tbuckley/cabot-search huggingface dataset:
EGFR amplification predicted selective sensitivity to PARP inhibitors with high PARP-DNA trapping potential in human GBM.
Authors: W. K. Alfred Yung, Shaofang Wu, Feng Gao, Siyuan Zheng, Jie Ding, Chen Zhang, Xialong Li, Ravesanker Ezhilarasan, Ningping Feng, John Frederick De Groot, Erik P. Sulman, Timothy Heffernan, Dimpy Koul
Journal: Journal of Clinical Oncology (2019)

2047 Background: Poly-ADP-ribose polymerase (PARP) is an enzyme critical for regulating a variety of DNA damage repair mechanisms such as BER/SSBR, and PARP inhibitors have been shown to have single agent activity in breast and ovarian cancer patients with BRCA ½ mutations. However, PARP inhibitor such as veliparib has limited single agent activity in GBM and identifying markers predicting sensitivity is critical to select individuals or certain groups of patients for PARP inhibitor therapy. Methods: Potency and selectivity of PARP inhibitors were analyzed in a panel of glioma stem cells (GSCs) with varying genetic background. In vivo anti-tumor activity was evaluated in xenograft models. Results: In this study, we report that PARP inhibitor, talazoparib, showed strong single-agent cytotoxicity and remarkable selective activity in glioma stem cells (GSCs). This single agent activity was strongly correlated with EGFR amplification. GSCs with EGFR amplification (which occurs in about 45% of GBMs) showed higher oxidative base damage, DNA breaks, and genomic instability than non-amplified GSCs. To sustain the elevated basal oxidative stress, EGFR-amplified GSCs had increased basal expression of DNA repair proteins. As a result of blocked DNA damage repair by talazoparib treatment, DNA damage accumulated and lead to increased PARP-DNA complexes, which was then trapped by talazoparib and resulted in high toxicity. The PARP-DNA trapping function of PARPi is essential as olaparib and veliparib, two PARP inhibitors with weak DNA-PARP trapping potential did not show sensitivity in GSCs. In contrast, Pamiparib, another PARP inhibitor with similar PARP-DNA trapping ability to that of talazoparib, showed selective sensitivity in EGFR-amplified GSC. Conclusions: Our data showed that EGFR amplified GSCs with higher basal DNA damage exhibited therapeutic vulnerability to PARP inhibitors with high PARP-DNA trapping ability, and that EGFR amplification is a potential selection or predictive biomarker for PARP inhibitor therapy in GBM.
Prospective cohort study of the impact of hospital-wide dihydropyrimidine dehydrogenase (<i>DPYD)</i> genotype testing for fluoropyrimidine-based chemotherapy on adverse events and hospital costs.
Authors: Theodore John Wigle, Brandi Povitz, Wendy Teft, Robin Legan, John Gordon Lenehan, Markus Gulilat, Stephanie Nevison, Justin Kritzinger, Veera Punaganty, Denise Keller, Suhair AlShanteer, Robin Francis, Victoria Siebring, Sisira Sarma, Yun-Hee Choi, Stephen Welch, Eric Winquist, Ute Schwarz, Richard B. Kim
Journal: Journal of Clinical Oncology (2019)

3028 Background: Fluoropyrimidines remain integral components of modern chemotherapy for solid tumors, and their toxicities can be reduced by pretreatment DPYD genotyping. Our main objective was to demonstrate the feasibility of implementing a hospital-wide pretreatment DPYD testing service based on the CPIC 2013 guideline on fluoropyrimidines and DPYD. Methods: We enrolled participants prior to planned fluoropyrimidine treatment as well as those who had experienced adverse events (AEs) after initiation of therapy, from December 1, 2013 to November 30, 2018. The patients tested pretreatment were analyzed as a prospective cohort to assess AEs within 90 days of fluoropyrimidine initiation and associated hospital cost. The primary outcome was the rate of severe global fluoropyrimidine-related toxicity in the pretreatment cohort (grade≥3, CTCAE v.4.0.3). Results: Of 1362 patients genotyped for DPYD within the study period 1041 were enrolled pretreatment and included in the primary analysis. The median age was 65 years (19-90), 57% male, 51% 5-FU, and 49% capecitabine. Dose reductions were recommended for 21 DPYD variant carriers who were detected pretreatment. There was no significant difference in the primary outcome between DPYD variant (29%) and wild type (18%) patients (Fisher’s exact test p = 0.25). Costs associated with ER visits and hospitalizations at our tertiary care centre were $1,268 (89-8,562) (Median (IQR)) and $2,961 (341-13,567) for DPYD variant (n = 4) and wild-type (n = 99) patients respectively. Post-AE genotyping (n = 70) found five DPYD variant patients; all experienced grade≥3 toxicity, costs were $15,825 (10,962-25,310), and one poor metabolizer died due to complications. Targeted next generation exome sequencing of DPYD wild-type patients who experienced severe AEs identified five potentially deleterious genetic variants in ABC efflux transporters. Conclusions: Pretreatment DPYD genotype guided dosing of fluorouracil and capecitabine is feasible and benefits patients, health care providers, and hospitals. Our data supports adoption of pretreatment DPYD genotyping as a standard of care.
DIPNECH: The Mayo experience.
Authors: Daniel Almquist, Arriana Cabrera, Mohamad Bassam Sonbol, Heidi E. Kosiorek, Thorvardur Ragnar Halfdanarson, Helen J. Ross, Harshita Paripati, Dawn E. Jaroszewski
Journal: Journal of Clinical Oncology (2019)

e20029 Background: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a pulmonary disorder with neuroendocrine cell proliferation with potential progression to lung neuroendocrine tumor (Lu-NET). Optimal diagnostic and treatment strategies have yet to be well defined. Herein, we aim to describe the Mayo Clinic experience with DIPNECH. Methods: A retrospective analysis was performed of patients diagnosed with DIPNECH within Mayo Clinic between January 2000-Febuary 2019. Cases were identified from clinical databases at Mayo Clinic. Data on demographics, disease characteristics, time of diagnosis, surgery, and last follow up date were extracted. Extent of symptom burden, treatment approaches, disease progression, and disease-free survival (DFS) were evaluated by chart review. Results: A total of 59 patients were identified with a median age of 63(43-81) years. The cohort was predominantly female (93.2%) and non-smoking (76.3%). Most patients (86.4%) had symptomatic disease with chronic cough being the most common (71.2%) followed by exertional dyspnea (44.1%). Imaging typically showed bilateral lung nodules (93.2%) with mosaic attenuation noted 69.5% of the time. Surgical resection was frequently completed to confirm diagnosis (94.9%). Most patients received inhaled glucocorticoids combined with a beta agonist (79.7%). Oral steroid use was seen in 49.2% of patients whereas a somatostatin analog was used in 15.3% following the diagnosis of DIPNECH. These medical interventions led to symptom relief in 23.7% of the patients. The median follow up for all patients was 19.5 months. Progression of tumorlets was seen in 48.7% of patients with only 7(17.9%) patients progressing to a diagnosis of Lu-NET. The 3-year DFS was 90.5%. Conclusions: This is amongst the largest studies completed evaluating DIPNECH patients. DIPNECH remains a rare disease more commonly diagnosed in women in their early 60’s. DIPNECH appears to have an indolent course with obstructive symptoms being the most common finding. A minority of patients experienced symptom relief with therapy. Overall, DIPNECH appears to have a low risk of progressing to Lu-NET based on the observation of this study.
Live-attenuated LCMV-based vector for active immunotherapy of HPV16+ cancer.
Authors: Sarah Schmidt, Weldy V. Bonilla, Mindaugas Pauzuolis, Andrea Reiter, Theresa Kleissner, Daniel Oeler, Felix Stemeseder, Ursula Berka, Bettina Kiefmann, Sophie Schulha, Igor Matushansky, Doron Merkler, Daniel Pinschewer, Klaus Karl Orlinger
Journal: Journal of Clinical Oncology (2019)

e14303 Background: Active immunization against cancer requires the induction of exquisitely potent tumor-specific CD8 + T cell (CTL) responses, which can be repeatedly boosted and reactivated. Hookipa Pharma engineered a replication-attenuated viral vector platform (TheraT) based on the arenavirus lymphocytic choriomeningitis virus (LCMV), which meets these aforementioned criteria. Here, we present a preclinical data package of Hookipa´s lead immunotherapy product HB-201, targeting HPV16-driven cancer. Methods: TheraT-E7E6 encodes a highly immunogenic, non-oncogenic version of the human papilloma virus 16 (HPV16) oncoproteins E7 and E6. Results: Attenuation and safety of TheraT-E7E6 were demonstrated by i) rapid viral clearance after systemic administration of the vector and ii) reduced neurovirulence in mice.TheraT-E7E6 can be administered intravenously as systemic therapy or intratumorally as local therapy with an abscopal-like effect. Treatment was shown to induce substantial CD8 + T cell expansion and high frequencies of E7- and E6-specific CTL responses with a balanced effector / central memory profile. These responses were boosted and reactivated upon TheraT-E7E6 re-administration. TheraT-E7E6 eradicated palpable tumors in a syngeneic mouse TC-1 tumor model of HPV-driven cancer. Even in mice with large tumors (~300mm 3 ) TheraT-E7E6 afforded significant tumor control and improved survival, with high frequencies of E7-specific CTLs persisting for several weeks. Animals which cleared the tumor after TheraT therapy were long term protected from tumor re-challenge. Furthermore, TheraT is efficacious in checkpoint inhibitory refractory models and can also synergize in combination with checkpoint inhibitors (CPIs). Conclusions: In conclusion, replication-attenuated TheraT-E7E6 is safe, highly immunogenic and shows excellent therapeutic efficacy as mono- or combination therapy in a preclinical model of HPV-induced cancer. Clinical trials for the treatment of HPV16+ cancers will be initiated in 2019.
Effect of PGK1 on radiosensitivity through regulation of CIN and CFL1 in human glioma cells.
Authors: Hongyi Liu, Yuchi Liu, Hong Xiao, Mengjie Zhao, Yong Xiao
Journal: Journal of Clinical Oncology (2019)

e14631 Background: Phosphoglycerate kinase 1 (PGK1) has been detected overexpressed in many malignancies and usually correlated with increased tumorigenesis and poor survival. Our previous study revealed that PGK1 significantly up-regulated and positively correlated with cofilin-1 (CFL1) expression in radioresistant astrocytomas samples. However, the further mechanism remains unknown. Methods: In the present study, functional interactions among PGK1, chronophin (CIN) and CFL1 were analyzed by co-immunoprecipitation and immunofluorescence experiments. Transfection of shRNA and pcDNA3.1-plasmid were respectively utilized to silence and overexpress PGK1 or CIN in both normal glioma cells (U251 and U373) and estabilshed radioresistant (RR-U251 and RR-U373) cells. The effect of PGK1 on CIN and CFL1 expression levels was investigated with Western-blot method; while the effect of PGK1 or CIN on radiosensitivity of glioma cells was evaluated using cell viability, migration and invasion assays after irradiation. Results: Cell proliferation, migration and invasion abilities significantly increased in RR-U251 and RR-U373 cells compared with those of normal cells, indicating the successful establishment of RR-glioma cell models. Laser confocal experiment in vitro showed the colocalization of PGK1 and CIN. Meanwhile, PGK1 specifically and directly combined with CIN, while did not interplay with CFL1. Elevated PGK1 expression level was observed in radioresistant cells compared with that of normal cells. The western blot analysis showed that CFL1 and CIN levels were positively correlated with the PGK1 expression in both normal and radioresistant cells. The proliferation, migration and invasion capabilities significantly decreased in PGK1-silenced and CIN-silenced glioma cells, indicating the improvement of the radiosensitivity of radioresistant cells. Conclusions: Our research implied the effect of CIN-mediated PGK1 regulation on CFL1 level, thereby altering the migration and invasion abilities in nomal and notably radioresistant glioma cells. These findings clarify a novel underlying mechanism of radioresistance in glioma cells and provide valid basis for further explorations concerning radiotherapy.
Main driver genes and BRCA mutation in Chinese patients with pancreatic adenocarcinoma.
Authors: Jiangfang Tian, Du He, Zhixi Huang, Bole Tian, Dan Cao
Journal: Journal of Clinical Oncology (2019)

e15741 Background: Data on pathogenic genetic alterations in Chinese patients with pancreatic adenocarcinoma (PAC) are limited. Especially, as BRCA mutations may become potential biomarkers guiding therapy for PAC patients, the prevalence of BRCA mutations in Chinese patients remains largely unknown.We performed the study to analyze genes mutational landscape and determine the prevalence of BRCA mutations in Chinese PAC patients. Methods: We reviewed clinical characteristics and genes mutations of 134 patients with a pathologically confirmed PAC from West China Hospital of Sichuan University between May 2016 and November 2018. All of them underwent gene-testing and genes variant evaluation with a panel of 381 genes by next-generation sequencing (NGS). The test samples were mainly from primary pancreatic lesions, other were from peripheral blood and metastatic sites. All main driver gene mutations and clinical stages were measured to determine associations of driver gene mutations, the number of altered genes, the level of CA199 with clinical stage. Results: Of the 134 patients, 73 (54.5%) were men with a median age of 58 (range from 34 to 82) years. The major driver mutations were KRAS (89.6%), TP53 (71.6%), CDKN2A (26.9%), SMAD4 (18.7%) and ARID1A (10.4%). The majority of patients (76.9%) had 2 genes or more genes mutations, KRAS/TP53 and KRAS/TP53/CDKN2A were the most frequently combinate types. Stages of PAC was relevant to numbers of altered genes (p = 0.040) and the level of CA199 (p = 0.002). Five (3.7%) patients with BRCA mutations were identified, two patients had somatic BRCA2 variants, one patient had somatic BRCA1 mutation and the other two patients had germline BRCA2 mutation. Two patients with germline BRCA2 mutations received olaparib and keep stable disease for 4 months and more than 8 months. Our finding revealed patients with PAC had a low TMB (median 3.81 per Mb (range 0.81-9 per Mb)) and PD-L1 expression (16/36, 44.4%), nearly all of them were MSS (50/51,98.0%), just three patients with dMMR (3/134,2.2%). Conclusions: The PAC patient commonly harbored two or more number of five major driver mutations including KRAS, TP53, CDKN2A, SMAD4 and ARID1A. The frequency of BRCA1/2 mutations in Chinese patients with PAC was 3.7%. Olaparib may be effective for PAC patients with BRCA mutations. The PAC may be poor response to immunotherapy.
FRI0529 SPREAD OF SENESCENCE AND JOINT INFLAMMATION VIA CONNEXIN43-POSITIVE EXOSOMES RELEASED BY OSTEOARTHRITIC CHONDROCYTES
Authors: Marta Varela-Eirín, Adrián Varela-Vázquez, Amanda Guitián-Caamaño, Susana B. Bravo-López, Carlos Paíno, Raquel Largo, Eduardo Fonseca, Mustapha Kandouz, Trond Aasen, Arantxa Tabernero, Alfonso Blanco, José R. Caeiro, María D. Mayán
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Chondrocytes (CHs) in articular cartilage undergo phenotypic changes and senescence, restricting cartilage regeneration and favoring osteoarthritis (OA) progression. CHs and synovial cells from OA patients show a chronic increase in the channel protein connexin43 (Cx43), which regulates signal transduction. Extracellular vesicles (EVs), including exosomes, have been shown to play important roles in many biological functions and harbour Cx channels that allow the formation of gap junctions (GJs) between the exosome and the target cell, but the role of these EVs and exosomal-Cx43 in OA progression has not been studied yet. <h3>Objectives</h3> The objective of this study was to investigate the role of EVs released by OA chondrocytes (OACs) in cellular plasticity, inflammation and senescence of surrounding joint tissues. <h3>Methods</h3> CHs, bone and synovial cells were isolated from healthy and OA donors. EVs were obtained by ultracentrifugation and their protein content was analysed by LC-MS/MS. Protein levels were evaluated by western blot, immunofluorescence and flow cytometry. RNA expression was evaluated by RT-qPCR. Senescence and GJ intercellular communication was studied by flow cytometry and scrape loading assay, respectively. <h3>Results</h3> OACs showed increased levels of Cx43 within their EVs in comparison to the EVs isolated from healthy donors. Overexpression of Cx43 in CHs increased senescence and exosomal Cx43 levels. Interestingly, the treatment of CHs, bone cells and synoviocytes (target cells) with Cx43-EVs released by OACs, led to a significant increase in both Cx43 mRNA and protein levels in the recipient cells. The increase of Cx43 in target cells acted as a positive regulator of the reversion to a less differentiated state via EMT by activation of Twist-1, associated with increased levels of the mesenchymal markers, as CD105/CD166. The phenotypic changes detected in OACs lead to a decrease in Col2A1 and aggrecan expression in CHs, and increased the levels of cellular senescence and the senescence-associated secretory phenotype (SASP) in the target cells in target cells via p53/p16 and NF-kß. These results were corroborated by analysing the protein cargo of these Cx43 positive EVs by LC-MS/MS, finding enrichment in proteins related with catabolic, senescence and wound-healing pathways. <h3>Conclusion</h3> Our results indicate that Cx43-positive exosomes released by OACs may be involved in the spread of cellular senescence and inflammation involved in wound healing failure. Further understanding of the role of exosomal Cx43 in OA will help to halt the disease spread and progression. <h3>Disclosure of Interests</h3> None declared
Single center experience: Management of metastatic appendiceal cancer with peritoneal carcinomatosis.
Authors: Sindhu Janarthanam Malapati, Uqba Khan, Jason Aboudi Mouabbi, Zyad Kafri, Tarik H. Hadid, Richard N. Berri, Ramen Sakhi, Paul Mazzara, Susan Szpunar
Journal: Journal of Clinical Oncology (2019)

e15103 Background: Appendiceal tumors constitute only 1% of intestinal malignancies with no established standard of care due to their relative rarity. Timing, preferred regimen and utility of chemotherapy in this malignancy are among the many questions that still remain unanswered. Methods: Retrospective chart review of patients treated for appendiceal carcinoma at our institution who had slides available for pathology review (96 patients met this criteria). Results: Mean age at diagnosis was 55.8 years. 84% were Caucasian and 13.8% were African American, 19.8% had a family history of colon cancer. Mucinous adenocarcinoma was the most frequent subtype (70.8%) followed by colonic (8.3%), signet ring, goblet cell and mixed. 63 had cytoreductive surgery, 63 had HIPEC, 23 had neo-adjuvant and 41 patients had adjuvant chemotherapy. 30 patients received bevacizumab with first line. 6 of 43 patient with CCR0, 0 of 10 patients with CCR1 and 1 of 10 patients with CCR2 died during follow-up. Eventually, 17 patients had second surgery (debulking in 6, debulking+HIPEC in 11). 52 patients had progression and this was most frequently diagnosed on surveillance imaging (73.1%.) Mean time to progression (TTP) was 39.3 months (8-432 months) and second progression was 62.4 months (21.5-177.6 months.) Median time from surgery to progression was 31.6 months (9.6-417.5 months). TTP and OS are not associated with age and although mean survival was numerically greater in women (303.9 months) than men (220.5 months), this was not statistically significant (p=0.903). Pathologic grade 1 had a longer time to progression compared to grade 2 and 3 (176.9 months versus 55.5 and 59.1 months, p= 0.001). There was a significant difference in TTP based on tumor differentiation (p=0.019) with 191.5 months, 45.3 months and 67.2 months in well, moderate and poorly differentiated respectively. Survival by pathologic grade approached significance (p=0.067), 336.3 months, 171.9 months, 129.1 months in grade 1, 2 and 3 respectively. Conclusions: 80% patients have peritoneal carcinomatosis at diagnosis and for every 1 increase in PCI, the risk of progression increases by 4.8% but this does not affect survival. FOLFOX/ Xelox in first line was associated with longer time to progression. [Table: see text]
Assessment of end-of-life care quality indicators in veterans with cancer.
Authors: Giselle Alexandra Suero-Abreu, Camille Michelle Johnson, Marshall McKenna, Jun Chih Wang, Aldo Barajas-Ochoa, Piyumika De Silva, Arturo Perez, Fengming Zhong, Shanthi Srinivas, Victor Tsu-Shih Chang
Journal: Journal of Clinical Oncology (2019)

e18327 Background: Many cancer patients (pts) receive aggressive medical care at the end-of-life (EOL) . The objective of this study was to assess quality of EOL (qEOL) care in cancer pts at our VA and to determine the implementation of do-not-resuscitate (DNR) orders. Methods: Records of Veterans followed at the VA NJ Health Care System who died from 2015-2017 were reviewed. The qEOL care was assessed using seven indicators by Earle et al. ( J Clin Oncol. 2003;21(6):1133-1138). EOL planning (use of DNRs and use of palliative and hospice services) was also assessed. Results: We identified 92 male pts with cancer (mean age 73 years ±10). There were Caucasian (n = 48, 52%) and African American (n = 38, 41%) pts. The most common malignancies were lung (22%), gastrointestinal (21%), prostate (16%) and hematological (14%). 87 pts (95%) had a DNR order at the time of death; the DNR was obtained a median of 60 days prior (IQR 7-135). Ten pts (11%) had DNR orders placed within 1 week of death. Seven pts (8%) received chemotherapy in the last 14 days of life while 6 pts (7%) received a new treatment in their last 30 days. In the last month of life, 35 pts (38%) had multiple hospitalizations and ER visits, 20 pts (22%) were admitted to the intensive care unit, 9 pts (10%) were intubated, and 3 pts [3%] received cardiopulmonary resuscitation. More pts (n = 47, 51%) died in an acute care setting, and 45 (49%) pts were admitted to hospice (median of 22 days before death, IQR 6-52). Four pts (4%) were admitted to hospice within 3 days of death. A next-of-kin was available for 64 pts (70%). Palliative care (PC) was provided to 83 pts (90%) and pain medications prescribed for 80 pts (87%). Conclusions: There was timely implementation of DNRs and referral to PC. The qEOL indicators used suggest that aggressive treatments were appropriately being held at the EOL. However, there was an increased use of acute care services. Limitations include lack of data on Veterans who died outside the VA. This data supports future quality improvement EOL interventions. [Table: see text]