Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011168 (dysphagia)
 15,644 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A family with multiple gastrointestinal stromal tumors (GISTs), a new type of germline mutation of KIT gene, and dysphagia is reported. The mutation was observed at Asp-820 in tyrosine kinase (TK) II domain. Mutations in TK II domain have been found in mast cell and germ cell tumors but not in GISTs, and the present family members are the first reported cases of GISTs with TK II domain mutations, including sporadic GISTs. Because interleukin 3-dependent Ba/F3 murine lymphoid cells transfected with the mutant KIT complementary DNA grew autonomously without any growth factors and formed tumors in nude mice, the mutation was considered to be gain-of-function type. Family members with the germline KIT mutation reported dysphagia, but those without the mutation did not. The mechanism of dysphagia was examined with gastrointestinal fiberscopy, endoscopic ultrasonography, and esophageal manometry. No mechanical obstruction was found, and the esophagus was not remarkably dilated. In the family members with dysphagia, endoscopic ultrasonography at the esophagocardiac junction showed a thickened hyperechoic layer between the circular and longitudinal muscle layers, suggesting hyperplasia of interstitial cells of Cajal at the myenteric plexus layer. Manometry showed low resting lower esophageal sphincter pressure and abnormal simultaneous contractions of the esophagus without normal peristalsis. These findings indicate that the dysphagia of the present family is different from typical achalasia. This is the first report of familial dysphagia caused by germline gain-of-function mutation of the KIT gene at the TK II domain.
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PMID:Familial gastrointestinal stromal tumors associated with dysphagia and novel type germline mutation of KIT gene. 1198 33

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

A-58-year old man presented with fluctuating ptosis and dysphagia. When he was 53 years old, he developed oral candidiasis and serum human immunodeficiency virus (HIV) RNA was detected. After starting highly active antiretroviral therapy, serum HIV RNA became undetectable. Neurological examination revealed ptosis and bulbar symptoms. Myasthenia gravis was comfirmed by a positive edrophonium test, showing 20% decrement of the compound muscle action potential on repetitive stimulation. Anti-acetylcholine receptor antibodies were negative and anti-muscle specific tyrosine kinase (MuSK) antibodies were positive. The chest CT scan was normal. He experienced transient clinical remission with pyridostigmine bromide and prednisolone. However relapse occurred after he returned to work. Persistent clinical remission was first observed after cyclosporin administration. There are eleven reports in which patients had concomitant myasthenia gravis and HIV infection. Most of those cases were benign in clinical course and required only anticholinesterase therapy. In our case, however, anti-MuSK antibodies were positive, and symptoms of myasthenia gravis remained despite prednisolone administration. Cyclosporin is directly active against HIV, and thus, cyclosporine therapy may be helpful in patients with concomitant myasthenia gravis and HIV infection.
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PMID:[Anti-MuSK antibody positive myasthenia gravis with HIV infection successfully treated with cyclosporin: a case report]. 1904 51

The use of cyclophosphamide and rituximab for patients with refractory myasthenia gravis has shown promising results. We report on a 31-year-old Chinese woman with acetylcholine receptor antibody-negative and muscle-specific tyrosine kinase antibody-positive generalised myasthenia gravis who had refractory bulbar dysfunction and respiratory failure despite immunosuppressive therapy and thymectomy, and partial and sustained responses to cyclophosphamide and rituximab treatment, respectively. Myasthenia crisis was diagnosed when she presented in the third trimester of pregnancy with dysphagia, bilateral ptosis, prominent fatigability, and respiratory failure. She required prolonged intensive care and non-invasive ventilatory support despite several courses of intravenous immunoglobulins and plasmapheresis. Pulse cyclophosphamide 500 mg/m(2) was given monthly for 4 consecutive months with a partial response. Rituximab 500 mg weekly was subsequently given for 4 weeks with a dramatic and sustained response. She remained symptom-free and assumed full maternal care at 1 year. To the authors' knowledge, this is the first report of a Chinese patient with refractory myasthenia gravis who responded to cyclophosphamide and rituximab.
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PMID:Refractory bulbar and respiratory dysfunction in a young Chinese woman with seronegative, muscle-specific tyrosine kinase antibody-positive myasthenia gravis: response to cyclophosphamide and rituximab treatment. 2128 32

Nilotinib, a potent orally bioavailable BCR-ABL tyrosine kinase inhibitor, is currently available as a hard gelatin capsule that must be swallowed whole. For patients who may have difficulty swallowing the intact capsule, an alternative mode of administration is desirable. The authors compared the bioavailability of nilotinib from the following administrations in 48 healthy subjects: (1) 400 mg nilotinib given as two 200-mg nilotinib intact capsules; (2) contents of two 200-mg nilotinib capsules, each capsule dispersed in 1 teaspoon of nonfat plain yogurt; and (3) contents of two 200-mg nilotinib capsules, each capsule dispersed in 1 teaspoon of applesauce. Nilotinib absorption was modestly increased following the administration of nilotinib dispersed in yogurt. The geometric mean ratios (90% confidence intervals) for nilotinib C(max), AUC(0-tlast), and AUC(0-inf) were 1.31 (1.22-1.41), 1.11 (1.05-1.16), and 1.08 (1.02-1.15), respectively. Administration of nilotinib dispersed in applesauce showed equivalent bioavailability compared with administration of nilotinib as intact capsules. The geometric mean ratios (90% confidence intervals) for nilotinib C(max), AUC(0-tlast), and AUC(0-inf) were 0.95 (0.88-1.02), 0.99 (0.94-1.04), and 0.97 (0.90-1.03), respectively. Each treatment was well tolerated in the study subjects. The data support a feasible alternative method of nilotinib administration; each capsule's contents may be dispersed in 1 teaspoon of applesauce and taken immediately.
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PMID:Effects of yogurt and applesauce on the oral bioavailability of nilotinib in healthy volunteers. 2171 97

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors in the digestive tract. In up to 90% of cases, they are characterized by activating mutations in the KIT or the PDGFRA gene. GIST represent a paradigm for successful targeted treatment with tyrosine kinase inhibitors (TKI). Since the approval of the TKI imatinib in 2002 the survival of patients with metastatic GIST has tripled. The next logical step was the concept of using imatinib in an adjuvant approach, which was recently shown to increase overall survival significantly. In both settings, the mutational status has high predictive implications. In detail, GIST with KIT exon 11 mutations show the best response rates with partial remission rates of up to 80%. In KIT exon 9 mutations, a doubled daily dose of 800 mg imatinib is now standard. The PDGFRA exon 18 mutation D842V has been shown to lead to primary resistance. The treatment strategy in GIST is driven by their molecular characterisation. Further research has increased our knowledge on resistance mechanisms in solid tumors against TKI. The number of patients with secondary resistance due to acquired KIT mutations is increasing with treatment duration. Strategies to address this situation are the introduction of novel pathway inhibitors targeting different levels of signal transduction pathways, such as the mTOR/Akt pathway, the RAS/RAF pathway, histone deacetylation, among others. Among the GIST without mutations in the common hot spot regions of KIT and PDGFRA, the so-called wildtype GIST, further genomic subgroups have been identified. One such subgroup carries inactivating germline mutations in the genes encoding succinate dehydrogenase B, C, or D. They are associated with the occurrence of paragangliomas, so-called Carney-Stratakis syndrome. Most frequently, these GIST are located in the stomach, showing an epithelioid phenotype and a multinodular growth pattern. They preferentially occur in young females and often show lymph node metastases, the latter being very unusual in sporadic GIST. In sporadic Carney's triad additional pulmonary chondromas are observed and there are no SDH mutations. Another small subgroup of sporadic GIST present with BRAF mutations as an alternative genomic event. Finally, very rare kindreds with germline mutations in either KIT or PDGFRA have been described who develop multiple GIST and depending on the mutational subtype mastocytosis, hyperpigmentation and/or dysphagia. In summary, the molecular characterisation of GIST has revolutionized their treatment due to increasing knowledge about the high relevance of predictive molecular typing in solid tumors.
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PMID:[Translational research and diagnosis in GIST]. 2296 35

A 69-year-old Japanese female was admitted because of progressive nasal voice and dysphagia. Neurological examination revealed paresis of the soft palate with marked dysphagia and rhinolalia. Otherwise there was no weakness or easy fatigability in extraocular muscles and extremities. On laboratory test, anti-acetylcholine receptor antibody (anti-AChR Ab) was positive, while anti-muscle-specific tyrosine kinase antibody (anti-MuSK Ab) was negative. Edrophonium test was positive, resulting in clear improvement in phonation and swallowing. Harvey-Masland test of ocular and extremity muscles did not show any waning. With the diagnosis of bulbar myasthenia gravis, the patient was treated with methylprednisolone and pyridostigmine, resulting in clear improvement of the symptoms. The present case shows that it is important to consider MG even in cases presenting solely with progressive bulbar palsy without easy fatigability. So far, cases of bulbar myasthenia gravis with positive anti-MuSK Ab have often been reported. As shown in the present case, bulbar myasthenia gravis can also be associated with positive anti-ACh-R Ab but negative anti-MuSK Ab.
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PMID:[A case of myasthenia gravis presenting solely with bulbar palsy unassociated with easy fatigability]. 2352 4

A 72-year-old woman with dysphagia was diagnosed with lung adenocarcinoma and metastatic meningeal tumour that impaired the medulla. Owing to a bulky tumour beside the medulla, radiosurgical control of the meningeal tumour was achieved before systemic therapy. Genomic examination of the tumour revealed an existing epidermal growth factor receptor (EGFR) exon 19 deletion, for which an EGFR tyrosine kinase inhibitor such as gefitinib was the standard therapy. However, because of dysphagia, the patient was unable to orally ingest gefitinib. Gefitinib was delivered via gastrostomy tube as a suspension after spontaneous dissolution in hot water. One month later, the patient's symptoms, including dysphagia, were drastically improved and she had recovered sufficiently to orally ingest gefitinib. Gefitinib-associated toxicity comprises only mild liver dysfunction and skin rash. CT scanning and MRI detected drastic shrinkage of the primary lung and meningeal tumours. The patient continued to take gefitinib and has remained symptom-free for 9 months.
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PMID:Successful gefitinib treatment administration via gastrostomy tube in a patient with non-small cell lung cancer with dysphagia. 2462 82

Mucoepidermoid carcinoma of the lung is exceedingly rare. Our case involves a 58-year-old male who presented with shortness of breath, dysphagia, and weight loss. He denied ever smoking. Chest x-ray revealed trapped lung, and CT demonstrated a right bronchial mass. Diagnosis of lung carcinoma was made by bronchoscopic FNA biopsy. EGFR mutation was negative. Staging workup demonstrated evidence of advanced disease. Performance status was good, and it was decided to start chemotherapy and radiation for palliation. Lung carcinomas often present as an obstructing hilar mass. There are different histological grades that affect progression and survival. Though uncommon, metastatic spread has been previously reported. Studies have investigated the possible role of tyrosine kinase inhibitors in both EGFR-mutated and non-mutated cases. Unfortunately, there has been little consensus as to which therapies are most beneficial.
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PMID:A rare case of lung carcinoma with mucoepidermoid histopathology: a case report and review of the literature. 2588 80

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


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