tbuckley/cabot-search huggingface dataset:
Atypical teratoid/rhabdoid tumors—current concepts, advances in biology, and potential future therapies
Authors: Michael C Frühwald, Jaclyn A Biegel, Franck Bourdeaut, Charles W M Roberts, Susan N Chi
Journal: Neuro-Oncology (2016)

Atypical teratoid/rhabdoid tumor (AT/RT) is the most common malignant CNS tumor of children below 6 months of age. The majority of AT/RTs demonstrate genomic alterations in SMARCB1 (INI1, SNF5, BAF47) or, to a lesser extent, SMARCA4 (BRG1) of the SWItch/sucrose nonfermentable chromatin remodeling complex. Recent transcription and methylation profiling studies suggest the existence of molecular subgroups. Thus, at the root of these seemingly enigmatic tumors lies a network of factors related to epigenetic regulation, which is not yet completely understood. While conventional-type chemotherapy may have significant survival benefit for certain patients, it remains to be determined which patients will eventually prove resistant to chemotherapy and thus need novel therapeutic strategies. Elucidation of the molecular consequences of a disturbed epigenome has led to the identification of a series of transduction cascades, which may be targeted for therapy. Among these are the pathways of cyclin D1/cyclin-dependent kinases 4 and 6, Hedgehog/GLI1, Wnt/ß-catenin, enhancer of zeste homolog 2, and aurora kinase A, among others. Compounds specifically targeting these pathways or agents that alter the epigenetic state of the cell are currently being evaluated in preclinical settings and in experimental clinical trials for AT/RT.
Combination chemotherapy with gemcitabine, oxaliplatin and paclitaxel in patients with cisplatin-refractory or relapsed germ cell tumors (gct)
Authors: K. Oechsle, C. Bokemeyer, F. Honecker, F. Mayer, C. F. Waller, I. Boehlke, J. T. Hartmann, C. Kollmannsberger
Journal: Journal of Clinical Oncology (2007)

5084 Background: Treatment of pts with cisplatin-refractory GCT remains a therapeutic challenge. The present phase II study investigates the toxicity and activity of triple combination of gemcitabine/oxaliplatin/paclitaxel (GOP) in pts with multiple relapse or cisplatin- refractory GCT. Patients and Methods: Between 04/03 - 10/06, 41 patients (pts) refractory to cisplatin-based chemotherapy or with relapse after high-dose chemotherapy plus autologous peripheral blood stem cell transplantation (PBSCT) received 800 mg/m 2 gemcitabine, 80 mg/m 2 paclitaxel, both on days 1+8, and oxaliplatin 130 mg/m 2 on day 1 of a three week cycle for at least 2 cycles. Treatment was continued until tumor progression or a maximum of 8 cycles. Results: Pts were pretreated with a median number of 2 previous lines of platin-based chemotherapy (range, 1 - 3) and 78 % had relapsed after either first- (39%) or second-line high-dose chemotherapy (39%) with PBSCT. Responses: 5% of the pts achieved a complete response (CR), 47% a partial response and 20% a disease stabilisation. 20% of the pts underwent a secondary complete tumor resection resulting in a total NED-rate of 22%. After a median follow up time of 5 months (mos) (0 - 20+) 17% of the pts are continuously disease-free with a median response duration of 8 mos (1–17+). Median progression free and overall survival was 3 mos (1–17+) and 6 mos (1–19+), respectively. Toxicity was acceptable. 51% of 150 cycles could be applied without dose modifications or delay. Leucocytopenia grade 3/4 was observed in 15%, anemia in 7%, and thrombocytopenia in 49% of the patients. Grade 3/4 nonhematologic toxicities (diarrhoea, nausea and neurotoxicity) occurred in one patient each (2%). Conclusion: The triple combination chemotherapy with gemcitabine, oxaliplatin and paclitaxel is feasible and effective in patients with cisplatin-refractory or multiply relapsed germ cell tumors exhibiting an overall response rate of &gt;50% and prolonged survival in about 20% of the pts. Despite a significant rate of grade 3/4 thrombocytopenia the overall toxicity profile is acceptable. No significant financial relationships to disclose.
Prostate cancer prognosis via integrative and co-localized glandular morphometry and immunofluorescent protein biomarker expression.
Authors: Michael J. Donovan, Faisal M Khan, Richard Scott, Gerardo Fernandez, Carlos Cordon-Cardo
Journal: Journal of Clinical Oncology (2015)

262 Background: Quantitative image analysis of both the prostate needle biopsy (PNB) and the radical prostatectomy sample (RPS) have proven to be robust and predictive for prostate cancer (PCa) prognosis. While metrics assessing morphology and protein biomarker expression separately have been published in prognostic risk prediction models, we sought to determine the performance of novel approaches which combine protein biomarker expression with the morphometry of the gland wherein they express. In order to assess robustness, we evaluated these metrics in both PNB and RPS cohorts. Methods: Novel quantitative biometric features were derived from computerized analysis of morphology and immunofluorescent (IF) biomarker expression in PCa images. A Bayesian probabilistic approach to co-locate and quantify IF biomarker expression within various glandular sub-types was developed. This permitted differentiable analysis of PCa biomarkers such as androgen receptor (AR) in high and low Gleason grade glands of the same patient. Performance in predicting significant clinical disease progression (including metastasis and death-of-disease) was assessed via the concordance index (CI). Performance was evaluated independently in a cohort of 326 PNB samples (median 8-year follow up) and a cohort of 373 RPS (median 5-year follow up). Results: In a univariate analysis, previously published glandular morphology features had a CI of 0.68 (PNB) and 0.76 (RPS). Quantitative AR had a CI of 0.67 (PB) and 0.72 (RPS). Novel metrics of integrative co-localization resulted in a significant increase in prognostic accuracy; CIs of 0.72 (PNB) and 0.83 (RPS). These features separately assessed AR expression depending on the multiple glandular sub-types within the tumor sample. Conclusions: Integrating quantitative image analysis of morphology and IF biomarker expression in the PNB and RPS outperformed previous quantitative metrics. Such robust and reproducible metrics may prove beneficial in improving risk stratification models for future treatment decision making.
FRI0508 Clinical Presentations, Outcomes of Juvenile Dermatomyositis Patients Admitted in the Pediatric Intensive Care Unit
Authors: A. Besançon, C. Gitiaux, K. Brochard, L. Dupic, P. Quartier, C. Bodemer, B. Bader-Meunier
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Juvenile dermatomyositis (JDM) is a rare and heterogeneous pediatric-onset idiopathic inflammatory myopathy. It is a heterogeneous disease which may be complicated by life-threatening complications. Identifying causes, clinical and biological manifestations and outcomes of such complications may be helpful for their better early management <h3>Objectives</h3> We aim to describe the causes of admission in paediatric intensive care unit (PICU), clinical and biological presentation and outcomes of JDM patients <h3>Methods</h3> Retrospective study of JDM patients admitted in two french paediatric PICUs from 2005 to 2013 among a cohort of 116 JDM patients followed during the same period. <h3>Results</h3> 11/116 JDM patients (9.5%) (8 girls and 3 boys, median age at diagnosis: 9.0±3.1 years) were admitted in ICUs because of digestive involvement (digestive perforation: 2 patients, digestive ulceration: 1 patient, severe ileus: 1 patient), cardiac involvement (severe bradycardia: 1 patient, cardiac arrest: 1 patient), respiratory failure resulting from hypoxemic pneumonia (1 patient), thrombotic microangiopathy (TMA) (2 patients), posterior reversible encephalopathy syndrome (PRES) related to cyclosporine use (1 patient), and anaphylactic shock after an infusion of Rituximab. At admission in ICU, patients presented with some manifestations which did not usually occur in typical JDM:) generalized edema (6/11 patients), hyponatremia (9/11 patients), hypoalbuminemia (9/11 patients) and thrombocytopenia (7/11 patients). Treatment consisted in corticosteroids (including pulses of methylprednisolone in 5 patients), intravenous immunoglobulin (7), plasmapheresis (7), infusions of rituximab (4) and cyclophosphamide (2). The mean duration of stay in PICU was 18.2 days. One patient died in ICU from <i>pneumocystis carinii</i> pneumonia. The remaining 10 patients are in complete or partial remission with a median duration of follow-up of 4,8 years. <h3>Conclusions</h3> Severe digestive vasculopathy, cardiac and pulmonary involvements, TMA and therapy-related adverse events were responsible for admissions in PICU in 9,5% of JDM patients in our cohorts. This report suggests that generalized edema, thrombocytopenia revealing TMA, hyponatremia and hypoalbuminemia are associated with severe JDM, and that pulses of methylprednisolone might favour digestive perforation in patients with preexisting gastrointestinal vasculitis. Outcomes was favourable in all the patients presenting with non-infectious severe complications. <h3>Disclosure of Interest</h3> None declared
ERCP practitioners in China: results from national surveys in 2007 and 2013
Authors: Liang-Hao Hu, Lei Xin, Luo-Wei Wang, Wei Qian, Zhuan Liao, Zhao-Shen Li
Journal: Endoscopy (2016)

<b>Background and study aims:</b> The endoscopist performing endoscopic retrograde cholangiopancreatography (ERCP) has an essential role in the development of that procedure. Given that the practice status and training background of Chinese ERCP practitioners (ERCPists) were largely unknown, two surveys were conducted to determine the status and development of this professional group. <b>Methods:</b> National surveys were conducted by the Chinese Society of Digestive Endoscopy in 2007 and 2013. Information regarding numbers, demographic characteristics, practice status, and training background of ERCPists was collected. <b>Results:</b> Total numbers of ERCPists in mainland China increased from 1155 to 3345 (0.88 to 2.47 per million inhabitants) between 2006 and 2012. Regional distribution of ERCPists showed significant imbalance, and the ERCPist – population ratio correlated with gross domestic product per capita (2006, <i>r</i> = 0.871, <i>P</i> < 0.001; 2012, <i>r</i> = 0.452, <i>P</i> = 0.005). The mean (standard deviation) age of ERCPists decreased from 42.5 (6.1) years to 37.4 (5.4) years; the proportion of female ERCPists increased from 11.1 % to 16.8 %. In 2006 and 2012, annual ERCP volumes per endoscopist were 55.2 and 58.5, respectively, similar to that in most Western countries. The most common training pathway was participation in a training program in an ERCP center within China (2006, 51.1 %; 2012, 73.4 %); the proportion of ERCPists with no standard training decreased from 20.8 % to 8.0 %. <b>Conclusions:</b> Between 2006 and 2012 in China there has been significant development in ERCP personnel and training. However, the shortage and regional imbalances are still obvious and a higher ERCP volume per endoscopist is needed.
Abstract P359: Cardiovascular Risk Factor and Diseases in the Italian Adult Population: The National Health Examination Surveys 2008-2012
Authors: Chiara Donfrancesco, Luigi Palmieri, Cinzia Lo Noce, Francesco Dima, Amalia De Curtis, Patrizia De Sanctis Caiola, Diego Vanuzzo, Simona Giampaoli
Journal: Circulation (2013)

Background: From 2008 to 2012 an Health Examination Survey (HES)-Osservatorio Epidemiologico Cardiovascolare (OEC) has been implemented in Italy with the aim of assessing cardiovascular (CV) risk factors, prevalence of risk conditions and CV diseases for the Italian adult population. Methods: Random samples of general population stratified by age and sex were examined in all Italian regions (participation rate 56%). Risk factor were collected using standardized procedures and methods; biochemical tests were assayed in a central laboratory; a questionnaire investigates behaviours and CVD history; a ECG read in Minnesota code was used to define previous myocardial infarction. Comparisons between men and women were assessed using t-test for means and chi-squared test for prevalence. Results: Data of 4371 men and 4339 women ages 35-79 years were analysed. Majority of risk factors mean levels resulted higher in men than in women: systolic blood pressure (SBP) was 134 mmHg and 129 mmHg (p&lt;0.0001), diastolic (DBP) was 84 mmHg and 79 mmHg (p&lt;0.0001), fasting plasma glucose was 103 mg/dl and 95 mg/dl (p&lt;0.0001), triglycerides was 135 mg/dl and 108 mg/dl (p&lt;0.0001), respectively; as well as many CV risk conditions: smoking habit was 21% in men and 18% in women (p&lt;0.0001), diabetes was 14% in men and 9% in women (p&lt;0.0001) (28% of diabetic unaware both in men and women), 56% of men and 43% of women have SBP&gt;=140 mmHg or DBP&gt;=90 mmHg or in treatment (p&lt;0.0001), 65% of men and 70% of women have total cholesterol (TC) &gt;=200 mg/dl or in treatment for (p&lt;0.0001), 48% of men and 33% of women are in overweight (BMI 25-29 kg/m 2 ) (p&lt;0.0001). TC, LDL and HDL cholesterol resulted lower in men than in women: 209 mg/dl and 218 (44) (p&lt;0.0001), 131 (38) mg/dl and 134 mg/dl (p&lt;0.0001), 51 mg/dl and 62 mg/dl (p&lt;0.0001), respectively. As well as prevalence of physical inactivity during leisure time: 31% in men and 43% in women (p&lt;0.0001). Prevalence of obesity (BMI&gt;=30 kg/m 2 ) resulted similar in men and women: 25% and 27% respectively (p=0.0818). Prevalence of myocardial infarction was 2.1% in men and 0.7% in women (p&lt;0.0001), prevalence of by-pass or angioplasty surgery was 5.1% and 1.0% (p&lt;0.0001), prevalence of angina pectoris was 3.2% and in 4.8% (p&lt;0.0001), respectively. Conclusions: At present obesity and smoking are still a priority in public health. In combination with other information sources, the OEC can contribute greatly to plan community actions and health services at national and regional level.
Circulating Cell-Free Tumor DNA Analysis of 50 Genes by Next-Generation Sequencing in the Prospective MOSCATO Trial
Authors: Cécile Jovelet, Ecaterina Ileana, Marie-Cécile Le Deley, Nelly Motté, Silvia Rosellini, Alfredo Romero, Celine Lefebvre, Marion Pedrero, Noémie Pata-Merci, Nathalie Droin, Marc Deloger, Christophe Massard, Antoine Hollebecque, Charles Ferté, Amélie Boichard, Sophie Postel-Vinay, Maud Ngo-Camus, Thierry De Baere, Philippe Vielh, Jean-Yves Scoazec, Gilles Vassal, Alexander Eggermont, Fabrice André, Jean-Charles Soria, Ludovic Lacroix
Journal: Clinical Cancer Research (2016)

Abstract Purpose: Liquid biopsies based on circulating cell-free DNA (cfDNA) analysis are described as surrogate samples for molecular analysis. We evaluated the concordance between tumor DNA (tDNA) and cfDNA analysis on a large cohort of patients with advanced or metastatic solid tumor, eligible for phase I trial and with good performance status, enrolled in MOSCATO 01 trial (clinical trial NCT01566019). Experimental Design: Blood samples were collected at inclusion and cfDNA was extracted from plasma for 334 patients. Hotspot mutations were screened using next-generation sequencing for 50 cancer genes. Results: Among the 283 patients with tDNA–cfDNA pairs, 121 had mutation in both, 99 in tumor only, 5 in cfDNA only, and for 58 patients no mutation was detected, leading to a 55.0% estimated sensitivity [95% confidence interval (CI), 48.4%–61.6%] at the patient level. Among the 220 patients with mutations in tDNA, the sensitivity of cfDNA analysis was significantly linked to the number of metastatic sites, albumin level, tumor type, and number of lines of treatment. A sensitivity prediction score could be derived from clinical parameters. Sensitivity is 83% in patients with a high score (≥8). In addition, we analyzed cfDNA for 51 patients without available tissue sample. Mutations were detected for 22 patients, including 19 oncogenic variants and 8 actionable mutations. Conclusions: Detection of somatic mutations in cfDNA is feasible for prescreening phase I candidates with a satisfactory specificity; overall sensitivity can be improved by a sensitivity score allowing to select patients for whom cfDNA constitutes a reliable noninvasive surrogate to screen mutations. Clin Cancer Res; 22(12); 2960–8. ©2016 AACR.
THE UNCOUPLING OF OXIDATIVE PHOSPHORYLATION AS A MECHANISM OF DRUG ACTION
Authors: THEODORE M. BRODY
Journal: Pharmacological Reviews (1955)

Under normal circumstances the oxidative metabolism of living cells and of certain isolated systems leads to the synthesis of compounds containing high-energy phosphate bonds. These compounds are known to be essential for such functions as growth, muscle contraction, nerve conduction, etc. A number of substances are able to alter this relationship by depressing the formation of high-energy bonds without depressing simultaneously the oxygen consumption of the system. This dissociation of oxidation and phosphorylation is termed uncoupling.

Many of the substances which have been shown to uncouple phosphorylation from oxidation are drugs which have been employed in experimental pharmacology and therapeutics. Whether the effectiveness of these substances as drugs is dependent upon their effectiveness as uncoupling agents is the consideration of this review. The fact that a substance has the ability to uncouple phosphorylation from oxidation does not indicate that it is devoid of other fundamental actions. The relative importance of uncoupling as a mechanism of action will differ, of course, with different drugs. That uncoupling is of major importance in the action of certain drugs is at present a most attractive hypothesis.

With each succeeding step in our inquiry, our questions become more sophisticated and the answers to the questions become more specific. At first it was sufficient to say that certain drugs acted by interfering with oxidation. Further study leads to the differentiation of substances which depress both oxygen consumption and phosphorylation from substances which depress phosphorylation but leave oxygen consumption relatively unaffected.

Study of these latter substances, the uncoupling agents, reveals further subgrouping: 1) those agents which stimulate oxygen consumption and are insensitive to magnesium ion changes ( e.g., dinitrophenol) and 2) agents which do not stimulate oxygen consumption while depressing phosphorylation and whose action is reversed by magnesium ions ( e.g., the tetracyclines). The significance of this difference remains to be explained.

Further study and formulation will surely reveal some of our present concepts to be naive. But so long as we consider the orderly flow of energy through cellular systems essential to normal function, we may consider important any agent capable of diverting this energy stream. It is from this frame of reference that the author has reviewed the phenomenon of uncoupling.
Abstract 9955: Suboptimal Diagnosis and Interventional Treatment of Patients with Bundle Branch Block and Acute Myocardial Infarction
Authors: Jacob T Sørensen, Carsten Stengaard, Christina A Sørensen, Kristian A Thygesen, Hans Erik Bøtker, Leif Thuesen, Christian J Terkelsen
Journal: Circulation (2012)

Several studies have shown the benefit of rapid revascularization in patients with presumed new-onset bundle branch block myocardial infarction (BBBMI). It is a major challenge to determine the age of the bundle branch block (BBB) and triage accordingly in the acute setting. Methods Prehospital ECGs, final diagnosis and mortality were assessed in 4905 consecutive patients with suspected AMI. BBB was defined as QRS duration &gt;120 ms in the absence of pace-rhythm, AV-block or ventricular rhythm. Mortality and angiography data were obtained from the Danish Cause of Death Registry and the Western Denmark Heart Registry. Final diagnosis of AMI and the onset of BBB were determined by expert consensus. Patients were divided into 4 groups +/-AMI and +/- BBB. Mortality was evaluated by Kaplan-Meier plots using Log rank statistics. Results AMI was diagnosed in 954 patients, of whom 118 had BBBMI. In the 3951 patients without AMI, 436 had BBB. Coronary angiography (CAG) was performed in significantly fewer patients with BBBMI compared to patients with AMI without BBB (41% vs. 68%, p&lt;0.001). In patients undergoing CAG, revascularization was more frequent in AMI patients without BBB (59% vs. 79%, p=0.002). BBBMI was categorized as new-onset in 43 patients. Significantly more patients with new-onset BBB underwent CAG compared to patients with established BBB (67% vs. 26%, p&lt;0.001). Among those undergoing CAG, there was no difference frequency of revascularization between the groups (59% vs. 58%, p=0.99). Among patients with an adjudicated diagnosis of new-onset BBBMI 2/43=5% were triaged for acute angioplasty. Patients with BBBMI had the highest mortality of all groups (Log-rank p&lt;0.001) (Figure). Conclusions: Patients with new-onset BBBMI seem to be difficult to diagnose based on ECG and symptoms, leading to low rates of invasive procedures despite high mortality. To improve outcome we recommend a more aggressive approach to diagnosing and triaging patients with BBB and chest pain.
Abstract 11572: Hyperuricemia Reflects Heart Failure Severity and Predicts Morbidity and Mortality in Patients After the Fontan Operation
Authors: Hideo Ohuchi, Yosuke Hayama, Jun Negishi, Kanae Noritake, Osamu Sasaki, Nobuyuki Tsujii, Toru Iwasa, Heima Sakaguchi, Aya Miyazaki, Osamu Yamada
Journal: Circulation (2014)

Background: Serum uric acid level (UA, mg/dl) not only associates with pathophysiology in adult patients with chronic heart failure but also predicts the cardiac events. However, the clinical significance of UA remains unclear in patients after the Fontan operation. Purpose: To clarify clinical significance of hyperuricemia (HUA, UA≥7.0) in Fontan patients. Methods and Results: We prospectively measured UA in consecutive 306 Fontan patients (16±8 years) and compared the results with the clinical variables, including hemodynamics, exercise capacity, plasma levels of norepinephrine (NE), brain natriuretic peptide (BNP), and unscheduled hospitalization (USH), including all-cause mortality. The UA was 5.8±1.7 and 70 (23%) patients showed HUA. On multivariate model, high levels of plasma creatinine and NE, use of diuretics, low cardiac index, hypoxia, and hyponatrenia independently associated with HUA (p&lt;0.05-0.001), however BNP level did not correlate with UA (p=0.35). During a follow-up of 49±27 months, 69 USH, including 16 deaths, occurred. In addition to BNP levels, HUA independently predicted USH (hazard ratio [HR]: 2.9, 95% confidence interval [CI]: 1.8-4.6, p&lt;0.0001) and mortality (HR: 3.8, 95%CI: 1.4-10, p&lt;0.01). When compared with Fontan patients with normal UA with low BNP, those with HUA and high BNP (≥18.4 pg/ml) had a high HR of 7.0 (CI:3.5-14.1, p&lt;0.0001) and 11.7 (CI:2.9-78.1, p&lt;0.001) for USH and all-cause mortality, respectively. Conclusions: UA is a simple and clinically useful marker for stratifying heart failure severity of Fontan patients and HUA predicts the morbidity and mortality.