RESUMO
Multiple sclerosis (MS) is a demyelinating disorder in which the myelin sheath covering the central nervous system axons is damaged or lost, disrupting action potential conduction and leading to various neurological complications. The pathogenesis of MS remains unclear, and no effective therapies are currently available. MS is triggered by environmental factors in genetically susceptible individuals. DNA damage and DNA repair failure have been proposed as MS genetic risk factors; however, inconsistent evidence has been found in multiple studies. Therefore, more investigations are needed to ascertain whether DNA damage/repair is altered in this disorder. In this context, therapies that prevent DNA damage or enhance DNA repair could be effective strategies for MS treatment. The overactivation of the extracellular-signal-related kinase 1 and 2 (Erk1/2) pathway can lead to DNA damage and has been linked to MS pathogenesis. In our study, we observed substantially elevated oxidative DNA damage and slower DNA repair rates in an experimentally autoimmune encephalomyelitis animal model of MS (EAE). Moreover, statistical decreases in oxidative DNA strand breaks and faster repair rates were observed in EAE animals injected with the Erk1/2 inhibitor PD98059 (PD). Moreover, the expression of several genes associated with DNA strand breaks and repair changed in EAE mice at both the mRNA and protein levels, as revealed by the RT2 Profiler PCR array and verified by RT-PCR and protein analyses. The treatment with PD mitigated these changes and improved DNA repair gene expression. Our results demonstrate clear associations between Erk1/2 activation, DNA damage/repair, and MS pathology, and further suggest that PD therapy may be a promising adjuvant therapeutic strategy.
Assuntos
Antineoplásicos , Encefalomielite Autoimune Experimental , Esclerose Múltipla , Camundongos , Animais , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/genética , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/genética , Camundongos Endogâmicos , Antineoplásicos/uso terapêutico , Transdução de Sinais , Reparo do DNA , DNA , Camundongos Endogâmicos C57BLRESUMO
Information regarding DNA repair in autism is limited to a few studies, which have reported inconsistent results. Therefore, we designed a study to determine whether DNA repair efficiency is altered in autism and to investigate whether the H4 ligand JNJ7777120 can enhance DNA repair efficiency in BTBR T+tf/J (BTBR) mice; we also attempted to elucidate the mechanism(s) underlying this amelioration. Evaluation of DNA damage using the comet assay on bone marrow cells showed increased levels of DNA damage in BTBR mice compared with age-matched control C57BL/6J mice. Conversely, BTBR animals pretreated with 20â¯mg/kg JNJ7777120 for five days exhibited significant decreases in DNA damage compared with that of control BTBR mice. Our results also indicated higher sensitivity of BTBR mice exposed to gamma rays to DNA damage generation. A marked difference was observed between BTBR and C57BL/6J mice at different sampling times after irradiation, with BTBR mice showing a higher percentage of DNA damage and slower repair rate than that of C57BL/6J mice. JNJ7777120 led to enhanced repair of the DNA damage induced by radiation when administered to BTBR mice five days prior to radiation. Additionally, oxidative stress in BTBR mice was significantly elevated with a reduced GSH/GSSG ratio; significant amelioration was subsequently observed in JNJ7777120-pretreated BTBR mice. Furthermore, repetitive behaviors were also attenuated in BTBR mice by JNJ7777120 treatment without altering locomotor activity. Our results suggest that JNJ7777120 can be developed for use as a therapeutic agent to enhance DNA repair efficiency in autism spectrum disorder.
Assuntos
Transtorno do Espectro Autista/genética , Reparo do DNA , Indóis/farmacologia , Piperazinas/farmacologia , Animais , Transtorno do Espectro Autista/metabolismo , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/efeitos da radiação , Modelos Animais de Doenças , Raios gama , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiaçãoRESUMO
Histone deacetylases (HDACs), which regulate transcription and specific functions such as tumor suppression by p53, are frequently altered in tumors and have a contentious role in carcinogenesis. HDAC inhibitors, which have a long history of use in psychiatry and neurology, have recently been tested as possible treatments for tumors. Belinostat received regulatory approval in the USA on July 3, 2014, for use against peripheral T-cell lymphoma. However, the unavailability of information on belinostat genotoxicity in normal cells and the molecular mechanisms involved in the genetic instability after exposure to belinostat encouraged us to conduct this study. Our data showed that the exposure of mice to belinostat at the recommended human doses induced chromosome breakage, whole-chromosome lagging, and oxidative DNA damage in bone marrow cells in a dose-dependent manner. The expression levels of 84 genes involved in the DNA damage signaling pathway were evaluated by using an RT2 Profiler PCR array. Belinostat exposure altered the expression of 25 genes, with statistically significant changes observed in 17 genes. The array results were supported by RT-PCR and western blotting experiments. Collectively, our results showed that belinostat exposure caused oxidative DNA damage and downregulated the expression of genes involved in DNA damage repair, which may be responsible for belinostat-induced genomic instability. Thus, the clinical usage of this drug should be weighed against the hazards of carcinogenesis, and the observed genotoxicity profile of belinostat may support further development of efficient HDAC inhibitors with weaker genotoxicity.
Assuntos
Análise Citogenética/métodos , Perfilação da Expressão Gênica/métodos , Instabilidade Genômica/efeitos dos fármacos , Inibidores de Histona Desacetilases/toxicidade , Ácidos Hidroxâmicos/toxicidade , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/toxicidade , Animais , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/genética , Relação Dose-Resposta a Droga , Instabilidade Genômica/fisiologia , Masculino , Camundongos , Transdução de Sinais/fisiologiaRESUMO
PURPOSE: Despite dexrazoxane's increasing use in mitigating doxorubicin-induced cardiotoxicity, no data are available in the literature on the potential aneugenicity of drug combination. Therefore, detailed evaluation of aneugenic potential of this combination is essential to provide more insights into aneuploidy induction that may play a role in the development of secondary malignancies and reproductive toxicity after treatment with doxorubicin. Thus, our aim was to determine whether dexrazoxane has influence on the aneuploidy induced by doxorubicin in germinal and somatic cells of male mice. METHODS: Sperm BrdU-incorporation assay, sperm FISH assay and the bone marrow micronucleus test complemented by FISH assay were used to determine aneuoploidy. Moreover, the formation of 8-OHdG, one of the oxidative DNA damage by-products, has been evaluated. RESULTS: Dexrazoxane was not aneugenic at the doses tested. Pre-treatment of mice with dexrazoxane significantly reduced doxorubicin-induced aneuploidy in a dose-dependent manner. Doxorubicin induced marked biochemical alterations characteristic of oxidative DNA damage, and prior administration of dexrazoxane before doxorubicin challenge ameliorated this biochemical marker. CONCLUSION: This study provides evidence that dexrazoxane has a protective role in the abatement of doxorubicin-induced aneuploidy. This activity resides, at least in part, in its radical scavenger activity. Thus, dexrazoxane can avert secondary malignancies and abnormal reproductive outcomes in cured cancer patients exposed to doxorubicin.
Assuntos
Aneuploidia , Dexrazoxano/farmacologia , Doxorrubicina/toxicidade , Espermatozoides/citologia , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/toxicidade , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Dexrazoxano/administração & dosagem , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Hibridização in Situ Fluorescente/métodos , Masculino , Camundongos , Testes para Micronúcleos , Espermatozoides/efeitos dos fármacosRESUMO
The ability of the anticancer drug, nocodazole, to induce dominant lethal mutations in male germ cells was investigated by the in vivo dominant lethal test. Mice were treated with single doses of 15, 30 and 60 mg/kg nocodazole. These males were mated at weekly intervals to virgin females for 6 weeks. Nocodazole clearly induced dominant lethal mutations in the early spermatid stage with the highest tested dose. Mice treated with 60 mg/kg nocodazole showed an additional peak of dominant lethal induction in mature spermatozoa during the first week matings after treatment. The percentage sperm count and sperm motility were significantly decreased after treatment of males with 30 and 60 mg/kg nocodazole. Moreover, the middle and highest doses of nocodazole significantly increased the percentage of abnormal sperm. Our study provides evidence that nocodazole is a germ cell mutagen. Marked alteration in the spermiogram analysis after nocodazole treatment possibly confirms that nocodazole has a significant effect on sperm maturation and development during storage and transit. The demonstrated mutagenicity profile of nocodazole may support further development of effective chemotherapy with less mutagenicity. Moreover, the cancer patients and medical personnel exposed to this drug chemotherapy may stand a higher risk for abnormal reproductive outcomes.
Assuntos
Antineoplásicos/efeitos adversos , Mutação , Nocodazol/efeitos adversos , Espermatozoides/efeitos dos fármacos , Animais , Antineoplásicos/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Genes Dominantes , Masculino , Camundongos , Testes de Mutagenicidade , Nocodazol/administração & dosagem , Reprodução/efeitos dos fármacos , Contagem de Espermatozoides , Motilidade dos Espermatozoides/efeitos dos fármacosRESUMO
Although chloroacetonitrile (CAN), a disinfection by-product of chlorination of drinking water, is considered a rodent carcinogen that induces lung adenomas in mice, previous studies on its genotoxicity have yielded inconclusive results. Thus, its cancer mode of action has not been clearly defined. We evaluated CAN-induced genotoxicity in mice using mouse bone marrow micronucleus test, comet assays and expression of genes associated with DNA damage repair. Mice exposed to CAN at 8.75, 17.5, 35 and 52.5mg/kg for 7 days did not exhibit any significant increases in the incidence of micronuclei formation at 24 and 48h after last exposure. However, CAN caused significant suppressions of erythroblast proliferation at the highest dose. In the alkaline comet assay, there was a significant increase in the incidence of DNA strand breaks in mice killed after 3h of last treatment with 35 and 52.5mg/kg/day CAN, while no significant difference in the DNA strand breaks was found in mice killed after 24h of the last treatment. However, slight (but significant) CAN-induced oxidative DNA damage was detected following Fpg digestion at 3-h sampling time, digestion with EndoIII resulted in considerable increases in oxidative DNA damage at 3 and 24h after the last exposure to 35 and 52.5mg/kg/day CAN as detected by oxidative comet assays. The expression of DNA repair genes OGG1 , Apex1, PARP1 and p53 were up-regulated in mice given 35mg/kg/day CAN at 3h but not in 24h after the last treatment except OGG1 . However, the significant up-regulation of OGG1 at 24h after the last treatment further indicates the occurrence of oxidative DNA damage. Overall, CAN exposure is associated with up-regulation of DNA repair gene expression and the induction of oxidative DNA damage, which may be at least partially responsible for CAN-induced genotoxicity and eventually cause carcinogenicity.
RESUMO
To investigate the ability of topotecan, a topoisomerase I-targeting anticancer drug, to induce dominant lethal mutations in male mouse germ cells, males were treated with single doses of 3, 6 and 12 mg/kg topotecan. Each male was mated at 4-day intervals to virgin females for a total of nine 4-day mating intervals. The two highest doses of topotecan are shown to be mutagenic in post-meiotic cells. The greatest effect occurred in those cells which were in the early-spermatid stage at the time of exposure. Mice treated with 12 mg/kg topotecan showed an additional peak of dominant lethal induction in mature sperm during the first 4-day matings after treatment. The mutagenic effects were directly correlated with free radicals accumulation as an obvious increase in the generation reactive oxygen species and 8-hydroxydeoxyguanosine was noted in animals treated with 6 and 12 mg/kg topotecan. Treatment of male mice with N-acetylcysteine, a free radical scavenger, significantly protected mice from topotecan-induce dominant lethality. Moreover, N-acetylcysteine had no antagonizing effect on topotecan-induce topoisomerase-I inhibition. Our study provides evidence that topotecan is a germ cell mutagen and its effect is more pronounced during the post-meiotic stages through a mechanism that may involves increases in DNA oxidative stress.
Assuntos
Mutagênicos/toxicidade , Espermatozoides/efeitos dos fármacos , Inibidores da Topoisomerase I/toxicidade , Topotecan/toxicidade , 8-Hidroxi-2'-Desoxiguanosina , Acetilcisteína/farmacologia , Animais , Antineoplásicos/toxicidade , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Relação Dose-Resposta a Droga , Feminino , Sequestradores de Radicais Livres/farmacologia , Masculino , Camundongos , Testes de Mutagenicidade , Gravidez , Espécies Reativas de Oxigênio/metabolismoRESUMO
The intention of the present study was to answer the question whether the catalytic topoisomerase-II inhibitor, dexrazoxane, can be used as a modulator of teniposide-induced DNA damage and programmed cell death (apoptosis) in the bone marrow cells in vivo. The alkaline single cell gel electrophoresis, scoring of chromosomal aberrations, micronuclei and mitotic activity were undertaken in the current study as markers of DNA damage. Apoptosis was analysed by the occurrence of a hypodiploid DNA peak and caspase-3 activity. Oxidative stress marker such as intracellular reactive oxygen species production, lipid peroxidation, reduced and oxidised glutathione were assessed in bone marrow as a possible mechanism underlying this amelioration. Dexrazoxane was neither genotoxic nor apoptogenic in mice at the tested dose. Moreover, for the first time, it has been shown that dexrazoxane affords significant protection against teniposide-induced DNA damage and apoptosis in the bone marrow cells in vivo and effectively suppresses the apoptotic signalling triggered by teniposide. Teniposide induced marked biochemical alterations characteristic of oxidative stress including accumulation of intracellular reactive oxygen species, enhanced lipid peroxidation, accumulation of oxidised glutathione and reduction in the reduced glutathione level. Prior administration of dexrazoxane ahead of teniposide challenge ameliorated these biochemical alterations. It is thus concluded that pretreatment with dexrazoxane attenuates teniposide-induced oxidative stress and subsequent DNA damage and apoptosis in bone marrow cells. Based on our data presented, strategies can be developed to decrease the teniposide-induced DNA damage in normal cells using dexrazoxane. Therefore, dexrazoxane can be a good candidate to decrease the deleterious effects of teniposide in the bone marrow cells of cancer patients treated with teniposide.
Assuntos
Apoptose/efeitos dos fármacos , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Dano ao DNA , Razoxano/farmacologia , Teniposídeo/toxicidade , Animais , Células da Medula Óssea/enzimologia , Caspase 3/metabolismo , Ciclo Celular/efeitos dos fármacos , Cromossomos de Mamíferos/metabolismo , Quebras de DNA/efeitos dos fármacos , Citometria de Fluxo , Glutationa/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Micronúcleos com Defeito Cromossômico/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Diabetes mellitus (DM) is a chronic disease that is characterized by deteriorating glycemic control. The disease is known to be caused by imbalance between reactive oxygen species (ROS) and antioxidant defense systems. Hyperglycemia is commonly observed in a wide variety of diseases, including cancer. Although, therapy against glycemic control, is used in all these diseases, the diabetic cancer patients are on additional therapy with anticancer drugs. The objective of present study was to study if Glucophage (metformin), a very popular antidiabetic agent can avert the mutagenicity and lipid peroxidation caused by adriamycin (ADR), which is a commonly used cytotoxic drug. The experimental protocol included oral treatment of mice with different doses (62.5, 125 and 250 mg/kg day) of metformin for 7 days. Some mice in each group were injected i.p. with ADR (15 mg/kg). In each case animals were killed, 30 or 24, 48 and 72 h after the last treatment and femurs were excised for cytological studies by micronucleus test. Additional experiments on estimation of glutathione (GSH) and malondialdehyde (MDA) were undertaken in blood and serum, respectively. Twenty-four hour after the treatment, blood from each mouse was collected from heart and preserved for analysis. The results obtained revealed that pretreatment with metformin: (i) reduced the ADR-induced frequency of micronuclei without any alteration in its cytotoxicity and (ii) protected against the ADR-induced increase and decrease of MDA and GSH, respectively. The exact mechanism of action is not known, however, the inhibition of ADR-induced clastogenicity and lipid peroxidation by metformin may be attributed to the antioxidant action of the latter. Our results demonstrate that metformin might be useful to avert secondary tumor risk by decreasing the accumulation of free radicals and inhibition of mutagenicity.
Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Doxorrubicina/efeitos adversos , Metformina/farmacologia , Animais , Glutationa/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Camundongos , Testes para MicronúcleosRESUMO
Radioactive iodine (131I) plays a major role in the diagnosis and management of differentiated thyroid cancer (DTC); however, data on the use of the 123I isotope in DTC are limited. We compared 238 diagnostic whole body scans performed 24 h after oral ingestion of 185-555 MBq 123I with their corresponding 131I posttherapy whole body scans obtained 4-5 d after 131I therapy. We studied scans in 3 clinical situations: with the first 131I therapy, with the second 131I therapy, and in cases of elevated Tg and negative diagnostic scan. One hundred and seventy-seven pairs were obtained with the first 131I therapy and showed complete concordance between pretreatment and posttreatment scans in 166 pairs (concordance rate, 93.8%). Six other posttreatment scans showed more foci in the thyroid bed than the pretreatment scans, but no evidence of uptake in new areas. Only 5 posttreatment scans showed foci in new locations: 3 in cervical lymph nodes (CLN), 1 in the lung, and 1 new bone metastasis in a patient with known skeletal metastases. With the second 131I therapy, 34 pairs were obtained and showed complete concordance in 28 pairs (concordance rate, 82.4%). Five discordant pairs showed additional foci in areas that were already positive on pretreatment scans. Only 1 posttreatment scan showed a new bone metastasis in a different site from the bone metastases that were seen on its corresponding pretreatment scan. Of 27 pairs of scans in patients with elevated Tg and negative pretreatment scans, 15 posttreatment scans remained negative, 6 posttreatment scans showed an uptake in the thyroid bed, and 3 other posttreatment scans showed lung uptake in patients whose computed tomography scans of the chest showed only bronchiectasis (in 2 patients) and lung scarring (in the third patient) without evidence of lung metastases. Three posttreatment scans showed definite uptake (in thyroid bed, thyroid bed and lung, and CLN) compared with their corresponding pretreatment scans, which were initially reported negative but were retrospectively thought to have had faint uptake. In 56 pretreatment scans, the 123I diagnostic activity was 185 MBq, and the results showed complete concordance in 54 pairs. Two posttreatment scans showed additional uptake: 1 in the bone and 1 in CLN. These data suggest that pretreatment scanning using 123I is highly comparable to 131I posttreatment scanning and that 123I is an excellent diagnostic agent in DTC.
Assuntos
Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/radioterapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Radioisótopos do Iodo/uso terapêutico , Masculino , Pessoa de Meia-Idade , Cintilografia , Compostos Radiofarmacêuticos/uso terapêutico , Tireoglobulina/metabolismo , Contagem Corporal TotalRESUMO
OBJECTIVES: The aim of this study was to assess the usefulness of 18-fluorodeoxyglucose positron emission tomography (PET) scanning for the evaluation of metastases (nodal and distant) in patients with carcinoma of the cervix. METHODS: A retrospective review was performed of 13 patients with carcinoma of the cervix who had a 18-fluorodeoxyglucose PET scan as part of their workup (10 during initial workup, 3 at time of relapse). Ten patients also underwent a fine needle aspiration (FNA) under imaging guidance for verification. RESULTS: All 10 patients with positive sites identified by PET scan who underwent an FNA were positive for cancer. In 3 situations PET identified sites where other imaging studies were negative. CONCLUSIONS: PET scanning is a useful imaging tool in the evaluation of patients with carcinoma of the cervix. This review supports other limited published data in this regard and suggests that further prospective studies are needed.
Assuntos
Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/secundário , Neoplasias do Colo do Útero/diagnóstico por imagem , Adulto , Biópsia por Agulha , Carcinoma de Células Escamosas/patologia , Feminino , Fluordesoxiglucose F18 , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/metabolismo , Metástase Linfática , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos Radiofarmacêuticos , Estudos Retrospectivos , Tomografia Computadorizada de Emissão , Neoplasias do Colo do Útero/patologiaRESUMO
A 50-year-old woman had an irregular, mobile, firm right breast mass that became progressively larger in the past 3 months that measured 18 x 15 cm at the time of examination. She had no nipple discharge or skin changes. A 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) showed a ring-shaped breast uptake consisting of high peripheral glycolytic activity and a cold center most likely representing necrosis or hemorrhage despite the absence of a history of trauma, surgical intervention, chemotherapy, or radiation to the breast. Whole-body images did not show any evidence of lymph node involvement or distant metastases. These results were confirmed by computed tomography of the chest, abdomen, and pelvis. Cytologic examination of a fine-needle aspiration of the breast mass showed diffuse large B-cell, intermediate grade, non-Hodgkin's lymphoma. Although it occurs infrequently, primary breast lymphoma should be considered in patients with a breast mass that shows a ring-shaped FDG uptake. A PET scan, in contrast to other imagining techniques, offers the advantage of screening the entire body, excluding the presence of metastases, and confirming the primary origin of the breast lymphoma.
Assuntos
Neoplasias da Mama/diagnóstico por imagem , Fluordesoxiglucose F18 , Linfoma não Hodgkin/diagnóstico por imagem , Compostos Radiofarmacêuticos , Tomografia Computadorizada de Emissão , Neoplasias da Mama/patologia , Feminino , Humanos , Linfoma não Hodgkin/patologia , Pessoa de Meia-Idade , Estadiamento de NeoplasiasRESUMO
PURPOSE: F-18 fluorodeoxyglucose (FDG) may accumulate at sites of inflammation or infection, making interpretation of whole-body scans difficult in patients with cancer. METHODS: More than 650 whole-body positron emission tomographic (PET) scans performed to examine patients with cancer were reviewed to identify uptake in pulmonary infection or inflammation based on the appearance of F-18 FDG chest uptake, chest radiographs, computed tomography, or all of these. RESULTS: Ten patients had uptake in benign lung disease. Eight patients had head and neck tumors and two patients had breast cancer. Intense focal or multifocal F-18 FDG chest uptake was seen in 6 of 10 scans. This was difficult to distinguish from pulmonary metastases based on the scan appearance. However, in the remaining patients, the uptake was atypical for malignancy and displayed an apical, segmental, or lobar pattern. In all patients, the F-18 FDG lung uptake corresponded to benign radiologic changes (infiltration, consolidation, or atelectasis), and the final diagnosis was pulmonary inflammation or infection. Nine patients were asymptomatic and one patient had clinical aspiration pneumonia. Follow-up PET scans were performed in five patients to evaluate their conditions. Chest uptake disappeared completely in three patients and partially in two patients, and there were no new findings. Variable degrees of F-18 FDG chest uptake have been reported with more than 40 different benign causes. They can be classified based on the underlying mechanism into four major categories: 1) Inflammation or infection, 2) benign tumor, 3) physiologic activity, and 4) iatrogenic. Most of these false-positive cases are included in the first category. CONCLUSIONS: Pulmonary infection or inflammation might predispose patients to localized F-18 FDG chest uptake mimicking pulmonary metastases and limiting the specificity of whole-body scans performed in patients with cancer.
Assuntos
Fluordesoxiglucose F18 , Pneumopatias/diagnóstico por imagem , Compostos Radiofarmacêuticos , Infecções Respiratórias/diagnóstico por imagem , Tomografia Computadorizada de Emissão , Adulto , Idoso , Neoplasias da Mama/diagnóstico por imagem , Diagnóstico Diferencial , Feminino , Radioisótopos de Flúor , Fluordesoxiglucose F18/farmacocinética , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos/farmacocinética , Sensibilidade e EspecificidadeRESUMO
The clinical, biochemical, and neuroradiologic findings and clinical follow-up of seven patients with glutaric aciduria type II are reported. Three phenotypes of the disease are encountered: neonatal-onset form with congenital anomalies (two patients) or without congenital anomalies (three patients) and late-onset form (two patients). The neonatal-onset form presents as an overwhelming illness, with severe hypoglycemia and metabolic acidosis leading to rapid death. Frequently it is associated with perinatal energy deprivation, a neonate with low birth weight and prematurity. The late-onset form presents with intermittent episodes of vomiting, hypoglycemia, and acidosis especially after meals rich in fat and/or proteins. All parents are consanguineous and have a first- or second-degree relationship. Initially, in the two phenotypes with neonatal onset and during crisis in the late-onset phenotype, routine laboratory evaluation showed severe metabolic acidosis, with an increased anion gap, hypoglycemia without ketonuria, and disturbed liver function tests. In the majority of patients with neonatal-onset forms, the kidneys, liver, and at times the spleen are enlarged with an increased echogenic pattern; however, no hepatic or renal cysts are detected. Cardiomegaly is observed in most patients. The diagnosis can be easily and rapidly reached through tandem mass spectrometry study of the blood and can further be confirmed by gas chromatography/mass spectrometry analysis of the urine organic acids. In this report, the magnetic resonance imaging/computed tomography brain studies showed brain atrophy, white matter disease, and in one patient, fluid-filled cavities in the periventricular area and putamina. Fluorine-18-labeled 2-fluoro-2-deoxyglucose positron emission tomographic (FDG PET) brain studies in two patients with late-onset disease showed slightly decreased activity in the cerebral cortex in one and in the caudate nuclei in the other. Brain FDG PET scan and magnetic resonance spectroscopy were normal in one patient with neonatal-onset disease. All patients were treated with a diet low in fat and protein, oral riboflavin, and carnitine. The results were promising for the late-onset disease. Intravenous carnitine gave rewarding results in one patient with neonatal-onset disease.
Assuntos
Acidose , Glutaratos/urina , Erros Inatos do Metabolismo/urina , Acidose/diagnóstico , Acidose/epidemiologia , Acidose/terapia , Idade de Início , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Carnitina/análogos & derivados , Carnitina/líquido cefalorraquidiano , Carnitina/uso terapêutico , Criança , Consanguinidade , Feminino , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Espectrometria de Massas , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/epidemiologia , Erros Inatos do Metabolismo/terapia , Tomografia Computadorizada de EmissãoRESUMO
We report a five-year-old boy with 4-hydroxybutyric aciduria. The child presented with global developmental delay, severe hypotonia and myoclonic seizures. The urine 4-hydroxybutyric acid was 1038 times that of normal, and other organic acids related to its further metabolism were also increased. Electroencephalography showed findings indicative of cerebral dysfunction. However, other neurophysiological studies were normal. Clinical improvement was observed after the administration of vigabatrin and dextromethorphan. Magnetic resonance imaging of the brain revealed cerebellar vermin atrophy and subtle white matter changes in the cerebral hemispheres. Fluorine-18 labeled 2-fluoro-2-deoxyglucose positron emission tomographic (FDG PET) scan of the brain showed a marked decrease in the cerebellar metabolism, probably related to atrophy of cerebellar vermis and secondary cerebellar deafferentation. FDG PET scan is found to be of value in the understanding and assessment of brain functional alterations. It may be useful in monitoring and optimizing treatment strategies of this rare disease.
Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Hidroxibutiratos/urina , Erros Inatos do Metabolismo/diagnóstico por imagem , Erros Inatos do Metabolismo/patologia , Pré-Escolar , Dextrometorfano/uso terapêutico , Fluordesoxiglucose F18 , Humanos , Imageamento por Ressonância Magnética , Masculino , Erros Inatos do Metabolismo/tratamento farmacológico , Arábia Saudita , Tomografia Computadorizada de Emissão , Vigabatrina/uso terapêuticoRESUMO
PURPOSE: Whole-body fluorine-18 fluorodeoxyglucose (F-18 FDG) positron emission tomography (PET) scanning has been useful in the management of breast cancer. However, F-18 FDG uptake sometimes has been associated with benign breast disease. Four cases are reported of F-18 FDG breast uptake caused by infectious or inflammatory mastitis that mimics malignant disease. METHODS AND RESULTS: Two women had F-18 FDG whole-body scans for the evaluation of a large breast mass after inconclusive results of ultrasonography. In both cases, intense focal F-18 FDG breast uptake was noted that mimicked breast cancer. Histologic examination showed, in one patient, chronic granulomatous infiltration that likely represented tuberculous mastitis, because she showed a good clinical response to empirical anti-tuberculous treatment. The second patient had lactational changes associated with acute inflammation, and the culture grew Staphylococcus aureus. The breast mass completely disappeared 3 weeks after a course of antibiotic treatment. The other two patients had staging F-18 FDG PET scans 1 and 12 months after lumpectomy for breast carcinoma to detect residual, recurrent, or metastatic disease. Both scans showed a ring-like uptake in the involved breast, with superimposed intense focal uptake suggesting tumor necrosis centrally and malignant foci peripherally. In both cases, histologic examination revealed hemorrhagic inflammation secondary to postsurgical hematomas and no evidence of malignancy. CONCLUSION: Acute or chronic infectious mastitis and postsurgical hemorrhagic inflammatory mastitis should be considered in patients who have a breast mass, especially those with a history of tenderness or surgery.
Assuntos
Doenças Mamárias/diagnóstico por imagem , Mama/diagnóstico por imagem , Radioisótopos de Flúor , Fluordesoxiglucose F18 , Compostos Radiofarmacêuticos , Tomografia Computadorizada de Emissão , Adulto , Neoplasias da Mama/diagnóstico por imagem , Diagnóstico Diferencial , Feminino , Hematoma/diagnóstico por imagem , Humanos , Mastite/diagnóstico por imagem , Mastite/microbiologia , Pessoa de Meia-Idade , Hemorragia Pós-Operatória/diagnóstico por imagem , Infecções Estafilocócicas/diagnóstico por imagem , Tuberculose/diagnóstico por imagemRESUMO
A 2-year, 6-month-old Saudi male with infantile Krabbe's disease was studied with fluorine-18-labeled-2-fluoro-2-deoxyglucose positron emission tomography (FDG PET) scan. The patient presented with a gradual loss of developmental milestones, irritability, and crying. At the advanced stage of the disease, he developed tonic-clonic seizures and became a microcephalic, extremely irritable, blind, spastic quadriplegic child, with no deep tendon reflexes. Laboratory studies revealed normal blood chemistry, muscle enzymes, very long chain fatty acids, and acylcarnitines. No abnormal urinary organic acids were detected. The cerebrospinal fluid protein concentration was increased. Magnetic resonance imaging of the brain revealed mild brain atrophy and white matter disease mainly in the centrum semiovale. Electroretinography was normal; however, electroencephalography and visual-evoked potentials were abnormal. Peripheral nerve conduction studies documented a demyelinating neuropathic process. The FDG PET study of the brain demonstrated a marked decrease in the metabolism of the left cerebral cortex and no uptake in the caudate heads. Normal glucose uptake was observed in the thalami, lentiform nuclei, and cerebellum. The patient did not present for subsequent clinic visits and is presumed dead.
Assuntos
Leucodistrofia de Células Globoides/diagnóstico por imagem , Tomografia Computadorizada de Emissão , Pré-Escolar , Fluordesoxiglucose F18 , Humanos , Masculino , Degeneração Neural/diagnóstico por imagem , Compostos RadiofarmacêuticosRESUMO
UNLABELLED: Protein-losing enteropathy (PLE) can be diagnosed scintigraphically using 99mTc-human serum albumin (HSA) scans. METHODS: To evaluate the usefulness of this method in detecting enteric protein loss, we retrospectively reviewed the 99mTc-HSA scans of 18 children presenting consecutively with PLE. RESULTS: Enteric 99mTc-HSA uptake was noted in 12 patients (8 boys, 4 girls) with a mean age of 7.4 y. Early dynamic images showed abdominal uptake that was most likely in the small bowel in 91% of the scans. Delayed images showed abnormal accumulation that was localized in the colon in 73% and in the small bowel in 27% of the scans. A 4-mo follow-up scan obtained in 3 patients showed reduced HSA uptake after a high-protein, low-fat, medium-chain triglyceride oil-based diet and fat-soluble vitamins. Mean serum albumin, total protein, gammaglobulin, and calcium levels were significantly decreased. Ten patients (from 4 families) were diagnosed to have primary intestinal lymphangectasia. One patient had active Salmonella enterocolitis, and 1 had giardiosis. 99mTc-HSA was normal in the remaining 6 patients (3 boys, 3 girls) with a mean age of 3.5 y (range, 2-5 y). Mean serum albumin, total protein, gammaglobulin, and calcium levels were less decreased than those of the first group. Five of these patients had primary intestinal lymphangactesia (associated with infantile systemic hyalinosis in 1 patient). The remaining patient had normal duodenal biopsy, and the cause of protein loss remained unknown. CONCLUSION: The 99mTc-HSA scan is useful in the evaluation of children with PLE, especially those with severe hypoproteinemia and hypoalbuminemia, presumably reflecting a high rate of protein loss.
Assuntos
Enteropatias Perdedoras de Proteínas/diagnóstico por imagem , Agregado de Albumina Marcado com Tecnécio Tc 99m , Criança , Pré-Escolar , Colo/diagnóstico por imagem , Feminino , Humanos , Intestino Delgado/diagnóstico por imagem , Masculino , Cintilografia , Compostos Radiofarmacêuticos , Estudos RetrospectivosRESUMO
OBJECTIVES: To evaluate the clinical, biochemical, neuroradiological, and neurophysiological findings of patients with X-linked adrenoleukodystrophy. METHODS: Retrospective study evaluating the data of 10 X-linked adrenoleukodystrophy patients diagnosed at King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. RESULTS: The common presenting symptoms were deterioration in school performance, vision and hearing, behavioral changes, and seizures. Eight patients survived 1-4 years and one patient 12 years after the initial presentation, while one patient expired. Six patients had the childhood form, 3 had the adolescent form and one had the adrenomyeloneuropathy form. Six are in an advanced stage of the disease and 3 have mild to moderate spasticity. All except 2 manifested moderate to severe dementia with variable degrees of visual loss. Decreased hearing and features of adrenal insufficiency were seen in 7 patients. Very long chain fatty acids were significantly increased in seven and mildly elevated in 2 patients, however the C26 to C22 ratio was increased in all. The characteristic high-signal intensity of parieto-occipital white matter on brain magnetic resonance imaging T2-weighted images was observed in all patients. Two patients had functional study of the brain, which showed hypometabolic activity in gray and white matter of the occipital lobes. Various neurophysiological abnormalities were detected. The response to different treatment modalities was not promising. CONCLUSION: The disease is more common than had been previously recognized due to phenotypic variability and a wide spectrum of presentations. This report describes various aspects of this disorder and emphasizes the importance of early identification and treatment of asymptomatic but biochemically affected individuals, since all current therapeutic approaches are disappointing if overt neurological abnormalities have been already developed.
Assuntos
Adrenoleucodistrofia/diagnóstico , Adrenoleucodistrofia/epidemiologia , Adolescente , Adrenoleucodistrofia/sangue , Adrenoleucodistrofia/genética , Criança , Transtornos do Comportamento Infantil/genética , Pré-Escolar , Variação Genética , Transtornos da Audição/genética , Humanos , Deficiência Intelectual/genética , Deficiências da Aprendizagem/genética , Imageamento por Ressonância Magnética , Linhagem , Fenótipo , Estudos Retrospectivos , Arábia Saudita/epidemiologia , Convulsões/genética , Análise de Sobrevida , Tomografia Computadorizada de Emissão , Transtornos da Visão/genéticaRESUMO
OBJECTIVE: To report two cases of sinusitis-associated radioiodine uptake in patients with thyroid cancer and to review the reported causes of false-positive radioiodine uptake in the head and neck area. METHODS: We present the radiologic findings in two patients who had undergone treatment for papillary thyroid cancer and discuss other settings in which radioiodine uptake suggested the presence of metastatic disease. RESULTS: Radioiodine whole-body scans of two patients who had had thyroid cancer demonstrated uptake in the sphenoid and maxillary sinuses, respectively, mimicking bone or brain metastatic involvement. The thyroglobulin levels were low. Computed tomographic (CT) scanning disclosed mucosal swelling in the sinuses, consistent with sinusitis. The radioiodine uptake cleared on a follow-up scan in one case and was more localized than the CT findings in the other. Eighteen causes of false-positive radioiodine uptake in the head and neck area have been reported. On the basis of the mechanism of uptake, they can be classified into four categories: (1) physiologic uptake (ectopic thyroid tissue), (2) nonthyroidal pathologic conditions (dacryocystitis, sinusitis, sinus mucocele, sialadenitis, folliculitis, Warthin's tumor, parotid cyst, porencephaly, posttraumatic cerebromalacia, and inflammation due to dental disease or a nose ring), (3) internal retention (ectasia of the carotid artery and an artificial eye), and (4) external contamination by body secretions (sweat and nasal, tracheobronchial, lacrimal, and salivary secretions). The estimated prevalence of external contamination in the head and neck area on whole-body radioiodine scans is 0.3%. CONCLUSION: Physicians should rule out the presence of radioiodine uptake by inflamed mucosa of the paranasal sinuses, as well as various other causes of false-positive radioiodine uptake, before metastatic thyroid cancer in the head and neck area is diagnosed.