bluuebunny/crossref_metadata_2025 huggingface dataset:
Posterior reversible encephalopathy syndrome in malignancy: Hypercalcemic storm?
Authors: Dandwani Mehndi , Chennapragada Suma Sri , Sharma Shivani , Ramphul Kamleshun , Lohana Petras
Published: June 2023

e17559

Background: Posterior reversible encephalopathy syndrome (PRES) is a clinical-radiological entity characterized by seizures, headaches, altered mental status and visual anomalies associated with vasogenic edema affecting the parietal-occipital lobes on brain magnetic resonance imaging. PRES is rarely described in hypercalcemia of malignancy although multiple mechanisms have been postulated in various case reports. Hence, we conducted this study to evaluate whether there is an increased risk of PRES with hypercalcemia of malignancy. Methods: We analyzed the 2016-2020 National Inpatient Sample (NIS) and extracted patient data with a diagnosis of ovarian cancer, lung cancer, multiple myeloma (MM), breast cancer, diffuse large B-cell lymphoma (DLBCL), and secondary bone cancer. Cases with a history of primary hyperparathyroidism, vitamin D intoxication and familial hypocalciuric hypercalcemia were excluded. The presence of hypercalcemia and PRES were estimated (per 10,000 cases), and their respective adjusted odds ratios (aOR) were calculated via multivariate regression analysis. Results: We identified 1,775 PRES cases in 3,781,899 cancer patients studied. Patients with breast cancers (26 per 10,000 hypercalcemia cases vs. 4 per 10,000 cases with no hypercalcemia, aOR 4.523, 95% CI 3.418-5.984, p < 0.01), ovarian cancers (41 per 10,000 hypercalcemia cases vs. 8 per 10,000 cases with no hypercalcemia, aOR 5.224, 95% CI 3.075-8.875, p < 0.010), and secondary bone neoplasms (14 per 10,000 hypercalcemia cases vs. 5 per 10,000 cases with no hypercalcemia, aOR 2.160, 95% CI 1.671-2.793, p < 0.01) exhibited a statistically significant increased outcome of PRES in association with hypercalcemia. The presence of hypercalcemia among lung cancer patients (aOR 0.755, 95% CI 0.451-1.263, p = 0.284), MM (aOR 1.005, 95% CI 0.751-1.346, p = 0.973), and DLBCL (aOR 1.393, 95% CI 0.806-2.408, p = 0.236) did not show a valid odds ratio for PRES. Conclusions: Our study found a higher association of PRES among hypercalcemia patients with ovarian cancer, breast cancer and secondary bone neoplasms. Prompt recognition of PRES and hypercalcemia-directed treatment can allay the morbidity related to PRES. While our study was limited in quantifying the cut-off values of hypercalcemia causing PRES, designated protocols entitled solely to determining serum calcium thresholds in these cancers warranting rigorous treatments are needed. PRES’s association with hypercalcemia in female-dominant cancers also paves way for further studies looking into the influences of sex hormones and hormonal therapies on the development of PRES with hypercalcemia.
Quality of life (QoL) in patients with recurrent ovarian clear cell carcinoma (rOCCC) receiving durvalumab (D) versus physician’s choice chemotherapy (PCC) in the randomized phase II MOCCA/APGOT-OV2/GCGS-OV3 trial.
Authors: Ngoi Natalie YL , Sun Haoyang , Choi Chel Hun , Heong Valerie , Ow Samuel Guan Wei , Chay Wen Yee , Kim Hee Seung , Goss Geraldine , Goh Jeffrey C. , Lin Meiqi , Lim Diana , Kim Jae-Weon , Friedlander Michael , Tai Bee Choo , Kim Kidong , Tan David Shao Peng
Published: June 2023

e17564

Background: In the phase II MOCCA/ APGOT-OV2/ GCGS-OV3 trial, D was not superior to PCC in prolonging progression-free survival in patients with rOCCC. Fewer all-grade and high-grade adverse events were observed for patients treated with D compared with PCC. We analysed health-related QoL by treatment arm. Methods: In this multicentre, open-label, randomised phase II trial, eligible patients were randomly assigned (2:1), using dynamic block randomization with block size of 6, and stratification by Eastern Cooperative Oncology Group performance status, to receive D (1500mg on day 1, in 28-day cycles) or PCC until disease progression, intolerable toxicity or withdrawal of consent. Patients treated with PCC were able to receive any agent deemed appropriate by the Investigator, however the addition of anti-angiogenic drugs was prohibited. Patients with disease progression on PCC were allowed to crossover to D. Patients completed European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-OV28 QoL questionnaires at baseline and every 4 weeks until end of study treatment. The minimal important difference for clinically relevant change was fixed at 10 points. Linear mixed-effects models were used to estimate the treatment effect on QoL outcomes, accounting for the intra-subject correlation in QoL scores at repeated visits from treatment cycles 2 to 6, while adjusting for baseline QoL scores (cycle 1 day 1) and time of visit. We included all patients whose QoL scores were available at both baseline and at least one visit from cycles 2 to 6. Results: 47 patients were randomly assigned to treatment with D (31 patients) or PCC (16 patients). Compliance to QoL questionnaires was 81.6 % (D) and 87.5% (PCC) at baseline. QoL data was available for 22.6-81.6% (D) and 31.3-87.5% (PCC) of patients over time. Longitudinal analysis of QoL data by domain revealed no significant differences in global health status, functional scales or most of the symptom scales based on EORTC QLQ-C30 or QLQ-OV28 between patients treated with D compared with PCC, except for the Constipation symptom scale on QLQ-C30 which showed an estimated mean difference of -20.8 points (95% confidence interval (CI), -31.5 to -10.2; p = 0.001) and the Hair loss symptom scale on QLQ-OV28 which showed an estimated mean difference of -19.6 points (95% CI -36.6 to -2.6; p = 0.025). Conclusions: D and PCC did not lead to significant differences in patient-reported global health status or functional scales. However, PCC was associated with increased patient-reported constipation and hair loss compared with D in rOCCC. Clinical trial information: NCT03405454 .
The landscape of BRCA1 and BRCA2 alterations in Chinese ovarian cancer patients.
Authors: Hou Minmin , Sun Li , Yu Xiuzhang , Du Pengyao , Liu Chuang , Meng Fanfan , Zhang Yaxuan , Li Ling
Published: June 2023

e17565

Background: BRCA1 and BRCA2 are tumour suppressor genes, involved in the homologous repair of double-stranded DNA breaks, located at 17q21.31 and 13q13.1, respectively. Germline BRCA1/2 mutations are identified in 13-15% of ovarian cancers (OC), while an additional 5-7% of ovarian cancers harbor somatic BRCA1/2 mutations among foreign populations. To determine the landscape of germline and somatic pathogenic BRCA1 and BRCA2 alterations in Chinese patients with ovarian cancer tested by next‐generation sequencing (NGS), with the aim of defining the best strategy to be implemented in future routine testing. Methods: 472 normal-paired samples from Chinese patients with ovarian cancers were analyzed using hybridization capture-based next generation sequencing. Somatic and germline mutations were identified including 500 genes associated with tumor development. Sequencing data were analyzed to call tumor specific single nucleotide variants (SNV), small insertions and deletions (InDels), copy number alterations (CNA) and gene fusions and rearrangements. Results: Overall, 472 ovarian cancer patients underwent somatic and/or germline NGS analysis, the BRCA1 and BRCA2 genes sequenced in this study covers all targeted coding exons and exon-intron boundaries. Among these patients, 54/472 (11.4%) patients carried BRCA( BRCA1/2) mutations. Inside, there were 43/472 (9.1%) patients occurred somatic BRCA mutations, 62.8% (27/43) of variants were in BRCA1 and 37.2% (16/43) were in BRCA2. Furthermore, 3 cases carried BRCA1 and BRCA2 somatic co-mutation, of which only 1 showed BRCA1/ BRCA2 copy number losses. In 54 OC patients who carried BRCA mutations, 10 patients occured copy number alterations, of which 6 patients showed BRCA1 copy number losses, 4 patients showed BRCA2 copy number losses, and 1 patient showed BRCA2 copy number gains. Germline BRCA variant was detected in 18/472 (3.8%) patients, 66.7% (12/18) of variants were in BRCA1 and 33.3% (6/18) were in BRCA2. Of the 12 BRCA1 germline mutations, 11 were pathogenic heterozygous mutations (c.2679_2682del; c.2101_2102del; c.5085_5086insT; c.1660G > T; c.4810C > T; c.1504_1508del; c.1465G > T; c.1480C > T; c.2110_2111del; c.4185+1G > A; c.81-2A > G), one was likely pathogenic heterozygous mutation (c.5216A > G). Of the 6 BRCA 2 germline mutations, four were pathogenic heterozygous mutations (c.5722_5723del; c.5291C > G; c.5164_5165del; c.3109C > T), one was likely pathogenic heterozygous mutation (c.869_870del), and one was uncertain significance heterozygous mutation (c.7976+3A > G). Conclusions: This study revealed the molecular features of BRCA1 and BRCA2 in Chinese ovarian cancer patients, which could help to identify therapeutic targets and personalize therapy management, leading to improved patient outcomes as predictive biomarkers or platinum-based therapy.
A web-based prediction model for overall survival of elderly patients with epithelial ovarian cancer: A population-based study.
Authors: Tang Lingliya , Song Kun , Chu Ran , Chen Zhongshao , Zhao Yong , Wang Shuaixin
Published: June 2023

e17570

Background: Epithelial ovarian cancer (EOC) has been extensively studied. However, no prediction model has been carried out on the prognosis of elderly patients. Our study aims to explore survival patterns in elderly EOC patients. Methods: Data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Patients over 65 with EOC between 2004 and 2014 were included for model training and validation, while 2015 for external validation. COX proportional-hazards regression model was used to identify risk factors and applied them to the prediction model. We then evaluated performance of our model through receiver operating characteristic (ROC) curve, calibration curve and decision curve analysis (DCA). Risk stratification system was used to reflect the survival. To facilitate daily use, we developed an online application. Results: A total of 6141 patients were included. COX regression models indicated 10 independent risk factors. Our model was proved to have good performance with AUC of ROC curve: 0.768(95CI:0.749-0.788), 0.748 (95CI:0.733-0.763), 0.766 (95CI:0.750-0.781) for 1-, 3-, 5-year OS in the training cohort and 0.776 (95CI:0.757-0.796), 0.760 (95CI:0.745-0.775), 0.784 (95CI:0.769-0.799) for CSS. In the validation cohort, 0.800 (95CI:0.773-0.827), 0.770 (95CI:0.748-0.793), 0.787 (95CI:0.765-0.810) for OS and 0.808 (95CI:0.780-0.836), 0.780 (95CI:0.758-0.803), 0.801 (95CI:0.779-0.824) for CSS. In the risk stratification system, the low-risk group had the highest survival rate. Almost all patients in the low- and intermediate-risk groups underwent surgery, about 1/3 patients in the high-risk group did not receive surgery. Their survival rates were not optimistic, and patients over 85 were more likely to be classified as high-risk. Conclusions: A predictive model was constructed to evaluate survival for elderly EOC patients and demonstrated good predictive value that we can apply to help physicians make clinical decisions and plan treatment. [Table: see text]
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.
Overall survival in treated ovarian cancer patients 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

e17595

Background: OCEANIA is a retrospective, real-world database study that evaluated treatment patterns and outcomes in a cohort of patients diagnosed with ovarian cancer (OC) in private healthcare settings in Latin America. The present analysis focused on evaluating up to five-year overall survival (OS) in a cohort of treated patients with OC in Argentina. Methods: Patients with an OC code diagnosed from 2010 to 2019 and with a cancer-related treatment claim (antineoplastics, surgery, and/or radiotherapy) were selected from a private healthcare provider’s database (Hospital Italiano de Buenos Aires) in Argentina. Patients were followed from diagnosis until the end of observation period or death. Frequency of OC patients by FIGO (International Federation of Gynecology and Obstetrics) stage was described. Cumulative treatment type was described through the whole follow-up period. One- to five-year survival Kaplan–Meier curves were built; patients who were lost to follow-up were censored. Results: 741 patients with OC were identified in the database with a mean (standard deviation) follow-up time of 31.7 (30.6) months; 539 (72.7%) were treated during this period. Among this population, 76.3% had information about FIGO staging: 73 (17.8%) were stage 1; 36 (8.8%) stage 2; 259 (63.0%) stage 3; and 43 (10.5%) stage 4. Cumulative distribution across treatment types revealed 355 (65.9%) patients received antineoplastics (321 [90.4%] received platinum-based treatment), 496 (92.0%) surgery and 18 (3.3%) radiotherapy. During a five-year observation window, 111 patients died (more than one half within two years of diagnosis). The adjusted cumulative OS for all treated patients in years 1–5 was 93.2%, 87.2%, 80.9%, 74.1%, and 69.0%, respectively (Table). Conclusions: OS is a key outcome in assessing the impact of current standards of care. Based on the results, although most (69.0%) of the patients survived after 5 years of follow-up, further improvement in OS presents a challenge. However, recent drug releases for OC management in Latin America may change this scenario. [Table: see text]
Circulating tumor DNA-based molecular residual disease detection for the monitoring of high-grade serous ovarian cancer.
Authors: Ying Xiang , Zheng Xiaocui , Wang Yizhi , Li Jiarui , Li Xing , Lin Guomin , Wang Kai , Wang Xipeng
Published: June 2023

e17600

Background: The current standard treatment of epithelial ovarian cancer includes surgery and platinum-based chemotherapy. Most of the patients are sensitive, but still over 70% of patients have recurrence or disease progression. Post-operative circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) test can be a potential biomarker for monitoring the disease. Methods: Stage II-IV high-grade serous ovarian cancer (HGSOC) patients were recruited in this study. Tumor tissues were collected for whole exome sequencing (WES; 300x). Germline mutations were excluded by paired white blood cell test. Proprietary algorithm was used to select 30-40 single nucleotide variants (SNV) for each patient. Blood samples were collected at diagnosis, after surgery, after chemotherapy, and during adjuvant treatment, and MRD was detected by multiplex polymerase chain reaction (PCR)-based sequencing (100,000x) using the customized panel. Results: At the time of analysis, WES was performed in 20 patients, of which 11 of them harbored HRR pathway-related mutations, including 5 BRCA1, 4 BRCA2, 1 ATM, and 1 FANCL. 7 patients had completed MRD monitoring for 3 times (pre-surgery, post-surgery, and post-chemotherapy). 71.4% (5/7) of patients were positive for MRD at baseline, with a median variant allelic frequency (VAF) of 2.79%. The VAF at baseline was positively associated with CA125 level at baseline (Pearson R = 0.937，p = 0.002). 2 patients were positive for MRD after surgery (VAF = 0.09% and 0.04%). One of them presented with multiple diverse lesions and the CA125 level returned normal after surgery and 8 cycles of chemotherapy. Another patient had an abnormal CA125 level of 1597 U/ml after surgery. All the 7 patients were negative for MRD after completion of chemotherapy. Follow-up is ongoing. Conclusions: We preliminary proved the feasibility of dynamic monitoring with MRD in epithelial ovarian cancer patients. Over 70% of HGSOC patients were MRD-positive at baseline. The MRD status was generally consistent with the clinical status of the patients. The performance of MRD in predicting recurrence of HGSOC is still under investigation. Clinical trial information: NCT05027828 .
GD2 and GD3 gangliosides as diagnostic biomarkers for all stages and subtypes of ovarian cancer.
Authors: Jeter Anna , Galan Alba , Papaluca Arturo , Nejatie Ali , Matanes Emad , Brahimi Fouad , Yasmeen Amber , Carmona Euridice , Klein Kathleen Oros , Billes Sonja , Dawod Ahmed E. , Gawande Prasad , Mes-Masson Anne-Marie , Greenwood Celia , Gotlieb Walter H. , Saragovi H. Uri
Published: June 2023

e17604

Background: Ovarian cancer (OC) is the deadliest gynecological cancer, often diagnosed at advanced stages. A fast and accurate diagnostic method for early-stage OC is needed. The tumor marker gangliosides, GD2 and GD3, exhibit properties that make them ideal potential diagnostic biomarkers but they have never before been quantified in OC. We investigated the diagnostic utility GD2 and GD3 for diagnosis of all subtypes and stages of OC. Methods: This retrospective study evaluated GD2 and GD3 expression in biobanked tissue and serum samples from patients with invasive epithelial OC, healthy donors, non-malignant gynecological conditions, and other cancers. GD2 and GD3 levels were evaluated in tissue samples by immunohistochemistry (n=299), and in two cohorts of serum samples by quantitative ELISA. A Discovery Cohort (n=379) showed feasibility of GD2 and GD3 quantitative ELISA for diagnosing OC, and a subsequent Model Cohort (n=200) was used to train and cross-validate a diagnostic model. Results: GD2 and GD3 were expressed in tissues of all OC subtypes and FIGO stages but not in surrounding healthy tissue or other controls. In serum, GD2 and GD3 were elevated in patients with OC. A novel diagnostic model that included serum levels of GD2 and GD3 was superior to the standard of care (CA125, p<0.001) at detecting OC, as well as, in early-stage (I/II) OC samples. Conclusions: GD2 and GD3 are high value candidates for building a novel diagnostic panel. A diagnostic model combining GD2 and GD3 quantification in serum had diagnostic power for all subtypes and all stages of OC, including early-stage. Further research exploring the utility GD2 and GD3 for diagnosis of OC is warranted. Future work will aim to validate these biomarkers in independent prospective studies. [Table: see text]
Development of a microbead based immunoassay to detect circulating soluble HLA-E: Application in cancer immunobiology.
Authors: Kanangat Varun , Auger Claire , Tarhoni Imad , Marshalla Megan K. , Gerard David , Abdelkader Ahmed , Borgia Jeffrey Allen
Published: June 2023

e17606

Background: The Human Leukocyte Antigens [HLA] gene complex is subdivided into classical (HLA-A, B, and C) and non-classical (HLA-E, F, G, and H) loci. These genes are associated with immune modulation and immunopathogenesis in cancer, though the roles of non-classical HLA molecules are poorly understood. Here, we explored potential expression patterns of soluble HLA-E (sHLA-E) in patient sera across a range of common malignancies to identify potential disease applications for future study. Methods: Quantitative Luminex immunobead assay were developed for sHLA-E using methods we previously defined. In the first phase of this study, we assessed sHLA-E protein levels across a range of treatment-naïve metastatic malignancies (n=5 each), including breast, lung adenocarcinoma, lung squamous cell carcinoma, colorectal, head and neck, ovarian, melanoma, and sarcoma. Based on these results, we refocused our efforts on a second cohort surgically treated by gynecologic oncology for either non-malignant (n=13) or malignant (n=42) lesions of ovarian origins. One-way ANOVA or Independent sample t tests, with normality confirmed via Levene's Test for Equality of Variances, were used to identify statistical relationships. Results: There were significantly (p<0.05) higher levels of sHLA-E protein in ovarian cancer relative to other cancer types surveyed. In the second phase of the study, serum specimens from patients undergoing surgery for a suspected gynecological malignancy were tested for sHLA-E. This study also showed the significantly high expression of sHLA-E in ovarian cancer relative to those with nonmalignant lesions of ovarian origins (p=0.035) that was independent of FIGO grade (p>0.05). For comparison, levels of sHLA-E were not significantly elevated for tumors of endometrium/ endomyometrium origins (n=76; p=0.270) relative to baseline of benign cases. Conclusions: We identified a highly specific statistical relationship for a circulating isoform of HLA-E in ovarian cancer in our cohorts. The significance of these findings in relation to clinical outcomes or treatment response will be explored in future studies. [Table: see text]
Multivariate index assay (MIA3G) to reduce preventive surgery for ovarian cancer.
Authors: Ghosh Srinka , Pappas Todd C. , Reilly Gerard P , Phan Ryan
Published: June 2023

e17607

Background: Ovarian cancer (OC) – most lethal gynecologic malignancy - is rare among women with adnexal mass. Preventive adnexal surgery is a common practice, despite pathology confirming malignancy in only 10-15% of these cases. This motivates a surveillance-based clinical management paradigm to prognosticate the risk for malignancy and channel appropriately for surgery. We recently developed a multivariate index assay -MIA3G[1] - to assess risk for OC in women with adnexal mass. In a multi-center prospective surveillance trial, we assessed the concordance between preventive surgery and clinical management using MIA3G. Methods: MIA3G risk prediction uses a DNN algorithm which models 7 serum biomarkers (CA125, HE4, BM2, APO, FSH, TFR, PreAlbumin), age and menopausal status. With NPV of 99.7% (CI:99.2–99.9) it risk stratifies patients into low probability of malignancy or indeterminate. Across 11 centers, the MIA3G cohort comprised of 546 women (IQR:41-61yo) with symptomatic or asymptomatic masses and/or presence of HBOC variants. Serial blood draws were timed with clinic-visits and the ultimate one coincident with surgery. The objectives were: 1) prognosticate the MIA3G based preventive surgery pool and 2) establish concordance between the MIA3G probabilistic risk and the pathology-based outcome of malignancy versus benign. Results: In the study cohort of 546 patients, 20.3% (111) underwent preventive surgery. Conservatively, at a 12.8% FPR[1], MIA3G would have stratified approximately 70 patients, a projection of 37% less for surgery. Partitioning by clinical characteristic: (i) symptomatic: In comparison to 27.8% (73/263) of patients referred to surgery, MIA3G projections would have resulted in a 54.8%(33/263) reduction. (ii) asymptomatic: 22.5%(31/138) of patients were referred to surgery; MIA3G projections would have resulted in a 45.2% (17/138) reduction. In the 111 preventive surgeries, pathology confirmed a malignancy rate of 6.3% (7/111). The overall concordance of MIA3G with pathology was 84.68% (94/111) which increased to 91.98% (102/111) in the pre-menopausal (PRE) sub-cohort. The malignant discordancy (MIA3G:FN), all in PRE, comprised of early-stage epithelial: endometreoid, Leiomysarcoma and Sertoli-Leydig cell where the masses were characterized as cystic benign/indeterminate by ultrasound. These findings underscore the power of MIA3G when preventive surgery is considered for patients with ovarian cancer risk. Conclusions: The multivariate index assay MIA3G reduces numbers of preventative surgery for ovarian cancer risk. The high concordance establishes that MIA3G non-invasive surveillance-based clinical management can be effective for the risk assessment of ovarian cancer in patients presented with adnexal mass. Surgical management should be reserved for high probability of malignancy. [1]: DOI 10.3389/fmed.2023.1102437.