RESUMO
A previously healthy 27-year-old man was admitted to the acute neurology ward with events involving his face, throat and upper limb, which video telemetry later confirmed were refractory focal seizures. He also had progressive pyramidal features, dysarthria and ataxia. MR scans of the brain identified progressive bilateral basal ganglia abnormalities, consistent with Leigh syndrome. However, extensive laboratory and genetic panels did not give a unifying diagnosis. A skeletal muscle biopsy showed no histopathological abnormalities on routine stains. Sequencing of the entire mitochondrial genome in skeletal muscle identified a well-characterised pathogenic variant (m.10191T>C in MT-ND3; NC_012920.1) at 85% heteroplasmy in skeletal muscle. We discuss the clinical and molecular diagnosis of an adult presenting with Leigh syndrome, which is more commonly a paediatric presentation of mitochondrial disease, and how early recognition of a mitochondrial cause is important to support patient care.
Assuntos
Doença de Leigh , Masculino , Adulto , Humanos , Criança , Doença de Leigh/genética , Mutação , Encéfalo/patologia , Músculo Esquelético/patologia , AtaxiaRESUMO
Supplementary motor area (SMA) syndrome is characterised by transient disturbance in volitional movement and speech production which classically occurs after injury to the medial premotor area. We present two cases of SMA syndrome following isolated surgical injury to the frontal aslant tract (FAT) with the SMA intact. The first case occurred after resection of a left frontal operculum tumour. The second case occurred after a transcortical approach to a ventricular neurocytoma. The clinical picture and fMRI activation patterns during recovery were typical for SMA syndrome and support the theory that the FAT is a critical bundle in the SMA complex function.
Assuntos
Córtex Motor , Humanos , Córtex Motor/diagnóstico por imagem , Córtex Motor/cirurgia , Imagem de Tensor de Difusão , Imageamento por Ressonância Magnética , Fala/fisiologiaRESUMO
Indirect effects may contribute to the efficacy of radiotherapy by sterilizing malignant cells that are not directly irradiated. However, little is known of the influence of indirect effects in targeted radionuclide treatment. We compared gamma-radiation-induced bystander effects with those resulting from exposure to three radiohaloanalogues of meta-iodoben-zylguanidine (MIBG): [(131)I]MIBG (low linear energy transfer (LET) alpha-emitter), [(123)I]MIBG (high LET Auger electron emitter), and meta-[(211)At]astatobenzylguanidine ([(211)At]MABG) (high LET alpha-emitter). Cells exposed to media from gamma-irradiated cells exhibited a dose-dependent reduction in survival fraction at low dosage and a plateau in cell kill at > 2 Gy. Cells treated with media from [(131)I]MIBG demonstrated a dose-response relationship with respect to clonogenic cell death and no annihilation of this effect at high radiopharmaceutical dosage. In contrast, cells receiving media from cultures treated with [(211)At]MABG or [(123)I]MIBG exhibited dose-dependent toxicity at low dose but elimination of cytotoxicity with increasing radiation dose (i.e. U-shaped survival curves). Therefore radionuclides emitting high LET radiation may elicit toxic or protective effects on neighboring untargeted cells at low and high dose respectively. We conclude that radiopharmaceutical-induced bystander effects may depend on LET and be distinct from those elicited by conventional radiotherapy.
RESUMO
UNLABELLED: Recent studies have shown that indirect effects of ionizing radiation may contribute significantly to the effectiveness of radiotherapy by sterilizing malignant cells that are not directly hit by the radiation. However, there have been few investigations of the importance of indirect effects in targeted radionuclide treatment. Our purpose was to compare the induction of bystander effects by external beam gamma-radiation with those resultant from exposure to 3 radiohaloanalogs of metaiodobenzylguanidine (MIBG): (131)I-MIBG (low-linear-energy-transfer [LET] beta-emitter), (123)I-MIBG (potentially high-LET Auger electron emitter), and meta-(211)At-astatobenzylguanidine ((211)At-MABG) (high-LET alpha-emitter). METHODS: Two human tumor cell lines-UVW (glioma) and EJ138 (transitional cell carcinoma of bladder)-were transfected with the noradrenaline transporter (NAT) gene to enable active uptake of MIBG. Medium from cells that accumulated the radiopharmaceuticals or were treated with external beam radiation was transferred to cells that had not been exposed to radioactivity, and clonogenic survival was determined in donor and recipient cultures. RESULTS: Over the dose range 0-9 Gy of external beam radiation of donor cells, 2 Gy caused 30%-40% clonogenic cell kill in recipient cultures. This potency was maintained but not increased by higher dosage. In contrast, no corresponding saturation of bystander cell kill was observed after treatment with a range of activity concentrations of (131)I-MIBG, which resulted in up to 97% death of donor cells. Cellular uptake of (123)I-MIBG and (211)At-MABG induced increasing recipient cell kill up to levels that resulted in direct kill of 35%-70% of clonogens. Thereafter, the administration of higher activity concentrations of these high-LET emitters was inversely related to the kill of recipient cells. Over the range of activity concentrations examined, neither direct nor indirect kill was observed in cultures of cells not expressing the NAT and, thus, incapable of active uptake of MIBG. CONCLUSION: Potent toxins are generated specifically by cells that concentrate radiohalogenated MIBG. These may be LET dependent and distinct from those elicited by conventional radiotherapy.
Assuntos
Efeito Espectador/efeitos da radiação , Sobrevivência Celular/efeitos da radiação , Glioma/patologia , Glioma/radioterapia , Radioterapia/métodos , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/radioterapia , Linhagem Celular Tumoral , Relação Dose-Resposta à Radiação , Elétrons/uso terapêutico , Raios gama/uso terapêutico , Humanos , Doses de Radiação , Radioisótopos/uso terapêutico , Compostos Radiofarmacêuticos/uso terapêuticoRESUMO
The goal of targeted radionuclide therapy is the deposition in malignant cells of sterilizing doses of radiation without damaging normal tissue. The radiopharmaceutical [(131)I]meta-iodobenzylguanidine ([(131)I]MIBG) is an effective single agent for the treatment of neuroblastoma. However, uptake of the drug in malignant sites is insufficient to cure disease. A growing body of experimental evidence indicates exciting possibilities for the integration of gene transfer with [(131)I]MIBG-targeted radiotherapy.
Assuntos
3-Iodobenzilguanidina/uso terapêutico , Marcação de Genes/métodos , Terapia Genética/métodos , Neuroblastoma/genética , Neuroblastoma/radioterapia , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Radioterapia/métodos , Animais , Sistemas de Liberação de Medicamentos/métodos , Humanos , Compostos Radiofarmacêuticos/uso terapêuticoRESUMO
OBJECTIVES: A targeted radiotherapy/gene therapy strategy for transitional cell carcinoma of bladder is described, using [131I]meta-iodobenzylguanidine ([131I]MIBG), a radionuclide combined with a tumour-seeking drug. The aim is to decrease side effects from radiation toxicity, while increasing radiation dose to tumour. This tumour cell kill approach is augmented by radiological bystander effects. METHODS: The bladder cancer cell line EJ138 was transfected with a gene encoding the noradrenaline transporter (NAT) under the control of tumour-specific telomerase promoters. Resulting uptake of [131I]MIBG was assessed by gamma-counting of cell lysates, and NAT transgene expression by real-time RT-PCR. Cell kill of monolayers and disaggregated spheroids, dosed with [131I]MIBG, was assessed by clonogenic assay. RESULTS: NAT gene transfected cells exhibited a significantly increased active uptake of [131I]MIBG, leading to dose-dependent cell kill. Clonogenic assay of disaggregated spheroids, a three-dimensional model, suggested cell kill via bystander effects. CONCLUSIONS: Expression of a functional NAT after in vitro transfection of bladder cancer cells with the NAT gene under the control of telomerase promoters leads to active uptake of [131I]MIBG and dose-dependent cell kill. This strategy could produce a promising new treatment option for bladder cancer.
Assuntos
Carcinoma de Células de Transição/terapia , Terapia Genética/métodos , Radioterapia/métodos , Neoplasias da Bexiga Urinária/terapia , 3-Iodobenzilguanidina/uso terapêutico , Linhagem Celular Tumoral , Humanos , Radioisótopos do Iodo/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de Norepinefrina , Simportadores/genética , Telomerase/genéticaRESUMO
Targeted radiotherapy using radiolabelled meta-iodobenzylguanidine (MIBG) is a promising treatment option for bladder cancer, restricting the effects of radiotherapy to malignant cells thereby increasing efficacy and decreasing morbidity of radiotherapy. We investigated the efficacy of a combined gene therapy and targeted radiotherapy approach for bladder cancer using radiolabelled MIBG. The effectiveness of alternative radiohalogens and alternative preparations of radiolabelled MIBG for this therapeutic strategy were compared. Bladder cancer cells, EJ138, were transfected with a gene encoding the noradrenaline transporter (NAT) under the control of a tumour specific telomerase promoter, enabling them to actively take up radiolabelled MIBG. This resulted in tumour-specific cell kill. Uptake and retention of radioactivity in cells transfected with the NAT gene were compared with that obtained in cells transfected with the sodium iodide symporter (NIS) gene. Substantially greater uptake and longer retention of radioactivity in NAT-transfected cells was observed. Carrier-added (c.a.) [131I]MIBG, no-carrier added (n.c.a.) [131I]MIBG, and [211At]-labelled benzylguanidine (i.e. [211At] meta-astatobenzylguanidine (MABG)) were compared with respect to efficiency of induction of cell kill. N.c.a[(131)I]MIBG was more cytotoxic than c.a.[131I]MIBG. However, the alpha-emitter [211At]MABG was, by three orders of magnitude, more effective in causing tumour cell kill than the beta-emitter [131I]MIBG. We conclude that NAT gene transfer combined with the administration of n.c.a.[131I]MIBG or [211At]MABG, is a promising novel treatment approach for bladder cancer therapy.