tbuckley/cabot-search huggingface dataset:
Novel immunotherapies for adult patients with B-lineage acute lymphoblastic leukemia
Authors: Guoqing Wei, Jiasheng Wang, He Huang, Yanmin Zhao
Journal: Journal of Hematology & Oncology (2017)

The past decade witnessed the rapid development of adult B-lineage acute lymphoblastic leukemia (ALL) treatment. Beyond the development of chemotherapy regimens, immunotherapy is starting a new era with unprecedented complete remission (CR) rate. Targeting B-lineage-specific surface markers such as CD19, CD20, CD22, or CD52, immunotherapy has been demonstrating promising clinical results. Among the immunotherapeutic methods, naked monoclonal antibodies (mAbs), antibody-drug conjugate (ADC), bispecific T cell engager (BiTE), and chimeric antigen receptor (CAR) T cells are the main types. In this review, we will examine the emerging preclinical and clinical development on (1) anti-CD20 naked mAbs rituximab, ofatumumab, and obinutuzumab; (2) anti-CD19 ADCs SAR3419 and SGN-CD19A and anti-CD19 BiTE blinatumomab; (3) anti-CD22 naked mAb epratuzumab and anti-CD22 ADC inotuzumab ozogamicin; (4) anti-CD52 naked mAb alemtuzumab; and (5) anti-CD19 CAR T cells. We will discuss their efficacy, adverse effects, as well as future development.
Tracking Brain Development and Dimensional Psychiatric Symptoms in Children: A Longitudinal Population-Based Neuroimaging Study
Authors: Ryan L. Muetzel, Laura M.E. Blanken, Jan van der Ende, Hanan El Marroun, Philip Shaw, Gustavo Sudre, Aad van der Lugt, Vincent W.V. Jaddoe, Frank C. Verhulst, Henning Tiemeier, Tonya White
Journal: American Journal of Psychiatry (2017)

Objective: Psychiatric symptomatology during childhood predicts persistent mental illness later in life. While neuroimaging methodologies are routinely applied cross-sectionally to the study of child and adolescent psychopathology, the nature of the relationship between childhood symptoms and the underlying neurodevelopmental processes remains unclear. The authors used a prospective population-based cohort to delineate the longitudinal relationship between childhood psychiatric problems and brain development. Method: A total of 845 children participated in the study. Psychiatric symptoms were measured with the parent-rated Child Behavior Checklist at ages 6 and 10. MRI data were collected at ages 8 and 10. Cross-lagged panel models and linear mixed-effects models were used to determine the associations between psychiatric symptom ratings and quantitative anatomic and white matter microstructural measures over time. Results: Higher ratings for externalizing and internalizing symptoms at baseline predicted smaller increases in both subcortical gray matter volume and global fractional anisotropy over time. The reverse relationship did not hold; thus, baseline measures of gray matter and white matter were not significantly related to changes in symptom ratings over time. Conclusions: Children presenting with behavioral problems at an early age show differential subcortical and white matter development. Most neuroimaging models tend to explain brain differences observed in psychopathology as an underlying (causal) neurobiological substrate. However, the present work suggests that future neuroimaging studies showing effects that are pathogenic in nature should additionally explore the possibility of the downstream effects of psychopathology on the brain.
KEYNOTE-001: 3-year overall survival for patients with advanced NSCLC treated with pembrolizumab.
Authors: Natasha B. Leighl, Matthew David Hellmann, Rina Hui, Enric Carcereny Costa, Enriqueta Felip, Myung-Ju Ahn, Joseph Paul Eder, Ani Sarkis Balmanoukian, Charu Aggarwal, Leora Horn, Amita Patnaik, Matthew A. Gubens, Suresh S. Ramalingam, Gregory M. Lubiniecki, Jin Zhang, Bilal Piperdi, Edward B. Garon
Journal: Journal of Clinical Oncology (2017)

9011 Background: Pembrolizumab (pembro) is approved as first-line (1L) treatment for advanced NSCLC patients (pts) with PD-L1 tumor proportion score (TPS) ≥50% and as treatment for previously treated advanced NSCLC pts with PD-L1 TPS ≥1%. Here we present 3-y OS results for pts enrolled in KEYNOTE-001 (NCT01295827), the first trial evaluating pembro in advanced NSCLC pts. Methods: 550 pts received pembro 2 or 10 mg/kg Q3W or 10 mg/kg Q2W until intolerable toxicity, progression, or investigator or pt decision to withdraw. PD-L1 expression was assessed by IHC using the 22C3 antibody. Survival was assessed every 2 mo after treatment discontinuation. Results: 550 advanced NSCLC pts enrolled; 101 were first line (1L), and 449 were previously treated. As of the Sept 1, 2016, data cutoff, median follow-up duration was 34.5 mo (range, 25.7-51.5 mo); 8 (7.9%) 1L pts and 28 (6.2%) previously treated pts were still on treatment. 3-y OS was 26.4% (95% CI, 14.3%-40.1%) in 1L pts and 19% (95% CI, 15.0%-23.4%) in previously treated pts. 3-y OS rate and median OS by PD-L1 status are in the Table. Additional description of the pts with long-term survival, including updated safety data as well as 3-y OS by smoking history, histology, EGFRstatus, and prior radiation therapy, will be presented. Conclusions: Pembro provides promising long-term OS benefit for 1L and previously treated advanced NSCLC pts expressing PD-L1. The current data represent the longest efficacy and safety follow-up for pts with advanced NSCLC treated with pembro. Clinical trial information: NCT01295827. [Table: see text]
Abstract 236: Myocardial Relaxation is Modified by Fast Stretch but not Titin Isoform Size
Authors: Charles S Chung
Journal: Circulation Research (2016)

Fast myocardial relaxation is important in vivo to reduce left ventricular pressure and promote efficient filling after cardiac contraction and ejection. Afterload is theorized to be a modifier of relaxation, but afterload reduction does not appear to help patients with diastolic dysfunction or Heart Failure with preserved Ejection Fraction. We hypothesized that a fast stretch, not afterload, modifies the relaxation rate, and that this relationship is modified by the giant elastic protein titin. A rat model carrying a spontaneous mutation in the RNA binding motif-20 (RBM20) results in long titin isoforms. Cardiac trabeculae from wild-type and RBM20 rats were dissected, paced at 0.5 Hz, and stretched to Lo, the length at which maximum isometric twitch force was developed. Isotonic load clamps maintained a specified afterload in experimental twitches by shortening and (if needed) relengthening the muscles using feedback control. Identical protocols were performed at reduced preload and two temperature conditions (37°C and 25°C). We determined that myocardial relaxation rate (1/tau) was modified by fast stretch (strain rate) just prior to relaxation; preventing stretch eliminated the inverse relationship between afterload and relaxation rate. Computational modeling indicates that fast stretch enhances crossbridge detachment and that passive tension compensates for some of the active force reduction during stretch. Stretch of 1 length•s -1 causes a 240% increase in relaxation rate (54.6 s -1 vs 22.5 s -1 ) at 37°C. Relaxation rate was preload independent and was slower but more responsive to stretch at 25°C. Trabeculae from long-titin mutant rats were not statistically different than control animals, but trend (p&lt;0.1) towards faster relaxation and may require faster stretch to maintain a load clamp at 50% peak developed force. The faster stretch may compensate for a reduced passive tension in the long-titin mutant rats that made it harder to maintain the load-clamp during stretch. In all, these data suggest that fast myocardial stretch (strain rate) at end systole is a preload independent mechanism to modify the relaxation rate. The fast stretch appears to enhance crossbridge detachment to accelerate relaxation independently of titin based stiffness.
Natural history of malignant bone disease in renal cancer: Final results of an Italian bone metastases survey.
Authors: Daniele Santini, Giuseppe Procopio, Camillo Porta, Calogero Mazzara, Sandro Barni, Andrea Fontana, Alfredo Berruti, Rossana Berardi, Bruno Vincenzi, Cinzia Ortega, Toni Ibrahim, Davide Ottaviani, Giacomo Carteni, Gaetano Lanzetta, Vladimir Virzì, Nicola Silvestris, Francesca Maria Tanca, Vincenzo Adamo, Giuseppe Tonini, Sergio Bracarda
Journal: Journal of Clinical Oncology (2012)

4627 Background: bone metastases (mts) are an emerging clinical problem in renal cancer patients related to survival increase. We report the final data of largest survey never published in literature. Methods: 398 renal cancer patients (pts) with evidence of bone mts, all died at the moment of study inclusion, have been included. Clinico-pathological data, data on survival and Skeletal Related Events (SRE) data and skeletal related therapies have been collected and statistically analyzed. Results: 286 males/112 females; median age: 63 (16-87); pts with bone mts at the moment of renal cancer diagnosis: 31.4%; pts with single bone mts: 31.1%. Type: lytic 77%, mixed: 14.6%, blastic: 7.6 %. Sites: spine (65.8%), pelvis (38.4%), long bones (31.6%), other (18.8%). Median time to bone mts: 8 months (0-288) (all patients); 24 months (1-288) (pts without bone mts at diagnosis). Pts with at least 1 SRE: 71.1%. Types of SREs: pathologic fracture (12.6%), radiotherapy (61.8%), spinal compression (7.6%), bone surgery (14.8%), hypercalcaemia (3.2%). Median number of SRE for patient: 1 (0-4). Median time to first SRE: 2 (0-72), to second SRE: 4 (0-113), to third SRE: 11 (1-108). Median survival after bone mts diagnosis: 12 (1-178). Median survival after first SRE: 10 (0-144). Median survival in pts with at least one SRE: 14 (1-178); median survival in pts without SREs: 9 (0-62). In according with MKSCC criteria median time to skeletal disease was in patients with good prognosis was 24 (0-288), intermediate was 5 (0-180) and poor prognosis was 0 (0-77). A total of 168 pts received zoledronic acid until performance status worsening or death. 162 pts have been analysed as control group. The median time to first SRE in the zoledronic treated pts was 3 mths (0-101) compared with 1 mth (0 - 25) in the control group (p&lt; 0.05). 5 cases of ONJ have been diagnosed. Conclusions: The present survey is the largest descriptive study concerning the natural history of bone disease in renal cancer patients. The effects of biological therpies on bone met will be presented during the meeting.
Informed Consent to Study Purpose in Randomized Clinical Trials of Antibiotics, 1991 Through 2011
Authors: Peter Doshi, Peter Hur, Mark Jones, Husam Albarmawi, Tom Jefferson, Daniel J. Morgan, Patricia A. Spears, John H. Powers
Journal: JAMA Internal Medicine (2017)

Potential research participants may assume that randomized trials comparing new interventions with older interventions always hypothesize greater efficacy for the new intervention, as in superiority trials. However, antibiotic trials frequently use "noninferiority" hypotheses allowing a degree of inferior efficacy deemed "clinically acceptable" compared with an older effective drug, in exchange for nonefficacy benefits (eg, decreased adverse effects). Considering these different benefit-harm trade-offs, proper informed consent necessitates supplying different information on the purposes of superiority and noninferiority trials.
Zika virus activates de novo and cross-reactive memory B cell responses in dengue-experienced donors
Authors: Thomas F. Rogers, Eileen C. Goodwin, Bryan Briney, Devin Sok, Nathan Beutler, Alexander Strubel, Rebecca Nedellec, Khoa Le, Michael E. Brown, Dennis R. Burton, Laura M. Walker
Journal: Science Immunology (2017)

Zika virus (ZIKV) shares a high degree of homology with dengue virus (DENV), suggesting that preexisting immunity to DENV could affect immune responses to ZIKV. We have tracked the evolution of ZIKV-induced B cell responses in three DENV-experienced donors. The acute antibody (plasmablast) responses were characterized by relatively high somatic hypermutation and a bias toward DENV binding and neutralization, implying the early activation of DENV clones. A DENV-naïve donor in contrast showed a classical primary plasmablast response. Five months after infection, the DENV-experienced donors developed potent type-specific ZIKV neutralizing antibody responses in addition to DENV cross-reactive responses. Because cross-reactive responses were poorly neutralizing and associated with enhanced ZIKV infection in vitro, preexisting DENV immunity could negatively affect protective antibody responses to ZIKV. The observed effects are epitope-dependent, suggesting that a ZIKV vaccine should be carefully designed for DENV-seropositive populations.
Validation of Immunohistochemical Assays for Integral Biomarkers in the NCI-MATCH EAY131 Clinical Trial
Authors: Joseph D. Khoury, Wei-Lien Wang, Victor G. Prieto, L. Jeffrey Medeiros, Neda Kalhor, Meera Hameed, Russell Broaddus, Stanley R. Hamilton
Journal: Clinical Cancer Research (2017)

Biomarkers that guide therapy selection are gaining unprecedented importance as targeted therapy options increase in scope and complexity. In conjunction with high-throughput molecular techniques, therapy-guiding biomarker assays based upon immunohistochemistry (IHC) have a critical role in cancer care in that they inform about the expression status of a protein target. Here, we describe the validation procedures for four clinical IHC biomarker assays-PTEN, RB, MLH1, and MSH2-for use as integral biomarkers in the nationwide NCI-Molecular Analysis for Therapy Choice (NCI-MATCH) EAY131 clinical trial. Validation procedures were developed through an iterative process based on collective experience and adaptation of broad guidelines from the FDA. The steps included primary antibody selection; assay optimization; development of assay interpretation criteria incorporating biological considerations; and expected staining patterns, including indeterminate results, orthogonal validation, and tissue validation. Following assay lockdown, patient samples and cell lines were used for analytic and clinical validation. The assays were then approved as laboratory-developed tests and used for clinical trial decisions for treatment selection. Calculations of sensitivity and specificity were undertaken using various definitions of gold-standard references, and external validation was required for the PTEN IHC assay. In conclusion, validation of IHC biomarker assays critical for guiding therapy in clinical trials is feasible using comprehensive preanalytic, analytic, and postanalytic steps. Implementation of standardized guidelines provides a useful framework for validating IHC biomarker assays that allow for reproducibility across institutions for routine clinical use. Clin Cancer Res; 24(3); 521-31. ©2017 AACR.
Lethal Heat Waves Expected to Increase
Authors: M.J. Friedrich
Journal: JAMA (2017)

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Neurologic Complications Associated With the Zika Virus in Brazilian Adults
Authors: Ivan Rocha Ferreira da Silva, Jennifer A. Frontera, Ana Maria Bispo de Filippis, Osvaldo Jose Moreira do Nascimento
Journal: JAMA Neurology (2017)

There are no prospective cohort studies assessing the incidence and spectrum of neurologic manifestations secondary to Zika virus (ZIKV) infection in adults.To evaluate the rates of acute ZIKV infection among patients hospitalized with Guillain-Barré syndrome (GBS), meningoencephalitis, or transverse myelitis.A prospective, observational cohort study was conducted at a tertiary referral center for neurological diseases in Rio de Janeiro, Brazil, between December 5, 2015, and May 10, 2016, among consecutive hospitalized adults (>18 years of age) with new-onset acute parainfectious or neuroinflammatory disease. All participants were tested for a series of arbovirosis. Three-month functional outcome was assessed.Samples of serum and cerebrospinal fluid were tested for ZIKV using real-time reverse-transcriptase-polymerase chain reaction and an IgM antibody-capture enzyme-linked immunosorbent assay. Clinical, radiographic (magnetic resonance imaging), electrophysiological, and 3-month functional outcome data were collected.The detection of neurologic complications secondary to ZIKV infection.Forty patients (15 women and 25 men; median age, 44 years [range, 22-72 years]) were enrolled, including 29 patients (73%) with GBS (90% Brighton level 1 certainty), 7 (18%) with encephalitis, 3 (8%) with transverse myelitis, and 1 (3%) with newly diagnosed chronic inflammatory demyelinating polyneuropathy. Of these, 35 patients (88%) had molecular and/or serologic evidence of recent ZIKV infection in the serum and/or cerebrospinal fluid. Of the patients positive for ZIKV infection, 27 had GBS (18 demyelinating, 8 axonal, and 1 Miller Fisher syndrome), 5 had encephalitis (3 with concomitant acute neuromuscular disease), 2 had transverse myelitis, and 1 had chronic inflammatory demyelinating polyneuropathy. Admission to the intensive care unit was required for 9 patients positive for ZIKV infection (26%), and 5 (14%) required mechanical ventilation. Compared with admission during the period from December 5, 2013, to May 10, 2014 (before the Brazilian outbreak of ZIKV), admissions for GBS increased from a mean of 1.0 per month to 5.6 per month, admissions for encephalitis increased from 0.4 per month to 1.4 per month, and admissions for transverse myelitis remained constant at 0.6 per month. At 3 months, 2 patients positive for ZIKV infection (6%) died (1 with GBS and 1 with encephalitis), 18 (51%) had chronic pain, and the median modified Rankin score among survivors was 2 (range, 0-5).In this single-center Brazilian cohort, ZIKV infection was associated with an increase in the incidence of a diverse spectrum of serious neurologic syndromes. The data also suggest that serologic and molecular testing using blood and cerebrospinal fluid samples can serve as a less expensive, alternative diagnostic strategy in developing countries, where plaque reduction neutralization testing is impractical.
Too hard to swallow!
Authors: Keith Siau, Akhmid Aziz, Lenny Liew, Sauid Ishaq
Journal: Gut (2017)

An 80-year-old woman presented with a 4-month history of intermittent oropharyngeal dysphagia and aspiration, particularly after eating peas. She had no significant medical history and denied additional symptomatology. Gastroscopy revealed a smooth lesion arising in the pharynx abutting the epiglottis (figure 1) but was otherwise unremarkable. Pillow sign was negative. No neck masses were palpable on examination after endoscopy.



Figure 1 
Endoscopic appearance of the pharynx.



1.  What is the endoscopic finding and what are the …
Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma
Authors: Thomas Powles, Peter H. O'Donnell, Christophe Massard, Hendrik-Tobias Arkenau, Terence W. Friedlander, Christopher J. Hoimes, Jae Lyun Lee, Michael Ong, Srikala S. Sridhar, Nicholas J. Vogelzang, Mayer N. Fishman, Jingsong Zhang, Sandy Srinivas, Jigar Parikh, Joyce Antal, Xiaoping Jin, Ashok K. Gupta, Yong Ben, Noah M. Hahn
Journal: JAMA Oncology (2017)

The data reported herein were accepted for assessment by the US Food and Drug Administration for Biologics License Application under priority review to establish the clinical benefit of durvalumab as second-line therapy for locally advanced or metastatic urothelial carcinoma (UC), resulting in its recent US approval.To report a planned update of the safety and efficacy of durvalumab in patients with locally advanced/metastatic UC.This is an ongoing phase 1/2 open-label study of 191 adult patients with histologically or cytologically confirmed locally advanced/metastatic UC whose disease had progressed on, were ineligible for, or refused prior chemotherapy from 60 sites in 9 countries as reported herein.Patients were administered durvalumab intravenous infusion, 10 mg/kg every 2 weeks, for up to 12 months or until progression, starting another anticancer therapy, or unacceptable toxic effects.Primary end points were safety and confirmed objective response rate (ORR) per blinded independent central review (Response Evaluation Criteria In Solid Tumors [RECIST], version 1.1).A total of 191 patients with UC had received treatment. As of October 24, 2016 (90-day update), the median follow-up was 5.78 months (range, 0.4-25.9 months). The median age of patients was 67.0 years and most were male (136 [71.2%]) and white (123 [71.1%]). All patients had stage 4 disease, and 190 (99.5%) had prior anticancer therapy (182 [95.3%] postplatinum). The ORR was 17.8% (34 of 191; 95% CI, 12.7%-24.0%), including 7 complete responses. Responses were early (median time to response, 1.41 months), durable (median duration of response not reached), and observed regardless of programmed cell death ligand-1 (PD-L1) expression (ORR, 27.6% [n = 27; 95% CI, 19.0%-37.5%] and 5.1% [n = 4; 95% CI, 1.4%-12.5%] in patients with high and low or negative expression of PD-L1, respectively). Median progression-free survival and overall survival were 1.5 months (95% CI, 1.4-1.9 months) and 18.2 months (95% CI, 8.1 months to not estimable), respectively; the 1-year overall survival rate was 55% (95% CI, 44%-65%), as estimated by Kaplan-Meier method. Grade 3/4 treatment-related adverse events (AEs) occurred in 13 patients (6.8%); grade 3/4 immune-mediated AEs occurred in 4 patients (2.1%); and treatment-related AEs led to discontinuation of 3 patients (1.6%), 2 of whom had immune-mediated AEs that led to death (autoimmune hepatitis and pneumonitis).Durvalumab, 10 mg/kg every 2 weeks, demonstrates favorable clinical activity and an encouraging and manageable safety profile in patients with locally advanced/metastatic UC.clinicaltrials.gov Identifier: NCT01693562.