tbuckley/cabot-search huggingface dataset:
<i>RAS</i> mutations in EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab (C) in MRI-defined, high-risk rectal cancer (RC).
Authors: Francesco Sclafani, David Gonzalez, David Cunningham, Sanna Hullki Wilson, Clare Peckitt, Josep Tabernero, Bengt Glimelius, Andres Cervantes, Andrew Wotherspoon, Gina Brown, Diana M. Tait, Jacqueline Rose Oates, Ian Chau
Journal: Journal of Clinical Oncology (2014)

489 Background: Studies indicate that RAS mutations beyond KRAS exons 2-3 may predict anti-EGFRs benefit. EXPERT-C was a randomized phase II trial of neoadjuvant CAPOX and CRT ± C in MRI-defined, high-risk RC. We have previously shown that adding C in KRAS (exons 2-3)/BRAF wild type (WT) patients did not improve complete response (CR) and was associated with a non-significant improvement in progression-free survival (PFS) (HR 0.62, p=0.23) and overall survival (OS) (HR 0.56, p=0.20). The aim of this study was to analyse the impact of RAS mutations on the outcome of C-treated patients in this trial. Methods: Between October 2005 and July 2008, 164 eligible patients were randomly assigned to 4 cycles of CAPOX followed by CRT, surgery, and 4 cycles of adjuvant CAPOX (n=81) or the same regimen plus C (CAPOX-C, n=83). KRAS (exons 2-3) and NRAS (exon 3) mutations were prospectively analysed. Of 90 KRAS/NRAS WT patients, 84 were retrospectively analysed for additional KRAS (exon 4) and NRAS (exons 2/4) mutations by using bi-directional Sanger sequencing. The effect of C on CR, PFS, and OS in patients with RAS WT tumors was analyzed. PFS and OS were estimated with the Kaplan-Meier method and treatment arms compared using a log-rank analysis. Results: Eleven (13%) of 84 patients initially classified as KRAS/NRAS WT were found to have tumours harbouring a mutation in KRAS exon 4 (11%) or NRAS exons 2/4 (2%). Overall, after this retrospective mutation analysis, 78/149 (52%) assessable patients were RAS WT (CAPOX, n=40; CAPOX-C, n=38). After a median follow-up of 63.8 months, in line with the initial analysis, the addition of C in the group of RAS WT patients, was associated with numerically higher, but not statistically significant, rates of CR (15.8% vs. 7.5%, p=0.31), 5-year PFS (78.4% vs. 67.5%, p=0.17) and 5-year OS (83.8% vs. 70%, p=0.20). Conclusions: Although the results of our analysis are potentially affected by the small numbers, in our locally advanced RC population the status of RAS did not appear to significantly improve the selection of patients who may benefit from the use of an anti-EGFR therapy.
Renegotiating medicine's contract with patients
Authors: R. Smith
Journal: BMJ (1998)

The social contract between doctors and the public is being renegotiated. The contract says in essence: “In return for guaranteeing that we will be treated by competent doctors who will respect our dignity and offer us services better than those of the local garage we the public will give you doctors status, above average incomes, and the privilege of regulating yourselves.” The contract is renegotiated not by bald men in suits in back rooms but rather by the public expressing its disquiet in a myriad of forms—align=baseline border=0>through, for example, parliament, the media, and patients' organisations—align=baseline border=0>and by the profession recognising the disquiet and responding. The BMA, the Academy of Medical Royal Colleges, and postgraduate and undergraduate deans last month produced a report on improving self regulation at the local level, 1 2 while the Royal College of Physicians of London has before it a document that calls on it to “put in place urgently evidence that robust mechanisms exist for self regulation of its members and fellows.” 3 But it is the General …
Abstract 77: Vitamin-C Compromises Cardiac Resuscitability in a Rat Model of Ventricular Fibrillation and Closed Chest Resuscitation
Authors: Jill R Motl, Jeejabai Radhakrishnan, Iyad M Ayoub, Stefek Grmec, Raul J Gazmuri
Journal: Circulation (2010)

Introduction: Resuscitation from cardiac arrest is in part limited by progressive reduction in left ventricular distensibility, which compromises the ability of chest compression to generate blood ...
Abstract 272: Disruption Of Cardiac Specific Sarcolemmal Atp Sensitive Potassium Channel (skAtp) Activity Diminishes Cardiac Stress Handling Capacity By Impairing Pgc-1alpha Dependent Mitochondrial Biogenesis
Authors: Xinli Hu, Xin Xu, Thomas P Flagg, Colin G Nichols, Robert J Bache, YingJie Chen
Journal: Circulation (2007)
Abstract 3276: Consumption Of Fatty Fish Is Negatively Associated With The Risk Of Acute Coronary Syndrome In Healthy Men
Authors: Albert Marni Joensen, Lone J Bjerregaard, Claus Dethlefsen, Majken K Jensen, Søren P Johnsen, Anne Tjønneland, Lars H Rasmussen, Kim Overvad, Erik B Schmidt
Journal: Circulation (2008)

Consumption of fish has been reported to decrease coronary mortality among subjects with known coronary heart disease (CHD), whereas such an effect is less documented in healthy subjects. Few studies have distinguished between intake of fatty fish (defined as a content of long-chained n-3 polyunsaturated fatty acid, greater than 1 g per 100 g of fish) and intake of lean fish. Objective To assess the hypothesis that consumption of fatty fish is negatively associated with the risk of acute coronary syndrome (ACS) in healthy men. Methods In the Danish cohort-study Diet, Cancer and Health 27,178 men between 50 and 64 years of age were enrolled. In a validated food frequency questionnaire, participants gave information on dietary intake of fatty fish. During a mean follow-up period of 7.6 years, we identified all cases from this cohort (n=854) with an incident ACS-diagnosis in the Danish National Patient Registry. Diagnoses were verified through medical record review. In Cox proportional hazard models, we adjusted for several well established risk factors for CHD. Results Conclusion The risk of ACS was 30% lower among men in the highest 4 quintiles of fatty fish consumption, compared with men in the lowest quintile, in this large Danish cohort study. There was no dose-response association.
Organic impairment in polydrug users: risk factors
Authors: Igor Grant, Kenneth M. Adams, Albert S. Carlin, Phillip M. Rennick, Lewis L. Judd, Kenneth Schooff, Robert Reed
Journal: American Journal of Psychiatry (1978)

In a national collaborative study to assess the neuropsychological status of 151 polydrug users, the Halstead-Reitan Neuropsychological Battery showed deficits in 37% two to three weeks after they entered treatment and in 34% at three-month follow-up. Comparative rates for a group of psychiatric patients were 26% and 27%, and for nonpatients, 8% and 4%. Extensive and intensive use of CNS depressants and opiates correlated positively with neuropsychological deficit. Older, less-educated subjects with adverse medical or developmental histories were more likely to show polydrug-related organic impairment. Although there is some evidence that such impairment is reversible, the condition appears to be of at least intermediate duration and may be long lasting.
Abstract 1927: High-dose Simvastatin Alone Inhibits Rho Kinase and Improves Flow-mediated Vasodilatation to a Greater Extent than Combination of Low-dose Simvastatin and Ezetimibe, Despite Comparable Lipid-Lowering
Authors: Ping-Yen Liu, Ping-Yen Liu, Yen-Wen Liu, Li-Jen Lin, Jyh-Hong Chen, James K Liao
Journal: Circulation (2008)

Background: By inhibiting HMG-CoA reductase, statins not only inhibit cholesterol biosynthesis, but also decrease the formation of isoprenoids, which are important for mediating signaling through the Rho/Rho kinase (ROCK) pathway. In animal studies, inhibition of ROCK by statins improves endothelial function, decreases inflammation, and prevents atherosclerosis. These so-called cholesterol-independent effects of statins are dose-related and may contribute to some of their clinical benefits. We hypothesize that ezetimibe, which inhibits cholesterol absorption, does not exert these cholesterol-independent effects in humans. Methods and Results: We studied 60 dyslipidemia subjects (n=20 in each arm) in a prospective, randomized, observer-blinded study comparing treatment with simvastatin 40 mg/d or simvastatin/ezetimibe 10/10 mg/d to corresponding placebo tablets for 28 days. Prior statin usage was comparable between the groups and a washout period of 2 weeks was instituted before enrollment. Blood samples for fasting lipids, leukocyte ROCK activity and C-reactive protein (CRP) were collected at days 0 and 28. Baseline demographics, lipid levels, ROCK activity and CRP were not different between the 3 groups. Compared to placebo group, both treatment regimens decreased low-density lipoprotein cholesterol (LDL-C) by 38% and CRP by 32– 42% after 28 days (p&lt;0.001 for both compared to placebo). Although LDL-C and CRP were reduced to comparable levels by either lipid-lowering regimen (p&gt;0.05 between the groups), only simvastatin 40 mg reduced ROCK activity and improved forearm flow-mediated vasodilatation (FMD) (p&lt;0.01 for both compared to baseline). The reduction of ROCK activity with simvastatin 40 mg remained significant even after controlling for changes in LDL-C (p=0.01) and correlated with improvement in FMD (R 2 =0.78, p&lt;0.01). However, there was no correlation between changes in FMD with changes in LDL-C or CRP. Conclusions: These findings suggest that despite comparable decrease in LDL-C and CRP, high-dose statin monotherapy has greater effects on both ROCK activity and endothelial function than low-dose statin and ezetimibe. These findings provide additional evidence of potential statin benefits beyond cholesterol lowering.
Rash severity and dose in phase I dose escalation cetuximab (C225) trial
Authors: R. S. Sangha, C. Ho, L. Beckett, M. Tanaka, D. H. Lau, D. B. Eisen, P. C. Mack, R. A. Burich, D. R. Gandara, A. M. Davies
Journal: Journal of Clinical Oncology (2008)

14573 Background: C225 is a monoclonal antibody targeting epidermal growth factor receptor (EGFR). The FDA-approved dose is 400 mg/m2 loading with weekly maintenance at 250 mg/m2. C225 efficacy has been correlated with grade of skin rash, which is reported to be dose dependent. This study examined the safety and feasibility of escalating weekly C225 doses, and evaluated skin rash as a surrogate for tumor response. Methods: Four dose levels were tested: C225 400 mg/m2 loading and 250, 300, 350, 400 mg/m2 weekly maintenance. Dose limiting toxicity (DLT) was defined as: grade (Gr) 4 platelets, Gr 3 platelets with bleeding, febrile neutropenia, Gr 4 cutaneous toxicity, Gr 3 cutaneous toxicity necessitating holding C225 for > 4 weeks, or other ≥ Gr 3 non-hematologic toxicity. Rash was evaluated using two additional validated dermatology methods: global acne grading scale (GAGS) and acne lesion counting (Int J Derml 36:416–18, 1997; J Am Acad Derm 35:559–65, 1996). Tumor specimens and blood samples were obtained for correlative analyses. Results: Twenty-six patients (pts) with advanced solid tumors were treated, including: 5 head & neck, 3 pancreas, 3 cholangiocarcinoma, 2 each of prostate, breast, colorectal, lung, and esophagus, and 5 others. Characteristics: Age range 44–84, median 60; Gender: 19 M; KPS ≥80 = 15; Prior chemo ≤1= 6; Median cycles 2 (1–8). Planned dose escalation was completed without DLTs nor reaching the MTD. The highest dose level was expanded to 17 pts total. Gr 3/4 toxicities were: lymphopenia (2), fatigue (2), acneiform rash (1), hypomagnesemia (1), and elevated GGT (1). In 22 evaluable pts, there was 1 partial response (PR) in a pt with cholangiocarinoma, and 7 with stable disease (SD). 65% of pts had a ≥ Gr 2 rash that was not dose dependent. GAGS and acne grading scale analyses will be described. In ongoing analyses, 1 of 9 pts had a KRAS mutation (pancreas, PD), 1 of 8 had EGFR amplification by FISH (heavily pre-treated breast, SD). Additional planned correlatives include EGFR polymorphisms and tumor/plasma levels of EGFR ligands. Conclusions: 1) C225 400 mg/m2 loading with 400 mg/m2 maintenance is feasible and well tolerated. 2) Grade of rash is not dose dependent using the CTCAE v3.0 and does not correlate with response in this limited cohort. 3) Novel methods of evaluating rash are required. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration OSI Oncology Bristol-Myers Squibb Bristol-Myers Squibb
Primary Sclerosing Cholangitis
Authors: Nicholas F. LaRusso, Russell H. Wiesner, Jurgen Ludwig, Robert L. MacCarty
Journal: New England Journal of Medicine (1984)

Primary sclerosing cholangitis is a progressive, ultimately fatal, chronic hepatobiliary disorder for which no effective medical or surgical therapy now exists. The syndrome occurs most commonly in young men and is characterized by a chronic cholestatic syndrome, frequent association with chronic ulcerative colitis, hepatic copper overload, a paucity of serologic markers, and characteristic abnormalities in some liver-biopsy specimens and most cholangiograms. The natural history of the syndrome is unclear; the disease is likely to progress slowly and relentlessly, over a decade or longer, from an asymptomatic stage to a condition characterized by symptoms of cholestasis and complicated by cirrhosis, portal hypertension, and possibly carcinoma of the bile ducts. Screening techniques based on automated biochemical analyses are likely to lead to a diagnosis of primary sclerosing cholangitis in increasing numbers of patients, perhaps in the early, preicteric stage. An increased level of serum alkaline phosphatase in a young man, particularly if he has chronic ulcerative colitis, should strongly suggest the presence of this syndrome and the need for additional diagnostic studies. Endoscopic retrograde cholangiography and liver biopsy should be considered under these circumstances.
WHO project is under way
Authors: R. Edwards
Journal: BMJ (1995)

critical determinant of excess weight gain for some people.This is why we have emphasised negative proxies for activity (ownership of cars and labour saving devices, television viewing, etc).We dis- pute Morris's claim that television viewing is declining to any great extent.According to figures published by the Central Statistical Office, average viewing was 26 hours 32 minutes a week in 1986 and 26 hours 44 minutes in 1992.4Over the same period the number of households owning a video recorder rose from 9 million to 17 million, which implies that secondary viewing will have risen sharply.With respect to food intake, space constraints prevented us from presenting cross sectional data that corroborate the apparent fall in energy intake recorded by the national food survey.The figure shows a compilation of weighed dietary surveys of adults in Britain.Overall intakes are higher than that found in the national food survey, reflecting the fact that weighed surveys record all foods and beverages, but the downward trend is similar.
Abstract 1800: Unfractionated Heparin Dosing and Major Bleeding in Non-ST-Segment Elevation Acute Coronary Syndromes
Authors: Chiara Melloni, Karen P Alexander, Anita Y Chen, Matthew T Roe, L. Kristin Newby, E. Magnus Ohman, W. Brian Gibler, Sidney C Smith, Charles V Pollak, Eric D Peterson
Journal: Circulation (2007)

Background : Unfractionated heparin (UFH) is a mainstay in the treatment of ACS, but failure to adjust UFH dosing based on pt weight is common. Methods : We used data from 31,445 high-risk ACS pts in 420 CRUSADE hospitals to assess initial UFH bolus and infusion doses relative to guidelines recommendations (60–70 U/Kg bolus and 12–15 U/Kg/h infusion). We evaluated the following: UFH excess dosing (&gt;70 U/kg bolus or &gt;15 U/kg/min infusion) vs. no excess dosing; excess dosing and major bleeding, overall and in subgroups; and factors associated with excess dosing. Results : An excess dose of UFH was given 35% of the time (8.9% excess infusion, 9.0% excess bolus, 17.1% both); more often to women, elderly, and those with low body weight (Figure). There was a digit preference for bolus doses of 5000 U (37%), and infusion doses of 1000 U/h (45%). The factors most associated with excess dosing were older age (OR 1.11, 95% CI 1.08–1.15) and female sex (OR 1.45, 95% CI 1.33–1.59). Although individually excess bolus (OR 1.03, 95% CI 1.00–1.06) and excess infusion (OR 1.16, 95% CI 1.05–1.28) each contribute to bleeding, considered together only excess infusion remained significantly associated with bleeding (OR 1.13, 95% CI 1.01–1.26). Although women and elderly bleed more, the relationship between UFH dose (bolus and infusion individually) and major bleeding did not vary across sex and age. Conclusion : In high-risk NSTE ACS pts, both UFH bolus and infusion dosing is often outside the recommended range. Excess dosing is common among elderly and women and is related to increased bleeding. Attention to dosing by weight rather than one-size-fits-all bolus and infusion dosing should improve safety in the use of UFH.
Abstract 12033: Complications and Outcomes of Bilateral, Bidirectional, Glenn Shunts versus Unilateral, Bidirectional, Glenn Shunts
Authors: Kenneth W McKinley, Thomas L Spray, Anirban Banerjee
Journal: Circulation (2012)

Background: It is not known if patients with bilateral, bidirectional, Glenn shunts (BBDG) are predisposed to lower oxygen saturations, need more catheter-based interventions or require earlier Fon...
Abstract 13794: Fibrosis in Atrial Walls is Associated with the Presence and Severity of Atrial Fibrillation but not with Age
Authors: Pyotr Platonov, Lubov Mitrofanova, Dmitry Lebedev, Siew Yen Ho
Journal: Circulation (2010)

Background: Development of fibrosis in atrial walls is associated with deterioration of atrial conduction and predisposes to atrial fibrillation (AF) in experiment. Human data, however, are scarce and whether fibrosis is the cause or consequence of AF in humans is not known. Aim of our study was to assess the association between the extent of fibrosis in human atria, age and history of AF. Methods: Human atria collected from autopsies in 21 pts (61±12 y., range 39–82, 9 females) died from myocardial infarction (n=15), stroke (n=1) and pulmonary embolism (n=5) were studied. According to medical records, 5 pts had no AF history (65±13 y.), 9 pts had paroxysmal AF (63±10 y.) and 7 pts had permanent AF (55±12 y.). Tissue samples were obtained from 3 locations in the left atrium: between superior pulmonary veins (SPV), in the center of the posterior LA wall (CPV) and between inferior pulmonary veins (IPV); and 2 locations in the right atrium: crista terminalis (CT) and Bachmann's bundle (BB). Histological sect...
Abstract 502: Long-Term Effects of a Rapid Response Team on Hospital-Wide Code Rates and Mortality
Authors: Paul S Chan, Adnan Khalid, Lance Longmore, Robert Berg, Mary Ann Peberdy, Mikhail Kosiborod, John A Spertus
Journal: Circulation (2008)

Background: Rapid response teams (RRTs) have been shown to decrease cardiopulmonary arrest (code) rates outside of the intensive care unit (ICU). Because a primary action of RRTs is to transfer patients to the ICU, their impact on hospital-wide code rates and mortality remains poorly understood. Methods: Data on RRT activations and codes were prospectively collected at a 404-bed tertiary care academic hospital. RRT education and program rollout occurred from September to December, 2005. A total of 24,193 patient admissions were evaluated pre-intervention (January 2004 to August 2005), and 24,978 admissions were evaluated post-intervention (January 2006 to August 2007). Main outcome measures were hospital-wide code rates and mortality; these were compared between the pre- and post-intervention periods using multivariable regression models that adjusted for pre-intervention trends and differences in demographics and hospital case mix. Results: After RRT implementation, mean hospital-wide code rates decreased from 11.2 to 7.5 per 1000 admissions. This was associated with a trend toward lower code rates (Odds Ratio [OR]=0.76; 95% CI: 0.57 to 1.01; p=0.06) and was mediated through lower rates of non-ICU codes (non-ICU: OR=0.59; 95% CI: 0.40 – 0.89 vs. ICU: OR=0.95; 95% CI: 0.64–1.43; p-value for interaction of 0.03). The effect of RRTs on code rates was similar for codes due to respiratory arrests, shockable cardiac arrests (ventricular fibrillation and pulseless ventricular tachycardia), and non-shockable cardiac arrests (pulseless electrical activity and asystole) (p-value for interaction of 0.42). However, hospital-wide mortality did not differ between the pre- and post-intervention periods (3.22 vs. 3.09 per 100 admissions; OR=0.95; 95% CI: 0.81 to 1.11; p=0.52). Post-hoc analyses revealed 18 instances of RRT under-treatment or underutilization that would not have significantly affected the mortality findings had these deaths been avoided (OR of 0.93; 95% CI: 0.79 to 1.09; p=0.35). Conclusions: RRT implementation was associated with a strong trend toward lower hospital-wide code rates, especially in non-ICU settings. However, further studies are required to demonstrate a mortality benefit before RRTs become the standard of care.
Abstract 509: Myocardial Fatty Acid Oxidation Rates Remain Elevated in ob/ob Mice Despite Reversal of Obesity and Diabetes by Caloric Restriction
Authors: Crystal Sloan, Joseph Tuinei, E. Dale Abel
Journal: Circulation (2007)

Leptin deficient ob/ob mice are commonly used to study the effects of obesity and insulin resistance on myocardial substrate metabolism. However, it is difficult to discern the specific contribution of obesity, insulin resistance and diabetes versus leptin deficiency to the observed phenotypes. We therefore adopted a strategy using caloric restriction to normalize body weight and reverse insulin resistance to study the effect of leptin deficiency on myocardial metabolism in lean ob/ob mice. Male 4-week old ob/ob mice were “pair fed” to a leptin-treated group (3mg/kg/day by i.p. injection) for three weeks. Glucose tolerance, serum insulin, serum triglycerides and FA oxidation rates in hearts perfused with 0.4mM palmitate ± 1 nM insulin were determined. Leptin-treated ob/ob mice ate significantly less than non-treated ob/ob mice, and their weight returned to wild type levels. Hyperglycemia, hyperinsulinemia, hypertriglyceridemia and cardiac hypertrophy were also completely reversed in leptin-treated ob/ob mice. In contrast, cardiac hypertrophy persisted in pair fed ob/ob mice and despite normalization of glucose tolerance and insulin levels, serum triglyceride concentrations increased by 2 and 6 -fold in pair fed ob/ob mice relative to untreated ob/ob and wildtype mice respectively (p&lt;0.05). As previously reported, palmitate oxidation rates were 2.1-fold increased in ob/ob hearts relative to controls (p&lt;0.005) and were normalized with leptin treatment. In contrast, palmitate oxidation rates remained elevated in pair fed ob/ob mice relative to wildtype controls (1.9-fold, p&lt;0.01). Insulin has a positive inotropic effect in perfused wildtype hearts, and this effect was absent in ob/ob hearts. The insulin-induced inotropic response was restored by leptin treatment in ob/ob mice but was not restored in pair fed ob/ob mice. These data support a direct antihypertrophic effect of leptin in the heart and suggest that leptin deficiency may directly contribute to myocardial insulin resistance and abnormal FA metabolism. Potential mechanisms include increased hepatic triglyceride production in leptin deficiency or direct effects of leptin signaling in the hypothalamus and/or the periphery on myocardial substrate utilization.