bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synthetic-lethal interactions between ATR inhibition and functional genetic and proteomic biomarkers to predict responses in endometriosis-associated cancers.
Authors: Gilad Oren , Li Dansu , George Erin , Chettier Rakesh , Simpkins Fiona , Ward Kenneth , Brown Eric J 
Published: May 2020

e18000 Background: Endometriosis is a common gynecologic disorder proven to be a precursor to several cancer types. We developed a potent and selective inhibitor (ATRN-119) of a critical DNA damage response (DDR) protein kinase: the ataxia telangiectasia and Rad3-related protein (ATR). Treatment with ATRN-119 is synthetically lethal with multiple cancer-associated changes in DDR pathways, representing a new and effective strategy to treat cancer. The objective of this study is to evaluate the overlap of DDR genes that respond to ATRN-119 and those mutated in endometriosis. Methods: We sequenced the exomes of 2,932 unrelated women with surgically-confirmed endometriosis (GERMLINE) and 274 tissue blocks containing endometriosis lesions (LESION). DNA was extracted using standard methods. Missense and truncation variants were analyzed. These data were compared to analysis of a whole proteome screen for factors that respond to exposure to ATRN-119 and may influence responsiveness to treatment. Factors observed in both methods were considered high-priority biomarker candidates and were experimentally tested for synthetic lethality with ATRN-119 treatment. Results: Analysis of endometriosis patients found 89% of the LESION samples had 2 or more DDR mutations vs 83% of the GERMLINE samples. There is an excess of DDR mutations per sample in LESION (5.5 mutations) vs GERMLINE (3.89 mutations) [p = 4.66x10-6, Mann Whitney test]. In parallel, we identified 92 genes as protein responders to ATRN-119 treatment. Mutations in 21 of these 92 genes show nominal association with surgical endometriosis (p < 0.05). However, of these responsive genes, 18 are known TIER 1 cancer-driver genes and well-characterized mutations were found in three dominant genes in the LESION tissue (ATM, DDB1, and ARID1A). Overall 20% of the patients who’s LESION we examined subsequently developed an endometriosis-associated cancer. Both in vitro and in vivo studies confirmed synthetic-lethal interactions between ATRN-119 treatment and alteration of these genes. Conclusions: The overlap between DDR genes responding to ATRN-119 and those mutated in endometriosis-associated cancer suggest that genetic markers underlying response and resistance will be critical to extend the use of these drugs while increasing efficacy and minimizing toxicities. Furthermore, our data support the inclusion of endometriosis-associated cancer patients in planned ATRN-119 clinical trials.
Prognostic value of dendritic cells in locally advanced cervical cancer patients.
Authors: Joseph Adrien , Castedo-Delrieu Maria , Bloy Norma , Labaied Nizar , Mondini Michele , Loi Mauro , Klein Christophe , Genestie Catherine , Pautier Patricia , Morice Philippe , Gouy Sebastien , Deutsch Eric , Chargary Cyrus , Kroemer Guido , Michels Judith 
Published: May 2020

e18016 Background: Cervical cancer is a Human papillomaviruses (HPV)-related disease. T cell infiltration is reported to be associated with a positive prognosis. We evaluated the prognostic value of the tumor-infiltrating dendritic cells (DC). Targeting this immune compartment might be clinically relevant. Methods: We characterized by immunohistochemistry the Dendritic cell lysosomal associated membrane glycoprotein (DC-Lamp) and CD8 T cell infiltration (high/low according to the median density) in patients with locally advanced cervical cancer (LACC) undergoing curative-intent concurrent chemoradiation followed by uterovaginal brachytherapy boost. They were treated in our institution between March 2004 and August 2011. The image acquisition was performed with a Zeiss Axio Scan Z1 microscope. CD8 T cells were detected using an algorithm created in Visiopharm software on manually selected regions of interest (ROI) and DC-Lamp was detected manually. We exported the number of cells and the surface of ROI to calculate the density. Results: A total of 91 patients were identified, with a median follow-up of 4.2 years (range: 0.1-10.3). Patient’s characteristics are listed in the table. DC-Lamphigh (n = 45) LACC patients showed a positive prognosis for overall survival (OS) by univariate (Odds Ratio (OR) = 0.20 [0.06 – 0.72], p = 0.013) and multivariate analyses (incorporating FIGO stage) (OR = 0.17 [0.05 – 0.61], p = 0.006). There was a positive correlation between DC-Lamp and CD8 (R = 0,25 et p = 0,095), which is significant in squamous cell carcinoma patients (R = 0.38, p = 0.039). There was a trend for improved risk stratification for the simultaneous assessment of DC-Lamp and CD8 levels, with DC-Lamphigh/CD8high patients having the best prognosis and DC-Lamplow/CD8low patients having the worst prognosis (p = 0.074). Conclusions: LACC patients with high intratumoral DC density have a favorable outcome. These results underscore the clinical potential of therapeutic strategies that target DC (e.g. Toll like receptor agonists) to render more patients responsive to immune checkpoint blockers. [Table: see text]
Evaluation of the constructed device along with the software for digital archiving, sending the data, and supporting the diagnosis of cervical cancer.
Authors: Gronwald Jacek , Lasyk Lukasz , Barbasz Jakub , Zuk Pawel , Prusaczyk Artur , Włodarczyk Tomasz , Prokurat Ewa , Olszewski Wlodzimierz Tadeusz , Bidziński Mariusz 
Published: May 2020

e18017 Background: The incidence and mortality of cervical cancer are high in Poland. There are effective methods of the prevention and the early diagnosis, however they require well-trained medical professionals including cytologists. Within this project we built a prototype of a new device together with implemented software to convert the currently used optical microscopes to fully independent scanning systems for cytological samples. The use of the device is intended to improve the effectiveness of cytological screening, and registration of cytological tests’ results. The features of the software include digital backup as well as transmission and telemedicine evaluation. Methods: The software uses the artificial neural network (U-NET architecture) designed to be able to recognize suspicious regions and enhanced CNN neural network (VGG) allowing to determine the type of disorder such as: ASCUS, ASC-H, HIS, AGC, cancer. 7128 liquid based (LBC) and 1700 conventional cytology samples were evaluated by trained cyto-sreeners. Cytological abnormalities like: ASCUS, ASC-H, HIS, AGC, cancer were found in 254 (3.6%) LBC cases and 51 (3.0%) conventional cytology cases. All samples were scanned and archived. Selected samples with diagnosed abnormality were a model to teach the artificial neural networks. Results: Preliminary results obtained with use of U-NET and VGG (CNN networks) so far indicate 90-96% (LBC samples) and 85-95% (conventional cytology) compliance with results obtained using standard methods. Conclusions: Further refinement of neural networks is necessary to reduce the number of false positives and false negatives. A study with a larger sample size is required to evaluate the software. This project is co-financed with European Regional Development Fund within the Priority Axis I, Support for R&D activities for companies, Measure 1.2, Sectoral R&D Programmes, Sectoral Programme: “INNOMED – scientific research and development programme for innovative medicine economy sector”.
Correlation of PR and ER expression in tumors in various growth patterns of cervical cancer as a prognostic factor.
Authors: Ulianova Elena P. , Spiridonova Diana A. , Nikitina Vera P. , Novikova Inna A. , Sagakyants Aleksandr B. , Nepomnyashchaya Evgeniya M. , Shulgina Oksana G. , Nikitin Ivan S. , Kit Oleg I. 
Published: May 2020

e18031 Background: Cervical cancer is the fourth leading cause of cancer deaths among women worldwide. Since the uterus has receptors through which hormonal effects are realized, studies on the tissue receptor apparatus for estrogen and progesterone are relevant. The purpose of the study was to evaluate the correlation of PR and ER expression as a prognostic factor in cervical cancer. Methods: The study included 60 patients aged 28-65 years diagnosed with cervical cancer. Patients were divided into two groups: group 1 – endophytic pattern of tumor growth (n = 30), group 2 – exophytic pattern (n = 30). Eligibility criteria included morphologically confirmed squamous cell carcinoma of the cervix T1b-2aN0M0, stage I-II. Rabbit monoclonal antibodies for ER (Thermo scientific) and PR (Cell Marque) with the Reveal Polyvalent HRP-DAB Detection System were used for the IHC analysis. Statisical analysis of the results was performed with the Statistica 10 program (StatSoft Inc., USA). Results: The average expression of the ER marker was 5.4±3.03% for group 1 (endophytic tumors) and 13.9±8.2% for group 2 (exophytic tumors). The average PR expression was 0.5±0.3% and 1.6±1.1%, respectively. The maximal accumulation of both PR and ER in the nuclei of tumor cells was registered in patients of group 2, being 3.2 times (p = 0.931) and 2.6 times (p = 0.815) higher than in group 1, respectively. However, the difference was not statistically significant (the Mann-Whitney test, p > 0.05). The Spearman rank correlation test did not show statistically significant correlation between the groups and the markers (r = -0.218, p = 0.338). Statistically significant correlation was observed only in the group with exophytic pattern of tumor growth (r = 0.786, p < 0.01). Conclusions: The IHC analysis revealed a tendency to an increase in the expression of PR and ER in patients with exophytic tumors. However, the correlation between the expression of these indicators cannot be considered as a predictive factor in cervical cancer.
Present-day management of uterine leiomyosarcoma: Evaluation of treatment sequencing and other prognostic factors.
Authors: Hinchcliff Emily , Rumpf Jennifer , Ratan Ravin , Fleming Nicole D. , Jazaeri Amir A. , Pitcher Brandelyn , Soliman Pamela T. 
Published: May 2020

e18035 Background: Uterine leiomyosarcoma (ULMS) is a rare tumor with limited therapeutic options and no clearly established best treatment sequence strategy. Methods: Women with ULMS between 2013-2018 were identified. Clinical data was collected; descriptive statistics were performed and predictors of overall survival (OS) and progression free survival (PFS) were analyzed. Results: 189 patients were included. Median age was 53 (20-84), 91% had grade 3 tumors and 51.3% had stage IB disease. 50% underwent surgery followed by chemotherapy (n = 94, 49.7%) and 37% had surgery only (n = 70). 49 patients retained their ovaries; there was no difference in OS by oophorectomy status (p = 0.71). Estrogen and progesterone receptor (ER/PR) status, positive in 41% and 33% respectively, was not independently associated with OS (p = 0.23, p = 0.12) nor did it impact OS among those with oophorectomy and without (p = 0.70). The most common adjuvant therapy regimens were gemcitabine/docetaxel (gem/doce, 64%) or ifosphamide/doxorubicin (ifos/doxo, 19%). There were no differences in the regimens prescribed by physician specialty (gynecologic oncology vs other, p = 0.21). 147 patients (78%) experienced a recurrence or progression. For the 73 patients who received gem/doce as adjuvant therapy, 58.9% recurred and were most commonly treated with doxo containing regimens (67%). Of the 22 patients treated with ifos/doxo, only 3 recurred and each received a different second line regimen. For those not treated with adjuvant therapy (70 patients), 58.2% recurred and were treated with gem/doce (62%) and ifos/doxo (24%). In early stage patients, the majority received surgery only (45%) or surgery followed by chemotherapy (44%). There was no difference in OS in those who received adjuvant therapy and those who did not (p = 0.39). 46 (24%) had molecular testing and 37 had identified mutations. The most common mutation found was P53 (n = 25, 54%) followed by RB1 (8, 17%), PTEN (7, 15%), and BRCA (2, 4%). Conclusions: Recurrence occurred in 78% of patient despite many women undergoing adjuvant therapy after surgery. Oophorectomy did not influence OS, even though 41% of tumors were ER positive. The sequence of treatment was not associated with OS, however, the risk for recurrence in patient treated with adjuvant Ifos/Doxo was 14% compared to 59% in gem/doce. This finding warrants additional evaluation to determine the optimal adjuvant therapy for these women.
Test identifies ovarian cancer patients with hyperactive c-Met and ErbB signaling tumors who may benefit from c-Met and pan-HER combination therapy.
Authors: Laing Lance G. , Rossetti Stefano , Kuzmicki Catherine , Broege Aaron , Sabat Joanna , Khan Salmaan , MacNeil Ian A. , Sullivan Brian 
Published: May 2020

e18038 Background: No sub-groups of ovarian cancer patients with clinically actionable ErbB genetic variants have yet been found. Measurement of ErbB signaling activity rather than genetic variants may identify ovarian cancer patients likely to benefit from ErbB targeted therapies. We have previously reported studies detecting dysregulated ErbB and c-Met signaling activity in 20%-25% of HER2-negative breast cancer patient tumors using the CELx Signaling Function Test. To determine whether ErbB or c-Met signaling dysregulation is involved in ovarian cancer, the CELx Test was adapted to analyze ovarian tumor cells. The current study set out to: 1) characterize c-Met and ErbB family signaling activity in ovarian patient tumor cells and tumor cell lines; 2) evaluate in vivo response to pan-HER and c-Met inhibitors in an ovarian tumor xenograft model. Methods: For the ex vivo studies, a set of fresh tumor specimens from 15 ovarian cancer patients and a set of 12 ovarian cancer cell lines was obtained. Cell samples were cultured from each. Live cell response to ErbB and c-Met agonists (NRG1b, EGF, or HGF) with or without an antagonist (2C4, a HER2 dimerization inhibitor or tepotinib, a c-Met kinase inhibitor) was measured using an xCELLigence impedance biosensor (Agilent Technologies). Signaling activity above a previously established cut-off value was used to identify abnormal levels of EGFR, HER2 and c-Met signaling activity. For the xenograft study, OVCAR-4, an ovarian cancer cell line, determined to have abnormal HER2, EGFR, and c-Met signaling with the CELx Test, was studied. 40 female NSG mice were each injected with two million cells. Mice were randomly assigned to either a control group or a treatment group that received neratinib, tepotinib, or neratinib and tepotinib for 16 days. Results: Of the patient cell and cell lines samples tested ex vivo with the CELx Test, 4 of 27 (15%; 95% CI = 6%-32%) had hyperactive HER2 and c-Met signaling pathways. In the xenograft study, tumor volume change was 40% less in the tepotinib + neratinib treated group than in the control arm change. There was no significant difference in tumor volume between the control and tepotinib or neratinib groups. Conclusions: These findings suggest that a significant sub-group of ovarian cancer patients have abnormal ErbB and c-Met signaling activity that may respond to treatment with a combination of ErbB and c-Met inhibitors. A clinical trial to evaluate treatment response of this patient sub-set to combined c-Met and pan-HER inhibitors is warranted.
Uptake of targeted therapy in clinical practice among US patients with ovarian cancer.
Authors: Chan John K. , Meyer Larissa , Luhn Patricia , Flores Carlos , Bastiere-Truchot Lydie , Downer Mary K , Lin Yvonne Gail , Wright Jason Dennis 
Published: May 2020

e18049 Background: Since first approvals for targeted therapies (TTs) in ovarian cancer (OC) patients (pts) in 2014, FDA approvals for TTs including bevacizumab (bev) and PARP inhibitors (PARPis) continue to expand. Approval of front line (1L) indications for bevacizumab (all-comers) and maintenance olaparib (BRCA-mutated) occurred in 2018. Here we describe real-world trends in the use of these TTs. Methods: Data were analyzed from the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database of patient-level data, curated via technology-enabled abstraction. We used descriptive statistics and significance tests to describe TT use in pts with OC. Results: We included 2975 treated OC pts diagnosed from 2011-18, with treatment data through 2019. Median follow-up was 32 months. 47% of OC pts received TT during follow-up, 12% of whom received TT during 1L. TTs were given as maintenance therapy in 54% of 1L and 37% of recurrent (2L+) OC pts. 40% of OC pts received bevacizumab anytime, 24% of whom received bevacizumab during 1L. Bevacizumab was given as maintenance therapy in 43% of 1L and 26% of recurrent OC pts. 20% of 2L and 17% of 3L bevacizumab-treated pts were platinum sensitive. From 2012-19, bevacizumab use changed biennially from 10% to 10% to 8% to 18% in FL (p < 0.001), 24% to 35% to 34% to 38% in 2L (p = 0.008), and 21% to 34% to 35% to 36% in 3L (p = 0.06). Corresponding changes in PARPis use were 0% to 0% to 5% to 13% in FL (p = 0.03), 0% to 1% to 11% to 23% in 2L (p = 0.09), and 0% to 3% to 10% to 20% in 3L (p = 0.02). TT use (ever vs. never during follow-up) was more common among pts with stage III-IV tumors (81% vs. 55%), serous histology (90% vs. 75%), history of BRCA (82% vs. 61%) or NGS (38% vs. 13%) testing, and BRCA mutations (21% vs. 33%) (p < 0.001 for all). Conclusions: Bevacizumab and PARPi use is expanding in 1L and 2L treatment; in 1L bevacizumab was more common than PARPis in 2019 (31% vs. 19%). These data reflect the evolving treatment landscape in 1L OC, which is expected to further evolve based on recent evidence from maintenance PARPi monotherapy and PARPi + bevacizumab combination studies. [Table: see text]
Evaluation of the occurrence and management of PARP inhibitor toxicities.
Authors: Hatch Rachel , Patel Sweta , Cambareri Christine , Uritsky Tanya , Martin Lainie P. 
Published: May 2020

e18073 Background: Poly-adenosine diphosphate ribose polymerase inhibitors (PARPi) have become a major cornerstone of therapy in the management of patients with ovarian cancer and other cancer types. The most common adverse events with PARPi therapy include bone marrow suppression, gastrointestinal (GI) toxicity, and fatigue. Currently, information is scarce regarding the management of some of these adverse events. Methods: A retrospective, descriptive observational study of adult patients with gynecologic malignancy, who received at least 2 weeks of PARPi therapy, was conducted at the University of Pennsylvania Health System. Data was collected on patients prescribed a PARPi between December 2014 and October 2019, from initiation of therapy through one-year post-initiation or last follow-up. The primary endpoint was the status of PARPi therapy at the end of the study period. Secondary endpoints included time to toxicity, progression free survival (PFS), and overall survival (OS). Descriptive statistics were used to analyze all endpoints. Results: Of the 85 patients included in the study, 45 (53%) received olaparib, 24 (28%) niraparib, and 16 (19%) rucaparib. Twenty-nine patients (34%) continued on PARPi therapy, 16 (19%) discontinued the due toxicity, and 40 (47%) discontinued due to progression. Of 147 unique toxicities, 67 (46%) were GI-related, 48 (33%) were hematologic, and 32 (22%) were other toxicities, including fatigue, elevated serum creatinine, hypertension, and rash. Twenty-three percent of all toxicities were categorized as grade 3 or 4 per the Common Terminology Criteria for Adverse Events v5.0. The median number of management strategies required for GI toxicities was 1 (range 1-7), hematologic toxicities was 2 (1-8), and fatigue was 1.5 (1-4). Primary management strategies included pharmacologic therapy (96%) for GI toxicities; transfusion support (65%), holding PARPi therapy (67%), and dose reduction (52%) for hematologic toxicities; and dose reduction (78%) for fatigue. Hospital admission due to PARPi toxicity occurred in 12% of patients. The median time to toxicity was 29 days (1-330) and the median time to discontinuation due to toxicity was 72.5 days (9-353). Fifty-four patients (64%) had progression of disease and 18 (21%) died within one-year of initiation. Median PFS was 181 days and median OS was 338 days, censored for time to last follow-up. Conclusions: This observational study outlines the incidence of PARPi toxicity and some of the management strategies within an academic health system, further guiding practitioners in an area with limited information.
OvarianTag biomarker panel in order guide treatment decisions cisplatin-based for women with epithelial ovarian cancer.
Authors: Braga Leticia da Conceição , Silva Luciana Maria , Souza Matheus Gomes de , Amaral Laurence Rodrigues do , Andrade Nara Rosana , Silva-filho Agnaldo Lopes da 
Published: May 2020

e18075 Background: Ovarian cancer (OC) represents the most lethal gynecologic cancer. Late-stage diagnosis associated with a lack of effective markers to detect chemotherapy resistance contributes to high mortality and poor prognosis of epithelial ovarian cancer (EOC). OvarianTag Biomarkers Panel was developed as biopsy-based gene expression assay to discriminate prognosis in EOC patients, to understand the aggressiveness and relapse causes of these patients. Methods: Patients were admitted into this study in two phases. First, 45 women were included prospectively, and RNA was obtained from fresh normal ovarian (NO) tissues (n = 18), ovarian serous cystadenoma tumors (n = 11) and EOC (n = 16). The total RNA content was quantified and quantitative PCR (qRT-PCR) was performed to determine relative gene expression, starting set genes related to apoptosis and necroptosis regulated cell death pathway. Machine Learning algorithms were used to classify patient’s data associated and to characterize molecular targets as prognostic markers, named OvarianTag panel. Later, others 55 EOC patients, attended between 2008 and 2016, were included. Within this cohort, tissues were obtained from 106 FFPE samples and shared into primary and metastatic EOC, and from the same NO tissues (as control). RNA was extracted and qRT-PCR determined the OvarianTag panel expression level from each sample. Then, hierarchical clustering allowed us to classify the samples using the cut off obtained by classifier algorithm. Results: Significant differences in gene expression profile were observed between patients’ groups. Molecular classifier algorithm proved the prognostic value of genes evaluated. Decisions trees and biomarker clusters were constructed. In the full training, were obtained 90% of correct classifications and in cross-validation, 89%. In the second phase, the classifier reported specificity of 100% and sensibility of 79% to predict tumor recurrence and platinum resistance. Conclusions: OvarianTag panel is a putative prognosis biomarker of EOC subgroups and could be considered to drive the clinical practice of EOC treatment options, improving outcomes because providing an opportunity for guide clinical intervention for increasing survival rates. Besides of that, it will be allowed include patients in clinical trials of new target drugs or for repositioning of target drugs that have already been tested in humans.