tbuckley/cabot-search huggingface dataset:
Phase IIb randomized trial of Pexa-Vec (pexastimogene devacirepvec; JX-594), a targeted oncolytic vaccinia virus, plus best supportive care (BSC) versus BSC alone in patients with advanced hepatocellular carcinoma who have failed sorafenib treatment (TRAVERSE).
Authors: Jeong Heo, Yee Chao, Derek J. Jonker, Ari David Baron, Francois Habersetzer, James Burke, Caroline Breitbach, Richard H. Patt, Riccardo Lencioni, Michel Homerin, Jean-Marc Limacher, Monika Lusky, Theresa Hickman, Lara Longpre, David H. Kirn
Journal: Journal of Clinical Oncology (2013)

TPS4161^ Background: Pexa-Vec is a targeted oncolytic and immunotherapeutic vaccinia virus engineered to express human granulocyte-macrophage colony stimulating factor (GM-CSF). Direct oncolysis plus GM-CSF expression stimulates tumor vascular disruption and anti-tumor immunity (Nature Rev Cancer, 2009). Pexa-Vec was well-tolerated in Phase 1 trials and was shown to replicate in metastatic tumors following intratumoral (IT) or intravenous (IV) administration (Lancet Oncol, 2008 and Nature, 2011). A randomized high vs low dose Phase 2 trial in 30 patients with advanced HCC, demonstrated prolonged survival in the high-dose Pexa-Vec arm (median survival 14.1 mo vs. 6.7 mo; Hazard Ratio 0.39, p=0.02) (AASLD Annual Meeting, 2011, LB1). Methods: TRAVERSE is a Phase 2b randomized, open-label, multi-center trial in patients with advanced HCC who have failed sorafenib treatment. Approximately 120 patients will be randomized 2:1 to Pexa-Vec plus BSC versus BSC, respectively. Randomization will be stratified by region (Asian vs. non-Asian); sorafenib intolerant vs refractory; and presence vs absence of extra-hepatic disease. The primary objective is to determine overall survival. Main inclusion criteria are advanced HCC having failed sorafenib (intolerance or radiographic progression during or &lt; 3 months following last sorafenib), Child-Pugh A-B7 (no ascites), acceptable hematologic function. Assuming a median overall survival of 4.0 months with BSC and a target hazard ratio of 0.57 (corresponding to an experimental arm median survival of 7.0 months), 73 events (deaths) will provide 70% power at 1-sided alpha = 0.05 to detect a difference in overall survival between the treatment groups using a stratified logrank test. Patients randomized to Pexa-Vec will receive a dose of 10 9 plaque forming units (pfu) IV on Day 1 followed by five IT treatments between Day 8 and Week 18. Enrollment has begun on this study with clinical trial registry number of NCT01387555. Clinical trial information: NCT01387555.
MNGO-16ESTABLISHMENT OF A PATIENT - DERIVED ORTHOTOPIC MALIGNANT MENINGIOMA MODEL FOR THE DEVELOPMENT OF TARGETED THERAPY
Authors: Fares Nigim, Samuel D. Rabkin, Priscilla Brastianos, Vijaya Ramesh, Daniel Cahill, Sandro Santagata, Robert L. Martuza, Hiroaki Wakimoto
Journal: Neuro-Oncology (2015)

The majority of meningiomas are benign (WHO Grade I) and can be cured by surgery alone. However, 20% are non-benign meningioma (NBM) including atypical (Grade II) and malignant meningioma (Grade III), and pose a clinical problem due to their high recurrence rates after treatment. Preclinical development of novel therapeutics requires disease model that is representative of human NBM. However, patient-derived tumor models that recapitulate the genotype and phenotype of NBM are lacking. We established an orthotopic xenograft model from a patient with recurrent malignant meningioma that is based on tumor-sphere culture. Subdural implantation of the cultured cells in SCID mice reproducibly generated meningiomas that are lethal within 3 months, and excised tumors were serially transplantable for at least 7 generations. Pathological analysis of xenografts showed hypercellularity with whorl formations, and exhibited frequent mitotic figures, high proliferation index (Ki67 labeling 25%) and invasion to the brain parenchyma, hallmarks of malignant meningioma. The patient tumor, xenografts and cultured cells had strong expression of vimentin, a mesenchymal marker. Western blot analysis revealed that the original tumor and xenografts are NF2 (Merlin) negative, and sequencing verified NF2 mutation. This novel tumor model set a stage for us to test targeted and biological therapeutics for NBM. Our preliminary investigations in vitro include the use of dual PI3K and mTOR inhibitors, focal adhesion kinase (FAK) inhibitor, and oncolytic herpes simplex virus (oHSVs) (G47Δ and MG18L). MTS cell viability assay showed PI3K and mTOR inhibitors and oHSVs efficiently killed the tumor cells, while FAK inhibitor was ineffective. Thus our novel patient-derived orthotopic NBM model has NF2 deletion, faithfully recapitulates the human disease, and is reproducible and lethal. This model provides us with superb opportunities to develop much needed targeted therapeutics for treatment-refractory NBM, and currently studies examining oHSV efficacy in orthotopic tumor model are ongoing.
Gentamicin Contaminated with Endotoxin
Authors: Jim A. Krieger, Lamar Duncan
Journal: New England Journal of Medicine (1999)

To the Editor: A succession of at least 57 moderate-to-severe endotoxin-like reactions has occurred in the western United States over an approximately six-month period. These reactions were associated with the administration of endotoxin-contaminated gentamicin for injection manufactured by Fujisawa USA.1 Endotoxin (a lipopolysaccharide) is a component of the cell wall of gram-negative bacteria and mediates many of the clinical features observed in gram-negative bacterial sepsis. These include fever, shaking chills, and cardiovascular symptoms, and in more severe cases include muscle proteolysis, uncontrolled intravascular coagulation, shock, and death. Endotoxin stimulates mononuclear cells to produce interleukin-1, tumor necrosis factor α, and possibly . . .
Molecular Profiling in Cutaneous Melanoma
Authors: Andrew L. Ji, Christopher K. Bichakjian, Susan M. Swetter
Journal: Journal of the National Comprehensive Cancer Network (2016)

Molecular profiling of malignant tumors is gaining increasing interest in oncology. In recent years, several molecular techniques have been studied in melanoma, with the goal to improve upon the diagnostic and prognostic abilities of currently available clinical and histopathologic parameters. Reliable tests performed early in the diagnosis and management of melanoma could lead to decreased morbidity and mortality by selecting appropriate patients for more-aggressive therapy and sparing those for whom it is not indicated. This article reviews the molecular diagnostic and prognostic techniques currently available for melanoma and evaluates their potential role in clinical practice.
Comparison of cecal intubation and adenoma detection between hospitals can provide incentives to improve quality of colonoscopy
Authors: Tim Belderbos, Elisabeth Grobbee, Martijn van Oijen, Maarten Meijssen, Rob Ouwendijk, Thjon Tang, Frank ter Borg, Peter van der Schaar, Doris Le Fèvre, Merijn Stouten, Onno van der Galiën, Theo Hiemstra, Wouter de Vos tot Nederveen Cappel, Pieter ter Borg, Manon Spaander, Leon Moons, Ernst Kuipers, Peter Siersema
Journal: Endoscopy (2015)

<b>Background and study aims:</b> Cecal intubation rate (CIR) and adenoma detection rate (ADR) have been found to be inversely associated with the occurrence of post-colonoscopy colorectal cancer. Depicting differences in CIR and ADR between hospitals could provide incentives for quality improvement. The aim of this study was to compare quality parameters of routine colonoscopies between seven hospitals in The Netherlands in order to determine the extent to which possible differences were attributable to procedural and institutional factors. <b>Patients and methods:</b> Consecutive patients undergoing colonoscopy were prospectively included between November 2012 and January 2013 at two academic and five nonacademic hospitals. Patients with inflammatory bowel disease or hereditary colorectal cancer syndromes were excluded. Main outcome measures were CIR and ADR. <b>Results:</b> A total of 3129 patients were included (mean age 59 ± 15 years; 45.5 % male). The majority of patients (86.2 %) had a Boston Bowel Preparation Scale (BBPS) score ≥ 6. Overall CIR was 94.8 %, ranging from 89.4 % to 99.2 % between hospitals. After adjustment for case mix (age, sex, American Society of Anesthesiologists score, and indication for colonoscopy), factors associated with CIR were hospital and a BBPS score ≥ 6. Overall ADR was 31.8 % and varied between hospitals, ranging from 24.8 % to 46.8 %. Independent predictors for ADR were hospital, BBPS score ≥ 6, and cecal intubation. By combining CIR and ADR for each hospital, a colonoscopy quality indicator (CQI) was developed, which can be used by hospitals to stimulate quality improvement. <b>Conclusion:</b> Differences in the quality of colonoscopy between hospitals can be demonstrated using CIR and ADR. As both indicators are affected by institution and bowel preparation, a comparison between hospitals based on the newly developed CQI could assist in further improving the quality of colonoscopy.
Soundings: A medical error
Authors: George Dunea
Journal: BMJ (2000)

In the dying days of the first half of the last century, when ward sisters wore starched veils and hospital walls were painted green, an intern 10 days out of medical school was summoned in the middle of the night to restart a clogged intravenous drip. This was done in those days by injecting 3.8% of sodium citrate, a procedure that doctors but not nurses were allowed to undertake.

Sleepily the intern made his way to the medical floor. A young nurse handed him the ampoule; the doctor pushed its contents into the plastic tube; the patient made an awful gurgling sound, turned blue, and stopped breathing, her head slumping on her chest.

By this time the nurse had left the floor. The young doctor stood transfixed, panic struck, uncertain what to do, then ran to the phone to get help, but found all lines were busy or not answering. He returned to the patient, who at that moment gave a deep snort, turned pink, and began to breath normally.

All this happened before the “error prevention movement,” so ably covered in a recent issue (18 March). Since then potassium chloride ampoules have been mercifully removed from medical floors, and there has been much talk about developing systems to prevent the most blatant errors in the way it is done in aviation and other industries. There has also been much discussion about reporting errors, an idea that populist politicians have quickly seized on, leading to the suggestion of mandatory reporting by hospitals to central, government run agencies or accrediting bodies.

Although such reporting should ideally be voluntary and non-punitive, in practice this is unlikely to end up being so. Even today in many hospitals such an intern might have been fired or severely disciplined for his or her mistake, the nurse reprimanded, the hospital and the doctors sued for malpractice. Many ethicists, however, would contend that none the less the doctor has an obligation to disclose his or her mistakes, that this particular intern should have told everybody, or at least his superior.

It seems, however, that this particular intern was possessed of a highly developed sense of self preservation. I am told that he put the ampoule in question in his pocket and walked away from the ward. So the question arises, what would you have done under the same circumstances, and what would you do now?
M19 The cost of high dose corticosteroid prescribing in London – how much is too much?
Authors: V Mak, G D’Ancona, R Rampersad, J Khambh
Journal: Thorax (2015)

<h3>Introduction</h3> A high dose ICS (HDICS) is defined as daily dose ≥ 1000 micrograms beclometasone dipropionate equivalent and is associated with an increased risk of side effects over their lower dose alternatives, but minimal increase in efficacy. In asthma, HDICS are reserved for severe disease, while in COPD, ICS are beneficial only in those with an FEV<sub>1</sub> &lt;50% and frequent exacerbations, but there is evidence for overuse (White P <i>et al</i>. PLoS One 2013 8:e75221). Currently, HDICS (as combination inhalers), comprise 2 of the top 4 highest spend medicines in the NHS (NHSBSA Mar 2015), so the aim of this study was to investigate trends in ICS prescribing across the London Clinical Commissioning Groups (CCGs) and reasons for variation. <h3>Methods</h3> The NHS London Procurement Partnership monitors prescribing across London. It has designed a dashboard of primary care prescribing initiatives in collaboration with London CCGs, one of which attempts to support optimised ICS prescribing. The prescribing data for the financial year 2014/15 was compared with 2013/14 for the 32 London CCGs and London as a whole. <h3>Results</h3> All but 2 London CCGs increased their total ICS spend between 2014/15 and 2013/14. Altogether, this was an increase of 3% to £67.6 million. In 2014/15, HDICS accounted for 20% of all ICS items prescribed (range 11–27%), or £23.5 million (36%) of total ICS spend (range 23–50%). 7/32 CCGs reduced expenditure on HDICS by &gt;1% compared with 2013/14, with one achieving a 16% reduction. Reduction in HDICS prescribing occurred mostly in CCGs with respiratory integrated care teams. <h3>Conclusion</h3> In light of the National Review of Asthma Deaths, the increase in total spend on ICS may be appropriate. However, 20% of all ICS prescribed in London are for HDICS preparations accounting for 36% of the total spend on ICS. With more than two fold variation across CCGs, some HDICS prescribing may be inappropriate and reduction may be associated with the presence of integrated care teams. If all CCGs in London could manage a 10% reduction in inappropriate HDICS prescribing, this could reduce the risk of side effects to patients and save over £2 million per annum.
Pan PPAR agonist IVA337 is effective in prevention and treatment of experimental skin fibrosis
Authors: Nadira Ruzehaji, Camelia Frantz, Matthieu Ponsoye, Jerome Avouac, Sonia Pezet, Thomas Guilbert, Jean-Michel Luccarini, Pierre Broqua, Jean-Louis Junien, Yannick Allanore
Journal: Annals of the Rheumatic Diseases (2016)

The pathogenesis of systemic sclerosis (SSc) involves a distinctive triad of autoimmune, vascular and inflammatory alterations resulting in fibrosis. Evidence suggests that peroxisome proliferator-activated receptors (PPARs) play an important role in SSc-related fibrosis and their agonists may become effective therapeutic targets.To determine the expression of PPARs in human fibrotic skin and investigate the effects of IVA337, a pan PPAR agonist, in in vitro and in vivo models of fibrosis.The antifibrotic effects of IVA337 were studied using a bleomycin-induced mouse model of dermal fibrosis. The in vivo effect of IVA337 on wound closure and inflammation were studied using an excisional model of wound healing.Low levels of PPARα and PPARγ were detected in the skin of patients with SSc compared with controls. In mice, IVA337 was associated with decreased extracellular matrix (ECM) deposition and reduced expression of phosphorylated SMAD2/3-intracellular effector of transforming growth factor (TGF)-β1. Although the antifibrotic effect of pan PPAR was similar to that of PPARγ agonist alone, a significant downregulation of several markers of inflammation was associated with IVA337. Despite its anti-inflammatory and antifibrotic properties, IVA337 did not interfere with wound closure. In vitro effects of IVA337 included attenuation of transcription of ECM genes and alteration of canonical and non-canonical TGF-β signalling pathways.These findings indicate that simultaneous activation of all three PPAR isoforms exerts a dampening effect on inflammation and fibrosis, making IVA337 a potentially effective therapeutic candidate in the treatment of fibrotic diseases including SSc.
P77 Hypoxic challenge testing for fitness to fly in severe asthma
Authors: CM Orton, PM George, S Ward, A Menzies-Gow, JH Hull
Journal: Thorax (2015)

<h3>Introduction and objectives</h3> Commercial airline travel poses a recognised risk to patients with respiratory disease, including in those with asthma. Hypoxic challenge testing (HCT) is typically employed to mitigate this risk by dictating in-flight oxygen requirement. The objective of this work was to evaluate the role of HCT in patients with severe asthma. <h3>Methods</h3> A retrospective analysis was performed of all BTS/SIGN Asthma Step 5 adult individuals under the Royal Brompton Hospital severe asthma service, who completed HCT between 2007 and 2014. In line with British Thoracic Society recommendations, under hypoxic conditions a reduction in PaO<sub>2</sub> to &lt;6.6 kPa was reported as a positive result. A PaO<sub>2</sub> level of 6.6–7.5 kPa was considered borderline and supplemental oxygen was advised if co-existent evidence of hyperventilation. Electrocardiograph monitoring was performed in all patients during the HCT. <h3>Results</h3> Of the 37 patients studied, 21 (57%) had a positive HCT. Individuals with a positive HCT had a lower PaO<sub>2</sub> under normoxic conditions (10.1 kPa v 11.4 kPa, p &lt; 0.01), but similar PaCO<sub>2</sub> level (4.80 kPa v 4.91 kPa, p &gt; 0.05). Baseline oxygen saturation was poorly predictive of the need for supplementary oxygen and two-thirds of patients, for whom supplementary oxygen was recommended, had a baseline SpO<sub>2</sub> level of greater than 95%; approximately half of these individuals de-saturated to less that 90% on HCT (Figure 1). Lung function was more obstructed in the positive HCT group (predicted FEV1 (52% v 78%, p &lt; 0.01). Across the entire cohort, HCT was associated with a mean rise in heart rate (HR) of 5 bpm and there was no evidence of dysrhythmia or change in QTc. A combination of any two of: baseline PaO<sub>2</sub> ≤ 10.5 kPa, FEV1 ≤ 60% predicted and PEF ≤ 350 L/min predicted the need for in-flight oxygen with a sensitivity of 90% and a specificity of 69%. <h3>Conclusions</h3> In patients with severe asthma, baseline oxygen saturation level is poorly predictive of the need for in-flight oxygen. Our findings indicate that a HTC should be considered for all BTS/SIGN Step 5 asthmatics in whom air travel is being considered and should certainly be recommended in those with impaired lung function.
Brief Communication: Cortisol-Induced Lymphocytolysis of P1798 Tumor Cells in Glucose-Free, Pyruvate-Free Medium 2
Authors: John Stevens, Vee-Wan Stevens
Journal: JNCI Journal of the National Cancer Institute (1975)

Exposure of corticoid-sensitive P1798 tumor lymphocytes to cortisol resulted in progressive cell dissolution either with or without exogenous glucose and pyruvate. Therefore, inhibition of glucose transport is not required for cortisol-induced lymphocytolysis.
Final Report on Phase II Trial of L-Asparaginase Plus Concurrent Chemoradiotherapy Followed By Midle (Methotrexate, Ifosfamide, Etoposide, Dexamethasone, and L-asparaginase) Chemotherapy for Patients with Newly Diagnosed Stage I/II Extranodal NK/T-Cell Lymphoma, Nasal Type
Authors: Dok Hyun Yoon, Seok Jin Kim, Seong Hyun Jeong, Dong-Yeop Shin, Sung Hwa Bae, Junshik Hong, Seong Kyu Park, Ho-Young Yhim, Deok-Hwan Yang, Hye Won Lee, Mark Lee, Hyeonseok Eom, Jae-Yong Kwak, Jae Hoon Lee, Cheolwon Suh, Won Seog Kim
Journal: Blood (2015)
Precordial Murmurs during Pregnancy and Lactation
Authors: J. Willis Hurst, Jean Staton, David Hubbard
Journal: New England Journal of Medicine (1958)

A VARIETY of innocent murmurs may develop during pregnancy and are often attributed to heart disease. Some of these murmurs are due to an increase in blood velocity and emanate from the heart itself, whereas others are of extracardiac origin. Grant,1 Gilston and McPhaul2 and others have described the extracardiac precordial murmurs that occur during pregnancy. Our recent experience indicates that this information should be re-emphasized. Accordingly, the purpose of this report is to describe the extracardiac murmurs in 2 cases. The precordial systolic murmur in Case 1 was due to an arterial bruit and persisted after delivery and vanished . . .
Role of bevacizumab on class III beta tubulin and HIF-1a in paclitaxel-treated gastric cancer.
Authors: J. Hwang, H. Shim, W. Bae, J. Yoon, S. Cho, I. Chung
Journal: Journal of Clinical Oncology (2010)

e13656 Background: At present, there are eight beta tubulin isotypes in mammalian cells. Among these isotypes, class III beta tubulin was shown to confer resistance to antitubulin agents, such as paclitaxel or docetaxel. Of the inducer of class III beta tubulin (TUBB3), recent report showed that HIF-1a (hypoxia inducible factor-1alpha), one of contributor to chemoresistance in gastric cancer. And HIF-1a was suppressed in addition with anti-vascular endothelial growth factor, bevacizumab, in hypoxia sensitive cell line. This study was undertaken to investigate the role of bevacizumab on expression of class III beta tubulin and HIF-1a. Methods: We evaluated TUBB3 and HIF-1a expression under normoxic and hypoxic condition in human gastric cancer cell lines. The role of TUBB3 to antitumor effect of paclitaxel was checked through knockdown of TUBB3. TUBB3 and HIF-1a were measured under blocking of VEGFR1/2 with anti-FLT1 and anti-KDR antibody. The effects of bevacizumab and paclitaxel on TUBB3 and HIF1a expression were monitored by western blot and MTT assay. Results: The chemoresistance of paclitaxel was overcome by siTUBB3. In hypoxic condition, elevated expression of TUBB3 and HIF-1a were reduced by treating with anti-KDR and anti-FLT1 antibody. Compare to paclitaxel alone, when added bevacizumab to paclitaxel, the protein expressions of TUBB3 and HIF-1a were significantly decreased. Also, cell proliferation was more reduced in bevacizumab and paclitaxel combination than paclitaxel alone. Conclusions: Previously, VEGF has been well known as a target molecule of HIF-1a downstream signals. However, we showed that VEGF can also control HIF-1a as an upstream signal. Bevacizumab, which is blocker of VEGF, and paclitaxel synergistically suppressed HIF-1a and TUBB3. This study showed the potential key role of combination chemotherapy with bevacizumab and paclitaxel in TUBB3 expressed cancer. No significant financial relationships to disclose.
Reduction of Biogenic Amine Levels in the Rett Syndrome
Authors: Huda Y. Zoghbi, Alan K. Percy, Daniel G. Glaze, Ian J. Butler, Vincent M. Riccardi
Journal: New England Journal of Medicine (1985)

The Rett syndrome is a progressive disorder in female patients that is characterized by autistic behavior, dementia, ataxia, loss of purposeful use of the hands, and seizures. The results of laboratory investigations are usually normal, with the exception of electroencephalography. In an attempt to understand the pathogenesis of this syndrome, we assayed biogenic amine metabolites in the cerebrospinal fluid of six patients, 2 to 15 years of age. 3-Methoxy-4-hydroxyphenylethylene glycol (MHPG, a metabolite of norepinephrine), homovanillic acid (a metabolite of dopamine), and 5-hydroxyindoleacetic acid (5-HIAA, a metabolite of serotonin) were quantitated by a method involving gas chromatography and mass spectrometry. Levels of MHPG and homovanillic acid were significantly reduced in all the patients as compared with those in controls of similar age (P = 0.01 and 0.008, respectively). The reduction in the level of 5-HIAA was not significantly different from that in the controls (P = 0.15). These findings suggest an underlying disorder of biogenic amines in the Rett syndrome and may provide new insight into its pathogenesis.