tbuckley/cabot-search huggingface dataset:
Next generation sequencing (NGS) as a useful tool to identify clinically meaningful somatic and germinal variants in the early stages of non-small-cell lung cancer (NSCLC).
Authors: Javier De Castro, Carlos Rodriguez Antolin, Olga Pernia, Elena Vallespin Garcia, Patricia Cruz, Rocio Rosas Alonso, Virginia Martinez, Angela Del Pozo Mate, Oliver Higuera Gomez, Kristina Ibáñez, Prudencio Diaz Agero, Julian Nevado Blanco, Inmaculada Ibañez de Cáceres
Journal: Journal of Clinical Oncology (2016)

e20068 Background: This is an innovative project that aims to implement NGS to detect new genetic alterations in the early stages of NSCLC and their potential role as biomarkers of the tumoral evolution or monitoring NSCLC patients (p) who have initially undergone surgery. Methods: 15 surgical and blood samples were collected from surgically treated NSCLC p in stage I-IIIA. PBMCs and tumor samples were prepared using the TruSight Cancer sequencing Panel representing 94 genes associated to a cancer predisposition. PBMC and tumor DNA were sequenced on the Illumina System. Somatic variants taken from matched tumor-PBMC p samples was carried out with VarScan and MuTect, and the variants were selected according to the potential or known clinical relevance. P were followed-up and further blood samples were collected, thus both DFS and OS were analysed. Results: Histology: adenocarcinoma: 13 p and squamous tumors: 2 p. Tumoral stages: IA: 6p, IB: 2p, IIA: 4p, IIB: 2p and IIIA: 1 p. We have established a pipeline that allowed the identification of somatic and/or germinal mutations in paired samples from tumor and PBMC´s DNA. From the obtained variant data we found 37/94 (39,36%) genes from the Panel that presented any kind of frequent missense mutation associated with Germinal, LOH and/or somatic or splice sites disruption in at least one p. 3/37 (SLX4, NF1 and TP53) genes are represented in 30% of the p with some of the described mutations. For SLX4 and NF1 we found variations with uncertain clinical relevance. We highlight the significant and frequent presence of Fanconi anemia (FA) pathway mutations in 80% (12/15) of the analysed p. In addition, only 12/37 carried exclusively somatic variants in 11/15 analysed p. Conclusions: With the help of NGS technology we found pathologic variants potentially associated to the biology of NSCLC. The identified somatic mutations could be valuable potential markers to be used in further studies in ffcDNA, in terms of early detection and follow-up studies in NSCLC p. Although the Panel is limited and validation is needed, these findings may be useful for screening and relapsing this pathology and identifying novel therapeutical targets.
Effect of Dronedarone on Cardiovascular Events in Atrial Fibrillation
Journal: New England Journal of Medicine (2011)

Background: Dronedarorie is a new antiarrhythniie drug that is being developed (or the treatment of patients with alnal iihrillalion. Methods: We conducted a multiceuter trial to evaluate the use of dronedarone in 4628 patienls with atrial fibrillation who had additional risk factors for death. Patients wen.' randomly assigned lo receive dronedarone, 400 mg twice a day, or placebo. The primary outcome was the first hospitalization due to cardiovascular e\ents or death. Secondary outcomes were death from any cause, death from cardiovascular causes, and hospilahzalion due to cardiovascular events. Results: The mean follow-up period was 21±5 months, with the study drug discontinued prematurely in 696 of the 2301 patients (30.2%) receiving dronedarone and in 716 of the 2327 patients (30.8%) receiving placebo, mostly because of adverse events. The primary outcome occurred in 734 patients (31 .9%) in the dronedarone group and in 9i7 patients (39.4%) in the placebo group, with a hazard ratio for dronedarone ol 0.76 (95% confidence interval [CIJ. 0.69 to 0.84; P<0.001). There were 1 16 deaths (5.0%) in the dronedarone group and 139 (6.0%) in the placebo group (hazard ratio, 0.84; 95% Cl. 0.66 to 1 .08: P = 0.18). There were 63 deaths from cardiovascular causes (2.7%) in the dronedarone group and 90 (3.9%) in ihe placebo group (hazard ratio. 0.71; 95% CI. 0.51 to 0.98; P = 0.03). largely due to a reduction in (he rale of death from arrhythmia with dronedarone. The dronedarone group had higher rates of bradycardia, QT-interval prolongation, nausea, diarrhea, rash, and an increased serum creatinine level than the placebo group. Hales of ihyroid- and pulmonary-related adverse events were nol significantly different between the two groups. (Conclusion: Dronedarone reduced the incidence of. hospitalization due to cardiovascular events or death in patients with atrial fibrillation. (ChnicalTrials.gov number. NCTOO 174785.).
Torsades de Pointes Occurring in Association With Terfenadine Use
Authors: David R. Mathews
Journal: JAMA (1991)

<h3>To the Editor.</h3> —Monahan et al<sup>1</sup>reported a case of torsades de pointes after concomitant administration of terfenadine (Seldane) and ketoconazole (Nizoral). We would like to comment on this report and share results from subsequent studies at Marion Merrell Dow Inc, Kansas City, Mo. Terfenadine normally undergoes extensive (99%) first-pass metabolism to two metabolites: an active acid metabolite and an inactive dealkylated metabolite. Therefore, unchanged terfenadine is normally undetectable (ie, &lt;10 ng/mL) in plasma. However, in cases of hepatic impairment or when certain concurrent medications (eg, ketoconazole) inhibit the metabolism of terfenadine, unchanged terfenadine can become detectable in plasma while metabolite formation is decreased. In cases of terfenadine overdose, unchanged terfenadine can become detectable and acid metabolite levels increase.<sup>2</sup> In a study of 24 subjects given a single 60-mg dose of terfenadine, the mean peak plasma acid metabolite level was 263 ng/mL and occurred 2.5 hours after dosing.
Engineered mesenchymal stem cells as vectors in a suicide gene therapy against preclinical murine models for solid tumors
Authors: Ikrame Amara, Elodie Pramil, Catherine Senamaud-Beaufort, Audrey Devillers, Rodney Macedo, Géraldine Lescaille, Johanne Seguin, Eric Tartour, François M. Lemoine, Philippe Beaune, Isabelle de Waziers
Journal: Journal of Controlled Release (2016)
Authors’ reply to Page and Rafi
Authors: Jennifer Zeitlin, Bradley N Manktelow, Aurelie Piedvache, Marina Cuttini, Elaine Boyle, Arno van Heijst, Janusz Gadzinowski, Patrick Van Reempts, Lene Huusom, Tom Weber, Stephan Schmidt, Henrique Barros, Dominico Dillalo, Liis Toome, Mikael Norman, Beatrice Blondel, Mercedes Bonet, Elisabeth S Draper, Rolf F Maier
Journal: BMJ (2016)

We agree with Page and Rafi about the importance of identifying the key evidence based obstetric and neonatal interventions that can be monitored to assess quality of care for very preterm infants.1 2 As our study shows,3 evaluating the use and impact of four evidence based practices together sets higher standards and focuses attention on care processes. The EPICE (Effective Perinatal Intensive Care in Europe) project’s international dimension is a strength, as it reveals underuse of evidence based care in many health systems and cultures.

But international …
The First Strictly Full-time Professor of Medicine in an American Medical School: Hopkins, Not Michigan-Reply
Authors: W. Bruce Fye
Journal: JAMA (1991)

<h3>In Reply.</h3> —Dr Weisse's claim that George Dock of the University of Michigan was the first full-time professor of medicine in an American medical school is not supported by the contemporary printed and manuscript evidence. The problem, I believe, stems from the multiple definitions that have been applied to the term "full-time." In my essay, I pointed out that I was discussing the original<i>strict</i>full-time system that prohibited clinical professors from earning any income from private practice. This plan was first instituted at Johns Hopkins in 1913, as was detailed in my article. Horace Davenport has written extensively on George Dock and the University of Michigan. His writings indicate that Dock had a private practice while he was professor of medicine at Michigan.<sup>1</sup>Davenport acknowledged that Michigan did not adopt the strict full-time system before Johns Hopkins. He wrote: "One reason Michigan had trouble finding a successor to
Influence of market access conditions on utilization of innovative drugs in Europe: Example of bevacizumab.
Authors: M. Toumi, J. Misset, L. Krukowski, S. Aballea, M. Lamure
Journal: Journal of Clinical Oncology (2010)

e12001 Background: Market access conditions of innovative drugs are expected to affect their utilization. Prices of recently launched monoclonal antibodies are relatively high and their accessibility differs between European countries. Bevacizumab (BVZ) was granted full access in Germany and France, but was rejected in United Kingdom. It was subject in Italy to payment by performance with a 50% discount for the first 6 weeks and free after 11 to 15 cycles. In France funding of BVZ is not charged by hospital budget (paid on top of Diagnostic-Related Group [DRG]). Methods: We reviewed how such differences might affect usage of BVZ in France, Germany, Italy, and the United Kingdom. Data on drug utilization from June 2006 to July 2009 were extracted from the Oncology Monitor database (Synovate). The Synovate Oncology Monitor covers over 20 countries and is an ongoing database tracking prescribing of anticancer therapies for patients within and across tumors over time. Total sample size varied between countries, from 7,766 to 9,463 patients within the year ending 2009 Q2. Results: Utilization rates over the period July 2008-June 2009 are shown below (Table) as percentage of patients receiving BVZ for France, Germany, and Italy by cancer type. The usage in the United Kingdom is below 1%. Dosages used and patient profiles were comparable across countries. Over the 3-year period the utilization was stable in France, increased slowly in Germany, and faster in Italy. Colorectal cancer represents the first indication for BVZ (56% Germany; 62% France; 75% Italy). Conclusions: Funding on top of DRG does not appear to increase drug usage, but contributes to early uptake. Health technology assessment conclusions influence utilization strongly. Payment by performance seems associated with significant development of drug penetration. The disparity of access for cancer patients raises the issue of associated outcome and equity. France Germany Italy Colorectal cancer 18% 14% 21% Non-small cell lung cancer 4% 5% 3% Breast cancer 3% 2% 2% Renal cell cancer 4% 4% 5% Brain cancer 6% 4% 1% No significant financial relationships to disclose.
Screening assessment of the burden of disease due to air pollution in eleven Polish agglomerations
Authors: Artur Badyda, James Grellier
Journal: European Respiratory Journal (2014)

Background   75% of Europeans live in cities (in Poland, 61%). The European Environment Agency estimates that exposure to concentrations of PM10 and PM2.5 above the limit values in cities of the EU concerns 20-33% of the population (and 85-96%, when taking into account the WHO guidelines).   Material   We used data from the Polish State Environmental Monitoring on concentrations of PM2.5 and PM10 in 11 urban areas (with over 250,000 inhabitants) from the years 2006-2011 and data on mortality due to lung cancer, IHD, cardiopulmonary diseases, and on total non-violent mortality from the same period. Using the exposure-response functions defined by Pope et al., JAMA 2002; 287:1132-1141 and Krewski et al., HEI 2009 (research report) we assessed the burden of diseases attributable to exposure to ambient PM pollution.   Results   In the analysed period the annual mean concentration of PM10 exceeded the EU reference levels in 7 (out of 11) cities (in 8 the PM2.5 level was exceeded). In 5 of the considered cities the concentrations of PM2.5 and PM10 were higher in 2011 comparing to 2006. Due to the relatively high concentrations of PM in Polish cities (one of the largest in the EU) population attributable fraction is also relatively high. Average PAF varied depending on the year and city from 0.10 to 0.53 for mortality due to lung cancer, from 0.15 to 0.53 for IHD and from 0.07 to 0.39 for all cardiopulmonary diseases.   Conclusion   A significant part of Polish cities population is exposed to concentrations exceeding the allowable PM level. This results in persistently high and even increasing rates of people dying from lung cancer, IHD or cardiopulmonary diseases due to the poor air quality.
Outcomes for UK service personnel indicate high quality trauma care and rehabilitation
Authors: John Etherington, Alexander N Bennett, Rhodri Phillip, Alan Mistlin
Journal: BMJ (2016)

Greenberg and colleagues highlight the health outcomes of the Iraq war.1 The multidisciplinary clinical teams of Headley Court have worked to enhance the outcomes of severely injured British battle casualties. Enhanced survivability has, by increasing the number of “unexpected survivors,” resulted in considerable rehabilitation challenges.

At discharge, 95% (62) of complex trauma patients are independent in all activities of daily …
SWOG 1211: Initial Report on PHASE I Trial of RVD-Elotuzumab for NEWLY Diagnosed High Risk Multiple Myeloma (HRMM)
Authors: Saad Z. Usmani, Rachael Sexton, Sikander Ailawadhi, Jatin J. Shah, Natalie S Callander, Todd Zimmerman, Jason Valent, Michael Rosenzweig, Brea C. Lipe, Jeffrey Zonder, Sandi Fredette, Brian G. M. Durie, Antje Hoering, S. Vincent Rajkumar, Paul G. Richardson, Robert Z. Orlowski
Journal: Blood (2014)
Patents: problem or panacea?
Authors: Chika E Uzoigwe, Jonathan McCann, George Iacob
Journal: BMJ (2016)

The cost of hepatitis C treatment has caused alarm.1 The exclusivity provided by patents allows Gilead considerable price control. The primary patent relating to the structure of sofosbuvir expires in 2024.2 The term of a patent is 20 years.3

Mazzucato argues that one way of improving accessibility is by curtailing patent longevity.1 However, EU and …
Impact Of HLA Allele and Haplotype On Acute Graft-Versus-Host Disease and Survival After Hematopoietic Stem Cell Transplantation From Unrelated Donor
Authors: Morishima Satoko, Koichi Kashiwase, Fumihiro Azuma, Toshio Yabe, Aiko Sato-Otsubo, Seishi Ogawa, Takashi Shiina, Masahiro Satake, Hiroo Saji, Shunichi Kato, Yoshihisa Kodera, Takehiko Sasazuki, Yasuo Morishima
Journal: Blood (2013)
Time to Reassess the Cancer Compendia for Off-label Drug Coverage in Oncology
Authors: Angela K. Green, William A. Wood, Ethan M. Basch
Journal: JAMA (2016)

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Therapy and outcomes of primary central nervous system lymphoma (PCSNL) in the United States: Analysis of the National Cancer Data Base (NCDB).
Authors: Lindor Qunaj, Jaleh Fallah, Adam J. Olszewski
Journal: Journal of Clinical Oncology (2016)

2026 Background: Although the role of radiation therapy (RT) and chemotherapy (Ch) in PCNSL has undergone a major evolution over the past decade, the application of these modalities in the community has not been studied. Our objective was to analyze the use of RT and Ch, and associated overall survival (OS), using the NCDB—an oncologic registry capturing ~70% of incident cancers in the US. Methods: We selected histologically confirmed PCNSL cases (diffuse large or unspecified B-cell lymphoma) reported to the NCDB between 2004 and 2012 excluding patients (pts) with HIV+ status. We identified the use of RT and Ch (single- or multiagent) as part of the initial therapy, and assessed factors associated with non-receipt of Ch in a multivariable modified Poisson model, adjusting for immortal-time bias by conditional landmark analysis at 3 months. OS was calculated from diagnosis and analyzed in a multivariable Cox model, reporting hazard ratio (HR) and 95% confidence intervals (CI). Results: Among 6,549 pts (median age, 67 years, 51% women), 71% received Ch (43% multiagent, 17% with RT), 11% RT alone, and 18% no active therapy for PCNSL. Between 2004 and 2012, the proportion receiving Ch increased from 65% to 73% (P for trend < .00001), while the proportion receiving any RT decreased from 36% to 22% (P< .00001). Non-receipt of Ct was significantly associated with age > 70 years, black race, lack of private insurance, higher comorbidity index, and unspecified histology (all P< .0001). Non-receipt of Ct was also significantly lower in academic/research cancer programs compared with community programs (adjusted relative risk, 0.61, CI, 0.49-0.76). OS at 3 years was 34.2% (CI, 32.9-35.5) for all pts, 49% (CI, 47-51) for pts receiving multi-agent Ct, 37% (CI, 34-39) for single-agent Ct, and 10% (CI, 7-12) for RT alone. Adjusting for confounding factors, OS was better after multi-agent Ct than after single-agent Ct (HR, 1.32, CI, 1.22-1.44) or RT alone (HR, 2.32, CI, 2.07-2.59). Conclusions: Disparities in the use of Ch for PCNSL are evident with regard to individual patient and facility characteristics. The proportion receiving Ch for PCNSL is increasing, and multiagent Ch is associated with better OS.
Abstract 14902: The Introduction of Novel Oral Anticoagulants Has Improved Overall Oral Anticoagulation Rates in Atrial Fibrillation: Insights From the NCDR PINNACLE Registry
Authors: Lucas N Marzec, Kensey L Gosch, Paul S Chan, Henry H Ting, Nilay D Shah, Thomas M Maddox
Journal: Circulation (2015)

Introduction: For patients with atrial fibrillation (AF), novel oral anticoagulants (NOACs) provide effective alternatives to warfarin. However, a better understanding is needed of how the introduction of NOAC therapy has improved use of any oral anticoagulation (OAC) for patients with AF. Methods: Within the NCDR PINNACLE registry, we identified 447,770 patients comprising 1,428,660 outpatient encounters with non-valvular AF and CHADS-VASc &gt;1 between April 1, 2008 and September 30, 2014. We examined use of any OAC, any NOAC, and of dabigatran, rivaroxaban, and apixaban individually over time. Multivariable logistic regression was performed to identify factors associated with any OAC and NOAC use at the end of the study period, including CHADS-VASc score, age, weight, CAD, PAD, dyslipidemia, stroke/TIA, heart failure, gender, hypertension, and diabetes. Results: Use of any OAC increased from 52.1 to 61.2% during the study period among patients without a documented contraindication (p for trend &lt;0.01) (Figure). Although warfarin use decreased from 52.1% to 36.8% (p for trend &lt;0.01), use of NOACs increased from 0% to 24.4% (p for trend &lt;0.01). Rivaroxaban was the most frequently prescribed NOAC at the end of the study period (12.1%), followed by dabigatran (6.6%), and apixaban (5.7%). Patient factors associated with use of OAC and NOACs are presented in the Table. Conclusions: In a large U.S. outpatient registry, introduction of NOACs into clinical practice has improved the use of any OAC for AF patients at high risk for stroke. However, more than 1 in 3 high risk patients without a documented contraindication were not treated with any OAC.
Long-Term Experience with FEIBA Prophylaxis for Hemophilia Patients with High Responder Inhibitors: Izmir Experience
Authors: Kaan Kavakli, Can Balkan, Deniz Yilmaz Karapinar, Nihal Ozdemir Karadas, Zuhal Onder Sivis, Burcu Deveci, Akkiz Sahin
Journal: Blood (2014)
Altered Expression of ARP2/3 Complex Signaling Pathway Genes in Prefrontal Layer 3 Pyramidal Cells in Schizophrenia
Authors: Dibyadeep Datta, Dominique Arion, Kaitlyn M. Roman, David W. Volk, David A. Lewis
Journal: American Journal of Psychiatry (2016)

Lower dendritic spine density on layer 3 pyramidal cells in the dorsolateral prefrontal cortex (DLPFC) appears to contribute to cognitive dysfunction in schizophrenia, whereas psychosis is associated with excessive dopamine release in the striatum. These findings may be related via excitatory projections from the DLPFC to the ventral mesencephalon, the location of dopamine cells projecting to the striatum. Consistent with this hypothesis, deletion of the actin-related protein-2/3 (ARP2/3) complex, which regulates the actin cytoskeleton supporting dendritic spines, produced spine loss in cortical pyramidal cells and striatal hyperdopaminergia in mice. The authors sought to determine whether the ARP2/3 complex is altered in schizophrenia.In matched pairs of schizophrenia and comparison subjects, transcript levels of ARP2/3 complex signaling pathway were assessed in laser-microdissected DLPFC layer 3 and 5 pyramidal cells and layer 3 parvalbumin interneurons, and in total DLPFC gray matter.Transcript levels of ARP2/3 complex subunits and of nucleation promotion factors that regulate the ARP2/3 complex were significantly lower in DLPFC layer 3 and 5 pyramidal cells in schizophrenia. In contrast, these transcripts were unaltered, or only modestly changed, in parvalbumin interneurons and DLPFC gray matter.Down-regulation of the ARP2/3 complex signaling pathway, a common final pathway for multiple signaling cascades that regulate the actin cytoskeleton, would compromise the structural stability of spines, leading to their loss. In concert with findings from deletion of the ARP2/3 complex in mice, these findings support the idea that spine deficits in the DLPFC may contribute to subcortical hyperdopaminergia in schizophrenia.