-
Intensive Care Medicine Jan 2024Status epilepticus (SE) is a common medical emergency associated with significant morbidity and mortality. Management that follows published guidelines is best suited to... (Review)
Review
Status epilepticus (SE) is a common medical emergency associated with significant morbidity and mortality. Management that follows published guidelines is best suited to improve outcomes, with the most severe cases frequently being managed in the intensive care unit (ICU). Diagnosis of convulsive SE can be made without electroencephalography (EEG), but EEG is required to reliably diagnose nonconvulsive SE. Rapidly narrowing down underlying causes for SE is crucial, as this may guide additional management steps. Causes may range from underlying epilepsy to acute brain injuries such as trauma, cardiac arrest, stroke, and infections. Initial management consists of rapid administration of benzodiazepines and one of the following non-sedating intravenous antiseizure medications (ASM): (fos-)phenytoin, levetiracetam, or valproate; other ASM are increasingly used, such as lacosamide or brivaracetam. SE that continues despite these medications is called refractory, and most commonly treated with continuous infusions of midazolam or propofol. Alternatives include further non-sedating ASM and non-pharmacologic approaches. SE that reemerges after weaning or continues despite management with propofol or midazolam is labeled super-refractory SE. At this step, management may include non-sedating or sedating compounds including ketamine and barbiturates. Continuous video EEG is necessary for the management of refractory and super-refractory SE, as these are almost always nonconvulsive. If possible, management of the underlying cause of seizures is crucial particularly for patients with autoimmune encephalitis. Short-term mortality ranges from 10 to 15% after SE and is primarily related to increasing age, underlying etiology, and medical comorbidities. Refractoriness of treatment is clearly related to outcome with mortality rising from 10% in responsive cases, to 25% in refractory, and nearly 40% in super-refractory SE.
Topics: Humans; Anticonvulsants; Midazolam; Propofol; Status Epilepticus; Intensive Care Units
PubMed: 38117319
DOI: 10.1007/s00134-023-07263-w -
Cell Aug 2023To improve the understanding of chemo-refractory high-grade serous ovarian cancers (HGSOCs), we characterized the proteogenomic landscape of 242 (refractory and...
To improve the understanding of chemo-refractory high-grade serous ovarian cancers (HGSOCs), we characterized the proteogenomic landscape of 242 (refractory and sensitive) HGSOCs, representing one discovery and two validation cohorts across two biospecimen types (formalin-fixed paraffin-embedded and frozen). We identified a 64-protein signature that predicts with high specificity a subset of HGSOCs refractory to initial platinum-based therapy and is validated in two independent patient cohorts. We detected significant association between lack of Ch17 loss of heterozygosity (LOH) and chemo-refractoriness. Based on pathway protein expression, we identified 5 clusters of HGSOC, which validated across two independent patient cohorts and patient-derived xenograft (PDX) models. These clusters may represent different mechanisms of refractoriness and implicate putative therapeutic vulnerabilities.
Topics: Female; Humans; Cystadenocarcinoma, Serous; Ovarian Neoplasms; Proteogenomics
PubMed: 37541199
DOI: 10.1016/j.cell.2023.07.004 -
Pharmacological Reviews Jul 2020Epilepsy is a chronic neurologic disorder that affects over 70 million people worldwide. Despite the availability of over 20 antiseizure drugs (ASDs) for symptomatic... (Review)
Review
Epilepsy is a chronic neurologic disorder that affects over 70 million people worldwide. Despite the availability of over 20 antiseizure drugs (ASDs) for symptomatic treatment of epileptic seizures, about one-third of patients with epilepsy have seizures refractory to pharmacotherapy. Patients with such drug-resistant epilepsy (DRE) have increased risks of premature death, injuries, psychosocial dysfunction, and a reduced quality of life, so development of more effective therapies is an urgent clinical need. However, the various types of epilepsy and seizures and the complex temporal patterns of refractoriness complicate the issue. Furthermore, the underlying mechanisms of DRE are not fully understood, though recent work has begun to shape our understanding more clearly. Experimental models of DRE offer opportunities to discover, characterize, and challenge putative mechanisms of drug resistance. Furthermore, such preclinical models are important in developing therapies that may overcome drug resistance. Here, we will review the current understanding of the molecular, genetic, and structural mechanisms of ASD resistance and discuss how to overcome this problem. Encouragingly, better elucidation of the pathophysiological mechanisms underpinning epilepsies and drug resistance by concerted preclinical and clinical efforts have recently enabled a revised approach to the development of more promising therapies, including numerous potential etiology-specific drugs ("precision medicine") for severe pediatric (monogenetic) epilepsies and novel multitargeted ASDs for acquired partial epilepsies, suggesting that the long hoped-for breakthrough in therapy for as-yet ASD-resistant patients is a feasible goal. SIGNIFICANCE STATEMENT: Drug resistance provides a major challenge in epilepsy management. Here, we will review the current understanding of the molecular, genetic, and structural mechanisms of drug resistance in epilepsy and discuss how the problem might be overcome.
Topics: Animals; Anticonvulsants; Drug Resistance; Epilepsy; Humans; Randomized Controlled Trials as Topic
PubMed: 32540959
DOI: 10.1124/pr.120.019539 -
Current Oncology (Toronto, Ont.) Feb 2023Multiple myeloma remains an incurable disease with the usual disease course requiring induction therapy, autologous stem cell transplantation for eligible patients, and... (Review)
Review
Multiple myeloma remains an incurable disease with the usual disease course requiring induction therapy, autologous stem cell transplantation for eligible patients, and long-term maintenance. Risk stratification tools and cytogenetic alterations help inform individualized therapeutic choices for patients in hopes of achieving long-term remissions with preserved quality of life. Unfortunately, relapses occur at different stages of the course of the disease owing to the biological heterogeneity of the disease. Addressing relapse can be complex and challenging as there are both therapy- and patient-related factors to consider. In this broad scoping review of available therapies in relapsed/refractory multiple myeloma (RRMM), we cover the pharmacologic mechanisms underlying active therapies such as immunomodulatory agents (IMiDs), proteasome inhibitors (PIs), monoclonal antibodies (mAbs), traditional chemotherapy, and Venetoclax. We then review the clinical data supporting the use of these therapies, organized based on drug resistance/refractoriness, and the role of autologous stem cell transplant (ASCT). Approaches to special situations during relapse such as renal impairment and extramedullary disease are also covered. Lastly, we look towards the future by briefly reviewing the clinical data supporting the use of chimeric antigen receptor (CAR-T) therapy, bispecific T cell engagers (BITE), and Cereblon E3 Ligase Modulators (CELMoDs).
Topics: Humans; Multiple Myeloma; Hematopoietic Stem Cell Transplantation; Quality of Life; Transplantation, Autologous; Neoplasm Recurrence, Local
PubMed: 36826140
DOI: 10.3390/curroncol30020179 -
Leukemia Sep 2019The introduction of CD38-targeting monoclonal antibodies (CD38 MoABs), daratumumab and isatuximab, has significantly impacted the management of patients with multiple...
The introduction of CD38-targeting monoclonal antibodies (CD38 MoABs), daratumumab and isatuximab, has significantly impacted the management of patients with multiple myeloma (MM). Outcomes of patients with MM refractory to CD38 MoABs have not been described. We analyzed outcomes of 275 MM patients at 14 academic centers with disease refractory to CD38 MoABs. Median interval between MM diagnosis and refractoriness to CD38 MoAB (T) was 50.1 months. The median overall survival (OS) from T for the entire cohort was 8.6 [95% C.I. 7.5-9.9] months, ranging from 11.2 months for patients not simultaneously refractory to an immunomodulatory (IMiD) agent and a proteasome inhibitor (PI) to 5.6 months for "penta-refractory" patients (refractory to CD38 MoAB, 2 PIs and 2 IMiDs). At least one subsequent treatment regimen was employed after T in 249 (90%) patients. Overall response rate to first regimen after T was 31% with median progression-free survival (PFS) and OS of 3.4 and 9.3 months, respectively. PFS was best achieved with combinations of carfilzomib and alkylator (median 5.7 months), and daratumumab and IMiD (median 4.5 months). Patients with MM refractory to CD38 MoAB have poor prognosis and this study provides benchmark for new therapies to be tested in this population.
Topics: ADP-ribosyl Cyclase 1; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Female; Humans; Immunologic Factors; Immunotherapy; Male; Membrane Glycoproteins; Middle Aged; Multiple Myeloma; Progression-Free Survival; Proteasome Inhibitors; Young Adult
PubMed: 30858549
DOI: 10.1038/s41375-019-0435-7 -
Technology in Cancer Research &... 2022Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of clonal plasma cells. Although advances in treatment have markedly improved... (Review)
Review
Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of clonal plasma cells. Although advances in treatment have markedly improved survival outcomes for patients with MM, this disease is still considered incurable owing to its high incidence of relapse and refractoriness. Isatuximab is an anti-CD38 monoclonal antibody that can induce apoptosis in myeloma cells through a variety of mechanisms. Many clinical studies have demonstrated the efficacy and efficiency of isatuximab in both relapsed/refractory multiple myeloma (RRMM) and newly diagnosed multiple myeloma, leading to its approval for the treatment of adults with RRMM in combination therapies. In this review, the structure, mechanisms of action, pharmacokinetics, pharmacogenetics, and safety profile of isatuximab in MM are summarized. Additionally, isatuximab is compared with daratumumab in terms of mechanism and efficacy.
Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Humans; Multiple Myeloma; Neoplasm Recurrence, Local
PubMed: 35903924
DOI: 10.1177/15330338221106563 -
Current Opinion in Neurology Apr 2021Randomized controlled trials investigating the initial pharmacological treatment of status epilepticus have been recently published. Furthermore, status epilepticus... (Review)
Review
PURPOSE OF REVIEW
Randomized controlled trials investigating the initial pharmacological treatment of status epilepticus have been recently published. Furthermore, status epilepticus arising in comatose survivors after cardiac arrest has received increasing attention in the last years. This review offers an updated assessment of status epilepticus treatment in these different scenarios.
RECENT FINDINGS
Initial benzodiazepines underdosing is common and correlates with development of status epilepticus refractoriness. The recently published ESETT trial provides high-level evidence regarding the equivalence of fosphenytoin, valproate, and levetiracetam as a second-line option. Myoclonus or epileptiform transients on electroencephalography occur in up to 1/3 of patients surviving a cardiac arrest. Contrary to previous assumptions regarding an almost invariable association with death, at least 1/10 of them may awaken with reasonably good prognosis, if treated. Multimodal prognostication including clinical examination, EEG, somatosensory evoked potentials, biochemical markers, and neuroimaging help identifying patients with a chance to recover consciousness, in whom a trial with antimyoclonic compounds and at times general anesthetics is indicated.
SUMMARY
There is a continuous, albeit relatively slow progress in knowledge regarding different aspect of status epilepticus; recent findings refine some treatment strategies and help improving patients' outcomes. Further high-quality studies are clearly needed to further improve the management of these patients, especially those with severe, refractory status epilepticus forms.
Topics: Anticonvulsants; Electroencephalography; Humans; Levetiracetam; Randomized Controlled Trials as Topic; Status Epilepticus
PubMed: 33664203
DOI: 10.1097/WCO.0000000000000899 -
ImmunoTargets and Therapy 2024Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a treatable autoimmune disorder, for which different treatment options are available. Current... (Review)
Review
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a treatable autoimmune disorder, for which different treatment options are available. Current first-line evidence-based therapies for CIDP include intravenous and subcutaneous immunoglobulins, corticosteroids and plasma exchanges. Despite lack of evidence, cyclophosphamide, rituximab and mycophenolate mofetil are commonly used in circumstances of refractoriness and, more debatably, of perceived overdependence on first-line therapies. Rituximab is currently the object of a randomized controlled trial for CIDP. Based on case series, and although rarely considered, haematopoietic autologous stem cell transplants may be effective in refractory disease, with low mortality and high remission rates. A new therapeutic option has appeared with efgartigimod, a neonatal Fc receptor blocker, recently shown to significantly lower relapse rate versus placebo, after withdrawal from previous immunotherapy. Other neonatal Fc receptor blockers, nipocalimab and batoclimab, are under study. The C1 complement-inhibitor SAR445088, acting in the proximal portion of the classical complement system, is currently the subject of a new study in treatment-responsive, refractory and treatment-naïve subjects. Finally, Bruton Tyrosine Kinase inhibitors, which exert anti-B cell effects, may represent another future research avenue. The widening of the therapeutic armamentarium enhances the need for improved evaluation of treatment effects and reliable biomarkers in CIDP.
PubMed: 38435981
DOI: 10.2147/ITT.S388151 -
Acta Psychiatrica Scandinavica Jul 2023The augmentation of serotonin reuptake inhibitors (SRIs) can be achieved by add-on therapy with different pharmacological agents in obsessive-compulsive disorder (OCD)... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
The augmentation of serotonin reuptake inhibitors (SRIs) can be achieved by add-on therapy with different pharmacological agents in obsessive-compulsive disorder (OCD) for a better clinical outcome. This network meta-analysis (NMA) was conducted to evaluate and compare the effects of available augmentation agents for SRIs in OCD.
METHOD
The data was extracted from 59 relevant clinical trials after a literature search on MEDLINE/PubMed, Scopus, Cochrane databases and clinical trial registries. PRISMA guidelines were followed in data extraction, analysis and reporting. Random effects Bayesian NMA was done to pool the effects across the interventions for the change in Yale-Brown Obsessive-Compulsive Scale (YBOCS) scoring from baseline to the end of the study. Network graph was built, consistency model was run, node splitting analysis was performed, treatments were ranked as per SUCRA score and meta-regression was done for refractoriness to SRIs and duration of augmentation therapy as the predictor variables.
RESULTS
The drugs showing significant reduction in YBOCS scoring were pregabalin (MD:-8.1;95% CrI: -16, -0.43), memantine (MD:-6.2;95% CrI: -9.9, -2.3), lamotrigine (MD:-6;95% CrI: -12, -0.47), ondansetron (MD:-5.7;95% CrI: -11, -0.67), granisetron (MD:-5.6;95% CrI: -11, -0.44), aripiprazole (MD:-5.4;95% CrI:-9.1, -1.6), risperidone (MD:-3.3;95% CrI: -6.4, -0.20) and topiramate (MD:-5.3;95% CrI: -9.6, -0.97). The node-split analysis showed that direct and indirect pooled effect sizes for all comparisons were comparable. Meta-regression showed a statistically non-significant association between YBOCS score reduction with the duration of augmentation therapy, but significant with SRI-refractory status. Finally, the results were sorted based on certainty of evidence.
CONCLUSION
Memantine was found to be most effective augmentation agent for SRIs in OCD, followed by lamotrigine, ondansetron and granisetron with moderate certainty of evidence. The augmentation agents showed better symptom reduction in patients with SRI-refractory OCD in comparison to non-refractory OCD.
PROSPERO REGISTRATION
CRD42022360110.
Topics: Humans; Selective Serotonin Reuptake Inhibitors; Ondansetron; Drug Therapy, Combination; Lamotrigine; Network Meta-Analysis; Bayes Theorem; Granisetron; Memantine; Obsessive-Compulsive Disorder; Treatment Outcome
PubMed: 37177823
DOI: 10.1111/acps.13568 -
Theranostics 2021The advanced, metastatic differentiated thyroid cancers (DTCs) have a poor prognosis mainly owing to radioactive iodine (RAI) refractoriness caused by decreased... (Review)
Review
Molecular mechanisms of radioactive iodine refractoriness in differentiated thyroid cancer: Impaired sodium iodide symporter (NIS) expression owing to altered signaling pathway activity and intracellular localization of NIS.
The advanced, metastatic differentiated thyroid cancers (DTCs) have a poor prognosis mainly owing to radioactive iodine (RAI) refractoriness caused by decreased expression of sodium iodide symporter (NIS), diminished targeting of NIS to the cell membrane, or both, thereby decreasing the efficacy of RAI therapy. Genetic aberrations (such as , , and RET/PTC rearrangements) have been reported to be prominently responsible for the onset, progression, and dedifferentiation of DTCs, mainly through the activation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways. Eventually, these alterations result in a lack of NIS and disabling of RAI uptake, leading to the development of resistance to RAI therapy. Over the past decade, promising approaches with various targets have been reported to restore NIS expression and RAI uptake in preclinical studies. In this review, we summarized comprehensive molecular mechanisms underlying the dedifferentiation in RAI-refractory DTCs and reviews strategies for restoring RAI avidity by tackling the mechanisms.
Topics: Autophagy; Cell Differentiation; Cell Membrane; Clinical Trials as Topic; Drug Resistance, Neoplasm; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Genetic Therapy; Humans; Iodine Radioisotopes; MicroRNAs; Neoplasm Proteins; Protein Transport; Receptors, Cytoplasmic and Nuclear; Receptors, Thyrotropin; Recombinant Proteins; Salvage Therapy; Signal Transduction; Symporters; Thyroid Neoplasms; Thyrotropin
PubMed: 33995657
DOI: 10.7150/thno.57689