tbuckley/cabot-search huggingface dataset:
Overall survival in COMBI-d, a randomized, double-blinded, phase III study comparing the combination of dabrafenib and trametinib with dabrafenib and placebo as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/Kmutation-positive cutaneous melanoma.
Authors: Georgina V. Long, Daniil Stroyakovskiy, Helen Gogas, Evgeny Levchenko, Filippo G. De Braud, James M. G. Larkin, Claus Garbe, Thomas Jouary, Axel Hauschild, Jean Jacques Grob, Vanna Chiarion-Sileni, Celeste Lebbe, Mario Mandalà, Michael Millward, Douglas James DeMarini, Jhangir G Irani, Fan Jin, R. Suzanne Swann, Bijoyesh Mookerjee, Keith Flaherty
Journal: Journal of Clinical Oncology (2015)

102 Background: This phase III study (NCT01584648) of dabrafenib (D) + trametinib (T) compared with D + placebo (P) demonstrated superior progression-free survival (PFS) for D+T compared with D+P (HR = 0.75 ; 95% CI: 0.57–0.99; p = 0.035) in pts with BRAF V600E/K mutant, metastatic melanoma at the primary analysis (N Engl J Med 2014;371:1877). The interim overall survival (OS) favored D+T (40 deaths on D+T vs 55 on D+P), but did not cross the pre-planned stopping boundary for efficacy. Median time on study at the primary analysis was 9 months (0–16 months). Rates of adverse events (AEs) were similar for both arms. More pts had AEs leading to dose modifications with D+T vs D+P, and fewer hyperproliferative skin AEs were reported with D+T. The study was continued after the primary analysis to evaluate OS without crossover from D+P to D+T. Methods: Pts were randomized 1:1 to receive D (150mg twice daily) + T (2mg once daily) or D+P as first-line therapy. Eligible pts were age 18 or older, ECOG performance status ≤ 1, and had histologically confirmed unresectable stage IIIC or IV, BRAF V600E/K mutant cutaneous melanoma. The primary endpoint was investigator-assessed PFS; secondary endpoints were OS, overall response rate (ORR), duration of response (DoR), and safety. The final statistical OS comparison was to be initiated when 220 events were reported. Results: From May 2012 to January 2013, 423 pts were randomized (211 to D+T, 212 to D+P). The 220th death was reported on Jan 12, 2015; analysis is expected to be completed in Mar 2015. Estimated median time on study at data cut off is 20 months (0-31 months). Conclusions: The statistical analysis will evaluate the superiority of D+T vs D+P for OS. A 2-year OS landmark analysis, updated PFS, ORR, DoR, and safety will be presented. Clinical trial information: NCT01584648.
Things Are Seldom What They Seem
Authors: George E. Thibault
Journal: New England Journal of Medicine (1992)

A 61-year-old man with a long history of heavy alcohol use went to the emergency room with symptoms of abdominal pain, early satiety, and a 10-lb weight loss. His wife had died seven months earlier, and he had been depressed ever since. He said that he was no longer drinking any alcohol.A man with a history of alcohol abuse is now reporting three new symptoms: abdominal pain, early satiety, and weight loss. Abdominal pain in an alcoholic can be caused by a number of things, including gastritis, pancreatitis, portal-vein thrombosis, and (if there is cirrhosis) a hepatoma. If I . . .
Neutrophil Chemotactic Activity in Antigen-Induced Late Asthmatic Reactions
Authors: Lajos Nagy, Tak H. Lee, A. B. Kay
Journal: New England Journal of Medicine (1982)

Nine patients with bronchial asthma who had early and late falls in forced expiratory volume in one second (FEV1)(10 minutes and six hours, respectively) after inhalational challenge with specific antigens were studied for the presence of circulating neutrophil chemotactic activity (NCA). NCA was detected during both the early and the late asthmatic responses; the time course of appearance of NCA in the circulation paralleled that of the falls in FEV1. In contrast, five patients with asthma who had early reactions had only a single early peak of NCA, with no further rise for up to 24 hours. The NCA detected during early and late reactions eluted with macromolecules of an estimated molecular weight greater than 500,000 daltons when applied separately to columns of Sephadex G-200. Since high-molecular-weight NCA is believed to be associated with mast cells, these observations support the view that mediators of hypersensitivity are released in both the late and the early asthmatic responses.
Impact of the gut microbiota on inflammation, obesity, and metabolic disease
Authors: Claire L. Boulangé, Ana Luisa Neves, Julien Chilloux, Jeremy K. Nicholson, Marc-Emmanuel Dumas
Journal: Genome Medicine (2016)

The human gut harbors more than 100 trillion microbial cells, which have an essential role in human metabolic regulation via their symbiotic interactions with the host. Altered gut microbial ecosystems have been associated with increased metabolic and immune disorders in animals and humans. Molecular interactions linking the gut microbiota with host energy metabolism, lipid accumulation, and immunity have also been identified. However, the exact mechanisms that link specific variations in the composition of the gut microbiota with the development of obesity and metabolic diseases in humans remain obscure owing to the complex etiology of these pathologies. In this review, we discuss current knowledge about the mechanistic interactions between the gut microbiota, host energy metabolism, and the host immune system in the context of obesity and metabolic disease, with a focus on the importance of the axis that links gut microbes and host metabolic inflammation. Finally, we discuss therapeutic approaches aimed at reshaping the gut microbial ecosystem to regulate obesity and related pathologies, as well as the challenges that remain in this area.
Reduced Circumferential Resection Margin Involvement in Rectal Cancer Surgery: Results of the Dutch Surgical Colorectal Audit
Authors: Lieke Gietelink, Michel W.J.M. Wouters, Pieter J. Tanis, Marion M. Deken, Martijn G. ten Berge, Rob A.E.M. Tollenaar, J. Han van Krieken, Mirre E. de Noo
Journal: Journal of the National Comprehensive Cancer Network (2015)

The circumferential resection margin (CRM) is a significant prognostic factor for local recurrence, distant metastasis, and survival after rectal cancer surgery. Therefore, availability of this parameter is essential. Although the Dutch total mesorectal excision trial raised awareness about CRM in the late 1990s, quality assurance on pathologic reporting was not available until the Dutch Surgical Colorectal Audit (DSCA) started in 2009. The present study describes the rates of CRM reporting and involvement since the start of the DSCA and analyzes whether improvement of these parameters can be attributed to the audit.Data from the DSCA (2009-2013) were analyzed. Reporting of CRM and CRM involvement was plotted for successive years, and variations of these parameters were analyzed in a funnelplot. Predictors of CRM involvement were determined in univariable analysis and the independent influence of year of registration on CRM involvement was analyzed in multivariable analysis.A total of 12,669 patients were included for analysis. The mean percentage of patients with a reported CRM increased from 52.7% to 94.2% (2009-2013) and interhospital variation decreased. The percentage of patients with CRM involvement decreased from 14.2% to 5.6%. In multivariable analysis, the year of DSCA registration remained a significant predictor of CRM involvement.After the introduction of the DSCA, a dramatic improvement in CRM reporting and a major decrease of CRM involvement after rectal cancer surgery have occurred. This study suggests that a national quality assurance program has been the driving force behind these achievements.
SAT0087 Family History of Arthritis-Related Diseases as Predictors of Response to TNFI Therapy in RA: Table 1
Authors: T. Frisell, S. Saevarsdottir, J. Askling
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Beyond the moderate to strong familial aggregation of RA itself, family history of other inflammatory arthritis or lupus and connective tissue diseases (CTD) approximately doubles the risk of developing RA. Being a summary measure of genetic and non-genetic risk factors, it would not be unexpected if family history of these diseases also carried information on RA prognosis, but this has not been studied. A family history of non-RA disease could potentially help distinguish etiological subsets of RA with different disease progression and treatment response. <h3>Objectives</h3> To assess if family history of several arthritis-related diseases predict response to TNFi in RA <h3>Methods</h3> We performed a cohort study using prospectively recorded data from Swedish nationwide registers. The cohort included all Swedish RA patients starting TNFi as first biologic treatment 2000-2011, with first degree relatives identified through the Multi-Generation Register, and relatives9 disease history assessed through the National Patient Register. The association of family history to treatment response (DAS28-based EULAR criteria), treatment switch, and change in disease activity at the evaluation visit at 5 (±3) months was estimated using linear and generalized logistic regression. <h3>Results</h3> Among 9249 identified patients, 1014 (11%) had a family history of RA, 201 (2%) of other inflammatory arthritis, 69 (1%) SLE, and 101 (1%) other CTD. There were no significant differences in TNFi response, a lack of association that remained after adjustment for sex, age, birth year, and disease duration (Table), and also when further adjusting for baseline HAQ and CRP. <h3>Conclusions</h3> Using a large population-based cohort, we found that despite being predictors of RA itself, family history of RA, inflammatory arthritis, SLE, and other CTD did not predict initial response to TNFi. Although we cannot reject the possibility of weak associations, information on family history of these diseases is not likely to be useful for clinical treatment decisions in this setting. <h3>Disclosure of Interest</h3> None declared
88P: Use of brain imaging in the management of patients with lymph node negative multifocal lung cancer
Authors: K. Leventakos, A.S. Mansfield, S. Blackmon, S. Cassivi, R. Shen, F.C. Nichols, J.R. Molina, M.S. Allen, M.C. Aubry, D. Wigle
Journal: Journal of Thoracic Oncology (2016)
Case 46-1983
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, Jeffrey M. Isner, Seok Suh Lee
Journal: New England Journal of Medicine (1983)

Presentation of Case First admission. A 69-year-old man was admitted to the hospital because of mitral-valve disease.The patient was considered an unreliable informant. He gave a history of rheumatic fever in childhood. Thereafter he was well until eight years before admission, when atrial fibrillation developed, accompanied by congestive heart failure. One year later hemoptysis occurred. The symptoms of congestive failure worsened, and the patient retired from his work as a gardener. Six years before entry examination revealed murmurs of mitral regurgitation and mitral stenosis, hypertension, and evidence of peripheral vascular disease. He entered several hospitals because of recurrent . . .
An Inherited Abnormality of Neutrophil Adhesion
Authors: Carol A. Crowley, John T. Curnutte, Richard E. Rosin, Janine André-Schwartz, John I. Gallin, Mark Klempner, Ralph Snyderman, Fredrick S. Southwick, Thomas P. Stossel, Bernard M. Babior
Journal: New England Journal of Medicine (1980)

Neutrophils from a five-year-old boy with recurrent bacterial infections failed to spread on surfaces, leading to a severe defect in chemotaxis and a mild impairment in phagocytosis. Failure to spread was also seen in a fraction of the neutrophils from the patient's mother and sister, but cells from his father and brother were normal. Gel electrophoresis revealed that a protein with a molecular weight of 110,000 daltons (designated gp 110) present in the particulate fraction of normal neutrophils was absent from the patient's cells, and that its levels were below normal in cells from his mother and sister but normal in neutrophils from his father and brother. These findings suggest that gp 110 is necessary for the spreading of neutrophils onto surfaces, that the functional abnormality in the patient's cells is caused by its absence, and that deficiency of gp 110 is an X-linked congenital disease.
GENO-23AMPLIFICATION OF CHROMOSOME Xq11.1 -Xq11.2 MIGHT PLAY A ROLE IN GLIOBLASTOMA
Authors: Tamar Canello, Tal Shahar, Bracha Zelikovitch, Anat Mordechai, Alexander Lossos, Iris Lavon
Journal: Neuro-Oncology (2015)

INTRODUCTION: Glioblastoma multiforme (GBM) is an extremely aggressive tumor with a very short survival time. New technologies developed in recent years have given us a deeper insight into the tumorgenesis of GBMs. METHODS AND RESULTS: We performed a genome-wide copy number and loss of heterozygosity analyzed on DNA extracted from 5 formalin fixed paraffin embedded samples of GBMs using molecular inversion probes (OncoScan FFPE Express, Affymetrix). Beside the known deleted and amplified regions, we found in all samples amplification in chromosome X (Xq11.1 -Xq11.2) that was not described before. From the amplified genes in this region we have analyzed the expression of 5 genes: ARHGEF9, ZC4H2, SPIN4, MTMR8 and ASB12 by quantitative real-time RT PCR (N = 30) and found a significant amplification (above 2) in 93% of the samples for SPIN4 and ASB12. CONCLUSION: SPIN4 is a member of the spindling family of proteins which play a crucial part in mitosis. High expression of SPIN1 was previously found to play a role in ovarian cancer and ectopic expression of SPIN1 promoted cancer cell proliferation and activation of the WNT signaling pathway. ASB12 is part of the ankyrin repeat and SOCS box (ASB) family that is composed of 18 proteins from ASB1 to ASB18. This family was shown to be highly expressed in different types of cancer and is suggested to be involved in tumorgenesis. Thus we hypothesis that these genes might play a role in brain tumors
Hyperandrogenism in Polycystic Ovary Syndrome -- Evidence of Dysregulation of 11β-Hydroxysteroid Dehydrogenase
Authors: Andrew Rodin, Hansa Thakkar, Norman Taylor, Richard Clayton
Journal: New England Journal of Medicine (1994)

Hyperandrogenemia is the hallmark of the polycystic ovary syndrome, yet the relative contributions of the adrenal cortex and ovary to the overproduction of androgen remain unclear. To identify possible causes of adrenocortical overactivity, we studied the metabolism of adrenal and ovarian steroid hormones in women with this disorder.We measured 24-hour urinary excretion of steroid hormone metabolites by high-resolution capillary gas chromatography in 65 women with the polycystic ovary syndrome and 45 normal women matched for body-mass index.After adjustment for body-mass index, the urinary excretion of testosterone and androstenedione metabolites was 1.9 times higher in the women with the syndrome than in the normal women, and the excretion of dehydroepiandosterone metabolites (C19 steroid sulfates) and cortisol metabolites was 1.5 and 1.3 times higher, respectively (P < 0.01 for all comparisons). The affected women also had significantly higher ratios of 11-oxo (oxygenated) metabolites to 11-hydroxy metabolites of cortisol (1.4 times higher, P < 0.001) and of 11-oxo to 11-hydroxy metabolites of corticosterone (1.8 times higher, P < 0.001). In the group with the polycystic ovary syndrome, 55 percent of the nonobese women and 24 percent of the obese women had ratios above the upper limit of normal; the ratios in the obese women did not differ significantly from those in the nonobese women.Adrenal secretion of cortisol and androgens is increased in women with the polycystic ovary syndrome. The increases may be explained by dysregulation of 11 beta-hydroxysteroid dehydrogenase causing increased oxidation of cortisol to cortisone, which cannot be accounted for by obesity.
Abstract 2593: Combination therapy with EGFR-TKI and cMET-TKIs in non-small cell lung cancer: the golden duo
Authors: Nele Van Der Steen, Vanessa Deschoolmeester, An Wouters, Filip Lardon, Christian Rolfo, Patrick Pauwels
Journal: Cancer Research (2015)

Abstract Intro: The use of targeted therapies confers great responses in non-small cell lung cancer patients, but ultimately results in acquired resistance, e.g. against epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) due to cMET amplification. Therefore, combination therapy with EGFR-TKI and cMET TKIs in cell lines with a different EGFR and cMET background was investigated. Materials &amp; methods: All experiments were performed in 5 cell lines with a different EGFR and cMET background: the cMET amplified squamous lung cancer cell line EBC-1, the HGF-secreting myeloma cell line JJN3, the HCC827 and H1975 lung adenocarcinoma cell lines with an activating EGFR exon 19 deletion and an L858 as well as a T790M resistance mutation, respectively. Finally LUDLU-1 is a squamous lung cancer cell line, wild-type for both EGFR and cMET. The cytotoxicity of combination therapy with erlotinib (EGFR-TKI) and crizotinib (cMET-ALK-ROS1-TKI) or PHA665752 (cMET-TKI) was determined by the sulforhodamine B assay after 72h of simultaneous/sequential treatment (Table 1). Results: For all treatments, the JJN3, EBC-1 and HCC827 cell lines showed no synergistic effect. For the H1975, a decrease in resistance could be observed, albeit not significant. For LUDLU-1, a trend towards synergism was observed when erlotinib was administered simultaneously with crizotinib (p = 0.074) and PHA665752 (p = 0.055). Also a significantly synergistic effect was observed when treatment with erlotinib was followed by PHA665752 (p = 0.014). Discussion: Synergism between erlotinib and crizotinib/PHA665752 depends on the genetic background of the cells and the treatment schedule. This was most pronounced in the EGFR and cMET wild-type cell line. These results open up the discussion to include EGFR and cMET wild-type patients into future clinical trials. Cell lineErlotinib (μM)Crizotinib (μM)PHA665752 (μM)Erlo+CrizErlo = &amp;gt;CrizCriz = &amp;gt;ErloErlo+PHAErlo = &amp;gt;PHAPHA = &amp;gt;ErloEBC-10-100-0.025-0.050-0.1-0.150-0.025-0.050-0.1-0.20-0.3-0.40-0.1-0.2JJN30-100-2-30-2-30-2-30-5-70-5-70-5-6HCC8270-50-3-50-3-50-1-20-7-90-7-90-4-5H19750-100-2-30-2-30-1-20-6-70-6-70-2-3LUDLU-10-100-3-50-3-50-2-30-7-80-7-80-3.5-4 Table 1: Therapeutic concentrations per cell line &amp; treatment schedule: control-IC20-IC40. Citation Format: Nele Van Der Steen, Vanessa Deschoolmeester, An Wouters, Filip Lardon, Christian Rolfo, Patrick Pauwels. Combination therapy with EGFR-TKI and cMET-TKIs in non-small cell lung cancer: the golden duo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2593. doi:10.1158/1538-7445.AM2015-2593
Review of<i>The Rebirth of the Clinic: An Introduction to Spirituality</i><sup>1</sup>and<i>A Balm for Gilead: Meditations on Spirituality</i><sup>2</sup>by David P. Sulmasy
Authors: Thomas L. Long
Journal: The American Journal of Bioethics (2010)

Click to increase image sizeClick to decrease image size Notes 1. Georgetown University Press, Washington, DC, 2006, 246 pp. $29.95 (paperback). 2. Georgetown University Press, Washington, DC, 2006, 154 pp. $18.95 (paperback).
A Controlled Trial of Acyclovir for Chickenpox in Normal Children
Authors: Lisa M. Dunkle, Ann M. Arvin, Richard J. Whitley, Harley A. Rotbart, Henry M. Feder, Sandor Feldman, Anne A. Gershon, Moise L. Levy, Gregory F. Hayden, Paul V. McGuirt, Janna Harris, Henry H. Balfour
Journal: New England Journal of Medicine (1991)

Chickenpox, the primary infection caused by the varicella-zoster virus, affects more than 3 million children a year in the United States. Although usually self-limited, chickenpox can cause prolonged discomfort and is associated with infrequent but serious complications.To evaluate the effectiveness of acyclovir for the treatment of chickenpox, we conducted a multicenter, double-blind, placebo-controlled study involving 815 healthy children 2 to 12 years old who contracted chickenpox. Treatment with acyclovir was begun within the first 24 hours of rash and was administered by the oral route in a dose of 20 mg per kilogram of body weight four times daily for five days.The children treated with acyclovir had fewer varicella lesions than those given placebo (mean number, 294 vs 347; P less than 0.001), and a smaller proportion of them had more than 500 lesions (21 percent, as compared with 38 percent with placebo; P less than 0.001). In over 95 percent of the recipients of acyclovir no new lesions formed after day 3, whereas new lesions were forming in 20 percent of the placebo recipients on day 6 or later. The recipients of acyclovir also had accelerated progression to the crusted and healed stages, less itching, and fewer residual lesions after 28 days. In the children treated with acyclovir the duration of fever and constitutional symptoms was limited to three to four days, whereas in 20 percent of the children given placebo illness lasted more than four days. There was no significant difference between groups in the distribution of 11 disease complications (10 bacterial skin infections and 1 case of transient cerebellar ataxia). Acyclovir was well tolerated, and there was no significant difference between groups in the titers of antibodies against varicella-zoster virus.Acyclovir is a safe treatment that reduces the duration and severity of chickenpox in normal children when therapy is initiated during the first 24 hours of rash. Whether treatment with acyclovir can reduce the rare, serious complications of chickenpox remains uncertain.