tbuckley/cabot-search huggingface dataset:
Current paradigms in the management of <scp>P</scp>hiladelphia chromosome positive acute lymphoblastic leukemia in adults
Authors: Riad El Fakih, Elias Jabbour, Farhad Ravandi, Mona Hassanein, Farhan Anjum, Syed Ahmed, Hagop Kantarjian
Journal: American Journal of Hematology (2017)

Abstract Philadelphia chromosome‐positive (Ph‐positive) acute lymphoblastic leukemia (ALL) is a biologically, clinically, and genetically distinct subtype of precursor‐B ALL. The Ph chromosome, results from a reciprocal translocation of the ABL1 kinase gene on chromosome 9 to the breakpoint cluster region ( BCR ) gene on chromosome 22. Depending on the translocation breakpoint, typically a p210 BCR‐ABL1 or a p190 BCR‐ABL onc protein are generated; both are constitutively active tyrosine kinases that play a central role to alter signaling pathways of cell proliferation, survival, and self‐renewal, leading to leukemogenesis. In Ph‐positive ALL, the p190‐ BCR‐ABL (minor [m]‐bcr) subtype is more frequent than the p210‐ BCR‐ABL (major [M]‐bcr) subtype, commonly found in chronic myeloid leukemia. The Philadelphia chromosome is the most frequent recurrent cytogenetic abnormality in elderly patients with ALL. Its incidence increases with age, reaching ∼50% in patients with ALL aged 60 years and over. Patients traditionally had a very poor outcome with chemotherapy, particularly if they do not undergo allogeneic hematopoietic cell transplantation (allo‐HCT) in first complete remission (CR1). With the availability of multiple tyrosine kinase inhibitors (TKI), the therapeutic armamentarium is expanding quickly. However, there is no consensus on how to best treat Ph‐positive ALL. With modern therapy, improved outcomes have led to the emergence of a number of controversies, including the need for intensive chemotherapy, the ideal TKI, and whether all eligible patients should receive an allo‐HSCT, and if so, what type. Here, we discuss these controversies in light of the available literature.
Abstract 19070: Hispanic/Latino Knowledge, Attitudes and Behaviors About Tobacco Use: Results of Focus Groups in 4 US Cities
Authors: Aida L Giachello, Rose M Robertson, Thomas J Payne, Carlos J Rodriguez, Kandi L Walker, Joy Hart, Allison Groom, Cristina Quiroz, Elena Navas, Anshula Kesh
Journal: Circulation (2015)

Despite the reduction in the overall prevalence of cigarette smoking in the US, use has remained high among Hispanics/Latinos (H/Ls), particularly Puerto Ricans (33.7%) and Cuban/Cuban Americans (27.2%) (HCHS/SOL Databook, 2013). There is limited understanding about H/Ls knowledge, attitudes and behaviors (KAB) toward the use of other tobacco products such as e-cigs and hookah and how they may differ across diverse ethnic backgrounds, SES and acculturation. Objective: To assess KAB and perception of risk about the use of tobacco products among H/Ls that can inform the development of a culturally appropriate campaign to reduce prevalence. Methods: During the summer of 2014, 26 English and Spanish-speaking focus groups (6-10 persons per group, N = 182) were conducted among smokers and non-smokers, young (18-35) and old (36-65), men and women, of different SES and acculturation levels in: Chicago (Central and South Americans), New York City (Puerto Ricans and Dominicans), San Diego (Mexican/Mexican Americans) and Miami (Cubans). During 1 ½ hrs. discussion, participants were asked about: tobacco use problem in the community, type of tobacco use, health consequences of tobacco use, tobacco industry policy, second hand smoke, efforts to quit cigarette use, and channels of communication, including information technology. Data were analyzed using Atlas.ti for prevalent themes, perceptions and KAB. Results: Regardless of ethnic background, Latino smokers were most likely to use regular cigarettes, e-cigs and hookah. Older H/Ls (36+) and Spanish-speaking immigrants were most likely to use regular cigarettes while younger adults (women and men), US-born or more acculturated, were most likely to report using e-cigarette and/or hookah. Users stated that easy access, appeal of the different flavored tobacco taste &amp; smell, no restrictions in their use, and socializing with others, made these products attractive. Differences did emerge in KAB and perceptions of tobacco risk by specific H/L group, smoking status, city, SES and acculturation. Conclusion: Tobacco use continues to be a serious problem in the H/L communities with growing use and acceptance of e-cigarettes and hookah among younger and more acculturated H/Ls.
Outcome of patients with pancreatic adenocarcinoma with complete pathological response following neo-adjuvant therapy
Authors: H.R. Kourie, A. Sa Cunha, S. Pernot, R. Coriat, A. Sauvanet, N. Regenet, S. Louafi, J-B. Bachet, D. Pietrasz, J. Taieb
Journal: Annals of Oncology (2017)
Abstract MP18: Hand Grip Strength is Inversely Related to Arterial Stiffness in 136,856 UK Adults: The UK Biobank Project
Authors: Youngwon Kim, Katrien Wijndaele, Nick Wareham, Soren Brage
Journal: Circulation (2016)

Introduction: Fitness is an important determinant of cardiovascular health in adults. Arterial stiffness has been shown to be a useful prognostic index of cardiovascular events. However, little is known about the relationships of muscular strength with arterial stiffness. Hypothesis: Muscular strength is inversely related to arterial stiffness index. Methods: We utilized baseline data collected from the UK Biobank project, an ongoing UK national cohort study of 502,656 adults. Of 169,835 adults that undertook arterial stiffness tests, 136,854 (aged 40-70yrs; 52.4% females) with all essential variables were included for cross-sectional analyses. Maximal hand grip strength was measured once in each hand via a Jamar J00105 hydraulic hand dynamometer (Lafayette Instrument, USA). Values from both hands were averaged, and then divided by body weight to normalize grip strength for body size. Arterial stiffness was assessed using the pulse waveform measured by photo-plethysmography of the index finger (PulseTrace PCA2, Carefusion, USA). Arterial stiffness index (m/s) was calculated by dividing participants’ height (m) by the difference in time (s) between the first systolic peak and early diastolic peak in the waveforms. Quantile regression was performed to examine cross-sectional associations of grip strength with 5 different percentiles of arterial stiffness index: 10th, 30th, 50th, 70th and 90th. The analyses were adjusted for age, gender, percent body fat, ethnicity, smoking status, employment, household income, deprivation index, self-rated health status, medication use, alcohol consumption, parental history of cardiovascular events, assessment centers, self-reported sedentary time and moderate-to-vigorous physical activity time. Analyses were also stratified by gender, age groups and weight status. Results: One unit increase in grip strength was significantly associated with reductions in arterial stiffness index by 0.68m/s (confidence interval [CI]: 0.54, 0.83), 1.25m/s (CI: 1.08, 1.42), 1.31m/s (CI: 1.13, 1.49), 1.23m/s (CI: 1.00, 1.45) and 1.32m/s (CI: 0.93, 1.71) at the 10th, 30th, 50th, 70th and 90th percentile of arterial stiffness index, respectively. However, stratified analyses revealed stronger negative associations at higher percentiles of the arterial stiffness index in females versus males, younger (&lt;65yrs) versus older individuals and normal versus overweight/obese individuals. Conclusions: Hand grip strength was inversely associated with arterial stiffness index; the relationships were, in general, stronger at the upper tail of the arterial stiffness index distribution. Additional research is needed to understand biological mechanisms through which various genetic and lifestyle factors improve muscular strength, as well as causal relationships between muscular strength and arterial stiffness.
Survival Outcomes of Men with Lymph Node-positive Prostate Cancer After Radical Prostatectomy: A Comparative Analysis of Different Postoperative Management Strategies
Authors: Karim A. Touijer, Robert Jeffery Karnes, Niccolo Passoni, Daniel D. Sjoberg, Melissa Assel, Nicola Fossati, Giorgio Gandaglia, James A. Eastham, Peter T. Scardino, Andrew Vickers, Cesare Cozzarini, Francesco Montorsi, Alberto Briganti
Journal: European Urology (2017)
Impact of next generation TKI and co-occurring mutations in ALK-positive NSCLC patients: Results of the Network Genomic Medicine
Authors: R. Riedel, A. Kron, S. Michels, J. Fassunke, M. Scheffler, R. Fischer, L. Nogova, D. Abdulla, C. Heydt, F. Ueckeroth, B. Pauli, M. Serke, S. Krueger, C. Grohe, M. Sebastian, D. Koschel, K.-O. Kambartel, T. Zander, R. Büttner, J. Wolf
Journal: Annals of Oncology (2017)
Prognostic value and optimal cut off of neutrophil/lymphocyte ratio (NLR) in patients with metastatic renal cell cancer (mRCC).
Authors: Gustavo Jankilevich, Matias Salazar, Gabriela Nacuzzi, Daniel Chirino, Luciana Gennari
Journal: Journal of Clinical Oncology (2017)

e16059 Background: Several biomarkers were tested in mRCC but only outcome scores showed prognostic significance. Neutrophil-to-lymphocyte ratio (NLR) has shown prognostic significance for OS in a number of cancer types but value and cutoff in mRCC is unknown. Methods: The aim of this study was to evaluate NLR as prognostic factor and find a cutoff in mRCC pts. The medical records of 103 pts with mRCC were reviewed. Analysis included adjusting for baseline disease and patient characteristics and investigating potential interaction effects between NLR status and significant BL predictors of outcome. Overal Survivall (OS) was estimated by the Kaplan-Meier method.Univariate and multivariate analysis was performed by Cox regression. Results: Total pts reviewed were 103, MSKCC risk groups (37% Good, 47% Intermediate,16% Poor).Median follow up were 50 months and median OS 29 months. Nephrectomy was performed in 81% of cases.Ninety six percent received treatment (tki – mTor inhibitors). The optimal cutoff was 4, pts with NLR ≤4 vs ≥4 have higher OS 32m vs 10m HR 3,38 (IC95%: 2,60- 4,50 p:0,0001) univariate and HR: 4,32 (IC 95%: 3,35-5,4 p:0,003) in the multivariate analysis. Conclusions: Our series show MSKCC score and RLN were prognostic factors in univariable and multivariable analisys. NRL ≥ 4 identify a group of patients with poor overall survival. The NLR provides independent prognostic information for patients with mRCC and could be useful in academic and community setting. [Table: see text]
Role of protein kinases CK1α and CK2 in multiple myeloma: regulation of pivotal survival and stress-managing pathways
Authors: Sabrina Manni, Marilena Carrino, Francesco Piazza
Journal: Journal of Hematology & Oncology (2017)

Multiple myeloma (MM) is a malignant tumor of transformed plasma cells. MM pathogenesis is a multistep process. This cancer can occur de novo (rarely) or it can develop from monoclonal gammopathy of undetermined significance (most of the cases). MM can be asymptomatic (smoldering myeloma) or clinically active. Malignant plasma cells exploit intrinsic and extrinsic bone marrow microenvironment-derived growth signals. Upregulation of stress-coping pathways is also instrumental to maintain MM cell growth. The phylogenetically related Ser/Thr kinases CSNK1A1 (CK1α) and CSNK2 (CK2) have recently gained a growing importance in hematologic malignancies arising both from precursors and from mature blood cells. In multiple myeloma, CK1α or CK2 sustain oncogenic cascades, such as the PI3K/AKT, JAK/STAT, and NF-κB, as well as propel stress-related signaling that help in coping with different noxae. Data also suggest that these kinases modulate the delivery of growth factors and cytokines from the bone marrow stroma. The "non-oncogene addiction" phenotype generated by the increased activity of CK1α and CK2 in multiple myeloma contributes to malignant plasma cell proliferation and survival and represents an Achilles' heel for the activity of small ATP competitive CK1α or CK2 inhibitors.
Australian health technology assessment of companion testing for cancer drugs.
Authors: Hansoo Kim, Greg Cook
Journal: Journal of Clinical Oncology (2014)

e17500 Background: Patients in Australia access oncology therapies and diagnostic tests through two universal tax funded schemes: the Pharmaceutical Benefits Scheme (PBS) and the Medical Benefits Scheme. Since 1993 health technology assessment (HTA) has been a mandatory requirement for listing new drugs on the PBS. In 2010 HTA of biomarker diagnostic tests have been performed in parallel with the dependant drug. Several cancer drugs have gone through this process since 2010. This study aims to review the process and outcome for these cancer drugs. Methods: The HTA companion testing process in Australia was sourced from Government websites. Public summary documents for all HTAs related to cancer drugs with a companion test were reviewed from 2010. Time from HTA initiation to approval was calculated and compared. Results: Eleven drugs have gone through the parallel diagnostic/drug HTA process since 2010 in five different tumor types (breast, colorectal, gastric, melanoma, NSCLC). Time to reimbursement approval for each of the drugs and companion tests are summarized in the Table. Conclusions: While targeted therapies should assist decision making and improve time to patient access, experience in Australia demonstrates that HTA of companion testing adds another layer of complexity to the overall cost-effectiveness assessment, with potential consequences being delay to patient access. Pharmaceutical companies need to take this into account when they plan late phase clinical trials as well as regulatory and reimbursement submissions. Drug Indication Biomarker Proportion with biomarker Reimbursement Panitumumab Colorectal KRAS 40% Initiated 22Jul12 Approved 5Apr13 Gefitinib NSCLC EGFR 10-20% Initiated 6Apr11 Deferred 1Aug13 Dabrafenib Melanoma BRAF 45.8% Initiated 22Sep11 Approved 1Aug13 Trastuzumab Gastric HER2 14-23% Initiated 21Apr11 Deferred 30Nov12 Vemurafenib Melanoma BRAF 45.8% Initiated 28Jun11 Deferred 2Aug12 Erlotinib NSCLC EGFR 10-20% Initiated 28Jun11 Deferred 1Aug13 Trastuzumab Breast HER2 15% Initiated N/A Approved 2Aug13 Afatinib NSCLC EGFR 10-20% Initiated May12 Deferred 1Aug13 Crizotinib NSCLC ALK 5% Initiated 28Nov11 Not assessed yet Cetuximab Colorectal KRAS 40% Initiated 7Jun13 Not assessed yet
Lenalidomide-mediated erythroid improvement in non-del(5q) myelodysplastic syndromes is associated with bone marrow immuno-remodeling
Authors: G Kerdivel, V Chesnais, E Becht, A Toma, N Cagnard, F Dumont, A Rousseau, P Fenaux, S Chevret, N Chapuis, V Boeva, W H Fridman, M Fontenay, O Kosmider
Journal: Leukemia (2017)
Integrated safety analysis of venetoclax monotherapy in chronic lymphocytic leukemia (CLL).
Authors: Matthew Steven Davids, John F. Gerecitano, Jalaja Potluri, Elisa Cerri, Su Young Kim, Mark Steinberg, Maria Verdugo, Todd A. Busman, Sari H. Enschede, Mehrdad Mobasher, Andrea Best, Monali B Desai, William G. Wierda
Journal: Journal of Clinical Oncology (2016)

7528 Background: Venetoclax is a potent, selective, oral BCL-2 inhibitor that has activity in patients (pts) with relapsed/refractory (R/R) CLL, with an objective response rate of > 70%. Here we report the aggregated venetoclax monotherapy safety analysis from 3 pooled trials in R/R CLL. Methods: An integrated safety analysis was conducted for pts with R/R CLL who received venetoclax monotherapy in a phase 1 dose escalation and two phase 2 trials (N = 328). Pts who received the recommended phase 2 dose of 400 mg once daily (QD) were analyzed for incidence and timing of adverse events (AEs) and are reported here. Results: Pts receiving 400 mg QD (n = 279) included 181 pts with del 17p and 75 pts with previous B cell receptor inhibitor failure. As of Aug 25, 2015, the median duration on treatment was 10.3 months and 65.6% of pts were still on study. Discontinuation occurred in 96 pts, with 24 pts discontinuing due to adverse events (AEs). The most common ( > 20% pts) AEs of any grade (Gr) were neutropenia (38%), diarrhea (38%), nausea (36%), anemia (26%), fatigue (24%), and upper respiratory tract infection (21%). The most common ( > 10% pts) Gr 3/4 AEs were neutropenia (36%), anemia (15%), and thrombocytopenia (13%). Cytopenias occurred early and rates decreased over time. Serious AEs ( > 2% pts) were pneumonia (5%), febrile neutropenia (5%), pyrexia (3%), and autoimmune hemolytic anemia (3%). There were 41 deaths, 11 due to AEs not associated with disease progression. Under the most recent tumor lysis syndrome (TLS) mitigation guidelines, which align prophylactic measures with the pt's relative risk, 4/105 pts (4%) experienced laboratory TLS, all Gr 3. All TLS events were observed within the initial 5-wk dose ramp-up and were managed with hydration, electrolyte correction, and dose interruption. All pts were able to resume dosing without clinical sequelae. Conclusions: Venetoclax 400 mg QD has an established and manageable safety profile for the treatment of R/R CLL pts, including those who may not be appropriate candidates for other approved treatments. Clinical trial information: NCT01328626; NCT01889186; NCT02141282.
GW28-e0985 CD31+CD42b+Platelet-Derived Microparticles: A New Biomarker Associated With Coagulation In Patients With Hypertension And Hyperlipidemia?
Authors: Tong Li, Xiaowan Han, Qiushuo Jin, Xiying Lv, Lei Wang, Tao Yang, Mingjing Zhao
Journal: Journal of the American College of Cardiology (2017)
Abstract 16704: Cardiorespiratory Fitness and Incident Heart Failure: The FIT (Henry Ford ExercIse Testing) Project
Authors: Daniel F Kupsky, Amjad M Ahmed, Sherif Sakr, Waqas Qureshi, Clinton A Brawner, Michael J Blaha, Jonathan K Ehrman, Steven J Keteyian, Mouaz Al-Mallah
Journal: Circulation (2016)

Background:  Prior studies have demonstrated low cardiorespiratory fitness as a strong marker for coronary heart disease. However, there is limited data investigating the association between fitness and risk of heart failure (HF).   Hypothesis:  Utilizing data from the Henry Ford Exercise Testing (FIT) Project, we hypothesized that a higher level of fitness is inversely associated with incident HF.   Methods:  We included 66,329 patients (53.8% males, mean age 55 years) free of HF who underwent clinician-referred exercise treadmill stress testing at Henry Ford Health System between 1991 and 2009. Incident HF was determined using ICD-9 codes from electronic medical records or administrative claims files. Cox proportional hazards models were performed to determine the independent association between fitness and incident HF.   Results:  A total of 4,652 patients developed HF after a median follow-up duration of 6.8 years. Patients with incident HF were older (63 years vs 54 years, p   Conclusions:  Our analysis suggests that higher level of fitness is associated with a lower incidence of HF independent of HF specific risk factors.
Cyclic Peptides to Improve Delivery and Exon Skipping of Antisense Oligonucleotides in a Mouse Model for Duchenne Muscular Dystrophy
Authors: Silvana M.G. Jirka, Peter A.C. ’t Hoen, Valeriano Diaz Parillas, Christa L. Tanganyika-de Winter, Ruurd C. Verheul, Begona Aguilera, Peter C. de Visser, Annemieke M. Aartsma-Rus
Journal: Molecular Therapy (2017)

Duchenne muscular dystrophy (DMD) is a severe, progressive muscle wasting disorder caused by reading frame disrupting mutations in the DMD gene. Exon skipping is a therapeutic approach for DMD. It employs antisense oligonucleotides (AONs) to restore the disrupted open reading frame, allowing the production of shorter, but partly functional dystrophin protein as seen in less severely affected Becker muscular dystrophy patients. To be effective, AONs need to be delivered and effectively taken up by the target cells, which can be accomplished by the conjugation of tissue-homing peptides. We performed phage display screens using a cyclic peptide library combined with next generation sequencing analyses to identify candidate muscle-homing peptides. Conjugation of the lead peptide to 2'-O-methyl phosphorothioate AONs enabled a significant, 2-fold increase in delivery and exon skipping in all analyzed skeletal and cardiac muscle of mdx mice and appeared well tolerated. While selected as a muscle-homing peptide, uptake was increased in liver and kidney as well. The homing capacity of the peptide may have been overruled by the natural biodistribution of the AON. Nonetheless, our results suggest that the identified peptide has the potential to facilitate delivery of AONs and perhaps other compounds to skeletal and cardiac muscle.
Epidémie d’infections à Salmonella enterica sérotype Manhattan associées à des produits à base de viande, France, 2005-06
Authors: H Noël, M Dominguez, F X Weill, A Brisabois, C Duchazeaubeneix, A Kerouanton, G Delmas, N Pihier, E Couturier
Journal: Eurosurveillance (2006)

Entre aout 2005 et mars 2006, 69 cas de Salmonella enterica serotype Manhattan (Salmonella Manhattan) ont ete recenses en France, dont 51 (74%) dans le sud-est du pays. 
Au moment de l’alerte (novembre 2005), 13 cas et 33 temoins ont ete interroges. La probabilite d’avoir consomme des saucisses de porc (OR=5.9, intervalle de confiance IC [1.3; 26.9]) et de la viande de boeuf (OR=9.3, IC [1.3; 68.6]) etait superieure chez les cas que chez les temoins. Parallelement, 19 souches de Salmonella Manhattan isolees dans des produits a base de viande dans le sud-est de la France et declarees a l’Afssa (Agence francaise de securite sanitaire des aliments) en septembre et novembre 2005, avaient un profil en PFGE indiscernable de celui des 7 isolats humains de Salmonella Manhattan provenant de l’epidemie du sud-est de la France. Les investigations veterinaires ont montre que les echantillons de viande de porc provenaient du grossiste dont les produits avaient ete testes positifs pour S. Manhattan lors d’un controle alimentaire de routine en aout 2005. Ce grossiste fournissait des detaillants dans le sud-est de la France. De plus, une inspection menee aupres de l’abattoir qui fournissait le grossiste a revele une large contamination par Salmonella spp. et S. Manhattan. La cooperation entre les agences nationales responsables de la sante humaine (Institut de veille sanitaire, InVS) et de la securite alimentaire (Afssa) a permis de determiner la source de contamination la plus probable et de prendre les mesures de controle adaptees.