bluuebunny/crossref_metadata_2025_split huggingface dataset:
PACSIN3 is a novel biomarker for platinum resistance BRCA mutated platinum resistance epithelial ovarian cancer.
Authors: Han Gwan Hee , Cho Hanbyoul , Yun Hee , Kim Jae-Hoon 
Published: June 2022

e17540 Background: Mutations in breast cancer susceptibility gene type 1 and type 2 (BRCA1 and BRCA2) put women at a higher risk of developing epithelial ovarian cancer (EOC). In individual carrying BRCA1 mutation has about 39-49% of the probability developing EOC in a lifetime. With BRCA2 mutations, the probability of developing EOC is about 11- 18 %. EOC patients with BRCA mutations shows an advanced histological grade compared to patients with BRCA wile type and respond better to platinum therapy, showing better survival. Patients with BRCA mutation shows better response to the platinum therapy, because in the absence of functional BRCA protein, cells fail to repair intra-strand crosslinks formed by DNA cross linking agents such as platinum drugs, leading to apoptotic cell death. However, despite the good response to platinum-based chemotherapy, EOC patients inevitably develop resistance to platinum drugs resulting in disease recurrent and is a major roadblock in a clinical management of cancer that carry BRCA mutation. Therefore, here we investigated the potential novel biomarkers with bioinformatics tools by analyzing an our own RNA sequencing. Methods: RNA sequencing data from 4 platinum sensitive BRCA mutated EOC patients and 4 Platinum resistance BRCA mutated EOC patients were analysed with various bioinformatic tools including Spatial Analysis of Functional Enrichment (SAFE) analysis, and the bioinformatic analysis result was verified with variuos ovarian cancer cell lines and public data. Results: Therefore, here we investigated the potential novel biomarkers with bioinformatics tools by analyzing an our own RNA sequencing data from 4 platinum sensitive BRCA mutated EOC patients and 4 Platinum resistance BRCA mutated EOC patients. The results of our study showed 308 total differentially expressed genes (DEGs) with 138 upregulated genes and 170 downregulated genes. By applying Spatial Analysis of Functional Enrichment (SAFE) analysis, we investigated that G2/M transition of mitotic cell cycle, MAPK cascade, double strand break repair via homologous recombination were the enriched pathways with upregulation of PABPC1, DCAF13, RAD21, PACSIN3 and downregulation of GCG11, HECW2, PSMA1. Their altered expression was verified in ovarian cancer cell lines and public database which showed the significant altered expression of PACSIN3 was observed in ovarian cancer cell lines suggesting as a potential biomarker for EOC treatment. Conclusions: Platinum resistance BRCA mutation EOC is an important issue to overcome the low survival rate for EOC patients. However, until now, there was relatively not much studies in discovring the biomarker or candidate gene of target therapy. Therefore, here we suggest the PACSIN3 as a new candidate gene for target therapy in platinum resistance BRCA mutation EOC.
Long-term survival in newly-diagnosed ovarian cancer patients.
Authors: Szamreta Elizabeth A. , Li Yeran , Monberg Matthew J. , Othus Megan 
Published: June 2022

e17543 Background: A proportion of women with ovarian cancer, even those with advanced-stage disease, will experience long-term survival post diagnosis. Mixture cure modeling provides insight into factors related to both short-term recurrence and death as well as long-term survival. The goals of this study were to estimate the long-term survival rate, and to evaluate associations between patient characteristics and the long-term survival rate and landmark 5- and 10- year survival, in a sample of newly-diagnosed ovarian cancer patients. Methods: The Tempus EMR dataset contains patients from academic & community oncology centers in the U.S. This study included adult women with a new primary diagnosis of ovarian, fallopian tube, or peritoneal cancer between 2000 and 2020. Women treated with a poly-ADP ribose polymerase inhibitor (PARPi), pembrolizumab, or nivolumab were excluded (n = 947; final sample size = 6,598). Mixture cure models were used to estimate the long-term survival rate (probability of living as long as an age- and gender-matched person without ovarian cancer), overall and stratified by patient demographic & clinical characteristics. Relative importance of variables associated with long-term survival was evaluated using logistic regression models with 5- and 10-year landmark outcomes. Results: Younger age, earlier stage, lower grade, favorable ECOG score, and platinum sensitivity were associated with better overall survival (OS). The long-term survival rate in our model was 25.0% (95% CI: 21.5-28.9). The long-term survival rate was higher for age < 65 vs. age 75+ [29.0% (24.8-33.6) vs. 10.5% (2.9-31.6)], early vs. advanced stage disease [62.0% (41.4-78.9) vs. 17.8% (14.1-22.2)], grade 1-2 vs. 3-4 [31.4% (12.1-60.3) vs. 20.4% (14.6-27.8)], ECOG 0-2 vs. 3-4 [26.1% (21.4-31.3) vs. 2.6% (0.05- 56.5)], and platinum sensitive vs. platinum resistant patients [47.5% (43.1-51.9) vs. 9.4% (7.0-12.5)]. Analyzing 5- and 10-year landmarks [n = 3,944 (59.8%), n = 3,107 (47.1%), respectively] in multivariable logistic regression models, platinum sensitivity had the strongest association, followed by cancer stage. Conclusions: Understanding differences in long-term survival based on patient characteristics is important for clinical decision-making and personalizing treatment. Overall, one quarter of ovarian cancer patients were long-term survivors; long-term survivors were more likely to be younger and have earlier stage disease, low grade disease, better performance status, or sensitivity to platinum-based therapy. These results also provide a baseline to evaluate long-term survival in patients on newer therapies such as PARPi when sufficient follow-up data are available.
Anlotinib plus letrozole in patients with platinum-resistant recurrent ovarian cancer: A prospective, single-arm, open-label, phase II study.
Authors: Wang Xipeng , Li Jiarui , Zhang Ping , Fang Xuhong , Wang Yizhi , Sun Huizhen 
Published: June 2022

e17545 Background: Studies have suggested that estrogen regulates the malignant transformation of ovarian surface epithelial cells, stimulates the growth and migration of cancer cells. and promotes the VEGF expression in epithelial ovarian cancer. Anlotinib is a novel multi-target tyrosine kinase inhibitor, inhibiting tumor angiogenesis and proliferative signaling. In this study, we evaluate the activity of anlotinib combined with letrozole in patients with estrogen receptor positive, platinum-resistant recurrent ovarian carcinoma (NCT04720807). Methods: Patients who have previously received two or more chemotherapy treatments, with histopathologically confirmed high-grade serous ovarian cancer (including salpingo carcinoma and peritoneal carcinoma), estrogen receptor (ER) positive and ECOG 0-2 were considered eligible for enrollment. Anlotinib was taken orally (10mg mg qd, d1-14, 21 days per cycle), and letrozole was taken orally (2.5mg qd, d1-21, 21 days per cycle). The treatment was continued until disease progression, death, or intolerant toxicity. The primary endpoint was objective response rate (ORR) and the secondary endpoints included disease control rate (DCR), duration of remission (DOR) progression free survival (PFS), overall survival (OS) and safety. Results: Between September 2020 and November 2021, 13 patients with a median age of 62 years (range:53-72), FIGO histopathological stage IC (23.1%), IIIC (53.8%) and IV (23.1%) were enrolled. Twelve of these patients have been evaluated for efficacy. In the efficacy-evaluable population (n=12), the therapeutic evaluation showed that 2 and 7 patients achieved partial response and Stable disease respectively, yielding the ORR of 16.7% (2/12, 95% CI: 3.3 to 54.3). The DCR was 75% (9/12, 95% CI: 39.3 to 93.3). The median PFS was 6.25 months (95% CI: 2.3m to not reached) and the median OS was not reached. The most common adverse events (AEs) were grade 1 or 2, which included laryngitis (69.2%), hypertension (53.8%), stomatitis (38.5%), diarrhea (30.8%), hand-foot syndrome (23.1%), and hyperuricemia (23.1%). The grade 3 AEs were hypertension (38.5%), diarrhea (7.7%) and hyperuricemia (7.7%). No higher AEs or treatment-related death were observed. Conclusions: Conclusions Anlotinib plus letrozole showed a promising efficacy with a favorable toxicity profile for patients with platinum-resistant recurrent ovarian cancer. The trial is ongoing and more data will be provided in the future. Clinical trial information: NCT04720807.
Effects of five prescriptions in Synopsis of Golden Chamber on the malignant phenotype and expression of CA125, CEA, HE4 proteins in human ovarian cancer cells.
Authors: Si Fuchun , Si Gao 
Published: June 2022

e17546 Background: Ovarian cancer(OC) is a common gynecological tumor with characteristics of low early diagnosis rate, late lack of effective treatment and high mortality. It is an important problem to find new effective treatment for ovarian cancer. Synopsis of the Golden Chamber is the miscellaneous diseases part of Treatise on Typhoid and Miscellaneous Diseases written by Zhang Zhongjing, a famous medical expert in Eastern Han Dynasty of China, and is also the earliest classical treatise on diagnosis and treatment of miscellaneous diseases, which records 205 prescriptions. This study aims to screen out formula with strong inhibitory effects on OC from 205 prescriptions of Synopsis of the Golden Chamber , and investigate the effects of screened prescriptions in Synopsis of the Golden Chamber on human ovarian cancer cell malignant phenotype and CA125, CEA and HE4 proteins expression. Methods: MTT method was applied to screen out the best effective prescription and determine the IC50 value of prescription on ovarian cancer ES-2 and OV-1063 cells. The effects of screened prescriptions on the proliferation, migration, invasion, cloning ability, cell cycle and CA125, CEA and HE4 proteins expression of ES-2 and OV-1063 cells were investigated by MTT assay, RTCA assay, soft agar assay, flow cytometry and western blot analysis. Results: Guizhi Fuling Pill, Dachaihu Decoction, Xuanfuhua Decoction, Baitouweng Decoction and Bentun Decoction were screened out, which all could obviously inhibit the proliferation of ES-2 and OV-1063 cells with dose-effect and time-dependent manner. The IC50 values of Guizhi Fuling Pill, Dachaihu Decoction, Xuanfuhua Decoction, Baitouweng Decoction and Bentun Decoction for ES-2 cell were 636.476, 315.859, 24.357, 9.519, 96.533μg/ml respectively; for OV-1063 were 403.119, 225.176, 12.977, 9.256, 115.86μg/ml respectively. The five prescriptions all significantly affected the cell morphology, proliferation, migration, invasion, cloning ability, cell cycle of ES-2 and OV-1063 cells. The five prescriptions all could decreased the protein expression levels of CA125 and CEA in ovarian cancer OV-1063 cells, while Guizhi Fuling Pill, Dachaihu Decoction, Xuanfuhua Decoction and Baitouweng Decoction decreased the expression of HE4 protein in OV-1063 cells. Conclusions: The five prescriptions in Synopsis of the Golden Chamber can inhibit the malignant phenotype of ovarian cancer, which may be related to the inhibition of CA125, CEA and HE4 proteins expression.
Characteristics of germline DNA damage response gene mutations in ovarian cancer in Southwest China.
Authors: Yin Rutie , Chen Jinghong , Li Qingli , Yan Xinyu , Wang Jie , Li Kemin , Song Liang , Zhong Lan , Ma Yu , Zhang Mengpei , Zeng Jing , Wang Danqing , Zhu Shida 
Published: June 2022

e17606 Background: DNA damage response (DDR) pathway is responsible for repairing endogenous or exogenous DNA damage to maintain the stability of the cell genome. Germline mutations of DDR genes are potentially predictive and prognostic biomarkers for oncotherapy and may predispose carries to some malignancies. We aimed to profile the characteristics of germline DDR gene mutations in ovarian cancer treated in our center to provide highlight on regional disparity and susceptibility genes. Methods: We retrospectively and unselectively enrolled a cohort of patients diagnosed as advanced epithelial ovarian cancer from October 2016 to October 2020, who had complete clinicopathological data and signed informed consent for gene testing. In total, peripheral blood samples from 432 patients were collected in our center and evaluated on specific germline alterations. This study was approved by the Medical Ethics Committee of West China Second University Hospital, Sichuan University (Ethical Lot Number 20200076). Results: The most observed mutated genes were FANCD2 (47%), BRCA1 (27%), BRCA2 (27%), ERCC5 (18%) and RECQL4 (17%). The frequency of missense mutation was higher than other mutation types in most genes, except FANCD2, TSC2 and PHOX2B. Deleterious DDR gene mutations and deleterious homologous recombination repair gene mutations were detected in 346 patients (80.1%) and 240 patients (55.6%), respectively. The most observed genes with deleterious mutation were BRCA1 (18.5%), BRCA2 (12.5%), ERCC5 (6%), MLH1 (5.8%), PALB2 (3.7%) and ERCC4 (3.7%). The prevalence of BRCA2 deleterious mutations is higher than other studies (patients mainly from Eastern China), and so are the mismatch repair genes. Furthermore, we pointed out that deleterious mutations of FNACD2 and RECQL4 are potential ovarian cancer susceptibility genes and may predispose carriers to ovarian cancer. Conclusions: Our study presented here showed the germline DDR gene mutation spectrum of ovarian cancer patients in Southwest China, which is different from other regions of China in some genes. And we found germline FANCD2 and RECQL4 deleterious mutations were likely ovarian cancer susceptibility sites, which should draw more attention in patient management and genetic counseling.
Methylated DNA markers discriminate ovarian cancer from benign tissue in BRCA carriers.
Authors: Weng Jessica , Bakkum-Gamez Jamie Nadine , Slettedahl Seth , Mahoney Douglas W. , Cao Xiaoming , Foote Patrick H. , Burger Kelli , Berger Calise K. , O'Connell Maria , Arndt Jacquelyn R. , Doering Karen A. , Sherman Mark E. , Taylor William R. , Chen Longwen , Couch Fergus , Kisiel John B. , Samadder Jewel 
Published: June 2022

e17610 Background: Methylated DNA markers (MDMs) associated with sporadic ovarian cancer (OC) are detected in plasma from patients with treatment naïve tumors, but not cancer-free controls. To assess potential benefits to patients at risk for hereditary OC, the aim of this study was to measure the performance of validated sporadic OC MDMs in OC and benign ovarian tissue (BOT), surgically obtained from germline BRCA1 or BRCA2 ( BRCA1/2) mutation carriers. Methods: BRCA1/2 carriers with OC and BRCA1/2 carriers who had undergone risk-reducing salpingo-oophorectomy (SO) were identified at a comprehensive cancer center. BRCA1/2 carriers in both OC and BOT groups were balanced on age and year of surgery with non- BRCA carriers with sporadic OC or benign indications for SO. OC and BOT formalin fixed paraffin embedded (FFPE) tissues were macrodissected following pathologist selection of representative sites; DNA was extracted, and bisulfite converted. 15 OC MDMs ( GDF6, IFFO1, MAX.chr1.147790358, MAX.chr6.10382190, MAX.chr11.14926602, C2CD4D, PDRM14, NCOR2, SKI, DSCR6, SIM2, PALLD, CDO1, GPRIN1, BCAT1) previously identified in sporadic OC were assayed by quantitative methylation specific PCR, normalized by β-actin, by blinded personnel. Areas under the receiver operating characteristic curve (AUC) were generated for each MDM to assess discrimination of OC from benign tissue and compared between BRCA1/2 and sporadic (non- BRCA) patients, using a z-test. Results: Among BRCA1/2 carriers, there were 48 OC ( BRCA-OC) and 48 BOT ( BRCA-BOT); among non- BRCA, we matched 48 OC (Sporadic-OC) and 48 BOT (non- BRCA-BOT). The median AUC for OC MDM discriminated between OC and BOT with AUCs in BRCA1/2 carriers was 0.87, (IQR, 0.83-0.93). Sporadic-OC vs non- BRCA-BOT median AUC was 0.88 (IQR, 0.83-0.92). AUCs were not significantly different for each MDM when stratified by BRCA or sporadic status. MDMs with an AUC of ≥0.9 in either group are shown (Table). Conclusions: OC MDMs identified and validated in sporadic OC are highly discriminant for OC from BOT in DNA extracted from tissues of people who carry a BRCA1/2 mutation. Testing the performance of these OC MDMs in plasma from BRCA1/2 carriers with and without OC may be of clinical value for high-risk patients and inform multi-cancer early detection testing strategies.[Table: see text]
Identifying targetable markers of resistance to dual TORC1/2 inhibition in endometrial cancer cell lines.
Authors: McGreal Katie , Crafton Sarah , David Jason , Stets Colin W. , Grosenbacher Nicholas , Chen James Lin , Hays John L. 
Published: June 2022

e17633 Background: For patients with endometrial cancer, the PI3K/AKT/mTOR pathway is an attractive target due to dysregulation of the pathway secondary to commonly found genetic alterations. Previous trials of mTOR inhibitors in endometrial cancer have shown modest clinical activity and tolerability. Here we present a proteomics based approach to identify novel partners that will enhance the efficacy of dual TORC1/2 inhibition. Methods: Five endometrial cell lines (AN3CA, ECC, HEC1A, HEC1B, RL952) were treated with the TORC1/2 inhibitor TAK228 or vehicle for one hour and protein concentrations were analyzed by reverse phase protein arrays (RPPA). We examined baseline protein and changes in individual proteins after treatment with TAK228 to determine correlations with sensitivity to TAK228. Identified proteins were then targeted with single agent pharmacologic inhibition and cytotoxicity measured by XTT analysis. Target inhibition was validated using WB analysis. Cooperativity in cytotoxicity for relevant combinations was measured using the methods of Chou-Talalay. Other phenotypic endpoints including migration, cell cycle alterations by flow cytometry and cell growth using live cell imaging were also collected. Results: Based on proteomics analysis, altered phosphorylation of CHK1(S296), CHK2(T68) and increasing concentration of VEGFR2 were strongly correlated with TAK228 resistance. TAK228 (TORC1/2, IC50 4-20nM), AZD7762 (CHK1/2, IC50 15-160nM), LY2603618 (CHK1, IC50 260nM-7.5mM) and cediranib (VEGFR2, 800nM-1mM) all had significant cytotoxic effects as individual agents on multiple endometrial cell lines. AZD7762 in combination with TAK228 led to synergism in all cell lines tested (mean combination index, 0.2-0.8). Single agent AZD7762 increased the number of cells in S-Phase and decreased cellular migration. Addition of recombinant VEGF-A to cell culture enhanced resistance to TAK228 in a dose dependent manner as measured by cell growth assays using live cell imaging. Combination of cediranib and TAK228 also showed significant synergism in multiple cell lines. Conclusions: RPPA identified changes in phosphorylated CHK1/2 and total VEGFR2 as being correlated to resistance to dual TORC1/2 inhibition with TAK228 in multiple endometrial cancer cell lines. While single agent activity of TORC1/2, CHK1/2 and VEGFR2 inhibitors showed varying activity, combinations of TAK228 with either cediranib or AZD7762 showed significant synergism in multiple cell lines. Clinical examination of these combinations agents may prove useful in recurrent endometrial cancer.
Neutrophil-to-lymphocyte ratio as a predictor of survival in head and neck squamous cell carcinoma patients treated with cisplatin.
Authors: Kao Derek , Ferrandino Rocco , Roof Scott , Sigel Keith Magnus 
Published: June 2022

e18004 Background: Neutrophil-to-lymphocyte ratio (NLR) is an easily attainable biomarker that is correlated with systemic inflammation and identifies increased risk of treatment complications and decreased survival in patients with cancer. Our objective was to investigate the use of NLR as an independent prognostic predictor of survival in patients with head and neck squamous cell carcinoma (HNSCC) treated with cisplatin chemotherapy. Methods: We conducted a retrospective study of 2,084 patients in the Veterans Health Affairs system with stages III–IVB head and neck squamous cell carcinoma diagnosed between 2000–2014 and treated with cisplatin-based chemoradiotherapy for curative intent. We calculated NLR values from laboratory values collected in the 30 days prior to initiation of chemoradiotherapy and dichotomized NLR using the Youden J-statistic (NLR = 3.64). We then compared outcomes using Cox proportional hazards methods, adjusting for sociodemographic characteristics (age, race, and sex), date of cancer diagnosis, smoking status, alcohol use, primary site of tumor, tumor characteristics (overall stage, T stage, and N stage), comorbidity score, eGFR, baseline neuropathy and hearing loss, BMI, and oncologic surgical procedures. Results: The cohort had a median age of 61. 99% of cases were male, 82% were white, 13% were black, and 4% were Hispanic. 36% of cases had an NLR > 3.64 prior to treatment initiation. Median overall survival was 32.6 months for the low-NLR group and 24.9 months for the high-NLR group. In unadjusted analyses, a high NLR was associated with an increased risk of all-cause death (hazard ratio [HR]: 1.21; 95% CI 1.08–1.34). In adjusted analyses, high NLR retained significance and predicted overall survival (HR: 1.15; 95% CI 1.02–1.30). We also performed a secondary analysis for death within six months of cancer diagnosis; high NLR was associated with > 50% increased risk of death after adjustment (HR: 1.56; 95% CI 1.04–2.33). Conclusions: In this large cohort of Veterans with advanced HNSCC undergoing chemoradiotherapy, NLR was an independent prognostic predictor of survival. NLR may be a useful clinical risk stratification tool prior to chemoradiotherapy initiation.
Real-world data of use of nivolumab in platinum refractory head and neck cancers.
Authors: Choudhary Jatin , Kumar Hemanth , Ravikrishna Madala , Patil Vijay Maruti , Prabhash Kumar 
Published: June 2022

e18686 Background: Nivolumab is one of the approved agents for platinum refractory and second line treatment in head and neck cancers as per NCCN guidelines. However, accessibility of nivolumab in low- and middle-income countries is less than 1-3%.There is data suggesting that low doses of nivolumab can also be effective. Hence in this analysis we explore the outcomes and adverse events with low doses of nivolumab in the second line and beyond setting. Methods: The head and neck medical oncology unit of Tata memorial hospital maintains a prospective database of all patients undergoing immunotherapy. A query was raised in this database to identify head and neck cancer patients who were treated with low doses of nivolumab. We identified 42 patients. The baseline characteristics, compliance to nivolumab, the reason for administration of low dose and the outcomes (progression free survival, date of progression, date of death) were recorded. The dose of nivolumab used in this study was 40 mg flat dose every 2 weeks. Descriptive statistics were performed. Kaplan Meier estimates were used to see overall survival (OS) and progression free survival (PFS). Results: The median age of the patients was 55.8 (IQR: 25.8-82.8) Male to female ratio was 53:11. All patients were platinum refractory and had progressive disease within the last 6 months of the last dose of platinum. The ECOG performance status was 0- 1 in 56 (88.9%) in patients and 2 in 8 (11.1%) patients. Median number of immunotherapy cycles received was 2 (1-4). The response was seen in 15 (23.1%) patients. The median OS was 6.7months (3.4-8.8) and PFS was 2.3 months (0.6-4.02) The details regarding PD L-1 expression and effectiveness of nivolumab will be presented at the conference. Conclusions: Low doses of nivolumab can be an option which is efficacious in patients who do not have access to standard dose nivolumab. There is a need for testing this regimen in large randomized studies as full doses of nivolumab are not accessible to the vast majority of the patients in low- and middle-income countries.