tbuckley/cabot-search huggingface dataset:
Risk of myelodysplasia in patients post solid organ transplant: A review of recent trends from a tertiary transplantation center.
Authors: Anish S Konde, Pallavi Srivastava, Mamta Puppala, Stephen Wong, Sai Ravi Pingali, Swaminathan Padmanabhan Iyer
Journal: Journal of Clinical Oncology (2016)

7064 Background: An increased incidence of AML has recently been documented in patients post-solid organ transplantation (SOT). However, little is known about the incidence and various types of Myelodysplastic syndromes (MDS) occurring in this patient population. We aimed to discover and examine these trends at the Houston Methodist Hospital. Methods: The patient data was queried from METEOR (Methodist Environment for Translational Enhancement and Outcomes Research), a clinical data warehouse and analytics environment that integrates existing business data warehouse with internal and external research databases and national registries to support clinical research and outcomes studies for improving patient care cost-effectively. Results: From the database of 6000 SOTs, we queried Pancytopenia and MDS and found 172 and 2 patients; for neutropenia and MDS - 732 and 2; thrombocytopenia and MDS -472 and 4; Anemia and MDS - 1908 and 4. An independent query for MDS revealed 20 confirmed pathology. Patient demographics included 10 each for male and female, with a median age of 68 (26-79); 14 Caucasian, 3 African-American, 2 Hispanic and 1 other. The solid organ transplants included kidney-7 between the years 1989 to 2013 (4 between 1996-1997; 6 between 2003-2010 and 6 between 2011 and 2013), Lung-7 between the years 2005 to 2012, liver-3 between 1996 and 2013 and heart -3 between 1990 and 2012. All but 2 MDS were diagnosed before 2013 and 7 out of 20 were on either Cyclosporine and Tacrolimus; median time to MDS varied from 6 months to 10 years. More details on the IPSS score, the subtypes of disease and the treatments provided will be presented at the annual meeting of the ASCO later this year. Conclusions: SOT patients have an elevated risk for MDS, partly from iatrogenic immune suppression and infections. Our database shows a 7 fold increase in the incidence of MDS compared to the general population (with a incidence of 4.6/10000). A prospective analysis of genomic factors pre-transplant particularly for p53 may give us a better understanding of the pathogenesis in these solid organ transplant patients.
Abstract 19713: The Electrocardiographic Effects of Intranasal Formulations of a New Calcium Channel Blocker, MSP-2017, are Consistent With a Potential Treatment of Paroxysmal Supraventricular Tachycardia: Results of a Phase I Dose Escalation Study
Authors: Francis Plat, Archer Broughton, Philippe Douville, Philip T Sager, Bob Soh, Douglas Wight
Journal: Circulation (2015)

Introduction: MSP-2017 is a new L-type calcium channel antagonist developed to be self-administered intranasally to convert episodes of PSVT into sinus rhythm. Hypothesis: This phase 1 study was designed to determine safety, tolerability of two formulations (A and B) of MSP-2017 and to test whether the effects on ECG intervals (PR, QTc) and HR were significantly different from placebo. Methods: A double-blind, dose-escalation, placebo-controlled study was conducted in healthy males, consisting of 7 cohorts each including 6 subjects on active drug and 2 on placebo. Cohorts 1 to 5 subjects received 2 single doses of 3.5, 7, 14, 30, 60 mg of MSP-2017 formulations A and B, 3 days apart, and cohorts 6 and 7 subjects received a single dose of 105 and 140 mg of MSP-2017 formulation B only due to lack of PK differences compared to formulation A. Twenty-four hour Holter recordings were performed at screening and on dosing Days 1 and 3. ECGs were analyzed prior to dosing and at 0.5, 1.5, 3, 5, 7, 10, 15 min post-dose and less frequently until 1440 min post-dose. Results: The intranasal administration of MSP-2017 was safe and well tolerated. The largest mean placebo-corrected PR increase was observed early, with a peak effect of 20 msec (90% CI: 14.9 to 25.1) at 12 minutes with 60 mg, 19.5 msec (90% CI: 8.4 to 30.5) at 10 min with 105 mg, and 24 msec (90% CI: 15.3 to 32.7) at 12 min with 140 mg of MSP-2017. At lower doses the peak effect was lower and time to onset longer. MSP-2017 did not have a notable effect on QRS intervals but had a dose-related effect on HR. HR increase with both formulations of MSP-2017 was different from placebo at all dose levels. Seven minutes post-dose mean HR increase reached 7, 21.4, 32.2 and 37.4 bpm at 30, 60, 105 and 140 mg doses, respectively. MSP-2017 caused a shortening of the QT duration corrected for individual heart rate (QTcI) at high doses but without dose-dependence. Conclusions: MSP-2017 caused significant PR prolongation at early time points after dosing, with 20 msec at higher doses (60, 105 and 140 mg) and smaller effects beyond 50 min post-dose. The HR increase and the QTcI shortening suggest a sympathetic stimulation may have contributed to these ECG changes. These results are consistent with a potential positive clinical effect to be tested in patients with PSVT.
Skin involvement by chronic lymphocytic leukaemia is frequently associated with unrelated neoplastic or inflammatory cutaneous disease and is not indicative of general disease progression
Authors: I. Thiesen, U. Wehkamp, M. Brüggemann, M. Ritgen, E.M. Murga Penas, W. Klapper, I. Oschlies
Journal: British Journal of Dermatology (2018)
Toxicity and tolerance of concurrent docetaxel with radiotherapy in cisplatin ineligible head and neck cancer patients.
Authors: Vijai Simha, Vijay Maruti Patil, Amit Joshi, Vanita Noronha, Vikas Talreja, Sachin Dhumal, Arun Chandrasekharan, Sameer Shrirangwar, Kumar Prabhash
Journal: Journal of Clinical Oncology (2018)

e18022 Background: Docetaxel can be administered in several situations like low creatinine clearance or pre existing grade 3-4 ototoxicity, where cisplatin is contraindicated. In this analysis, we present our data on toxicity and tolerance to docetaxel based chemoradiation in cisplatin ineligible patients. Methods: Patients who underwent docetaxel based chemoradiation between January 2015 to April 2017 for locally advanced head and neck cancer, either in radical or adjuvant setting in the Department of Medical Oncology at Tata memorial Hospital were selected for this analysis. SPSS version 16 was used for analysis. They received Docetaxel 15mg/m2 intravenously in a weekly schedule. Descriptive statistics is used to present the data. Continuous variables were described in terms of median and interquartile range while categorical variables were described in terms of percentages with 95%CI Results: Nineteen patients were identified and the median age of the cohort was 58 years ( range 41-71 years). The most common site of primary was oral cavity (n = 9, 47.4%). Sixteen patients (84.2%) had stage IV disease and 3 patients (15.8%) had stage 3 disease. The intent of chemoradiation was radical in 12 (63.9%) patients and adjuvant in 7 (36.1%) patients. Any grade 3 or above adverse events were seen in 12 patients (63.2%). The most common grade 3 or above adverse events observed were mucositis and hyponatremia in 9 patients (47.4%) each. Compliance to radiation and docetaxel was observed 16 (84.2%) and 15 patients (78.9%) respectively. The median progression free survival was 10.3 months (95%CI 2.3-18.3 months) while the median overall survival was 25.3 months ( 95%CI 6.7-43.9 months). Conclusions: Docetaxel based chemoradiation is a feasible and well tolerated regimen in cisplatin ineligible patients and needs further testing in large randomized studies to prove its worth.
Co-existance of <i>KRAS</i> and <i>LKB1</i> mutation as predictor of resistance to Erlotinib: Customized next-generation sequencing (NGS) of TAILOR trial.
Authors: Eliana Rulli, Mara Serena Serafini, Mirko Marabese, Elisa Caiola, Gabriella Sozzi, Massimo Moro, Emilio Bria, Michele Simbolo, Adele Busico, Elena Tamborini, Giulia Corrao, Gabriella Farina, Massimo Broggini, Monica Ganzinelli, Marina Chiara Garassino
Journal: Journal of Clinical Oncology (2017)

e20631 Background: The prognostic and predictive value of KRAS mutation in advanced NSCLC is still debatable. In TAILOR (NCT00637910) trial EGFR wild-type patients were randomized to receive 2nd line erlotinib versus docetaxel, and no interaction was detected according to KRAS mutational status. Recent evidences indicate that the concurrent mutation of KRAS and LKB1 (key factor for cell metabolism) may be associated with worse prognosis. Methods: Availableformalin-fixed embeddedtissue samples with annotated clinical data from TAILOR were gathered. Customized deep sequencing (Ion proton Technology) of 111 genes most frequently associated with cancer, was performed; 5% of frequency was used to identify mutations. Association between genes and clinical features was performed with non-parametric tests; Cox regression analysis was used to assess the prognostic and predictive value of LKB1. Results: 123 out of 222 (55%) randomized patients had available tissue and were successfully sequenced. 42/123 (34%) patients had a KRAS mutation. KRAS and LKB1 mutations were found in 11/42 (26%) KRAS patients, while only 6 patients had a LKB1 mutation without KRAS. The presence of a concurrent KRAS-LKB1 mutation did not adversely influence progression-free (PFS) or overall (OS) survival [hazard ratio (HR) PFS 1.08, 95% confidence interval (CI) 0.57-2.05, P = 0.81; OS 1.09, 95% CI 0.56-2.14, P = 0.78]. Patients receiving docetaxel experienced longer survival regardless of the KRAS-LKB1 mutational status (mutated KRAS-LKB1 HR 0.42, 95% CI 0.08-2.29; wild-type KRAS-LKB1 HR 1.16, 95% CI 0.72-1.87, P = 0.55; interaction P = 0.10). Conclusions: Although the significant attrition and the limited number, these data generate the hypothesis that the concurrent mutation of KRAS and LKB1 may potentially be associated with resistance to erlotinib. Overall, the coexistence of mutation in KRAS and LKB1 is not associated with worse prognosis in NSCLC. For these patients refractory to EGFR targeting, metabolic strategies represent a future research opportunity.
TCT-17 Tricuspid Valve Regurgitation Reduction Following Concomitant Subvalvular and Annulus-level Treatment – Ex-vivo Study
Authors: Michal Jaworek, Claudia Romagnoni, Omar Pappalardo, Matteo Selmi, Guido Gelpi, Federico Lucherini, Alberto Redaelli, Gianfranco Fiore, Emiliano Votta, Carlo Antona, Riccardo Vismara
Journal: Journal of the American College of Cardiology (2018)
Identifying new biomarkers and targeted molecules for immunotherapy using targeted RNA next generation sequencing.
Authors: Wanlong Ma, Ivan De Dios, Vincent Anthony Funari, Mohammad Sheikholeslami, Nicholas Stavrou, Forrest Blocker, Baback Shahbaba, Maher Albitar, Sucha Sudarsanam
Journal: Journal of Clinical Oncology (2018)

3088 Background: Predictive biomarkers for selecting of patients who may benefit or experience serious adverse effects from checkpoint blockade therapy are urgently needed. These biomarkers may vary from one type of tumor to next. Developing a broad approach for the discovery of new tissue-specific predictive biomarkers may also help guide combination therapy. We used targeted RNA sequencing for the discovery of biomarkers that are co-regulated with PD-L1. Methods: We used RNA sequencing of 1385 genes to profile tissues from solid tumors and lymphomas and correlated RNA levels with PD-L1 expression as detected by IHC in tumor and inflammatory cells. Results: After normalization, adjusting for group effect and multiple hypothesis testing, 21 genes correlated with PD-L1 expression; fourteen genes correlated positively and 7 correlated negatively. Using the first principle component, we demonstrated that these 21 genes are highly redundant in predicting levels of IHC PD-L1 expression and practically any one can be used as a biomarker. Using LASSO to develop a multivariate model, we demonstrated that RNA levels of CD274, PLAU (uPA), and RAC1 are independent biomarkers predictive of IHC PD-L1 expression. Conclusions: RNA expression, measured using targeted NGS, is a reliable alternative to IHC PD-L1 expression testing. We showed that RNA levels of CD274, which codes for PD-L1, and 20 other genes can be used interchangeably in predicting IHC PD-L1 expression. Further, as RNA expression of PLAU and RAC1 are independent from CD274, targeting PLAU and RAC1 in combination with PD-L1 inhibitors potentially may augment the therapeutic effects of anti-PD-L1 therapy. % PD-L1 in Tumor q-value q-value CD274 0.0000 CD74 0.0019 PLAU 0.0001 CHD6 0.0020 PDCD1LG2 0.0001 RASGRP1 0.0020 STAT1 0.0007 KANK1 0.0026 IRF1 0.0013 CIITA 0.0029 CCNB1IP1 0.0014 MBTD1 0.0030 MIR4683 0.0014 C10 0.0073 SOD2 0.0014 PLCB4 0.0079 FAS 0.0018 IGF1R 0.0079 GBP2 0.0018 SIRT1 0.0079 IL21R 0.0018
Disruption of the β1L Isoform of GABP Reverses Glioblastoma Replicative Immortality in a TERT Promoter Mutation-Dependent Manner
Authors: Andrew Mancini, Ana Xavier-Magalhães, Wendy S. Woods, Kien-Thiet Nguyen, Alexandra M. Amen, Josie L. Hayes, Christof Fellmann, Michael Gapinske, Andrew M. McKinney, Chibo Hong, Lindsey E. Jones, Kyle M. Walsh, Robert J.A. Bell, Jennifer A. Doudna, Bruno M. Costa, Jun S. Song, Pablo Perez-Pinera, Joseph F. Costello
Journal: Cancer Cell (2018)
Bayesian individual exposure estimation of dabrafenib alone or in combination with trametinib in mutated-BRAF V600E metastatic melanoma patients.
Authors: Lauriane Goldwirt, Claire Pressiat, Ichrak Chami, Vincent Jullien, Helene Sauvageon, Isabelle Madelaine, Celeste Lebbe, Samia Mourah
Journal: Journal of Clinical Oncology (2016)

e14105 Background: Dabrafenib (DAB) has clinical activity with a manageable safety profile in mutated-BRAF(V600E) metastatic melanoma patients (MMP). However, resistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase pathway and combinations of BRAF and MEK inhibitors are now considered to be the standard of care of targeted therapy in BRAF mutated MMP. As higher exposure of DAB has been associated to higher probability of response, and considering the wide inter-individual variability in DAB pharmacokinetics, a method for estimating the area under the curve (AUC) of DAB was necessary to perform therapeutic drug monitoring (TDM). The objective of this study was to implement a Bayesian estimation of DAB AUC0-12h in mutated-BRAFV600E MMP treated with DAB alone, and to assess the robustness of this model in MMP treated with DAB in combination with trametinib, as trametinib may have a slight inhibitory effect on DAB elimination clearance (+23% AUC) . Methods: This monocentric study was conducted in onco-dermatology department of Saint-Louis Hospital and included patients from April 2014 to November 2015. Plasma samples were collected monthly, at any time during a dosing interval at steady steate. DAB concentrations were analyzed using a nonlinear mixed effects modeling, with NONMEM software (version 7.2). Population pharmacokinetic model of Dabrafenib was used to estimated individual PK parameters in order to calculate individual exposures. Results: Seventy plasma concentrations were collected from 39 MPP aged from 18 years to 87 years (n = 19 treated with DAB only, n = 20 treated with DAB and trametinib). Visual Predictive Check validated the use of the model for monotherapy and combo. Individual predictions matched the observed concentrations (MPE = 18%, RMSE = 20.4%; R2 = 0.96). As expected, median AUC of DAB was significantly higher when combined to trametinib (6.3 [4.2 ; 10.8] ng/ml.h-1 vs 4.5 [1.5 ; 18.1] ng/ml.h-1, p = 1.67.10-6, Mann-Whitney test). Conclusions: This Bayesian estimation allowed us to determine patient DAB plasma AUC0-12h . It can be used as a routine procedure to perform TDM in patients.
TCT-56 High-resolution Intravascular OCT-NIRF Molecular Imaging for In Vivo Assessment of Inflammation in Atherosclerosis and Vascular Injury
Authors: Zhonglie Piao, Kanwarpal Singh, Mohammed Chowdhury, Joseph Gardecki, Kensuke Nishimiya, Biwei Yin, Matthew Beatty, Ara Bablouzian, Sarah Giddings, Adam Mauskapf, Farouc Amin Jaffer, Guillermo Tearney
Journal: Journal of the American College of Cardiology (2018)
Safety and efficacy of low-dose metronomic cyclophosphamide plus vinorelbine in patients with metastatic breast cancer previously treated with anthracyclines and taxanes.
Authors: Shun Kudo
Journal: Journal of Clinical Oncology (2018)

e13089 Background: Metronomic chemotherapy has recently gained attention as a promising experimental strategy, involving alternative or complementary ways of using old and new anticancer chemotherapeutic agents. This study aimed to determine the toxicity, safety, and efficacy of a combination of low-dose metronomic cyclophosphamide (CPA) and vinorelbine in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes. Methods: Eligibility criteria were as follows: human epidermal growth factor receptor 2 -negative MBC previously treated with anthracyclines and taxanes, ECOG PS 0~1, and adequate bone marrow and organ function. Prior hormone therapy for MBC was permitted. In this study, patients received vinorelbine (40 mg/m2) intravenously on days 1 and 8, and CPA (100 mg) orally once daily on days 1~14, every third week. The primary endpoints were the objective response rate (ORR) at 6 months and median time to progression (TTP). Secondary endpoints included safety and tolerability. Results: Between July /2010 and May /2017, 25 patients (median 55.6 years) were enrolled. 77% were estrogen receptor and/or progesterone receptor positive, and 23% were triple negative. Sites of metastasis included the lymph nodes (46%), lungs (42 %), liver (50%), and bone (50%). Nine patients (35%) had ≥3 sites of metastasis. A total of 328 cycles of chemotherapy were administered (median, 10 cycles; range, 1–34 cycles). The ORR at 6 months was 44% (11 patients with partial responses). The median TTP was 22.0 months (95%CI [6.0-29.0]). The most common hematologic toxicity was grade 2 neutropenia (40%); no grade 3/4 hematologic toxicity was observed. The most common non-hematologic toxicities were grade 1/2 hair loss (40%) and grade 2 urinary cystitis (8%). Discontinuation to adverse events did not occur. Conclusions: The combination of low-dose cyclophosphamide and vinorelbine is safe, with minimal adverse effects; it shows promising antitumor activity in patients with MBC refractory to anthracyclines and taxanes. Further clinical evaluation of this combination is warranted.
Avelumab (MSB0010718C; anti-PD-L1) + best supportive care (BSC) vs BSC ± chemotherapy as third-line treatment for patients with unresectable, recurrent, or metastatic gastric cancer: The phase 3 JAVELIN Gastric 300 trial.
Authors: Yung-Jue Bang, Lucjan Wyrwicz, Young Iee Park, Min-Hee Ryu, Alina Muntean, Carlos Gomez-Martin, Rosine Guimbaud, Fortunato Ciardiello, Narikazu Boku, Eric Van Cutsem, Julien Taïeb, Huiling Xiong, Jenny Zhang, Jean-Marie Cuillerot, Jayne S. Gurtler
Journal: Journal of Clinical Oncology (2016)

TPS4135 Background: Programmed death-1 receptor ligand (PD-L1) is a key therapeutic target in the reactivation of the immune response against multiple cancers. Avelumab* is a fully human anti-PD-L1 IgG1 antibody that has shown promising efficacy and an acceptable safety profile in multiple tumor types, including adenocarcinoma of the stomach or gastroesophageal junction (AS/GEJ). This open-label phase 3 trial (NCT02625623) compares avelumab + best supportive care (BSC) vs BSC ± chemotherapy as third-line treatment for patients (pts) with AS/GEJ. Methods: The primary objective of this global, multicenter trial is to demonstrate superiority, defined by overall survival, of avelumab + BSC vs BSC ± chemotherapy. Approximately 330 pts stratified by region (Asia vs non-Asia) will be randomized. Main eligibility criteria include: histologically confirmed unresectable locally advanced or metastatic AS/GEJ, fresh or archival tumor tissue for PD-L1 expression assessment, ECOG PS 0-1, 2 prior lines of systemic treatment, no prior therapy with any drug targeting T cell coregulatory proteins, and no concurrent anticancer treatment or immunosuppressive agents. Pts are not preselected for PD-L1 expression. Pts receive either BSC with avelumab 10 mg/kg as a 1h intravenous infusion Q2W or BSC ± chemotherapy (physician's choice of irinotecan 150 mg/m2 Q2W or paclitaxel 80 mg/m2 weekly for 3 out of 4 weeks, in a 4-week treatment cycle for pts eligible to receive chemotherapy). Pts not eligible for chemotherapy will receive BSC only. Treatment is given until disease progression, unacceptable toxicity, or consent withdrawal. Secondary endpoints include progression-free survival, objective response rate, quality of life (assessed via EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ-STO22), safety as per NCI-CTCAE v4.03, and tumor biomarkers. Responses are evaluated according to RECIST 1.1 and adjudicated by a blinded independent review committee. Trial enrollment began in Dec 2015. *Proposed INN. Clinical trial information: NCT02625623.
TCT-776 Duration of dual antiplatelet therapy after drug-coated balloon implantation
Authors: Franz Kleber, Bruno Scheller, Paul Ong, Tuomas Rissanen, Uwe Zeymer, Jochen Wöhrle, Takaaki Komatsu, None Simon Eccleshall, Philine Köln, Antonio Colombo, Ran Kornowski
Journal: Journal of the American College of Cardiology (2018)
Age and Sex but Not ATP7B Genotype Effectively Influence the Clinical Phenotype of Wilson Disease
Authors: Peter Ferenci, Wolfgang Stremmel, Anna Członkowska, Ferenc Szalay, André Viveiros, Albert Friedrich Stättermayer, Radan Bruha, Roderick Houwen, Tudor Lucian Pop, Rudolf Stauber, Michael Gschwantler, Jan Pfeiffenberger, Cihan Yurdaydin, Elmar Aigner, Petra Steindl‐Munda, Hans‐Peter Dienes, Heinz Zoller, Karl Heinz Weiss
Journal: Hepatology (2018)

Wilson disease (WD) is an inherited disorder of hepatic copper metabolism with considerable variation in clinical presentations, the most common ones being liver disease and neuropsychiatric disturbances. This study investigated the clinical presentation in relation to mutations in a large cohort of patients with WD. A total of 1,357 patients (702 children, 655 adults; 1,172 index patients, 185 siblings, all with a Leipzig score ≥4, male/female: 679/678) were studied. The age and the symptoms at presentation were used as key phenotypic markers. Index patients were clinically classified as having either hepatic (n = 711) or neurologic disease (n = 461). Seven hundred fifteen (52.7%) patients had a liver biopsy at diagnosis. DNA was sequenced by the Genetic Analyzers ABI Prism 310 (Perkin Elmer) or 3500 (Applied Biosystems). Three hundred ninety-four different mutation combinations were detected. The most frequent mutation was H1069Q (c.3207C>A; allele frequency: 46.9%), followed by P767P-fs (c.2304dupC; 2.85%), P1134P-fs (c.3402delC; 2.8%), and R969Q (c.2755C>T; 2.18%). There was no correlation between mutations and individual clinical manifestation. There was a gender effect in index patients: Hepatic presentation was more common in females (male/female: 328/383) and neurologic presentation in males (259/202; P < 0.001). At diagnosis, 39.5% of children/adolescents (≤18 years) and 58% of adults already had cirrhosis. The presence of cirrhosis did not correlate with the genotype. Conclusion: These findings refine and extend our understanding of the natural history and individual spectrum/manifestations of WD. Initially, there is asymptomatic hepatic involvement, which may progress and become symptomatic. Neurologic symptoms present many years later.