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British Journal of Haematology Oct 2023Refractory immune thrombocytopenia (ITP) is a challenging disease that can be defined by refractoriness to second-line treatments. In this review, we list and comment... (Review)
Review
Refractory immune thrombocytopenia (ITP) is a challenging disease that can be defined by refractoriness to second-line treatments. In this review, we list and comment available evidence about clinical and biological factors associated with refractoriness to splenectomy, thrombopoietin receptor agonists (TPO-RAs), rituximab and fostamatinib, as well as those associated with multirefractory ITP (active disease with failure of rituximab, TPO-RAs and splenectomy).
Topics: Humans; Purpura, Thrombocytopenic, Idiopathic; Receptors, Fc; Receptors, Thrombopoietin; Recombinant Fusion Proteins; Rituximab; Splenectomy; Thrombopoietin; Biomarkers
PubMed: 38019080
DOI: 10.1111/bjh.19076 -
Revista Espanola de Medicina Nuclear E... 2023Radioiodine therapy represents a fundamental pillar in the routine adjuvant therapy of patients with high-risk differentiated thyroid carcinoma. However, a... (Review)
Review
Radioiodine therapy represents a fundamental pillar in the routine adjuvant therapy of patients with high-risk differentiated thyroid carcinoma. However, a non-negligible percentage of these patients will develop iodine refractoriness, showing a worse prognosis, as well a lower survival, which demonstrates a clear need to explore different therapeutic approaches. Iodine refractory patient treatment continues to be a challenge, currently having different novel therapeutic options that should be known by the different specialties related to differentiated thyroid carcinoma (DTC). The aim of this work is to review iodine refractory thyroid carcinoma treatment, focusing especially on the definition of iodine refractoriness, highlighting its importance due to its high mortality, and introducing the different therapeutic options available for these patients.
Topics: Humans; Adenocarcinoma; Iodine; Iodine Radioisotopes; Prognosis; Thyroid Neoplasms
PubMed: 37442524
DOI: 10.1016/j.remnie.2023.07.003 -
Science Advances Jun 2022We combine novel laboratory experiments and exospheric modeling to reveal that "dynamic" Ly-α photolysis of Plutonian methane generates a photolytic refractory...
We combine novel laboratory experiments and exospheric modeling to reveal that "dynamic" Ly-α photolysis of Plutonian methane generates a photolytic refractory distribution on Charon that increases with latitude, consistent with poleward darkening observed in the New Horizons images. The flux ratio of the condensing methane to the interplanetary medium Ly-α photons, φ, controls the distribution and composition of Charon's photoproducts. Mid-latitude regions are likely to host complex refractories emerging from low-φ photolysis, while high-φ photolysis at the polar zones primarily generate ethane. However, ethane being colorless does not contribute to the reddish polar hue. Solar wind radiolysis of Ly-α-cooked polar frost past spring sunrise may synthesize increasingly complex, redder refractories responsible for the unique albedo on this enigmatic moon.
PubMed: 35714189
DOI: 10.1126/sciadv.abq5701 -
British Journal of Haematology Oct 2023Patients with refractory immune thrombocytopenia (rITP) have increased morbidity and mortality. Currently, there is limited understanding of the cause of refractoriness... (Review)
Review
Patients with refractory immune thrombocytopenia (rITP) have increased morbidity and mortality. Currently, there is limited understanding of the cause of refractoriness and no markers to help direct novel treatment options. Understanding the reason(s) for refractoriness is crucial to determining novel treatment options. The pathogenesis underlying rITP has generally been thought to be an underlying genetic predisposition with an environmental trigger. Familial ITP remains rare, and there are few twin studies, suggesting that a simple genetic cause is unlikely. However, genetic mutations provide the background for several autoimmune diseases. In this review, we explore the evidence of either an inherited genetic cause of rITP or an acquired mutation, in particular one resulting in clonal expansion of cytotoxic T cells.
Topics: Humans; Purpura, Thrombocytopenic, Idiopathic; Genetic Predisposition to Disease; Mutation; T-Lymphocytes, Cytotoxic
PubMed: 37735556
DOI: 10.1111/bjh.19110 -
Hematology/oncology Clinics of North... Jun 2016Platelet refractoriness occurs when there is an inadequate response to platelet transfusions, which typically has nonimmune causes, but is also associated with... (Review)
Review
Platelet refractoriness occurs when there is an inadequate response to platelet transfusions, which typically has nonimmune causes, but is also associated with alloantibodies to human leukocyte antigens (HLAs) and/or human platelet antigens. Immune-mediated platelet refractoriness is suggested when a 10-minute to 1-hour corrected count increment of less than 5 × 10(9)/L is observed after 2 sequential transfusions using ABO-identical, freshest available platelets. When these antibodies are identified, one of 3 strategies should be used for identifying compatible platelet units: HLA matching, crossmatching, and antibody specificity prediction. These strategies seem to offer similar results in terms of posttransfusion platelet increments.
Topics: ABO Blood-Group System; Antibody Specificity; Blood Platelets; HLA Antigens; Histocompatibility Testing; Humans; Isoantibodies; Platelet Transfusion
PubMed: 27113003
DOI: 10.1016/j.hoc.2016.01.008 -
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 -
Pituitary Jun 2023Treatment-refractory pituitary tumors demonstrate characteristics resembling those of highly aggressive tumors, in which the local tumor microenvironment (TME) plays a... (Review)
Review
PURPOSE
Treatment-refractory pituitary tumors demonstrate characteristics resembling those of highly aggressive tumors, in which the local tumor microenvironment (TME) plays a dominant role in promoting aggressiveness and refractoriness. However, role of the TME in pituitary tumors is not well studied.
METHODS
Literature on the TME and development of refractory pituitary tumors was reviewed RESULTS: TME harbors tumorigenic immune cells, cancer-associated fibroblasts (CAF), extracellular matrix, and other factors that have been shown to affect behavior of tumor tissue. For example, tumor-associated macrophages and tumor-infiltrating lymphocytes correlate with aggressive and invasive tumor behavior in nonfunctioning and growth hormone-secreting (GH) pituitary tumors, while CAF release of TGFβ, FGF2, cytokines, chemokines, and growth factors may promote treatment resistance, tumor fibrosis, and inflammation in prolactinomas and GH-secreting tumors. In turn, Wnt pathway activation can further promote cell growth in dopamine-resistant prolactinomas. Finally, proteins secreted by extracellular matrix are associated with increased angiogenesis in invasive tumors.
CONCLUSION
It is likely that multiple mechanisms, including TME, contribute to the development of aggressive refractory pituitary tumors. Given the increased morbidity and mortality associated with pituitary tumor refractoriness, more research on the role of TME is warranted.
Topics: Humans; Pituitary Neoplasms; Prolactinoma; Tumor Microenvironment; Pituitary Gland; Growth Hormone; Human Growth Hormone
PubMed: 36870010
DOI: 10.1007/s11102-023-01301-y -
Gut Jul 1984A refractory duodenal ulcer was arbitrarily defined as one that had failed to heal completely after treatment with cimetidine 1 g daily for three months. Of 66 patients...
A refractory duodenal ulcer was arbitrarily defined as one that had failed to heal completely after treatment with cimetidine 1 g daily for three months. Of 66 patients with refractory duodenal ulcer, healing eventually occurred in 37 patients, after treatment for an average of 7.4 months. But 28 patients did not heal despite treatment for an average of 9.4 months; and one patient defaulted. In 41 patients the daily dose of cimetidine was increased to 2 g: the ulcers in 31 patients healed. In eight patients the daily dose was increased to 3 g and healing occurred in four patients. Eighteen patients required admission on 22 occasions because of severe symptoms despite treatment. Nine patients underwent surgery but in five the results were poor. Differences in clinical and endoscopic features between refractory and non-refractory ulcer patients were small. Acid and pepsin secretion were similar and gastrin concentrations normal. Blood levels of the drug and suppression of acid secretion were both satisfactory. Identification of refractory ulcer patients at the start of treatment was therefore not possible. Refractoriness could occur at any time during the course of the disease, previous treatment with cimetidine often having resulted in rapid healing, but subsequent relapses were also usually refractory. The cause of refractoriness remains unknown and the rather poor results of surgery in this series suggests that optimal management of these patients remains to be determined. Refractoriness probably indicates a changed natural history of the disease and in some patients a more poor prognosis.
Topics: Adult; Cimetidine; Dose-Response Relationship, Drug; Drug Resistance; Duodenal Ulcer; Female; Gastric Acid; Humans; Male; Middle Aged; Pepsin A
PubMed: 6428982
DOI: 10.1136/gut.25.7.711 -
World Journal of Gastrointestinal... May 2014Chronic constipation is a frequently encountered disorder in clinical practice. Most constipated patients benefit from standard medical approaches. However, current... (Review)
Review
Chronic constipation is a frequently encountered disorder in clinical practice. Most constipated patients benefit from standard medical approaches. However, current therapies may fail in a proportion of patients. These patients deserve better evaluation and thorough investigations before their labeling as refractory to treatment. Indeed, several cases of apparent refractoriness are actually due to misconceptions about constipation, poor basal evaluation (inability to recognize secondary causes of constipation, use of constipating drugs) or inadequate therapeutic regimens. After a careful re-evaluation that takes into account the above factors, a certain percentage of patients can be defined as being actually resistant to first-line medical treatments. These subjects should firstly undergo specific diagnostic examination to ascertain the subtype of constipation. The subsequent therapeutic approach should be then tailored according to their underlying dysfunction. Slow transit patients could benefit from a more robust medical treatment, based on stimulant laxatives (or their combination with osmotic laxatives, particularly over the short-term), enterokinetics (such as prucalopride) or secretagogues (such as lubiprostone or linaclotide). Patients complaining of obstructed defecation are less likely to show a response to medical treatment and might benefit from biofeedback, when available. When all medical treatments prove to be unsatisfactory, other approaches may be attempted in selected patients (sacral neuromodulation, local injection of botulinum toxin, anterograde continence enemas), although with largely unpredictable outcomes. A further although irreversible step is surgery (subtotal colectomy with ileorectal anastomosis or stapled transanal rectal resection), which may confer some benefit to a few patients with refractoriness to medical treatments.
PubMed: 24868488
DOI: 10.4292/wjgpt.v5.i2.77 -
Seizure Mar 2002Intractable seizures are just one manifestation of 'refractory epilepsy', which can be recognized as a distinct condition with multifaceted dimensions, including... (Review)
Review
Intractable seizures are just one manifestation of 'refractory epilepsy', which can be recognized as a distinct condition with multifaceted dimensions, including neurobiochemical plastic changes, cognitive decline and psychosocial dysfunction, leading to dependent behaviour and a restricted lifestyle. The biological basis of 'refractoriness' is likely to be multifactorial, and may include the severity of the syndrome and/or underlying neuropathology, abnormal reorganization of neuronal circuitry, alteration in neurotransmitter receptors, ion channelopathies, reactive autoimmunity, and impaired antiepileptic drug (AED) penetration to the seizure focus. Some of these deleterious changes may be a consequence of recurrent seizures. We hypothesize that 'refractory epilepsy' may be prevented by interrupting this self-perpetuating progression. There is increasing evidence that these patients can be identified early in the clinical course and, thus, be targeted early for effective therapeutic intervention. Failure of two first-line AEDs due to lack of efficacy or poor tolerability should prompt consideration of epilepsy surgery in a patient with a resectable brain abnormality. For the majority not suitable for 'curative' surgery, AEDs should be combined with the aim of achieving 'synergism'. This strategy has the potential to improve outcome by preventing the insidious progression to intractable 'refractoriness' and a downward spiraling quality of life.
Topics: Animals; Anticonvulsants; Disease Progression; Epilepsy; Humans
PubMed: 11945093
DOI: 10.1053/seiz.2002.0593