tbuckley/cabot-search huggingface dataset:
Predictors of survival in patients with advanced hepatocellular carcinoma who permanently discontinued sorafenib
Authors: Massimo Iavarone, Giuseppe Cabibbo, Marco Biolato, Cristina Della Corte, Marcello Maida, Marco Barbara, Michele Basso, Sara Vavassori, Antonio Craxì, Antonio Grieco, Carlo Cammà, Massimo Colombo
Journal: Hepatology (2015)

Treatment with sorafenib of patients with advanced hepatocellular carcinoma is challenged by anticipated discontinuation due to tumor progression, liver decompensation, or adverse effects. While postprogression survival is clearly determined by the pattern of tumor progression, understanding the factors that drive prognosis in patients who discontinued sorafenib for any reason may help to improve patient management and second‐line trial design. Patients consecutively admitted to three referral centers who were receiving best supportive care following permanent discontinuation of sorafenib for any reason were included. Postsorafenib survival (PSS) was calculated from the last day of treatment to death or last visit available. Two hundred and sixty patients were included in this prospective study, aged 67 years, 60% with hepatitis C, 51% Child‐Pugh A, 83% performance status (PS) ≥1, 41% with macroscopic vascular invasion, and 38% with extrahepatic tumor spread. Overall, median PSS was 4.1 (3.3‐4.9) months, resulting from 4.6 (3.3‐5.7) months for 123 progressors, 7.3 (6.0‐10.0) months in 77 with adverse effects, and 1.8 (1.6‐2.4) months in 60 decompensated patients ( P &lt; 0.001). Postsorafenib survival was independently predicted by PS, prothrombin time, extrahepatic tumor spread, macrovascular invasion, and reason for discontinuation. Two hundred patients potentially eligible for second‐line therapy had a PSS of 5.3 (4.6‐7.1) months, which was dependent on reasons of discontinuation ( P = 0.004), PS ( P &lt; 0.001), macrovascular invasion ( P &lt; 0.001), and extrahepatic metastases ( P &lt; 0.002). Conclusion: Discontinuation due to adverse effects in the absence of macrovascular invasion, extrahepatic metastases, and deteriorated PS predicts the best PSS in compensated patients, thereby setting the stage for both improved patient counseling and selection for second‐line therapy. (H epatology 2015;62:784–791)
Stem Cells and the Natural History of Lung Cancer: Implications for Lung Cancer Screening
Authors: Rob J. van Klaveren, Susan C. van't Westeinde, Bart-Jan de Hoop, Henk C. Hoogsteden
Journal: Clinical Cancer Research (2009)

Lung cancer is not simply a single disease, but a collection of several phenotypically very diverse and regionally distinct neoplasias. Its natural history is complex and not yet fully understood. Stem cells and the complex interaction with the microenvironment of the tumor and the immune system play an important role in tumor progression and metastasizing capacity. This finding explains why lung cancer does not always follow the multistep carcinogenetic and exponential growth model and why small lesions do not always equate to early-stage disease. Despite the fact that volume doubling times are increasingly used as surrogate markers for the natural history of lung cancer and as estimates for the proportion of overdiagnosed cases, it is only a momentary impression. At baseline screening especially, screen-detected lung cancer cases are preferably detected when they are in the indolent phase of their growth curve (length-biased sampling), from which it can by no means be concluded that they may not progress or metastasize at a later stage. Because the natural history of lung cancer is only partly elucidated, conclusions on the impact of overdiagnosis in lung cancer screening are premature.
A Phase I Trial of Radioimmunotherapy with 131I-A5B7 Anti-CEA Antibody in Combination with Combretastatin-A4-Phosphate in Advanced Gastrointestinal Carcinomas
Authors: Tim Meyer, Andrew M. Gaya, Gairin Dancey, Michael R.L. Stratford, Shokri Othman, Surinder K. Sharma, David Wellsted, N. Jane Taylor, J. James Stirling, Linda Poupard, Lisa K. Folkes, Pei-san Chan, R. Barbara Pedley, Kerry A. Chester, Karen Owen, John A. Violet, Alessandra Malaroda, Alan J. Green, John Buscombe, Anwar R. Padhani, Gordon J. Rustin, Richard H. Begent
Journal: Clinical Cancer Research (2009)

In preclinical models, radioimmunotherapy with (131)I-A5B7 anti-carcinoembryonic antigen (CEA) antibody ((131)I-A5B7) combined with the vascular disruptive agent combretastatin-A4-phosphate (CA4P) produced cures unlike either agent alone. We conducted a phase I trial determining the dose-limiting toxicity (DLT), maximum tolerated dose, efficacy, and mechanism of this combination in patients with gastrointestinal adenocarcinomas.Patients had CEA of 10 to 1,000 microg/L, QTc < or =450 ms, no cardiac arrhythmia/ischaemia, and adequate hematology/biochemistry. Tumor was suitable for blood flow analysis by dynamic contrast enhanced-magnetic resonance imaging (MRI). The starting dose was 1,800 MBq/m(2) of (131)I-A5B7 on day 1 and 45 mg/m(2) CA4P given 48 and 72 hours post-(131)I-A5B7, then weekly for up to seven weeks.Twelve patients were treated, with mean age of 63 years (range, 32-77). Two of six patients at the first dose level had DLTs (grade 4 neutropenia). The dose was reduced to 1,600 MBq/m(2), and CA4P escalated to 54 mg/m(2). Again, two of six patients had DLTs (neutropenia). Of ten assessable patients, three had stable disease and seven had progressive disease. Single-photon emission computed tomography confirmed tumor antibody uptake in all 10 patients. DCE-MRI confirmed falls in kinetic parameters (K(trans)/IAUGC(60)) in 9 of 12 patients. The change of both pharmacokinetic parameters reached a level expected to produce efficacy in one patient who had a minor response on computed tomography and a reduced serum tumor marker level.This is believed to be the first trial reporting the combination of radioimmunotherapy and vascular disruptive agent; each component was shown to function, and myelosuppression was dose-limiting. Optimal dose and timing of CA4P, and moderate improvements in the performance of radioimmunotherapy seem necessary for efficacy.
Inhibition of PDGF, VEGF and FGF signalling attenuates fibrosis
Authors: N. I. Chaudhary, G. J. Roth, F. Hilberg, J. Müller-Quernheim, A. Prasse, G. Zissel, A. Schnapp, J. E. Park
Journal: European Respiratory Journal (2007)

BIBF 1000 is a small molecule inhibitor targeting the receptor kinases of platelet-derived growth factor (PDGF), basic fibroblast growth factor and vascular endothelial growth factor, which have known roles in the pathogenesis of pulmonary fibrosis. The anti-fibrotic potential of BIBF 1000 was determined in a rat model of bleomycin-induced lung fibrosis and in an ex vivo fibroblast differentiation assay. Rats exposed to a single intra-tracheal injection of bleomycin were treated with BIBF 1000 starting 10 days after bleomycin administration. To gauge for anti-fibrotic activity, collagen deposition and pro-fibrotic growth factor gene expression was analysed in isolated lungs. Furthermore, the activity of BIBF 1000 was compared with imatinib mesylate (combined PDGF receptor, c-kit and c-abl kinase inhibitor) and SB-431542 (transforming growth factor (TGF)-β receptor I kinase inhibitor) in an ex vivo TGF-β-driven fibroblast to myofibroblast differentiation assay, performed in primary human bronchial fibroblasts. Treatment of rats with BIBF 1000 resulted in the attenuation of fibrosis as assessed by the reduction of collagen deposition and the inhibition of pro-fibrotic gene expression. In the cellular assay both SB-431542 and BIBF 1000 showed dose-dependent inhibition of TGF-β-induced differentiation, whereas imatinib mesylate was inactive. BIBF 1000, or related small molecules with a similar kinase inhibition profile, may represent a novel therapeutic approach for the treatment of idiopathic pulmonary fibrosis.
Validation of assays for inflammatory mediators in sputum
Authors: R.a Stockley, D.l Bayley
Journal: European Respiratory Journal (2000)

Commercially available immune assays are being used with increasing frequency in the study of lung inflammation. However, their performance in complex biological fluids is rarely assessed. The authors wished to assess their reliability to determine whether the results obtained in sputum samples can be easily interpreted. The reproducibility of several such assays was therefore determined together with their ability to recover known amounts of pure reagent. Sputum sol phase was obtained from several patients with chronic lung disease and used together with the reagents in a series of "spiking" and dilutional experiments. Results confirmed that the enzyme assay for myeloperoxidase and the immune assays for interleukin-8, leukotriene B4 and secretory leukoproteinase inhibitor were all reproducible (intra-assay coefficient of variation 3.8-7.7%). Furthermore, each of these assays gave &gt;85% recovery of a "spike" with pure reagent. However, the immune assay for myeloperoxidase (although reproducible) gave poor recovery and was dependent on the degree of sample dilution and elastase content. These studies confirm that the reliabilities of fluid phase measurements should be assessed before being widely applied to complex biological samples.
Intranasal challenge with aspirin in the diagnosis of aspirin intolerant asthma: evaluation of nasal response by acoustic rhinometry
Authors: J Casadevall
Journal: Thorax (2000)

<h3>BACKGROUND</h3> Nasal provocation tests with lysine-aspirin have recently been introduced for assessment of aspirin intolerant asthma. A study was undertaken to evaluate the usefulness of acoustic rhinometry, a new non-invasive technique, in the diagnosis of aspirin intolerant asthma/rhinitis. <h3>METHODS</h3> Fifteen patients with aspirin intolerant asthma/rhinitis (nine women, mean (SD) age 54.7 (14) years), eight patients with aspirin tolerant asthma/rhinitis (three women, mean (SD) age 52.6 (7.8) years), and eight healthy subjects (two women, mean (SD) age 32.5 (9.7) years) were studied. All subjects were challenged with saline (0.9% NaCl) and 25 mg lysine acetylsalicylic acid (L-ASA) instilled into each nostril of the nose on two separate days. The clinical response was evaluated based on nasal symptoms (sneezes, itching, secretion and blockage). The nasal response was measured by acoustic rhinometry. Symptoms and rhinometry curves were recorded at 10 minute intervals for three hours, one hour before challenge and two hours after challenge. <h3>RESULTS</h3> L-ASA challenge induced a significant increase in symptoms in patients with aspirin intolerant asthma/rhinitis. No differences in the clinical response were detected in those with aspirin tolerant asthma/rhinitis or healthy subjects. L-ASA challenge induced a significant decrease in nasal volume measured by acoustic rhinometry in aspirin intolerant patients. No differences were detected between the challenges in aspirin tolerant patients. If a 25% decrease in nasal volume is taken as the cut off point, the specificity of the test was 94% and the sensitivity reached 73%. The nasal challenge was well tolerated by all subjects. <h3>CONCLUSION</h3> Acoustic rhinometry may be used to study the nasal response to L-ASA. Nasal challenge with L-ASA is safe and can be used as a diagnostic test even in asthmatic patients with severe bronchial obstruction.
Effects of golimumab, an anti-tumour necrosis factor-α human monoclonal antibody, on lipids and markers of inflammation
Authors: Bruce W Kirkham, Mary Chester Wasko, Elizabeth C Hsia, Roy M Fleischmann, Mark C Genovese, Eric L Matteson, Hongjuan Liu, Mahboob U Rahman
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> To assess the effect of golimumab, with or without methotrexate (MTX), on serum lipids and inflammatory markers of cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA) in two phase 3, randomised, placebo-controlled trials (GO-BEFORE and GO-FORWARD). <h3>Methods</h3> Patients in GO-BEFORE (n=637, MTX-naïve) and GO-FORWARD (n=444, MTX-inadequate response) were randomised to placebo+MTX, golimumab 100 mg+placebo, golimumab 50 mg+MTX, or golimumab 100 mg+MTX. Subcutaneous injections (placebo and golimumab) were given every 4 weeks. Patients with an insufficient response entered early escape at week 16 (GO-FORWARD) or 28 (GO-BEFORE). All placebo+MTX patients in GO-FORWARD crossed over to golimumab 50 mg+MTX at week 24. Changes from baseline to weeks 14 (GO-FORWARD) or 24 (GO-BEFORE), and 52 in serum lipid levels and inflammatory markers were assessed. <h3>Results</h3> At week 14 in the GO-FORWARD trial, total cholesterol (TC), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) increased in golimumab+MTX patients versus MTX-only patients (16.00 vs 2.00 (p&lt;0.001); 3.00 vs 0.00 (p&lt;0.05); 8.00 vs 4.00 (p&lt;0.001); respectively); favourable changes in LDL subfractions were only observed in golimumab-treated patients. At week 24 in GO-BEFORE, TC and LDL increased, and LDL subfractions improved in the MTX-only and golimumab+MTX groups. Inflammatory markers of CVD risk improved significantly with golimumab+MTX versus placebo+MTX in both studies and were generally maintained through week 52. Atherogenic indices were generally stable. <h3>Conclusions</h3> While TC and LDL levels increased mildly in RA patients receiving golimumab+MTX, atherogenic indices generally remained stable, favourable changes in LDL subfractions were observed, and inflammatory markers improved.
PTH-095 Portal Hypertension Due To Splanchnic Venous Thrombosis Following Open Or Skunk Wire Necrosectomy Of Acute Severe Pancreatitis: Abstract PTH-095 Table 1
Authors: EJ Britton, S Mahoney, J Garry, C Halloran, P Richardson
Journal: Gut (2014)

<h3>Introduction</h3> Isolated splenic vein thrombosis (ISVT) is a well recognised complication of acute pancreatitis with incidences ranging widely but more recently in a large meta analysis reported as approximately 14% with a reported incidence of varices of 53% and a GI haemorrhage rate of 12.3%. There is however less available published data on the incidence and natural history of splanchnic vein thrombosis that occurs with severe necrotizing pancreatitis requiring percutaneous or open necrosectomy. Our aim was to retrospectively review all patients who underwent minimal access retroperitoneal pancreatic necrosectomy (MARPN) at RLUH from 1998 to 2012 to assess the incidence, natural history and complications of splanchnic vein thrombosis. <h3>Methods</h3> Using a hospital held database we identified all patients who had undergone MARPN or open necrosectomy and had an electronic hospital record. We assessed patient characteristics the incidence of splanchnic vein thrombosis at presentation, at most recent cross sectional imaging, complications of portal hypertension including incidence of varices and variceal haemorrhage. <h3>Results</h3> We identified 191 patients who had undergone necrosectomy. 46 cases were excluded from the final analysis as imaging reports made no comment on the portal venous system. The mean age was 56.1 years with a mean apache score of 9 on admission. Overall 31.7% (n = 46) underwent open necrosectomy and 68.3% MARPN necrosectomy. The results are outlined in Table 1. <h3>Conclusion</h3> The incidence of splanchnic venous thrombosis in pancreatitis requiring necrosectomy is much higher than previously reported cases series assessing ISVT in patients with acute pancreatitis. The true natural history remains splanchnic venous thrombosis related to pancreatitis remains unknown, however in our case series the recanalisation rate was low. However in severe necrotizing pancreatitis portal venous complications should be actively investigated and UGI endoscopy to examine for varices should be carried out such that prophylaxis against variceal haemorrhage can be used where appropriate. <h3>Disclosure of Interest</h3> None Declared.
Lysophosphatidic Acid Signaling May Initiate Fetal Hydrocephalus
Authors: Yun C. Yung, Tetsuji Mutoh, Mu-En Lin, Kyoko Noguchi, Richard R. Rivera, Ji Woong Choi, Marcy A. Kingsbury, Jerold Chun
Journal: Science Translational Medicine (2011)

Blockade of lysophosphatidic acid signaling provides a new strategy for treating fetal hydrocephalus.
The Puzzling Role of CXCR4 in Human Immunodeficiency Virus Infection
Authors: Elisa Vicenzi, Pietro Liò, Guido Poli
Journal: Theranostics (2013)

The human immunodeficiency virus type-1 (HIV-1) is the etiological agent of the acquired immunodeficiency syndrome (AIDS), a disease highly lethal in the absence of combination antiretroviral therapy.HIV infects CD4 + cells of the immune system (T cells, monocyte-macrophages and dendritic cells) via interaction with a universal primary receptor, the CD4 molecule, followed by a mandatory interaction with a second receptor (co-receptor) belonging to the chemokine receptor family.Apart from some rare cases, two chemokine receptors have been evolutionarily selected to accomplish this need for HIV-1: CCR5 and CXCR4.Yet, usage of these two receptors appears to be neither casual nor simply explained by their levels of cell surface expression.While CCR5 use is the universal rule at the start of every infection regardless of the transmission route (blood-related, sexual or mother to child), CXCR4 utilization emerges later in disease coinciding with the immunological deficient phase of infection.Moreover, in most instances CXCR4 use as viral entry co-receptor is associated with maintenance of CCR5 use.Since antiviral agents preventing CCR5 utilization by the virus are already in use, while others targeting either CCR5 or CXCR4 (or both) are under investigation, understanding the biological correlates of this "asymmetrical" utilization of HIV entry co-receptors bears relevance for the clinical choice of which therapeutics should be administered to infected individuals.We will here summarize the basic knowledge and the hypotheses underlying the puzzling and yet unequivocal role of CXCR4 in HIV-1 infection.
Resistance of cloned cytotoxic T lymphocytes to cell-mediated cytotoxicity.
Authors: A Blakely, K Gorman, H Ostergaard, K Svoboda, C C Liu, J D Young, W R Clark
Journal: The Journal of Experimental Medicine (1987)

Cloned CTLs show an unusually high resistance to lysis by effector CTLs. Several cloned CTL lines in our laboratories are absolutely refractory to lysis by other cloned CTLs, either (a) directly, (b) in the presence of lectin, or (c) by PMA-induced CTLs. They can be lysed to some extent by primary CTL, although they are less than 5% as sensitive as target cells normally used to assay primary CTL lytic activity. Lysis of cloned CTLs by primary CTL effector cells is not enhanced by the presence of lectin, and cloned T cells are also highly resistant to lysis by primary lymphokine-activated killer cells. Cloned CTLs are highly resistant to lysis by isolated CTL granules that contain the membranolytic pore-forming protein (PFP or perforin), while non-CTL targets are highly susceptible to granule-mediated killing, indicating that cloned CTLs resist lysis not only at the intact effector cell level but also when soluble effector proteins are used. This resistance mechanism may explain how CTLs kill but spare themselves from being killed during the cytolytic event.
Raising the profile of the anterior thalamus
Authors: John C. Dalrymple-Alford, Anna M. Gifkins, Michael A. Christie
Journal: Behavioral and Brain Sciences (1999)

Three questions arising from Aggleton &amp; Brown's target article are addressed. (1) Is there any benefit to considering the effects of partial lesions of the anterior thalamic nuclei (AT)? (2) Do the AT have a separate role in the proposed extended hippocampal system? (3) Should perirhinal cortex function be restricted to familiarity judgements?
Patient engagement as a risk factor in personalized health care: a systematic review of the literature on chronic disease
Authors: Leigh Ann Simmons, Ruth Q Wolever, Elizabeth M Bechard, Ralph Snyderman
Journal: Genome Medicine (2014)

The role of patient engagement as an important risk factor for healthcare outcomes has not been well established. The objective of this article was to systematically review the relationship between patient engagement and health outcomes in chronic disease to determine whether patient engagement should be quantified as an important risk factor in health risk appraisals to enhance the practice of personalized medicine.A systematic review of prospective clinical trials conducted between January 1993 and December 2012 was performed. Articles were identified through a medical librarian-conducted multi-term search of Medline, Embase, and Cochrane databases. Additional studies were obtained from the references of meta-analyses and systematic reviews on hypertension, diabetes, and chronic care. Search terms included variations of the following: self-care, self-management, self-monitoring, (shared) decision-making, patient education, patient motivation, patient engagement, chronic disease, chronically ill, and randomized controlled trial. Studies were included only if they: (1) compared patient engagement interventions to an appropriate control among adults with chronic disease aged 18 years and older; (2) had minimum 3 months between pre- and post-intervention measurements; and (3) defined patient engagement as: (a) understanding the importance of taking an active role in one's health and health care; (b) having the knowledge, skills, and confidence to manage health; and (c) using knowledge, skills and confidence to perform health-promoting behaviors. Three authors and two research assistants independently extracted data using predefined fields including quality metrics.We reviewed 543 abstracts to identify 10 trials that met full inclusion criteria, four of which had 'high' methodological quality (Jadad score ≥ 3). Diverse measurement of patient engagement prevented robust statistical analyses, so data were qualitatively described. Nine studies documented improvements in patient engagement. Five studies reported reduction in clinical markers of disease (for example HbA1C). All studies reported improvements in self-reported health status.This review suggests patient engagement should be quantified as part of a comprehensive health risk appraisal given its apparent value in helping individuals to effectively self-manage chronic disease. Patient engagement measures should include assessment of the knowledge, confidence and skills to prevent and manage chronic disease, plus the behaviors to do so.