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Annals of Oncology : Official Journal... Dec 2022The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety.
PATIENTS AND METHODS
One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015.
RESULTS
With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome.
CONCLUSION
With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals.
Topics: Humans; Female; Breast Neoplasms; Phthalazines; Germ Cells; BRCA1 Protein
PubMed: 36228963
DOI: 10.1016/j.annonc.2022.09.159 -
The Journal of Clinical Investigation Mar 2019Chimeric antigen receptor (CAR) T cells are a promising therapy for hematologic malignancies. B-cell maturation antigen (BCMA) is a rational target in multiple myeloma...
BACKGROUND
Chimeric antigen receptor (CAR) T cells are a promising therapy for hematologic malignancies. B-cell maturation antigen (BCMA) is a rational target in multiple myeloma (MM).
METHODS
We conducted a phase I study of autologous T cells lentivirally-transduced with a fully-human, BCMA-specific CAR containing CD3ζ and 4-1BB signaling domains (CART-BCMA), in subjects with relapsed/refractory MM. Twenty-five subjects were treated in 3 cohorts: 1) 1-5 x 108 CART-BCMA cells alone; 2) Cyclophosphamide (Cy) 1.5 g/m2 + 1-5 x 107 CART-BCMA cells; and 3) Cy 1.5 g/m2 + 1-5 x 108 CART-BCMA cells. No pre-specified BCMA expression level was required.
RESULTS
CART-BCMA cells were manufactured and expanded in all subjects. Toxicities included cytokine release syndrome and neurotoxicity, which were grade 3-4 in 8 (32%) and 3 (12%) subjects, respectively, and reversible. One subject died at day 24 from candidemia and progressive myeloma, following treatment for severe CRS and encephalopathy. Responses (based on treated subjects) were seen in 4/9 (44%) in cohort 1, 1/5 (20%) in cohort 2, and 7/11 (64%) in cohort 3, including 5 partial, 5 very good partial, and 2 complete responses, 3 of which were ongoing at 11, 14, and 32 months. Decreased BCMA expression on residual MM cells was noted in responders; expression increased at progression in most. Responses and CART-BCMA expansion were associated with CD4:CD8 T cell ratio and frequency of CD45RO-CD27+CD8+ T cells in the pre-manufacturing leukapheresis product.
CONCLUSION
CART-BCMA infusions with or without lymphodepleting chemotherapy are clinically active in heavily-pretreated MM patients.
TRIAL REGISTRATION
NCT02546167.
FUNDING
University of Pennsylvania-Novartis Alliance and NIH.
Topics: Adult; Aged; Autografts; B-Cell Maturation Antigen; Cyclophosphamide; Disease-Free Survival; Female; Humans; Immunotherapy, Adoptive; Lymphocyte Depletion; Male; Middle Aged; Multiple Myeloma; Neoplasm Proteins; Receptors, Chimeric Antigen; Survival Rate; T-Lymphocytes; Transduction, Genetic
PubMed: 30896447
DOI: 10.1172/JCI126397 -
BMJ (Clinical Research Ed.) Sep 2021To establish if the use of early computed tomography (CT) coronary angiography improves one year clinical outcomes in patients presenting to the emergency department... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
To establish if the use of early computed tomography (CT) coronary angiography improves one year clinical outcomes in patients presenting to the emergency department with acute chest pain and at intermediate risk of acute coronary syndrome and subsequent clinical events.
DESIGN
Randomised controlled trial.
SETTING
37 hospitals in the UK.
PARTICIPANTS
Adults with suspected or a provisional diagnosis of acute coronary syndrome and one or more of previous coronary heart disease, raised levels of cardiac troponin, or abnormal electrocardiogram.
INTERVENTIONS
Early CT coronary angiography and standard of care compared with standard of care only.
MAIN OUTCOME MEASURES
Primary endpoint was all cause death or subsequent type 1 or 4b myocardial infarction at one year.
RESULTS
Between 23 March 2015 and 27 June 2019, 1748 participants (mean age 62 years (standard deviation 13), 64% men, mean global registry of acute coronary events (GRACE) score 115 (standard deviation 35)) were randomised to receive early CT coronary angiography (n=877) or standard of care only (n=871). Median time from randomisation to CT coronary angiography was 4.2 (interquartile range 1.6-21.6) hours. The primary endpoint occurred in 51 (5.8%) participants randomised to CT coronary angiography and 53 (6.1%) participants who received standard of care only (adjusted hazard ratio 0.91 (95% confidence interval 0.62 to 1.35), P=0.65). Invasive coronary angiography was performed in 474 (54.0%) participants randomised to CT coronary angiography and 530 (60.8%) participants who received standard of care only (adjusted hazard ratio 0.81 (0.72 to 0.92), P=0.001). There were no overall differences in coronary revascularisation, use of drug treatment for acute coronary syndrome, or subsequent preventive treatments between the two groups. Early CT coronary angiography was associated with a slightly longer time in hospital (median increase 0.21 (95% confidence interval 0.05 to 0.40) days from a median hospital stay of 2.0 to 2.2 days).
CONCLUSIONS
In intermediate risk patients with acute chest pain and suspected acute coronary syndrome, early CT coronary angiography did not alter overall coronary therapeutic interventions or one year clinical outcomes, but reduced rates of invasive angiography while modestly increasing length of hospital stay. These findings do not support the routine use of early CT coronary angiography in intermediate risk patients with acute chest pain and suspected acute coronary syndrome.
TRIAL REGISTRATION
ISRCTN19102565, NCT02284191.
Topics: Acute Coronary Syndrome; Acute Disease; Aged; Chest Pain; Computed Tomography Angiography; Early Diagnosis; Emergency Service, Hospital; Female; Heart Disease Risk Factors; Humans; Length of Stay; Male; Middle Aged; Myocardial Infarction; Outcome Assessment, Health Care; Proportional Hazards Models; Risk Assessment; Standard of Care; Time Factors
PubMed: 34588162
DOI: 10.1136/bmj.n2106 -
Frontiers in Neurology 2019The neuromuscular junction, also called myoneural junction, is a site of chemical communication between a nerve fiber and a muscle cell. There are many types of channels... (Review)
Review
The neuromuscular junction, also called myoneural junction, is a site of chemical communication between a nerve fiber and a muscle cell. There are many types of channels at neuromuscular junction that play indispensable roles in neuromuscular signal transmission, such as voltage-gated calcium channels and voltage-gated potassium channels on presynaptic membrane, and acetylcholine receptors on post-synaptic membrane. Over the last two decades, our understanding of the role that autoantibodies play in neuromuscular junction disorders has been greatly improved. Antibodies against these channels cause a heterogeneous group of diseases, such as Lambert-Eaton syndrome, Isaacs' syndrome and myasthenia gravis. Lambert-Eaton syndrome is characterized by late onset of fatigue, skeletal muscle weakness, and autonomic symptoms. Patients with Isaacs' syndrome demonstrate muscle cramps and fasciculation. Myasthenia gravis is the most common autoimmune neuromuscular junction channelopathy characterized by fluctuation of muscle weakness. All these disorders have a high risk of tumor. Although these channelopathies share some common features, they differ for clinical features, antibodies profile, neurophysiological features, and treatments. The purpose of this review is to give a comprehensive insight on recent advances in autoimmune channelopathies at the neuromuscular junction.
PubMed: 31156543
DOI: 10.3389/fneur.2019.00516 -
Science Translational Medicine Jul 2017We conducted a first-in-human study of intravenous delivery of a single dose of autologous T cells redirected to the epidermal growth factor receptor variant III...
We conducted a first-in-human study of intravenous delivery of a single dose of autologous T cells redirected to the epidermal growth factor receptor variant III (EGFRvIII) mutation by a chimeric antigen receptor (CAR). We report our findings on the first 10 recurrent glioblastoma (GBM) patients treated. We found that manufacturing and infusion of CAR-modified T cell (CART)-EGFRvIII cells are feasible and safe, without evidence of off-tumor toxicity or cytokine release syndrome. One patient has had residual stable disease for over 18 months of follow-up. All patients demonstrated detectable transient expansion of CART-EGFRvIII cells in peripheral blood. Seven patients had post-CART-EGFRvIII surgical intervention, which allowed for tissue-specific analysis of CART-EGFRvIII trafficking to the tumor, phenotyping of tumor-infiltrating T cells and the tumor microenvironment in situ, and analysis of post-therapy EGFRvIII target antigen expression. Imaging findings after CART immunotherapy were complex to interpret, further reinforcing the need for pathologic sampling in infused patients. We found trafficking of CART-EGFRvIII cells to regions of active GBM, with antigen decrease in five of these seven patients. In situ evaluation of the tumor environment demonstrated increased and robust expression of inhibitory molecules and infiltration by regulatory T cells after CART-EGFRvIII infusion, compared to pre-CART-EGFRvIII infusion tumor specimens. Our initial experience with CAR T cells in recurrent GBM suggests that although intravenous infusion results in on-target activity in the brain, overcoming the adaptive changes in the local tumor microenvironment and addressing the antigen heterogeneity may improve the efficacy of EGFRvIII-directed strategies in GBM.
Topics: Aged; Brain Neoplasms; Cell- and Tissue-Based Therapy; ErbB Receptors; Female; Glioblastoma; Humans; Immunohistochemistry; Immunotherapy, Adoptive; Male; Middle Aged; Neoplasm Recurrence, Local; Receptors, Antigen, T-Cell
PubMed: 28724573
DOI: 10.1126/scitranslmed.aaa0984 -
The Western Journal of Medicine Aug 1975
Topics: Humans; Neuromuscular Diseases; Phenytoin; Syndrome
PubMed: 1179720
DOI: No ID Found -
Annals of the Rheumatic Diseases Jun 2023Targeting interleukin (IL)-6 has become a major therapeutic strategy in the treatment of immune-mediated inflammatory disease. Interference with the IL-6 pathway can be...
BACKGROUND
Targeting interleukin (IL)-6 has become a major therapeutic strategy in the treatment of immune-mediated inflammatory disease. Interference with the IL-6 pathway can be directed at the specific receptor using anti-IL-6Rα antibodies or by directly inhibiting the IL-6 cytokine. This paper is an update of a previous consensus document, based on most recent evidence and expert opinion, that aims to inform on the medical use of interfering with the IL-6 pathway.
METHODS
A systematic literature research was performed that focused on IL-6-pathway inhibitors in inflammatory diseases. Evidence was put in context by a large group of international experts and patients in a subsequent consensus process. All were involved in formulating the consensus statements, and in the preparation of this document.
RESULTS
The consensus process covered relevant aspects of dosing and populations for different indications of IL-6 pathway inhibitors that are approved across the world, including rheumatoid arthritis, polyarticular-course and systemic juvenile idiopathic arthritis, giant cell arteritis, Takayasu arteritis, adult-onset Still's disease, Castleman's disease, chimeric antigen receptor-T-cell-induced cytokine release syndrome, neuromyelitis optica spectrum disorder and severe COVID-19. Also addressed were other clinical aspects of the use of IL-6 pathway inhibitors, including pretreatment screening, safety, contraindications and monitoring.
CONCLUSIONS
The document provides a comprehensive consensus on the use of IL-6 inhibition to treat inflammatory disorders to inform healthcare professionals (including researchers), patients, administrators and payers.
Topics: Adult; Humans; Arthritis, Rheumatoid; COVID-19; Interleukin-6; Receptors, Interleukin-6; Still's Disease, Adult-Onset; Inflammation
PubMed: 35953263
DOI: 10.1136/ard-2022-222784 -
Nature Human Behaviour Dec 2021Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual...
Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual intercourse, N = 387,338; age at first birth, N = 542,901), we identify 371 single-nucleotide polymorphisms, 11 sex-specific, with a 5-6% polygenic score prediction. Heritability of age at first birth shifted from 9% [CI = 4-14%] for women born in 1940 to 22% [CI = 19-25%] for those born in 1965. Signals are driven by the genetics of reproductive biology and externalising behaviour, with key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility and spermatid differentiation. Our findings suggest that polycystic ovarian syndrome may lead to later age at first birth, linking with infertility. Late age at first birth is associated with parental longevity and reduced incidence of type 2 diabetes and cardiovascular disease. Higher childhood socioeconomic circumstances and those in the highest polygenic score decile (90%+) experience markedly later reproductive onset. Results are relevant for improving teenage and late-life health, understanding longevity and guiding experimentation into mechanisms of infertility.
Topics: Adolescent; Age Factors; Coitus; Female; Genetic Association Studies; Humans; Male; Parturition; Polymorphism, Single Nucleotide; Reproduction
PubMed: 34211149
DOI: 10.1038/s41562-021-01135-3 -
Clinical Neurophysiology : Official... Aug 2021Possessing a discrete functional repertoire, the anterior horn cell can be in one of two electrophysiological states: on or off. Usually under tight regulatory control... (Review)
Review
Possessing a discrete functional repertoire, the anterior horn cell can be in one of two electrophysiological states: on or off. Usually under tight regulatory control by the central nervous system, a hierarchical network of these specialist neurons ensures muscular strength is coordinated, gradated and adaptable. However, spontaneous activation of these cells and their axons can result in abnormal muscular twitching. The muscular twitch is the common building block of several distinct clinical patterns, namely fasciculation, myokymia and neuromyotonia. When attempting to distinguish these entities electromyographically, their unique temporal and morphological profiles must be appreciated. Detection and quantification of burst duration, firing frequency, multiplet patterns and amplitude are informative. A common feature is their persistence during sleep. In this review, we explain the accepted terminology used to describe the spontaneous phenomena of motor hyperexcitability, highlighting potential pitfalls amidst a bemusing and complex collection of overlapping terms. We outline the relevance of these findings within the context of disease, principally amyotrophic lateral sclerosis, Isaacs syndrome and Morvan syndrome. In addition, we highlight the use of high-density surface electromyography, suggesting that more widespread use of this non-invasive technique is likely to provide an enhanced understanding of these motor hyperexcitability syndromes.
Topics: Amyotrophic Lateral Sclerosis; Electromyography; Fasciculation; Humans; Isaacs Syndrome; Motor Neurons; Myokymia; Peripheral Nervous System Diseases
PubMed: 34130251
DOI: 10.1016/j.clinph.2021.03.053