tbuckley/cabot-search huggingface dataset:
Defining an allogeneic CAR-T approach by shRNA-mediated knockdown of the T-cell receptor.
Authors: David Suhy, Patty Garcia, Vanessa Strings-Ufombah, Natalie Suhy, Peter Roelvink, Georgina Kilfoil
Journal: Journal of Clinical Oncology (2017)

e14551 Background: An allogeneic approach for CAR T-Cell therapy can significantly streamline manufacturing, provide more accessible options to patients as well as enhance safety by reducing the possibility of graft-versus-host-disease. The T-Cell Receptor (TCR) is comprised of multiple subunits and functions to activate T-cells by a signal transduction cascade that is initiated upon antigen binding. Eliminating expression of the endogenous TCR on modified CAR-T-Cells may eliminate the ability to recognize major and minor histocompatibility antigens in the recipient. This study assessed if simultaneous expression of multiple short hairpin RNAs that knockdown levels of individual TCR subunits could result in the loss of TCR expression and TCR-mediated T-Cell activation. Methods: Recombinant DNA producing short hairpin RNAs against the TCR complex was transfected into T-cells. Cell surface TCR was analyzed by FACS. Following CD3 activation or co-culture with B-cells, T-Cell activation was quantified by measuring the levels of IL-2 by ELISA and QPCR. Results: When expressed individually, each shRNA inhibited it’s cognate TCR subunit by up to 93% of the endogenous levels. However, upon simultaneous expression of the shRNAs against the different subunits from the same vector, we observed a near complete depletion of the TCR complex from the cell surface ( &gt; 99%) as measured by FACS analyses. Furthermore, TCR functionality was inhibited when treated cells were stimulated with either CD3 or in B cell co-cultures with Staphylococcal enterotoxins. IL-2 secretion was inhibited to undetectable levels by ELISA by the multi-shRNA treatment and &gt; 98% by qPCR. Conclusions: Though knockdown of any single component of TCR never exceeded 93%, simultaneous knockdown of several TCR subunits abrogated surface TCR and downstream activation suggesting that disruption of stoichiometric expression the subunits prevented TCR formation. The small size of the shRNA expression cassette ( &lt; 2 Kb) permits co-expression from the same lentiviral vector as the CAR. Altogether, these data point to a viable strategy towards generating a single vector approach for the production of allogeneic T-Cells for immunotherapies against certain cancers.
Detection of MGMT promoter methylation in malignant gliomas.
Authors: Michelle Afkhami, Vandana Sharma, Maria Cuellar, Massimo D'Apuzzo, Behnam Badie, Jana Portnow, Raju K. Pillai, Patricia A. Aoun, Milhan Telatar
Journal: Journal of Clinical Oncology (2016)

e23131 Background: The O6-methylguanine methyltransferase (MGMT) is a DNA repair enzyme that is responsible for de-alkylation of naturally occurring O6-methylguanines in DNA and aids in the prevention of errors during DNA replication and transcription. Epigenetic silencing of the MGMT compromises DNA repair making tumor cells more sensitive to alkylating drugs and resulting in better response and longer survival in patients with glioma. We have validated the methylation specific multiplex ligation-dependent probe amplification (MS-MLPA)-based method to determine the MGMT methylation status in patients with glioma. Methods: Twenty-two formalin fixed paraffin embedded (FFPE) brain tissue samples from glioma cases, 7 FFPE brain tissue samples from non-tumor cases and 23 FFPE non-tumor samples from other organ sites were used in the study. MS-MLPA probemix ME012-X1 (MRC-Holland, Amsterdam, The Netherlands) was used to detect the methylation status in the MGMT promoter. The ME012-X1 contains 6 MS-MLPA probes that detect the methylation status of the MGMT gene promoter based on sequence recognition by the methylation-sensitive restriction enzyme HhaI. Greater than 40% methylation in one or MS-MLPA probes in the sample indicated hypermethylation. Results: MGMT methylation status in all 52 tissue specimens was determined. Hypermethylation was not detected in the 7 FFPE normal brain tissue samples and 23 FFPE non-tumor samples from other organ sites, as expected. Of the 22 glioma cases 14 were hypermethylated in one or more probe locations. Hypermethylation was not detected in the rest of the 8 glioma cases. The comparison of our results of the 22 glioma cases to reference laboratory results done by MethyLight assay, revealed discrepancies in two samples: one sample identified as hypermethylated MGMT by MS-MLPA was negative by MethyLight assay, and the other result was vice versa. This discrepancy was due to the differences in locations of the primer/probes between two assays. The MS-MLPA assay showed 100 % reproducibility and was capable of detecting hypermethylation in FFPE specimen with at least 50% tumor cellularity. Conclusions: The MS-MLPA assay represents a reliable and sensitive detection method to analyze promoter hypermethylation of MGMT.
Familial association of lung cancer patients with liver cancer in first-degree relatives.
Authors: Chongrui Xu, Huan Lin, Xuchao Zhang, Xuening Yang, Qing Zhou, Wenzhao Zhong, Jinji Yang, Yi-Long Wu
Journal: Journal of Clinical Oncology (2018)

e13597 Background: Besides the smoking and occupational exposures, heritable factors have been proved to be a risk factor for the lung cancer by several population-based studies while the over-report may misestimate the risk of lung cancer during such studies. Methods: To find the magnitude of the high risk of lung cancer with family history, from 2009 to 2012 we performed a case-based study enrolled 1373 individuals. First-degree relatives (FDRs) and spouses of the probands were defined as case group and control group respectively interviewed with a standardized lifestyle questionnaire collecting information including age, gender, smoking status, histories of diseases, histology, TNM stage and etc. Odds ratio(OR) and 95% confidence interval (95% CI) were calculated and all tests were two-sided, and p values less than 0.05 were considered statistically significant. Results: Risk of lung cancer was higher of people with lung cancer family history than the controlled group (OR 2.50, p < 0.001). Individuals with family history of liver cancer also had a high risk of lung cancer than the controlled group (OR 1.78, p = 0.038) while there was no significant difference within the individuals with the family history of colorectal cancer, esophageal cancer, nasopharyngeal cancer or breast cancer. Conclusions: The result of this study proved that the familial aggregation of lung cancer and liver cancer manifests higher risks of lung cancer. Chongrui Xu & Huan Lin contribute equal to the abstract.Table 1. Risks of First-degree Relatives Developing Different Types of Cancers FDRs’ History of Cancer Case Group N(%) Control Group N(%) OR(95%CI) p-value Lung cancer No 640(88.2) 614(94.9) 2.50(1.65, 3.79) < 0.001 Yes 86(11.8) 33(5.1) Liver cancer No 687(94.63) 627(96.91) 1.78(1.03,3.08) 0.038 Yes 39(5.37) 20(3.09) Colorectal cancer No 701(96.56) 627(96.91) 1.12(0.61,2.03) 0.714 Yes 25(3.44) 20(3.09) Esophageal cancer No 698(96.14) 631(97.53) 1.58(0.85,2.95) 0.146 Yes 28(3.86) 16(2.47) Nasopharyngeal cancer No 710(97.8) 636(98.3) 1.30(0.6,2.83) 0.502 Yes 16(2.2) 11(1.7) Breast cancer No 715(98.48) 642(99.23) 1.98(0.68,5.72) 0.201 Yes 11(1.52) 5(0.77)
Whole exome sequencing analysis of the neoadjuvant bevacizumab plus pemetrexed and carboplatin for unresectable stage III lung adenocarcinoma: Results of the phase II GASTO 1001 trial.
Authors: Si-Yu Wang, Wei Ou, Ning Li, Peng-Fei Xu, Xiao-Yong Mao, Bao-Xiao Wang
Journal: Journal of Clinical Oncology (2016)

e20045 Background: GASTO 1001 is a phase II trial investigating the efficacy and safety of induction bevacizumab plus chemotherapy followed by surgery in unresectable stage III lung adenocarcinoma. The induction response differed in patients in GASTO 1001. To identify the somatic alterations that correlate with the response to bevacizumab for patients with adenocarcinoma, we conducted this study. Methods: We performed whole-exome sequencing of formalin-fixed, paraffin-embedded tumor samples from 20 samples from GASTO 1001. Clinical association with somatic alterations was investigated by KEGG pathway. Results: Comparative analysis revealed several significantly mutated genes in patients with PR or CR, including CD34, CDH1, CDH2, CDH15, CNTNAP2, NLGN4X, VCAN, ALCAM, ITGAM, and NCAM1. Of note, gene analysis revealed a significant enrichment of mutations in the cell adhesion molecules signaling pathway in patients with a response. On the other hand, genes that take part in the longevity regulating pathway were frequently mutated in patients with SD or PD, including PIK3CA, RPTOR、KRAS、STK11、TP53, suggesting the possible relevance of these gene to the unresponsiveness to bevacizumab. Conclusions: These findings may provide insight into the identification of optimal candidates for precision medicine in patients with lung adenocarcinoma who receive bevacizumab. Further study will focus on cell adhesion molecules pathway in these patients.
Clinical characterization of febrile neutropenia episodes in patients with testicular germ cell tumors.
Authors: Angelika Bezan, Florian Posch, Thomas Bauernhofer, Martin Pichler, Joanna Szkandera, Georg C. Hutterer, Karl Pummer, Richard Partl, Brigitte Zurl, Karin Kapp, Herbert Stoger, Armin Gerger, Michael Stotz
Journal: Journal of Clinical Oncology (2017)

e16038 Background: Febrile neutropenia (FN) is a serious complication of chemotherapy (CTX). Here, we aim to characterize the clinical course of FN in patients (pts) with testicular germ cell tumors (TGCT). Methods: 413 TGCT patients who underwent at least one cycle of CTX in adjuvant or curative intent were studied within this single-center observational cohort study. Baseline characteristics of the subpopulation with FN are reported in Table 1. Results: During a total number of 1,196 CTX cycles in 413 patients, we observed 70 episodes of febrile neutropenia (16.9%). 55 (79%) of these episodes occurred during the 1 st cycle of CTX. The median time between CTX start and FN onset was 14 days [IQR: 12-15, range: 7-18]. One (1%) FN episode was fatal, and 56 patients (80%) had to be hospitalized. Median time in hospital was 7 days [IQR: 6-8, range: 3-12], and the median number of days with an absolute neutrophil count below 0.5G/L was 2 [IQR: 2-3, range: 1-7]. Twelve (20%) FN episodes occurred in the 60 pts who received primary G-CSF support. There was very little treatment delay due to FN (median: 0 days [IQR: 0-0, range: 0-7]. 3 patients (4%) developed a second FN episodes. Conclusions: This study supports prior reports that FN is a relatively frequent complication of CTX in TGCT. However, the case-fatality-rate of FN in TGCT appears to be very low. [Table: see text]
Initial experience of combination nivolumab and local-regional treatment in patients with advanced hepatocellular carcinoma (HCC).
Authors: Ping Gu, James Park, Judy Zhong, Songchuang Guo, Ryan Hickey, Eric Aaltonen, Jeremy Horn, Kevin Lee Du, Krishna Shanbhogue, Alec Megibow, Ruliang Xu, Irene Kyritsis, Deirdre Jill Cohen, Elliot Newman, George Miller, Theodore Welling
Journal: Journal of Clinical Oncology (2018)

e16149 Background: HCC is the second-leading cause of cancer-related deaths in the world and has the fastest rising incidence and mortality in the U.S. The high mortality rate is due to the late stage of disease, decompensation of underlying cirrhosis, and the lack of effective treatment options. Nivolumab (Nivo), a fully humanized IgG4 monoclonal antibody against the programmed death receptor-1 (PD-1), has recently demonstrated safety and initial efficacy in the CheckMate-040 study in HCC patients resulting in its FDA approval for second line use. We sought to retrospectively evaluate the safety and initial efficacy of combined Nivo and local-regional (LR) therapy in advanced HCC patients. Methods: Following IRB approval, we retrospectively reviewed consecutive advanced HCC patients treated with Nivo with or without local-regional treatment at a single center. Adverse events were assessed using NCI CTCAE version 4.03 criteria and tumor response rates were determined using RECIST1.1 criteria. Kaplan-Meier analysis was used to calculate survival rate. Results: Twenty-eight consecutive advanced HCC patients received at least six doses of Nivo. Median age was 64 (44-79), 82% were male, 96% were ECOG 0-1, 57% were HBV+, 36% were HCV+, and 89% had Childs A cirrhosis. Portal vein invasion was noted in 39% and 25 % had extrahepatic metastasis. Prior sorafenib had been used in 32%. Combined Nivo and LR therapy was used in 71%. Median follow up period was 10.4 months (range 4-27). Grade 3 possible treatment related AEs occurred in two patients (7%). Objective response occurred in 14 (50%) of patients with three CRs (11%) and five PRs (18%). Six (21%) had stable disease. Responses based on mRECIST are still being determined. Median overall survival for the entire cohort was 13.6 months. Conclusions: Nivo in combination with LR therapy in advanced HCC patients appears to be safe. Further study may show additional efficacy for the combination over the use of monotherapy.
P01.020 Results of treatment with bevacizumab in patients with recurrent high grade brain glioma
Authors: S Javadinia, K Anvari, M Shahabadi
Journal: Neuro-Oncology (2018)

Glioblastoma, the most common primary malignant brain tumor in adults, is highly aggressive and associated with a poor prognosis. Bevacizumab has been used in patients with GBM as a salvage therapy since its approval in the United States for recurrent GBM in 2009.We report our two centers experience with bevacizumab in a cohort of patients treated for a relapsing glioblastoma. We performed a retrospective analysis of consecutive patients treated with bevacizumab for a relapsed glioblastoma, between 2007 and 2017 in Omid Hospital and Emam Reza Hospital. Tumor responses, time to progression and overall survival rates were analyzed. Most of 40 patients had glioblastoma multiforme (67.5%) and initial plan of 92.5% them was The Stupp protocol. With the Stupp protocol, 55% of patients had favorable response. The median progression free survival (PFS) after first line of adjuvant treatment was 11 month. All patients received second line of treatment (mostly bevacizumab-based chemotherapy, 82%). The median PFS after second line was 6 month. Third and fourth lines of treatment were administrated in 12% and 2.5% of patients, respectively, accompanied with the median PFS of 5 and 8 months. With a follow up of 125 months, 45% of patients were dead, Ten (25%) had evidence of active disease (which the treatment was discontinued and were candidated for palliative care), and 30% of patients had stable disease/no evidence of disease). The median overall survival (OS) was 8 month which was correlated just with age (the median OS for patients <45 and 45> was 33 and 23, respectively, p=0.01). The median of bevacizumab related PFS was 8 months and there was no significant relation between it and other contributing factors This retrospective experience suggests that bevacizumab is active for recurrent glioblastoma. Median survival times were in the range of those reported in therapeutic trials. This study questions the validity of usual predictive factors in the era of bevacizumab.
P04.24 MTOR signaling in glioma-associated microglia and macrophages
Authors: P S Zeiner, N I Lorenz, M Burger, A L Luger, P N Harter, J P Steinbach, M W Ronellenfitsch
Journal: Neuro-Oncology (2018)

In patients with glioblastoma (GBM) overall survival is still dismal despite improved diagnostic precision and aggressive treatment strategies including recent trials that target selective cancer alterations or immune cell-based therapies. While the central nervous system (CNS) is considered an immunoprivileged site and brain tumors display immunosuppressive features, both innate and adaptive immune responses affect GBM progression and treatment resistance. The impact of the major immune cell population in gliomas, represented by glioma-associated microglia/macrophages (GAMs), onto patients’ clinical course is still unclear, although different GAM subpopulations are positively associated with patients’ survival. Likewise, only limited data exists on the effect of established as well as novel targeted therapies on GAMs and the resulting potential impact on therapeutic responses. We analyzed GAM properties (proliferation, cell death, migration, cytokine expression) in a GBM co-culture in vitro model under standard chemotherapy with temozolomide and targeted therapy with mTOR inhibition. We identified the mTOR signaling cascade not only as a central regulator of glioma cells but also GAM function. MTOR inhibition regulated the proliferation and cytokine expression profile of GAMs with an increase of the inflammatory cytokines macrophage migration inhibitory factor (MIF) and plasminogen activator inhibitor-1 (PAI-1). These effects might influence the efficacy of mTOR inhibitor therapies in GBM patients. A more detailed understanding of therapy-mediated effects on GAMs will augment the design of effective treatment combinations and identification of patient subgroups most likely to benefit from therapeutic interventions with established and novel targeted therapies.
The role of adjuvant chemotherapy in stage IB non-small cell lung cancer: A decision, effectiveness, and cost-effectiveness analysis.
Authors: Jessica Lynn Hudson, Wint Y Aung, Carlos AQ Santos, Su-Hsin Chang, Margaret A Olsen, Bryan F Meyers, Daniel Morgensztern, Varun Puri
Journal: Journal of Clinical Oncology (2017)

8526 Background: Despite complete surgical resection (SR), half of stage I non-small cell lung cancer (NSCLC) patients die from systemic relapse. An independent risk factor for systemic progression is pathologic stage IB subtype (T2aN0M0, AJCC 7). The role of adjuvant chemotherapy (AC) in stage IB NSCLC is controversial. We studied the effectiveness and cost-effectiveness of AC after SR in stage IB NSCLC. Methods: Propensity score matching was performed on the National Cancer Database (2004-2011). The Kaplan-Meier method generated conditional probabilistic incremental 1- to 5-year survival after SR stratified by receipt of AC. Medicare allowable charges for SR, AC, and their respective complications were used. Decision analysis modeling and microsimulation were performed to account for proportions of chemotherapeutic agents administered in real-world settings. The incremental cost-effectiveness ratio (ICER) was calculated over a 5-year horizon. Probabilistic and two-way sensitivity analyses were performed. Results: 3662 of 18709 patient (19.6%) who met inclusion criteria received AC for SR stage IB NSCLC, with usage ranging from 15-27% annually. After propensity score matching, an overall survival benefit of AC was conferred over SR alone (at 5 years: 68.9% vs 60.4%, p &lt; 0.001). The incremental cost of AC over SR alone was $11,541. The incremental effectiveness of AC was 0.28 life-years, with an ICER of $41,218. In two-way sensitivity analysis, AC plus SR dominated for the entire range of cost and survival estimates. In probabilistic sensitivity analysis, AC plus SR dominated the model above a willing-to-pay threshold of $16,000. AC costs could nearly double and the ICER remained under conventional thresholds. However, only 3 of the 4 common AC regimens were cost effective. Conclusions: In stage IB NSCLC, surgery is insufficient to render a cure. The addition of AC to SR extends life-expectancy and is cost-effective compared to SR alone. These conclusions are valid over a range of clinically meaningful variations in cost and treatment outcomes, though a cost-conscious approach is needed when selecting an AC regimen. This represents a novel change in the treatment of stage IB NSCLC.
MKNK1 SNP rs8602 to predict outcome for mCRC patients treated with first-line FOLFIRI and bevacizumab: Data from FIRE-3 trial.
Authors: Martin D. Berger, Sebastian Stintzing, Volker Heinemann, Dongyun Yang, Yu Sunakawa, Yan Ning, Satoshi Matsusaka, Satoshi Okazaki, Yuji Miyamoto, Mitsukuni Suenaga, Marta Schirripa, Jordan David West, Diana L. Hanna, Afsaneh Barzi, Wu Zhang, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2016)

11588 Background: The MAPK-interacting kinase 1 (MKNK1) is localized downstream of the RAS/RAF/ERK and the MAP3K1/MKK/p38 signaling pathway. Through phosphorylation MKNK1 regulates the function of eukaryotic translation initiation factor 4E (eIF4E), a key player in translational control, whose expression is mostly upregulated in cancer patients. Preclinical data also suggest an influence of MKNK1 on angiogenesis and endothelial cell migration. We therefore hypothesize that variations in the MKNK1 gene may predict outcome in patients (pts) with metastatic colorectal cancer (mCRC) treated with first-line FOLFIRI and bevacizumab (bev). Methods: 295 pts with mCRC enrolled in the phase III FIRE-3 trial and treated with first-line FOLFIRI and bev were included in this study. Genomic DNA was extracted from formalin fixed paraffin embedded tissue. 6 functional SNPs in 6 genes (MKNK1, EIF4E, EIF4G, 4EBP1, hnRNPA1 and Spry2) were analyzed by PCR-based direct sequencing. Candidate SNPs and their correlation with outcome were analyzed by uni- and multivariate analysis. Results: Baseline characteristics were as follows: female/male = 99/196; median age = 65y; primary tumor site right/left = 74/215;median PFS/OS = 10.2/24.2 months. The MKNK1 rs8602 SNP showed significant association with progression-free survival (PFS). C allele carriers had a longer median PFS than those with an AA genotype (10.3 vs 7.7 months) in both univariate (HR 1.79, p = 0.009) and multivariate analysis (HR 1.80, p = 0.019). Additionally males and pts with left-sided cancers harboring any C allele had a better overall survival (OS) than those with an AA genotype (26.1 vs 18.2 months, HR 1.94, p = 0.025) and (28.1 vs 18.4 months, HR 2.28, p = 0.002) respectively. These associations remained significant in multivariate analysis (HR 1.94, p = 0.047 and HR 2.28, p = 0.008). Conclusions: Our results provide the first evidence that the MKNK1 SNP rs12218 might serve as a predictive marker in pts with mCRC treated with FOLFIRI and bev in the first line setting. Additionally MKNK1 rs12218 might also be prognostic depending on gender and tumor location. Targeting MKNK1 might be a promising approach to improve our treatment options against mCRC.