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Archives of Endocrinology and Metabolism 2017Radioiodine (RAI)-refractory thyroid cancer is an uncommon entity, occurring with an estimated incidence of 4-5 cases/year/million people. RAI refractoriness is more... (Review)
Review
Radioiodine (RAI)-refractory thyroid cancer is an uncommon entity, occurring with an estimated incidence of 4-5 cases/year/million people. RAI refractoriness is more frequent in older patients, in those with large metastases, in poorly differentiated thyroid cancer, and in those tumors with high 18-fluordeoxyglucose uptake on PET/CT. These patients have a 10-year survival rate of less than 10%. In recent years, new therapeutic agents with molecular targets have become available, with multikinase inhibitors (MKIs) being the most investigated drugs. Two of these compounds, sorafenib and lenvatinib, have shown significant objective response rates and have significantly improved the progression-free survival in the two largest published prospective trials on MKI use. However, no overall survival benefit has been achieved yet. This is probably related to the crossover that occurs in most patients who progress on placebo treatment to the open treatment of these studies. In consequence, the challenge is to correctly identify which patients will benefit from these treatments. It is also crucial to understand the appropriate timing to initiate MKI treatment and when to stop it. The purpose of this article is to define RAI refractoriness, to summarize which therapies are available for this condition, and to review how to select patients who are suitable for them.
Topics: Antineoplastic Agents; Disease Management; Humans; Iodine Radioisotopes; Protein Kinase Inhibitors; Radiation Tolerance; Retreatment; Thyroid Neoplasms; Treatment Failure
PubMed: 28225999
DOI: 10.1590/2359-3997000000245 -
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 -
Frontiers in Immunology 2022Transcatheter arterial chemoembolization LIHC, Liver hepatocellular carcinoma; (TACE) is a valid therapeutic method for hepatocellular carcinoma (HCC). However, many...
Development and Validation of TACE Refractoriness-Related Diagnostic and Prognostic Scores and Characterization of Tumor Microenvironment Infiltration in Hepatocellular Carcinoma.
BACKGROUND
Transcatheter arterial chemoembolization LIHC, Liver hepatocellular carcinoma; (TACE) is a valid therapeutic method for hepatocellular carcinoma (HCC). However, many patients respond poorly to TACE, thus leading to an adverse outcome. Therefore, finding new biomarkers for forecasting TACE refractoriness occurrence and prognosis becomes one of the current research priorities in the field of HCC treatment.
MATERIALS AND METHODS
Based on microarray datasets and a high-throughput sequencing dataset, the TACE refractoriness-related genes (TRGs) were identified by differential expression analysis. LASSO and Cox regression were applied to construct TACE refractoriness diagnostic score (TRD score) and prognostic score (TRP score) and validated their accuracy in external datasets. Functional correlation of TRP score was analyzed by gene set variation analysis and Gene Ontology. CIBERSORT and IMMUNCELL AI algorithms were performed to understand the correlation between the two scores and immune activity. We further carried out the efficacy analysis of immunotherapy and targeted drugs in the different TRP score groups. Furthermore, a nomogram was built by integrating various independent prognostic factors and validated its effectiveness in different datasets.
RESULTS
We identified 487 TRGs combined with GSE104580 and TCGA datasets. Then four novel TRGs (TTK, EPO, SLC7A11, and PON1) were screened out to construct TRD score and TRP score models, and both two scores had good predictive ability in external datasets. Tumors with high TRP score show an immunosuppressive phenotype with more infiltrations of regulatory T cells and macrophages. Immunotherapy and chemotherapy response evaluation revealed patients with a high TRP score demonstrated well reactions to immune checkpoint inhibitors (ICIs) and sorafenib. TRP score, TNM stage, and cancer type were brought into the combined nomogram with optimum prediction.
CONCLUSIONS
Our research provided dependable and simplified methods for patients with HCC to assess tumors' susceptibility to TACE refractoriness and prognosis and guide patients' clinical therapy choices.
Topics: Aryldialkylphosphatase; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Humans; Liver Neoplasms; Prognosis; Tumor Microenvironment
PubMed: 35493518
DOI: 10.3389/fimmu.2022.869993 -
CNS Neuroscience & Therapeutics Mar 2012Defining refractoriness in bipolar disorder is complex and should concern and include either every phase and pole or the disorder as a whole. The data on the treatment... (Review)
Review
Defining refractoriness in bipolar disorder is complex and should concern and include either every phase and pole or the disorder as a whole. The data on the treatment of refractory bipolar patients are sparse. Combination and add-on studies suggest that in acutely manic patients partial responders to lithium, valproate, or carbamazepine, a good strategy would be to add haloperidol, risperidone, olanzapine, quetiapine, or aripiprazole. Adding oxcarbazepine to lithium is also a choice. There are no reliable data concerning the treatment of refractory bipolar depressives and also there is no compelling data for the maintenance treatment of refractory patients. It seems that patients stabilized on combination treatment might do worse if shifted from combination. Conclusively there are only limited and sometimes confusing data on the treatment of refractory bipolar patients. Further focused research is necessary on this group of patients.
Topics: Antimanic Agents; Bipolar Disorder; Depressive Disorder, Treatment-Resistant; Evidence-Based Medicine; Humans; Treatment Outcome
PubMed: 22070611
DOI: 10.1111/j.1755-5949.2011.00259.x -
Frontiers in Psychiatry 2020
PubMed: 32158408
DOI: 10.3389/fpsyt.2020.00093 -
Drug, Healthcare and Patient Safety 2016Significant advances in the management of patients with ulcerative colitis (UC) have been made since the introduction of anti-tumor necrosis factor (TNF)-alpha agents,... (Review)
Review
Significant advances in the management of patients with ulcerative colitis (UC) have been made since the introduction of anti-tumor necrosis factor (TNF)-alpha agents, especially for those who fail or do not tolerate conventional therapies. Two drugs, infliximab first, then adalimumab afterward, showed effectiveness in inducing and maintaining long-term remission both in pivotal trials as well as in clinical practice. However, approximately 25% of patients with UC, who fail or do not tolerate all available therapies, require a colectomy for refractory disease. The therapeutic scenario of UC has been recently upgraded by the introduction of golimumab, the latest anti TNF-alpha agent to be approved. Golimumab is a totally humanized monoclonal antibody, administered by a subcutaneous injection every 4 weeks. Treatment with golimumab has shown to be effective to induce sustained clinical benefit in tough-to-treat patients with UC, including steroid and/or immunosuppressive refractory and steroid-dependent patients. In this review, we summarize all available efficacy and safety data of golimumab in UC, analyzing the potential therapeutic position for the treatment of refractory patients with UC.
PubMed: 26893582
DOI: 10.2147/DHPS.S62649 -
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 -
OncoTargets and Therapy 2021Collectively, hematological malignancies account for the fourth most common malignancy. Myeloma and lymphoma are the most common types of hematological malignancies.... (Review)
Review
Collectively, hematological malignancies account for the fourth most common malignancy. Myeloma and lymphoma are the most common types of hematological malignancies. Unfortunately, the management of refractory myeloma and lymphoma remains challenging. The discovery of new immunological therapies, namely chimeric antigen receptors T cells (CAR-T), outlined unprecedented B cell malignancies results. In this context, the CAR-T-based approach has led to the proliferation of many clinical studies. In this review, we will deal with the CAR-T structure, and we will summarize the primary clinical studies assessing the risks and benefits of CAR-T cell therapy. We will also deal with the adverse events and management of cytokine release syndromes/immune effector cell-associated neurotoxicity syndrome (ICANS). Subsequently, we will review potential future improvements to overcome refractoriness and improve expansion while decreasing CAR-T's off-target effects. The advances in the CAR-T platform represent a step forward with promising unlimited future possibilities that made it a paradigm-shifting for the management of B cell malignancies.
PubMed: 33814917
DOI: 10.2147/OTT.S242018 -
European Journal of Neurology Jun 2019Juvenile myoclonic epilepsy (JME) is a common epilepsy syndrome for which treatment response is generally assumed to be good. We aimed to determine the prevalence and... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND PURPOSE
Juvenile myoclonic epilepsy (JME) is a common epilepsy syndrome for which treatment response is generally assumed to be good. We aimed to determine the prevalence and prognostic risk factors for refractoriness of JME.
METHODS
We systematically searched PubMed and EMBASE and included 43 eligible studies, reporting seizure outcome after antiepileptic drug (AED) treatment in JME cohorts. We defined refractory JME as persistence of any seizure despite AED treatment and performed a random-effects meta-analysis to assess the prevalence of refractory JME and of seizure recurrence after AED withdrawal in individuals with well-controlled seizures. Studies reporting potential prognostic risk factors in relation to seizure outcome were included for subsequent meta-analysis of risk factors for refractoriness.
RESULTS
Overall, 35% (95% confidence interval, 29-41%) of individuals (n = 3311) were refractory. There was marked heterogeneity between studies. Seizures recurred in 78% (95% confidence interval, 52-94%) of individuals who attempted to withdraw from treatment after a period of seizure freedom (n = 246). Seizure outcome by publication year suggested that prognosis did not improve over time. Meta-analysis suggested six variables as prognostic factors for refractoriness, i.e. having three seizure types, absence seizures, psychiatric comorbidities, earlier age at seizure onset, history of childhood absence epilepsy and praxis-induced seizures.
CONCLUSION
One-third of people with JME were refractory, which is a higher prevalence than expected. Risk factors were identified and can be used to guide treatment and counselling of people with JME.
Topics: Anticonvulsants; Humans; Myoclonic Epilepsy, Juvenile; Prevalence; Prognosis; Risk Factors
PubMed: 30223294
DOI: 10.1111/ene.13811 -
Journal of Experimental & Clinical... Nov 2020Papillary thyroid cancer (PTC) is the most frequent endocrine tumor. Radioiodine (RAI) treatment is highly effective in these tumors, but up to 60% of metastatic cases...
BACKGROUND
Papillary thyroid cancer (PTC) is the most frequent endocrine tumor. Radioiodine (RAI) treatment is highly effective in these tumors, but up to 60% of metastatic cases become RAI-refractory. Scanty data are available on either the molecular pattern of radioiodine refractory papillary thyroid cancers (PTC) or the mechanisms responsible for RAI resistance.
METHODS
We analyzed the molecular profile and gene/miRNA expression in primary PTCs, synchronous and RAI-refractory lymph node metastases (LNMs) in correlation to RAI avidity or refractoriness. We classified patients as RAI+/D+ (RAI uptake/disease persistence), RAI-/D+ (absent RAI uptake/disease persistence), and RAI+/D- (RAI uptake/disease remission), and analyzed the molecular and gene/miRNA profiles, and the expression of thyroid differentiation (TD) related genes.
RESULTS
A different molecular profile according to the RAI class was observed: BRAF cases were more frequent in RAI-/D+ (P = 0.032), and fusion genes in RAI+/D+ cases. RAI+/D- patients were less frequently pTERT mutations positive, and more frequently wild type for the tested mutations/fusions. Expression profiles clearly distinguished PTC from normal thyroid. On the other hand, in refractory cases (RAI+/D+ and RAI-/D+) no distinctive PTC expression patterns were associated with either tissue type, or RAI uptake, but with the driving lesion and BRAF-/RAS-like subtype. Primary tumors and RAI-refractory LNMs with BRAF mutation display transcriptome similarity suggesting that RAI minimally affects the expression profiles of RAI-refractory metastases. Molecular profiles associated with the expression of TPO, SLC26A4 and TD genes, that were found more downregulated in BRAF than in gene fusions tumors.
CONCLUSIONS
The present data indicate a different molecular profile in RAI-avid and RAI-refractory metastatic PTCs. Moreover, BRAF tumors displayed reduced differentiation and intrinsic RAI refractoriness, while PTCs with fusion oncogenes are RAI-avid but persistent, suggesting different oncogene-driven mechanisms leading to RAI refractoriness.
Topics: Adult; Female; Humans; Iodine Radioisotopes; Male; MicroRNAs; Middle Aged; Retrospective Studies; Thyroid Cancer, Papillary; Transcriptome
PubMed: 33198784
DOI: 10.1186/s13046-020-01757-x