tbuckley/cabot-search huggingface dataset:
Phase II study of the HSP90 inhibitor AUY922 in patients with previously treated, advanced non-small cell lung cancer (NSCLC).
Authors: Edward B. Garon, Teresa Moran, Fabrice Barlesi, Leena Gandhi, Lecia V. Sequist, Sang-We Kim, Harry J.M. Groen, Benjamin Besse, Egbert F Smit, Dong-Wan Kim, Mikhail Akimov, Emin Avsar, Stuart Bailey, Enriqueta Felip
Journal: Journal of Clinical Oncology (2012)

7543 Background: AUY922 is a highly potent, non-geldanamycin, HSP90 inhibitor. A Phase I study in advanced solid tumors provided a recommended Phase II dose of 70 mg/m 2 . HSP90 acts as a chaperone of client proteins, including those relevant in NSCLC pathogenesis. This Phase II study assessed AUY922 in pts with previously treated advanced NSCLC stratified by molecular status. Methods: Pts with advanced NSCLC who progressed following ≥2 prior lines of chemotherapy, received AUY922 70 mg/m 2 as a 1-hr infusion once-weekly. Pts were assigned to 4 strata: EGFR activating mutations (EGFR mut), KRAS mut, ALK rearranged (ALK+), or EGFR/KRAS/ALK wild type (wt). Phase II Bayesian hypothesis testing design allowed sharing of information between strata based on assessing similarity in observed response data. Primary endpoint was confirmed (RECIST) objective response rate (ORR) or stable disease (SD) at 18 wks. Secondary endpoints included OS, PFS, and safety/tolerability. Results: A total of 112 pts (median age 60 years; 45% male; 86% adenocarcinoma; 28 [25%] pts KRAS mut; 35 [31%] EGFR mut; 14 [12%] ALK+; 31 [28%] EGFR/KRAS/ALK wt) were treated at the December 16 th 2011 cutoff. Most pts were heavily pretreated: 61% had received ≥3 prior systemic regimens; 64% had WHO PS 1 or 2. Mean duration of exposure was 9.1 wks. The most frequent adverse events (AEs, any grade [Gr]) were diarrhea (73%), visual AEs (71%), and nausea (43%). Most AEs were Gr 1/2; Gr 3/4 AE’s were rare (all &lt;10%). The study is ongoing, and 29 pts were still receiving treatment at the cutoff date. Preliminary clinical activity of AUY922 (RECIST; investigator assessed) was seen with partial responses in 13/101 (13%) pts: 2/8 (25%) ALK+ pts, 6/33 (18%) EGFR mut pts, 4/30 (13%) EGFR/KRAS/ALK wt pts, 0/26 (0%) KRAS mut pts, and 1/4 (25%) pts of unknown status. In ALK+ pts, responses were seen in crizotinib (CRZ)-naive pts, and SD was seen with tumor shrinkage in CRZ-resistant pts. PFS data will be presented. Conclusions: AUY922 had an acceptable safety profile and demonstrated preliminary activity in heavily pretreated pts with advanced NSCLC. This trial demonstrates clinical activity of AUY922 in EGFR mut and EGFR/KRAS/ALK wt NSCLC pts in addition to ALK+ pts.
Beige Adipocyte Maintenance Is Regulated by Autophagy-Induced Mitochondrial Clearance
Authors: Svetlana Altshuler-Keylin, Kosaku Shinoda, Yutaka Hasegawa, Kenji Ikeda, Haemin Hong, Qianqian Kang, Yangyu Yang, Rushika M. Perera, Jayanta Debnath, Shingo Kajimura
Journal: Cell Metabolism (2016)
The effect of cephalexin in influencing the pharmacokinetics of a novel drug – 5′-valyl-cytarabine hydrochloride
Authors: Xiaotong Song, Yinghua Sun, Chenyao Zhao, Zhonggui He
Journal: Asian Journal of Pharmaceutical Sciences (2016)

The aim of this study is to investigate the pharmacokinetics of 5′-valyl-cytarabine hydrochloride (OPC) when co-administered with cephalexin, which are both the substrates of PepT1. The drugs were administered orally by gavage. Blood samples were collected from the orbital plexus of the rats after oral administration of drug solutions. A new high-performance liquid chromatographic method was validated and used for determination of the two drugs. Pharmacokinetic parameters were calculated using DAS 2.1.1 software with noncompartmental analysis. After oral administration of OPC and co-administration of OPC and cephalexin, there were significant differences in the main pharmacokinetic parameters. The main pharmacokinetic parameters for the OPC group and the co-administrative group were as follows: AUC0-10 (18,168.7 ± 2561.4) ng⋅h/ml and (13,448.5 ± 2544.73) ng⋅h/ml, AUC0-∞ (18,683.1 ± 3066.5) ng⋅h/ml and (13,721.1 ± 2683.0) ng⋅h/ml, Cmax (6654.8 ± 481.3) ng/ml and (4765.1 ± 928.9) ng/ml, respectively. The results showed that the bioavailability of OPC could be reduced when co-administered with cephalexin, suggesting that the efficacy of a novel drug might be reduced when it came to combination use of β-lactam antibiotics.
Medical Use of Cannabinoids
Authors: Igor Grant
Journal: JAMA (2015)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor
Authors: W. Jeffrey Elias, Nir Lipsman, William G. Ondo, Pejman Ghanouni, Young G. Kim, Wonhee Lee, Michael Schwartz, Kullervo Hynynen, Andres M. Lozano, Binit B. Shah, Diane Huss, Robert F. Dallapiazza, Ryder Gwinn, Jennifer Witt, Susie Ro, Howard M. Eisenberg, Paul S. Fishman, Dheeraj Gandhi, Casey H. Halpern, Rosalind Chuang, Kim Butts Pauly, Travis S. Tierney, Michael T. Hayes, G. Rees Cosgrove, Toshio Yamaguchi, Keiichi Abe, Takaomi Taira, Jin W. Chang
Journal: New England Journal of Medicine (2016)

Uncontrolled pilot studies have suggested the efficacy of focused ultrasound thalamotomy with magnetic resonance imaging (MRI) guidance for the treatment of essential tremor.We enrolled patients with moderate-to-severe essential tremor that had not responded to at least two trials of medical therapy and randomly assigned them in a 3:1 ratio to undergo unilateral focused ultrasound thalamotomy or a sham procedure. The Clinical Rating Scale for Tremor and the Quality of Life in Essential Tremor Questionnaire were administered at baseline and at 1, 3, 6, and 12 months. Tremor assessments were videotaped and rated by an independent group of neurologists who were unaware of the treatment assignments. The primary outcome was the between-group difference in the change from baseline to 3 months in hand tremor, rated on a 32-point scale (with higher scores indicating more severe tremor). After 3 months, patients in the sham-procedure group could cross over to active treatment (the open-label extension cohort).Seventy-six patients were included in the analysis. Hand-tremor scores improved more after focused ultrasound thalamotomy (from 18.1 points at baseline to 9.6 at 3 months) than after the sham procedure (from 16.0 to 15.8 points); the between-group difference in the mean change was 8.3 points (95% confidence interval [CI], 5.9 to 10.7; P<0.001). The improvement in the thalamotomy group was maintained at 12 months (change from baseline, 7.2 points; 95% CI, 6.1 to 8.3). Secondary outcome measures assessing disability and quality of life also improved with active treatment (the blinded thalamotomy cohort)as compared with the sham procedure (P<0.001 for both comparisons). Adverse events in the thalamotomy group included gait disturbance in 36% of patients and paresthesias or numbness in 38%; these adverse events persisted at 12 months in 9% and 14% of patients, respectively.MRI-guided focused ultrasound thalamotomy reduced hand tremor in patients with essential tremor. Side effects included sensory and gait disturbances. (Funded by InSightec and others; ClinicalTrials.gov number, NCT01827904.).
A hidden residential cell in the lung
Authors: Marc E. Rothenberg
Journal: Journal of Clinical Investigation (2016)

Eosinophils are classically known as proinflammatory cells, as they are equipped with a variety of preformed cytotoxic mediators and have been shown to definitively contribute to asthma. The connection between eosinophils and asthma development has led to a new class of asthma therapeutics based on blocking eosinophils with humanized antibodies that neutralize IL-5, a potent eosinophil growth, activation, and survival factor. Yet, recent studies have led to an increasing appreciation that eosinophils have a variety of homeostatic functions, including immunomodulation. In this issue of the JCI, Mesnil et al. identify a notable population of lung-resident eosinophils and demonstrate that, compared with traditional eosinophils, these cells have distinct characteristics, including nuclear structure, surface markers, IL-5 independence, and immunoregulatory function that is capable of polarizing adaptive immune responses, at least in vitro. Thus, these results reinforce a key homeostatic role for this enigmatic cell population, particularly in residing and regulating immunity in the lung.
Taking vitamin D in addition to drugs reduces severe asthma attacks, finds review
Authors: Susan Mayor
Journal: BMJ (2016)

Taking an oral vitamin D supplement in addition to standard asthma drugs reduces the risk of severe asthma attacks that require systemic corticosteroids and lowers exacerbations needing hospital admission or emergency department care, a Cochrane review of clinical trials in adults and children with asthma has found.1

Low blood levels of vitamin D have been associated with increased risk of asthma attacks in children and adults with asthma. Several clinical trials have investigated whether vitamin D might improve control of asthma but have …
Differential expression of the protein phosphatase 2 (PP2A) complex and breast cancer signature genes following suppression of mTOR signalling
Authors: C. Saliba, S. Baldacchino, R. Gauci, M.P. Grixti, V. Petroni, A. Zerafa Simler, N. Mallia, A. Fenech, C. Scerri, G. Grech
Journal: Annals of Oncology (2015)
THE IMPACT OF MILD RENAL IMPAIRMENT ON THE TOXICITY OF OXALIPLATIN AND FLUOROPYRIMIDINE REGIMENS: EXPERIENCE IN THE MRC COIN TRIAL
Authors: A Madi, R Wilson, R Adams, M Seymour, A Meade, J Cassidy, D Fisher, S Kenny, R Kaplan, T Maughan
Journal: Annals of Oncology (2010)
Letter from Kosiuk et al Regarding Article, “Ablation Versus Amiodarone for Treatment of Persistent Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted Device: Results From the AATAC Multicenter Randomized Trial”
Authors: Jedrzej Kosiuk, Gerhard Hindricks, Andreas Bollmann
Journal: Circulation (2016)
Comorbidity, Measured By The Charlson Index, Has No Negative Impact On Remission In Patients With Chronic Myeloid Leukemia: Results Of The Randomized CML-Study IV
Authors: Susanne Saussele, Marie Paloma Krauss, Michael Lauseker, Rüdiger Hehlmann, Ulrike Proetel, Annette Schreiber, Lida Kalmanti, Benjamin Hanfstein, Hermann Einsele, Christiane Falge, Lothar Kanz, Andreas Neubauer, Michael Kneba, Frank Stegelmann, Michael Pfreundschuh, Cornelius F. Waller, Gabriela M. Baerlocher, Dominik Heim, Stefan W. Krause, Wolf Karsten Hofmann, Joerg Hasford, Andreas Hochhaus, Markus Pfirrmann, Martin C. Müller
Journal: Blood (2013)
Hematopoietic Stem Cells Are the Major Source of Multilineage Hematopoiesis in Adult Animals
Authors: Catherine M. Sawai, Sonja Babovic, Samik Upadhaya, David J.H.F. Knapp, Yonit Lavin, Colleen M. Lau, Anton Goloborodko, Jue Feng, Joji Fujisaki, Lei Ding, Leonid A. Mirny, Miriam Merad, Connie J. Eaves, Boris Reizis
Journal: Immunity (2016)
Tension-free Vaginal Tape–Obturator for Treatment of Pure Urodynamic Stress Urinary Incontinence: Efficacy and Adverse Effects at 10-year Follow-up
Authors: Maurizio Serati, Andrea Braga, Stavros Athanasiou, Giovanni A. Tommaselli, Giorgio Caccia, Marco Torella, Fabio Ghezzi, Stefano Salvatore
Journal: European Urology (2016)
Evidence, Policy, and E-Cigarettes
Authors: Matthew L Myers
Journal: New England Journal of Medicine (2016)

In their Perspective article in the April 7 issue, 1 Green et al. argue that the English approach to e-cigarettes could reframe the debate on these products.They cite our article, 2 implying that we were concerned about only one of the many studies in the Public Health England (PHE) review.That study was only one of our concerns, being the only source for the widely cited "95% safer" claim, especially given questions about conflicts of interest. 3We also discussed other evidence, some not quoted in the review, that raised serious questions about the safety of these products. 4Green et al. disregard the fact that harm reduction is only one element of a comprehensive drug strategy that, as in the successful Australian model, also encompasses reduction of demand and supply.It is misleading to suggest that there is a consensus on e-cigarettes in England, given that many members of the health community have continuing reservations. 5f we are to reframe the debate, maybe we should instead look to Australia, where adult smoking rates are now under 13%, without e-cigarettes.
Drug prices are kept high in US by protection and price negotiations, study finds
Authors: Michael McCarthy
Journal: BMJ (2016)

The high cost of prescription drugs in the United States is due in large part to the monopoly power granted to manufacturers through the drug and patent approval processes, together with restrictions that limit the ability of payers to negotiate prices, researchers have concluded in a study in JAMA .1

Currently, per capita prescription drug spending in the US is the highest in the world, reaching $858 (£660; €760) in 2013, more than twice the average of $400 in 19 other industrialized nations.

In the new study, Aaron S Kesselheim, of Harvard Medical …
Phase II trial of dose-dense BEP for intermediate- and poor-prognosis metastatic germ cell tumors.
Authors: Y. L. Rimmer, J. D. Chester, D. P. Stark, J. K. Joffe, J. Shamash, J. D. White, N. Upton, J. Wason, D. Parashar, M. V. Williams
Journal: Journal of Clinical Oncology (2010)

e15011 Background: Granulocyte colony-stimulating factor (G-CSF) permits shorter cycle intervals and increased dose density with potential for improved therapeutic ratio. We report a phase II study to assess the feasibility of an ‘accelerated’ dose-dense BEP regimen in male patients (pts) with germ cell tumors. Methods: Eligible pts with intermediate- and poor-prognosis metastatic germ cell tumour according to the IGCCCG criteria entered this study. Pts consented to receive four 14-day (d) cycles of cisplatin (P) (50mg/m2, d1-2), etoposide (E) (165mg/m2, d1-3), bleomycin (B) (30,000IU, 3 doses/cycle at 4-6 d intervals) and G-CSF (PEG-filgrastin 6mg sc, d4), for a planned relative dose density of 1.5 for each drug compared to standard BEP. Results: 16 pts were recruited from 4 UK centers (2004-2008). 11 pts had intermediate and 5 had poor-prognosis disease. 14/16 pts (87.5%) completed the study treatment as per protocol. In these 14 pts the mean relative dose density achieved of P was 1.5 (range,1.3-1.6), of E was 1.5 (range,1.3-1.5) and B was 1.4 (range,0.9-1.5). Two pts reverted to standard BEP after two cycles due to haematological toxicity. All pts were eligible for response analysis. Complete response (radiological and tumour marker) was achieved in 69% of pts- after chemotherapy alone in 2 pts (13%) and following surgery in 9 pts (56%). A further 4 pts (25%) had a partial response and normalized their marker levels; 1 pt (7%) completed the study regimen but did not achieve a remission due to progressive disease. The percentage of pts with grade3/4 haematological toxicity recorded during at least one cycle was: thrombocytopenia 56%; neutropenia 62.5% and febrile neutropenia 37.5%. One pt experienced Grade 3 skin toxicity. No Grade 3/4 pulmonary toxicity was reported. One pt developed disease-related Grade 3 hypoxia. No Grade 3/4 renal toxicity was recorded. The mean change in EDTA clearance was 31% (range, +4% to -53%). At a median follow-up of 24 months (range:3-46), there has been one disease-related death and no treatment-related deaths. Estimated 3 year progression free survival is 71.4% (95% CI [33.0, 90.3]) Conclusions: Accelerated BEP is a feasible and effective regimen with acceptable toxicity in the majority of pts. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen
Clostridia: An Alternative Cause of 'Ethylene Dibromide' Fatalities-Reply
Authors: Gideon Letz
Journal: JAMA (1985)

<h3>In Reply.—</h3> We were aware of the correspondents' alternative theory on the cause of death for the two workers described in our article. However, we concluded that this alternative "explanation" was medically and scientifically untenable on the following grounds. The first worker died<i>13 hours</i>after he collapsed inside the tank. To describe a death secondary to tissue invasion by clostridial species in a previously healthy adult in this time frame is implausible; there are no cases described in the literature that would support such a hypothesis. Furthermore, the patient had no evidence of pneumonia by symptoms, blood gas values, or chest x-ray films. Previous case reports of nontraumatic clostridial myonecrosis have always occurred in patients with serious predisposing factors such as malignant disorders, perforated hollow viscus, or previous parenteral administration of certain clostridial species in contaminated medications.<sup>1,2</sup>No published data support the only possible primary route of entry
Avelumab (MSB0010718C; anti-PD-L1) in combination with other cancer immunotherapies in patients with advanced malignancies: The phase 1b/2 JAVELIN Medley study.
Authors: Antoni Ribas, Laura Q. Chow, Jason Keith Boyd, Georgina V. Long, Michele Gorczyca, Craig Davis, Dmitri Pavlov, Aron D. Thall
Journal: Journal of Clinical Oncology (2016)

TPS3106 Background: Programmed death-1 receptor ligand (PD-L1) is a key therapeutic target in the reactivation of the immune response against multiple cancers. Additionally, 4-1BB agonists have been shown to enhance T-cell proliferation and anti-tumor immunity. Avelumab*, a fully human anti-PD-L1 IgG1 antibody, and PF-05082566, a fully human anti-4-1BB (CD137) IgG2 antibody, are being investigated in separate trial programs. In preclinical models, anti-4-1BB/anti-PD-L1 combination therapy had significantly improved anti-tumor activity compared with monotherapy of either agent. This open-label, phase 1b/2 study (NCT02554812) evaluates the combination of avelumab + anti-4-1BB in patients (pts) with selected advanced solid tumors. Other avelumab + immune modulator combinations are planned. The goal of this study is to determine safety, tolerability, and clinical activity of these combination therapies. Methods: A total of approximately 147 pts with histologically confirmed advanced selected solid tumors, ECOG PS 0-1, and archival or fresh tumor tissue (not preselected for PD-L1 expression) will be enrolled in this combination study. During the phase 1b lead-in for the study arm with PF-05082566, pts with NSCLC that has progressed on standard therapy will be randomized (1:1:1) to receive avelumab (10 mg/kg; 1h intravenous [IV] infusion Q2W) + PF-05082566 (500 mg, 100 mg, or 20 mg; 1h IV infusion Q4W). Based on dose-limiting toxicity (DLT) analysis in these cohorts, phase 2 will continue enrolling pts with NSCLC with expanded enrollment criteria at selected dose levels. In addition, pts with melanoma or squamous cell carcinoma of the head and neck will be enrolled at a single dose level selected for phase 2. Treatment will continue until disease progression, unacceptable toxicity, or withdrawal. Primary endpoints are DLT (phase 1b) and confirmed objective response (RECIST 1.1). Secondary endpoints include progression-free survival, overall survival, duration of response, pharmacokinetics, immunogenicity, tumor biomarkers, and adverse events (NCI-CTCAE v4.03). Enrollment began in Nov 2015. *Proposed INN. Clinical trial information: NCT02554812.
Allergen-loaded strontium-doped hydroxyapatite spheres improve allergen-specific immunotherapy in mice
Authors: M. Garbani, W. Xia, C. Rhyner, M. Prati, A. Scheynius, B. Malissen, H. Engqvist, M. Maurer, R. Crameri, D. Terhorst
Journal: Allergy (2016)

Background Immunomodulatory interventions play a key role in the treatment of infections and cancer as well as allergic diseases. Adjuvants such as micro- and nanoparticles are often added to immunomodulatory therapies to enhance the triggered immune response. Here, we report the immunological assessment of novel and economically manufactured microparticle adjuvants, namely strontium-doped hydroxyapatite porous spheres (SHAS), which we suggest for the use as adjuvant and carrier in allergen-specific immunotherapy (ASIT). Methods and results Scanning electron microscopy revealed that the synthesis procedure developed for the production of SHAS results in a highly homogeneous population of spheres. Strontium-doped hydroxyapatite porous spheres bound and released proteins such as ovalbumin (OVA) or the major cat allergen Fel d 1. SHAS-OVA were taken up by human monocyte-derived dendritic cells (mdDCs) and murine DCs and did not have any necrotic or apoptotic effects even at high densities. In a murine model of ASIT for allergic asthmatic inflammation, we found that OVA released from subcutaneously injected SHAS-OVA led to a sustained stimulation of both CD4+ and CD8+ T cells. Allergen-specific immunotherapy with SHAS-OVA as compared to soluble OVA resulted in similar humoral responses but in a higher efficacy as assessed by symptom scoring. Conclusion We conclude that SHAS may constitute a suitable carrier and adjuvant for ASIT with great potential due to its unique protein-binding properties.
Acute MI is initially misdiagnosed in nearly a third of patients, study finds
Authors: Susan Mayor
Journal: BMJ (2016)

Nearly a third of patients with acute myocardial infarction (MI) initially have it misdiagnosed on admission to hospital in England and Wales, a large cohort study has found.1

The study, reported in the European Heart Journal: Acute Cardiovascular Care , analysed data from the Myocardial Ischaemia National Audit Project on patients discharged with a final diagnosis of MI from all 243 acute hospitals in England …
Regression of Left Ventricular Hypertrophy
Authors: Philip R. Liebson
Journal: JAMA (1996)

To the Editor.  —We read with great interest the results of the meta-analysis by Dr Schmieder and colleagues. 1 In their Comment section, the authors indicated that the Treatment of Mild Hypertension Study (TOMHS) 2 was not included in the meta-analysis, among other studies, because it did not fulfill 1 of the 12 inclusion criteria, namely, that the primary goal of the study was to analyze the effects of antihypertensive compounds on left ventricular hypertrophy.  We feel that this is a weak reason for exclusion of a study (and possibly other studies) that were randomized, doubleblinded and also placebo-controlled (not an absolute criterion for the meta-analysis). Change in left ventricular mass was 1 of several end points in TOMHS. In fact, a criterion for inclusion in the TOMHS study was an adequate echocardiographic study. The total number of participants in TOMHS in the 4 drug treatment groups corresponding to the
Phase 1 Study of AMG 900, an Orally Administered Pan-Aurora Kinase Inhibitor, in Adult Patients (Pts) with Acute Myeloid Leukemia (AML)
Authors: Michael W. Schuster, Mikkael A. Sekeres, Erick Gamelin, Erik Rasmussen, Gloria Juan, Abraham Anderson, Vincent Chow, Greg Friberg, Florian D. Vogl, Hagop Kantarjian
Journal: Blood (2015)