tbuckley/cabot-search huggingface dataset:
Virus Surveillance and Diagnosis With a CRISPR-Based Platform
Authors: Tracy Hampton
Journal: JAMA (2020)

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
Infection during the first year in patients treated with CD19 CAR T cells for diffuse large B cell lymphoma
Authors: Kitsada Wudhikarn, M. Lia Palomba, Martina Pennisi, Marta Garcia-Recio, Jessica R. Flynn, Sean M. Devlin, Aishat Afuye, Mari Lynne Silverberg, Molly A. Maloy, Gunjan L. Shah, Michael Scordo, Parastoo B. Dahi, Craig S. Sauter, Connie L. Batlevi, Bianca D. Santomasso, Elena Mead, Susan K. Seo, Miguel-Angel Perales
Journal: Blood Cancer Journal (2020)

Abstract CD19-targeted chimeric antigen receptor (CAR) T cell therapy is an effective treatment for diffuse large B cell lymphoma (DLBCL). In addition to cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS), B cell aplasia and hypogammaglobulinemia are common toxicities predisposing these patients to infections. We analyzed 60 patients with DLBCL treated with FDA-approved CD19 CAR T cells and report the incidence, risk factors, and management of infections during the first year after treatment. A total of 101 infectious events were observed, including 25 mild, 51 moderate, 23 severe, 1 life-threatening, and 1 fatal infection. Bacteria were the most common causative pathogens. The cumulative incidence of overall, bacterial, severe bacterial, viral, and fungal infection at 1 year were 63.3%, 57.2%, 29.6%, 44.7%, and 4%, respectively. In multivariate analyses, the use of systemic corticosteroids for the management of CRS or ICANS was associated with an increased risk of infections and prolonged admission. Impaired performance status and history of infections within 30 days before CAR T cell therapy was a risk factor for severe bacterial infection. In conclusion, infections were common within the first 60 days after CAR T cell therapy, however, they were not associated with an increased risk of death.
Immune effector cell–associated neurotoxicity syndrome after chimeric antigen receptor T-cell therapy for lymphoma: predictive biomarkers and clinical outcomes
Authors: Noa G Holtzman, Hao Xie, Soren Bentzen, Vivek Kesari, Ali Bukhari, Firas El Chaer, Forat Lutfi, Jonathan Siglin, Elizabeth Hutnick, Natalie Gahres, Kathleen Ruehle, Haroon Ahmad, Carl Shanholtz, Mehmet H Kocoglu, Ashraf Z Badros, Jean A Yared, Nancy M Hardy, Aaron P Rapoport, Saurabh Dahiya
Journal: Neuro-Oncology (2020)

CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CAR-T) has emerged as effective for relapsed/refractory large B-cell lymphoma (R/R LBCL). The neurologic toxicity seen with CAR-T, referred to as immune effector cell-associated neurotoxicity syndrome (ICANS), is poorly understood. To better elucidate the clinical characteristics, treatment outcomes, and correlative biomarkers of ICANS, we review here a single-center analysis of ICANS after CAR T-cell therapy in R/R LBCL.Patients (n = 45) with R/R LBCL treated with axicabtagene ciloleucel (axi-cel) were identified. Data regarding treatment course, clinical outcomes, and correlative studies were collected. Patients were monitored and graded for ICANS via CARTOX-10 scoring and Common Terminology Criteria for Adverse Events (CTCAE) v4.03 criteria, respectively.Twenty-five (56%) patients developed ICANS, 18 (72%) of whom had severe (CTCAE grades 3-4) ICANS. Median time to development of ICANS was 5 days (range, 3-11). Elevated pre-infusion (day 0 [D0]) fibrinogen (517 vs 403 mg/dL, upper limit of normal [ULN] 438 mg/dL, P = 0.01) and D0 lactate dehydrogenase (618 vs 506 units/L, ULN 618 units/L, P = 0.04) were associated with ICANS. A larger drop in fibrinogen was associated with ICANS (393 vs 200, P < 0.01). Development of ICANS of any grade had no effect on complete remission (CR), progression-free survival (PFS), or overall survival (OS). Duration and total dose of steroid treatment administered for ICANS did not influence CR, PFS, or OS.ICANS after CAR-T with axi-cel for R/R LBCL was seen in about half of patients, the majority of which were high grade. Contrary to previous reports, neither development of ICANS nor its treatment were associated with inferior CR, PFS, or OS. The novel finding of high D0 fibrinogen level can identify patients at higher risk for ICANS.
Abstract B57: A combination of IL7Rα and NRAS mutations sheds light on the oncogenesis of T-cell acute lymphoblastic leukemia in a murine model
Authors: Hila Winer, Gisele Rodrigues, Wenqing Li, Julie Hixon, Scott Durum
Journal: Cancer Research (2020)

Abstract Acute lymphoblastic leukemia (ALL) is the most common cancer in children. While most cases of ALL arise from B-cell precursors, 15% originate from T cells in the thymus (T-ALL). With current treatments, survival rate is high, but relapse occurs in 15-20% of children. In addition, most treatments are highly toxic, with severe side effects. Approximately 10% of T-ALL patients have somatic gain-of-function mutations in IL7Rα gene, and 15-22% of ALL patients have mutations in NRAS or KRAS. Furthermore, Ras pathway mutations are responsible for 30%-50% of ALL relapse. Recently, our lab showed that mutations in human IL7Rα alone (c.731_732insTTGTCCCAC) or human NRAS alone (G13D) are not sufficient to induce T-ALL from primary cells. However, a combination of both causes severe T-ALL in mice. Treatment with inhibitors against IL7Rα and NRAS signaling led to prolonged survival in these mice. Our new data indicate that the correct ratio between IL7Rα and NRAS expression is necessary to generate T-ALL in mice. Using RAG-/- mice injected with primary thymocytes transduced with mutated IL7Rα and NRAS in the optimal sequence in a polycistronic vector led to fatal disease 3 weeks after injection. These mice showed a 30-fold increase of leukocytes in the blood, spleen, and thymus, 80-fold increase in the lymph nodes, and a 5-fold increase in spleen weight, all indications of severe T-ALL. There was no indication of disease progression in mice injected with either empty vector or wild-type IL7Rα and mutated NRAS. To identify the pathways involved in T-ALL by these mutations, we used mass spectrometry and RNA sequencing. Our analysis showed significant increases in the well-known antiapoptotic, B-cell lymphoma 2 (BCL-2), mRNA, and protein levels and a major decrease in the proapoptotic BCL-2 antagonist/killer 1 (BAK-1) protein levels. In this manner, combination of both IL7Rα and NRAS mutations resulted in high Bcl-2:Bak-1 ratio, supported also by Western blot analysis. In addition, we observed a significant increase in the protein cytokinesis midbody regulator citron kinase (Cit), potentially leading to increased thymocytes proliferation and driving T-ALL formation. Taken together, our lab developed a strong model to study T-ALL in mice, shedding light on novel pathways of oncogenesis and targets for better therapeutic development. Citation Format: Hila Winer, Gisele Rodrigues, Wenqing Li, Julie Hixon, Scott Durum. A combination of IL7Rα and NRAS mutations sheds light on the oncogenesis of T-cell acute lymphoblastic leukemia in a murine model [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B57.
Precipitant Factors of Heart Failure Decompensation in Patients Attended in Primary Care, the Hefestos Study
Authors: Miguel-Angel Munoz, Helene Vaillant-Roussel, Liam Glynn, Radost Assenova, Peter Torsza, Lea Gril, Heidrun Lingner, Jacopo Demurtas, Hans Thulesius, Djurdjica Lazic, Jose-Maria Verdu-Rotellar, Rosa Abellana
Journal: Circulation (2019)

Introduction: Most knowledge about the main causes of heart failure decompensation come from hospital setting. However, evidence coming from primary care is scarce.Hypothesis: It is possible to ide ...
Methods matter: instrumental variable analysis may be a complementary approach to intention-to-treat analysis and as treated analysis when analysing data from sports injury trials
Authors: Pascal Edouard, Kathrin Steffen, Laurent Navarro, Mohammad Ali Mansournia, Rasmus Oestergaard Nielsen
Journal: British Journal of Sports Medicine (2020)

Imagine a sports injury researcher claiming: ‘the effect of the injury prevention programme we reported in the trial is unbiased because we analysed according to the intention-to-treat principle’ (ITT). This sounds appealing for clinicians, coaches and athletes. However, before implementing results from such trial, readers should consider whether the athletes in the trial actually complied with the intervention. The appealing message above from the researcher strongly depends on the ‘whereabouts’ of the athletes. Those in the intervention group(s) need to be fully compliant to draw a meaningful conclusion regarding the effect of the intervention.

In studies affected by low compliance, we believe that drawing a conclusion on the effect of an intervention may be misleading as low compliance may bias results if data are analysed according to the ITT principle.1 We encourage clinicians, coaches and athletes to take a sceptical, cautious step back when reading bombastic conclusions in the sports injury literature. Researchers should do their best to deal with low compliance during (1) study design, (2) data collection and (3) when analysing data from sports injury trials. As a part of a BJSM educational series on methods in randomised controlled trials (RCTs), we discuss here an alternative analytical approach to the ITT—‘instrumental variable (IV) analysis’.2

To illustrate the problem of compliance, we used a data set from an RCT with 40-week follow-up investigating the efficacy of an Athletics Injury Prevention Programme (AIPP) to reduce injury complaints leading to restrictions in athletics participation (PREVATHLE: CPP Ouest II-Angers, number: 2017-A01980-53; ClinicalTrials.gov Identifier: NCT03307434). In this trial, track and field athletes (n=840) were allocated to either a control group (n=391, reference group), who were asked to continue their usual training, or an intervention group (n=449), who were asked to perform the specifically designed AIPP twice a week. Interestingly and thought-provokingly, …
Pleiotropic Roles of Platelets and Neutrophils in Cell Death and Recovery During Acetaminophen Hepatotoxicity
Authors: Hartmut Jaeschke, Anup Ramachandran
Journal: Hepatology (2020)

Jaeschke, Hartmut Ph.D.; Ramachandran, Anup Ph.D.Editor(s): Corey, Kathleen E.2; Malhi, Harmeet3 Author Information
Research and Development Costs of New Drugs
Authors: Joseph A. DiMasi
Journal: JAMA (2020)

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
Brain Death—Moving Beyond Consistency in the Diagnostic Criteria
Authors: Robert D. Truog, Kandamaran Krishnamurthy, Robert C. Tasker
Journal: JAMA (2020)

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 Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Abstract A21: Time-to-event Bayesian optimal interval design to accelerate phase I pediatric oncology trials
Authors: Ying Yuan, Ruitao Lin, Daniel Li, Lei Nie, Katherine Warren
Journal: Cancer Research (2020)

Abstract Late-onset toxicity is common for novel molecularly targeted agents and immunotherapy. It causes major logistic difficulty for existing adaptive phase I trial designs, which require the observance of toxicity early enough to apply dose escalation rules for new patients. The same logistic difficulty arises when the accrual is rapid. We propose the time-to-event Bayesian optimal interval (TITE-BOIN) design to accelerate phase I trials by allowing for real-time dose assignment decisions for new patients while some enrolled patients’ toxicity data are still pending. Similar to the rolling six design, the TITE-BOIN dose escalation/de-escalation rule can be tabulated before the trial begins, making it transparent and simple to implement, but is more flexible in choosing the target DLT rate and has higher accuracy to identify the MTD. Compared to the more complicated model-based time-to-event continuous reassessment method (TITE-CRM), the TITE-BOIN has comparable accuracy to identify the MTD but is simpler to implement with substantially better overdose control. A numerical study shows that the TITE-BOIN design supports continuous accrual, without sacrificing patient safety or the accuracy of identifying the MTD, and therefore has great potential to accelerate early-phase drug development. Note: This abstract was not presented at the conference. Citation Format: Ying Yuan, Ruitao Lin, Daniel Li, Lei Nie, Katherine Warren. Time-to-event Bayesian optimal interval design to accelerate phase I pediatric oncology trials [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A21.
Systemic ALK-Positive Anaplastic Large-Cell Lymphoma (ALCL): Final Analysis of an International, Individual Patient Data Study of 263 Adults
Authors: David Sibon, Dinh-Phong Nguyen, Norbert Schmitz, Ritsuro Suzuki, Andrew L Feldman, Remy Gressin, Laurence Lamant, Dennis D. Weisenburger, Shigeo Nakamura, Marita Ziepert, Matthew J Maurer, Martin Bast, James O. Armitage, Julie M. Vose, Herve Tilly, Jean-Philippe Jais, Kerry J Savage
Journal: Blood (2017)
Abstract A40: Integration of high-throughput drug screening on patient-derived organdies into pediatric precision medicine programs: The future is now!
Authors: Karin Langenberg, Emmy Dolman, Jan Molenaar
Journal: Cancer Research (2020)

Abstract Background/Objectives: The most promising option to improve outcomes for pediatric cancer patients with relapsed or refractory disease is through mutation-based targeted therapeutic strategies. However, only 50% of these tumors harbor actionable events. Therefore, compound screening on organoids grown from tumor tissue might reveal additional treatment options. Design/Methods: The Dutch Childhood Oncology Group-individualized Therapies (DCOG-iTHER) clinical trial in collaboration with INFORM consists of whole-exome sequencing (WES), low-coverage whole-genome sequencing (WGS), RNA profiling using RNAseq and Affymetrix microarrays, and a methylation array. Data are analyzed using the Dutch R2 bioinformatic platform. In addition, tumor-derived organoids are cultured profiled through the same pipeline. Semi-high-throughput screening of a 170-compound library is performed, and effect on cell viability using the CellTiter-Glo® 3D cell viability assay is assessed. Results: To date, 133 patients with relapsed/refractory pediatric malignancies have been enrolled and analysis has been completed in 80 study subjects. In 47 patients, a total of 128 molecular targets were identified and 29 patients harbored an actionable event with priority score ≥ moderate (46%). In 14% a matched targeted therapy was initiated, and one-third of these patients achieved complete remission. In addition, tumor organoids have been cultured of neuroblastoma tumors and molecular profiling was performed to confirm they reflect the patient’s tumor biology. High-throughput drug screen confirmed existing molecular targets such as ALK and c-kit and in addition revealed increased compound sensitivity to drugs not previously found through sequencing. Conclusions: Our proof of concept of patient-specific drug testing on tumor organoids within our pediatric precision medicine program might reveal additional treatment options for children who currently have none. Clinical benefit will be evaluated in our upcoming clinical trial iTHER 2.0. Citation Format: Karin Langenberg, Emmy Dolman, Jan Molenaar. Integration of high-throughput drug screening on patient-derived organdies into pediatric precision medicine programs: The future is now! [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A40.
Assessment and Treatment Outcomes of Persistent Radiation-Induced Alopecia in Patients With Cancer
Authors: Gregory S. Phillips, Morgan E. Freret, Danielle Novetsky Friedman, Sabrina Trelles, Oluwaseun Kukoyi, Azael Freites-Martinez, Robin H. Unger, Joseph J. Disa, Leonard H. Wexler, Christopher L. Tinkle, James G. Mechalakos, Stephen W. Dusza, Kathryn Beal, Suzanne L. Wolden, Mario E. Lacouture
Journal: JAMA Dermatology (2020)

Persistent radiation-induced alopecia (pRIA) and its management have not been systematically described.To characterize pRIA in patients with primary central nervous system (CNS) tumors or head and neck sarcoma.A retrospective cohort study of patients from January 1, 2011, to January 30, 2019, was conducted at 2 large tertiary care hospitals and comprehensive cancer centers. Seventy-one children and adults diagnosed with primary CNS tumors or head and neck sarcomas were evaluated for pRIA.The clinical and trichoscopic features, scalp radiation dose-response relationship, and response to topical minoxidil were assessed using standardized clinical photographs of the scalp, trichoscopic images, and radiotherapy treatment plans.Of the 71 patients included (median [range] age, 27 [4-75] years; 51 female [72%]), 64 (90%) had a CNS tumor and 7 (10%) had head and neck sarcoma. Alopecia severity was grade 1 in 40 of 70 patients (56%), with localized (29 of 54 [54%]), diffuse (13 of 54 [24%]), or mixed (12 of 54 [22%]) patterns. The median (range) estimated scalp radiation dose was 39.6 (15.1-50.0) Gy; higher dose (odds ratio [OR], 1.15; 95% CI, 1.04-1.28) and proton irradiation (OR, 5.7; 95% CI, 1.05-30.8) were associated with greater alopecia severity (P < .001), and the dose at which 50% of patients were estimated to have severe (grade 2) alopecia was 36.1 Gy (95% CI, 33.7-39.6 Gy). Predominant trichoscopic features included white patches (16 of 28 [57%]); in 15 patients, hair-shaft caliber negatively correlated with scalp dose (correlation coefficient, -0.624; P = .01). The association between hair density and scalp radiation dose was not statistically significant (-0.381; P = .16). Twenty-eight of 34 patients (82%) responded to topical minoxidil, 5% (median follow-up, 61 [interquartile range, 21-105] weeks); 4 of 25 (16%) topical minoxidil recipients with clinical images improved in severity grade. Two patients responded to hair transplantation and 1 patient responded to plastic surgical reconstruction.Persistent radiation-induced alopecia among patients with primary CNS tumors or head and neck sarcomas represents a dose-dependent phenomenon that has distinctive clinical and trichoscopic features. The findings of this study suggest that topical minoxidil and procedural interventions may have benefit in the treatment of pRIA.
The pandemic is being used as a screen to privatise, fragment, and weaken the NHS
Authors: John Puntis
Journal: BMJ (2020)

Who could disagree with Roderick and colleagues’ clear and sensible proposals for moving contact tracing onto a footing that might go some way to making it effective in suppressing covid-19?1

Reading through the litany of disasters, with around 65 000 excess deaths so far and every likelihood of a rapid upturn in cases with the cavalier easing of lockdown, one can only weep …