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Naunyn-Schmiedeberg's Archives of... Feb 2024Clinically, thymoma patients are often complicated with myasthenia gravis (MG). Dexamethasone, a glucocorticoid with anti-inflammatory effects, could be used as an...
Clinically, thymoma patients are often complicated with myasthenia gravis (MG). Dexamethasone, a glucocorticoid with anti-inflammatory effects, could be used as an immunosuppressant for thymoma-associated MG, but the mechanism of action remains to be explored. In this study, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, weighted gene co-expression network analysis (WGCNA) of potential targets was performed by screening the intersection targets of dexamethasone and thymoma-associated MG from the database. Furthermore, the key targets and core active components were identified by topological analysis of the protein-protein interaction (PPI) network. Molecular docking technology was applied to screen the complexes with stable binding of dexamethasone and core targets. Patients with thymoma were divided into two groups according to whether they received dexamethasone before operation, and immunohistochemistry and western blot were used to verify the selected target of dexamethasone in treating thymoma-associated MG. The results showed that the action pathway of dexamethasone on the disease was closely enriched to phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB/AKT), mammalian target of rapamycin (mTOR) signaling pathways. The expressions of AKT1 and its downstream molecule mTOR in the thymoma microenvironment of thymoma-associated MG patients who did not receive dexamethasone before operation were higher than those in the group receiving dexamethasone before operation. This study demonstrates that dexamethasone can promote apoptosis through the AKT-mTOR pathway for the treatment of thymoma-associated MG, as validated by network pharmacology predictions and clinical specimen experiments, and can be verified by large-scale clinical trials in the future. This study also provides theoretical support and new research perspectives for this disease.
Topics: Humans; Thymoma; Proto-Oncogene Proteins c-akt; Molecular Docking Simulation; Phosphatidylinositol 3-Kinases; TOR Serine-Threonine Kinases; Thymus Neoplasms; Dexamethasone; Tumor Microenvironment
PubMed: 37498332
DOI: 10.1007/s00210-023-02641-z -
CNS Neuroscience & Therapeutics Feb 2024This comprehensive review aimed to compile cases of patients with thymoma diagnosed with both autoimmune encephalitis (AE) and myasthenia gravis (MG), and describe their... (Review)
Review
OBJECTIVES
This comprehensive review aimed to compile cases of patients with thymoma diagnosed with both autoimmune encephalitis (AE) and myasthenia gravis (MG), and describe their clinical characteristics.
METHODS
Clinical records of 3 AE patients in the first affiliated hospital of Sun Yat-sen University were reviewed. All of them were diagnosed with AE between 1 November 2021 and 1 March 2022, and clinical evidence about thymoma and MG was found. All published case reports were searched for comprehensive literature from January 1990 to June 2022.
RESULTS
A total of 18 cases diagnosed with thymoma-associated autoimmune encephalitis (TAAE) and thymoma-associated myasthenia gravis (TAMG) were included in this complication, wherein 3 cases were in the first affiliated hospital of Sun Yat-sen University and the other 15 were published case reports. 5/18 patients had alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antibody (AMPAR-Ab) in their serum and cerebrospinal fluid (CSF). All of them had positive anti-acetylcholine receptor antibody (AChR-Ab). And 12/18 patients showed a positive response to thymectomy and immunotherapy. Besides, thymoma recurrences were detected because of AE onset. And the shortest interval between operation and AE onset was 2 years in patients with thymoma recurrence.
CONCLUSIONS
There was no significant difference in the clinical manifestations between these patients and others with only TAMG or TAAE. TAAE was commonly associated with AMPAR2-Ab. Significantly, AE more commonly heralded thymoma recurrences than MG onset. And the intervals of thymectomy and MG or AE onset had different meanings for thymoma recurrence and prognoses of patients.
Topics: Humans; Thymoma; Thymus Neoplasms; Myasthenia Gravis; Encephalitis; Hashimoto Disease
PubMed: 38421083
DOI: 10.1111/cns.14568 -
European Journal of Neurology May 2024Generalized myasthenia gravis (MG) with antibodies against the acetylcholine receptor is a chronic disease causing muscle weakness. Access to novel treatments warrants...
BACKGROUND
Generalized myasthenia gravis (MG) with antibodies against the acetylcholine receptor is a chronic disease causing muscle weakness. Access to novel treatments warrants authoritative treatment recommendations. The Nordic countries have similar, comprehensive health systems, mandatory health registers, and extensive MG research.
METHODS
MG experts and patient representatives from the five Nordic countries formed a working group to prepare treatment guidance for MG based on a systematic literature search and consensus meetings.
RESULTS
Pyridostigmine represents the first-line symptomatic treatment, while ambenonium and beta adrenergic agonists are second-line options. Early thymectomy should be undertaken if a thymoma, and in non-thymoma patients up to the age of 50-65 years if not obtaining remission on symptomatic treatment. Most patients need immunosuppressive drug treatment. Combining corticosteroids at the lowest possible dose with azathioprine is recommended, rituximab being an alternative first-line option. Mycophenolate, methotrexate, and tacrolimus represent second-line immunosuppression. Plasma exchange and intravenous immunoglobulin are used for myasthenic crises and acute exacerbations. Novel complement inhibitors and FcRn blockers are effective and fast-acting treatments with promising safety profiles. Their use depends on local availability, refunding policies, and cost-benefit analyses. Adapted physical training is recommended. Planning of pregnancies with optimal treatment, information, and awareness of neonatal MG is necessary. Social support and adaptation of work and daily life activities are recommended.
CONCLUSIONS
Successful treatment of MG rests on timely combination of different interventions. Due to spontaneous disease fluctuations, comorbidities, and changes in life conditions, regular long-term specialized follow-up is needed. Most patients do reasonably well but there is room for further improvement. Novel treatments are promising, though subject to restricted access due to costs.
Topics: Pregnancy; Female; Infant, Newborn; Humans; Middle Aged; Aged; Myasthenia Gravis; Receptors, Cholinergic; Neuromuscular Diseases; Pyridostigmine Bromide; Immunosuppressive Agents; Thymus Neoplasms; Autoantibodies; Thymectomy
PubMed: 38321574
DOI: 10.1111/ene.16229 -
Handbook of Clinical Neurology 2024Paraneoplastic neurologic syndromes (PNS) represent a rare group of immune-mediated complications associated with an underlying tumor. Ectopic protein expression in... (Review)
Review
Paraneoplastic neurologic syndromes (PNS) represent a rare group of immune-mediated complications associated with an underlying tumor. Ectopic protein expression in neoplastic cells or an aberrant immune regulation in the course of hematooncologic diseases or thymomas trigger an autoimmune response that may affect any part of the central and/or peripheral nervous system. Recent advances in drug therapies as well as novel animal models and neuropathologic studies have led to further insights on the immune pathomechanisms of PNS. Although the syndromes share common paths in pathogenesis, they may differ in the disease course, prognosis, and therapy targets, depending on the localization and type of antibody epitope. Neuropathologic hallmarks of PNS associated with antibodies directed against intracellular epitopes are characterized by T cell-dominated inflammation, reactive gliosis including microglial nodules, and neuronal degeneration. By contrast, the neuropathology of cell surface antibody-mediated PNS strongly depends on the targeted antigen and varies from B cell/plasma cell-dominated inflammation and well-preserved neurons together with a reduced expression of the target antigen in anti-NMDAR encephalitis to irreversible Purkinje cell loss in anti-P/Q-type VGCC antibody-associated paraneoplastic cerebellar degeneration. The understanding of different pathomechanisms in PNS is important because they strongly correspond with therapy response and prognosis, and should guide treatment decisions.
Topics: Animals; Humans; Autoantibodies; Paraneoplastic Syndromes, Nervous System; Nervous System Diseases; Neoplasms; Inflammation
PubMed: 38494287
DOI: 10.1016/B978-0-12-823912-4.00027-X -
Advances in Anatomic Pathology Jan 2024The classification of thymoma continues to be a source of controversy in pathology. The difficulties in histologic classification are evident from the number of...
The classification of thymoma continues to be a source of controversy in pathology. The difficulties in histologic classification are evident from the number of proposals that have been offered over the years, as well as for the continuous changes and modifications introduced by the World Health Organization to their classification system over the past 20 years. We analyze here some of the issues involved in the classification of these tumors and the difficulties encountered for practicing pathologists in deciphering the "letters and numbers" system devised by the World Health Organization. We would like to propose an alternate approach to thymoma histologic classification that capitalizes on the basic observation of their cytologic features and incorporates the pattern of growth resulting from the interplay of the tumor cells with other cellular constituents as a secondary characteristic. The proposed histologic classification provides a simplified, reproducible means of histologically categorizing these tumors and can be easily understood by most practicing pathologists in simple and clear morphologic terms.
Topics: Humans; Thymoma; Prognosis; Thymus Neoplasms; World Health Organization; Pathologists
PubMed: 37702296
DOI: 10.1097/PAP.0000000000000412 -
Asian Journal of Surgery Sep 2023Whether thymectomy (TM) or thymomectomy (TMM) is better for non-myasthenic patients with early-stage thymoma. We conducted a meta-analysis to compare the clinical... (Meta-Analysis)
Meta-Analysis Review
Whether thymectomy (TM) or thymomectomy (TMM) is better for non-myasthenic patients with early-stage thymoma. We conducted a meta-analysis to compare the clinical outcomes and prognoses of non-myasthenic patients with early-stage thymoma treated using thymectomy versus thymomectomy. PubMed, Embase, Cochrane Library and CNKI databases were systematically searched for relevant studies on the surgical treatment (TM and TMM) of non-myasthenic patients with early-stage thymoma published before March 2022. The Newcastle-Ottawa scale was used to evaluate the quality of the studies, and the data were analyzed using RevMan version 5.30. Fixed or random effect models were used for the meta-analysis depending on heterogeneity. Subgroup analyses were performed to compare short-term perioperative and long-term tumor outcomes. A total of 15 eligible studies, including 3023 patients, were identified in the electronic databases. Our analysis indicated that TMM patients might benefit from a shorter duration of surgery (p = 0.006), lower blood loss volume (p < 0.001), less postoperative drainage (p = 0.03), and a shorter hospital stay (p = 0.009). There were no significant differences in the overall survival rate (p = 0.47) or disease-free survival rate (p = 0.66) between the two surgery treatment groups. Likewise, TM and TMM were similar in the administration of adjuvant therapy (p = 0.29), resection completeness (p = 0.38), and postoperative thymoma recurrence (p = 0.99). Our study revealed that TMM might be a more appropriate option in treating non-myasthenic patients with early-stage thymoma.
Topics: Humans; Thymoma; Thymectomy; Neoplasm Staging; Retrospective Studies; Thymus Neoplasms; Prognosis; Disease-Free Survival
PubMed: 37005182
DOI: 10.1016/j.asjsur.2023.03.063 -
Neurology(R) Neuroimmunology &... Jan 2024Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy but come with immune-related adverse events (irAEs) that provide a novel challenge for treating...
OBJECTIVE
Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy but come with immune-related adverse events (irAEs) that provide a novel challenge for treating physicians. Neuromuscular irAEs, including myositis, myasthenia gravis (MG), and demyelinating polyradiculoneuropathy, lead to significant morbidity and mortality.
METHODS
We present a case of severe myasthenia-myositis-myocarditis overlap in a patient receiving ICIs for breast cancer. Clinical findings were recorded.
RESULTS
A 47-year-old woman developed tetraparesis, dysphagia, and muscle pain during ICI treatment. MG with a thymoma had been diagnosed earlier. Neuromuscular overlap irAEs with cardiac affection was confirmed, and ICI treatment was discontinued. Given a lack of clinical response to standard therapies, a muscle biopsy was performed demonstrating complement deposition. Eculizumab treatment led to rapid improvement in muscle strength and cardiac function.
DISCUSSION
Neuromuscular irAEs are associated with a high in-hospital mortality, and specific treatment strategies remain an unmet need. Here, early muscle biopsy enabled targeted therapy after standard approaches failed, thereby highlighting the value of identifying a specific treatment target. To improve therapeutic outcomes, the development of patient-tailored strategies for neuromuscular irAEs requires further studies.
Topics: Female; Humans; Middle Aged; Immune Checkpoint Inhibitors; Myocarditis; Muscle Weakness; Myasthenia Gravis; Myositis
PubMed: 37884388
DOI: 10.1212/NXI.0000000000200177 -
Neurological Sciences : Official... Nov 2023Myasthenia gravis (MG) is a classic autoimmune neuromuscular disease with strong clinical heterogeneity. The concept of subgroup classification was proposed to guide the... (Review)
Review
Myasthenia gravis (MG) is a classic autoimmune neuromuscular disease with strong clinical heterogeneity. The concept of subgroup classification was proposed to guide the precise treatment of MG. Subgroups based on serum antibodies and clinical features include ocular MG, early-onset MG with AchR antibodies, late-onset MG with AchR antibodies, thymoma-associated MG, MuSK-associated MG, LRP4-associated MG, and seronegative MG. However, reliable objective biomarkers are still needed to reflect the individualized response to therapy. MicroRNAs (miRNAs) are small non-coding RNA molecules which can specifically bind to target genes and regulate gene expression at the post-transcriptional level, and then influence celluar biological processes. MiRNAs play an important role in the pathogenesis of autoimmune diseases, including MG. Several studies on circulating miRNAs in MG have been reported. However, there is rare systematic review to summarize the differences of these miRNAs in different subgroups of MG. Here, we summarize the potential role of circulating miRNAs in different subgroups of MG to promote personalized medicine.
Topics: Humans; Receptors, Cholinergic; Circulating MicroRNA; Precision Medicine; Autoantibodies; Receptor Protein-Tyrosine Kinases; Myasthenia Gravis; MicroRNAs; Thymus Neoplasms
PubMed: 37402938
DOI: 10.1007/s10072-023-06933-3 -
Biomedicines Oct 2023Thymic epithelial tumors (TET) are rare neoplasms of the anterior mediastinum. Surgery is the mainstay treatment for resectable TET, whereas systemic treatments are... (Review)
Review
BACKGROUND
Thymic epithelial tumors (TET) are rare neoplasms of the anterior mediastinum. Surgery is the mainstay treatment for resectable TET, whereas systemic treatments are reserved for unresectable and metastatic tumors. The development of new treatments, such as immune checkpoint inhibitors (ICI) and targeted therapies, with promising results in other types of solid tumors, has led to the investigation of their potential efficacy in TET. The study of tumor microenvironments (TME) is another field of investigation that has gained the interest of researchers. Taking into account the complex structure of the thymus and its function in the development of immunity, researchers have focused on TME elements that could predict ICI efficacy.
MATERIALS AND METHODS
The primary objective of this systematic review was to investigate the efficacy of ICI in TET. Secondary objectives included the toxicity of ICI, the efficacy of targeted therapies in TET, and the evaluation of the elements of TME that may be predictive factors of ICI efficacy. A literature search was conducted in February 2023 using the Ovid Medline and SciVerse Scopus databases.
RESULTS
2944 abstracts were retrieved, of which 31 were retained for the systematic review. Five phase II and one retrospective study assessed ICI efficacy. The overall response rate (ORR) varied from 0% to 34%. Median progression-free survival (PFS) ranged from 3.8 to 8.6 months, being lower in thymic carcinoma (TC) (3.8-4.2 months). Median overall survival (OS) ranged from 14.1 to 35.4 months. Treatment-related adverse events occurred in 6.6% to 27.3% of patients. Sixteen studies assessed targeted therapies. The most active molecule was lenvatinib, with 38% ORR in patients with TC while no activity was detected for imatinib, erlotinib plus bevacizumab, and saracatinib. Ten studies assessed TME elements that could predict ICI efficacy. Four studies focused on the tumor-infiltrating immune cells suggesting improved outcomes in patients with TC and high tumor-infiltrating lymphocyte densities. Another study showed that CD8+, CD20+, and CD204+ tumor-infiltrating immune cells in cancer stroma might be prognostic biomarkers in TC. Another study identified the immune-related long non-coding RNAs as a predictor of response to ICI. Tumor mutational burden was identified as a predictive factor of ICI efficacy in one study.
CONCLUSIONS
Despite study heterogeneity, this review shows that ICI could be a therapeutic option for selected patients with TET that are not amenable to curative radical treatment after first-line chemotherapy.
PubMed: 37893096
DOI: 10.3390/biomedicines11102722 -
BMC Neurology Apr 2024Non-motor symptoms in myasthenia gravis (MG) are rarely confirmed. Although there are some small cohort studies, a large-systemic survey has not yet been performed.
BACKGROUND
Non-motor symptoms in myasthenia gravis (MG) are rarely confirmed. Although there are some small cohort studies, a large-systemic survey has not yet been performed.
METHODS
We investigated the incidence and clinical characteristics of patients with MG who had taste disorders and alopecia using data of 1710 patients with MG enrolled in the Japan MG Registry 2021.
RESULTS
Among them, 104 (6.1%) out of 1692 patients and 138 (8.2%) out of 1688 patients had histories of taste disorders and alopecia, respectively. Among the patients with MG, taste disorders were significantly more common in women, those with severe symptoms, refractory MG, or thymoma-associated MG, and were less common in those with ocular MG. The taste disorders often occurred after the onset of MG and often responded to MG treatments. Alopecia was more common in MG patients with a history of bulbar palsy and thymoma, and it often occurred before the onset of MG and sometimes responded to MG treatments. Multivariate logistic regression analysis revealed taste disturbance was associated with worst quantitative MG score and thymoma-associated MG; and alopecia was associated with thymoma-associated MG.
CONCLUSION
Clinicians should be aware of the non-motor symptoms in MG, especially in patients with severe myasthenic symptoms and thymoma-associated MG.
Topics: Humans; Myasthenia Gravis; Alopecia; Female; Male; Taste Disorders; Middle Aged; Adult; Aged; Japan; Registries; Thymoma; Incidence
PubMed: 38664714
DOI: 10.1186/s12883-024-03644-w