tbuckley/cabot-search huggingface dataset:
P8 Pooled analysis of data from the TOMORROW and INPULSIS® trials of nintedanib in IPF
Authors: L Richeldi, KK Brown, V Cottin, M Selman, T Kimura, S Stowasser
Journal: Thorax (2015)

<h3>Background</h3> The 52-week, Phase II TOMORROW trial and two replicate 52-week, Phase III INPULSIS® trials investigated the efficacy and safety of nintedanib 150 mg twice daily (bid) versus placebo in patients with idiopathic pulmonary fibrosis (IPF). <h3>Aim</h3> A pooled analysis of data from the TOMORROW and INPULSIS® trials was conducted to obtain a more precise estimate of the treatment effect of nintedanib. <h3>Methods</h3> Results for annual rate of decline in forced vital capacity (FVC), time to first investigator-reported acute exacerbation, change from baseline in St George’s Respiratory Questionnaire (SGRQ) total score and mortality over 52 weeks were analysed. <h3>Results</h3> 1231 patients (nintedanib 150 mg bid n = 723, placebo n = 508, reflecting the 3:2 randomisation in the INPULSIS® trials) were included. Baseline characteristics were comparable between treatment groups and across trials. The overall adjusted annual rate of decline in FVC was −112.4 mL/year with nintedanib and −223.3 mL/year with placebo (difference: 110.9 mL/year [95% CI: 78.5, 143.3]; p &lt; 0.0001). The overall hazard ratio for time to first acute exacerbation was 0.53 (95% CI: 0.34, 0.83; p = 0.0047) in favour of nintedanib. The overall adjusted mean change from baseline in SGRQ total score at week 52 was 2.92 with nintedanib and 4.97 with placebo (difference: −2.05 [95% CI: −3.59, −0.50; p = 0.0095]). Hazard ratios for time to all-cause and on-treatment mortality were 0.70 (95% CI: 0.46, 1.08; p = 0.0954) and 0.57 (95% CI: 0.34, 0.97; p = 0.0274), respectively, in favour of nintedanib. <h3>Conclusion</h3> Pooled data from the TOMORROW and INPULSIS® trials confirm a significant beneficial effect of nintedanib on reducing disease progression in patients with IPF.
Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)
Authors: Jesus M. Banales, Vincenzo Cardinale, Guido Carpino, Marco Marzioni, Jesper B. Andersen, Pietro Invernizzi, Guro E. Lind, Trine Folseraas, Stuart J. Forbes, Laura Fouassier, Andreas Geier, Diego F. Calvisi, Joachim C. Mertens, Michael Trauner, Antonio Benedetti, Luca Maroni, Javier Vaquero, Rocio I. R. Macias, Chiara Raggi, Maria J. Perugorria, Eugenio Gaudio, Kirsten M. Boberg, Jose J. G. Marin, Domenico Alvaro
Journal: Nature Reviews Gastroenterology & Hepatology (2016)

Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies with features of biliary tract differentiation. CCA is the second most common primary liver tumour and the incidence is increasing worldwide. CCA has high mortality owing to its aggressiveness, late diagnosis and refractory nature. In May 2015, the "European Network for the Study of Cholangiocarcinoma" (ENS-CCA: www.enscca.org or www.cholangiocarcinoma.eu) was created to promote and boost international research collaboration on the study of CCA at basic, translational and clinical level. In this Consensus Statement, we aim to provide valuable information on classifications, pathological features, risk factors, cells of origin, genetic and epigenetic modifications and current therapies available for this cancer. Moreover, future directions on basic and clinical investigations and plans for the ENS-CCA are highlighted.
Hereditary Hemorrhagic Telangiectasia (Osler–Weber–Rendu Disease)
Authors: A Nicoleau, C A Nicoleau
Journal: New England Journal of Medicine (1999)

Figure 1. A 67-year-old woman has multiple telangiectasias on her hands, as well as on her arms, legs, ears, lips, and nasal mucosa. She has had numerous episodes of epistaxis and gastrointestinal bleeding since her mid-20s. Endoscopic evaluation revealed multiple telangiectasias in her stomach and colon. She has a strong maternal family history of similar lesions. She is otherwise healthy and requires only iron supplements.
S21 Early Contrast Enhancement: A Perfusion-based Magnetic Resonance Imaging Biomarker of Pleural Malignancy
Authors: S Tsim, CA Humphreys, DB Stobo, GW Cowell, R Woodward, JE Foster, C Dick, KG Blyth
Journal: Thorax (2015)

<h3>Introduction and objectives</h3> Radiological detection of pleural malignancy (PM) remains challenging. In early-stage Malignant Pleural Mesothelioma (MPM) a pleural effusion may be the only significant abnormality, indistinguishable from benign asbestos-related pleural effusion (BAPE). PM is associated with neovascularisation. We report the diagnostic performance of a novel perfusion-based Magnetic Resonance Imaging (MRI) biomarker of PM – Early Contrast Enhancement (ECE). <h3>Methods</h3> 24 patients with suspected PM were recruited prospectively. All underwent contrast-enhanced Computed Tomography (CT) scanning, 3T Pleural MRI and Thoracoscopy. 18/24 had complete MRI examinations: T1-weighted 3D-spoiled-gradient-echo sequences acquired at baseline, 40 s, 80 s and 4.5, 9 and 13.5 min after intravenous Gadobutrol contrast. Mean signal intensity (SI) of representative parietal pleura was derived from 15 regions of interest placed by two respiratory physicians. ECE was defined objectively by an early peak in mean SI (≤4.5 min) on the resulting SI/time curve (Figure 1). Morphology suggestive of PM on CT and MRI was recorded by two thoracic radiologists. Diagnostic performance and inter-observer agreement for ECE, MRI and CT morphology were compared. All analyses were blinded. Pleural SI data were correlated against Microvessel Density (MVD) measured in paraffin-embedded pleural biopsies stained with CD34 and Factor VIII immunostains. <h3>Results</h3> Mean patient age was 73 (SD 8) years. 18/24 were asbestos-exposed and 12/18 had pleural thickening ≤5 mm. ECE was present in 10/11 patients with PM (MPM (n = 10); lung cancer (n = 1)). The false negative case had MPM. ECE was absent in 6/7 patients with benign pleural disease (BAPE (n = 4), fibrothorax (n = 2), TB (n = 1)). The false positive case had TB. Overall diagnostic accuracy of ECE, MRI and CT morphology: sensitivity 91%, 91%, 90%; specificity 86%, 71%, 50%; negative predictive value 86%, 83%, 80%; positive predictive value 91%, 83%, 69% respectively. Inter-observer agreement was 0.766 for ECE, 0.727 for MRI and 0.753 for CT. Figure 1 shows the relationship between MVD and Pleural SI. <h3>Conclusions</h3> ECE appears an accurate and reproducible, perfusion-based, objective biomarker of PM, out-performing subjectively-defined CT and MR morphology. ECE assessment can be performed in patients with minimal pleural thickening, suggesting potential utility as a biomarker of early-stage MPM or low-volume metastatic PM.
Hemodynamics of Mephentermine in Man
Authors: Tsung-Han Li, Shiro Shimosato, Benjamin Etsten, Charles A. Gamble
Journal: New England Journal of Medicine (1962)

THE clinical use of mephentermine¶ to elevate the arterial-blood pressure in man is presumably based upon the rationale that its pressor action is primarily due to an increase in myocardial contractility, with little effect upon the peripheral arteriolar resistance. This concept is mainly derived from animal studies.1 , 2 Recently, it was reported3 that this agent caused an increase in the height of the I-J wave as measured by the ballistocardiograph and an increase of the vascular resistance of the fingers as recorded by a segmental and digital plethysmograph. The inference was that mephentermine had both cardiac and peripheral action. There has . . .
Gordon Thomas Dickinson
Authors: Geoff Watts
Journal: BMJ (2015)

Canadian psychiatrist and medical editor

From general practitioner to journalist to stockbroker to psychiatrist to psychoanalyst: such was the curiously meandering career of Gordon Dickinson, sometime editor of the Canadian Medical Association Journal ( CMAJ ). These abrupt changes of direction inevitably had an impact on his family. “Over the time I was married to him,” his ex-wife Mary Lou reflects, “I felt like I’d been married to five different people.” His daughter, Andrea Dickinson, says, “He did tell me that he liked the opportunity to do different things. Nowadays it’s not unusual for people to have a number of careers over the course of their life, but in those days it was less common to go to a different discipline for a while.” Mary Lou Dickinson accepts the suggestion that her husband seems to have spent much of his working life finding out what he wanted to do. “But also making a contribution on the way,” she insists.



CMAJ

Dickinson was born to parents who had emigrated from England. …
CSIG-02GBM STEM CELL MIGRATION AND THE HYPOXIC MICROENVIRONMENT
Authors: Monica Chau, Subhas Mukherjee, Reema Kola, Daniel Brat
Journal: Neuro-Oncology (2015)

Glioblastoma (GBM) is the most aggressive primary brain tumor and carries a poor prognosis due to its infiltrative nature. GBM stem cells are a small tumor-initiating population found in GBM and are enriched by hypoxia, which supports their self-renewal and tumorigenicity. In particular, CD133 cells have been found in hypoxic/necrotic microenvironments such as the pseudopalisades of the GBM tumor; however, the source of these stem cells is not well understood. We have shown that there is a migrating population of cells at the pseudopalisades. As proliferation and migrating immune cells do not account for the increased cellularity at the pseudopalisade, we hypothesized that there is a GBM stem cell subpopulation that migrates towards hypoxia. Understanding GBM stem cell homing and hypoxic microenvironments would enable us to therapeutically target a cell subpopulation. GBM stem cells were treated with hypoxia in vitro, and probed for hypoxia inducible factor-1α (HIF-1α) and stem cell markers. Hypoxia-ischemia was induced in NOD/SCID mice via middle cerebral artery occlusion to model pseudopalisade conditions. GBM stem cells in PBS were delivered intranasally to test migration preference for microenvironment. Coronal sections of brain tissue were analyzed 24h after intranasal delivery. Human GBM tissues were stained with H&E for pseudopalisade identification. Hypoxia-treated GBM cells showed a trend of increased HIF-1α and c-Myc expression. In vivo, we demonstrated that hypoxic-ischemic tissue models certain aspects of pseudopalisades including necrosis, and the presence of HIF-1α, MMP2, and MMP9. Further, CD133-sorted cells delivered intranasally can migrate into the brain parenchyma. These data demonstrate that GBM cells upregulate stem cell markers after hypoxia. The pseudopalisade microenvironment can be modeled in mice with vaso-occlusion, and GBM stem cells can migrate into the brain through intranasal delivery. Understanding the migration directionality of GBM stem cells relative to the microenvironment has implications for treatment by targeting certain subpopulations.
A Two-in-One Antibody against HER3 and EGFR has Superior Inhibitory Activity Compared with Monospecific Antibodies
Authors: G. Schaefer, L. Haber, L.M. Crocker, S. Shia, L. Shao, D. Dowbenko, K. Totpal, A. Wong, C.V. Lee, S. Stawicki, R. Clark, C. Fields, G.D.L. Phillips, R.A. Prell, D.M. Danilenko, Y. Franke, J.-P. Stephan, J. Hwang, Y. Wu, J. Bostrom, M.X. Sliwkowski
Journal: Cancer Research (2013)
Osteoclast induction by bone marrow metastatic myeloma cells was mediated by M-CSF production from endothelial cells
Authors: Tomoko Okada, Masato Kodaka
Journal: Cancer Research (2005)

4682  Using the B9/BM1 murine bone marrow metastasis model, we have examined the role of adhesion molecules in the adhesion and transendothelial invasion. Interleukin (IL)-6-dependent, IL-1-producing B9/BM1 cells, which colonize the vertebral and femoral marrow after i.v. injection show great similarity in cell surface phenotype to human myeloma. We have investigated the interaction of these cells with endothelial cells of bone marrow origin and osteoclasts in bone marrow in the process of metastasis. Existence of both myeloma and endothelial cells derived from bone marrow promoted primary osteoclast precursor cells to osteoclasts (detected by TRAP staining) in the presence of activated vitamin D3 and M-CSF. It was found out by flowcytometry analysis that the endothelial cells had RANKL (Receptor Activator of NF-kB Ligand) on their surface and the expression of RANKL was increased by the co-culture with B9/BM1 for 4 days. Moreover, RT-PCR analysis revealed that RANKL mRNA was increased with this stimulation by co-culture. When separated with porous polycarbonate membrane from B9/BM1, the endothelial cells never promoted the induction of osteoclast. Exogenous OPG (osteoprotegerin) added to co-culture system completely inhibited the osteoclast induction and anti-CD44 antibody added to co-culture system suppressed the osteoclast induction to the level of without co-culture. Furthermore, ELISA analysis revealed that the endothelial cells produced IL-6 and M-CSF and the production was up-regulated by the co-culture with B9/BM1 cells. These results indicate that the B9/BM1 myeloma cells stimulate endothelial cells and promote the production of IL-6 which is essential for the growth of the myeloma, up-regulate the production of M-CSF which is necessary for the osteoclast differentiation, and promote the expression of RANKL on the surface of endothelial cells which in turn physically interact with osteoclast progenitors to promote their differentiation to osteoclasts and metastasis in bone marrow.
pH as a Factor in External Otitis
Authors: Floyd B. Goffin
Journal: New England Journal of Medicine (1963)

The etiology of otitis externa is probably as varied as the treatments that have been recommended. With the present adequate antibacterial and anti-fungal agents the anti-infectious approach has about reached its full potential. If further improvement in treatment is to be found, attention should probably be focused on the host rather than on the offending micro-organisms. The host factors that have received particular consideration of late in external otitis are the pH of the meatal skin,1 the physicochemical characteristics of cerumen2 and the reactivity of the skin. At least two of these factors — namely, the pH and the skin . . .
The Changing Epidemiology of Autism Spectrum Disorders
Authors: Kristen Lyall, Lisa Croen, Julie Daniels, M. Daniele Fallin, Christine Ladd-Acosta, Brian K. Lee, Bo Y. Park, Nathaniel W. Snyder, Diana Schendel, Heather Volk, Gayle C. Windham, Craig Newschaffer
Journal: Annual Review of Public Health (2017)

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with lifelong impacts. Genetic and environmental factors contribute to ASD etiology, which remains incompletely understood. Research on ASD epidemiology has made significant advances in the past decade. Current prevalence is estimated to be at least 1.5% in developed countries, with recent increases primarily among those without comorbid intellectual disability. Genetic studies have identified a number of rare de novo mutations and gained footing in the areas of polygenic risk, epigenetics, and gene-by-environment interaction. Epidemiologic investigations focused on nongenetic factors have established advanced parental age and preterm birth as ASD risk factors, indicated that prenatal exposure to air pollution and short interpregnancy interval are potential risk factors, and suggested the need for further exploration of certain prenatal nutrients, metabolic conditions, and exposure to endocrine-disrupting chemicals. We discuss future challenges and goals for ASD epidemiology as well as public health implications.
Absorption of Radioactive Vitamin B<sub>12</sub>in Nonanemic Patients with Combined-System Disease
Authors: Irwin M. Arias, Leonard Apt, Myron Pollycove
Journal: New England Journal of Medicine (1955)

BEFORE the advent of liver or vitamin B12 treatment of pernicious anemia, approximately 80 per cent of patients who died of this disease had neurologic signs resulting from demyelinization of the posterior and lateral columns of the spinal cord.1 This neurologic disorder has been variously termed combined-system disease, posterolateral sclerosis, subacute combined degeneration of the spinal cord and funicular degeneration. Its pathology, clinical course and response to treatment are well kno-n.2 3 4 5 6 7 In vitamin B12 deficiency, anemia usually precedes the development of neurologic signs and symptoms, but occasionally this sequence is reversed and extensive neurologic damage may occur in . . .
Induction of Immune Responses in Patients with B-Cell Lymphoma against the Surface-Immunoglobulin Idiotype Expressed by Their Tumors
Authors: Larry W. Kwak, Michael J. Campbell, Debra K. Czerwinski, Sarah Hart, Richard A. Miller, Ronald Levy
Journal: New England Journal of Medicine (1992)

The idiotypic determinants of the surface immunoglobulin of a B-cell lymphoma can serve as a clonal tumor-specific marker, which may have implications for immunotherapy. We sought to determine whether idiotype-specific immune responses against this autologous antigen could be induced in patients with B-cell lymphoma.
Epigenetic Modulation in Hematologic Malignancies: Challenges and Progress
Authors: Constantine S Mitsiades, Kenneth C Anderson
Journal: Journal of the National Comprehensive Cancer Network (2009)

Genetic alterations, including gene mutations, and chromosomal amplifications, deletions, inversions, and translocations, are hallmarks of the molecular biology of cancer. These events lead to oncogene activation, formation of chimeric oncoproteins, and/or inactivation of tumor suppressor genes. Such genetic changes contribute to the neoplastic transformation of cells, as well as the eventual acquisition by malignant cells of a more aggressive biologic and clinical behavior. However, in recent years, it has become apparent that these genetic events are not the sole determinants of the biologic behavior of tumor cells. Indeed, it is becoming increasingly apparent that tumor cells with a given genotype exhibit a differential phenotype depending on the microenvironment in which they reside. Furthermore, extensive data have shown that derivative daughter cells of neoplastic, as well as normal cells, inherit changes in the patterns of gene expression that are not associated with changes in the primary DNA sequence but are instead related to changes in chromatin structure and its accessibility for transcriptional activity. These heritable gene expression changes that are not associated with changes in the primary nucleotide sequence are referred to as epigenetic changes. This review provides an overview of the regulation of the “epigenome” in neoplastic cells, with particular emphasis on DNA methylation and histone acetylation as therapeutic targets for hematologic malignancies.
Treatment and Long-Term Risks for Patients With a Diagnosis of Ductal Carcinoma In Situ
Authors: Kimberly J. Van Zee, Andrea V. Barrio, Julia Tchou
Journal: JAMA Oncology (2016)

To the Editor The recent article by Narod and colleagues1 and editorial by Esserman and Yau2 have received much attention in the press, often with contradictory interpretations. This has caused confusion in the public and even among medical professionals.
Treatment of Varicella–Zoster Virus Infection in Severely Immunocompromised Patients
Authors: David H. Shepp, Paula S. Dandliker, Joel D. Meyers
Journal: New England Journal of Medicine (1986)

In a prospective, randomized trial, we compared intravenous acyclovir and vidarabine in the treatment of varicella–zoster virus infection in severely immunocompromised patients who presented within 72 hours of onset of the infection. Eleven patients were treated in each group. Cutaneous dissemination of infection occurred in none of the 10 acyclovir recipients and in 5 of the 10 vidarabine recipients who had presented with localized dermatomal disease (P = 0.016). As compared with vidarabine, acyclovir treatment shortened the median periods during which cultures were positive for the virus (four vs. seven days, P = 0.004) and new lesions formed (three vs. six days, P = 0.03). Acyclovir also shortened the median interval until the first decrease in pain (4 vs. 7 days, P = 0.005), the pustulation of all lesions (4 vs. 7 days, P = 0.0004), the crusting of all lesions (7 vs. 17 days, P = 0.0003), and the complete healing of lesions (17 vs. 28 days, P = 0.003). In addition, acyclovir reduced the incidence of fever (two vs. eight patients, P = 0.015). We conclude that acyclovir is better than vidarabine for the treatment of varicella–zoster infection in immunocompromised patients. (N Engl J Med 1986; 314:208–12.)
Reply to T. Finazzi and H. Kim et al
Authors: Jonathan Knisely
Journal: Journal of Clinical Oncology (2016)

Finazzi and Kim et al raise important questions of whether a noninferiority margin was properly and prospectively designated in the International Atomic Energy Agency protocol of the study recently reported by Roa et al. Finazzi and Kim et al also wonder whether noninferiority could be justifiably claimed after an initial interim analysis led to trial closure. Additional concerns about protocol eligibility criteria were also raised—might some patients designated as elderly or frail in this International Atomic Energy Agency–sponsored trial possibly be better treated with courses of radiation that are longer than 1 week, with or without chemotherapy? Inartfully phrased protocol language indicating that “...changing the [radiotherapy] regimen from 1 week to 3 weeks would improve survival by 15%” does not mean that the protocol was conducted as anything but a noninferiority trial, with a noninferiority margin of 15%, and the rules for discontinuing the trial are clearly set out in the section on sample size and duration of study in the study protocol. It would certainly have been difficult to justify continuing the trial, given the purview of the independent data monitoring and evaluation committee and their obligation to mandate trial closure at the time of the first interim analysis—after 98 of 144 planned patients had been accrued—on the basis of these same guidelines. What might have happened if an approximate additional 50 patients had been accrued? We will never know, but the data we have do not indicate that the results would be any different. Finally, the question of whether the 1-week radiotherapy course is the best option for all patients who fit the protocol eligibility criteria may be simply answered. The results of this trial justify it in relation to a 3-week course of radiation treatment, but it is not clear whether increasingly aggressive treatment regimens that incorporate chemotherapy might provide better outcomes for some subsets of patients.
The Herniated Intervertebral Disk
Authors: James L. Poppen
Journal: New England Journal of Medicine (1945)

IN THE last ten years considerable material has appeared in publications indicating that the presence of herniated intervertebral disks is not a myth but a proved entity, producing a train of symptoms and signs that are as characteristic as are those of renal colic or appendicitis. As is so true of all new developments, there are always those who are overenthusiastic in the treatment of this disease and those who are skeptical about it.It is astounding to find that so many proved ruptured disks have been discovered in such a comparatively short time. Inasmuch as it is known that . . .