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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 -
Journal of Neurogastroenterology and... Jan 2024Gastroesophageal reflux disease (GERD) is common, with increasing worldwide disease prevalence and high economic burden. A significant number of patients will remain... (Review)
Review
Gastroesophageal reflux disease (GERD) is common, with increasing worldwide disease prevalence and high economic burden. A significant number of patients will remain symptomatic following an empiric proton pump inhibitor (PPI) trial. Persistent symptoms despite PPI therapy are often mislabeled as refractory GERD. For patients with no prior GERD evidence (unproven GERD), testing is performed off antisecretory therapy to identify objective evidence of pathologic reflux using criteria outlined by the Lyon consensus. In proven GERD, differentiation between refractory symptoms (persisting symptoms despite optimized antisecretory therapy) and refractory GERD (abnormal reflux metrics on ambulatory pH impedance monitoring and/or persistent erosive esophagitis on endoscopy while on optimized PPI therapy) can direct subsequent management. While refractory symptoms may arise from esophageal hypersensitivity or functional heartburn, proven refractory GERD requires personalization of the management approach, tapping from an array of non-pharmacologic, pharmacologic, endoscopic, and surgical interventions. Proper diagnosis and management of refractory GERD is critical to mitigate undesirable long-term complications such as strictures, Barrett's esophagus, and esophageal adenocarcinoma. This review outlines the diagnostic workup of patients presenting with refractory GERD symptoms, describes the distinction between unproven and proven GERD, and provides a comprehensive review of the current treatment strategies available for the management of refractory GERD.
PubMed: 38173155
DOI: 10.5056/jnm23145 -
British Journal of Haematology Oct 2023Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder affecting approximately 1 in 20 000 people. While most patients with ITP are successfully managed with... (Review)
Review
Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder affecting approximately 1 in 20 000 people. While most patients with ITP are successfully managed with the current set of standard and approved therapeutics, patients who cannot be adequately managed with these therapies, considered to have refractory ITP, are not uncommon. Therefore, there remains an ongoing need for novel therapeutics and drug development in ITP. Several agents exploiting novel targets and mechanisms in ITP are presently under clinical development, with trials primarily recruiting heavily pretreated patients and those with otherwise refractory disease. Such agents include the neonatal Fc receptor antagonist efgartigimod, the Bruton tyrosine kinase inhibitor rilzabrutinib, the complement inhibitors sutimlimab and iptacopan and anti-CD38 monoclonal antibodies such as daratumumab and mezagitamab, among others. Each of these agents exploits therapeutic targets or other aspects of ITP pathophysiology currently not targeted by the existing approved agents (thrombopoietin receptor agonists and fostamatinib). This manuscript offers an in-depth review of the current available data for novel therapeutics in ITP presently undergoing phase 2 or 3 studies in patients with heavily pretreated or refractory ITP. It additionally highlights the future directions for drug development in refractory ITP, including discussion of innovative clinical trial designs, health-related quality of life as an indispensable clinical trial end-point and balancing potential toxicities of drugs with their potential benefits in a bleeding disorder in which few patients suffer life-threatening bleeding.
Topics: Infant, Newborn; Humans; Purpura, Thrombocytopenic, Idiopathic; Quality of Life; Thrombocytopenia; Complement Inactivating Agents; Drug Development
PubMed: 37735554
DOI: 10.1111/bjh.19078 -
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 -
Journal of Crohn's & Colitis Dec 2023Acute severe ulcerative colitis [ASUC] is a medical emergency treated with intravenous steroids followed by infliximab or cyclosporin in the case of steroid failure with...
BACKGROUND AND AIMS
Acute severe ulcerative colitis [ASUC] is a medical emergency treated with intravenous steroids followed by infliximab or cyclosporin in the case of steroid failure with emergent colectomy required in refractory or severe cases. Case series have reported on the effectiveness of tofacitinib for refractory disease, but data regarding the effectiveness of upadacitinib in this setting have not been previously reported. We describe the use of upadacitinib therapy for steroid-refractory ASUC in patients with prior loss of response to infliximab.
METHODS
Six patients who received upadacitinib for steroid-refractory ASUC were identified at two Australian tertiary inflammatory bowel disease centres. Patients were followed for up to 16 weeks after discharge with clinical, biochemical and intestinal ultrasound [IUS] outcomes.
RESULTS
All six patients demonstrated clinical response to upadacitinib induction during their inpatient admission. Four patients achieved corticosteroid-free clinical remission by week 8, including complete resolution of rectal bleeding and transmural healing assessed by IUS, and sustained clinical remission at week 16. One patient proceeded to colectomy at week 15 due to refractory disease. No adverse events directly attributable to upadacitinib were identified.
CONCLUSIONS
Upadacitinib may have a role as a safe and effective salvage therapy for steroid-refractory ASUC in patients who have previously failed to respond to infliximab therapy. Prospective studies are required to determine the safety and efficacy of upadacitinib use in this setting before routine use can be recommended.
Topics: Humans; Infliximab; Colitis, Ulcerative; Salvage Therapy; Treatment Outcome; Australia; Steroids; Colectomy; Retrospective Studies; Heterocyclic Compounds, 3-Ring
PubMed: 37422724
DOI: 10.1093/ecco-jcc/jjad115 -
Molecular Diagnosis & Therapy Jul 2024Talicabtagene autoleucel (NexCAR19™) is a chimeric antigen receptor (CAR) T-cell therapy being developed by the Indian Institute of Technology, Bombay (IIT-B) and... (Review)
Review
Talicabtagene autoleucel (NexCAR19™) is a chimeric antigen receptor (CAR) T-cell therapy being developed by the Indian Institute of Technology, Bombay (IIT-B) and Immunoadoptive Cell Therapy (ImmunoACT) for the treatment of relapsed/refractory B-cell malignancies. Talicabtagene autoleucel contains autologous T cells from the patient, which have been modified to express a humanized anti-CD19 CAR that targets B cells. A single intravenous dose of talicabtagene autoleucel was associated with high response rates in pooled results from a phase I and phase II trial in patients with relapsed/refractory B-cell malignancies. Talicabtagene autoleucel was approved in India for the treatment of relapsed/refractory B-cell lymphomas and relapsed/refractory B-cell acute lymphoblastic leukaemia on 13 October 2023. This article summarizes the milestones in the development of talicabtagene autoleucel leading to this first approval for relapsed/refractory B-cell lymphomas and relapsed/refractory B-cell acute lymphoblastic leukaemia.
Topics: Humans; Immunotherapy, Adoptive; Antigens, CD19; Receptors, Chimeric Antigen; Lymphoma, B-Cell; T-Lymphocytes; India; Treatment Outcome; Clinical Trials as Topic
PubMed: 38780683
DOI: 10.1007/s40291-024-00719-9