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Revista Espanola de Enfermedades... Nov 2022We report the first clinical-practice case to date of treatment with upadacitinib for ulcerative colitis, prior refractoriness to all therapeutic options, and preventing...
We report the first clinical-practice case to date of treatment with upadacitinib for ulcerative colitis, prior refractoriness to all therapeutic options, and preventing proctocolectomy as of today after treatment for 14 months.
Topics: Humans; Colitis, Ulcerative; Proctocolectomy, Restorative
PubMed: 35548867
DOI: 10.17235/reed.2022.8870/2022 -
Cancer Control : Journal of the Moffitt... Jan 2012Recent advances in the treatment of chronic lymphocytic leukemia (CLL) have moved beyond the traditional use of alkylating agents and purine analogs into regimens... (Review)
Review
BACKGROUND
Recent advances in the treatment of chronic lymphocytic leukemia (CLL) have moved beyond the traditional use of alkylating agents and purine analogs into regimens combining these two chemotherapy classes with monoclonal antibodies.
METHODS
This article reviews treatments options for patients with relapsed or refractory CLL.
RESULTS
Several studies have investigated novel agents in treating patients with 17p deletion, TP53 mutation, and fludarabine-refractory CLL, as well as patients with suboptimal response to intense treatment. These investigational agents include rituximab, alemtuzumab, ofatumumab, bendamustine, high-dose methylprednisolone, lenalidomide, lumiliximab, cyclin-dependent kinase inhibitors, small modular immunopharmaceuticals, Bcl-2 inhibitors, and histone deacetylase inhibitors. While these newer drugs and combination therapies have shown promise as treatment options for CLL, additional studies are needed to determine the immunosuppression, toxicities, and infections associated with their use.
CONCLUSIONS
Despite improvement in initial overall response rates, most patients relapse and require further treatment. CLL remains incurable with standard therapies due to development of disease refractoriness. As such, novel approaches such as those noted above warrant continued research to improve outcomes for patients with CLL.
Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Recurrence
PubMed: 22143061
DOI: 10.1177/107327481201900105 -
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 -
The European Journal of Neuroscience Oct 2022The main question addressed in this study was whether the refractoriness of nerve fibres can be modulated by their depolarisation and, if so, whether depolarisation of...
The main question addressed in this study was whether the refractoriness of nerve fibres can be modulated by their depolarisation and, if so, whether depolarisation of nerve fibres evokes a long-term decrease in the duration of the refractory period as well as the previously demonstrated increase in their excitability. This was investigated on nerve fibres within the dorsal columns, dorsal roots and peripheral nerves in deeply anaesthetised rats in vivo. The results revealed major differences depending on the sites of fibre stimulation and polarisation. Firstly, the relative refractory period was found to be shorter in epidurally stimulated dorsal column fibres than in fibres stimulated at other sites. Secondly, the minimal effective interstimulus intervals reflecting the absolute refractory period were likewise shorter for nerve fibres within the dorsal columns even though action potentials evoked by the second of a pair of stimuli were similarly delayed with respect to the preceding action potentials at all the stimulation sites. Thirdly, the minimal interstimulus intervals were reduced by epidurally applied cathodal direct current polarisation but not at other stimulation sites. Consequently, higher proportions of dorsal column fibres could be excited at higher frequencies, especially following their depolarisation, at interstimulus intervals as short as 0.5-0.7 ms. The results demonstrate that epidural depolarisation results in long-lasting effects not only on the excitability but also on the refractoriness of dorsal column fibres. They also provide further evidence for specific features of afferent fibres traversing the dorsal columns previously linked to properties of their branching regions.
Topics: Action Potentials; Animals; Axons; Electric Stimulation; Nerve Fibers; Neurons, Afferent; Rats; Spinal Cord
PubMed: 35999192
DOI: 10.1111/ejn.15801 -
Journal of Clinical Medicine Oct 2020Belching is a common phenomenon. However, it becomes bothersome if excessive. Impedance-pH monitoring can classify the belching into two types: gastric belching and... (Review)
Review
Belching is a common phenomenon. However, it becomes bothersome if excessive. Impedance-pH monitoring can classify the belching into two types: gastric belching and supragastric belching (SGB). The former is a physiological mechanism to vent swallowed air from the stomach, whereas the latter is a behavioral disorder. Gastroesophageal reflux disease (GERD) is the most relevant condition in both types of belching. Recent findings have raised awareness that excessive SGB possibly sheds light on the pathogenesis of a part of proton pump inhibitor (PPI) refractoriness in GERD. SGB could cause typical reflux symptoms such as heartburn, regurgitation or chest pain in two ways: SGB-induced gastroesophageal reflux or SGB-induced esophageal distension. In PPI-refractory GERD, it is important to detect hidden SGB as a cause of reflux symptoms since SGB requires psychological treatment instead of high dose PPIs or pain modulators. In the case of PPI-refractory GERD with excessive SGB, recent studies imply that the combination of a psychological approach and conventional treatment can improve treatment outcome.
PubMed: 33092195
DOI: 10.3390/jcm9103360 -
Frontiers in Neurology 2020Gilles de la Tourette syndrome (GTS) is a childhood onset neuropsychiatric disorder characterized by the presence of motor and vocal tics. The clinical spectrum of GTS... (Review)
Review
Gilles de la Tourette syndrome (GTS) is a childhood onset neuropsychiatric disorder characterized by the presence of motor and vocal tics. The clinical spectrum of GTS is heterogeneous and varies from mild cases that do not require any medical attention to cases that are refractory to standard treatments. One of the unresolved issues is the definition of what constitutes treatment-refractory GTS. While for some other neuropsychiatric disorders, such as obsessive-compulsive disorder (OCD), a clear definition has been established, there is still no consensus with regard to GTS. One important issue is that many individuals with GTS also meet criteria for one or more other neurodevelopmental and neuropsychiatric disorders. In many individuals, the severity of these comorbid conditions contributes to the degree to which GTS is treatment refractory. The scope of this paper is to present the current state-of-the-art regarding refractory GTS and indicate possible approaches to define it. In closing, we discuss promising approaches to the treatment of individuals with refractory GTS.
PubMed: 33391155
DOI: 10.3389/fneur.2020.589511 -
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 -
Cureus Aug 2022Amiodarone is frequently used to control cardiac arrhythmias, like atrial fibrillation. Despite its benefits, it has many adverse effects, particularly on the thyroid...
Amiodarone is frequently used to control cardiac arrhythmias, like atrial fibrillation. Despite its benefits, it has many adverse effects, particularly on the thyroid gland. We describe the case of a patient treated with amiodarone for paroxysmal atrial fibrillation, admitted to the emergency room with atrial fibrillation with a rapid ventricular response. Type II thyrotoxicosis was identified as the cause of the refractory arrhythmia. Since its refractoriness to both pharmacological and electrical therapy, there was a need to proceed with plasmapheresis and total thyroidectomy for hormonal and cardiac rhythm control. Therefore, it is essential to monitor the toxicity of amiodarone, a drug that can have both beneficial and devastating effects.
PubMed: 36185869
DOI: 10.7759/cureus.28527 -
Oncotarget Dec 2016Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Although rituximab therapy improves clinical outcome, some patients develop...
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Although rituximab therapy improves clinical outcome, some patients develop resistant DLBCL; however, the genetic alterations in these patients are not well documented. To identify the genetic background of refractory DLBCL, we conducted whole-exome sequencing and transcriptome sequencing for six patients with refractory and seven with responsive DLBCL. The average numbers of pathogenic somatic single nucleotide variants and indels in coding regions were 71 in refractory patients (range 28-120) and 38 (range 19-66) in responsive patients. Missense mutations of TP53 were exclusive in 50% (3/6) of refractory patients and involved the DNA-binding domain of TP53. All missense mutations of TP53 were accompanied by copy number deletions. RAB11FIP5, PRKCB, PRDM15, FNBP4, AHR, CEP128, BRE, DHX16, MYO6, and NMT1 mutations were recurrent in refractory patients. MYD88, B2M, SORCS3, and WDFY3 mutations were more frequent in refractory patients than in responsive patients. REL-BCL11A fusion was found in two refractory patients; one had both fusion and copy number gain. Recurrent copy gains of POU2AF1, SLC1A4, REL11, FANCL, CACNA1D, TRRAP, and CUX1 with significantly increased average expression were found in refractory patients. The expression profile revealed enriched gene sets associated with treatment resistance, including oxidative phosphorylation and ATP-binding cassette transporters. In conclusion, this study integrated both genomic and transcriptomic alterations associated with refractory DLBCL and found several treatment-resistance alterations that may contribute to refractoriness.
Topics: DNA Copy Number Variations; Exome; Gene Fusion; Genes, p53; Humans; Lymphoma, Large B-Cell, Diffuse; Mutation; Transcriptome
PubMed: 27835906
DOI: 10.18632/oncotarget.13239 -
European Neurology 2009About one third of patients with newly diagnosed epilepsy do not achieve seizure control despite medical therapy and should be assessed in detail to confirm the... (Review)
Review
About one third of patients with newly diagnosed epilepsy do not achieve seizure control despite medical therapy and should be assessed in detail to confirm the diagnosis, to determine the epilepsy syndrome and to plan treatment strategy. Refractory epilepsy is established when there is inadequate seizure control despite using potentially effective antiepileptic drugs (AEDs) at tolerable levels for 1-2 years, and excluding nonepileptic events and poor compliance. An overview of patient management in everyday clinical practice is given. Risk factors for refractoriness include (1) generalized epilepsy with lesions; (2) focal epilepsy with hippocampal sclerosis, cortical dysplasia or hemorrhages; (3) early epilepsy onset; (4) high seizure frequency; (5) absence of response to the first 2 AEDs; (6) high frequency of interictal spikes, and (7) multifocal spikes. The efficacy of surgery ranges from curative (resection) to palliative (vagus nerve stimulation, callosotomy, multiple subpial transections) depending on the epilepsy syndrome and etiology. Using a new antiepileptic drug benefits about one third of patients. Refractoriness is constitutive in most patients and shows a progressive or remission-relapse course in others. As the transporter and target hypotheses do not entirely explain refractoriness, other hypotheses are emerging. New treatments under investigation are described.
Topics: Age of Onset; Anticonvulsants; Brain; Epilepsy; Humans; Intracranial Hemorrhages; Malformations of Cortical Development; Risk Factors; Sclerosis
PubMed: 19521080
DOI: 10.1159/000222775