival. However, approximately 30% of patients survive more than 5 years, some of them without relapse. A better understanding of these patients may uncover novel factors contributing to their long survival beyond those known to be related to HGSOC prognosis (age, stage and residual disease after surgery). This descriptive study aims to analyze the clinical characteristics of these exceptional survivors and describe them in contrast to patients with worse survival in a cohort of patients diagnosed before the introduction of PARP inhibitors as first-line maintenance therapy. Methods: A descriptive analysis of patients newly diagnosed with advanced HGSOC at our University Hospital between 2009 and 2018 was conducted. We report clinical characteristics of long-term survivors (LTS), defined as patients alive after 5 years(y) from the date of diagnosis and characteristics of patients who survived less than two years from the date of diagnosis, classified as short- term survivors (STS). Results: Among 195 patients with advanced HGSOC 42 (21,5%) survived less than 2y and 48 (24,6%) more than 5y, 18 of them (37,5%) without relapse. The Median age was 61.1y for LTS and 64.8 for STS. In the LTS group, 77.1% of patients were stage III, and 22.9% were stage IV. In the STS group, the distribution of patients with stage III and IV was 42.9% and 57.1%, respectively. A higher proportion of LTS underwent surgery n=44 (91,7%), most of them as interval debulking surgery (59.1%). Almost half of STS did not undergo surgery (45,2%), being interval debulking surgery the most frequent systematic approach when surgery was performed (73.9%). Only 9,1% of LTS who underwent surgery had residual disease compared to 27,3% of STS. Harboring mutations in the BRCA1/2 genes is a favorable prognostic factor also associated with chemotherapy sensitivity, in our serires 23% of LTS were BRCA1&2 mutation carriers (11 patients (23%) patients with germline BRCA mutations being 7patients(15%) BRCA1mut and 4patients(8%) BRCA2mut with 4patients(8%) of patients not analyzed). Conclusions: In our cohort, stage III and cytoreduction surgery were more frequent among LTS. Classical clinical characteristics are not enough to identify advanced HGSOC LTS. More investigation on their molecular profile might help to to identify exceptional LTS in order to elucidate better management approaches and new treatments for patients with worse prognosis.
Investigating the association between BRCA1/2 copy number variation and homologous recombination deficiency score in ovarian cancer: A cross-sectional study.
Authors: Yang Liufeng , Li Yuanyue , Hu Qian , Zhang Tingting , Cui Mengyue , Zhang Jie 
Published: June 2023

e17584 Background: PARP inhibitors (PARPi) have shown significant clinical benefit as maintenance or systematic therapy in patients with ovarian cancer (OC) with BRCA1/2 mutation or positive homologous-recombination deficiency (HRD) status. However, patients with BRCA1/2 mutation not only showed better efficiency of PARPi, but also higher HRD score than other populations. Therefore, patients with BRCA1/2 mutation have received much attention. However, there are many kinds of variants in BRCA1/2 of OC patients. The purpose of this study is to explore the distribution of BRCA1/2 copy number variation (CNV) in OC patients and its association with HRD score. Methods: A cross-sectional analysis of 1636 OC patient who were retrospectively analyzed with a customized 3D-HRD panel (panel of Next-generation sequencing) between 2020 and 2022 was carried out. The HRD score was calculated as the sum of the LOH, TAI, and LST and we defined HRD score more than 30 and deleterious BRCA1/2 mutation as HRD positivity. Results: In this cohort (n = 1636), we divided the patients into 4 groups according to the BRCA1/2 status. Group1: patients with BRCA1/2 SNV (single-nucleotide variation) combined with CNV (n = 45); Group2: patient with BRCA1/2 CNV (n = 155); Group3: patient with BRCA1/2 SNV (N = 308); Group4: patient with BRCA1/2 WT (wild type, n = 1128). HRD scores decreased significantly from Group1 to Group4. And the proportion of HRD positive patients decreased significantly from Group1 to Group4. Conclusions: Different BRCA1/2 statuses lead to different HRD characterization in OC patients. OC patients with BRCA1/2 CNV (with/without BRCA1/2 SNV) showed higher HRD score than patients with BRCA1/2 SNV. These patients may deserve opportunity for PARPi treatment besides patients with germline or somatic BRCA1/2 mutation, especially for PARPi with specific requirements for patients, such as Olaparib.
Cost-effective analysis of rotational intraperitoneal aerosol chemotherapy (RIPAC) in patients with platinum-resistant ovarian cancer.
Authors: Park Soo Jin , Lim Juwon , Kim Hee Seung 
Published: June 2023

e17585 Background: We developed RIPAC, which improves distribution and penetration compared to pressurized intraperitoneal aerosol chemotherapy (PIPAC). To introduce this newly developed device in the real world, we analyzed the cost-effectiveness of rotational intraperitoneal aerosol chemotherapy (RIPAC) device to improve quality of life (QoL) compared to conventional palliative chemotherapy for platinum-resistant ovarian cancer patients. Methods: A decision tree was designed to compare the quality-adjusted life year (QALY) and cost consisting of RIPAC and palliative chemotherapy regimens, such as pegylated liposomal doxorubicin (PLD), gemcitabine (GEM), and topotecan (TOP). Also, to reflect the clinician’s variable preferred regimens for palliative chemotherapy, the average direct and indirect medical costs of belotecan, docetaxel, vinorelbine, and vinblastine were also considered in addition to the three regimens (ANY). The model included quality of life which was measured by European Organization for Research and Treatment of Cancer (EORTC)-Quality of life Questionnaire 30 (QLQ-C30) data gathered from previous clinical trial reports on PIPAC and palliative chemotherapy for recurrent ovarian cancer willingness-to-pay (WTP) threshold was set at US$40,000 per quality-adjusted life year saved. Results: To complete three cycles of palliative chemotherapy using PLD, GEM, TOP, and ANY, the total medical costs were US$15,267, US$9,013, US$16,144, and US$12,631, respectively, and the corresponding QALYs for each regimen were 0.633, 0.553, 0.783, and 0.65. Since RIPAC has not yet been introduced into the medical market, when the maximum RIPAC cost is calculated from ANY considering WTP, the cost of RIPAC excluding the ward, outpatient, and anesthesia-related costs among direct medical costs was estimated to be up to US$4,391. Conclusions: The cost-effective analysis results for the palliative treatment of recurrent ovarian cancer implied that RIPAC could be a cost-effective strategy to improve the QoL of platinum-resistant recurrent ovarian cancer patients.
Resistance mechanism and microenvironment changes after PARPi treatment: Paired analysis of ovarian cancer samples pre and post treatment.
Authors: Li Qingli , Lin Xiaojuan , Song Liang , Zhang Wenhao , Zhong Lan , Wang Wei , Cheng Peng , Zhu Changbin , Yin Rutie 
Published: June 2023

e17586 Background: PARP inhibitors (PARPi) have been widely used in the maintenance therapy of ovarian cancer (OC) and have shown strong anti-tumor effect in tumors with homologous recombination defects (HRD). However, there is still a lack of systematic clinical data on drug resistance mechanisms and tumor microenvironment changes. Methods: 13 OC patients who were treated with PARPi at West China Second University Hospital were enrolled. PARPi treatment-naive samples (PNS, n = 11) and post-PARPi progression samples (PPS, n = 13) were acquired. Two next-generation sequencing (NGS) panels (Master panel, 563 genes for exons of DNA plus 1831 genes for RNA; HRD panel, 70,000 SNPs for HRD score evaluation, AmoyDx) were used to analyze gene variation, expression, and HRD score changes in tumors. Results: Median duration of treatment for PARPi was 17 months (9-36), and the median lines of chemotherapy before PARPi was 2 (1-3). 38.5% (5/13) patients achieved R0 resection. BRCA reversion mutations were observed in 30.0% (3/10) of the g BRCA+ PPS, including 1 splicing variant and 2 frameshift mutations. High-frequency variants also included MYC amplification (30.8%, 4/13) and ZFHX4 mutations (23.1%, 3/13); Amplification of ch11 q13 were observed in two patients (15.4%). HRD scores and tumor mutation burden (TMB) were significantly increased in PPS. RNA expression profiling showed that the expression of NGFR, CCL18, C7 and other 85 genes in PPS was up regulated. GO/KEGG analysis showed that NF-κb pathway, immune response related cell activation, cytokine - cytokine receptor interaction, B cell receptor signaling pathway, NK cytotoxicity pathways, and etc., were significantly upregulated in PPS, suggesting that PARPi may activated immune-related pathways of the tumor microenvironment (TME). Downregulated pathways in PPS include JAK-STAT signaling pathway, Wnt signaling pathway, and etc. In PPS, the level of memory B cells and neutrophils were significantly up-regulated, while the levels of immune suppression by myeloid cells were significantly down-regulated. Conclusions: Our small-scale study confirmed that BRCA reversion mutation is one of the important resistance mechanisms of PARPi, and the reversion mutation is located near the germline pathogenic mutation to counteract the reading frame change caused by the frameshift mutation. The up-regulation of B-cell receptor, NK cytotoxic cytokine receptor interaction and other related pathways suggested that PARPi may activate immune response, and the changes in the levels of memory B cells, C7 and neutrophils also confirmed the results above. Epithelial mesenchymal transition induced by CCL18 may also lead to PARPi resistance and activate the NF-κb pathway simultaneously, increasing the inflammatory characteristics of TME. These findings can provide ideas for future treatment, and larger samples are needed to verify later.
Maintenance therapy with a poly(ADP-ribose) polymerase inhibitor (PARP) in patients with newly diagnosed ovarian cancer: A systematic review and meta-analysis.
Authors: Stecca Carlos , Vilbert Maysa , Michelon Isabella , Castro Caio , Dacoregio Maria Inez , Fin Fabio , Tsunoda Audrey Tieko , Melo Andreia Cristina De , Da Costa Alexandre Andre B. A. 
Published: June 2023

e17587 Background: PARP inhibitors (PARPi) have been approved for maintenance therapy in newly diagnosed ovarian cancer patients with or without homologous recombination deficiency (HRD). In this meta-analysis, the latest clinical data to assess the efficacy and safety of this approach across different subgroups were synthesized. Methods: PubMed, Scopus, and Cochrane databases were searched for randomized controlled trials that compared maintenance PARPi with placebo in newly diagnosed ovarian cancer. The outcomes of interest included progression-free survival (PFS) according to HRD status, overall survival (OS), second PFS (PFS2), and time-to-first subsequent treatment (TFST). Heterogeneity was examined with I2 statistics. A random-effects model was used for outcomes with high heterogeneity. Results: A total of 6 Randomized clinical trials with 3609 patients were included, of whom 2348 (65%) received maintenance PARPi. PFS was significantly longer for HRD-positive patients receiving PARPi [Hazard ratio (HR) 0.44, 95% Confidence interval (CI) 0.37 – 0.52 p<0.001] and for HRD-negative patients [HR 0.71, 95% CI 0.54 – 0.92 p=0.009]. Maintenance PARPi was associated with improved OS in HRD-positive patients [HR 0.59, CI 0.47 -0.73, p<0.001] but not in unselected patients. PFS2 in the HRD-positive population was reported in three trials, and it favored the use of PARPi [HR 0.57, CI 0.43 – 0.76, p<0.001]. Adverse events ≥grade 3 were more common in patients on maintenance PARPi (p<0.001). The occurrence of myelodysplastic syndrome was numerically but not significantly higher in the PARPi group. Conclusions: Maintenance with PARPi in patients with newly diagnosed ovarian cancer significantly prolongs PFS regardless of HRD status. Moreover, PARPi maintenance improves OS and PFS2 in patients with BRCA and/or HRD-positive tumors compared to placebo. [Table: see text]
Progression-free survival in patients receiving first-line platinum-based therapy in Argentina: OCEANIA study.
Authors: Abreu Gabriela , Queiroz Juliana , Nogueira Thiago , Soares Claudia , Menezes Patricia , Carrizo Mariano Nicolas , Criniti Juan , Felice Rosana , Scibona Paula , Simonovich Ventura , Riggi Maria Cecilia , Cravero Florencia , Odetto Diego , Saadi José , Jotimliansky Laura Fabia 
Published: June 2023

e17593 Background: OCEANIA is a retrospective database study that evaluated treatment patterns and outcomes in a cohort of patients diagnosed with all ovarian cancer (OC) types in private healthcare settings in Brazil and Argentina. The present analysis described up to 5-year real-world (RW) outcomes in an OC cohort of patients who received first-line platinum-based treatment (PBT) in Argentina. Methods: Patients with an OC code diagnosed from 2010 to 2019 who received a PBT alone or in combination with other therapeutic modalities (other antineoplastics, surgery, and/or radiotherapy) were selected from a private healthcare provider’s database (Hospital Italiano de Buenos Aires) in Argentina. Frequency of PBT patients by FIGO (International Federation of Gynecology and Obstetrics) stage was described. Cumulative risk of progression to subsequent treatment or death was calculated for one year up to five years after the end of first PBT from the survival analysis (using Kaplan–Meier analyses). RW progression-free survival (RW-PFS) was defined as the time between the end of first PBT and the beginning of subsequent treatment or death; patients who were lost to follow-up were censored at the end of the study period. Results: From 741 OC patients in the database, 321 (43.3%) were exposed to a PBT. Among this population, 89.4% had information about FIGO staging: 39 (13.6%) were stage 1; 23 (8.0%) stage 2; 195 (67.9%) stage 3; and 30 (10.5%) stage 4. During the follow-up period, 209 events were recorded, including 181 progressions to subsequent treatments and 28 deaths. The unadjusted mean (standard deviation) and median RW-PFS were 16 (22.3) months and 6 months, respectively. The adjusted cumulative risks of progression or death for years 1–5 were 53.8%, 67.6%, 71.2%, 74.4%, and 76.1%, respectively. Conclusions: Almost two thirds (65.1%) of patients with OC exposed to PBT progressed to subsequent treatment or death during follow-up. The greatest risk of progression was observed within the first year after end of PBT, likely because almost 80% of patients were at stages 3 and 4 and the therapeutic options available during the study period were limited. Funding: GSK213815.