tbuckley/cabot-search huggingface dataset:
PD-L1 expression in Epstein-Barr virus-infected gastric cancers.
Authors: Sarah Derks, Xiaoyun Liao, Xinsen Xu, M. Constanza Camargo, Anna M Chiaravalli, Enrico Solcia, Tania Fleitas, Gordon J. Freeman, Scott J. Rodig, Charles S. Rabkin, Adam Joel Bass
Journal: Journal of Clinical Oncology (2016)

4052 Background: Gastric cancer (GC) is a deadly disease with limited treatment options. Recent studies with PD-1 inhibitor Pembrolizumab have shown promising results in GC. Key questions remain which GC subclass may respond best. In a comprehensive molecular analysis of gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) we identified that 15% of Epstein Barr Virus (EBV)+ GCs have amplification of chromosomal region 9p24.1, the locus of PD-1 ligands PD-L1 and PD-L2. As EBV+ cancers have multiple mechanisms to induce PD-L1 expression, we hypothesize that PD-L1 status may differ specifically in EBV+ GCs, regardless of 9p24.1 status, indicating a broader potential role for PD-1 blockade in this GC subtype. Methods: PD-L1 expression was analyzed with immunohistochemistry (IHC) using whole tissues slides of EBV+ (n = 32) and EBV negative (n = 49) GCs. The transcriptional landscape of EBV+ and EBV negative GCs was determined using mRNA sequencing results from the TCGA study. Results: With IHC we showed that EBV+ GCs have PD-L1 expression in tumor and immune cells in 50% (16/32) and 94% (30/32) of GCs respectively. This in contrast to EBV negative GCs that have PD-L1+ tumor and immune cells in only 10% (5/49) and 39% (19/49) of cases respectively (P< 0.001). Furthermore, PD-L1+ immune cells infiltrated the center of the majority of EBV+ GCs, while in EBV negative GCs PD-L1+ immune cells remained at the invasive margin (P = 0.007). mRNA sequencing analyses of 12 EBV+ GCs and 10 EBV- GCs showed that PD-L1+/EBV+ GCs have enrichment of an interferon-γ driven gene signature. Single-sample gene set enrichment analyses on a bigger series of 214 individual GCs demonstrated that besides EBV+ GCs (n = 19), microsatellite instable (MSI) GCs (n = 47) have strong enrichment of IFN-γ response gene expression, in contrast to genomic stable (GS) (n = 42) and chromosomal instable (CIN) (n = 106) gastric cancer subtypes (P< 0.001). Conclusions: As the presence of PD-L1+ tumor and/or tumor infiltrating immune cells as well as an interferon-mediated adaptive immune response are associated with PD-1 blockade vulnerability in other cancers, we here provide a strong rationale for testing of PD-1 blockade in EBV+ GC and for evaluating EBV and MSI status as variables for response.
Chimeric antigen receptor T cells targeting the lambda light chain of human immunoglobulin as a viable target for B cell non-Hodgkin lymphoma.
Authors: Raghuveer Ranganathan
Journal: Journal of Clinical Oncology (2018)

12079 Background: Mantle Cell Lymphoma (MCL) is an uncommon and clinically aggressive subtype of B cell derived non-Hodgkin lymphomas (B-NHL) which continues to have poor outcomes of all B-NHLs. Chemotherapy plus CD20-targeting antibodies make remission possible, with fit patients consolidated with autologous stem cell transplant but effects are invariably short-lived and MCL continues to principally be incurable. Adoptive chimeric antigen receptor T cells targeting CD19 (CD19.CAR-T) has shown therapeutic promise for B-NHL. Targeting this antigen, however, does not distinguish between normal and malignant B cells and causes profound B-cell aplasia since CD19.CAR-T can persist long-term. MCL, along with many diffuse large B cell lymphoma (DLBCL) subsets, expresses surface immunoglobulin (Ig) that carries the lambda light chain. We explored targeting Ig-lambda with CAR-T, which would possibly spare B lymphocytes expressing the reciprocal kappa light chain, and consequently reduce the impairment of humoral immunity. Methods: We genetically modified CAR-T cells to target the tumor-associated immunoglobulin lambda light chain (CAR.λ). We conducted in vitro trials with B-NHL derived tumor cell lines expressing the lambda light chain, and in vivo experiments using a NOD-scid xenograft murine model injected with these same tumor cell lines. We also established a murine model that reconstituted human B lymphocytes within immunosuppressed NSG mice using CD34+ umbilical cord blood cells. We then measured the selective ability of CAR.λ cells to eliminate normal human B-lymphocytes. Results: We found that the CAR.λ showed high cytotoxic activity against Ig-lambda+ B-cell tumor cell lines in vitro and in vivo within the NOD-scid xenograft murine model. We also demonstrated the selective elimination by the CAR.λ of lambda light chain-expressing B lymphocytes, with sparing of kappa chain-expressing B lymphocytes, in a humanized murine model. Conclusions: Adoptive transfer of CAR-T targeting the lambda light chain can be a very useful immunotherapy approach to treating both MCL and DLBCL clinically, without entirely compromising humoral immunity.
Expression of aldehyde deshydrogenase 1 ( ALDH1) in inflammatory breast cancer: A cohort study.
Authors: Fouzia Mamouch, Abdelilah Laraqui, Narjiss Berrada, Hind Mrabti, Siham Lemsanes, Mustapha Elkabous, Ibrahim El Ghissassi, Saber Boutayeb, Hafid Hachi, Y Sekhsokh, Basma Elkhanoussi, Hassan Errihani
Journal: Journal of Clinical Oncology (2018)

e13064 Background: Inflammatory breast cancer (IBC) is the most aggressive breast carcinoma, with the clinical and biological characteristics of a rapidly proliferating disease. A number of molecular changes have been described in IBC including ALDH1 gene. This study aimed to evaluate ALDH1 expression, using immunohistochemistry and RT-PCR, in IBC tumors. The results were correlated with molecular characteristics and stage. Methods: A total of 83 cases with IBC from the National Oncology Institute in Rabat; were recruited during the period of July, 2014 to July, 2017. Standardized structured questionnaires were developed and used for the interview. Paraffin-embedded tumor tissues were obtained from all cases. Immunohistochemically (IHC) was performed for protein expression with monoclonal ALDH1 antibody (5A11 ABBIOTEC 1:100) using DAKO REAL TM Envision detection system. Real-time two-step RT-PCR (qRT-PCR) was performed in technical triplicates starting with the same cDNA using SYBR Green I technology. The GAPDH was selected as an internal control. The expression levels were calculated based on the 2-ΔΔCT method. Results: In our cohort of 83 IBC cases, the median age was 48.24 year. ALDH1 testing was done for 79 patients. The results of immunohistochemistry staining of ALDH1 revealed that tumor tissues from 21 % (n = 18) of patients showed ALDH1 expression. Using qRT-PCR, ALDH1 were highly expressed in 84.9 % (n = 67). No correlation was found between the expression of the ALDH1 and molecular subtypes or stages. Additionally, we performed a comparison of FFPE IBC specimens of 79 cases using IHC staining and qRT-PCR detection methods. Conclusions: In our study, ALDH1 expression was associated with IBC, and this marker may be a potential biomarker for these tumors. There were no significant correlation between ALDH1 expression and molecular characteristics . Further studies are required to elucidate the significance of ALDH1 in IBC biology. Our data support the efficiency and reliability of real-time PCR technology to assess the ALDH1 expression in cases with IBC
Abstract 20468: Regional Myocardial Blood Flow Variability Is Associated With the Presence of Coronary Artery Disease in Clinical Rubidium-82 Cardiac Positron Emission Tomography
Authors: Marie A Guerraty, Venkatesh Y Anjan, H. S Rao, Hannah Szapary, David Mankoff, Daniel Pryma, Daniel J Rader, Jacob Dubroff
Journal: Circulation (2016)

Introduction: Myocardial Perfusion Imaging (MPI) with Rb-82 PET is increasingly used clinically and has improved sensitivity and specificity for detecting the presence of coronary artery disease (CAD). In addition to MPI, Rb-82 PET provides global and regional quantitative myocardial blood flow (MBF) measurements. The interpretation of regional MBF and myocardial blood flow reserve (MBFR) is still unclear, however, as both epicardial CAD and microvascular function contribute to MBF and MBFR for a given territory. Hypothesis: Coronary microvascular disease (CMVD) is a global myocardial process reflected in global MBFR, whereas CAD is predominantly regional. We therefore hypothesize that regional MBF can be used to differentiate between CAD and CMVD and that increased regional variability in MBF indicates the presence of CAD. Methods: This is a single center retrospective study of consecutive patients who underwent dipyridamole Rb-82 PET studies between February 2012 and August 2014. Studies were performed ...
Objective response rate (ORR) and time to treatment failure (TTF) for BRAF v600 mutated metastatic melanoma (BRAF+ MM) patients receiving first-line (1L) targeted therapy (TT) or immuno-oncology (I-O) agents at US-based community oncology practices.
Authors: Jason J. Luke, Sameer R. Ghate, Jonathan Kish, Choo Hyung Lee, Lindsay McAllister, Sonam Mehta, Briana Ndife, Bruce A. Feinberg
Journal: Journal of Clinical Oncology (2018)

e21516 Background: Combination TT, dabrafenib/trametinib (D+T) or vemurafenib/cobimetinib (V+C) and combination I-O (ipilimumab/nivolumab [I+N]) or PDL1 monotherapy (nivolumab [N] or pembrolizumab [P]) are approved for the treatment of BRAF+ MM. Without head to head trials comparing TT and I-O comparative effectiveness of real world clinical outcomes may better inform treatment decisions. Methods: Physicians from the Cardinal Health Oncology Provider Extended Network identified BRAF+ MM patients initiating 1L with D+T, I+N, N or P after 01/01/2014 through 6/31/2017. Treatment and clinical data (including target lesion measurements) were entered into electronic case-report forms which were validated by clinical research staff. 1L ORR using RECIST v1.1 and TTF was compared between TT and I-O. Odds ratio (OR) for objective response (complete or partial) using multivariate logistic regression models and hazard ratio (HR) for TTF using a Cox proportional hazards model adjusted for patient characteristics was calculated. Results: 53 providers contributed 440 patients: TT = 283 (D+T = 188, V+C = 95), I-O = 157 (I+N = 86, N or P = 71). Patient characteristics, ORR, median TTF, and model estimates are in the table. ORR was significantly higher in TT v I-O (60.1% v 45.9%, p < 0.01); adjusted odds of objective response 42% less for I-O (OR = 0.58). Median TTF: TT = 11.4 v I-O = 7.1 (p < 0.001); adjusted risk of treatment failure increased by 64% for I-O treated compared to TT: HR: 1.64; 95% CI: 1.25-2.14, p < 0.001. Conclusions: In the largest community-based study of 1L outcomes for BRAF+ MM ORR was significantly higher for TT (unadjusted and adjusted) and TTF longer for TT v I-O. We observe an apparent preference for TT in the community in higher risk patients (liver metastases and LDH value). TT N = 283 I-O N = 157 Median Age (Yr) 61 61 Female (%) 40.6 41.4 LDH Normal (%) 36.4 51.6 Sites of Metastases (%) Lung 67.8 70.1 Liver* 46.3 35.0 Brain 9.9 9.6 ORR (%)* 60.1 45.9 Adjusted OR; 95% CI* REF 0.58; 0.36-0.94 Median TTF (mo)* 11.4; 10.2-13.1 7.2; 6.2-10.0 Adjusted HR: 95% CI* REF 1.64*; 1.25-2.14 * p < 0.05
TCT-337 The Effect of Transcatheter Laceration of Degenerated Bioprosthetic Valve Leaflets on the Likelihood of leaflet thrombosis following Transcatheter Aortic Valve-in-Valve Implantation: A Computational Simulation Study
Authors: Farhan Khodaee, Danny Dvir, Ali Azadani
Journal: Journal of the American College of Cardiology (2018)
Abstract 19422: Newt Exosomes Are Shuttles of Bioactive RNAs and Proteins That Have Signaling Capabilities in Mammalian Systems of Cardiac Repair
Authors: Ryan C Middleton, Eleni Tseliou, Travis J Antes, Eduardo Marbán
Journal: Circulation (2016)

Introduction: Adult newts can regenerate amputated cardiac tissue, and whole limbs, without fibrosis, unlike adult mammals which lack such regenerative capacity. Exosomes are nanoparticles which mediate intercellular communication and play a critical role in therapeutic regeneration. Hypothesis: We have previously shown that exosomes from a newt blastema cells have bioactivity in mammalian models of heart regeneration. We hypothesized that we could identify factors responsible for inducing the observed proliferation and cardiac tissue repair. Thus, we extended our studies into exploring the molecular entities associated with these nanoparticles to identify potential key players involved in the therapeutic effects of exosome-mediated heart repair. Methods: A1 cells, derived from the amputated limb buds of Notopthalmus viridescense, were expanded in culture and their exosomes isolated for RNA cargo and protein content analyses via RNA-Seq and Mass spectrometry. RNA-Seq was also performed on neonatal rat ven...
Immunologic and clinical implications of CD73 expression in non-small cell lung cancer (NSCLC).
Authors: Lee Chun Park, Kyunghoon Rhee, Won Bin Kim, Anderson Cho, Junho Song, Jonathan Forrest Anker, Michael Oh, Preeti Bais, Sandeep Namburi, Jeffrey Chuang, Young Kwang Chae
Journal: Journal of Clinical Oncology (2018)

12050 Background: CD73, known as ecto-5'-nucleotidase and encoded by the NT5E gene, is a pivotal enzyme that converts extracellular adenosine monophosphate (AMP) into adenosine, which promotes tumor growth by impairing anti-tumor T cell immunity. Several preclinical studies noted that the pharmacologic inhibition of CD73 led to improved immune response and thus highlighted the value of CD73 as a therapeutic target for cancer immunotherapy. Methods: CD73 expression was explored from The Cancer Genome Atlas (TCGA) database including patients with adenocarcinoma (n = 517) and squamous cell carcinoma (n = 501) of the lung. We stratified samples based on mRNA expression level (low, low-intermediate, intermediate-high, high). Immune profiling (immune cell infiltration, immune checkpoints, and cytokines), tumor mutational burden (TMB), neoantigen burden, and survival outcome were analyzed between the CD73 high group (CD73-H) and CD73 low group (CD73-L). The tumor immune landscape was analyzed using the signatures derived from 812 'immune metagenes' that predict the immune infiltration of 31 distinct immune cells for each tumor sample (Angelova, M. et al, 2015). Results: In NSCLC, CD73-H showed significantly lower infiltration of activated CD4 and CD8 T cells compared with CD73-L (41% vs 20%, P< 0.01; 47% vs 28%, P< 0.01 respectively). In addition, PD-L1 (CD274), ICOS, TGFB1, and IL1B expression positively correlated with CD73 expression. However, TMB and neoantigen burden demonstrated no significant differences between the two groups. CD73-H had significantly shorter overall survival (OS) and disease free survival (DFS) compared with CD73-L (OS median 62 vs 44 months, P< 0.01; DFS median 83 vs 34 months, P< 0.01). Additionally, CD73 expression was significantly increased in samples with EGFR mutations when compared with wild type (mean z-score 0.77 vs -0.06, P= 0.03). Conclusions: This is the first report to illustrate an inverse association between CD73 expression and tumor infiltration of activated CD4 and CD8 T cells, as analyzed in over 1,000 human lung cancer samples. In addition, CD73-H demonstrated unfavorable survival outcome compared with CD73-L. CD73 remains a promising target for cancer immune modulation.
Physical Activity and Incidence of Heart Failure in Postmenopausal Women
Authors: Michael J. LaMonte, JoAnn E. Manson, Andrea K. Chomistek, Joseph C. Larson, Cora E. Lewis, Jennifer W. Bea, Karen C. Johnson, Wenjun Li, Liviu Klein, Andrea Z. LaCroix, Marcia L. Stefanick, Jean Wactawski-Wende, Charles B. Eaton
Journal: JACC Heart Failure (2018)
National outbreak of Pseudomonas aeruginosa associated with an aftercare solution following piercings, July to September 2016, England
Authors: Hannah Evans, Hikaru Bolt, Ellen Heinsbroek, Bryony Lloyd, Peter English, Samia Latif, Nicola Elviss, Jane Turton, Peter Hoffman, Paul Crook, Richard Puleston
Journal: Eurosurveillance (2018)

We report a national Pseudomonas aeruginosa outbreak from a common source following piercings between July and September 2016 in England. The multi-agency outbreak investigation included active case finding, microbiological testing of environmental samples and case specimens including Variable Number Tandem Repeat (VNTR) typing and a retrospective cohort study. Overall, 162 outbreak cases (29 confirmed, 14 probable and 119 possible) and 14 non-outbreak cases were identified; all confirmed cases had ear piercings (93% cartilage). Outbreak cases were predominantly female (95%) and had a median age of 18 years (interquartile range: 13–56 years). Nineteen outbreak cases required surgery under general anaesthetic The same outbreak VNTR type (11,3,5,3,3,3,6,4,7) was isolated from bottles of an aftercare solution from a single manufacturer and in specimens from confirmed cases who attended eight different piercing studios supplied with this product. In the cohort study, use of aftercare solution was associated with becoming a case (aOR: 4.60, 95% confidence interval: 1.65–12.90). Environmental, microbiological and epidemiological investigations confirmed that contamination during production of aftercare solution was the source of this national outbreak; highlighting challenges in the regulation of a cosmetic products used in the piercing industry and that guidance on piercing aftercare may need to be reviewed.
Differential expression of immune inhibitory markers in association with HLA class I and the immune microenvironment in resected lung adenocarcinomas.
Authors: Mingjuan Lisa Zhang, Marina Kem, Meghan Mooradian, Jean-Pierre Eliane, Tiffany Huynh, A. John Iafrate, Justin F. Gainor, Mari Mino-Kenudson
Journal: Journal of Clinical Oncology (2017)

8551 Background: Similar to programed death ligand 1 (PD-L1), indoleamine 2,3-Dioxygenase 1 (IDO1) is known to exert immunosuppressive effects and be variably expressed in human lung cancer. However, IDO1 expression has not been well-studied in lung adenocarcinoma (ADC). Methods: PD-L1 and IDO1 expression were evaluated in 261 resected ADC using tissue microarrays and H-scores (cutoff 5). We compared IDO1 with PD-L1 expression in association with clinical features, tumor-infiltrating lymphocytes (TILs), HLA class I (β-2 microglobulin; B2M) expression, molecular alterations, and patient outcomes. Results: There was expression of PD-L1 in 89 (34.1%) and IDO1 in 74 (28.5%) cases, with co-expression in 49 (18.8%). Both PD-L1 and IDO1 were significantly associated with smoking, aggressive pathologic features, and abundant CD8+ and T-bet+ (Th1 marker) TILs. PD-L1 expression and abundant CD8+ were inversely associated with a loss of B2M membranous expression (p = 0.0019 and p &lt; 0.001, respectively). Compared to PD-L1+/IDO1+ and PD-L1+ only cases, significantly fewer IDO1+ only cases had abundant CD8+ and T-bet+ TILs (p &lt; 0.001, respectively). PD-L1 expression was significantly associated with EGFR wild-type (p &lt; 0.001) and KRAS mutants (p = 0.021), whereas there was no difference in IDO1 expression between different molecular alterations. As for survival, PD-L1 was significantly associated with decreased progression-free (PFS) and overall survival (OS), while IDO1 was associated only with decreased OS. Interestingly, there was a significant difference in the 5-year PFS and OS (p = 0.004 and 0.038, respectively), where cases without PD-L1 or IDO1 expression had the longest survival, and those with PD-L1 alone had the shortest survival. Conclusions: While PD-L1 +/- IDO1 expression is observed in association with B2M expression, CTL/Th1 microenvironments, EGFR wild-type, and KRAS mutations, isolated IDO1 expression does not demonstrate these associations, suggesting that IDO1 may serve a distinct immunosuppressive role in ADC. Thus, blockade of IDO1 may represent an alternative and/or complementary therapeutic strategy to reactivate anti-tumor immunity.
Frequency of <i>NOTCH</i> pathway mutation in primary tumor of SCLC compared to metastatic biopsies and association with better survival.
Authors: Fatemeh Ardeshir-Larijani, Gary Wildey, Pingfu Fu, Priyanka Bhateja, Afshin Dowlati
Journal: Journal of Clinical Oncology (2018)

e20574 Background: Small cell lung cancer (SCLC) is a neuroendocrine tumor characterized by early distant metastasis. NOTCH signaling controls neuroendocrine cell differentiation. In mouse models, NOTCH pathway suppression was associated with lower liver metastasis, but there is no clinical data supporting this observation in SCLC patients. Here we examined NOTCH (1,2 and 3) mutation in different SCLC tumor biopsy sites and, more importantly, correlated NOTCH mutation with patient survival Methods: A cohort of 67 extensive stage SCLC patients (2012 to 2017) with clinical and targeted exome-sequencing data on their tumors was used. The median follow-up was 9.4 (range: 0.5 – 78.6) months. We analyzed NOTCH mutations based upon the site of tumor biopsy using Chi-square. The association of NOTCH 1,2, or 3 mutations with progression-free survival (PFS) and overall survival (OS) was examined using Kaplan–Meier method. The predictive values of NOTCH 1,2, or 3 mutations on PFS and OS were estimated using multivariable Cox proportional hazards regression model adjusting known clinical and other genomic prognostic features. Results: Among 161 genes targeted by the exome sequencing panel with a mutation frequency of > 3, NOTCH family mutations were the most which significantly found in lung compared to other biopsy sites (73%, N= 19, p = 0.008). A total of 19 patients were identified with either NOTCH1, 2 or 3 mutations. The majority of mutations were categorized as missense (82%, total N = 19/23). NOTCH 1 was the most commonly mutated family member (N = 12), followed by NOTCH 2 (N = 6) and NOTCH 3 (N = 5). Most notably, out of 23 total NOTCH mutations, only one mutation, in NOTCH 2, (p = 0.026) was observed in liver specimens. After adjusting for the effects of confounders such as MYC mutation (important tumor suppressor and downstream gene in NOTCH pathway), sex, age, stage, NOTCH mutation (1, 2, and 3 combined) was significantly associated with increased OS (p = 0.032, HR:0.37) and PFS (p = 0.018, HR = 0.033). Conclusions: NOTCH mutation in SCLC is more frequent in lung compared to metastatic biopsy sites, including liver, and is associated with significantly improved survival.