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SAGE Open Medicine 2023C5 inhibitors such as eculizumab and ravulizumab are the first-line treatment in the management of paroxysmal nocturnal hemoglobinuria (PNH). However, some patients... (Review)
Review
OBJECTIVES
C5 inhibitors such as eculizumab and ravulizumab are the first-line treatment in the management of paroxysmal nocturnal hemoglobinuria (PNH). However, some patients develop novel symptoms as part of their treatment with eculizumab, and the disease is termed as eculizumab refractory PNH. The aim of this study was to conduct a systematic review on the available treatment modalities for the management of eculizumab refractory PNH.
METHODS
Two authors independently searched two databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of 70 studies were obtained: 4 out 70 studies were found to meet the inclusion criteria.
RESULTS
Four studies were found to meet the inclusion criteria of our study. Two studies were published in 2021 and two studies were published in 2020. All four studies were multicenter clinical trials. Two studies were phase III clinical trials, one study was a phase II clinical trial, and one study was a phase I clinical trial. Two studies were about pegcetacoplan, one was about danicopan, and one was about iptacopan.
CONCLUSION
Based upon the findings of our systematic review, we recommend an individualized treatment plan based on the mechanism of eculizumab refractoriness and the mechanism of PNH breakthrough. This recommendation is subject to the available resources and clinical expertise available at different hospitals. More studies using study designs such as randomized controlled trials comparing multiple drugs should be performed to accurately assess the different medications and aid in designing guidelines of the management of eculizumab refractory PNH.
LEVEL OF EVIDENCE
Level I.
PubMed: 37388903
DOI: 10.1177/20503121231181267 -
Mediterranean Journal of Hematology and... 2015Classical Hodgkin lymphoma (cHL) is a relatively rare disease, with approximately 9,200 estimated new cases and 1,200 estimated deaths per year in the United States.... (Review)
Review
Classical Hodgkin lymphoma (cHL) is a relatively rare disease, with approximately 9,200 estimated new cases and 1,200 estimated deaths per year in the United States. First-line chemo-radiotherapy leads to cure rates approaching 80% in patients with advanced-stage disease. However, 25 to 30% of these patients are not cured with chemotherapy alone (i.e., the ABVD regimen) and show either primary refractoriness to chemotherapy, early disease relapse or late disease relapse. Second-line salvage high-dose chemotherapy (HDC) and autologous stem cell transplantation (SCT) have an established role in the management of refractory/relapsed cHL, leading to durable responses in approximately 50% of relapsed patients and a minority of refractory patients. However, due to the poor responses to second-line salvage chemotherapy and dismal long-term disease control of primary refractory and early relapsed patients, their treatment represents an unmet medical need. Allogeneic SCT represents, by far, the only strategy with a curative potential for these patients; however, as discussed in this review, it's role in cHL remains controversial. Despite a general consensus that early relapsed and primary refractory patients represent a clinical challenge requiring effective treatments to achieve long-term disease control, there has been no consensus on the optimal therapy that should be offered to these patients. This review will briefly discuss the clinical results and the main issues regarding autologous SCT as well as the current role of allogeneic SCT.
PubMed: 25745542
DOI: 10.4084/MJHID.2015.015 -
Progress in Biophysics and Molecular... 2003Atrial fibrillation frequently occurs under conditions associated with atrial dilatation suggesting a role of mechano-electric feedback in atrial arrhythmogenesis.... (Review)
Review
Atrial fibrillation frequently occurs under conditions associated with atrial dilatation suggesting a role of mechano-electric feedback in atrial arrhythmogenesis. Although atrial arrhythmias may be due both to abnormal focal activity and reentrant mechanisms, the majority of sustained atrial arrhythmias have been ascribed to reentrant activity. Atrial stretch may contribute to focal arrhythmias by inducing afterdepolarizations and to reentrant arrhythmias by increasing the atrial surface, by shortening the refractory period and/or slowing the conduction velocity and by increasing their spatial dispersion. Experimental and clinical studies have demonstrated that changes in mechanical loading conditions may modulate the electrophysiological properties of the atria. These studies have, for the most part, involved the effects of acute stretch on atrial refractoriness. While studies in humans and intact animals yield divergent results due to the variety of loading conditions and neurohumoral influences, experimental studies in isolated preparations clearly show that atrial refractory period and action potential duration at early levels of repolarization shorten by acute atrial dilatation. Both experimental and human studies have shown that acute atrial stretch is arrhythmogenic and may induce triggered premature beats and atrial fibrillation.
Topics: Animals; Arrhythmias, Cardiac; Atrial Fibrillation; Calcium; Electrophysiology; Feedback, Physiological; Heart Atria; Humans; Ions; Models, Biological; Pressure; Time Factors; Water
PubMed: 12732274
DOI: 10.1016/s0079-6107(03)00011-7 -
Hematology Reports Apr 2024The treatment landscape of chronic lymphocytic leukemia (CLL), the most frequent leukemia in adults, is constantly changing. CLL patients can be divided into three risk... (Review)
Review
The treatment landscape of chronic lymphocytic leukemia (CLL), the most frequent leukemia in adults, is constantly changing. CLL patients can be divided into three risk categories, based on their IGHV mutational status and the occurrence of disruption and/or complex karyotype. For the first-line treatment of low- and intermediate-risk CLL, both the BCL2 inhibitor venetoclax plus obinutuzumab and the second generation BTK inhibitors (BTKi), namely acalabrutinib and zanubrutinib, are valuable and effective options. Conversely, venetoclax-based fixed duration therapies have not shown remarkable results in high-risk CLL patients, while continuous treatment with acalabrutinib and zanubrutinib displayed favorable outcomes, similar to those obtained in wild-type patients. The development of acquired resistance to pathway inhibitors is still a clinical challenge, and the optimal treatment sequencing of relapsed/refractory CLL is not completely established. Covalent BTKi-refractory patients should be treated with venetoclax plus rituximab, whereas venetoclax-refractory CLL may be treated with second generation BTKi in the case of early relapse, while venetoclax plus rituximab might be used if late relapse has occurred. On these grounds, here we provide an overview of the current state-of-the-art therapeutic algorithms for treatment-naïve patients, as well as for relapsed/refractory disease.
PubMed: 38804280
DOI: 10.3390/hematolrep16020027 -
Materials (Basel, Switzerland) Feb 2021The presented study is focused on optimization and characterization of a high-alumina refractory aggregate based on natural raw materials-kaolins, claystone, and mullite...
The presented study is focused on optimization and characterization of a high-alumina refractory aggregate based on natural raw materials-kaolins, claystone, and mullite dust by-product (used to increase the alumina and mullite contents, respectively). In total, four individual formulas with the AlO contents between 45 and 50 wt.% were designed; the samples were subsequently fired, both in a laboratory oven and an industrial tunnel furnace. The effects of repeated firing were examined during industrial pilot tests. Mineral and chemical compositions and microstructures, of both the raw materials and designed aggregates, were thoroughly investigated by the means of X-ray fluorescence spectroscopy, powder X-ray diffraction, and optical and scanning electron microscopies. Porosity, mineral composition, and mullite crystal-size development during the firing process were also studied. Based on the acquired results, the formula with the perspective to be used as a new mullite grog, featuring similar properties as the available commercial products, however, with reduced production expenses, was selected. The quality of grog determines to a large extent the properties of the final product. Hence, optimization of aggregates for specific refractories is of a great importance. The production of engineered aggregates provides the opportunity to utilize industrial by-products.
PubMed: 33562214
DOI: 10.3390/ma14040779 -
Philosophical Transactions of the Royal... 2014Semantic impairments have been divided into storage deficits, in which the semantic representations themselves are damaged, and access deficits, in which the... (Review)
Review
Semantic impairments have been divided into storage deficits, in which the semantic representations themselves are damaged, and access deficits, in which the representations are intact but access to them is impaired. The behavioural phenomena that have been associated with access deficits include sensitivity to cueing, sensitivity to presentation rate, performance inconsistency, negative serial position effects, sensitivity to number and strength of competitors, semantic blocking effects, disordered selection between strong and weak competitors, correlation between semantic deficits and executive function deficits and reduced word frequency effects. Four general accounts have been proposed for different subsets of these phenomena: abnormal refractoriness, too much activation, impaired competitive selection and deficits of semantic control. A combination of abnormal refractoriness and impaired competitive selection can account for most of the behavioural phenomena, but there remain several open questions. In particular, it remains unclear whether access deficits represent a single syndrome, a syndrome with multiple subtypes or a variable collection of phenomena, whether the underlying deficit is domain-general or domain-specific, whether it is owing to disorders of inhibition, activation or selection, and the nature of the connection (if any) between access phenomena in aphasia and in neurologically intact controls. Computational models offer a promising approach to answering these questions.
Topics: Aphasia; Humans; Memory Disorders; Mental Recall; Models, Psychological; Refractory Period, Psychological; Semantics
PubMed: 24324232
DOI: 10.1098/rstb.2012.0388 -
Cardiology Journal 2011Atrial remodeling is a term introduced in 1995 to describe alterations in atrial structure or function. Atrial electrical remodeling is characterized by a reduction of... (Review)
Review
Atrial remodeling is a term introduced in 1995 to describe alterations in atrial structure or function. Atrial electrical remodeling is characterized by a reduction of refractory period and action potential duration, dispersion in refractoriness, and a reduction in conduction velocity of impulse propagation. Numerous animal and human studies have demonstrated that atrial electrical remodeling impairs normal atrial conduction and provides an environment for ectopic and re-entrant activity, thus creating a substrate for the initiation or maintenance of atrial fibrillation. Interestingly, atrial electrical remodeling has been shown to be reversible. In this systematic review, we examine the occurrence of reverse atrial electrical remodeling in various clinical settings.
Topics: Action Potentials; Animals; Atrial Fibrillation; Atrial Function; Heart Conduction System; Humans; Refractory Period, Electrophysiological; Risk Assessment; Risk Factors
PubMed: 22113749
DOI: 10.5603/cj.2011.0025 -
Targeted Oncology Dec 2020Multiple myeloma (MM) is an incurable malignancy of plasma cells with a clinical course characterized by multiple relapses and treatment refractoriness. While recent... (Review)
Review
Multiple myeloma (MM) is an incurable malignancy of plasma cells with a clinical course characterized by multiple relapses and treatment refractoriness. While recent treatment advancements have extended overall survival (OS), refractory MM has a poor prognosis, with a median OS of between 4 and 6 months. Nuclear export inhibition, specifically inhibition of CRM1/XPO1, is an emerging novel treatment modality that has shown promise in treatment-refractory MM. Initially discovered in yeast in 1983, early clinical applications were met with significant toxicities that limited their utility. The creation of small molecule inhibitors of nuclear export (SINE) has improved on toxicity limitations and has led to investigation in a number of malignancies at the preclinical and clinical stages. Preclinical studies of SINEs in MM have shown that these molecules are cytotoxic to myeloma cells, play a role in therapy resensitization, and suggest a role in limiting bone disease progression. In July 2019, selinexor became the first nuclear export inhibitor approved for use in relapsed/refractory MM based on the STORM trial. As of May 2020, there were eight ongoing trials combining selinexor with standard treatment regimens in relapsed/refractory MM. Eltanexor, a second-generation SINE, is also under investigation and has shown preliminary signs of efficacy in an early clinical trial while potentially having an improved toxicity profile compared with selinexor. Results in ongoing trials will help further define the role of SINEs in MM.
Topics: Active Transport, Cell Nucleus; Antineoplastic Combined Chemotherapy Protocols; Humans; Multiple Myeloma
PubMed: 33074469
DOI: 10.1007/s11523-020-00758-2 -
Revista Brasileira de Psiquiatria (Sao... Oct 2007Mood disorders are the most prevalent psychiatric disorders. Despite new insights and advances on the neurobiological basis and therapeutic approaches for bipolar... (Review)
Review
OBJECTIVE AND METHOD
Mood disorders are the most prevalent psychiatric disorders. Despite new insights and advances on the neurobiological basis and therapeutic approaches for bipolar disorders and recurrent depression, elevated prevalence of recurrence, persistent sub-syndromal symptoms and treatment resistance are challenging aspects and need to be urgently addressed. The objective of this literature review is to evaluate the current concepts of treatment resistance and refractoriness in mood disorders.
RESULTS
Genetic factors, misdiagnosis, use of inappropriate pharmacological approaches, non-compliance and biological/psychosocial stressors account for dysfunctions in mood regulation, thus increasing the prevalence of refractory mood disorders. Regarding available treatments, the use of effective doses during an adequate period followed by augmentation with a second and/or third agent, and finally switching to other agent are steps frequently necessary to optimize efficacy. However, in the treatment-resistant paradigm, drugs mimicking standard strategies, which target preferentially the monoaminergic system, can present reduced therapeutic effects. Thus, the search for new effective treatments for mood disorders is critical to decreasing the overall morbidity secondary to treatment resistance.
CONCLUSION
Emerging strategies targeting brain plasticity pathways or 'plasticity enhancers', including antiglutamatergic drugs, glucocorticoid receptor antagonists and neuropeptides, have been considered promising therapeutic options for difficult-to-treat mood disorders.
Topics: Antidepressive Agents; Antipsychotic Agents; Bipolar Disorder; Depressive Disorder, Major; Drug Resistance; Drug Therapy, Combination; Humans; Mood Disorders; Neuronal Plasticity; Refractory Period, Psychological; Stress, Psychological
PubMed: 17713691
DOI: 10.1590/s1516-44462006005000058 -
Materials (Basel, Switzerland) Dec 2021Carbon-bonded alumina refractories offer excellent thermal shock performance but are lacking in terms of mechanical strength. In the present contribution, the influence...
Carbon-bonded alumina refractories offer excellent thermal shock performance but are lacking in terms of mechanical strength. In the present contribution, the influence of the particle packing and the addition of graphene oxide (GO) to carbon-bonded alumina refractories on the physical and mechanical properties before and after thermal shock was investigated. Coarse tabular alumina grains were coated by a GO suspension and used to prepare dry-pressed compacts. The included graphite fraction (15 wt%) was either regarded as a lubricating matrix component or as a quasi-spherical component of a calculated density-optimized aggregate size distribution. During coking, the GO was reduced to thermally reduced graphene. The porosity, true density and thermal shock behavior in terms of the cold modulus of rupture (CMOR) and Young's modulus were compared. Samples with a higher density were obtained when the irregularly shaped graphite was considered as the matrix component (lubricant). The results showed that the use of GO had a positive impact on the mechanical properties of the graphene-reinforced AlO-C refractories, especially in the case of a less optimized packing, due to the bridging of delamination gaps. In addition, the thermal shock only had a minor impact on the Young's modulus and CMOR values of the samples. SEM investigation revealed very similar microstructures in coked as well as thermally shocked samples.
PubMed: 35009331
DOI: 10.3390/ma15010186