tbuckley/cabot-search huggingface dataset:
CB-839, panitumumab, and irinotecan in RAS wildtype (WT) metastatic colorectal cancer (mCRC): Phase I results.
Authors: Kristen Keon Ciombor, Jennifer Whisenant, Dana Backlund Cardin, Laura Williams Goff, Satya Das, Michael Schulte, Allison Cohen, Robert J. Coffey, Gregory Dan Ayers, Rachel Krumsick, Susan Demo, Sam H. Whiting, H. Charles Manning, Jordan Berlin
Journal: Journal of Clinical Oncology (2019)

574 Background: Epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) are approved in RAS WT mCRC; however, patients (pts) will develop resistance to these agents. Alterations in glutamine (Gln) metabolism play a critical role in cancer cell growth. In cancers such as CRC, EGFR and Gln cooperate to provide signals and fuel for mitogen activated protein kinase-dependent cell growth. Our in vitro data show that Gln abrogates EGFR inhibition, and blockade of Gln transport restores sensitivity. We also observed a greater antitumor response in vivo with EGFR mAb plus CB-839, an inhibitor of a rate-limiting enzyme of Gln metabolism, than either agent alone. We designed a phase I/II study (NCT03263429) to evaluate CB-839 + panitumumab + irinotecan in anti-EGFR refractory RAS WT mCRC. Methods: Dose escalation used a Bayesian continual reassessment method targeting a 25% toxicity probability. CB-839 (600 mg or 800 mg twice daily [BID]) were evaluated with panitumumab (6 mg/kg) and irinotecan (180 mg/m 2 ). Irinotecan was included in phase I to establish a future phase II dose of the triplet. Prior EGFR mAb treatment (tx) was not required for phase I. Dose-limiting toxicity (DLT) was any tx-related non-hematologic ≥Gr 3 toxicity (except fatigue, rash, or elevated liver enzymes) or ≥Gr 4 hematologic toxicity during the first 28 days. Results: Nine pts have been enrolled; 2 were not evaluable for DLT and replaced. Zero DLTs were observed at dose level 1 (n = 3) or 2 (n = 4); 2 more pts are needed to confirm the maximum tolerated dose (MTD). Most frequent toxicities were anemia and hypomagnesemia (88%) and elevated alkaline phosphatase, nausea, and rash (75%), most ≤Gr 2. One of 7 evaluable pts (14%) has an ongoing partial response, and 5 pts had stable disease (SD; 71%). Three pts have been on tx &gt; 6 months, and 3 pts with prior EGFR mAb tx achieved SD. Conclusions: Triplet combination was tolerable at full doses of each drug, and preliminary antitumor activity was observed in a majority of pts. Phase II will begin after phase I completion and will evaluate efficacy of CB-839 (800 mg BID) and panitumumab (6 mg/kg). Imaging studies using investigational PET tracers to evaluate Gln metabolism as a function of tumor response are planned. Clinical trial information: NCT03263429.
An analysis of the safety and efficacy of rivaroxaban (Riv) and low molecular weight heparin (LMWH) in gastrointestinal cancer-associated venous thromboembolism (GICA-VTE).
Authors: Alejandro Recio Boiles, Sumana Veeravelli, Jessi Vondrak, Hani M. Babiker, Aaron James Scott, Ali McBride, Emad Elquza
Journal: Journal of Clinical Oncology (2019)

374 Background: CAVTE has a significant morbidity and mortality burden, with higher incidence and bleeding complications of anticoagulation (AC) in GICA. Current guidelines prefer LMWH, and recently added Riv, as an alternative standard after the SELECT-D trial (S-D). There is a paucity of data comparing the safety and efficacy of other DOACs in pts with GICA. We indirectly compared the safety and efficacy of Riv vs LMWH of our pts with active GICA-VTE at the University of Arizona Cancer Center (UACC) to the S-D GI-population. Methods: Pts with biopsy proven GICA, symptomatic or incidental VTE, and 6 months or more treatment with Riv or LMWH at UACC from 11/2013 - 12/2017 were retrospectively reviewed. S-D GICA data was extracted. Primary efficacy outcome was recurrent deep vein thrombosis (DVT), nonfatal pulmonary embolism (PE), or fatal PE. Safety outcomes for major bleeding (MB) include Hg drop ≥ 2 g/dL, transfusion of ≥ 2 units PRBC, bleeding in critical site, or bleeding contributing to death. Fisher exact test was used for p-value &lt; 0.05. Results: Our review included pts on LMWH (n = 40), and Riv (n = 37) balanced population to the S-D trial. Recurrent VTE at 6mo was noted in 7.5% and 2.7% of pts, compared to S-D trial 11% and 4%, for LMWH and Riv respectively. MB at 6mo was 5% and 21.6% [p &lt; 0.04] of pts, compared to S-D trial 5.8% and 8.7%, for LMWH and Riv, respectively. There was a non-significant difference [p &gt; 0.07] between Riv and LMWH efficacy and safety beyond 6mo of AC. Conclusions: VTE secondary prophylaxis in GICA pts is complicated by high rates of recurrence and bleeding risk, DOACs provide another AC option. The most recent systemic review that included the two published DOACs RCTs for CAVTE [Hokusai and SELECT-D 2018], showed a higher incidence at 6-month of MB compared to LMWH RR: 1.74 (95% CI: 1.05–2.88) [Ang Li 2018], mainly driven by GICA. Our retrospective study showed a non-significant improved efficacy outcome although worse safety profile with Riv versus LMWH in GICA pts, by indirect comparison. Future RCTs with multi-center participation, particularly focused on GICA, can further provide information to guide safe and effective AC selection.
No impact of RASs on the high efficacy of SOF/VEL/VOX for 8 weeks in DAA-naïve patients: an integrated resistance analysis of the POLARIS-2 and POLARIS-3 studies
Authors: D. Wyles, A. Thompson, E. Lawitz, B. Willems, E.J. Gane, E. Svarovskaia, H. Dvory-Sobol, R. Martin, G. Camus, B.P. Doehle, L.M. Stamm, R.H. Hyland, D.M. Brainard, H.M. Mo, T. Asselah, I. Jacobson, G.R. Foster, S. Roberts
Journal: Journal of Hepatology (2017)
Risk Assessment After a Severe Hospital-Acquired Infection Associated With Carbapenemase-Producing <i>Pseudomonas aeruginosa</i>
Authors: Joost Hopman, Corianne Meijer, Nikki Kenters, Jordy P. M. Coolen, Mohammad R. Ghamati, Shaheen Mehtar, Reinout van Crevel, Wim J. Morshuis, Ad F. T. M. Verhagen, Michel M. van den Heuvel, Andreas Voss, Heiman F. L. Wertheim
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Resistance of gram-negative bacilli to carbapenems is rapidly emerging worldwide. In 2016, the World Health Organization defined the hospital-built environment as a core component of infection prevention and control programs. The hospital-built environment has recently been reported as a source for outbreaks and sporadic transmission events of carbapenemase-producing gram-negative bacilli from the environment to patients. <h3>Objective</h3> To assess risk after the identification of an unexpected, severe, and lethal hospital-acquired infection caused by carbapenemase-producing<i>Pseudomonas aeruginosa</i>in a carbapenemase-low endemic setting. <h3>Design, Settings, and Participants</h3> A case series study in which a risk assessment was performed on all 11 patients admitted to the combined cardiothoracic surgery and pulmonary diseases ward and the hospital-built environment in the Radboud University Medical Center, the Netherlands, in February 2018. <h3>Exposures</h3> Water and aerosols containing carbapenemase-producing (Verona integron-mediated metallo-β-lactamase [VIM])<i>P aeruginosa.</i> <h3>Main Outcomes and Measures</h3> Colonization and/or infection of patients and/or contamination of the environment after the detection of 1 patient infected with carbapenemase-producing (VIM)<i>P aeruginosa</i>. <h3>Results</h3> A total of 5 men (age range, 60-84 years) and 6 women (age range, 55-74 years) were admitted to the combined cardiothoracic surgery and pulmonary diseases ward. The risk assessment was performed after carbapenemase-producing (VIM)<i>P aeruginosa</i>was unexpectedly detected in a man in his early 60s, who had undergone a left-sided pneumonectomy and adjuvant radiotherapy. No additional cases (colonization or infection) of carbapenemase-producing (VIM)<i>P aeruginosa</i>were detected. Plausible transmission of carbapenemase-producing<i>P aeruginosa</i>from the hospital environment to the patient via the air was confirmed by whole-genome sequencing, which proved the relation of<i>Pseudomonas</i>strains from the patient, the shower drains in 8 patient rooms, 1 sink, and an air sample. <h3>Conclusions and Relevance</h3> This study suggests that rethinking the hospital-built environment, including shower drains and the sewage system, will be crucial for the prevention of severe and potential lethal hospital-acquired infections.
Adoptive Therapy with EBV-Specific T Cells for Treatment of CNS EBV Post-Transplant Lymphoproliferative Disease Arising after Hematopoietic Stem Cell Transplant or Solid Organ Transplant
Authors: Susan Prockop, Stephanie Suser, Ekaterina Doubrovina, Hugo R. Castro-Malaspina, Esperanza B. Papadopoulos, Craig S. Sauter, James W. Young, Victoria Szenes, Alison Slocum, Karim Baroudy, Richard J. O'Reilly
Journal: Blood (2018)
A dose-finding study for irinotecan, cisplatin, and S-1 (IPS) in patients with advanced gastric cancer (OGSG 1106).
Authors: Hiroki Yukami, Masahiro Goto, Takayuki Kii, Tetsuji Terazawa, Toshifumi Yamaguchi, Fukutaro Shimamoto, Hitoshi Nishitani, Hisato Kawakami, Toshio Shimokawa, Yoshihiro Matsubara, Daisuke Sakai, Yukinori Kurokawa, Taroh Satoh
Journal: Journal of Clinical Oncology (2019)

144 Background: In Japan, S-1 plus cisplatin is regarded as one of the standard first line treatment of advanced gastric cancer (AGC). However, the prognosis of AGC remains dismal. The development of more effective chemotherapeutic regimen is thus warranted. A combination of irinotecan, cisplatin, and S-1 (IPS) can be a promising triplet therapy for advanced gastric cancer. We conducted a phase I study of IPS to determine the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD) and recommended dose (RD), and to assess its safety and antitumor activity in patients with AGC. Methods: This phase I study was designed and conducted in a 3 + 3 manner to determine the recommended dose (RD) of IPS for the subsequent phase II study. Patients received an escalating dose of intravenous irinotecan (level 1: 100/level 2: 125/level 3: 150 mg/m²) on day 1, a fixed dose of intravenous cisplatin (60 mg/m²) on day 1, a fixed dose of S-1 (80 mg/m² b.i.d.) orally on days 1-14, every 4 weeks. Results: Twelve patients were enrolled between June 2013 and February 2017. During the first cycle, one of the six patients in level 1 and two of six patients in level 2 developed the DLT (grade 4 leucocytopenia and grade 3 febrile neutropenia). The MTD of irinotecan was 125 mg/m 2 (level 2) and the RD of irinotecan was considered to be 100 mg/m² (level 1). The most common grade 3 or 4 adverse events included neutropenia 75 % (9/12), anemia 25% (3/12), anorexia 8% (1/12), and febrile neutropenia 17% (2/12). Among six patients with measurable lesions, the response rate was 66.7% (4/6) [95% CI, 33.3-90.7%]. Two patients were performed R0 resection after IPS, with one patient achieved pathological complete response. The median survival time is under analysis. Conclusions: RD of IPS was determined to be 100 mg/m² of irinotecan, 60 mg/m² of cisplatin, and 80 mg/m² of S-1. Our data showed that this regimen provided acceptable antitumor activity and a favorable toxicity profile. Further evaluation of this regimen is warranted. Clinical trial information: UMIN000006864.
Abstract 214: Serum VEGF Levels Are Inversely Associated with Ionized Calcium Levels During the Early Postarrest Period
Authors: Scott Youngquist, Atman P Shah, John P Rosborough, James T Niemann
Journal: Circulation (2014)

BACKGROUND: Vascular endothelial growth factor (VEGF) is a signaling peptide released in response to hypoxia that induces the influx of calcium into endothelial cells. Decreases in serum levels of ionized calcium (iCa2+) are observed following resuscitation from cardiac arrest. We hypothesized that elevations in VEGF would correlate with the decrease in iCa2+ observed in a swine model of cardiac arrest. METHODS: Thirty-five mixed breed Yorkshire swine were premedicated, intubated, and placed under general anesthesia with inhaled isoflurane and nitrous oxide. Under fluoroscopic guidance, balloon occlusion of the left anterior descending coronary artery was performed, just distal to the first septal perforator to induce ventricular fibrillation (VF). Following 7 minutes of untreated VF, standard ALS resuscitation was attempted. Upon return of spontaneous circulation, blood was sampled at 0, 15, and 30 min post arrest for levels of iCa2+ and VEGF. RESULTS: iCa2+ demonstrated an inverse correlation with VEGF levels, with a Spearman rank correlation of rho=-0.52, p&lt;0.0001. In generalized linear mixed modeling (FIGURE 1), a 1 pg/mL increase in VEGF concentrations was associated with a decrease in iCa2+ of 0.001 mg/dL (95% CI 0.003-0.001, p&lt;0.0001). CONCLUSIONS: VEGF is inversely associated with iCa2+ during the early post arrest period. Its production may be responsible for the observed decrease in circulating iCa2+, which may in turn contribute to post arrest hypotension and myocardial dysfunction.
Local Delivery of<i>Ox40l</i>,<i>Cd80</i>, and<i>Cd86</i>mRNA Kindles Global Anticancer Immunity
Authors: Ole Audun Werner Haabeth, Timothy R. Blake, Colin J. McKinlay, Anders A. Tveita, Adrienne Sallets, Robert M. Waymouth, Paul A. Wender, Ronald Levy
Journal: Cancer Research (2019)

Abstract Localized expression of effector molecules can initiate antitumor responses through engagement of specific receptors on target cells in the tumor microenvironment. These locally induced responses may also have a systemic effect, clearing additional tumors throughout the body. In this study, to evoke systemic antitumor responses, we utilized charge-altering releasable transporters (CART) for local intratumoral delivery of mRNA coding for costimulatory and immune-modulating factors. Intratumoral injection of the CART–mRNA complexes resulted in mRNA expression at the site of administration, transfecting a substantial proportion of tumor-infiltrating dendritic cells, macrophages, and T cells in addition to the tumor cells, resulting in a local antitumor effect. Using a two-tumor model, we further show that mRNA therapy locally administered to one tumor stimulated a systemic antitumor response, curing both tumors. The combination of Ox40l-, Cd80-, and Cd86-encoding mRNA resulted in the local upregulation of proinflammatory cytokines, robust local T-cell activation, and migration of immune cells to local draining lymph node or to an anatomically distant tumor. This approach delayed tumor growth, facilitated tumor regression, and cured tumors in both A20 and CT26 tumor models. These results highlight mRNA-CART therapy as a viable approach to induce systemic antitumor immunity from a single localized injection. Significance: The mRNA-CART system is a highly effective delivery platform for delivering immunostimulatory genes into the tumor microenvironment for potential therapeutic development.
Multicriteria decision analysis process to develop new classification criteria for systemic lupus erythematosus
Authors: Sara K Tedeschi, Sindhu R Johnson, Dimitrios T Boumpas, David Daikh, Thomas Dörner, Betty Diamond, Søren Jacobsen, David Jayne, Diane L Kamen, W Joseph McCune, Marta Mosca, Rosalind Ramsey-Goldman, Guillermo Ruiz-Irastorza, Matthias Schneider, Murray Urowitz, David Wofsy, Josef S Smolen, Raymond P Naden, Martin Aringer, Karen H Costenbader
Journal: Annals of the Rheumatic Diseases (2019)

European League Against Rheumatism and are jointly supporting multiphase development of systemic lupus erythematosus (SLE) classification criteria based on weighted criteria and a continuous probability scale. Prior steps included item generation, item reduction and hierarchical organisation of candidate criteria using an evidence-based approach. Our objectives were to determine relative weights using multicriteria decision analysis (MCDA) and to set a provisional threshold score for SLE classification. An SLE Expert Panel (8 European, 9 North American) submitted 164 real, unique cases with a wide range of SLE probability in a standardised format. Using the candidate criteria, experts scored and rank-ordered 20 representative cases. At an in-person meeting, experts reviewed inter-rater reliability of scoring, further refined criteria definitions and participated in an MCDA exercise. Based on expert consensus decisions on pairwise comparisons of criteria, 1000minds software calculated criteria weights and rank-ordered the remaining 144 cases based on their additive scores. The score of the lowest-ranked case for which complete expert consensus was achieved defined the provisional threshold classification score. Inter-rater reliability of scoring cases with the candidate criteria was good. MCDA involved 74 pairwise decisions and was repeated for the arthritis and mucocutaneous domains when the initial ranking of some cases did not match expert opinion. After criteria weights and additive scores were recalculated once, experts reached consensus for SLE classification for all cases scoring>83. Using an iterative process, the candidate criteria definitions were refined, preliminary weights were calculated and a provisional threshold score for SLE classification was determined.
Late-Stage Preclinical Characterization of Switchable CD123-Specific CAR-T for Treatment of Acute Leukemia
Authors: Simon Loff, Jan-Erik Meyer, Josephine Dietrich, Johannes Spehr, Riewaldt Julia, Malte von Bonin, Cordula Gründer, Kristin Franke, Anja Feldmann, Michael Bachmann, Gerhard Ehninger, Armin Ehninger, Marc Cartellieri
Journal: Blood (2018)
Association of consensus molecular subtypes (CMS) with time to progression (TTP), progression free survival (PFS), and overall survival (OS) with second-line FOLFIRI ± regorafenib in metastatic colorectal cancer (mCRC).
Authors: Michael Sangmin Lee, Sara R. Selitsky, Joel S. Parker, James Todd Auman, Yunhan Wu, Kelli Hammond, Bert O'Neil, Hanna Kelly Sanoff, Federico Innocenti
Journal: Journal of Clinical Oncology (2019)

597 Background: LCCC1029 was a 2:1 randomized phase II trial of second-line FOLFIRI plus either regorafenib or placebo in mCRC that showed no statistically significant difference in PFS or OS. CMS, defined using gene expression, is prognostic for PFS and OS in previously untreated mCRC, but the impact of CMS in second-line treatment is unclear, as well as its impact on regorafenib efficacy. Methods: RNAseq on archival tumor tissue was successfully performed in 68 LCCC1029 patients (49 on regorafenib, 19 on placebo). A multinomial elastic net CMS classifier was trained using 6 CRC gene expression data sets with known CMS classification. We built our model with only CMS1-4 classified samples and then applied it to normalized and median adjusted RNASeq from LCCC1029 to classify all samples into CMS1-4. TTP, PFS, and OS were compared using Kaplan-Meier method and log-rank tests, and hazard ratios were estimated using Cox proportional hazards method. Results: Our model had &gt; 93% sensitivity and specificity for CMS1-4 in the training data set; the 17% of non-consensus samples in the training data were predominantly labeled CMS2. We classified the LCCC1029 samples as CMS1 (12%), CMS2 (63%), CMS3 (4%), and CMS4 (21%). CMS was prognostic for TTP (log-rank p=0.03), with median for CMS1 of 2.0 months (95% CI 0.0-4.8) versus 5.6 months (5.3-5.9) for CMS2 and 7.8 months (5.5-10.1) for CMS4. There was a trend toward association between CMS and either PFS (log-rank p = 0.11) or OS (log-rank p = 0.085). CMS2 had superior OS compared to CMS1 (HR 0.39, 95% CI 0.17-0.87, p = 0.02). With our limited sample size, we found no significant interaction between CMS and treatment arm for TTP, PFS, or OS. Conclusions: CMS is associated with significant differences in TTP in second-line treatment of mCRC in LCCC1029, and specific CMS types also have differences in OS. Thus, the prognostic impact of CMS extends to second-line treatment in mCRC, meriting further study of CMS classification in additional non-first-line studies.
Abstract P014: Associations of Depression, and Perceived Stress With Telomere Length in African Americans: The Minority Health Genomics and Translational Research Bio-Repository Database Study
Authors: Rumana J Khan
Journal: Circulation (2018)

Background: African Americans (AA) experience higher levels of psychological distress. Adverse psychological conditions and mental stress could be associated with accelerated cellular aging, evidenced by shortened leukocyte telomere length (TL), which could underlie this association. Hypothesis: In this study, we hypothesized that depressive symptoms and higher stress level would be associated with shorter telomere length in AA. We also hypothesized that the associations would be attenuated after adjusting for individual-level sociodemographic variable, various disease conditions, and lifestyle factors. Methods: The analysis included 225 women and 142 men aged 30-55 years from the Minority Health Genomics and Translational Research Bio-Repository Database Study. Relative TL (T/S ratio) was measured using quantitative polymerase chain reaction. The 20-item Center for Epidemiologic Studies Depression Scale and 14-item Perceived Stress Scale were used to assess the presence of depressive symptoms and perceived stress respectively. Summation of the scores and the Principal Component Analysis were performed for both the scales. Multivariable linear regression models were used to estimate mean differences in log T/S associated with depressive symptoms and perceived stress after adjusting for sociodemographic variable, various disease conditions, and lifestyle factors. Results: No evidence of association between stress and TL was observed. We found effect modification by hypertension affecting the association between depressive symptoms and log T/S. Depressive symptom, especially higher psychosomatic symptoms, was associated with increased TL in normotensive participants (β= 0.11 for mid-level psychosomatic symptoms and β= 0.12 for high-level psychosomatic symptoms; p value &lt;0.05 for both). No association was observed in hypertensive participants. Conclusions: We found a positive association between psychosomatic depressive symptoms and TL, which do not support the hypothesis that depression is associated with shorter TL and aging in AA. Longitudinal studies with larger samples are needed to better understand and confirm this relationship.
Utility of Leucovorin Rescue in Patients with Acute Lymphoblastic Leukemia (ALL) Treated with the Mini-Hypercvd Regimen
Authors: Caitlin R. Rausch, Shilpa Paul, Hagop M. Kantarjian, Farhad Ravandi, Nicholas J Short, Koji Sasaki, Maria Khouri, Jovitta Jacob, Kathryn S Montalbano, Philip A. Thompson, Nitin Jain, Musa Yilmaz, Kiran Naqvi, Maro N. Ohanian, Patrice Nasnas, Zeev E. Estrov, Susan M. O'Brien, Elias J. Jabbour
Journal: Blood (2018)
Abstract 15576: Clinical Validation of a Smartphone Based, 6-lead ECG Device
Authors: Stavros Stavrakis, Paul J Garabelli, Landgrave Smith, David Albert, Sunny S Po
Journal: Circulation (2017)

Introduction: We previously reported the equivalency of a single lead smartphone-based ECG with the same lead of a 12-lead ECG. In the present study, we sought to compare the clinical equivalency o...