tbuckley/cabot-search huggingface dataset:
Regulatory CD4 <sup>+</sup> T Cells Recognize Major Histocompatibility Complex Class II Molecule–Restricted Peptide Epitopes of Apolipoprotein B
Authors: Takayuki Kimura, Kouji Kobiyama, Holger Winkels, Kevin Tse, Jacqueline Miller, Melanie Vassallo, Dennis Wolf, Christian Ryden, Marco Orecchioni, Thamotharampillai Dileepan, Marc K. Jenkins, Eddie A. James, William W. Kwok, David B. Hanna, Robert C. Kaplan, Howard D. Strickler, Helen G. Durkin, Seble G. Kassaye, Roksana Karim, Phyllis C. Tien, Alan L. Landay, Stephen J. Gange, John Sidney, Alessandro Sette, Klaus Ley
Journal: Circulation (2018)

Background: CD4 + T cells play an important role in atherosclerosis, but their antigen specificity is poorly understood. Immunization with apolipoprotein B (ApoB, core protein of low density lipoprotein) is known to be atheroprotective in animal models. Here, we report on a human APOB peptide, p18, that is sequence-identical in mouse ApoB and binds to both mouse and human major histocompatibility complex class II molecules. Methods: We constructed p18 tetramers to detect human and mouse APOB-specific T cells and assayed their phenotype by flow cytometry including CD4 lineage transcription factors, intracellular cytokines, and T cell receptor activation. Apolipoprotein E–deficient ( Apoe −/− ) mice were vaccinated with p18 peptide or adjuvants alone, and atherosclerotic burden in the aorta was determined. Results: In human peripheral blood mononuclear cells from donors without cardiovascular disease, p18 specific CD4 + T cells detected by a new human leukocyte antigen-antigen D related-p18 tetramers were mostly Foxp3 + regulatory T cells (Tregs). Donors with subclinical cardiovascular disease as detected by carotid artery ultrasound had Tregs coexpressing retinoic acid-related orphan receptor gamma t or T-bet, which were both almost absent in donors without cardiovascular disease. In Apoe −/− mice, immunization with p18 induced Tregs and reduced atherosclerotic lesions. After peptide restimulation, responding CD4 + T cells identified by Nur77-GFP (green fluorescent protein) were highly enriched in Tregs. A new mouse I-A b -p18 tetramer identified the expansion of p18-specific CD4 + T cells on vaccination, which were enriched for interleukin-10–producing Tregs. Conclusions: These findings show that APOB p18–specific CD4 + T cells are mainly Tregs in healthy donors, but coexpress other CD4 lineage transcription factors in donors with subclinical cardiovascular disease. This study identifies ApoB peptide 18 as the first Treg epitope in human and mouse atherosclerosis.
High intra- and inter-tumoral heterogeneity of <i>RAS</i> mutations in colorectal cancer.
Authors: David Tougeron, Marion Jeantet, Ulrich Cortes, Celine Archambaut, Gaelle Fromont, Jean-Marc Tourani, Lucie Karayan-Tapon
Journal: Journal of Clinical Oncology (2016)

3577 Background: Anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR mAbs) are a standard treatment in metastatic colorectal cancer (mCRC) with wild-type (WT) RAS status. However, approximately 30% of patients with RAS WT mCRC are non-responders to anti-EGFR mAbs, possibly due to undetected tumoral subclones harboring RAS mutations. The aim of this study was to analyze the distribution of RAS mutations in different areas of the primary tumor, metastatic lymph nodes and distant metastasis. Methods: A retrospective cohort of 18 patients with a CRC was included in the study. All tumors were tested for KRAS, NRAS (codon 12, 13, 59, 61, 117 and 146) and BRAFV600E mutations using transparietal sections. Six were KRAS mutant, one NRAS mutant and one BRAF mutant. Multiregion analysis was performed in 60 spatially separated tumor areas according to the pTNM staging, including 49 in primary tumors (submucosa (pT1), musculosa (pT2) and/or subserosa (pT3)), 10 in metastatic lymph nodes and 1 in metastasis. KRAS, NRAS and BRAF mutations were tested using pyrosequencing. Intra-tumoral heterogeneity is defined by the presence of different tumoral subclones within the same tumor mass. Inter-tumoral heterogeneity consists in the presence of different tumor subclones in various tumor sites (i.e. primary tumor, metastatic lymph nodes or metastases). Results: Among the 60 tumor areas, 35 were KRAS mutated (in 11 tumors), 8 NRAS mutated (in 3 tumors) and one BRAF mutated(in 1 tumor). In primary tumors (n = 18), intra-tumoral heterogeneity for RAS mutation was found in 8 patients (44%). Inter-tumoral heterogeneity for RAS mutation between primary tumors and metastatic lymph nodes or distant metastasis (n = 11) was found in 6 patients (54%). Moreover, 5 tumors had multiple RAS mutated subclones in the same tumor (28%). Indeed, we observed the coexistence of different KRAS mutations (n = 3) as well as KRAS and NRAS mutations (n = 4). Conclusions: A high proportion of CRC presented intra- and/or inter-tumoral heterogeneity, which has relevant clinical implications for anti-EGFR mAbs prescription. These results suggest the need for multiple RAS testing in different part of the same tumor and/or more sensitive techniques.
Correlation between an automated functional assay that predicts targeted agent (TA) sensitivity and the tumor response of the sorafenib treatment evaluated within the MOST clinical trial
Authors: O. Tredan, O. Zelichov, Z. Barbash, Y. Daitsh, L. Birnbaum, G. Tarcic, B. You, P. Cassier, C. de la Fouchardiere, I.L. Ray-Coquard, M. Brahmi, Q. Wang, V. Attignon, C. Baudet, G. Fournier Garin, V. Agrapart, A. Dargenio, S. Chabaud, D. Perol, J.-Y. Blay
Journal: Annals of Oncology (2018)

Background: MOST (My Own Specific Therapy) is a prospective, randomized, open-label, adaptive phase II trial conducted in patients (pts) with progressive solid tumors (any subtype) after at least one prior therapy in advanced setting. This trial aims to evaluate the clinical benefit of therapies targeting molecular alterations identified in the patient's tumor. NovellusDx' technology measures the functional impact of alterations including Variants of Uncertain Significance (VUS), and TA efficacy based on NGS findings. Methods: Pts were treated with sorafenib 400 mg BID based on KRAS/KDR, HRAS and BRAF (non-V600) oncogenic mutations/amplification. After 12 weeks of treatment (induction period), pts with stable disease were randomly assigned to continuation or interruption of sorafenib. NGS data from the treated pts were blindly analyzed by the functional assay: synthesized mutated genes and florescent reporter genes were transfected into live cells and scanned in a microscopy system. The specific pathways activation was evaluated by quantifying the subcellular localization of the reporter proteins. Sorafenib response prediction based on the assay was compared with the best change tumor size assessed in the MOST trial, and the maintenance treatment duration. Results: 17 patients treated for at least 12 weeks with sorafenib were analyzed. Tumor genomic alterations that indicated the sorafenib treatment consisted in KRAS mutations (n = 9), KRAS amplifications (n = 3), HRAS mutation (n = 3), KDR amplification/mutation (n = 2). However, NGS data showed additional molecular aberrations. Of which, the functional impact and response to TA of 18 unique variants in 10 different genes was measured. The correlation between the assay-based response prediction and the variation in the tumor volume of the patients will be presented. Conclusions: Multidisciplinary molecular tumor board recommends TA based on single actionable oncogenic mutations. Taking into account significant other genomic variants is crucial to accurately predict targeted agent efficacy. Clinical trial identification: NCT02029001. Legal entity responsible for the study: Centre Léon Bérard. Funding: Fundation ARC, INCa. Disclosure: O. Zelichov, Z. Barbash, Y. Daitsh, L. Birnbaum, G. Tarcic: Full time employee of NovellusDx. All other authors have declared no conflicts of interest.
TCT-29 Procedural and anatomic predictors of response in RADIANCE-HTN SOLO: a multicenter, randomized, sham-controlled trial of endovascular ultrasound renal denervation
Authors: Ajay Jayant Kirtane, Roland Schmieder, Felix Mahfoud, Michael Weber, Joost Daemen, Jan Basile, Andrew Sharp, Melvin Lobo, Philipp Lurz, Kintur Sanghvi, Marc Sapoval, Atul Pathak, Yale Wang, Michel Azizi
Journal: Journal of the American College of Cardiology (2018)
Identification of a High-Level MET Amplification in CTCs and cfTNA of an ALK-Positive NSCLC Patient Developing Evasive Resistance to Crizotinib
Authors: Lars-Arne Berger, Melanie Janning, Janna-Lisa Velthaus, Isabel Ben-Batalla, Stefanie Schatz, Markus Falk, Peter Iglauer, Ronald Simon, Ru Cao, Claudio Forcato, Nicolò Manaresi, Kelli Bramlett, Genny Buson, Annkathrin Hanssen, Markus Tiemann, Guido Sauter, Carsten Bokemeyer, Sabine Riethdorf, Martin Reck, Klaus Pantel, Harriet Wikman, Sonja Loges
Journal: Journal of Thoracic Oncology (2018)
P05.40 Clinical and radiological outcome of vestibular schwannomas (Koos grade I - IV) after stereotactic radiosurgery
Authors: R Daniel, L Poehlmann, H Treuer, M Kocher, K Jablonska, S Grau, M Ruge
Journal: Neuro-Oncology (2018)

In the management of vestibular schwannoma (VS) stereotactic radiosurgery (SRS) has evolved as widely accepted treatment option for small-sized tumors (Koos I and II). For larger VS (Koos III and IV) microsurgery is treatment of choice. However, for patients not suitable for microsurgery SRS might also be an alternative that balances tumor control, hearing preservation and adverse effects. The purpose of this analysis was to evaluate the efficacy and toxicity of SRS for different Koos grades including VS Koos III and IV. In this single center retrospective analysis (1991 - 2016) we included all patients with previously untreated VS who underwent single session LINAC or Cyberknife® based SRS. Patient data were analyzed and correlated using cox proportional hazard model in terms of the different Koos grades. Data analysis considered tumor control, preservation of serviceable hearing, course of median pure tone averages (PTA) at last follow up and procedure related early and late adverse events rated by Common Terminology Criteria for Adverse Events (CTCAE; v4.03). 265 patients (median age 59 years, range 17–84) were identified with a mean follow-up of 50.9 months (range 3–265 months). Mean tumor volume was 1.8 ml (range 0.1–23.7 ml). The mean marginal dose was 12.4 Gy ± 0.8 (range 11–20) and the mean isodose was 69.3 % ± 12.5 (range 32.9–86.2). 193 patients were considered as Koos grade I or II and 72 patients as grade III or IV. Actuarial tumor control was 98.5%, 88% and 88% after 2, 5 and 10 years respectively without significant difference between Koos grades I/II vs III/IV (hazard ratio (HR) 1.1, p=0.8, 95% CI, 0.4–3.6). Likewise, median PTA increase of Koos I/II tumors compared to Koos III/IV tumors revealed no significant difference (HR 0.5, p=0.07, 95% CI, 0.3–1.0). New permanent CN V and VII impairment could be objectified in 7.1% (n=19/265). The rate of permanent CN V and CN VII impairment showed no significant difference between Koos grades I/II vs III/IV (HR 0.5, p=0.07, 95% CI, 0.3–1.0). SRS for VS shows reliable long term tumor control and a high rate of hearing preservation and with low permanent side effects. Therefore, SRS can be proposed as safe and effective treatment option for VS, even with higher Koos grades.
P04.38 Orai2 related transcriptome profile and clinical outcome in classical and mesenchymal subtype of glioblastoma
Authors: F YUAN, X Yang
Journal: Neuro-Oncology (2018)

Ca2+ release-activated Ca2+ channels (CRAC) is the main Ca2+ entry pathway regulating intracellular Ca2+ concentration in a variety of cancer types. Orai2 is the main pore-forming subunit of CRAC channels in central neurons; To characterize the role of Orai2 in glioma, we investigated its related biological process, molecular function and KEGG pathways at transcriptome level and its clinical prognostic value. Through TCGA, French, Sun and GEO (GSE23806) dataset, we systematically reviewed a total of 1231 cases with RNA-seq data and analyzed the functional annotation of Orai2 by Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway analysis. Univariate and multivariate survival analysis were performed in 823 patients with survival data. We found Orai2 was significantly upregulated in glioblastoma. Survival analysis suggested that higher Orai2 expression was independently associated with worse prognosis of patients with classical and mesenchymal subtype of glioblastoma. According to TCGA transcriptional classification scheme, Orai2 expression was higher in tumors of classical and mesenchymal subtype than other subtypes, and shown significantly correlation with classical and mesenchymal related genes. GO KEGG Pathway analysis revealed that genes significantly correlated with Orai2 were involved in essential functions associated with stemness, apoptosis and EMT process. Through screening transcriptomic data, we found a strong correlation between Orai2 and apoptosis, stemness and Epithelial to mesenchymal(−like) transition (EMT) related genes including Nestin, SOX2, NOTCH1, TP53, Caspase 3, Cytochrome C, CDH2, ZEB1, VIM. Orai2 is a prognostic factor that is distinctly activated in the classical and mesenchymal subtype of glioblastoma and that promotes glioma GSCs selfrenewal, apoptosis process and mesenchymal transition via the JNK pathway. These findings suggested Orai2 as a candidate for a therapeutic target for classical and mesenchymal subtype of GBM.
Is obstructive sleep apnoea an innocent bystander in the pathophysiology of arterial stiffening?
Authors: Craig L Phillips, Luciano F Drager
Journal: Thorax (2018)

Arterial compliance is an important mechanical property of the arterial tree that is crucial for the maintenance of vascular homeostasis and cardiovascular health.There are a number of factors that variably decrease arterial compliance and therefore increase arterial stiffness in different arterial segments.For example, arteries become less distensible and therefore stiffer as blood pressure (BP) increases, and this effect occurs throughout the arterial tree.On the other hand, an increase in the collagen-elastin ratio in the arterial wall, such as occurs with ageing, increases arterial stiffness predominantly in large elastic arteries like the aorta.In contrast, an increase in the quantity and tone of arterial smooth muscle mainly increases arterial stiffness in the smaller conduit arteries such as the femoral arteries. 1 2 Overall, a loss of arterial compliance gives rise to increased arterial stiffness and poorer maintenance of vascular homeostasis, and this is likely to be a key driver of cardiovascular disease (CVD).The process of arterial stiffening occurs in ageing populations and in conditions that are strongly associated with CVD including chronic kidney disease, 3 type II diabetes and various components of the metabolic syndrome. 4 This has led to the development of many methods for quantifying arterial stiffness, 5 as a means of improving CVD risk stratification in populations with comorbid disease.However, in order to standardise the assessment of risk, the American Heart Association Council for high blood pressure research recommends the non-invasive
Application of a real world endpoint to identify and characterize genetic profiles of patients (pts) with poor prognosis in advanced non-small-cell lung cancer (aNSCLC).
Authors: Gracy Crane, Kerstin Trunzer, Sam Whipple, Karen Cuenco, Jonathan Tolson, Bishember Kathuria, Ashis Das-Gupta
Journal: Journal of Clinical Oncology (2018)

12006 Background: There is an unmet need to identify and characterize pts who rapidly progress on currently available therapies. Recent availability of linked clinico-genomic information offers an opportunity to characterize genetic profiles of rapid progressors to increase treatment options available to these patients. Methods: Pts diagnosed with NSCLC (n=2,139) within the Flatiron (FIH)-Foundation Medicine (FMI) linked database (Jan 2011–Dec 2016) were grouped by treatment class: cancer immunotherapy (CIT), targeted therapy (TKIs) or chemotherapy (CT). A composite real world endpoint of time to treatment failure (rwTTF) <2 months was created using the earliest of: a) time to next treatment, or b) real world progression (based on abstraction of clinician’s assessment in electronic health records), or c) death within 60 days. A rwTTF <2 months was used to define rapid progressive (RPD). Baseline characteristics, overall survival (OS) and genetic profiles by NGS (using FMI) were analyzed for pts with RPD vs non rapid progressive disease (NRPD) by treatment class. Results: Baseline characteristics were mostly balanced. Median OS was substantially longer in pts with NRPD vs RPD across treatment classes confirming that the rwTTF definition can be used to identify RPD in real world databases. In CIT median OS was 4.4m (3.32–5.72) in the RPD vs 17.1m (14.26–NA) in the NPRD. In addition, higher tumor mutational burden (TMB) correlated with higher likelihood of response to CIT (median TMB was 9.9 (3.60–15.31) in NRPD patients vs. 5.4 (2.70–9.91) in RPD patients). This difference was not observed in the TKI or CT groups. In the CIT group, HER2 and EGFR mutations were suggestive of an association with RPD status; however, EGFR and BRAF mutations were suggestive of an association with NRPD in the CT group. In the TKI group, CDKN2A/CDKN2B copy number variants were suggestive of an association with NRPD status. Conclusions: Applying a real world endpoint, we identified and characterized genetic profiles of pts with rapid progression. Rapid advances in data capture and linkage availability and quality can help with optimal management of patients at the point of care.
Retrospective cohort analysis of adjuvant NY-ESO-1 vaccines in stage III melanoma.
Authors: Michael William Lattanzi, Joseph Han, Una Moran, Kiersten Utter, Jeremy Tchack, Rachel Lubong Sabado, Nina Bhardwaj, Iman Osman, Anna C. Pavlick
Journal: Journal of Clinical Oncology (2016)

3084 Background: Cancer-testis antigen NY-ESO-1 is a highly immunogenic melanoma antigen which has been adopted for adjuvant vaccine trials. Three such trials (NCT00124124, NCT00821652, NCT01079741) in high-risk melanoma patients were conducted at our center. Although exact treatment regimens differed between trials, all enrolled patients received an NY-ESO-1-based peptide vaccine. Methods: All vaccine trial patients had histologically-proven melanoma and were without evidence of disease at trial entry; every stage III patient for whom records were available was included for analysis. For comparison, a control cohort of stage III patients who received no adjuvant therapy was identified via our clinicopathological database; every such patient in the database was included for analysis. Recurrence patterns were compared via a chi-squared test. Overall survival (OS) was estimated by Kaplan-Meier analysis, and a Cox proportional hazard model was employed to control for thickness and ulceration, and calculate a hazard ratio (HR). Results: Information was available for 62 vaccinated patients and 116 control patients (median follow-up: 62.8 and 30.5 months, respectively). The vaccine and control groups had the following characteristics, respectively: male (52% vs 62%), median thickness (2.0 vs 2.7), ulceration (41% vs 47%), positive lymph nodes (81% vs 93%), and nodular histotype (52% vs 56%); only lymph node status was significantly different (p = 0.02). At last follow-up, 35 patients (56%) in the treatment group had recurred, compared to 84 patients (64%) in the control group. At first recurrence, vaccinated patients tended to recur with resectable disease more often than control patients (79% vs 60%, p = 0.10), though this result was not significant. OS, however, was significantly longer in the vaccine group compared to the control group (median not reached vs 57.5 months, HR 0.58, 95%CI 0.34 – 0.99, p = 0.047). Conclusions: In this small retrospective cohort of stage III melanoma patients, adjuvant NY-ESO-1 vaccination was associated with improved OS. NY-ESO-1 vaccination may exert an immunologic advantage reflected in a pattern of locally resectable disease upon recurrence compared to diffusely metastatic recurrences.
A multicenter study of the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib plus durvalumab in patients with relapsed/refractory (R/R) solid tumors.
Authors: David S. Hong, Drew W. Rasco, Michael H. Veeder, Jason J. Luke, Jason Chandler, Ani Sarkis Balmanoukian, Thomas J. George, Pamela Munster, Jordan Berlin, Martin Gutierrez, Alain C. Mita, Heather A. Wakelee, Selda Samakoglu, Shanhong Guan, Isaiah W. Dimery, Erkut Borazanci
Journal: Journal of Clinical Oncology (2018)

2578 Background: Ibrutinib (ibr), a first-in-class, once-daily inhibitor of BTK, is approved in the US for the treatment of various B-cell malignancies. In solid tumors, ibr may inhibit EGFR, HER2, mast cell function, and alter Th1/Th2 polarity. Preclinical data suggest benefit with PD-L1 inhibitors for pancreatic adenocarcinoma (PC), non–small cell lung cancer (NSCLC), HER2+ breast cancer (BC), and triple neg BC (TNBC). These mechanisms may act synergistically. This study assessed the safety and efficacy of ibr plus durvalumab, a PD-L1–targeting antibody, in patients (pts) with R/R solid tumors. Methods: This open-label, multicenter, ph 1b/2 trial enrolled pts with R/R stage III/IV PC, BC (HER2+, TNBC), or NSCLC (adenocarcinoma, squamous). Pts must have failed ≥1 (PC, NSCLC) or ≥2 (BC) prior systemic therapy lines. Ph 1b (6+3 dose de-escalation design) determined the recommended ph 2 dose (RP2D). PD-L1 expression was assessed retrospectively. Results: In ph 1b, 560 mg ibr PO daily and 10 mg/kg durvalumab IV every 2 wk was identified as the RP2D. Of 124 pts enrolled, 122 pts were treated at the RP2D (PC n = 49; BC n = 45; NSCLC n = 28). Median age was 60.5 y; 94% had stage IV disease; median prior radiation/cancer therapies was 4 (range: 1–20); 5 NSCLC pts, but no PC or BC pts, had tumors with high PD-L1 expression. Response rates in evaluable pts were 3% for BC (1 complete response in a TNBC pt; duration of response [DOR]: 23 mo), 2% for PC (1 partial response; DOR: 10 mo), and 0% for NSCLC. Median progression-free survival was 2 mo in each cohort; median overall survival was 4, 4, and 8 mo in the PC, BC, and NSCLC cohorts, respectively. No clinically meaningful differences in the safety profile were observed across tumor types, except differences due to tumor type, location, and prior therapies. Gr ≥3 treatment-emergent adverse events in ≥5% of pts were hyponatremia (10%), dyspnea (7%), maculopapular rash (7%), pneumonia (7%), anemia (6%), and diarrhea (6%). Conclusions: The combination of 560 mg ibr daily and 10 mg/kg durvalumab every 2 wk had an acceptable safety profile, but limited activity in the solid tumors studied, which may be due in part to heavy pretreatment and low PD-L1 expression. Clinical trial information: NCT02401048.