Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) is commonly associated with the A3243G mitochondrial DNA (mtDNA) mutation encoding the transfer RNA of leucine (UUR) (tRNA (Leu(UUR))). The pathogenetic mechanisms of this mutation are not completely understood. Neuronal functions are particularly vulnerable to alterations in oxidative phosphorylation, which may affect the function of the neurotransmitter glutamate, leading to excitotoxicity. In order to investigate the possible effects of A3243G upon glutamate homeostasis, we assessed glutamate uptake in osteosarcoma-derived cytoplasmic hybrids (cybrids) expressing high levels of this mutation. High-affinity Na(+)-dependent glutamate uptake was assessed as radioactive [(3)H]-glutamate influx mediated by specific excitatory amino acid transporters (EAATs). The maximal rate (V(max)) of Na(+)-dependent glutamate uptake was significantly reduced in all the mutant clones. Although the defect did not relate to either the mutant load or magnitude of oxidative phosphorylation defect, we found an inverse relationship between A3243G mutation load and mitochondrial ATP synthesis, without any evidence of increased cellular or mitochondrial free radical production in these A3243G clones. These data suggest that a defect of glutamate transport in MELAS neurons may be due to decreased energy production and might be involved in mediating the pathogenic effects of the A3243G mtDNA mutation.
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PMID:MELAS mitochondrial DNA mutation A3243G reduces glutamate transport in cybrids cell lines. 1845 61

Posterior reversible encephalopathy syndrome (PRES) is a clinico-neuroradiologic disease entity represented by characteristic magnetic resonance image (MRI) findings of subcortical/cortical hyperintensity in T2-weighted sequences, more often observed in parieto-occipital lobes, accompanied by clinical neurologic alterations. PRES is a rare central nervous system complication in childhood hematologic-oncologic patients and shows very different neurologic symptoms between patients, from numbness on extremities to generalized seizure. The etiology of PRES was not well known until these days. In this study, 8 patients with PRES were reviewed, retrospectively. There were 4 patients with acute lymphocytic leukemia, 1 with aplastic anemia, and 3 with solid tumors (1 patient each for neuroblastoma, Ewing sarcoma, and osteosarcoma). Allogeneic stem cell transplantation was performed in 2 patients. Immunosuppressive agents such as tacrolimus and cyclosporine A were used in 3 patients. One neuroblastoma patient was in immediate postoperative status. All patients experienced seizure attacks of different types and showed typical MRI findings. Follow-up MRIs revealed significant improvements. From this review, we might consider chemotherapy and surgery as additive causes for PRES other than immunosuppressive agents. Therefore, careful examination of the patients receiving chemotherapy and surgery was needed to find out this uncommon but good prognostic complication.
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PMID:Posterior reversible encephalopathy syndrome in childhood with hematologic/oncologic diseases. 1956 46

Methotrexate, administered for treatment of pediatric and adult malignancies, is a direct renal toxin, which can lead to renal dysfunction, decreased methotrexate clearance, elevated methotrexate concentrations, and systemic toxicity. Although plasma methotrexate concentrations have been shown to decline precipitously after a single dose of glucarpidase, this drug is investigational and available only through compassionate use. Therefore, alternative treatments for methotrexate removal may be required. We describe a 13-year-old girl (body surface area 1.2 m(2)) with osteosarcoma who was treated with high-dose methotrexate 12 g/m(2) infused over 4 hours. Forty-eight hours after the infusion, her plasma methotrexate concentrations were elevated at 446 micromol/L. She exhibited severe signs of methotrexate toxicity, including encephalopathy, liver failure, and acute kidney injury, and could not tolerate conventional hemodialysis. Over the next 12 days, the patient was treated with continuous venovenous hemodialysis (CVVHD), single-pass albumin dialysis (SPAD), continuous venovenous hemodiafiltration (CVVHDF), and glucarpidase to enhance methotrexate elimination. Compared with standard CVVHD, SPAD did not significantly increase methotrexate removal as measured by elimination half-life and methotrexate saturation coefficient. The highest clearance rate among extracorporeal therapies was achieved by CVVHDF, with an effluent rate of 4950 ml/hour. The patient's clinical condition steadily improved, and all extracorporeal therapies were stopped 168 hours after methotrexate administration. The patient was discharged home and continued with chemotherapy, including methotrexate, which was dosed based on iothalamate glomerular filtration rates on the day before infusion. Although extracorporeal treatments appeared to enhance methotrexate clearance, the administration of glucarpidase resulted in the most rapid percentage decline (86%) in methotrexate concentration. Until glucarpidase is readily available, intermittent hemodialysis should be used to enhance methotrexate clearance. If the patient is unable to tolerate hemodialysis, use of CVVHDF with maximum effluent rates will enhance methotrexate clearance.
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PMID:Treatment of methotrexate intoxication with various modalities of continuous extracorporeal therapy and glucarpidase. 2003 Apr 80

Pyruvate treatment was found to alleviate clinical symptoms of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome and is highly promising therapeutic. Using capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS), we measured time-changes of 161 intracellular and 85 medium metabolites to elucidate metabolic effects of pyruvate treatment on cybrid human 143B osteosarcoma cells harboring normal (2SA) and MELAS mutant (2SD) mitochondria. The results demonstrated dramatic and sustainable effects of pyruvate administration on the energy metabolism of 2SD cells, corroborating pyruvate as a metabolically rational treatment regimen for improving symptoms associated with MELAS and possibly other mitochondrial diseases.
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PMID:Metabolomic profiling rationalized pyruvate efficacy in cybrid cells harboring MELAS mitochondrial DNA mutations. 2288 39

Nitric oxide (NO) is a free radical and a signaling molecule in several pathways, produced by nitric oxide synthase (NOS) from the conversion of L-arginine to citrulline. Supplementation of L-arginine has been used to treat MELAS (mitochondrial encephalopathy with lactic acidosis and stroke like syndrome), a mitochondrial disease caused by the m.3243A>G mutation. Low levels of serum arginine and endothelium dysfunction have been reported in MELAS and this treatment may increase NO in endothelial cells and promote vasodilation, decreasing cerebral ischemia and strokes. Although clinical benefits have been reported, little is known about NO synthesis in MELAS. In this study we found that osteosarcoma derived cybrid cells with high levels of m.3243A>G had increased nitrite, an NO metabolite, and increased intracellular NO, demonstrated by an NO fluorescent probe (DAF-FM). Muscle vessels from patients with the same mutation had increased staining in NADPH diaphorase, suggestive of increased NOS. These results indicate increased production of NO in cells harboring the m.3243A>G, however no nitrated protein was detected by Western blotting. Further studies are necessary to clarify the exact mechanisms of L-arginine effect to determine the appropriate clinical use of this drug therapy.
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PMID:Nitric oxide synthesis is increased in cybrid cells with m.3243A>G mutation. 2326 69

Ifosfamide and methotrexate are widely used for the treatment of pediatric osteosarcoma. However, both these chemotherapeutic drugs can cause encephalopathy. A 17-year-old girl presented with profound hearing loss and dizziness during a postoperative course of ifosfamide, 20 days after a course of methotrexate. Cerebral magnetic resonance imaging (MRI) showed bilateral white matter hypersignal in Fluid Attenuated Inversion Recovery sequences. The clinical evolution was rapidly favorable after methylene blue infusion. This is the second reported case of acute deafness, possibly associated with ifosfamide, whereas MRI data revealed unnoticed chronic methotrexate toxicity. Systematic MRI screening and hearing evaluation may be useful in such cases.
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PMID:Hearing loss during osteosarcoma chemotherapy: when acute ifosfamide toxicity revealed unnoticed methotrexate encephalopathy. 2430

Osteosarcoma is the most frequent primary cancer of the bones, and a combination of primary chemotherapy, surgery, and adjuvant chemotherapy is its current treatment. In adults, some authors have reported problems with memory and concentration following chemotherapy, but in children, severe neurologic dysfunction has been rarely reported. This report describes a 13-year-old patient with primary high-grade nonmetastatic osteosarcoma of the tibia who developed encephalopathy with super-refractory status epilepticus related to chemotherapy. He received methotrexate (MTX) and cisplatin (CDDP)-containing polychemotherapy, and after the first course of drug administration, he developed fever, confusion, a state of psychomotor agitation, and super-refractory status epilepticus with normal laboratory and imaging findings. The causal relationship between the administration of the first polychemotherapy course and his neurological manifestations may be supported by the evaluation and exclusion of other causes. The administration of antiepileptic drugs and off-label atypical antipsychotics was necessary to treat his neurological complications and behavioral changes. This patient represents the first known example of super-refractory status epilepticus in a child treated with MTX and CDDP-containing chemotherapy. Physicians should be aware that encephalopathy and seizures are possible consequences of CDDP therapy when administered alone or in combination with other chemotherapeutic agents. Further studies are needed to better define this relationship in children.
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PMID:Chemotherapy-Related Encephalopathy With Super-Refractory Status Epilepticus in a Child With Osteosarcoma: A Case Report With a Review of Literature. 3155 75


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