tbuckley/cabot-search huggingface dataset:
Circulating tumor DNA (ctDNA) as a molecular monitoring tool in metastatic breast cancer (MBC).
Authors: Laura Katherine Austin, Paolo Fortina, Dragan Sebisanovic, LaiMun Siew, Aubrey Zapanta, AmirAli Talasaz, Massimo Cristofanilli
Journal: Journal of Clinical Oncology (2014)

11093 Background: MBC is an incurable disease with complex molecular features including somatic mutations that evolve in relation to genomic instability and selective treatment pressure. Circulating DNA fragments carrying tumor-specific sequence alterations (ctDNA) are found in blood and offer the possibility of longitudinal non-invasive molecular monitoring of the disease by detecting actionable mutations. Methods: This is a prospective evaluation of 18 patients with locally advanced or metastatic breast cancer who failed standard therapies and had plasma analyzed for ctDNA detection. Selection criteria: progression of disease after standard therapies, need to detect novel molecular abnormalities for possible therapeutic targeting, or confirmation of genomic abnormalities already demonstrated in tissue analysis. Guardant Health performed the plasma analysis; first ctDNA was isolated from plasma using a Qiagen circulating nucleic acid kit, then a panel of 54 gene mutations associated with solid tumors as reported in the COSMIC database were sequenced using single-molecule digital sequencing technology. Results: 89% of patients had metastatic disease; 55% of patients were ER+/HER2-, 6% ER+/HER2+, 22% ER-/HER2+, 17% ER-/HER2-, and 78% had IBC. All patients with MBC had ctDNA alterations. The most common mutations: TP53 (44%), PIK3CA (44%), ALK (39%), ERBB2 (33%), and EGFR(28%). Seven patients also had NGS analysis of tissue biopsy and 71% of these patients demonstrated having at least one concordant mutation. HER2 targeted therapy was continued in 3 patients with HER2+ disease after ctDNA confirmed ERBB2 alteration or amplification. Moreover, HER2 targeted therapy was initiated on two HER-2 negative patients that had ERBB2 mutations in ctDNA. Two patients were initiated on everolimus (Afinitor) combinations prior to ctDNA testing, had therapeutic benefit and ctDNA revealed alternations in PIK3CA. Conclusions: This is a sensitive test, 100% of patients with MBC had ctDNA alterations. ctDNA offers the possibility of non-invasive genomic analysis of MBC, providing tailored information on mutation status, new molecular targets for therapeutic interventions and allowing molecular monitoring of disease.
Abstract 19956: Differential Effects of Clopidogrel on Platelet Activation Measured by Annexin Binding vs. Platelet Aggregation: An Explanation for Rapid Antithrombotic Properties Even in the Presence of Clopidogrel "Resistance"
Authors: Paul Gurbel, Kevin Bliden, Mark Antonino, Tania Gesheff, William Herzog, Charles Cummings, Benjamin Dubois, Udaya S Tantry
Journal: Circulation (2010)

Background: The antithrombotic effect of clopidogrel is related primarily to the inhibition of platelet aggregation (PA). However, modulation of coagulation system activity by platelets may also be...
Perspectives prometteuses pour la formation en épidémiologie de terrain en Europe
Authors: Arthur L. Reingold
Journal: Eurosurveillance (2001)

La publication d’une serie d’articles sur differents programmes de formation en epidemiologie de terrain coincide avec le 50eme anniversaire du Service d’Investigation Epidemique (Epidemic Intelligence Service, EIS) des Centers for Disease Control and Prevention (CDC). S’il etait encore en vie, Alex Langmuir, son fondateur, se rejouirait certainement de constater la multiplication et le succes de ces formations en Europe. En Amerique Latine, en Asie et en Afrique egalement, on assiste au bourgeonnement de programmes similaires, visant a doter les professionnels de sante publique des competences pratiques necessaires a une investigation epidemiologique rapide et pertinente dans le monde  reel . Certains sont en cours de developpement et sont proposes par des etablissements universitaires locaux, d’autres impliquent un partenariat formel avec le CDC, d’autres encore resultent des efforts isoles d’agences locales de sante publique.
Impact of Chronic Total Occlusion Location on LV Function in ST-Segment Elevation Myocardial Infarction Patients
Authors: Joëlle Elias, Loes P. Hoebers, Ivo M. van Dongen, Bimmer E.P.M. Claessen, René J. van der Schaaf, Jan G. Tijssen, Alexander Hirsch, José P.S. Henriques
Journal: Journal of the American College of Cardiology (2017)
Hybrid Cellular Metabolism Coordinated by Zic3 and Esrrb Synergistically Enhances Induction of Naive Pluripotency
Authors: Masamitsu Sone, Nobuhiro Morone, Tomonori Nakamura, Akito Tanaka, Keisuke Okita, Knut Woltjen, Masato Nakagawa, John E. Heuser, Yasuhiro Yamada, Shinya Yamanaka, Takuya Yamamoto
Journal: Cell Metabolism (2017)
Caring about what happens to people with COPD
Authors: Nicholas S Hopkinson
Journal: Thorax (2017)

Even in an adequately resourced system, admission to hospital with an acute exacerbation of COPD (AECOPD) could be a frightening and unpleasant experience for patients with the condition and for their relatives. Unfortunately, the UK Government has made a political choice to underfund the National Health Service (NHS) by more than £20 billion per year by 2020 and there has already been a 26% cut in the number of people over 65 receiving local authority social care since 2010.1 The latest report from the UK's 2014 National COPD audit programme— COPD: who cares when it matters most? 2 warns of patients ‘on a continuous cycle of admission’ with an ‘overriding impression provided by the data of a system that is not only stressed, but is ultimately failing COPD patients’. The report found that 8% of patients discharged following an AECOPD died within 90 days of admission, 25% were readmitted within 30 days and 43% within 90 days. Fewer than half (43%) of the readmissions were due to COPD. The number of prior admissions to hospital was associated with postdischarge mortality and subsequent readmission risk. Readmission was much more likely in those with a longer length of stay and in patients who had been discharged to sheltered accommodation.

In Thorax , Echevarria and colleagues describe the development of a new prognostic tool for use in patients admitted with an AECOPD.3 The initial derivation and subsequent validation cohorts, including six UK centres, were those that were also used in the development of the Dyspnoea, Eosinopenia, Consolidation, Acidaemia, and atrial Fibrillation (DECAF) score, a tool to identify patients who can be safely discharged.4 ,5 Patient characteristics, selected on the basis of literature review and clinical plausibility, and which were consistently recorded across sites, were related to the risk of readmission or death …
Modeling Renal Cell Carcinoma in Mice: <i>Bap1</i> and <i>Pbrm1</i> Inactivation Drive Tumor Grade
Authors: Yi-Feng Gu, Shannon Cohn, Alana Christie, Tiffani McKenzie, Nicholas Wolff, Quyen N. Do, Ananth J. Madhuranthakam, Ivan Pedrosa, Tao Wang, Anwesha Dey, Meinrad Busslinger, Xian-Jin Xie, Robert E. Hammer, Renée M. McKay, Payal Kapur, James Brugarolas
Journal: Cancer Discovery (2017)

Clear cell renal cell carcinoma (ccRCC) is characterized by BAP1 and PBRM1 mutations, which are associated with tumors of different grade and prognosis. However, whether BAP1 and PBRM1 loss causes ccRCC and determines tumor grade is unclear. We conditionally targeted Bap1 and Pbrm1 (with Vhl) in the mouse using several Cre drivers. Sglt2 and Villin proximal convoluted tubule drivers failed to cause tumorigenesis, challenging the conventional notion of ccRCC origins. In contrast, targeting with PAX8, a transcription factor frequently overexpressed in ccRCC, led to ccRCC of different grades. Bap1-deficient tumors were of high grade and showed greater mTORC1 activation than Pbrm1-deficient tumors, which exhibited longer latency. Disrupting one allele of the mTORC1 negative regulator, Tsc1, in Pbrm1-deficient kidneys triggered higher grade ccRCC. This study establishes Bap1 and Pbrm1 as lineage-specific drivers of ccRCC and histologic grade, implicates mTORC1 as a tumor grade rheostat, and suggests that ccRCCs arise from Bowman capsule cells.Significance: Determinants of tumor grade and aggressiveness across cancer types are poorly understood. Using ccRCC as a model, we show that Bap1 and Pbrm1 loss drives tumor grade. Furthermore, we show that the conversion from low grade to high grade can be promoted by activation of mTORC1. Cancer Discov; 7(8); 900-17. ©2017 AACR.See related commentary by Leung and Kim, p. 802This article is highlighted in the In This Issue feature, p. 783.
Collagen V and decorin is involved in systemic sclerosis pulmonary fibrosis
Authors: Patricia Martin, Ana Paula Velosa, Adriana Santos, Solange Carrasco, Angela Santos, Edwin Parra, Claudia Goldenstein-Schainberg, Natalino Yoshinari, Vera Capelozzi, Teodoro Walcy
Journal: European Respiratory Journal (2011)

Background: Systemic sclerosis (SSc) is characterized by vasculopathy, inflammation, autoimmunity and fibrosis. Collagen V (COLV) is involved in SSc since immunization of health rabbits with this protein induces an experimental model reproducing pathogenic manifestation of disease. We have demonstrated an increased amount of unusual COLV in SSc lung patients indicating a role for this protein in fibrosis. Fibrosis can be induced by cytokines and cell-matrix interactions that involves signalization mechanism. COLV and decorin participate of this mechanism interfering with fibrilogenesis.

Objectives: To evaluate COLV and decorin in tissue and to characterize COLV lung fibroblasts culture biochemically.

Methods: We evaluated COLV and decorin expression and tridimensional reconstruction by immunofluorescence in SSc patients without pulmonary hypertension that underwent surgical lung biopsy (n=6) and health controls from trauma (n=6). Biochemical characterization of COLV from lung fibroblasts culture used quantitative imunoblotting.

Results: COLV fibers was distorted and thickened in SSc lung tissue compared to thin fibers of controls. Decorin was distributed around COLV fibrils in the bronchovascular interstitium and vascular walls. Histomorphometric analysis of SSc demonstrated increased expression of COLV (p<0,01) and decorin (p=0,01) when compared to control. Imunoblotting detected an increased high molecular weight COLV fraction in SSc (p=0.02).

Conclusion: Over expression and unusual organization of COLV fibers with biochemical changes associated to increased decorin indicates that matrix signalization pathway is involved in COLV fibrillogenesis process in SSc pulmonary fibrosis.
Severe eosinophilic asthma: a roadmap to consensus
Authors: Roland Buhl, Marc Humbert, Leif Bjermer, Pascal Chanez, Liam G. Heaney, Ian Pavord, Santiago Quirce, Johann C. Virchow, Stephen Holgate
Journal: European Respiratory Journal (2017)

Asthma is widely accepted as a complex heterogeneous condition with diverse pathophysiological mechanisms, clinical presentations, comorbidities, physiological characteristics, pathology and outcomes that is typically best managed by a multidisciplinary team [1–4]. Severe asthma is recognised as a major unmet need with a high personal and social impact, as well as a high burden on healthcare resources [4]. As a consequence of advances in the development of precision medicines for patients with severe asthma, the need to identify asthma subtypes by phenotype based on clinical, functional or inflammatory parameters is becoming a mandatory part of management [4–6]. A task force has identified key consensus issues for defining, diagnosing and treating severe eosinophilic asthma <http://ow.ly/zrvO30axYWx> The contents of this paper reflect the discussions between attending participants at the European Consensus Meeting for Severe Eosinophilic Asthma (November 24 2016, Amsterdam, The Netherlands) where medical attendees from TEVA Pharmaceuticals Europe B.V. were present as observers. The authors have been given full editorial control and independence and TEVA has had no influence on the contents. The following members of the expert group made important contributions at the initial meeting and/or made useful comments on earlier drafts of this editorial: Ratko Djukanovic (University of Southampton, Southampton, UK), Kian Fan Chung (Imperial College, London, UK), Walter Canonica (Humanitas University, Milan, Italy), Alberto Papi (Ferrara University, Ferrara, Italy), Chris Brightling (University of Leicester, Leicester, UK), Ildiko Horváth (Semmelweis University, Budapest, Hungary), Samantha Walker (Asthma UK, London, UK), Guy Brusselle (Ghent University Hospital, Ghent, Belgium), Vibeke Backer (Bispebjerg Hospital, Copenhagen, Denmark), Piotr Kuna (University of Lodz, Lodz, Poland), Elisabeth Bel (University of Amsterdam, Amsterdam, The Netherlands), Luis Perez de Llano (Lucus Agusti University Hospital, Lugo, Spain), and Klaus Rabe (University of Kiel, Kiel, Germany).
Euroflow-Based Immunophenotypic Characterization of CD34+ Cell Compartment in Juvenile Myelomonocytic Leukemia (JMML): A New Tool for Differential Diagnosis
Authors: Giuseppe Gaipa, Cristina Bugarin, Sergio Matarraz, Chiara Buracchi, Lukasz Sedek, Vincent H.J. van der Velden, Tomasz Szczepanski, Alita van der Sluijs, Elaine Sobral da Costa, Michaela Novakova, Ester Mejstrikova, Carmen Aanei, Jacques JM van Dongen, Andrea Biondi, Alberto Orfao
Journal: Blood (2016)
Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis
Authors: Bradley N. Smith, Simon D. Topp, Claudia Fallini, Hideki Shibata, Han-Jou Chen, Claire Troakes, Andrew King, Nicola Ticozzi, Kevin P. Kenna, Athina Soragia-Gkazi, Jack W. Miller, Akane Sato, Diana Marques Dias, Maryangel Jeon, Caroline Vance, Chun Hao Wong, Martina de Majo, Wejdan Kattuah, Jacqueline C. Mitchell, Emma L. Scotter, Nicholas W. Parkin, Peter C. Sapp, Matthew Nolan, Peter J. Nestor, Michael Simpson, Michael Weale, Monkel Lek, Frank Baas, J. M. Vianney de Jong, Anneloor L. M. A. ten Asbroek, Alberto Garcia Redondo, Jesús Esteban-Pérez, Cinzia Tiloca, Federico Verde, Stefano Duga, Nigel Leigh, Hardev Pall, Karen E. Morrison, Ammar Al-Chalabi, Pamela J. Shaw, Janine Kirby, Martin R. Turner, Kevin Talbot, Orla Hardiman, Jonathan D. Glass, Jacqueline De Belleroche, Masatoshi Maki, Stephen E. Moss, Christopher Miller, Cinzia Gellera, Antonia Ratti, Safa Al-Sarraj, Robert H. Brown, Vincenzo Silani, John E. Landers, Christopher E. Shaw
Journal: Science Translational Medicine (2017)

Annexin A11 mutations, implicated in ALS, prevent binding to calcyclin and induce the formation of cytoplasmic inclusions.
Investigating the utilization of pharmacokinetic-guided fluorouracil in colorectal cancer.
Authors: Jai Narendra Patel, Bert H. O'Neil, Howard L. McLeod, Gary Bradley Sherrill, Oludamilola Olijade, John J. Inzerillo, Prashanti Atluri, Christopher H. Chay, Christine Marie Walko
Journal: Journal of Clinical Oncology (2012)

e13109 Background: Fluorouracil (FU) has remained the cornerstone of colorectal cancer (CRC) therapy for &gt; 40 years; however, recent evidence suggests inter-individual pharmacokinetic (PK) variability in response. Methods: A total of 58 CRC patients from 6 academic and community sites received mFOLFOX6 (FU 2400 mg/m 2 over 46 hours every 2 weeks) +/- bevacizumab. FU doses for cycles 2-4 were adjusted based on an algorithm to target an AUC of 20-25 mg*h/L. Peripheral blood was obtained 2-46 hours post beginning of infusion (BOI) and AUCs were determined using an immune-based assay (OnDose ). The primary objective of this study is to describe the feasibility of PK-guided FU in clinical practice using descriptive statistics with a secondary objective of toxicity assessment. Results: Mean AUC post cycle 1 in evaluable patients (n=39) was 19.8 +/- 6.3 mg*h/L (range 7-38) with 31% within, 51% under, and 18% over the AUC target. Based on cycle 1 results, the mean dose estimated to achieve AUC 20-25 mg*h/L would be 2,505 +/- 304 mg/m 2 (range 2,040-3,600). For cycle 1, the mean AUC at 2 and 18-24 hours post BOI was 17.5 +/- 6.9 and 21.6 +/- 6.3, respectively. Of 58 patients, 19 were not evaluable due to logistical issues such as sampling errors, dosage deviation from protocol, no stabilizing agent added to sample, or the patient was unable to return to clinic for sampling. Three hospitalizations due to serious adverse events occurred, with 2 at AUCs &gt; 30. See the table for toxicities. Conclusions: Significant heterogeneity is noted in FU AUC with BSA-based dosing, with the majority of patients below the protocol-specified AUC threshold. Although FU should be at steady-state 2 hours post BOI until the end of infusion, a difference in AUC was seen between samples taken at 2 and 18-24 hours. With little study withdrawal observed after initial patient enrollment, appropriate logistical training can allow for individualization of FU in the front-line, community setting for the treatment of CRC; however, larger clinical trials are needed to define the clinical utility of PK-guided FU. [Table: see text]
Association of circulating VEGF-A levels with outcome in patients with vascular sarcomas receiving sorafenib (Sor): Exploratory analysis from AngioNext study.
Authors: Christine Bal-Mahieu, Charles Fournier, Isabelle Ray-Coquard, Christine Chevreau, Axel Le Cesne, Antoine Italiano, Emmanuelle Bompas, Yves Marie Robin, Jacques-Olivier Bay, Sophie Piperno-Neumann, Nicolas Isambert, Brigitte Baldeyrou, Amelie Lansiaux, Jean-Yves Blay, Stephanie Clisant, Nicolas Penel
Journal: Journal of Clinical Oncology (2013)

10525 Background: We have carried out a stratified phase II study of Sor in pts with advanced angiosarcoma (AA, n=32), malignant solitary tumour (SFT, n=4) &amp; epithelioid hemangioendothelioma (EE, n=13). We report here the correlative analysis of predictive value of circulating pro/anti-angiogenetic biomarkers. Methods: Using ELISA method (R&amp;D SYSTEMS) Circulating biomarkers (VEGF-A [pg/mL], Thrombospondin-1 (TSP1) [µg/mL], Stem Cell Factor (SCF) [pg/mL], Placental growth factor (PlGF) [pg/mL], VEGF-C [pg/mL] &amp; E-selectin [ng/mL]) have been measured before Sor treatment &amp; after 7 days. We analyze the correlation with histological subtypes, presence of metastases, best response and occurrence of hemorrhage and Gr3-4 arterial hypertension. Results: VEGF-A (mean value 475 vs 541 pg/mL, p=0.002), TSP1 (16 vs 24 µg/mL, p=0.0002), PlGF (20.9 vs 40.7 pg/mL, p=0.0001) significantly increased during the treatment. Sor treatment did not affect the levels of SCF, VEGF-C &amp; E-selectin. The distributions of all biomarkers were similar across the histological subtypes, whatever the presence of metastasis, the occurrence of hemorrhage or arterial hypertension. 2 biomarkers were associated with better outcome:VEGF-A &amp; PlGF. Best objective response and non-progression at 180 days were associated with low level of VEGF-A at baseline (p=0.04 and p= 0,03 respectively). There was a correlation between circulating level of VEGF-A &amp; time to progression (TTP) (r=-0.47, p=0.001). Best objective response and non-progression at 180 days were not associated with baseline level of PlIGF (p=0.34 and 0.07), but there was a correlation between circulating level of PlIGF at baseline and TTP (-0.31, p=0.02). Conclusions: In pts with vascular sarcomas receiving Sor, we have observed a significant decrease in circulating level of VEGF-A. Low level of VEGF-A at baseline (&lt;500 pg/mL) was significantly associated with better outcome, especially best objective response rate, non-progression at 180 days and time to progression. Clinical trial information: 2007-004651-10.
Marginal resection for osteosarcoma: Long-term outcomes.
Authors: Norio Yamamoto, Akihiko Takeuchi, Toshiharu Shirai, Katsuhiro Hayashi, Hiroaki Kimura, Kentaro Igarashi, Hiroyuki Tsuchiya
Journal: Journal of Clinical Oncology (2012)

e20505 Background: When a favorable response to chemotherapy is clinically obtained, we usually perform intentional marginal resection, which preserves the surrounding areas that are normally resected, such as ligament, nerves, blood vessels, and epiphysis region. We report on the long-term outcomes of osteosarcoma patients who underwent the combination therapy and subsequently underwent intentional marginal resection. Methods: The subjects were 43 patients with osteosarcoma. The mean age was 15 years and the mean follow-up period was 101 months. Tumors were Enneking’s surgical stage IIB in 36 patients and IIIB in 7 patients. The patients received preoperatively 3-5 courses of intraarterial fusion of caffeine combined with CDDP and ADM. The effectiveness of chemotherapy was evaluated using plain x-ray, angiography, MRI, and thallium scintigraphy. If the results of two or more imaging examinations showed effectiveness of the treatment, the patient was considered to have a complete response or partial response. Results: The treatment was effective in 14 patients (Grade III) and 29 patients (Grade IV) by histological evaluation (Rosen &amp; Huvos) that correlated with the results of imaging evaluation. Limb function was evaluated according to ISOLS scoring system, excellent is 32 patients (74.4%), good in 7 patients (16.3%), fair in 3 patients (7.0%), and poor in 1 patient (2.3%). Local recurrence was observed in only 2 patients (4.7%). For stage IIB patients, both 5- and 10-year cumulative survival rates were 93.8%. The outcome (IIB + IIIB) was CDF in 26 patients, NED in 8 patients, AWD in 1 patient, and DOD in 7 patients. Conclusions: It is important to minimize surgical margin and to preserve healthy tissue and important structures for improving the function of the affected limb and providing optimal quality of life for the osteosarcoma patients. In the present study, intentional marginal resection was performed in osteosarcoma patients who were clinically obtained favorable responses to a combination of chemotherapy and caffeine administration. They had a good clinical course and there was no negative effect on the survival rate or local recurrence rate.
Clinical governance and the role of NHS boards: learning lessons from the case of Ian Paterson
Authors: Kieran Walshe, Naomi Chambers
Journal: BMJ (2017)

Medicine’s enduring professional “club” culture must be eradicated

Last week, surgeon Ian Paterson was found guilty of 17 counts of wounding with intent to cause grievous bodily harm, in relation to 10 patients who had needless surgery at the Spire hospitals in the Midlands.1 These cases were just a sample of a larger number of patients he had harmed while working in the NHS and privately. The Heart of England NHS Foundation Trust (HEFT) has already spent almost £18m (€21m; $23m) on 265 claims for compensation; solicitors are bringing a civil class action on behalf of a further 350 women against both Spire Healthcare and the NHS; and it is thought there could be hundreds of other victims.2 Paterson did breast surgery on over 4400 women at HEFT during his time there, including 1207 mastectomies, and an unknown number of procedures in the private sector.3

In 2013 the trust published the report from an inquiry it commissioned from Sir Ian Kennedy.4 It sets out how problems with Paterson’s clinical performance were …