tbuckley/cabot-search huggingface dataset:
Expert opinions and scientific evidence for colonoscopy key performance indicators
Authors: Colin J Rees, Roisin Bevan, Katharina Zimmermann-Fraedrich, Matthew D Rutter, Douglas Rex, Evelien Dekker, Thierry Ponchon, Michael Bretthauer, Jaroslaw Regula, Brian Saunders, Cesare Hassan, Michael J Bourke, Thomas Rösch
Journal: Gut (2016)

Colonoscopy is a widely performed procedure with procedural volumes increasing annually throughout the world. Many procedures are now performed as part of colorectal cancer screening programmes. Colonoscopy should be of high quality and measures of this quality should be evidence based. New UK key performance indicators and quality assurance standards have been developed by a working group with consensus agreement on each standard reached. This paper reviews the scientific basis for each of the quality measures published in the UK standards.
Cardiac Fabry Disease With Late Gadolinium Enhancement Is a Chronic Inflammatory Cardiomyopathy
Authors: Sabrina Nordin, Rebecca Kozor, Heerajnarain Bulluck, Silvia Castelletti, Stefania Rosmini, Amna Abdel-Gadir, Shanat Baig, Atul Mehta, Derralynn Hughes, James C. Moon
Journal: Journal of the American College of Cardiology (2016)
Discordance between tender and swollen joint count as well as patient's and evaluator's global assessment may reduce likelihood of remission in patients with rheumatoid arthritis and psoriatic arthritis: data from the prospective multicentre NOR-DMARD study
Authors: Brigitte Michelsen, Eirik Klami Kristianslund, Hilde Berner Hammer, Karen Minde Fagerli, Elisabeth Lie, Ada Wierød, Synøve Kalstad, Erik Rødevand, Frode Krøll, Glenn Haugeberg, Tore K Kvien
Journal: Annals of the Rheumatic Diseases (2016)

To investigate the predictive value of discordance between (1) tender and swollen joint count and (2) patient's and evaluator's global assessment on remission in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA).From the prospective, multicentre Norwegian-Disease-Modifying Antirheumatic Drug study, we included patients with RA and PsA starting first-time tumour necrosis factor inhibitors and DMARD-naïve patients starting methotrexate between 2000 and 2012. The predictive value of ΔTSJ (tender minus swollen joint counts) and ΔPEG (patient's minus evaluator's global assessment) on remission was explored in prespecified logistic regression models adjusted for age, sex, disease duration and smoking.A total of 2735 patients with RA and 1236 patients with PsA were included (mean (SD) age 55.0 (13.5)/48.3 (12.4) years, median(range) disease duration 0.7 (0.0-58.0)/1.3 (0.0-48.3) years, 69.7/48.4% females). Baseline ΔTSJ/ΔPEG reduced the likelihood of achieving DAS28<2.6, SDAI≤3.3, CDAI≤2.8, ACR/EULAR Boolean and DAPSA<4 remission after 3 and 6 months in RA (OR 0.95-0.97, p<0.001/OR 0.96-0.99, p≤0.01) and PsA (OR 0.91-0.94, p≤0.004/OR 0.89-0.99, p≤0.002), except for ΔPEG and 6-month DAS28 remission in PsA.Discordance between patient's and physician's evaluation of disease activity reflected through ΔTSJ and partly ΔPEG may reduce likelihood of remission in RA and PsA. The findings are relevant for use of the treat-to-target strategy in individual patients.
Randomized Trial Comparing R-CHOP Versus High-Dose Sequential Chemotherapy in High-Risk Patients With Diffuse Large B-Cell Lymphomas
Authors: Sergio Cortelazzo, Corrado Tarella, Alessandro Massimo Gianni, Marco Ladetto, Anna Maria Barbui, Andrea Rossi, Giuseppe Gritti, Paolo Corradini, Massimo Di Nicola, Caterina Patti, Antonino Mulé, Manuela Zanni, Valerio Zoli, Atto Billio, Andrea Piccin, Giovanni Negri, Claudia Castellino, Francesco Di Raimondo, Andrés J.M. Ferreri, Fabio Benedetti, Giorgio La Nasa, Guido Gini, Livio Trentin, Maurizio Frezzato, Leonardo Flenghi, Simona Falorio, Marco Chilosi, Riccardo Bruna, Valentina Tabanelli, Stefano Pileri, Arianna Masciulli, Federica Delaini, Cristina Boschini, Alessandro Rambaldi
Journal: Journal of Clinical Oncology (2016)

Purpose The benefit of high-dose chemotherapy with autologous stem-cell transplantation (ASCT) as first-line treatment in patients with diffuse large B-cell lymphomas is still a matter of debate. To address this point, we designed a randomized phase III trial to compare rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)-14 (eight cycles) with rituximab plus high-dose sequential chemotherapy (R-HDS) with ASCT. Patients and Methods From June 2005 to June 2011, 246 high-risk patients with a high-intermediate (56%) or high (44%) International Prognostic Index score were randomly assigned to the R-CHOP or R-HDS arm, and 235 were analyzed by intent to treat. The primary efficacy end point of the study was 3-year event-free survival, and results were analyzed on an intent-to-treat basis. Results Clinical response (complete response, 78% v 76%; partial response, 5% v 9%) and failures (no response, 15% v 11%; and early treatment-related mortality, 2% v 3%) were similar after R-CHOP versus R-HDS, respectively. After a median follow-up of 5 years, the 3-year event-free survival was 62% versus 65% ( P = .83). At 3 years, compared with the R-CHOP arm, the R-HDS arm had better disease-free survival (79% v 91%, respectively; P = .034), but this subsequently vanished because of late-occurring treatment-related deaths. No difference was detected in terms of progression-free survival (65% v 75%, respectively; P = .12), or overall survival (74% v 77%, respectively; P = .64). Significantly higher hematologic toxicity ( P < .001) and more infectious complications ( P < .001) were observed in the R-HDS arm. Conclusion In this study, front-line intensive R-HDS chemotherapy with ASCT did not improve the outcome of high-risk patients with diffuse large B-cell lymphomas.
Autoimmune-Like Hepatitis Following Allogeneic Hematopietic Stem Cell Transplantation: Different Manifestation From Hepatic Graft-Versus-Host Disease
Authors: Daisuke Koyama, Masafumi Ito, Sonoko Kamoshita, Naomi Kubota, Emi Yokohata, Tatsunori Goto, Aika Seto, Yukiyasu Ozawa, Takeo Yamaguchi, Koichi Miyamura
Journal: Blood (2011)
Neoadjuvant combination immunotherapy with ipilimumab (3 mg/kg or 10mg/kg) and high dose IFN-a2b in locally/regionally advanced melanoma.
Authors: Ahmad A. Tarhini, Zahra Rahman, Yan Lin, Priyanka Vallabhaneni, Hussein Abdul-Hassan Tawbi, Andrew Gnan, Amanda McFadden, Amy Rose, Chelsea Pruckner, Melissa Wilson, James F. Pingpank, Matthew Peter Holtzman, Robert L. Ferris, Uma N. M. Rao, John M. Kirkwood
Journal: Journal of Clinical Oncology (2016)

9585Background: Neoadjuvant ipilimumab (ipi) at 3 or 10 mg/kg in combination with high dose IFNα2b (HDI) for locally/regionally advanced or recurrent melanoma may improve the clinical outcomes of t...
Independent or employed? There is a third way. . .
Authors: Des Spence
Journal: BMJ (2016)

General practice is in crisis. Many posts lie empty and large numbers of older doctors are due to retire soon. The current system is failing, with patients waiting weeks for appointments. Something radical has to be done. Currently we are small groups of self employed doctors with limited career progression, a blank cheque of responsibility, and seeing in excess of 30 patients a day in 10 minute appointments.1 The combination of acute and routine work required means that GPs often finish surgeries then do house calls over lunchtime. Paperwork is done in the margins of the day. Increasing pressure is making general practices dysfunctional, chaotic, unhappy, and lonely places. A sickness absence can …
TRPA1 Mediates Aromatase Inhibitor–Evoked Pain by the Aromatase Substrate Androstenedione
Authors: Francesco De Logu, Raquel Tonello, Serena Materazzi, Romina Nassini, Camilla Fusi, Elisabetta Coppi, Simone Li Puma, Ilaria M. Marone, Laura R. Sadofsky, Alyn H. Morice, Tommaso Susini, Alessandro Terreni, Gloriano Moneti, Mariarosaria Di Tommaso, Pierangelo Geppetti, Silvia Benemei
Journal: Cancer Research (2016)

Aromatase inhibitors (AI) induce painful musculoskeletal symptoms (AIMSS), which are dependent upon the pain transducing receptor TRPA1. However, as the AI concentrations required to engage TRPA1 in mice are higher than those found in the plasma of patients, we hypothesized that additional factors may cooperate to induce AIMSS. Here we report that the aromatase substrate androstenedione, unique among several steroid hormones, targeted TRPA1 in peptidergic primary sensory neurons in rodent and human cells expressing the native or recombinant channel. Androstenedione dramatically lowered the concentration of letrozole required to engage TRPA1. Notably, addition of a minimal dose of androstenedione to physiologically ineffective doses of letrozole and oxidative stress byproducts produces AIMSS-like behaviors and neurogenic inflammatory responses in mice. Elevated androstenedione levels cooperated with low letrozole concentrations and inflammatory mediators were sufficient to provoke AIMSS-like behaviors. The generation of such painful conditions by small quantities of simultaneously administered TRPA1 agonists justifies previous failure to identify a precise link between AIs and AIMSS, underscoring the potential of channel antagonists to treat AIMSS. Cancer Res; 76(23); 7024-35. ©2016 AACR.
A phase II trial of thalidomide, α-Interferon +/–octreotide in patients with advanced hepatocellular carcinoma
Authors: K. Rasila, F.-C. Lee, I. Rabinowitz
Journal: Journal of Clinical Oncology (2004)

4272 Background: Based on clinical efficacy observed in single agent phase II trials, we conducted a novel chemotherapeutic trial with a regimen consisting of thalidomide, α-interferon +/- octreotide for advanced hepatocellular carcinoma. Methods: Eligibility criteria included histologically proven unresectable or metastatic HCC, measurable disease, ECOG PS ≤ 2, age ≥ 18 yrs, may have had prior systemic or intra hepatic chemotherapy with other agents except the 3 study drugs, may have had previous surgery or regional therapy, adequate hematologic, renal and hepatic function, and informed consent. Treatment consisted of thalidomide initiated at 200 mg/day and increased up to 800 mg/day as tolerated, α-interferon 3 MU subcutaneous three times a week and octreotide 30 mg every month added for patients who had a positive octreotide scan. Results: Between December 2000 and November 2002, six patients (5 males and 1 female), median age 53.5 yrs (range 47–73 yrs) were enrolled. 50% of the patients were stage III and 50% were stage IV; 66.7% were anti-HCV positive; 83.3% had positive octreotide scans; 5/6 (83.3%) patients had not received any prior chemotherapy (systemic or intrahepatic). 1 patient received prior chemotherapy with single agent doxorubicin. Median ECOG PS was 1 and median number of cycles administered was 2 (range 1–4). Five patients were evaluable for response (1 patient withdrew before completing cycle 1). Treatment was stopped in 4 patients due to disease progression, and 1 withdrew because of toxicities. No responses were seen. Treatment was well tolerated with only 2 episodes of grade III/IV toxicity comprising neutropenia (n=1) and fatigue (n=1). Median survival after enrollment was 5 months (range 4–21 months) and the median time to progression was 2 months (range 1–4 months). Conclusion: Although demonstrating a favorable toxicity profile, combination chemotherapy with Thalidomide,α-Interferon +/- Octreotide has little activity in the treatment of advanced hepatocellular carcinoma. No significant financial relationships to disclose.
Immune monitoring of antibody responses to complex immunotherapies using custom protein microarrays
Authors: K. S. Anderson, N. Ramachandran, J. Wong, E. Hainsworth, G. Dranoff, J. LaBaer
Journal: Journal of Clinical Oncology (2008)

3028 Background: Multiple autologous and allogeneic cellular tumor vaccines, as well as targeted immunotherapies such as CTLA-4 antibodies, are in current clinical trials. Vaccination can induce coordinated antitumor immune responses, but immune monitoring is difficult due to the complex nature of the cellular product. To monitor antibody responses to these immunotherapies, we have adapted novel high-density custom protein microarrays (NAPPA) expressing candidate tumor antigens for immune monitoring. These arrays are probed with sera to identify antibodies induced by vaccination. Using this approach, we identified known and novel antibodies in the sera of breast and lung cancer patients who have undergone autologous GM-CSF-secreting tumor vaccination. Methods: 1,991 full-length human antigens were expressed using mammalian reticulocyte lysate and captured onto NAPPA protein microarrays. Protein expression was confirmed with anti-GST antibodies. Patient sera were added, and bound IgG detected with secondary antibodies. Serial serum samples were obtained from three patients with metastatic breast cancer, and one patient with non-small cell lung cancer who underwent autologous tumor vaccination with irradiated GM-CSF- secreting tumor cells. Antigenic hits were defined as Z-score>3 and not present in 53 healthy donor sera. Results: Of 1,991 protein antigens, 40 unique antigens were detected in the sera of the breast and lung cancer patients and not in the healthy donor sera (Z-score>3). Of these, 20 antigens were unique to breast cancer sera, and 7 antigens were unique to the lung cancer serum. 22 antigens were more strongly detected after vaccination in at least one patient. Known tumor antigens, such as MAGE3, MAGE6, and p53 were detected, as well as novel antigens such as cyclinE2. These antigens were distinct from antigens detected with commercially available protein microarrays. Conclusions: Custom in situ protein microarrays can be used to detect tumor antigen-specific antibodies and enables the rapid, simultaneous detection of immunogenic tumor antigens from patient sera. Patients undergoing cellular vaccines develop antibodies to multiple tumor antigens, which are potential targets for immunotherapy development. No significant financial relationships to disclose.
Efficacy and toxicity of docetaxel in elderly men with castrate-resistant metastatic prostate cancer.
Authors: D. R. Shepard, A. Weil, J. A. Garcia, R. Dreicer, D. Raghavan
Journal: Journal of Clinical Oncology (2010)

4687 Background: Docetaxel is currently the standard cytotoxic therapy for patients (pts) with castrate resistant metastatic prostate cancer. As the number of very elderly men in the population rises, it is important to assess the efficacy and tolerance of this therapy, specifically in very old pts with this disease. Methods: Prospectively obtained electronic medical records of all pts ≥ 74 yrs of age with metastatic prostate cancer who received docetaxel between 2005 and 2008 at Cleveland Clinic were reviewed. Data on previous therapy, surrogate measures of comorbidity, and response and toxicity of docetaxel were collected. Results: 26 pts ≥ 74 yrs of age (median age 76 yrs, range 74-87) with prostate cancer received docetaxel 60-75 mg/m2 q 3 weeks. The median ECOG score was 1 (range 0-3) with documented bone or visceral metastases in 22 and 11 pts, respectively. Cumulatively, pts received 154 cycles of docetaxel (median 5, range 1-10) with 9 treatment delays and dose reduction in 6 pts. Pts >80 yrs received a median of 4 cycles. Clinical benefit was noted for 50% of pts with a 50% reduction in PSA in 11 of 22 assessable pts. Among 13 pts with CT and 11 pts with bone scans, 61% and 64% had stable disease with progression in 15% and 27%, respectively. No pts died on therapy; however, 9 pts (34%) including 3 of 5 pts > 80 years of age were hospitalized for toxicity including neutropenic fever, diarrhea, and dehydration. Docetaxel was discontinued due to adverse events in 7 pts (median of 5 cycles) and disease progression or lack of clinical benefit in 7 pts (median of 3 cycles). Median overall survival was 9.6 months. Conclusions: Although many pts 74-87 yrs of age responded to docetaxel, disease progression or toxicities, including need for hospitalization in 67% of pts over 80 years of age, limited the use of this agent. Although a small retrospective analysis, these data suggest that even at a large, experienced center, very elderly pts have a lower response and higher toxicity than observed in trials which include younger patients. Clinical trials targeting elderly pts are necessary to determine efficacy and tolerance in this population and to determine factors to predict which pts are likely to benefit from therapy. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Celgene, EMD Serono, Endo Pharmaceuticals, Lilly, MethylGene, Ortho sanofi-aventis
Results of phase I clinical trials of Coramsine in patients with advanced solid tumors
Authors: M. Millward, A. Powell, P. Daly, S. Tyson, R. Ferguson, S. Carter
Journal: Journal of Clinical Oncology (2006)

2070 Background: Coramsine (C) is a 1:1 mixture of solasonine and solamargine, plant glycoalkaloids found in the species Solanum Linneanum, with single agent and synergistic combination in vitro and in vivo preclinical efficacy in various tumor models through interaction with rhamnose-containing cell membrane glycoproteins and subsequent internalization. Methods: C initially as a 2-hr IV infusion daily × 5 every 2 weeks to define the MTD, recommended Phase II dose, toxicity and pharmacokinetics. Based on preclinical toxicology the infusion duration was increased to 4 hours and 24 hours (120 hr continuous infusion). Doses studied range from 0.75 mg/kg/day to 3.0 mg/kg/day. Results: 27 pts were treated. DLT occurred in 2/2 pts at 1.5 mg/kg/day (2 hr) and 2/2 pts each at 3.0 mg/kg/day (4 hr and 24 hr). Preceding dose levels 1.0 mg/kg (2 hr) and 1.5 mg/kg (4 hr) produced DLT in 2/6 pts each with no grade IV. Over 24 hr, 2.25 mg/kg/day produced DLT in 4/6 patients. Limiting toxicity at all schedules was grade III/IV transaminitis with grade I-III increases of bilirubin and grade I-II creatinine. Hepatotoxicity was maximal at days 3–5, resolved over 10–21 days, was clinically asymptomatic apart from grade I-II fatigue, and was not cumulative. No myelosuppression or other serious drug-related toxicity was recorded. Partial responses were documented in 2 pts (renal, NSCLC) and minor response in 1 pt with unknown primary. Responses were seen using both 2 hr and 4 hr infusions. Pharmacokinetic parameters for solasonine and solamargine are linear across the narrow range of doses studied with elimination T 1/2 of 5.57 ± 1.27 hr (solasonine), 8.40 ± 2.00 hr (solamargine) and Cl of 5.6 ± 1.6 L/hr (solasonine), 3.0 ± 0.7 L/hr (solamargine). Peak levels of both exceed active in vitro levels (&gt;2,000 ng/ml). Conclusions: Coramsine produces dose-limiting hepatotoxicity at doses above 1.0 mg/kg/day over 2 hours or 1.5 mg/kg/day over 4 hours. 2.25 mg/kg/day over 24 hours exceeds the MTD. Activity has been seen against resistant solid tumors. Phase II studies in renal cancer and melanoma will be performed using 1.5 mg/kg/day over 4 hours. [Table: see text]
Global Outreach Using a Systematic, Competency-Based Training Paradigm for Inguinal Hernioplasty
Authors: Justin P. Wagner, Alexander D. Schroeder, Juan C. Espinoza, Jonathan R. Hiatt, John D. Mellinger, Robert A. Cusick, Robert J. Fitzgibbons, Giampiero Campanelli, Marta Cavalli, Sergio Roll, Rodrigo A. Silva, Wolfgang Reinpold, Louis-Franck Télémaque, Brent D. Matthews, Charles J. Filipi, David C. Chen
Journal: JAMA Surgery (2016)

Sustainable, capacity-building educational collaborations are essential to address the global burden of surgical disease.To assess an international, competency-based training paradigm for hernia surgery in underserved countries.In this prospective, observational study performed from November 1, 2013, through October 31, 2015, at 16 hospitals in Brazil, Ecuador, Haiti, Paraguay, and the Dominican Republic, surgeons completed initial training programs in hernia repair, underwent interval proficiency assessments, and were appointed regional trainers. Competency-based evaluations of technical proficiency were performed using the Operative Performance Rating Scale (OPRS). Maintenance of proficiency was evaluated by video assessments 6 months after training. Certified trainees received incentives to document independent surgical outcomes after training.An OPRS score of 3.0 (scale of 1 [poor] to 5 [excellent]) indicated proficiency. Secondary outcomes included initial vs final scores by country, scores among surgeons trained by the regional trainers (second-order trainees), interval scores 6 months after training, and postoperative complications.A total of 20 surgeon trainers, 81 local surgeons, and 364 patients (343 adult, 21 pediatric) participated in the study (mean [SD] age, 47.5 [16.3] years; age range, 16-83 years). All 81 surgeons successfully completed the program, and all 364 patients received successful operations. Mean (SD) OPRS scores improved from 4.06 (0.87) before the initial training program to 4.52 (0.57) after training (P < .001). No significant variation was found by country in final scores. On trainee certification, 20 became regional trainers. The mean (SD) OPRS score among 53 second-order trainees was 4.34 (0.68). After 6-month intervals, the mean (SD) OPRS score among participating surgeons was 4.34 (0.55). The overall operative complication rate during training series was 1.1%.Competency-based training helps address the global burden of surgical disease. The OPRS establishes an international standard of technical assessment. Additional studies of long-term surgeon trainer proficiency, community-specific quality initiatives, and expansion to other operations are warranted.
Notch-Mediated Epigenetic Regulation of Voltage-Gated Potassium Currents
Authors: Aditi Khandekar, Steven Springer, Wei Wang, Stephanie Hicks, Carla Weinheimer, Ramon Diaz-Trelles, Jeanne M. Nerbonne, Stacey Rentschler
Journal: Circulation Research (2016)

Ventricular arrhythmias often arise from the Purkinje-myocyte junction and are a leading cause of sudden cardiac death. Notch activation reprograms cardiac myocytes to an induced Purkinje-like state characterized by prolonged action potential duration and expression of Purkinje-enriched genes.To understand the mechanism by which canonical Notch signaling causes action potential prolongation.We find that endogenous Purkinje cells have reduced peak K+ current, Ito, and IK,slow when compared with ventricular myocytes. Consistent with partial reprogramming toward a Purkinje-like phenotype, Notch activation decreases peak outward K+ current density, as well as the outward K+ current components Ito,f and IK,slow. Gene expression studies in Notch-activated ventricles demonstrate upregulation of Purkinje-enriched genes Contactin-2 and Scn5a and downregulation of K+ channel subunit genes that contribute to Ito,f and IK,slow. In contrast, inactivation of Notch signaling results in increased cell size commensurate with increased K+ current amplitudes and mimics physiological hypertrophy. Notch-induced changes in K+ current density are regulated at least in part via transcriptional changes. Chromatin immunoprecipitation demonstrates dynamic RBP-J (recombination signal binding protein for immunoglobulin kappa J region) binding and loss of active histone marks on K+ channel subunit promoters with Notch activation, and similar transcriptional and epigenetic changes occur in a heart failure model. Interestingly, there is a differential response in Notch target gene expression and cellular electrophysiology in left versus right ventricular cardiac myocytes.In summary, these findings demonstrate a novel mechanism for regulation of voltage-gated potassium currents in the setting of cardiac pathology and may provide a novel target for arrhythmia drug design.
Black and Hispanic Caregivers’ Behaviors, Motivations, and Barriers to Sun Protection in Children Aged 4 to 12 Years in Miami, Florida
Authors: Vidhi V. Shah, Audrey A. Jacobsen, Stephanie Mlacker, Adam S. Aldahan, Nick Carcioppolo, Fleta N. Bray, Keyvan Nouri
Journal: JAMA Dermatology (2016)