tbuckley/cabot-search huggingface dataset:
Economic point of view of novel therapeutic agents in oncology.
Authors: Carlos Camps
Journal: Journal of Clinical Oncology (2015)

e17794 Background: The relevance of pharmacoeconomic analyses is becoming crucial. The economic situation has shown that the resources devoted to health spending are limited, making rationalization of their consumption necessary. The ECO Foundation, with the goal of promoting the quality of Oncology care, decided to analyze the degree of consensus on the inclusion of new therapeutic targets and the integration of pharmacoeconomics when evaluating their effectiveness Methods: The project was developed in four stages: 1) set-up of the steering committee; 2) panel of experts selection; 3) submission of conclusions; 4) analysis of results. Using modified Delphi method a group of experts discussed about pharmacoeconomic estimations, costs and clinical benefits and analyzed the degree of consensus reached Results: 35 senior experts participated in the project. Concerning the approval of new drugs, for tumours with a median survival of less than two years, the median value considered clinically relevant was an increase of three months, either in the time to progression (TTP), or the overall survival (OS). In tumours with more than two years in mean survival, an increase in TTP of 3-4 months, and of 4-6 months in OS was considered clinically relevant. 68.8% of the panel considered acceptable a cost per life-year-gained between €30,000-100,000 and 9.3% higher than €150,000. Standard chemotherapy was considered to be effective if it produced an improvement in median survival of at least 3-4 months in at least 20% of the patients treated Conclusions: It is a priority to identify patient subgroups with specific molecular profiles as candidates for higher-efficiency targeted therapies because the costs of new drugs are higher than those of traditional treatments. The allocation of the available resources to the most effective interventions, in order to achieve the best clinical outcomes with lower costs, allows expenditure to be rationalised. Pharmacoeconomic studies are a basic tool for obtaining better health outcomes according to the limited resources available
Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia
Authors: Ian W. Flinn, John G. Gribben, Martin J. S. Dyer, William Wierda, Michael B. Maris, Richard R. Furman, Peter Hillmen, Kerry A. Rogers, Swaminathan Padmanabhan Iyer, Anne Quillet-Mary, Loic Ysebaert, Harriet S. Walter, Maria Verdugo, Christian Klein, Huang Huang, Yanwen Jiang, Gerard Lozanski, Daniela Soriano Pignataro, Kathryn Humphrey, Mehrdad Mobasher, Thomas J. Kipps
Journal: Blood (2019)
QALY’s cost reported to the gross domestic product as a suggested index to evaluate and compare the financial impact on society of expensive molecules in oncology.
Authors: Boukir Anwar, Ilham Azghari, El Kabous Mustapha, Saber Boutayeb, Brahim el Ghissassi, Hind Mrabti, Hassan Errihani
Journal: Journal of Clinical Oncology (2015)

e17767 Background: The prescription of expensive molecules in oncology implies a high cost for society. The prescription of such therapies can only be adopted if it guarantees a significant efficiency. However, the guidelines are based on pharmaco-economic studies that are conducted in rich countries, which do not match the economic reality of developing countries.Even though the cost of the generated benefit of these molecules has been sufficiently covered in the literature, the measure of its real financial impact on society has been less so. The aim of this study is to estimate this impact considering the economic reality of Morocco as a developing country. Methods: We tried to estimate the additional cost generated by the use of Bevacizumab as a case study in first line for metastatic colorectal cancer in Morocco, and then measure its societal impact.For this, we introduce a new economic index. This index considers the total cost of the use of Bevacizumab, the Quality Adjusted Life Year (QALY) as it is reported in literature, and the national Gross Domestic Product per capita according to the World Bank. QALY’s Cost reported to the Gross domestic product (QCG onwards) can be estimated through the following ratio: Cost per QALY/Gross Domestic Product per capita. Results: Bevacizumab’s use in first line therapy provides a 0.289 additional QALY at a cost of 23,326 USD. This amounts to 80,716 USD/QALY. QCG is then equal to 25.72, which represents the annual share of the GDP for more than 25 inhabitants. Bevacizumab’s QCG in the United States is equal to 1.43, 2.15 in France, 3.03 in Saudi Arabia, 1.99 in United Kingdom, 23.70 in Egypt and 14.65 in Algeria. These results clearly show the big difference in the societal impact of the cost of Bevacizumab between countries. Conclusions: The results of our study suggest the need to work on a universal index that considers the economic means of each country when introducing an expensive molecule. QCG index can be a tentative response to that need.
The immunometabolic role of indoleamine 2,3-dioxygenase in atherosclerotic cardiovascular disease: immune homeostatic mechanisms in the artery wall
Authors: Daniel F J Ketelhuth
Journal: Cardiovascular Research (2019)

Coronary heart disease and stroke, the two most common cardiovascular diseases worldwide, are triggered by complications of atherosclerosis. Atherosclerotic plaques are initiated by a maladaptive immune response triggered by accumulation of lipids in the artery wall. Hence, disease is influenced by several non-modifiable and modifiable risk factors, including dyslipidaemia, hypertension, smoking, and diabetes. Indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme in the kynurenine pathway of tryptophan (Trp) degradation, is modulated by inflammation and regarded as a key molecule driving immunotolerance and immunosuppressive mechanisms. A large body of evidence indicates that IDO-mediated Trp metabolism is involved directly or indirectly in atherogenesis. This review summarizes evidence from basic and clinical research showing that IDO is a major regulatory enzyme involved in the maintenance of immunohomeostasis in the vascular wall, as well as current knowledge about promising targets for the development of new anti-atherosclerotic drugs.
Targeting the untargetable KRAS in cancer therapy
Authors: Pingyu Liu, Yijun Wang, Xin Li
Journal: Acta Pharmaceutica Sinica B (2019)

RAS is one of the most well-known proto-oncogenes. Its gain-of-function mutations occur in approximately 30% of all human cancers. As the most frequently mutated RAS isoform, KRAS is intensively studied in the past years. Despite its well-recognized importance in cancer malignancy, continuous efforts in the past three decades failed to develop approved therapies for KRAS mutant cancer. KRAS has thus long been considered to be undruggable. Encouragingly, recent studies have aroused renewed interest in the development of KRAS inhibitors either directly towards mutant KRAS or against the crucial steps required for KRAS activation. This review summarizes the most recent progress in the exploration of KRAS-targeted anticancer strategies and hopefully provides useful insights for the field.
Health promotion by International Olympic Sport Federations: priorities and barriers
Authors: Margo Mountjoy, Astrid Junge, Richard Budgett, Dominik Doerr, Michel Leglise, Stuart Miller, Jane Moran, Jeremy Foster
Journal: British Journal of Sports Medicine (2019)

Objective To identify changes in International Federations’ priorities and the barriers to implementing athlete and global health initiatives. Results should influence the work of the International Federation medical committees, the IOC and the Association of Summer Olympic International Federation. Methods The 28 Summer and 7 Winter International Federations participating in the most recent Olympic Games (2016; 2018) were surveyed to (i) identify the importance of 27 health topics, (ii) assess their progress on implementation health-related programmes and (iii) the barriers to implementation of these programmes. We compared International Federations’ activities in 2016 and 2017. Results The response rate was 83%. Health topics which most International Federations regarded as important and in which the International Federations felt insufficiently active were ‘ team physician certification ’, ‘ prevention of harassment and abuse ’, ‘ eating disorders/disordered eating ’, ‘ mental health ’ and ‘ injury surveillance ’. Compared with 2016, there was a decrease in International Federations’ activities in ‘ injury surveillance ’, ‘ nutritional supplements ’ and ‘ hyperandrogenism ’. The main barrier to implementing health-related programmes was ‘ International Federation political support/willingness ’, followed by ‘ knowledge ’. ‘ Time ’ and ‘ coach support ’ were more often reported than ‘ finances ’, or ‘ IOC or Association of Summer Olympic International Federations partnership ’. Conclusion If International Federations are going to promote health of athletes and global health promotion through physical activity (sport), International Federation leadership must change their focus and provide greater political support for related initiatives. Improving coach and athlete knowledge of the health issues could also facilitate health programme delivery. Time constraints could be mitigated by sharing experiences among the International Federations, Association of Summer Olympic International Federations and the IOC. International Federations should focus on those health-related topics that they identified as being important, yet rate as having insufficient activity.
The role of phosphoglycerate mutase 2 in UM-UC3 bladder cancer cell metabolism.
Authors: Ryan Didde, Weiya Liu, Karim Pirani, Gaurav Kaushik, Benjamin L. Woolbright, Erika Abbott, John Arthur Taylor, Shrikant Anant, Jeffrey M. Holzbeierlein, Eugene K. Lee
Journal: Journal of Clinical Oncology (2019)

410 Background: Bladder cancer remains the fourth most common cancer in American males with a higher risk of recurrence and progression for patients with diabetes mellitus. Urothelial bladder cancer is characterized by aerobic glycolysis with upregulation of glycolytic enzymes (known as the Warburg effect) such as phosphoglycerate mutase. Phosphoglycerate mutase 2 (PGAM2), a reversible glycolytic enzyme expressed highly in muscle, represents a target for modulation because of its differential expression from another isoform, phosphoglycerate mutase 1. PGAM2 knockdown may impact bladder cancer growth significantly via its effect on glucose metabolism at different glucose concentrations seen in patients with diabetes mellitus. Methods: UM-UC3 bladder cancer cells were assessed for PGAM2 expression at different glucose concentrations via Western blot and quantitative PCR. One native UM-UC3 line, three PGAM2 knockdown lines, and one vector control cell line were included in the western blot study. Cellular proliferation was analyzed using an enzyme based hexoseaminidase assay and was further supported with an automated cell counter. The effects of cisplatin were also investigated. Results: Increased PGAM2 expression at increased glucose concentrations in UM-UC3 was confirmed by Western blot and quantitative PCR. PGAM2 knockdown cells responded differently to changes in glucose concentration compared to the control cell lines, with a large increase in growth at a low glucose level of 25mg/dL after day 4. Cell proliferation demonstrated similar growth between the knockdown and controls at higher glucose concentrations of 100 and 200mg/dL. Proliferation data using automated cell counter demonstrate the same growth trend. Conclusions: Increased cell growth of PGAM2 knockdowns, most notably at 25mg/dL, suggests that PGAM2 may play a different role in glycolysis than expected, possibly serving as a modulator in cell growth instead of a simple reversible enzyme. We are currently investigating its differential expression compared to PGAM1, an enzyme recently characterized to have an opposite effect to PGAM2.
Clinical predictors of sarcomatoid kidney cancer: The results of a UCLA and french UroCCR network collaboration.
Authors: Cedric Michel Lebacle, Aydin Pooli, Jean-Christophe Bernhard, Philippe Paparel, Karim Bensalah, Jean Baptiste Beauval, Arnaud Mejean, Charles Dariane, Pierre Bigot, Herve Lang, Thomas Bessede, Alexandre De La Taille, Morgan Roupret, Jacques Irani, Jean-Jacques Patard, Arie S. Belldegrun, Brian Shuch, Karim Chamie, Alexandra Drakaki, Allan J. Pantuck
Journal: Journal of Clinical Oncology (2019)

598 Background: Predisposing factors for sarcomatoid dedifferentiation of renal cell carcinoma (sRCC) remain unknown. We highlighted the association of potential contributing medical conditions with the presence of sRCC. Methods: Patients with a renal cell carcinoma (RCC) from UCLA and the French UroCCR-45 study (only sRCC) were included in the study. Characteristics of patients with sRCC were compared with patients with RCC without sarcomatoid features (nsRCC) in univariable and multivariable logistic regression analyses. We quantified the association of age, gender, smoking status, hypertension, kidney function, and endocrine disorders: diabetes and hypothyroidism with sRCC. Results: A total of 2764 were included in the study (586 sRCC vs. 2178 nsRCC). On univariable analysis, age (OR=1.02, 95%CI [1.01-1.03], p&lt;.0001), male gender (OR=1.35, 95%CI [1.10-1.65], p=.004), active smoking (OR=1.87, 95%CI [1.48-2.36], p&lt;.0001), and diabetes (OR=1.32, 95%CI [1.03-1.70], p=.026) were associated with the presence of sRCC (Table 1). On multivariable analysis, age (+2.1% per year, OR=1.02, 95%CI [1.01-1.03], p&lt;0.0001), male gender (OR=1.33, 95%CI [1.08-1.64], p=.008), and active smoking (OR=1.95, 95%CI [1.54-2.47], p&lt;0.0001) were independently associated with the presence of sRCC. The AUC of the model was 0.61. Conclusions: In this study we found that sarcomatoid dedifferentiation was associated with age, male gender, and active smoking. Further studies are needed to confirm these findings and establish the underlying biology. Univariable logistic regression analysis of the association between potential pathogenic factors and sRCC. N=2764 [Table: see text]
Impact of bone metastasis on clinical outcomes in metastatic urothelial bladder cancer (mUC) for patients treated with first-line platinum-based chemotherapy.
Authors: Jamila Jama Almi Riromar, Zachary William Neil Veitch, Adrian G. Sacher, Manjula Maganti, Nazanin Fallah-Rad, Aaron Richard Hansen, Srikala S. Sridhar
Journal: Journal of Clinical Oncology (2019)

431 Background: Prognostic nomograms have identified patients with mUC less likely to benefit from treatment. Yet, analyses have relied on grouped patient variables (ie: bone plus visceral metastases) and refinement is needed. This study aims to evaluate the clinical outcomes of bone metastases (BM) on patients with mUC treated with first-line platinum-based chemotherapy. Methods: Patients receiving first-line platinum-based chemotherapy for mUC at the Princess Margret Cancer Centre from 12/2009-10/2016 were selected from central pharmacy records. Patient and tumor characteristics, in addition to treatment history were collected retrospectively. Oncologist assessed best response (OABR; complete [CR] or partial [PR] response; stable (SD] or progressive [PD] disease) was evaluated by chart review. Progression-free (PFS) and overall survival (OS) were estimated by Kaplan-Meier (log-rank). Overall response rate (ORR) was calculated from OABR. Multivariable analysis (MVA) was performed using Cox-regression. Significance was evaluated at the p &lt; 0.05 level. Results: Of 112 patients receiving platinum-based chemotherapy, 62 (55%) had mUC. Most patients were male (73%), had ECOG PS of 0-1 (71%), and de novo metastases (23%). Patients received a median of 5 chemotherapy cycles (range 1-8), and median follow-up was 12.7 months. Number of organs involved with metastases varied (1 = 32%; 2 = 45%; 3+ = 23%); with lymphnode (77%), bone (37%), and lung metastases (34%) frequently involved. Median PFS (months) was shorter (p &lt; 0.05) in patients with BM (5.6; 95%CI:2.7-7.0) compared to no BM (8.0; 95%CI:6.5-9.5). Median OS (months) was shorter (p &lt; 0.05) in patients with BM (8.9; 95%CI:7.2-15.9) compared to no BM (16.1; 95%CI:10.5-23.4). ORR was lower for those with BM (22%) compared to no BM (56%). MVA using BM and prognostic nomogram criteria showed significance for ECOG 2+ (HR = 2.72; p &lt; 0.05) with a trend towards significance for BM (HR = 1.85; p = 0.06). Conclusions: mUC patients with BM have lower response and inferior survival by log-rank. This could have direct implications for clinical decision making and stratification of factors in clinical trials.
Calcium-dependent blood-brain barrier breakdown by NOX5 limits postreperfusion benefit in stroke
Authors: Ana I. Casas, Pamela W.M. Kleikers, Eva Geuss, Friederike Langhauser, Thure Adler, Dirk H. Busch, Valerie Gailus-Durner, Martin Hrabê de Angelis, Javier Egea, Manuela G. Lopez, Christoph Kleinschnitz, Harald H.H.W. Schmidt
Journal: Journal of Clinical Investigation (2019)

Ischemic stroke is a predominant cause of disability worldwide, with thrombolytic or mechanical removal of the occlusion being the only therapeutic option. Reperfusion bears the risk of an acute deleterious calcium-dependent breakdown of the blood-brain barrier. Its mechanism, however, is unknown. Here, we identified type 5 NADPH oxidase (NOX5), a calcium-activated, ROS-forming enzyme, as the missing link. Using a humanized knockin (KI) mouse model and in vitro organotypic cultures, we found that reoxygenation or calcium overload increased brain ROS levels in a NOX5-dependent manner. In vivo, postischemic ROS formation, infarct volume, and functional outcomes were worsened in NOX5-KI mice. Of clinical and therapeutic relevance, in a human blood-barrier model, pharmacological NOX inhibition also prevented acute reoxygenation-induced leakage. Our data support further evaluation of poststroke recanalization in the presence of NOX inhibition for limiting stroke-induced damage.
Mitigation of Olanzapine-Induced Weight Gain With Samidorphan, an Opioid Antagonist: A Randomized Double-Blind Phase 2 Study in Patients With Schizophrenia
Authors: William F. Martin, Christoph U. Correll, Peter J. Weiden, Ying Jiang, Sanjeev Pathak, Lauren DiPetrillo, Bernard L. Silverman, Elliot W. Ehrich
Journal: American Journal of Psychiatry (2019)

Preclinical evidence and data from a proof-of-concept study in healthy volunteers suggest that samidorphan, an opioid antagonist, mitigates weight gain associated with olanzapine. This study prospectively compared combination therapy of olanzapine plus either samidorphan or placebo for the treatment of schizophrenia.This was an international, multicenter, randomized phase 2 study of olanzapine plus samidorphan in patients with schizophrenia. The study had a 1-week open-label olanzapine lead-in period followed by a 12-week double-blind treatment phase in which patients were randomly assigned in a 1:1:1:1 ratio to receive olanzapine plus placebo (N=75) or olanzapine plus 5 mg (N=80), 10 mg (N=86), or 20 mg (N=68) of samidorphan. The primary aims were to confirm that the antipsychotic efficacy of olanzapine plus samidorphan was comparable to olanzapine plus placebo, to assess the effect of combining olanzapine with samidorphan on olanzapine-induced weight gain, and to assess the overall safety and tolerability of olanzapine plus samidorphan.Antipsychotic efficacy, as assessed by total score on the Positive and Negative Syndrome Scale (PANSS), was equivalent across all treatment groups. Treatment with olanzapine plus samidorphan resulted in a statistically significant lower weight gain (37% lower weight gain compared with olanzapine plus placebo). The least square mean percent change from baseline in body weight was 4.1% (2.9 kg) for the olanzapine plus placebo group and 2.6% (1.9 kg) for the olanzapine plus samidorphan group (2.8% [2.1 kg] for the 5 mg group, 2.1% [1.5 kg] for the 10 mg group, and 2.9% [2.2 kg] for the 20 mg group). Adverse events reported at a frequency ≥5% in any of the olanzapine plus samidorphan groups and occurring at a rate ≥2 times greater than in the olanzapine plus placebo group were somnolence, sedation, dizziness, and constipation. Other safety measures were comparable between the olanzapine plus samidorphan groups and the olanzapine plus placebo group.The antipsychotic efficacy of olanzapine plus samidorphan was equivalent to that of olanzapine plus placebo, and olanzapine plus samidorphan was associated with clinically meaningful and statistically significant mitigation of weight gain compared with olanzapine plus placebo. Olanzapine plus samidorphan was generally well tolerated, with a safety profile similar to olanzapine plus placebo.
Transient receptor potential Vanilloid 1-based gene therapy alleviates orthodontic pain in rats
Authors: Rui Guo, Yang Zhou, Hu Long, Di Shan, Jing Wen, Huimin Hu, Hong Yang, Zhouqiang Wu, Wenli Lai
Journal: International Journal of Oral Science (2019)

Orthodontic pain that is induced by tooth movement is an important sequela of orthodontic treatment and has a significant effect on patient quality of life. Studies have shown that the high expression of transient receptor potential vanilloid 1 (TRPV1) in trigeminal ganglions plays a vital role in the transmission and modulation of orofacial pain. However, little is known about the role of TRPV1 in orthodontic pain. In this study, male Sprague-Dawley rats were randomly assigned to six groups to study the role of TRPV1 in the modulation of tooth-movement pain. The expression levels of TRPV1 mRNA and protein were determined by real-time PCR and western blot, respectively. Moreover, pain levels were assessed using the rat grimace scale (RGS). The role of TRPV1 in modulating tooth-movement pain was examined by injecting a TRPV1 antagonist into the trigeminal ganglia of rats. A lentivirus containing a TRPV1 shRNA sequence was constructed and transduced into the rats' trigeminal ganglia. The results showed that the expression levels of TRPV1 protein and mRNA were elevated following tooth-movement pain. Pain levels increased rapidly on the 1st day, peaked on the 3rd day and returned to baseline on the 14th day. The TRPV1 antagonist significantly reduced tooth-movement pain. The lentivirus containing a TRPV1 shRNA sequence was able to inhibit the expression of TRPV1 and relieved tooth-movement pain. In conclusion, TRPV1-based gene therapy may be a treatment strategy for the relief of orthodontic pain.
Serum Levels of MicroRNA-371a-3p (M371 Test) as a New Biomarker of Testicular Germ Cell Tumors: Results of a Prospective Multicentric Study
Authors: Klaus-Peter Dieckmann, Arlo Radtke, Lajos Geczi, Cord Matthies, Petra Anheuser, Ulrike Eckardt, Jörg Sommer, Friedemann Zengerling, Emanuela Trenti, Renate Pichler, Hanjo Belz, Stefan Zastrow, Alexander Winter, Sebastian Melchior, Johannes Hammel, Jennifer Kranz, Marius Bolten, Susanne Krege, Björn Haben, Wolfgang Loidl, Christian Guido Ruf, Julia Heinzelbecker, Axel Heidenreich, Jann Frederik Cremers, Christoph Oing, Thomas Hermanns, Christian Daniel Fankhauser, Silke Gillessen, Hermann Reichegger, Richard Cathomas, Martin Pichler, Marcus Hentrich, Klaus Eredics, Anja Lorch, Christian Wülfing, Sven Peine, Werner Wosniok, Carsten Bokemeyer, Gazanfer Belge
Journal: Journal of Clinical Oncology (2019)

Previous studies suggested that serum levels of microRNA (miR)-371a-3p (so-called M371 test) have a much higher sensitivity and specificity than the classic markers of testicular germ cell tumors (GCTs) and are applicable toward both seminoma and nonseminoma. We sought to confirm the usefulness of this test as a novel biomarker for GCT.