tbuckley/cabot-search huggingface dataset:
Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor–Positive Metastatic Breast Cancer: ALTERNATIVE
Authors: Stephen R.D. Johnston, Roberto Hegg, Seock-Ah Im, In Hae Park, Olga Burdaeva, Galina Kurteva, Michael F. Press, Sergei Tjulandin, Hiroji Iwata, Sergio D. Simon, Sarah Kenny, Severine Sarp, Miguel A. Izquierdo, Lisa S. Williams, William J. Gradishar
Journal: Journal of Clinical Oncology (2017)

Purpose Human epidermal growth factor receptor 2 (HER2) targeting plus endocrine therapy (ET) improved clinical benefit in HER2-positive, hormone receptor (HR)–positive metastatic breast cancer (MBC) versus ET alone. Dual HER2 blockade enhances clinical benefit versus single HER2 blockade. The ALTERNATIVE study evaluated the efficacy and safety of dual HER2 blockade plus aromatase inhibitor (AI) in postmenopausal women with HER2-positive/HR-positive MBC who received prior ET and prior neo(adjuvant)/first-line trastuzumab (TRAS) plus chemotherapy. Methods Patients were randomly assigned (1:1:1) to receive lapatinib (LAP) + TRAS + AI, TRAS + AI, or LAP + AI. Patients for whom chemotherapy was intended were excluded. The primary end point was progression-free survival (PFS; investigator assessed) with LAP + TRAS + AI versus TRAS + AI. Secondary end points were PFS (comparison of other arms), overall survival, overall response rate, clinical benefit rate, and safety. Results Three hundred fifty-five patients were included in this analysis: LAP + TRAS + AI (n = 120), TRAS + AI (n = 117), and LAP + AI (n = 118). Baseline characteristics were balanced. The study met its primary end point; superior PFS was observed with LAP + TRAS + AI versus TRAS + AI (median PFS, 11 v 5.7 months; hazard ratio, 0.62; 95% CI, 0.45 to 0.88; P = .0064). Consistent PFS benefit was observed in predefined subgroups. Overall response rate, clinical benefit rate, and overall survival also favored LAP + TRAS + AI. The median PFS with LAP + AI versus TRAS + AI was 8.3 versus 5.7 months (hazard ratio, 0.71; 95% CI, 0.51 to 0.98; P = .0361). Common adverse events (AEs; ≥ 15%) with LAP + TRAS + AI, TRAS + AI, and LAP + AI were diarrhea (69%, 9%, and 51%, respectively), rash (36%, 2%, and 28%, respectively), nausea (22%, 9%, and 22%, respectively), and paronychia (30%, 0%, and 15%, respectively), mostly grade 1 or 2. Serious AEs were reported similarly across the three groups, and AEs leading to discontinuation were lower with LAP + TRAS + AI. Conclusion Dual HER2 blockade with LAP + TRAS + AI showed superior PFS benefit versus TRAS + AI in patients with HER2-positive/HR-positive MBC. This combination offers an effective and safe chemotherapy-sparing alternative treatment regimen for this patient population.
Effectiveness and costs of specialised physiotherapy given via ParkinsonNet: a retrospective analysis of medical claims data
Authors: Jan H L Ypinga, Nienke M de Vries, Lieke H H M Boonen, Xander Koolman, Marten Munneke, Aeilko H Zwinderman, Bastiaan R Bloem
Journal: The Lancet Neurology (2017)
A Milestone for CAR T Cells
Authors: Eric Tran, Dan L. Longo, Walter J. Urba
Journal: New England Journal of Medicine (2017)

More than 7 years have passed since the regression of advanced lymphoma was first reported in a patient who had undergone the infusion of T cells engineered to express a chimeric antigen receptor (CAR) targeting the CD19 antigen expressed on the surface of both normal and malignant B cells.1 Subsequent trials of CD19-targeted CAR T-cell therapy showed a complete response in some patients with relapsed or chemotherapy-refractory hematologic cancers for which there were no effective therapies.2-5 This personalized therapeutic approach entails the removal of peripheral-blood T cells from a patient, followed by in vitro activation, genetic modification, and expansion of . . .
123I-FP-CIT SPECT Accurately Distinguishes Parkinsonian From Cerebellar Variant of Multiple System Atrophy
Authors: Nicolas Nicastro, Valentina Garibotto, Pierre R. Burkhard
Journal: Clinical Nuclear Medicine (2017)

Dopamine transporter SPECT imaging is a valuable tool to estimate the integrity of presynaptic dopaminergic pathways in degenerative parkinsonisms. Evidence about SPECT differential pattern between parkinsonian and cerebellar forms of multiple system atrophy (MSA-P and MSA-C) is lacking. We aimed at assessing whether MSA-P and MSA-C variants have a distinct semiquantitative I-FP-CIT SPECT pattern.We studied a unicentric 13-year (2003-2016) retrospective cohort of subjects with possible or probable MSA and scanned with the same acquisition and reconstruction SPECT protocol. Age-dependent semiquantitative reference limits for striatal volumes of interest, asymmetry indices, and caudate/putamen ratio were previously established with a percentile approach on a cohort of subjects with nondegenerative conditions and normal visual scan.Thirty-four subjects with clinical MSA (28 MSA-P and 6 MSA-C) were identified (mean age, 68.2 ± 10.1 years; male/female ratio 1.00; disease duration, 2.5 ± 2.2 years; Movement Disorders Society Unified Parkinson's Disease Rating Scale III score, 33.8 ± 12.4). The MSA-P subjects exhibited lower uptake values for all volumes of interest, for example, striatal uptake on the more affected side (1.10 ± 0.51) compared with MSA-C (2.30 ± 0.41, P = 0.0005), as well as significantly higher asymmetry indices % (24.7 ± 24.8 vs 6.3 ± 4.5, P = 0.028) and caudate/putamen ratio (2.26 ± 1.23 vs 1.13 ± 0.17, P = 0.00148).The MSA-P and MSA-C subjects exhibited significantly distinct semiquantitative SPECT pattern with severe uptake impairment and high asymmetry for MSA-P and borderline uptake values for MSA-C. Clinical distinction of these 2 phenotypical entities is necessary in order to evaluate SPECT potential to discriminate between degenerative parkinsonisms.
Merkel Cell Carcinoma in the Age of Immunotherapy: Facts and Hopes
Authors: Aric Colunga, Thomas Pulliam, Paul Nghiem
Journal: Clinical Cancer Research (2017)

Merkel cell carcinoma (MCC) is a rare (∼2,000 U.S. cases/year) but aggressive neuroendocrine tumor of the skin. For advanced MCC, cytotoxic chemotherapy only infrequently (<10% of cases) offers durable clinical responses (>1 year), suggesting a great need for improved therapeutic options. In 2008, the Merkel cell polyomavirus (MCPyV) was discovered and is clonally integrated in approximately 80% of MCC tumors. The remaining 20% of MCC tumors have large numbers of UV-associated mutations. Importantly, both the UV-induced neoantigens in virus-negative tumors and the MCPyV T antigen oncogenes that are required for virus-positive tumor growth are immunogenic. Indeed, antigen-specific T cells detected in patients are frequently dysfunctional/"exhausted," and the inhibitory ligand, PD-L1, is often present in MCC tumors. These findings led to recent clinical trials involving PD-1 pathway blockade in advanced MCC. The combined data from these trials involving three PD-1 pathway blocking agents-avelumab, pembrolizumab, and nivolumab-indicated a high frequency of durable responses in treated patients. Of note, prior treatment with chemotherapy was associated with decreased response rates to PD-1 checkpoint blockade. Over the past year, these striking data led to major changes in advanced MCC therapy, including the first-ever FDA drug approval for this disease. Despite these successes, approximately 50% of patients with MCC do not persistently benefit from PD-1 pathway blockade, underscoring the need for novel strategies to broaden antitumor immune responses in these patients. Here, we highlight recent progress in MCC including the underlying mechanisms of immune evasion and emerging approaches to augment the efficacy of PD-1 pathway blockade.
Precision Medicine and Testing for Tumor Biomarkers—Are All Tests Born Equal?
Authors: Daniel F. Hayes
Journal: JAMA Oncology (2017)

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 Oncology HomeNew OnlineCurrent IssueFor Authors Podcast 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) 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 Oncology journal
Phase II clinical trial of eribulin in advanced or recurrent cervical cancer (CC).
Authors: Jocelyn Garcia, Yvonne Gail Lin, Stan Louie, EunJeong Yoo, Denice D Tsao-Wei, Katherine E. Tierney, Laurie Leigh Brunette, Koji Matsuo, Huyen Q. Pham, Annie A. Yessaian, Susan G. Groshen, Grace Facio, Kristy Watkins, Lynda D. Roman, Laila I. Muderspach, Agustin A. Garcia
Journal: Journal of Clinical Oncology (2015)

TPS5617 Background: Eribulin (E), a Halichondrin B analog from the marine sponge H. okadai shows anticancer effects via G2/M cell cycle arrest, mitotic spindle disruption, and apoptosis. E has efficacy in pretreated metastatic breast cancer (BC) patients (pts), and preclinical antitumor activity in squamous cell carcinoma (SCC) tumor models. Microtubules (MT) have a dynamic and critical role in cancer growth and metastasis. Increasing data support their role in endoplasmic reticulum stress (ERS) and the unfolded protein response. The glucose-regulated protein-78 (GRP78), a key regulator of the ERS response, is upregulated by taxane-chemotherapy (CT) and is associated with clinical outcome. Previous reports show that high GRP78 levels predict response to MT inhibitors (paclitaxel) in BC. Given the novel tubulin-specific mechanism of action of E and its activity in SCC, we conducted a 2-stage phase 2 study of E in pts with advanced/recurrent CC to examine the clinical activity and potential predictors of response (e.g., MT-associated proteins, GRP78). We hypothesize that (1) primary CC tumors with higher GRP78 levels may be associated with better response (i.e., longer time to progression) to E; (2) pts with increasing levels of serum GRP78 during E-treatment will show improved clinical responses to E. Methods: Pts with recurrent/advanced CC after ≤ 1 prior CT regimens, measurable disease and ECOG performance status ≤ 2 were treated with E (1.4mg/m2 IV day 1 and 8 every 21 days) with tumor assessments every 2 cycles. Primary endpoint was 6-month progression free survival (PFS6); secondary were best overall response (RECISTv1.1), toxicity (CTCAEv4.03), and overall survival; and exploratory were associations of tumor and serum GRP78 as well as tubulin sub-types with clinical activity. This study has 80% power when the true PFS6= 26% with a 1-sided α ≤ 0.1 (Ho: PFS6= 10%). A prespecified futility analysis gating stage 2 was set if 0/15pts showed at least stable disease at 6 months. Archival tumor samples were evaluated by immunohistochemistry for GRP78, τ, and Tubulin-α, -β, -βIII,-βIV. Serum GRP78 levels were quantified by ELISA. The first pt was enrolled in Nov. 2012. Stage 2 began in Dec. 2014. Currently, 16 of the 30 planned pts have been enrolled. Clinical trial information: NCT01676818.
A novel automatic electrocardiographic algorithm for assessing Sclarovsky-Birnbaum Severity of Ischemia from pre-hospital ECG in ST-Segment Elevation Myocardial Infarction
Authors: Yama Fakhri, Jacob Melgaard, Hedvig Andersson, Mikkel Malby Schoos, Claus Graff, Maria Sejersten, Jens Kastrup, Peter Clemmensen
Journal: Circulation (2017)

Background: Terminal “QRS distortion” on the electrocardiogram (ECG) (based on Sclarovsky-Birnbaum Severity Grades of Ischemia) is a sign of severe ischemia and is associated with adverse cardiovas...
Abstract 19872: Safety and Efficacy of Digital Symptom Triage Tool Developed for Decreasing Emergency Department Overutilization in Patients With Chest Pain
Authors: Bicky Vettichira, Michael Goyfman, John Asheld, Regina Druz, Smadar Kort
Journal: Circulation (2016)

Introduction:  According to the CDC, >70% of the emergency department (ED) visits in 2013 were due to a non-emergent conditions. Chest pain accounts for one of the top reasons for such visits. We tested safety and efficacy of digital symptom triage tool (DSTT) designed to re-direct lower risk patients with chest pain into less expensive medical care setting.   Methods:  Three hundred consecutive patients >18 years old who presented to a tertiary center ED with chest pain were evaluated retrospectively. DSTT was used to assign a risk score, defined as warning flag, to guide medical setting disposition. Actual outcomes were obtained from the medical records. Investigators were double blinded to the risk scores and the actual disposition.   Results:  Average age was 51.7±17.1 years, 158 men (52.7%), and 142 women. Actual disposition was: 117 admitted (39%), and 183 (61%) discharged from ED. The DSTT risk score was 10.96±3.4 in the admitted group, and 5.46±3.0 in the discharged group (P   Conclusion:  DSTT was more conservative than ED physicians in re-directing lower risk patients, providing a sizable safety margin while diverting patients to lower cost setting. A prospective investigation is currently in progress, and will utilize outcome-adjusted adaptive algorithm to maximize risk fit and cost savings.
Las fiebres hemorrágicas víricas en Europa: su control eficaz exige una respuesta coordinada
Authors: N Crowcroft, D Morgan, D W Brown
Journal: Eurosurveillance (2002)

Las fiebres hemorragicas viricas (FHV) atraen la atencion del mundo medico y del publico en general por muchos motivos, algunos basados en la realidad y otros en informacion erronea. Figuran entre las infecciones que mas preocupan al publico, porque se consideran muy contagiosas y causantes de una muerte espantosa de casi todas sus victimas (1,2). Por si esto fuera poco, sigue siendo un misterio el origen de algunos de los virus implicados. Aparecen y reaparecen en muchos paises, los mas recientes en Uganda (3) y Gabon (4), con los casos de Ebola detectados en 2000 y 2001/02 respectivamente, y en Kosovo (5) y Pakistan (6) donde en 2001 se registraron casos de fiebre hemorragica de Congo-Crimea (FHCC). Los grandes brotes han afectado a las poblaciones de regiones endemicas que habitan sobre todo en zonas inaccesibles o en campos de refugiados con unas condiciones de vida muy dificiles. Las instalaciones medicas dotadas de escasos recursos han contribuido a favorecer la expansion de la transmision y las medidas de lucha contra la infeccion han sido dificiles o practicamente imposibles de llevarse a cabo. Mientras no se identifique el reservorio de estos virus y mientras las regiones endemicas sigan sufriendo las consecuencias de los cambios ecologicos, de la pobreza y de la inestabilidad social, es muy probable que continuen siendo una amenaza. Los acontecimientos ocurridos desde el 11 de septiembre de 2001 nos recuerdan su potencial uso como armas, y el temor que representa este riesgo para la salud publica.
Biomarkers of Primary Resistance to Trastuzumab in HER2-Positive Metastatic Gastric Cancer Patients: the AMNESIA Case-Control Study
Authors: Filippo Pietrantonio, Giovanni Fucà, Federica Morano, Annunziata Gloghini, Simona Corso, Giuseppe Aprile, Federica Perrone, Ferdinando De Vita, Elena Tamborini, Gianluca Tomasello, Ambra Vittoria Gualeni, Elena Ongaro, Adele Busico, Elisa Giommoni, Chiara Costanza Volpi, Maria Maddalena Laterza, Salvatore Corallo, Michele Prisciandaro, Maria Antista, Alessandro Pellegrinelli, Lorenzo Castagnoli, Serenella M. Pupa, Giancarlo Pruneri, Filippo de Braud, Silvia Giordano, Chiara Cremolini, Maria Di Bartolomeo
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Refining the selection of HER2-positive metastatic gastric cancer patient candidates for trastuzumab is a challenge of precision oncology. Preclinical studies have suggested several genomic mechanisms of primary resistance, leading to activation of tyrosine kinase receptors other than HER2 or downstream signaling pathways. Experimental Design: We carried out this multicenter, prospective, case-control study to demonstrate the negative predictive impact of a panel of candidate genomic alterations (AMNESIA panel), including EGFR/MET/KRAS/PI3K/PTEN mutations and EGFR/MET/KRAS amplifications. Hypothesizing a prevalence of candidate alterations of 30% and 0% in resistant and sensitive HER2-positive patients, respectively, 20 patients per group were needed. Results: AMNESIA panel alterations were significantly more frequent in resistant (11 of 20, 55%) as compared with sensitive (0% of 17) patients (P &amp;lt; 0.001), and in HER2 IHC 2+ (7 of 13, 53.8%) than 3+ (4 of 24, 16.7%) tumors (P = 0.028). Patients with tumors bearing no candidate alterations had a significantly longer median progression-free [5.2 vs. 2.6 months; HR, 0.34; 95% confidence interval (CI), 0.07–0.48; P = 0.001] and overall survival (16.1 vs. 7.6 months; HR, 0.38; 95% CI, 0.09–0.75; P = 0.015). The predictive accuracy of the AMNESIA panel and HER2 IHC was 76% and 65%, respectively. The predictive accuracy of the combined evaluation of the AMNESIA panel and HER2 IHC was 84%. Conclusions: Our panel of candidate genomic alterations may be clinically useful to predict primary resistance to trastuzumab in patients with HER2-positive metastatic gastric cancer and should be further validated with the aim of molecularly stratifying HER2-addicted cancers for the development of novel treatment strategies. Clin Cancer Res; 24(5); 1082–9. ©2017 AACR.
Complement activation in vitro and reactogenicity of low-molecular weight dextran-coated SPIONs in the pig CARPA model: Correlation with physicochemical features and clinical information
Authors: Tamás Fülöp, Réka Nemes, Tamás Mészáros, Rudolf Urbanics, Robbert Jan Kok, Joshua A. Jackman, Nam-Joon Cho, Gert Storm, János Szebeni
Journal: Journal of Controlled Release (2017)
Milder disease stage in patients with primary biliary cholangitis over a 44‐year period: A changing natural history
Authors: Carla F. Murillo Perez, Jorn C. Goet, Willem J. Lammers, Aliya Gulamhusein, Henk R. van Buuren, Cyriel Y. Ponsioen, Marco Carbone, Andrew Mason, Christophe Corpechot, Pietro Invernizzi, Marlyn J. Mayo, Pier Maria Battezzati, Annarosa Floreani, Albert Pares, Frederik Nevens, Kris V. Kowdley, Tony Bruns, George N. Dalekos, Douglas Thorburn, Gideon Hirschfield, Nicholas F. LaRusso, Keith D. Lindor, Kalliopi Zachou, Raoul Poupon, Palak J. Trivedi, Xavier Verhelst, Harry L.A. Janssen, Bettina E. Hansen
Journal: Hepatology (2017)

Changes over time in the presenting features and clinical course of patients with primary biliary cholangitis are poorly described. We sought to describe temporal trends in patient and disease characteristics over a 44‐year period across a large international primary biliary cholangitis cohort of 4,805 patients diagnosed between 1970 and 2014, from 17 centers across Europe and North America. Patients were divided into five cohorts according to their year of diagnosis: 1970‐1979 (n = 143), 1980‐1989 (n = 858), 1990‐1999 (n = 1,754), 2000‐2009 (n = 1,815), and ≥2010 (n = 235). Age at diagnosis, disease stage, response to ursodeoxycholic acid, and clinical outcomes were compared. Mean age at diagnosis increased incrementally by 2‐3 years per decade from 46.9 ± 10.1 years in the 1970s to 57.0 ± 12.1 years from 2010 onward ( P &lt; 0.001). The female to male ratio (9:1) and antimitochondrial antibody positivity (90%) were not significantly variable. The proportion of patients presenting with mild biochemical disease (according to Rotterdam staging) increased from 41.3% in the 1970s to 72.2% in the 1990s ( P &lt; 0.001) and remained relatively stable thereafter. Patients with a mild histological stage at diagnosis increased from 60.4% (1970‐1989) to 76.5% (1990‐2014) ( P &lt; 0.001). Correspondingly, response to ursodeoxycholic acid according to Paris‐I criteria increased; 51.7% in the 1970s and 70.5% in the 1990s ( P &lt; 0.001). Recent decades were also characterized by lower decompensation rates (18.5% in the 1970s to 5.8% in the 2000s, P &lt; 0.001) and higher 10‐year transplant‐free survival (48.4%, 68.7%, 79.7%, and 80.1% for each respective cohort; P &lt; 0.001). Conclusion: In recent decades, a pattern of primary biliary cholangitis presentation consistent with an older age at diagnosis alongside reduced disease severity has been noted; the observed trends may be explained by an increase in routine testing of liver function and/or a changing environmental trigger. (H epatology 2018;67:1920‐1930).
Rate-Response Programming Tailored to the Force-Frequency Relationship Improves Exercise Tolerance in Chronic Heart Failure
Authors: John Gierula, Maria F. Paton, Judith E. Lowry, Haqeel A. Jamil, Rowenna Byrom, Michael Drozd, Jack O. Garnham, Richard M. Cubbon, David A. Cairns, Mark T. Kearney, Klaus K. Witte
Journal: JACC Heart Failure (2017)

This study sought to examine whether the heart rate (HR) at which the force-frequency relationship (FFR) slope peaks (critical HR) could be used to tailor HR response in chronic heart failure (CHF) patients with cardiac pacemakers and whether this favorably influences exercise capacity.CHF secondary to left ventricular (LV) systolic dysfunction is characterized by blunting of the positive relationship between HR and LV contractility known as the FFR.This observational study was carried out in patients with CHF and healthy subjects with pacemaker devices. The study assessed the 3 important features of the FFR (critical HR, peak contractility, and the FFR slope), and their reproducibility was measured noninvasively using echocardiography. The investigators then undertook a double-blind, randomized, controlled crossover study comparing the effects of tailored pacemaker rate-response programming on the basis of the FFR with conventional rate-response programming on exercise time and maximal oxygen consumption.The study enrolled 90 patients with CHF into the observational cohort study: mean age, 73.6 ± 8.9 years; mean left ventricular ejection fraction (LVEF), 33.5 ± 10.9%. The study investigated 15 control subjects with normal LV function (LVEF, 55.6 ± 5.3%). The critical HR (103 ± 22 beats/min vs. 126 ± 15 beats/min; p = 0.0002), peak contractility (3.8 ± 3.7 SBP/LVESVI vs. 9.8 ± 4.1 SBP/LVESVI; p = 0.0001), and the slope of the FFR (p < 10-15) were lower in patients with CHF than in control subjects. A total of 52 patients, with a mean LVEF of 32 ± 11% on optimal therapy, took part in the crossover study. Rate-response settings limiting HR rise to below the critical HR led to greater exercise time (475 ± 189 s vs. 425 ± 196 s; p = 0.003) and higher peak oxygen consumption (17.3 ± 4.6 ml/kg/min vs. 16.6 ± 4.7 ml/kg/min; p = 0.01).A personalized approach to rate-response programming, determined using a reproducible noninvasive method for assessing the FFR, improves exercise time in patients with CHF and pacemaker devices. (Bowditch Revisited: Defining the Optimum Heart Rate Range in Chronic Heart Failure; NCT02563873).