tbuckley/cabot-search huggingface dataset:
JS1.4 Neurological follow-up of neurotoxicity after CAR T cell therapy in lymphoma patients: A French neurological multi-center survey
Authors: C Belin, C Simard, A Dos Santos, X Ayrignac, C Berger, G Cartron, S Le Gouill, P Sesques, C Thieblemont, A F Carpentier
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Chimeric antigen receptor-modified T (CAR T) cell therapy is a highly promising treatment for haematological malignancies but is frequently associated with cytokine-release syndrome (CRS) and neurotoxicity. The physiopathological mechanisms of neurological complications and their links with CRS remain largely unknown. The aims of this study are: a) to follow-up longitudinally patients treated with CAR-T cell therapy; b) to exhaustively identify neurological signs and symptoms and; c) to describe their occurrence over time. MATERIAL AND METHODS Since September 2018, all patients treated with CD19-targeted CAR T cell therapy for relapsing lymphoma were systematically followed-up and monitored for signs of neurotoxicity by a neurologist. Five different centres (Paris-Saint-Louis, Nantes, Lyon, Montpellier, and Rennes) participated in this study. RESULTS As of April 1st 2019, 57 patients, mean age 49 years (range from 22 to 72 years, median age 50 years), 22 females / 35 males, all treated for lymphoma, were included in this study Neurotoxicity, defined as the presence of at least one neurological sign or symptoms appearing after treatment infusion, was present in 33 % of patients. The median time to onset was 7.5 days after infusion with a median duration of symptoms of 5 days. Neurological symptoms were: Encephalopathy (52%), cerebellar syndrome (26%), aphasia (15%), agraphia (15%), executive syndrome (10%), myoclonus (10%), dysarthria (10%), meningismus (5%), transverse myelitis (5%), seizure (5%), neuralgia (5%), and dysesthesia (5%). The severity grade of neurotoxicity was grade 4: 2 patients, Grade 3: 7 patients, grade 2: 5 patients and grade 1: 5 patients (CTCAE grading). CRS was observed in 75% of patients. All patients who developed neurological disorders also had CRS (grade 1: 68%, grade 2: 10%, grade 3: 15%, grade 4: 5%) that preceded neurotoxicity. As the study is still ongoing, updated results will be presented at the EANO meeting. CONCLUSION Neurotoxicity associated with CAR-T therapies occurs in one third of patients. This high frequency underlines the need: 1 - to neurologically assess all patients before and repeatedly after therapy infusions; 2 - to provide guidelines for neurological assessment and relevant investigations to improve early recognition of neurotoxicity and its management
Noninferiority Designed Cardiovascular Trials in Highest-Impact Journals
Authors: Behnood Bikdeli, John W. Welsh, Yasir Akram, Natdanai Punnanithinont, Ike Lee, Nihar R. Desai, Sanjay Kaul, Gregg W. Stone, Joseph S. Ross, Harlan M. Krumholz
Journal: Circulation (2019)

Noninferiority trials are increasingly being performed. However, little is known about their methodological quality. We sought to characterize noninferiority cardiovascular trials published in the highest-impact journals, features that may bias results toward noninferiority, features related to reporting of noninferiority trials, and the time trends.We identified cardiovascular noninferiority trials published in JAMA, Lancet, or New England Journal of Medicine from 1990 to 2016. Two independent reviewers extracted the data. Data elements included the noninferiority margin and the success of studies in achieving noninferiority. The proportion of trials showing major or minor features that may have affected the noninferiority inference was determined. Major factors included the lack of presenting the results in both intention-to-treat and per-protocol/as-treated cohorts, α>0.05, the new intervention not being compared with the best alternative, not justifying the noninferiority margin, and exclusion or loss of ≥10% of the cohort. Minor factors included suboptimal blinding, allocation concealment, and others.From 2544 screened studies, we identified 111 noninferiority cardiovascular trials. Noninferiority margins varied widely: risk differences of 0.4% to 25%, hazard ratios of 1.05 to 2.85, odds ratios of 1.1 to 2.0, and relative risks of 1.1 to 1.8. Eighty-six trials claimed noninferiority, of which 20 showed superiority, whereas 23 (21.1%) did not show noninferiority, of which 8 also demonstrated inferiority. Only 7 (6.3%) trials were considered low risk for all the major and minor biasing factors. Among common major factors for bias, 41 (37%) did not confirm the findings in both intention-to-treat and per-protocol/as-treated cohorts and 4 (3.6%) reported discrepant results between intention-to-treat and per-protocol analyses. Forty-three (38.7%) did not justify the noninferiority margin. Overall, 27 (24.3%) underenrolled or had >10% exclusions. Sixty trials (54.0%) were open label. Allocation concealment was not maintained or unclear in 11 (9.9%). Publication of noninferiority trials increased over time (P<0.001). Fifty-two (46.8%) were published after 2010 and had a lower risk of methodological or reporting limitations for major (P=0.03) and minor factors (P=0.002).Noninferiority trials in highest-impact journals commonly conclude noninferiority of the tested intervention, but vary markedly in the selected noninferiority margin, and frequently have limitations that may impact the inference related to noninferiority.
Are Antiplatelet Agents Beneficial in Prevention of Infective Endocarditis?
Authors: Ruth Heying, Thomas Vanassche, Philippe Moreillon
Journal: JAMA Cardiology (2019)

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 Cardiology 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 Cardiology journal
P14.35 The modern management of brain metastases
Authors: N D Wallace, P J Kelly
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Technological and clinical advances have improved outcomes for patients with brain metastases. They have also added significantly to the complexity of decision-making in such cases. We set out to review the roles of different treatment options to guide management for patients with newly-diagnosed brain metastases. MATERIAL AND METHODS We undertook a comprehensive literature review to examine all treatment options for brain metastases. We particularly focused on recent advances and where these can be applied to clinical practice.We examined the impact of the improvement of SRS technology from older frame-based setups to modern linear accelerator based treatment with the capacity for fractionated stereotactic radiotherapy (SRT). We identified clinical situations where either SRS or WBRT, or a combination of the two, should be most strongly considered. Several novel targeted systemic therapies cross the blood-brain-barrier so we have explored their outcomes for patients with brain metastases from BRAF-mutated melanoma and EGFR or ALK/ROS1 mutated NSCLC. By examining these techniques in detail, we have formulated an algorithm-based approach which can inform management. RESULTS Surgery is most beneficial in patients with a reasonable prognosis and where other treatment options are unlikely to provide equivalent control. SRS to the surgical cavity can frequently be used alone for post-operative consolidation. SRS and fractionated SRT are valuable treatment options for increasingly large lesions and for increasing numbers of lesions. The choice between SRS and WBRT is, in many cases, a trade-off between the improved intracranial control of WBRT and the more favourable side effect profile of SRS. Upfront therapy with some systemic agents with CNS penetration is an acceptable approach in carefully-selected patients whose outcome is felt to be more related to their extracranial disease. Best supportive care is preferable for many patients with poor performance status and/or short prognosis, although more aggressive measures have a role in the case of symptomatic lesions. CONCLUSION A multidisciplinary approach involving Neurosurgeons, and both Radiation and Medical Oncologists is needed to fully evaluate the options for individual patients. As many of the treatment decisions are a trade-off between quality of life and outcome metrics, shared decision-making with patients is also critical to ensure that patients receive the best treatment for them.
Cognitive function in chronic lymphocytic leukemia (CLL): Examining effects of disease, treatment, and inflammation.
Authors: AnnaLynn Williams, Edwin van Wijngaarden, Christopher Seplaki, Charles E. Heckler, Miriam Weber, Paul M. Barr, Clive Zent, Michelle Christine Janelsins
Journal: Journal of Clinical Oncology (2019)

11584 Background: Cancer-related cognitive impairment (CRCI) is an important clinical problem that may occur through pro-inflammatory pathways, cancer-related pathology, or cancer treatment. However, their relative contribution to CRCI is unknown. We used CLL, an indolent cancer of the immune system, as a novel model to study differential roles of disease, treatment, and inflammation in CRCI. Methods: We assessed cognitive function and serum pro-inflammatory marker levels in 150 CLL patients (100 treatment naïve and 50 chemotherapy treated) including 84 patients with high risk of CLL progression (deletion 17p, deletion 11q, unmutated IGHV, Zap70+, or CD38+). Objective neuropsychological tests assessed global cognition, processing speed, attention, memory, and executive function (NIH Toolbox Cognition, Hopkins Verbal Learning Test Revised (HVLT), Trail Making Test (TMTA/B)). Linear regression models examined cognitive outcomes in relation to risk, treatment, and pro-inflammatory markers while adjusting for sociodemographic covariates. Results: High risk patients recalled almost 2 fewer words on a memory task (HVLT immediate recall β = -1.8, 95%CI -3.3, -0.3) and took 15 seconds longer on an executive function task (TMTB β = 15.4, 95%CI 3.1, 27.6) than low risk patients, independent of treatment status. Treated patients reported significantly greater cognitive difficulties than treatment naive patients (FACT-Cog β = -5.2, 95%CI -8.7, -1.6) but did not perform worse on objective cognitive measures. Higher CRP was significantly associated with more self-reported cognitive difficulties, but higher levels of interleukin-6 and interferon-γ were significantly associated with better performance on objective measures of global cognition, attention, and executive function. Conclusions: High risk patients experienced impairments in executive function and memory suggesting that disease biology contributes to CRCI independent of treatment. Increasing levels of pro-inflammatory cytokines were associated with better cognitive performance indicating that the role of inflammation with respect to CRCI in CLL may be complex, possibly due to tumor-related immune deficiencies.
Aromatase, a novel therapeutic target for human pancreatic, glioblastoma and lung cancer
Authors: Ildiko Csiki, Allie Fu, Christopher Willey, Ling Geng, Dennis Hallahan
Journal: Cancer Research (2007)

3278  Pancreatic, glioblastoma and lung cancers are aggressive tumors with few therapeutic options resulting in poor survival of the majority of affected patients. Since estrogens and estrogen receptor signaling have been previously implicated in the growth and progression of many tumors we sought to determine the role of aromatase, the enzyme responsible for estrogen synthesis, in the above cancers. As potential radiosensitizers, we examined the effect of aromatase inhibitors (AI) in conjunction with radiation therapy (RT) in an in vitro and in vivo glioblastoma, pancreatic and non-small cell lung cancer (NSCLC) model. We hypothesized that aromatase is present and biologically active in these cancers, and that cancer cell growth can be down-regulated due to growth inhibitory and radiosensitizing effects of AIs. We examined over 50 human cancer cell lines and found high aromatase expression in NSCLC, glioblastoma and pancreatic cancer cell lines. Aromatase expression was also increased in tumor samples obtained from NSCLC patients compared to matched normal tissue. Cell lines with elevated aromatase expression showed estrogen dependence and their proliferation was decreased by >50% in cell number determinations and >80% in clonogenic assays when treated with 5 μM AI, with the strongest growth inhibitory effect of AI and radiation observed in pancreatic cancer cells. Flow cytometry analyses revealed a considerable increase in the percentage of apoptotic pancreatic cancer cells treated with AI and RT (28.7%±13.1% live cells, p
P11.46 Discovery of a new HDAC6 inhibitor for the treatment of glioblastoma
Authors: J Auzmendi-Iriarte, A Saenz-Antoñanzas, J Andermatten, A Elua-Pinin, E Aldaba, Y Vara, A Matheu
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Glioblastoma’s origin and development is not only associated to genetic alterations, but also to epigenetic changes. Indeed, an altered expression or activity of epigenetic enzymes such as histone deacetylases (HDAC) has been associated to cancer stem cell activity, which has been widely described as a major feature for therapy resistance and tumor recurrence. In particular, inhibition of HDAC6 is an increasingly attractive pharmacological strategy, due to its association with low toxicity. Thus, the aim of the present study was to determine the impact of a new HDAC6-selective-inhibitor in glioblastoma and glioma stem cells. MATERIAL AND METHODS To test the effect of QTX compound in glioblastoma and glioma stem cell lines, cell viability after 72h of treatment was studied by MTT assay. After evaluation of IC50, QTX in vitro activity was analyzed, focusing on proliferation, apoptosis and stemness of U87-MG cell line and confirmed in a patient-derived glioma stem cell line. In vivo antitumor effect was evaluated using U87-MG cells xenografted in immunocompromised mice; after tumor formation, 5 mice were randomly selected as control group and another 5 for QTX treatment (intraperitoneal administration of 50 mg/kg; 5 days of dosing / 2 days off for 2 weeks). Mice weight was measured daily and tumor volume every two days. RESULTS We demonstrated that QTX reduces viability of all tested glioblastoma cells, even more greatly than normal astrocytes. Indeed, QTX diminishes proliferation and induces apoptosis in both conventional and patient-derived glioma cell lines. In particular, this effect was accompanied by a reduction of self-renewal properties of glioma stem cells. Interestingly, QTX in vitro activity was more effective comparing to the pan-inhibitor SAHA or the HDAC6-selective inhibitor Tubastatin A. Furthermore, QTX delayed tumor initiation and progression in vivo, without presenting significant side effects. CONCLUSION QTX compound presents a promising anti-tumor effect both in vitro and in vivo in glioblastoma, at least in part, inhibiting glioma stem cell activity.
Safety of Continuing Trastuzumab Despite Mild Cardiotoxicity
Authors: Darryl P. Leong, Tammy Cosman, Muhammad M. Alhussein, Nidhi Kumar Tyagi, Sarah Karampatos, Carly C. Barron, Douglas Wright, Vikas Tandon, Patrick Magloire, Philip Joseph, David Conen, P.J. Devereaux, Peter M. Ellis, Som D. Mukherjee, Sukhbinder Dhesy-Thind
Journal: JACC CardioOncology (2019)

This study sought to evaluate the safety of continuing trastuzumab in patients with human epidermal growth factor receptor-positive breast cancer who developed mild cardiotoxicity.Cardiotoxicity is the most common dose-limiting toxicity associated with trastuzumab. Current standard of care is discontinuation of trastuzumab, which can lead to worse cancer outcomes. It is unknown whether it is safe to continue trastuzumab despite mild cardiotoxicity.Patients were eligible for this phase I, prospective, single-arm trial if left ventricular ejection fraction (LVEF) was between 40% and the lower limit of normal or if it fell ≥15% from baseline. Participants were treated with angiotensin-converting enzyme (ACE) inhibitors and/or beta-blockers in a cardio-oncology clinic and were followed clinically and with serial echocardiograms for 1 year. The primary outcome was cardiac dose-limiting toxicity, defined as cardiovascular death, LVEF <40% together with any heart failure symptoms, or LVEF <35%.All 20 participants received ACE inhibitors and/or beta-blockers. A total of 18 participants (90%) received all planned trastuzumab doses. Two (10%) participants developed cardiac dose-limiting toxicity (heart failure with LVEF <40%). Their LVEF and heart failure symptoms improved to nearly normal following permanent trastuzumab discontinuation. There were no deaths. LVEF rose progressively from a mean of 49% at enrollment to 55% at 12 months (p < 0.001).It may be feasible to continue trastuzumab despite mild cardiotoxicity in the setting of a cardio-oncology clinic, where ACE inhibitors and beta-blockers are administered. Approximately 10% of patients may develop moderate to severe heart failure using this approach. (Safety of Continuing Chemotherapy in Overt Left Ventricular Dysfunction Using Antibodies to Human Epidermal Growth Factor Receptor-2 [SCHOLAR]; NCT02907021).
Hypoxia-inducible-factor 2 alpha mediates cisplatin resistance in the lung adenocarcinoma cell line A549
Authors: F. Rose, B. Eul, G. Kwapiszewska, L. Marsh, F. Kamlah, W. Seeger, F. Grimminger, J. Lohmeyer, J. Haenze
Journal: Journal of Clinical Oncology (2007)

10573 Background: Hypoxia in solid tumors is associated with cancer progression, metastasis and resistance to chemotherapy. The hypoxia inducible factors (HIF-1a and HIF-2a) are key players in the response to hypoxia affecting angiogenesis, proliferation and apoptosis. Here we investigated the role of HIF-1a and HIF-2a in cellular resistance to cisplatin in non small lung cancer cells (A549). Results: Hypoxia reduced the efficiency of cisplatin treatment on A549 cells via enhancement of drug efflux activity. In addition, hypoxia induced the hypoxia-responsive-element (HRE) reporter gene assay, demonstrating the transcriptional activity of HIF-1a and HIF-2a. Administration of cisplatin further increased the reporter activity under both normoxic and hypoxic conditions. This correlated with the induction of HIF-2a protein expression upon cisplatin treatment in normoxia and hypoxia, whereas HIF-1a was suppressed. Additionally, cisplatin induced nuclear accumulation of HIF-2a. Suppression of HIF-2a by RNA interference potentiated the sensitivity to cisplatin treatment in hypoxic A549 cells. In vivo growth delay assay gave analogues results for subcutaneous A549 tumors treated with cisplatin and suppression of HIF-2a. In comparison, other cytostatic drugs such as doxorubicin and gemcitabine differed with respect to HIF signalling. Doxorubicin induced both HIF-1a and HIF- 2a. Cellular sensitivity to doxorubicin was increased via suppression of HIF-1a and HIF-2a. Gemcitabine appeared to act independent of HIF. The underlying mechanism of hypoxia-induced resistance was due to increased mRNA expression of drug resistance proteins such as MDR1, MRP1 and LRP. These were found to be HIF-2a but not HIF-1a dependent. Conclusion: This data identified HIF-2a as a key player in the hypoxia induced cisplatin resistance and show on the molecular level that HIF-2a is a credible target for therapeutic strategies. No significant financial relationships to disclose.
Evidence Supporting US Food and Drug Administration Drug Safety Communications
Authors: Joseph S. Ross
Journal: JAMA Internal Medicine (2019)

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Diagnosis and Treatment of Diseases of the Rectum, Anus and Contiguous Textures.
Journal: JAMA (1896)

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
Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence
Journal: The Lancet (2019)

Published findings on breast cancer risk associated with different types of menopausal hormone therapy (MHT) are inconsistent, with limited information on long-term effects. We bring together the epidemiological evidence, published and unpublished, on these associations, and review the relevant randomised evidence.
Abstract 20887: Masked Uncontrolled Hypertension is Not Attributable to Medication Non-Adherence
Authors: Mohammed Siddiqui, Eric K Judd, Pankaj Gupta, Maciej Tomaszewski, Prashanth Patel, Suzanne Oparil, David A Calhoun
Journal: Circulation (2017)

Introduction: Masked uncontrolled hypertension (MUCH) in treated hypertensive patients is defined as controlled automated office blood pressure (AOBP; < 135/85 mmHg) in clinic, but uncontrolled out...