Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0013362 (dysarthria)
 3,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The clinical efficacy of gefitinib, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), on brain metastases (BMs) from non-small-cell lung cancer (NSCLC) was evaluated. Fifteen patients with recurrent NSCLC with metastasis to the brain were treated with gefitinib. The objective tumor response rate (60%; 9 of 15 patients) for BM was the same as for primary tumors. The median time to response of BM was 26 days. In 8 of 9 patients who exhibited partial response in the thoracic lesion, BM showed dramatic regression, including 1 complete response. One patient with stable primary tumor also exhibited partial response in BM with this monotherapy. Brain metastasis-related neurologic symptoms such as hemiparesis, dysarthria, dysphagia, and vertigo improved or disappeared with the objective response of BM as confirmed by magnetic resonance imaging. Central nervous system toxicities were not observed during the treatment. Four of the 9 BM responders are still under treatment with neither adverse events nor disease progression. Two discontinued the treatment because of severe hepatic toxicity and 3 died because of acquired resistance in pulmonary lesions, even though partial response was observed in the BMs. Finally, median duration of response of BM was 8.7 months and median overall survival was 8.3 months (range, 1.8 to > 15.7 months). Molecular targeted therapy against EGFR could be an option for the treatment of BM from NSCLC refractory to conventional chemotherapy plus radiation therapy because it has demonstrated a distinct therapeutic potential against BM compared with primary lung tumor and extracranial metastases.
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PMID:Gefitinib in patients with brain metastases from non-small-cell lung cancer: review of 15 clinical cases. 1547 98

Neuromuscular junction disorders in children are either genetic, such as congenital myasthenic syndrome, or autoimmune with circulating antibodies most commonly against acetylcholine receptors. There is limited experience recognizing and treating children with myasthenia associated with muscle-specific tyrosine kinase antibodies. We report a seven-year-old child with intermittent esotropia since age 3 months, and two years of progressive and severe diplopia, dysarthria, dysphagia, and facial weakness. Acetylcholine receptor antibodies and genetic testing for congenital myasthenic syndrome were negative. Muscle specific tyrosine kinase antibodies were significantly elevated. Ophthalmoplegia and bulbar weakness were refractory to treatment with acetylcholinesterase inhibitors, corticosteroids and IVIg but completely resolved following treatment with rituximab. Her neurologic examination remained normal at the most recent follow-up, 15 months after initiation of rituximab. Children with MuSK myasthenia, like adults, can respond to rituximab despite long standing disease and failure to improve on other immunosuppressant medications.
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PMID:Selective response to rituximab in a young child with MuSK-associated myasthenia gravis. 2599 11

Myasthenia gravis is an autoimmune neuromuscular disease caused by antibodies directed against the postsynaptic muscle membrane. The clinical hallmark of the disease is fluctuating and fatigable weakness that affects the ocular muscles (resulting in diplopia and ptosis), the bulbar muscles (causing dysphagia, dysarthria, and dyspnea), and extremity muscles. The diagnosis is most often made with serological testing that identifies either acetylcholine receptor antibodies or muscle-specific tyrosine kinase antibodies. Electrodiagnostic testing has a role in supporting the diagnosis. There are many available treatments that result in improvement of function and quality of life. Treatment should be individualized after consideration of many factors, including disease distribution and severity, patient comorbidities, age, serological status, and what is known about the efficacy and safety of the various treatments.
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PMID:Myasthenia Gravis. 2650 57

Myasthenia gravis (MG) with antibodies against muscle-specific tyrosine kinase (MuSK) is a rare disorder of neuromuscular transmission affecting preferentially bulbar, neck and respiratory muscles. We report the case of a 22-year-old man who presented with diplopia on lateral gaze to both sides, facial diplegia, nasal dysarthria and dysphagia. Repetitive nerve stimulation of the trapezius and orbicularis oculi muscles showed amplitude decrements of 19% and 41% respectively supporting the diagnosis of myasthenia gravis. MUsK antibodies were positive. Corticosteroids were introduced and then tapered and discontinued at 6 months after initiation. The patient remained in remission and asymptomatic for 4 years without ongoing treatment or prior treatment with rituximab after this first relapse of MuSK-MG. MuSK- MG is considered a hard-to-treat condition and patients generally remain dependent on immunosuppression or prior treatment with rituximab. Our observation highlights that patients with MuSK-MG can have a benign course and that continued immunosuppressive or immunomodulatory therapy may not always be required.
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PMID:Anti-MuSK myasthenia gravis with prolonged remission. 2716 84

A vailable tyrosine kinase inhibitors for chronic myeloid leukemia bind in an adenosine 5'-triphosphate-binding pocket and are affected by evolving mutations that confer resistance. Rebastinib was identified as a switch control inhibitor of BCR-ABL1 and FLT3 and may be active against resistant mutations. A Phase 1, first-in-human, single-agent study investigated rebastinib in relapsed or refractory chronic or acute myeloid leukemia. The primary objectives were to investigate the safety of rebastinib and establish the maximum tolerated dose and recommended Phase 2 dose. Fifty-seven patients received treatment with rebastinib. Sixteen patients were treated using powder-in-capsule preparations at doses from 57 mg to 1200 mg daily, and 41 received tablet preparations at doses of 100 mg to 400 mg daily. Dose-limiting toxicities were dysarthria, muscle weakness, and peripheral neuropathy. The maximum tolerated dose was 150 mg tablets administered twice daily. Rebastinib was rapidly absorbed. Bioavailability was 3- to 4-fold greater with formulated tablets compared to unformulated capsules. Eight complete hematologic responses were achieved in 40 evaluable chronic myeloid leukemia patients, 4 of which had a T315I mutation. None of the 5 patients with acute myeloid leukemia responded. Pharmacodynamic analysis showed inhibition of phosphorylation of substrates of BCR-ABL1 or FLT3 by rebastinib. Although clinical activity was observed, clinical benefit was insufficient to justify continued development in chronic or acute myeloid leukemia. Pharmacodynamic analyses suggest that other kinases inhibited by rebastinib, such as TIE2, may be more relevant targets for the clinical development of rebastinib (clinicaltrials.gov Identifier:00827138).
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PMID:Phase 1 dose-finding study of rebastinib (DCC-2036) in patients with relapsed chronic myeloid leukemia and acute myeloid leukemia. 2792 66

A 31-year-old woman presented with a nasal voice, dysarthria, and upper limb weakness during her first pregnancy. Soon after delivery of her first baby, her symptoms disappeared. At the age of 34 years, during her second pregnancy, her nasal voice re-appeared. After delivery of the second baby, her nasal voice worsened, and bilateral eyelid ptosis and easy fatigability were also evident. She was referred to our hospital. Because of her myasthenic symptoms and anti-muscle-specific tyrosine kinase (MuSK) antibody (Ab)-positive status, she was diagnosed as having myasthenia gravis (MG). Her symptoms were worse than those in her first pregnancy. She was treated with oral steroid and double filtration plasmapheresis. After initiation of treatment, her myasthenic symptoms improved completely. In addition, her baby developed transient neonatal MG (TNMG) on the fourth day after birth and then gradually recovered over 30 days. It should be noted that symptoms of patients with anti-MuSK Ab-positive MG (MuSK-MG) can deteriorate during pregnancy, and the babies delivered of patients with MuSK-MG have a high probability of developing TNMG.
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PMID:Myasthenia Gravis with Anti-Muscle-Specific Tyrosine Kinase Antibody during Pregnancy and Risk of Neonatal Myasthenia Gravis: A Case Report and Review of the Literature. 3230 6

Introduction. Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors and constitute the largest group of nonepithelial digestive neoplasms. However, they do not represent more than 1% of primary digestive tumors. They commonly metastasize to the liver and peritoneum, but brain metastases are extremely rare. Clinical Case. A 76-year-old woman with a diagnosis of esophageal GIST with liver and lung metastases for 13 years, medicated with imatinib, is presented. She was brought to the emergency department after falling and due to changes in behavior and vertigo with 24 hours of evolution. On physical examination, she presented changes in behavior, dysarthria, dysmetria on the right, gait imbalance, and no motor or sensory deficits. On brain computed tomography and posteriorly on magnetic resonance, 2 lesions were observed, left frontal and right cerebellar, compatible with metastatic lesions. After contribution of neurosurgery, histology was obtained that confirmed the lesions were GIST metastases. Imatinib was maintained, and whole brain radiotherapy was performed. After 6 months, she died. Discussion. The rarity of GIST brain metastases is noteworthy, and because of that, there is not enough experience to be certain of the best treatment. Our patient lived for 13 years with excellent disease control with imatinib, but the fact that it does not cross the blood-brain barrier makes it not useful in preventing or treating brain lesions. New tyrosine kinase inhibitors that may cross the blood-brain barrier could be the answer to these cases.
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PMID:Esophageal Gastrointestinal Stromal Tumor with Rare Intracranial Metastasis. 3310 38