tbuckley/cabot-search huggingface dataset:
The CANOPY program: Canakinumab in patients (pts) with non-small cell lung cancer (NSCLC).
Authors: Luis G. Paz-Ares, Edward B. Garon, Andrea Ardizzoni, Fabrice Barlesi, Byoung Chul Cho, Gilberto Castro, Pedro De Marchi, Enriqueta Felip, Yasushi Goto, Alastair Greystoke, Shun Lu, Darren Wan Teck Lim, Vassiliki Papadimitrakopoulou, Martin Reck, Benjamin J. Solomon, David R. Spigel, Daniel Shao-Weng Tan, Michael Thomas, James Chih-Hsin Yang, Bruce E. Johnson
Journal: Journal of Clinical Oncology (2019)

TPS9124 Background: Inflammatory pathways can be pro-tumorigenic or anti-tumorigenic. The cytokine interleukin-1β (IL-1β) can promote the infiltration of immunosuppressive cells into the tumor microenvironment leading to a pro-tumorigenic microenvironment that promotes carcinogenesis, tumor invasiveness, and immunosuppression. Canakinumab is a human monoclonal antibody that binds and neutralizes IL-1β. Previous clinical data (CANTOS study) has shown that canakinumab could significantly reduce lung cancer incidence and mortality. This data along with the preclinical results that IL-1β does support tumorigenic inflammation provide the rationale to investigate the therapeutic role of canakinumab in lung cancer. Methods: Three Phase 3 trials have been designed in parallel to evaluate canakinumab in NSCLC (Table). Clinical trial information: NCT03447769, NCT03631199, NCT03626545. [Table: see text]
Mechanical Ventilation Management during Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome. An International Multicenter Prospective Cohort
Authors: Matthieu Schmidt, Tài Pham, Antonio Arcadipane, Cara Agerstrand, Shinichiro Ohshimo, Vincent Pellegrino, Alain Vuylsteke, Christophe Guervilly, Shay McGuinness, Sophie Pierard, Jeff Breeding, Claire Stewart, Simon Sin Wai Ching, Janice M. Camuso, R. Scott Stephens, Bobby King, Daniel Herr, Marcus J. Schultz, Mathilde Neuville, Elie Zogheib, Jean-Paul Mira, Hadrien Rozé, Marc Pierrot, Anthony Tobin, Carol Hodgson, Sylvie Chevret, Daniel Brodie, Alain Combes
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: Current practices regarding mechanical ventilation in patients treated with extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome are unknown.Objectives: To report current practices regarding mechanical ventilation in patients treated with ECMO for severe acute respiratory distress syndrome (ARDS) and their association with 6-month outcomes.Methods: This was an international, multicenter, prospective cohort study of patients undergoing ECMO for ARDS during a 1-year period in 23 international ICUs.Measurements and Main Results: We collected demographics, daily pre- and per-ECMO mechanical ventilation settings and use of adjunctive therapies, ICU, and 6-month outcome data for 350 patients (mean ± SD pre-ECMO PaO2/FiO2 71 ± 34 mm Hg). Pre-ECMO use of prone positioning and neuromuscular blockers were 26% and 62%, respectively. Vt (6.4 ± 2.0 vs. 3.7 ± 2.0 ml/kg), plateau pressure (32 ± 7 vs. 24 ± 7 cm H2O), driving pressure (20 ± 7 vs. 14 ± 4 cm H2O), respiratory rate (26 ± 8 vs. 14 ± 6 breaths/min), and mechanical power (26.1 ± 12.7 vs. 6.6 ± 4.8 J/min) were markedly reduced after ECMO initiation. Six-month survival was 61%. No association was found between ventilator settings during the first 2 days of ECMO and survival in multivariable analysis. A time-varying Cox model retained older age, higher fluid balance, higher lactate, and more need for renal-replacement therapy along the ECMO course as being independently associated with 6-month mortality. A higher Vt and lower driving pressure (likely markers of static compliance improvement) across the ECMO course were also associated with better outcomes.Conclusions: Ultraprotective lung ventilation on ECMO was largely adopted across medium- to high-case volume ECMO centers. In contrast with previous observations, mechanical ventilation settings during ECMO did not impact patients' prognosis in this context.
Diagnostic accuracy of the Videssa protein-based liquid biopsy for breast cancer in suspicious mammography.
Authors: Cynthia Chen, Lisa Poole, Lina Sizer, W. Bradford Carter, Thomas G. Frazier
Journal: Journal of Clinical Oncology (2019)

e13034 Background: The Videssa protein-based blood test (Provista Diagnostics) is a combined proteomic biomarker assay that aims to detect established breast cancer – rendering it useful in patients with abnormal or difficult-to-interpret mammograms. Since the incidence of malignancy for BI-RADS 4 biopsies is approximately 20%, a significant percentage of patients undergo needle biopsy unnecessarily. The Videssa assay provides an alternative diagnostic method by way of a non-invasive liquid biopsy. Methods: Our goal was to assess whether this liquid biopsy combined with 3D tomographraphic mammography could accurately predict disease status to reduce the amount of unnecessary tissue biopsies. An IRB-approved, prospective, single-arm study had patients with BI-RADS4 lesions with calcifications requiring tissue biopsy undergo the blood test prior to stereotactic core biopsy. Subsequent results and biopsy pathology were correlated. Results: 46 patients were initially entered with BI-RADS4 calcifications. 9 patients had DCIS (19.6%) and 37 patients had benign calcifications (80.4%). No patient had invasive cancer. Liquid biopsy results were elevated in 2 patients with DCIS (22% sensitivity) and in 5 patients with benign biopsies (10.8%). At interim analysis, the liquid biopsy demonstrated a 28.5% positive predictive value (PPV) and 82% negative predictive value (NPV). Tumor grade did not affect results. We subsequently discontinued using the blood test for BI-RADS4 calcifications and enrolled 13 patients with non-palpable solid lesions to determine the correlation. The liquid biopsy was elevated in 1 of 4 patients with invasive cancer (25% sensitivity) and was not elevated in all 9 patients with benign biopsies (100% NPV). At one-year follow-up, 3 of the 5 patients with an elevated blood assay and negative biopsy have had no incidence of cancer on subsequent imaging. The remaining 2 patients are scheduled for follow-up. Conclusions: In our study, the NPV of the Videssa liquid biopsy is not robust enough to defer tissue biopsy in any patient with indeterminate calcifications on imaging, nor is it specific enough to help predict results in high risk solid lesions. We do not see this liquid biopsy changing our current practice.
2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies
Authors: Yingxi Xu, Qian Liu, Mengjun Zhong, Zhenzhen Wang, Zhaoqi Chen, Yu Zhang, Haiyan Xing, Zheng Tian, Kejing Tang, Xiaolong Liao, Qing Rao, Min Wang, Jianxiang Wang
Journal: Journal of Hematology & Oncology (2019)

Chimeric antigen receptor engineered T cells (CAR-T) have demonstrated extraordinary efficacy in B cell malignancy therapy and have been approved by the US Food and Drug Administration for diffuse large B cell lymphoma and acute B lymphocytic leukemia treatment. However, treatment of T cell malignancies using CAR-T cells remains limited due to the shared antigens between malignant T cells and normal T cells. CD5 is considered one of the important characteristic markers of malignant T cells and is expressed on almost all normal T cells but not on NK-92 cells. Recently, NK-92 cells have been utilized as CAR-modified immune cells. However, in preclinical models, CAR-T cells seem to be superior to CAR-NK-92 cells. Therefore, we speculate that in addition to the short lifespan of NK-92 cells in mice, the costimulatory domain used in CAR constructs might not be suitable for CAR-NK-92 cell engineering. Two second-generation anti-CD5 CAR plasmids with different costimulatory domains were constructed, one using the T-cell-associated activating receptor-4-1BB (BB.z) and the other using a NK-cell-associated activating receptor-2B4 (2B4.z). Subsequently, BB.z-NK and 2B4.z-NK were generated. Specific cytotoxicity against CD5+ malignant cell lines, primary CD5+ malignant cells, and normal T cells was evaluated in vitro. Moreover, a CD5+ T cell acute lymphoblastic leukemia (T-ALL) mouse model was established and used to assess the efficacy of CD5-CAR NK immunotherapy in vivo. Both BB.z-NK and 2B4.z-NK exhibited specific cytotoxicity against CD5+ malignant cells in vitro and prolonged the survival of T-ALL xenograft mice. Encouragingly, 2B4.z-NK cells displayed greater anti-CD5+ malignancy capacity than that of BB.z-NK, accompanied by a greater direct lytic side effect versus BB.z-NK. Anti-CD5 CAR-NK cells, particularly those constructed with the intracellular domain of NK-cell-associated activating receptor 2B4, may be a promising strategy for T cell malignancy treatment.
Determination of the immunogenetic risk of developing cancer.
Authors: István Miklós, Eniko Rita Toke, Mónika Megyesi, Levente Molnar, József Tóth, Orsolya Lőrincz, Eszter Somogyi, Zsolt Csiszovszki, Katalin Pántya, Péter Páles, Franco Lori, Julianna Lisziewicz
Journal: Journal of Clinical Oncology (2019)

e13132 Background: Association between certain HLA types and cancer is well known. We hypothesized that the number of epitopes of tumor antigens presented by autologous HLAs characterizes a patient’s capacity to kill tumor cells. These CD8+ T cell epitopes are presented by 6 out of &gt;13,000 known HLA class I alleles and induce extremely variable tumor-specific T-cell responses. Methods: We predicted HLA-binding epitopes from 48 frequently expressed tumor antigens in subjects characterized with 6 HLA class I alleles. To develop the “HLA Score” cancer risk predictor we used epitopes binding to multiple HLAs of a subject. The predictor was trained on 5,789 non-American subjects. To identify populations with high and low immunogenetic risk to develop cancer we compared the HLA Score of American cancer subjects to a general population of American subjects (1,400 subjects). The performance of the predictor was characterized with AUC and Risk Ratio. Due to Bonferroni correction, AUC values with p-value p&lt;0.007 was accepted as significant. Results: “HLA Score” predictor significantly separated cancer patients from the general population in six out of the seven investigated cancer types. The Risk Ratios between the most protected and most at risk subpopulations ranged between 2.38 and 5.67 (Table). Cancer risk prediction with HLA Score. Conclusions: Subjects with certain HLA class I alleles have high risk of developing cancer. The novel “HLA Score” predictor we introduced here could complement current testing used for determination of the genetic risk of cancer.[Table: see text]
Nab-paclitaxel plus gemcitabine versus FOLFIRINOX in the first-line chemotherapy for patients with advanced pancreatic ductal adenocarcinoma: A national cohort (Comunica-TTD working group).
Authors: Federico Longo, Oscar Alfredo Castillo Trujillo, Juan José Serrano Domingo, Roberto Martin Huertas, Elena Corral de la Fuente, Alberto San Juan del Moral, Jaime Portela, Juana Maria Cano, Pablo Reguera Puertas, Mercedes Rodríguez Garrote, Marta Izquierdo Manuel, Paula Jiménez-Fonseca, Alfredo Carrato, Enrique Aranda
Journal: Journal of Clinical Oncology (2019)

e15707 Background: Advanced pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with a five-year overall survival (OS) of less than 5%. Folfirinox and Nab-Paclitaxel plus Gemcitabine (NabPacGem) are the most active treatments in the first-line (1L). The decision to use Folfirinox or NabPacGem is a matter of debate. Methods: A retrospective cohort of advanced PDAC patients treated from January 2011 to May 2018 in four Spanish institutions was analyzed. The principal objective was to compare OS among patients receiving Folfirinox versus NabPacGem in 1L. Progression-free survival (PFS) was a secondary objective. Results: Characteristics of 251 patients included: median age 66.6 years; male 54.4%; stage IV at diagnosis 66.7%; ECOG 0/1/2 18/70/12%; treated with Folfirinox 18.3% and NabPacGem 81.7%. Patients treated with Folfirinox versus NabPacGem were younger (median age 58.3 vs. 67.9; p&lt;0.001) and had lower ECOG (0/1/2 of 46/54/0% vs. 13/71/16%; p&lt;0.001). Univariate analysis: median PFS 5.8 months (95%CI, 4.3 – 7.3) for Folfirinox and 4.2 months (95%CI, 3.7 – 5.2) for NabPacGem, HR=1.53 (95%CI, 1.1 – 2.1; p=0.012); median OS 12.7 months (95%CI, 8.4 – 14.3) for Folfirinox and 7.6 months (95%CI, 5.8 – 8.8) for NabPacGem, HR=1.38 (95%CI, 0.96 – 1.98; p=0.081). Multivariate Cox analysis (including type of treatment, ECOG and age) showed that ECOG was the only variable associated with PFS and OS (Table). Conclusions: In our study, advanced PDAC patients treated with Folfirinox were younger and had a better performance status than those treated with NabPacGem. We found no differences in survival between both treatments when adjusting by ECOG and age.[Table: see text]
Progression free survival (PFS) benefits of immuno-oncology agents (IOs) and implications for market cost-sharing inefficiencies.
Authors: Syed Muhammad Mushtaq Ashraf, Shruti Pandita, Emmanouil Alimpertis, Talal Khan, Cherian Verghese
Journal: Journal of Clinical Oncology (2019)

6643 Background: Cancer care expense has high financial toxicity with 6 in 10 patients reporting distress about finances. System wide cost has also increased with new treatment approvals; from 2011 to 2016 FDA approved 52 cancer treatments. During this time, US healthcare spending increased from $26.8 billion to $42.1 billion. Lung cancer has high mortality- in 2018 American Cancer Society estimated 234,030 new cases with 50% likely to die from the disease. Hence new treatments are important societal need but costs are concerning. Methods: We selected Phase 3 trials of IO based regimens for non-small cell lung cancer (NSCLC) in first line setting, approved by FDA in 2018. Median PFS was compared between intervention and no-intervention group (NIG). Total costs were evaluated using 2018 Medicare reimbursements rates. Cost and PFS were converted to represent expenditures accrued for 12 months (mths) PFS gain. Results: Study 1 (NCT02125461) for stage 3 NSCLC; looked at maintenance Durvalumab after platinum doublet chemoradiation induction. Median PFS 17.2 vs 5.6 mths in NIG. 1 year PFS cost $155,391 vs $27,477. Study 2 (NCT02578680) for stage 4 NSCLC; looked at maintenance Pembrolizumab, Pemetrexed or Pemetrexed alone after platinum doublet induction. Median PFS 8.8 vs 4.9 mths in NIG. 1 year PFS cost $283,949 vs $116,159. Study 3 (NCT02775435) for stage 4 NSCLC (squamous); looked at maintenance Pembrolizumab after platinum doublet induction. Median PFS 6.4 vs 4.8 mths in NIG. 1 year PFS cost $195,820 vs $119,146. Study 4 (NCT02366143) for stage 4 NSCLC; looked at maintenance Atezolizumab, Bevacizumab or Bevacizumab alone after platinum doublet induction. Median PFS 8.3 vs 6.8 mths in NIG. 1 year PFS cost $316,499 vs $199,278. Conclusions: Median PFS doubled from IOs in NSCLC but costs accrued, more than doubled. The expense has to be quantified in relation to per capita GNP in US- $53,128 in 2017. Accepting even a higher threshold of $100,000 for 1 quality adjusted life year gained, costs appear economically unsustainable. But PFS gains are significant indicating need to enable IOs utilization, by making innovative cost sharing platforms.
Defining the role of <i>RUNX1T1</i> in "combined" small cell lung cancer.
Authors: Tian He, Gary Wildey, Karen McColl, Adam Kresak, Aik-Choon Tan, Afshin Dowlati
Journal: Journal of Clinical Oncology (2019)

e20101 Background: The RUNX1T1 gene, also known as ETO, was first identified in the fusion transcript AML1/ETO, generated by the translocation between chromosome 8 and 21, which occurs in 12%-15% of AML. We recently discovered that RUNX1T1 was specifically amplified only in the small cell lung cancer (SCLC) but not the non-small cell lung cancer (NSCLC) component of combined SCLC tumors. Here, we investigated if RUNX1T1 expression plays a role in transforming NSCLC to SCLC in combined SCLC tumor formation. Methods: We examined tumors from 92 of our SCLC patients by targeted exome and CNV analyses. RUNX1T1 mRNA expression was determined in various cancers by analysis of the CCLE and TCGA databases. RUNX1T1 mRNA expression was detected by RNAscope analysis of another 22 patient SCLC tumors. Stable overexpression of RUNX1T1 in NSCLC and SCLC cell lines used commercial RUNX1T1 lentiviral constructs. The resulting stable cell lines were analyzed by RT-qPCR, western blotting, Affymetrix gene array, and E2F-luciferase assays. Results: We found that 2 of 2 patients with combined SCLC demonstrated RUNX1T1 amplification in the SCLC component. Notably, only 2 of the remaining 90 patients with pure SCLC demonstrated RUNX1T1 amplification. RUNX1T1 mRNA is highly expressed in SCLC compared to the majority of other cancers, including NSCLC, using either CCLE or TCGA databases. Western blots confirmed higher RUNX1T1 protein expression in SCLC vs NSCLC cell lines, and RNAscope analysis confirmed greater RUNX1T1 mRNA expression in SCLC vs NSCLC patient tumors. When we stably overexpressed RUNX1T1 in NSCLC cell lines, there was no increase in neuroendocrine protein expression, however we did find an increased sensitivity to etoposide. Bioinformatic analysis of microarray data demonstrated significantly altered E2F pathway activity, and we could show a significant increase in E2F-luciferase activity after RUNX1T1 overexpression. Interestingly, this was associated with decreased p21 expression, which is a putative suppressor of E2F activity. Conclusions: RUNX1T1 expression is specifically upregulated in SCLC compared to NSCLC. E2F pathway activity is elevated after RUNX1T1 overexpression, consistent with an increased SCLC phenotype.
Anti-EGFR target therapy in advanced thymic epithelial tumors.
Authors: Mario Giuliano, Margaret Ottaviano, Marianna Tortora, Roberta Gallinoro, Mirella Marino, Angela Pizzuti, Dario Arundine, Fernanda Picozzi, Vincenzo Di Lauro, Vittorio Riccio, Sabino De Placido, Giovannella Palmieri
Journal: Journal of Clinical Oncology (2019)

8567 Background: Thymic epithelial tumors (TETs), show a high rate of EGFR immunohistochemistry (IHC) positivity, however, the prognostic and predictive role of EGFR has not yet been well defined, and contradictory data have emerged regarding the delivering of anti-EGFR monoclonal antibodies in TETs. The outcomes of the largest series of thymoma patients treated with cetuximab, and its hypothetic immune-modulatory role, are here described. Methods: Seven patients with diagnosis of pre-treated advanced thymoma and score positivity 2+ and 3+ at EGFR-IHC, were treated with cetuximab as off-label modality, with a dose of 400 mg/m2 in the first cycle and 250 mg/m2 in the following cycles every 7 days, until disease progression, unacceptable toxicity, withdrawal of consent. Primary endpoint was Overall Response Rate ORR, assessed radiologically. Secondary endpoints were progression Free Survival (PFS), safety, and relationship between time to cetuximab progression (TTPc) and time to previous treatment progression (TTP1). During treatment with cetuximab lymphocyte subpopulations have been carefully monitored in 4 patients affected by both thymoma and Good syndrome (GS) defined as B-cell lymphocyte counts (CD19+) &lt;100 cells/mm3 and/or Immunoglobulin G (IgG) levels &lt;8 g/L. Results: With a median response duration of 17 months, a partial response was achieved in five patients (ORR=71%). Statistically significant correlation was found between disease response and EGFR-IHC score 2+ vs 3+ (P, .008), which statistically correlated also with the mPFS of 14 months (95% CI, 0.0-34.5). No grade 3 or 4 adverse events were registered. TTPc was longer than TTP1 in 6/7 patients (86%), with a TTPc / TTP1 ratio equal to 2.12. During cetuximab treatment, in the longest responder patient affected also by GS, a progressive increase of IgG level and of CD4/CD8 ratio has been registered as well as an increase of both CD19+lymphocytes and CD16+ 56+ lymphocytes has been detected in all the included patients with GS. Conclusions: Despite of the small number of patients and the off-label treatment modality, the data presented are worthy of confirmation in validated prospective studies in selected population with hyper-expression of EGFR. Further studies are also needed for deeply investigate the immunomodulatory role of cetuximab which seemed to temporarily revert sever immunodeficiency in our population.
Sex is a strong prognostic factor for overall survival in advanced non small cell lung cancer patients and should be considered for survival rates estimations.
Authors: Miguel Barquin, Francisco Garcia-Garcia, Atocha Romero, Enric Carcereny, Delvys Rodriguez-Abreu, Rafael Lopez Castro, Maria Guirado, Carlos Camps, Joaquim Bosch-Barrera, Bartomeu Massuti, Ana Laura Ortega, Jose-Luis Gonzalez-Larriba, Rosario Garcia-Campelo, Manuel Domine, Sara Agraso Busto, María Ángeles Sala, Juana Oramas, Reyes Bernabé, Mariano Provencio-Pulla
Journal: Journal of Clinical Oncology (2019)

e20580 Background: Biological differences between sexes have a major impact on disease and treatment outcome. In this paper, we evaluate the prognostic value of sex in advance NSCLC in the context of real world data. Methods: Clinical data from stage IV non-small cell lung cancer (NSCLC) patients from Hospital Puerta de Hierro (HPH) was retrieved from Electronical records using BigData Analytics (N = 387). In addition, data from Spanish Lung Cancer Group (GECP) Tumor Registry (N = 1382) and from a published study through cBioPortal (MSK) (N = 601) was analyzed. Survival curves were estimated using Kaplan-Meier analysis. Cox proportional hazards regression model was used to assess the prognostic factor of sex. Results: The median overall survival (OS) time was 12 months for men and 19 months for women (P &lt; 0.001). Similarly, women with stage IV NSCLC harbouring an EGFR sensitizing mutation lived longer than men (median overall survival was 19 months for men and 32 months for women). Gender effect was still significant after adjustment by Cox regression for other potential confounding factors. The adjusted hazard ratios for sex were 0.65 (95% CI, 0.51-0.83), 0.84 (95% CI, 0.66-1.1) and 0.76 (95% CI, 0.65-0.88) for HPH, MSK and GECP data sets respectively. Similarly, in EGFR positive population adjusted hazard ratios for sex were 0.53 (95% CI, 0.25-1.1), 0.59 (95% CI, 0.35-0.98) and 0.60 (95% CI, 0.45-0.86) for HPH, MSK and GECP data sets respectively. Conclusions: Using real world data we confirm previous finding that among stage IV NSCLC patients, women live almost twice longer than men. This effect persisted after adjusting for several factors highlighting the fact that survival rates estimations which are usually performed grouping men and women together might not be accurate enough for prognosis assessments