bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation of longtime efficacy maintenance PARP inhibitor therapy with pre-treatment in a single-institution experience.
Authors: Nicoletto Maria Ornella , Grego Andrea , Baldoni Alessandra , Tasca Giulia , Sommariva Antonio , Tonello Marco , Torri Valter , Pilati Pierluigi 
Published: May 2020

e18084 Background: The use of PARP inhibitors (Olaparib-Niraparib) has shown an important benefit in PFS in patients with relapsed ovarian cancer both with gBRCA and non-BRCA mutation. Methods: This was a single-institution, retrospective cohort study of 93 patients. Clinical data were obtained by the review of the electronic medical report. The 93 patients were treated with PARP Inhibitors(PARP-I) between Apr 2014 and Dic 2019. The patients were evaluated according to age, BRCA mutation, pretreatment with Trabectedin, Bevacizumab, last line of pretreatment with Platinum-Gemcitabine+Paclitaxel versus Caelyx-Oxaliplatin, number of previous lines of chemotherapy, residual disease before PARP-I. Statistical analysis of survival was performed with Kaplan-Meyer, univariate and multivariate analysis with Cox regression. Disease Free Survival (DFS) was evaluated from the start of PARP-I therapy while Overall Survival (OS) from the diagnosis. Results: Median age was 64 (42-90), patients with germinal mutation BRCA were 34 (36.6%), 58 without mutation and 1 patient without genetical analysis. 20 (21,5%) patients were pretreated with Trabectedin plus Pegylated Liposomal Doxorubicine (PLD), while 8 (8,6%) with Trabectedin-Bevacizumab, 26 (28%) patients were pretreated with Bevacizumab +/- Trabectedin. Before PARP-I patients more frequently were pretreated with 2-3 line 60, 64.5%): in the last line of pretreatment chemotherapy 47 (50,4%) patients received PLD+-Oxaliplatin versus Carboplatin-Taxol or Carboplatin-Gemcitabine. In 64% of the patients CTscan or ecography showed residual disease > 1 cm before starting PARP-I treatment . Median follow-up was 17 months: 54 (58.1%) patients in PARP-I treatment relapsed, while 32 (34.1%) patients died. Multivariate analysis showed a significant association in the number of lines pretreatment: in more than 3 lines HR was 2.00 (CI 1.2-3.4, p = 0.012), according to residuum less or more 1 cm prior to start PARP therapy (logrank p = 0,0286). Conclusions: The administration of PARP is important for OS immediately after 2° line chemotherapy in platinum sensitive patients Logrank p = 0.0065, with higher response not significant, about OS specially if following non-anemic PLD-Oxaliplatin therapy (p = 0,0849 Logrank) Also significant is OS according to residuum less or more 1 cm prior to start PARP therapy (logrank p = 0,0286) The doses and relative reductions in PARP-I did not change efficacy.
The development of a homologous recombination deficiency (HRD) score to identify HR-deficient tumors.
Authors: Wu Xiaohua , Wen Hao , Feng Zheng , Shao Lin , Liu Chenglin , Liu Hao , Zhang Lu , Mao Xinru , Guan Xiaoqian , Hou Ting , Han-Zhang Han , Zhang Zhou 
Published: May 2020

e18085 Background: BRCA1/2 mutated cancers are homologous recombination repair (HRR) deficient and often sensitive to drugs targeting DNA repair pathway. Emerging evidences suggest tumors with mutations in other HRR genes might also respond favorably to DNA repair pathway targeted drugs; however, the results were inconclusive. Genomic instability is characterized by telomeric allelic imbalance (TAI), large-scale transition (LST) and loss of heterozygosity (LOH). Here, we developed an HRD score based on assessing the status of these patterns in tumors. Methods: 73 cancer patients, including 36 breast cancer (BC), 35 ovarian cancer (OC) and 2 prostate cancer (PC) patients were recruited. 28 were BRCA-deficient tumors (10 BCs, 17OCs and 1 PC) harboring pathogenic/likely pathogenic (P/LP) germline mutation in BRCA1/2 with LOH. 13 BRCA-mutated tumors (10 BCs, 2 OCs and 1 PC) carried P/LP BRCA1/2 mutation without LOH. The rest 33 were HRR wild type controls (16 BCs and 16 OCs). All samples were profiled using a panel consisting of 24 classic HRR genes and their adjacent SNPs. The scores for TAI, LST and LOH were developed separately and an incorporated HRD score based on the 3 patterns was established. Clinical data of 42 OC pts were collected to validate the algorithm. Results: All pairwise correlations of TAI, LST and LOH scores showed high correlations (TAI vs. LOH: r = 0.89; TAI vs. LST: r = 0.92; LST vs. LOH: r = 0.83). The univariate logistic regression was used to assess the correlation of the score with BRCA deficiency. In the cohort of BRCA-deficient vs. HRR-negative, the scores of TAI (P = 9.72 x 10−4), LST (P = 8.75 x 10−5), LOH (P = 0.01) and HRD (P = 3.35 x 10−4) all showed significant associations with BRCA-deficiency. In the cohort of BRCA-deficient vs. BRCA-mutated +HRR-negative, all the scores also highly correlated with BRCA-deficiency (TAI: P = 2.35 x 10−4, LST: P = 1.48 x 10−5; LOH: P = 2.36 x 10−4, HRD: P = 6.29 x 10−5). Using 42 as a cutoff, it achieved sensitivities of 94.1%, 60% and 82% for identifying BRCA-deficient tumors in the 35 OCs, 36 BCs and in all 73 tumors, respectively. We further validated the predictive value of HRD score in an additional 42 OC pts and found significantly higher HRD sore in pts sensitive to platinum therapy (P = 0.036). Patients having an HRD score > 42 had a significantly longer PFS than pts with a score < 42 (p = 0.04). Conclusions: Our study developed a HRD score base on assessing 3 patterns of genomic instability (TAI, LST and LOH). The HRD score revealed a promising value in detecting HR-deficient tumors (especially BRCA-deficient).
Real-world conditional survival analysis of women with newly diagnosed ovarian cancer.
Authors: Szamreta Elizabeth A. , Monberg Matthew J. , Desai Kaushal , Chen Xin , Othus Megan 
Published: May 2020

e18087 Background: A critical question in determining long-term prognosis for women with newly diagnosed ovarian cancer (OC) is whether or not their risk of death changes with time. The emergence of large, well-populated real-world datasets permits assessment of conditional survival (CS) given prior overall survival (OS) or progression-free survival (PFS). Methods: The Tempus EMR clinical dataset consists of patients from both National Cancer Institute designated centers and a sample of community oncology centers in the U.S. This study included adult women with a primary diagnosis of ovarian, fallopian tube, or peritoneal cancer from 1982 to 2018; women treated with a poly-ADP ribose polymerase (PARP) inhibitor were excluded due to low numbers & limited follow-up (final n = 2,031). The effects of patient attributes on OS were estimated using Cox regression. We calculated CS as the Kaplan-Meier probability of surviving an additional y years (from first line chemotherapy initiation), given no OS or PFS event in the previous x (< y) years. Results: Median age was 61 years and 68% of patients were Caucasian. The majority (92%) had epithelial histology, 58% were stage 3 or 4, and 49% were ECOG 0 or 1. Median OS was 37 months (95% CI: 36-39), and OS differed by age, stage, and performance status; adjusted hazard ratios (HRs) for OS were 1.3 (95% CI: 1.0, 1.5) for age > 65 versus < 45, 2.4 for stage 4 versus stage 1 (95% CI: 1.7, 3.4), and 1.4 for ECOG 2 to 4 versus 0 or 1 (95% CI: 1.2, 1.7). Conditional 1- or 5-year survival rate did not vary based on prior OS. However, CS rates among women alive without disease progression increased with time: 1-year and 5-year survival rates (with 95% CI) were 86% (84-87) and 28% (26-31), respectively, in women alive without progression at 6 months, but increased to 94% (89-97) and 53% (44-62) in women alive without progression at 3 years. Conclusions: Long-term prognosis, as shown by conditional survival rates, did not improve based on time alive since initiation of chemotherapy. However, women with longer time without disease progression had lower rates of death and a better prognosis. [Table: see text]
Clinicopathologic analysis of MMR gene mutations and uterine adenocarcinomas: An updated population-based study.
Authors: Wang Aifen , Holloway Robert W. , Yang Jinsong , Pei Zhe , Sun Yan , Zhao Yingyan 
Published: May 2020

e18100 Background: Endometrial carcinoma frequently harbors genetic alterations in genes encoding mismatch repair (MMR) enzymes, a finding which has important implications for adjuvant therapy. The aim of this study is to determine an optimal screening strategy to detect MMR mutations for each histologic subtype of endometrial carcinoma (EC). Methods: We performed a comparative analysis of the demographic, clinical, pathologic, and molecular data, including MLH1, MLH3, PMS1, PMS2, MSH2, MSH3, MSH6, and EPCAM, for 562 patients from The Cancer Genome Atlas database (TCGA), stratified by tumor histologic subtype. Results: Molecular data was available for 562 patients, of which 162 (28.8%) had tumors that were positive for MMR mutations. We did not separate somatic and germline mutation. Of these tumors, the penetrate rate of FIGO grade 3 endometrioid endometrial carcinoma (EEC G3) (84/184, 45.7%) was significantly higher than the one of uterine serous carcinoma (USC) (35/156, 22.4%) ( p < 0.001), grade 2 (EEC G2) (26/129, 20.2%) ( p < 0.001), and grade 1 (EEC G1) (17/93, 18.3%) ( p < 0.001). Of EEC G3 tumors, patients with MMR gene mutations were significantly older ( p = 0.024) or had lower BMI's than MMR mutation noncarriers ( p = 0.028). Of 562 endometrial carcinomas, alterations in MSH2 (n = 55), MSH6 (n = 54), MSH3 (n = 50) were the most frequent mutations. There were no differences in overall survival and progression-free interval between MMR mutation carriers and nonmutation carriers (p > 0.05) except that PFI with MMR gene mutation was higher than with MMR proficiency in EEC G3 ( p = 0.014). Conclusions: EEC G3 harbored the most MMR mutations among EC. EEC G3 and USC could be more considered to screen MMR mutation due to more MMR mutations occurred in EEC G3 and USC than did among EEC G2 and EEC G1. Besides MLH1, MSH2, MSH6, PMS2 and EPCAM mutation , MLH3, MSH3, PMS1 mutation could be screened in patients with newly diagnosed endometrial carcinoma. [Table: see text]
Validation of secreted protein OASEP1 as a prognostic biomarker and therapeutic target for oral cancer.
Authors: Takano Atsushi , Yoshitake Yoshihiro , Shinohara Masanori , Daigo Yataro 
Published: May 2020

e18520 Background: Although current treatments for oral cancer (OC) include surgery, radiotherapy, and chemotherapy, their effectiveness is still limited. Therefore, the development of novel prognostic biomarkers and/or therapeutic agents is urgently needed. Methods: Our strategies are as follows: i) Identification of up-regulated genes in cancers by means of gene expression microarray, ii) Validation of clinicopathological significance of their protein expression by tissue microarray, iii) Examination of their growth effect on cancer cells by siRNAs and active ligand protein for growth assays. Results: We selected a secreted protein, OASEP1 (OC-associated serum protein 1) as a candidate. Real-Time qPCR and Western blotting showed that OASEP1 gene and its gene product were expressed in the majority of OC cells. Immunohistochemical staining showed that OASEP1 expression was observed in 73 (74.4%) of 98 OCs that had undergone curative surgery. In addition, high level of OASEP1 expression was associated with poor prognosis for OC patients ( P = 0.0158, by log-rank test). Suppression of OASEP1 expression by siRNAs for OASEP1 (si-OASEP1) significantly suppressed the growth and invasion of OC cell lines. Flowcytometry and live cell imaging showed that si-OASEP1 induced the apoptosis of OC cells. siRNAs against OASEP1-receptor also suppressed the growth of OC cells. Addition of active OASEP1 recombinant protein into culture media enhanced the growth of OC cells probably through AKT pathway. Our data suggest that OASEP1 and its receptor could play a significant role in the growth of OC cells in probable autocrine/paracrine manner. Conclusions: OASEP1 is a possible prognostic biomarker and therapeutic target for OC.
Performance of machine learning-augmented analysis of radiomics for the head and neck cancer histopathological diagnosis: A systematic review and meta-analysis.
Authors: Bisdas Sotirios , Seguin Jade , Roettger Diana , Yoneoka Daisuke , Shaikh Faiq 
Published: May 2020

e18526 Background: The imaging criteria used for head and neck cancers (HNC) staging are mostly anatomical with basic quantitative measures, such as size, and admittedly radiologists’ reading of images is dependent on their expertise level. Radiomics, a term referring to extracting and investigating higher dimensional data from images, has been suggested to address these shortcomings. Assisted by machine learning (ML), highly efficient prediction models could revolutionise our diagnostic practices. Our goal was to study the role of ML in the histopathological diagnosis of HNC based on radiomics. Methods: A systematic review and meta-analysis was conducted using electronic databases (PubMed, Scopus, EMBASE, Google Scholar) and including MRI, PET, and CT studies in patients with HNC. Our study was aimed only at diagnosis utilising radiomics and artificial intelligence (ML). A PRISMA diagram retracing the steps of this search process was completed. QUADAS-2 and EQUATOR checklists were completed. A weighted mean, a mean and a median of the performance indicators were recorded. Results: 7 studies were found eligible for meta-analysis. Patient sample sizes ranged between 2-107 patients (median: 18). CT was the most common modality used (4/7 studies). All but one studies were retrospective. Support vector machine and random forest techniques were the main ML techniques used but how the model was built was rarely described. Furthermore, studies did not make clear the exact number of patients in the testing set. Other issues included the reporting of the final model performance with few studies reporting confidence intervals and 2 studies not reporting the exact performance metrics. The accuracy values for the testing set ranged from 58% -94.1%. The meta-analysis showed an overall weighted-mean accuracy of 78.53%, a mean of 82.9% and a median of 84.4%. The weighted mean of the sensitivity was 76.5%, the mean was 83.3%, and for specificity was 83.9% and 88.5%., respectively. The AUC was 0.8. The neuroradiologists’ overall accuracy was 50.4% if weighted, and 54.5% if not, and the corresponding accuracy of the ML classifiers were 78.4% and 79.6%. The ML scored an accuracy of 20% higher than the radiologists. Conclusions: The results are overall encouraging, keeping in perspective the possible calculation biases and small number of studies. There is need for better documentation and standardisation of the applied ML models, which show initially superior performance compared to radiologists.
Genomic landscape of head and neck cancers.
Authors: Subash Anand , Rao Vishal Uchila Shishir 
Published: May 2020

e18530 Background: Head and neck squamous cell carcinoma (HNSCC) encompasses a heterogeneous group of tumours. In India it accounts for about 40% of all the malignancies. HNSCC in the subcontinent behaves differently as compared to the western world. As heterogenous as they are so are their response to treatment. Deciphering the human genome has indeed been one of the biggest contribution to science. Genomic profiling would help identify the variants that separate these HNSCC patients and facilitate development of newer targeted therapeutic strategies. Methods: At Healthcare Global Cancer Centre, Bangalore we retrospectively analysed 35 cases of Head and Neck squamous cell carcinoma as a pilot. Whole exome analysis of the patient samples were done using the Illumina Hi-Seq 2500 machine with a depth of 70-100X. Results: Of the 35 patients, 27 were oral cavity squamous cell carcinoma. About 2/3rd of these patients had history of tobacco or alcohol use. At the time of analysis 20 patients were alive and disease free,3 were alive with disease,11 were dead and 2 were lost to follow up. It was observed that the maximum number of variations were mis-sense mutations. Known oncogenic proteins like TP53 and NOTCH1 showed a mutation frequency of more than 50%, while DNA damage and repair genes like XRCC1 and ERCC2 were seen to have almost 90% mutation frequency, some of which have not been previously documented in literature. Conclusions: The preliminary data has brought to light some very novel mutations, many of them until now unknown to be implicated in HNSCC. This study holds the potential to predict response to treatment and factors which contribute to this. We have classified these novel mutations into different pathways so that specific targeted therapies can be developed in future.
Association of driver genes with high-tumor mutation burden and outcome in patients with head and neck cancer: Implications for immunotherapy.
Authors: Chen Yu , Chen Chuan-ben , Zheng Xiao-bin , Gao Xuan , Jun Liu , Xiong Jia-ni , Lin Jin , Xu Yaping , Guan Yan-Fang , Li Yi , Huang Yingying , Xia Xuefeng 
Published: May 2020

e18533 Background: While the immune checkpoint blockades had demonstrated promising benefits in head and neck cancer (HNSC), its clinical efficacy is limited to a selected subset of less than 20% HNSC patients. Tumor mutation burden (TMB) has been reported as a predictor for ICBs in multiple tumors, including HNSC. However, the association of driver genes with TMB and outcomes in patients with HNSC has not yet been established. Methods: Somatic mutation landscape was characterized by interactively analyzed the sequencing data of 495 HNSC samples obtained from The Cancer Genome Atlas (TCGA) database and 185 samples from a Chinese cohort (Geneplus-database). Hybrid capture of a 1021 gene panel with potential clinical relevance was performed on tumor and paired Peripheral blood lymphocytes (PBLs) from 185 HNSC samples in a Chinese cohort. Results: In the Chinese cohort, patients harboring ≥5 muts/Mb (the top quartile of tTMB distribution) were classified as the TMB-H group; while ≥4.7 muts/Mb were classified as the TMB-M group. TMB -H was associated with better OS in the TCGA cohort. The rest were classified as TMB-L patients. Thirteen aberrant genes were significant correlation with TMB-H, including TSC2, POLE, CDK4, TSC1, MLH1, PTCH1, NF1, MSH3, RAD50, MSH2, CDH1, TNFRSF14, TERC. Among them,10 were further verified in the TCGA Head and Neck Cancer cohort, including TNFRSF14, MSH3, NF1, TSC2, RAD50, MSH2, PTCH1, POLE, MLH1, TSC1. Moreover, aberrant genes such as CDH1, MSH2 and RAD50 implicated better DFS (DFS:HR = .296, p = .034; HR = 0.128, p = .016; HR = .0422, p = .043) in HNSC of the TCGA cohort. Transcriptomic analysis in the TCGA Head and Neck Cancer cohort showed various degrees of immune upregulation in the tumor microenvironment (TME) in CDH1, MSH2, and RAD50 mutated population. Conclusions: These findings indicated that CDH1, MSH2, and RAD50 mutations may be associated with TMB-H, immuno-upregulation in TME and better survival outcomes. Combined with TMB, genes mentioned above may give us some insights into how ICB therapeutic strategies assist natural host immune responses against HNSC in Chinese population.
Effects of prexasertib, a CHK1 inhibitor, in the immune microenvironment of head and neck squamous cell carcinoma (HNSCC).
Authors: Chaudhary Ritu , Slebos Robbert , Song Feifei , McCleary-Sharpe Keegan , Masannat Jude , Tan Aik Choon , Wang Xuefeng , Amaladas Nelusha , Wu Wenjuan , Hall Gerald , Chung Christine H. 
Published: May 2020

e18541 Background: Despite considerable advancements in the standard therapies including surgery, chemotherapy and radiotherapy, the clinical outcome for head and neck squamous cell carcinoma (HNSCC) remains poor due to tumor recurrence and metastasis. Molecular-targeted therapies have evolved as novel and promising treatment for HNSCC patients. Herein, we identified a CHK1 inhibitor, prexasertib, as a therapeutic target that enhanced the infiltration of innate and adaptive immune markers in the mice tumor immune microenvironment (TIME) and subsequently sensitizes the tumors. Methods: For this study we used syngeneic mouse model of HNSCC developed using mouse tonsil epithelial cells transformed with HRAS expression and PTPN13 knockdown to represent tobacco-induced HNSCC (MTE-Ras). In vitro drug activity of prexasertib was determined using immunoblotting, flow cytometry, cell proliferation and colony formation assays. The effect of prexasertib on TIME was quantified by Quantigene Plex panel and multiplex immunohistochemistry (mIHC). Results: We found that in vitro treatment with prexasertib increased the amount of DNA damage in the cancer cells and eventually lead to their death. Similarly, our in vivo data showed that treatment with prexasertib resulted in significant tumor regression and increased mice survival. At the molecular level, prexasertib treatment resulted in an upregulation of transcripts associated with T-cell activation, cytokines, chemokines and macrophages indicating an upregulation of inflammatory gene signature. This was further supported by our findings from mIHC staining of mice tumors showing increased infiltration of natural killer cells, natural killer T cells and dendritic cells, following prexasertib treatment. Interestingly, we also saw an increase in the Tregs after prexasertib treatment, which is indicative of an immunosuppressive environment, and we speculate this could be as a result of negative feedback following immune activation by prexasertib treatment. Conclusions: Our results uncover a previously unidentified role of prexasertib in regulating the innate and adaptive immune response in HNSCC, and therefore further corroborate CHK1 as a promising therapeutic target in HNSCC.
Survival for oropharyngeal and oral cavity cancer patients based on time to recurrence and HPV status.
Authors: Means Jeffrey , Stram Douglas , Katzel Jed Abraham 
Published: May 2020

e18544 Background: It is unknown whether patients with recurrent oral cavity (OC) or oropharyngeal squamous cell carcinoma (OPSCC) have improved survival if the recurrence occurs beyond one year. We analyzed a cohort of recurrent OC/OPSCC patients to study survival outcomes stratified by time to recurrence and human papillomavirus (HPV) status. Methods: From a cohort of 3201 OC/OPSCC patients initially diagnosed between 1/1/2008 and 6/30/2019, 235 recurrent cases were identified. Time from the end of treatment until first recurrence was ascertained by chart review. HPV status was determined by HPV testing or based on anatomical site. Overall survival (OS) rates and median OS time after diagnosis of recurrence was evaluated across the time-to-recurrence and HPV groups using the Kaplan-Meier method. Differences in the survival curves tested for using the log-rank test. Results: 130 (56%) of the recurrent tumors recurred <1 year after end of treatment, and 104 (44%) ≥1 year. Patients with HPV-related tumors that recurred beyond one year had the best survival, with two-year OS at 0.62 (95% CI: 0.42-0.76), while patients with non-HPV related tumors that recurred <1 year had the worst survival, two-year OS of 0.38 (95% CI: 0.28-0.48). HPV-related tumors that recurred <1 year had roughly similar survival (two-year OS of 0.45, 95% CI: 0.30-0.59) to non-HPV-related tumors that recurred < 1 year (two-year OS of 0.51, 95% CI: 0.38-0.62). The log-rank test for difference in survival across time-to-recurrence and HPV groups was significant at p=0.03. Conclusions: In our cohort, patients with HPV-related head and neck cancer with recurrence ≥1 year had improved survival compared to all other recurrent head and neck cancer patients. In addition, our findings suggest that patients with HPV-related head and neck squamous cell carcinoma who recur prior to 12 months have long-term survival similar to patients with HPV-unrelated cancers. This has important implications for clinicians treating patients with recurrent head and neck cancer and may help guide the design of future clinical trials. [Table: see text]