RESUMEN

BACKGROUND AND PURPOSE: Osmotic disruption of the blood-brain barrier (BBB) provides a method for transvascular delivery of therapeutic agents to the brain. The apparent global delivery of viral-sized iron oxide particles to the rat brain after BBB opening as seen on MR images was compared with the cellular and subcellular location and distribution of the particles. METHODS: Two dextran-coated superparamagnetic monocrystalline iron oxide nanoparticle contrast agents, MION and Feridex, were administered intraarterially in rats at 10 mg Fe/kg immediately after osmotic opening of the BBB with hyperosmolar mannitol. After 2 to 24 hours, iron distribution in the brain was evaluated first with MR imaging then by histochemical analysis and electron microscopy to assess perivascular and intracellular distribution. RESULTS: After BBB opening, MR images showed enhancement throughout the disrupted hemisphere for both Feridex and MION. Feridex histochemical staining was found in capillaries of the disrupted hemisphere. Electron microscopy showed that the Feridex particles passed the capillary endothelial cells but did not cross beyond the basement membrane. In contrast, after MION delivery, iron histochemistry was detected within cell bodies in the disrupted hemisphere, and the electron-dense MION core was detected intracellularly and extracellularly in the neuropil. CONCLUSION: MR images showing homogeneous delivery to the brain at the macroscopic level did not indicate delivery at the microscopic level. These data support the presence of a physiological barrier at the basal lamina, analogous to the podocyte in the kidney, distal to the anatomic (tight junction) BBB, which may limit the distribution of some proteins and viral particles after transvascular delivery to the brain.

Asunto(s)

Barrera Hematoencefálica , Encéfalo/metabolismo , Imagen por Resonancia Magnética , Animales , Barrera Hematoencefálica/efectos de los fármacos , Encéfalo/anatomía & histología , Encéfalo/irrigación sanguínea , Capilares , Permeabilidad Capilar , Arterias Carótidas , Medios de Contraste/administración & dosificación , Medios de Contraste/farmacocinética , Dextranos , Endotelio Vascular/fisiología , Compuestos Férricos/administración & dosificación , Compuestos Férricos/análisis , Compuestos Férricos/farmacocinética , Óxido Ferrosoférrico , Histocitoquímica , Inyecciones Intraarteriales , Inyecciones Intraventriculares , Hierro/administración & dosificación , Hierro/farmacocinética , Nanopartículas de Magnetita , Manitol/administración & dosificación , Manitol/farmacología , Concentración Osmolar , Óxidos/administración & dosificación , Óxidos/farmacocinética , Tamaño de la Partícula , Ratas

RESUMEN

OBJECTIVE: To compare transient blood-brain barrier disruption (BBBD) by hypertonic mannitol with pharmacological modification of the blood-tumor barrier by the vasoactive peptide bradykinin for delivery of small and large agents to nude rat intracerebral xenografts. METHODS: Female nude rats (n = 104) with 6-day intracerebral human small cell lung carcinoma tumors were treated using BBBD (n = 24), intracarotid bradykinin (n = 38), or saline (controls, n = 32) administered intra-arterially. During or immediately after infusion, the rats were given radiolabeled agent (methotrexate or dextran 70; Dupont NEN, Boston, MA). The rats were killed 10 minutes later, and samples of tumor and brain regions were obtained for scintillation counting. Twenty-two additional rats were examined using magnetic resonance imaging after administering one of two contrast agents (gadoteridol or iron oxide nanoparticles) or saline (controls) in conjunction with BBBD or bradykinin. RESULTS: After BBBD, the delivery of both small (methotrexate) and large (dextran 70) radiolabeled tracers was increased 2- to 6-fold in the tumor and 3- to 20-fold in surrounding brain, as compared with saline controls. After bradykinin treatment, there was minimal change in delivery of methotrexate or dextran 70 to tumor and brain around tumor, with the greatest increase less than 60% over controls. Magnetic resonance imaging demonstrated increased delivery of both small and large contrast agents to the treated hemisphere after BBBD. In comparison, no increased tumor enhancement could be detected after bradykinin treatment. CONCLUSION: BBBD resulted in global delivery of a variety of agents in a wide range of sizes. In this human brain tumor xenograft model, bradykinin was not effective at increasing delivery to the tumor of any agent tested.

Asunto(s)

Barrera Hematoencefálica/efectos de los fármacos , Bradiquinina/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Manitol/farmacología , Animales , Encéfalo/metabolismo , Neoplasias Encefálicas/irrigación sanguínea , Neoplasias Encefálicas/secundario , Carcinoma de Células Pequeñas , Femenino , Humanos , Soluciones Hipertónicas , Neoplasias Pulmonares , Trasplante de Neoplasias , Ratas , Ratas Desnudas , Células Tumorales Cultivadas

RESUMEN

OBJECTIVE AND IMPORTANCE: Primary central nervous system lymphoma is a disease with increasing incidence. Atypical presentations are becoming more frequent. CLINICAL PRESENTATION: Three patients bearing cavernous sinus lesions presented initially with periorbital pain and diplopia. Tolosa-Hunt syndrome was the initial presumptive diagnosis for two patients, and meningioma was the diagnosis for the third patient. A fourth patient presented with left ear pain, and a mass in the left internal auditory canal was thought to represent an acoustic neuroma. INTERVENTION: For all four patients, an operative pathological diagnosis was obtained and was compatible with central nervous system lymphoma. All patients were treated with osmotic blood-brain barrier disruption with intra-arterial chemotherapy using a methotrexate-based regimen. CONCLUSION: All four cases included atypical presentations of lymphoma. These cases again illustrate that a correct diagnosis cannot be obtained based only on imaging and clinical findings.

Asunto(s)

Neoplasias Encefálicas/diagnóstico , Linfoma/diagnóstico , Adulto , Anciano , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/uso terapéutico , Barrera Hematoencefálica , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Diagnóstico Diferencial , Femenino , Humanos , Inyecciones Intraarteriales , Linfoma/tratamiento farmacológico , Linfoma/metabolismo , Imagen por Resonancia Magnética , Masculino , Metotrexato/administración & dosificación , Metotrexato/uso terapéutico , Persona de Mediana Edad , Base del Cráneo

RESUMEN

PURPOSE: Radiographic tumor response and survival were evaluated in the pediatric and young adult population with germ cell tumor, primary CNS lymphoma, or primitive neuroectodermal tumor receiving intra-arterial carboplatin- or methotrexate-based chemotherapy with osmotic blood-brain barrier disruption (BBBD). PATIENTS AND METHODS: Thirty-four patients with histologically confirmed germ cell tumor (n = 9), primary CNS lymphoma (n = 9), or primitive neuroectodermal tumor (n = 16) were treated at the Oregon Health Sciences University from August 1981 through April 1995. Ages ranged from 1 to 30 years (mean, 18 years). Prior treatments included cranial radiation (n = 10) and chemotherapy (n = 18). All patients underwent extensive baseline neuropsychological evaluation and follow-up evaluation upon completion of the protocol, except for two patients who declined follow-up assessment. RESULTS: Six hundred and forty-five BBBD procedures were performed with no mortality. Significant complications included one episode of tonsillar herniation with no neurologic sequelae, 4% incidence of seizures, and 3% incidence of sepsis or granulocytopenic fever. Ototoxicity was seen in 61% of patients who received carboplatin chemotherapy. Eighty-two percent of the patients had an objective response to treatment, including 62% with complete response and 20% with partial response. For most patients, cognitive functioning was maintained or improved at follow-up; this pattern was statistically significant. Three of the test scores for the seven patients who did not receive radiation therapy showed a cognitive decline of at least one standard deviation. Among the nine patients who received radiation therapy before or after BBBD chemotherapy, 11 test scores showed a decline in cognitive function at one standard deviation or more. DISCUSSION: Durable responses were seen in patients with germ cell tumor and primary CNS lymphoma when treated with BBBD. Primitive neuroectodermal tumor requires post-chemotherapy radiotherapy for a durable response to be attained. Ototoxicity was a major form of toxicity in the patients who received carboplatin, but with the recent introduction of sodium thiosulfate, this problem has been markedly alleviated. Favorable cognitive outcomes appeared more likely for patients treated solely with BBBD chemotherapy and not with radiotherapy. Trends in the results for this sample are similar to those of previous research showing that radiotherapy is associated with cognitive decline. Current alternatives to enhanced drug delivery after BBBD include bone marrow transplantation; however, the increment in drug delivery is less, the number of courses is limited, and the morbidity and mortality are greater for bone marrow transplant than for BBBD. The current results suggest that in future trials, irradiation may not be needed in lymphoma and may not be necessary in some CNS germ cell tumors and that more focal radiotherapy should be further assessed in localized primitive neuroectodermal tumors.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Germinoma/tratamiento farmacológico , Linfoma/tratamiento farmacológico , Tumores Neuroectodérmicos Primitivos/tratamiento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Barrera Hematoencefálica/efectos de los fármacos , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Niño , Preescolar , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Diuréticos Osmóticos/administración & dosificación , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Estudios de Seguimiento , Germinoma/mortalidad , Germinoma/patología , Humanos , Lactante , Inyecciones Intraarteriales , Linfoma/mortalidad , Linfoma/patología , Masculino , Manitol/administración & dosificación , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Tumores Neuroectodérmicos Primitivos/mortalidad , Tumores Neuroectodérmicos Primitivos/patología , Pruebas Neuropsicológicas , Tasa de Supervivencia , Resultado del Tratamiento

RESUMEN

Vasculitis confined to the central nervous system (CNS) is a rare disease usually characterized by headache and focal neurologic symptoms. Patients with primary vasculitis of the CNS may have symptoms and laboratory findings of systemic disease such as fatigue and elevated erythrocyte sedimentation rate, but by definition, focal inflammation should not be present outside the CNS. We describe 3 patients with uveitis in association with this diagnosis. The recognition of this association adds to the complex differential diagnosis of uveitis in association with CNS disease, and indicates that "isolated" angiitis of the CNS may display clinical features outside the brain and spinal cord.

Asunto(s)

Enfermedades del Sistema Nervioso Central/complicaciones , Uveítis/complicaciones , Vasculitis/complicaciones , Adulto , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Uveítis/diagnóstico , Uveítis/patología , Vasculitis/diagnóstico , Vasculitis/patología

RESUMEN

OBJECTIVE: The goal was to evaluate, at 1 year, 75 Long-Evans rats for survival rates and toxicity associated with the sequencing of cranial irradiation and enhanced chemotherapy delivery. METHODS: Seventy-five Long-Evans rats were randomized into four groups and evaluated at 1 year for survival rates and toxicity associated with the sequencing of cranial irradiation and enhanced chemotherapy delivery. Radiation (2,000 cGy) was administered as a single fraction, by using parallel opposed portals, 30 days before chemotherapy (Group 1), 24 hours before chemotherapy (Group 2), 30 days after chemotherapy (Group 3), or without chemotherapy or without radiation (control group, Group 4). Five subgroups within each treatment group included rats receiving intra-arterially administered methotrexate (1 g/m2) or intravenously administered etoposide (200 mg/m2) combined with intra-arterially administered carboplatin (200 mg/m2), administered with or without osmotic blood-rain barrier disruption, and a group receiving normal saline solution after blood-brain barrier disruption. RESULTS: There was a significant increase in total toxic effects when the three experimental groups were compared with the control group (P = 0.001, 0.006, and 0.013 for Groups 1, 2, and 3, respectively). All groups receiving radiation and chemotherapy (particularly carboplatin and etoposide) had an increased incidence of hind limb paralysis, resembling experimental allergic neuritis (P = 0.053). Statistical analysis showed a trend toward increased mortality rates in Group 1 (antecedent radiation), compared with the control group (P = 0.082), and an increased incidence of intracerebral calcification (P = 0.019). No differences in mortality rates were observed for Group 2 or 3, compared with the control group. CONCLUSION: Radiation before chemotherapy was a more toxic sequence and, surprisingly, carboplatin/etoposide administered in combination with radiotherapy was more detrimental than methotrexate. Additional studies are in progress to evaluate the toxicity and efficacy of sequences of cranial irradiation and enhanced chemotherapy in tumor-bearing rats.

Asunto(s)

Antineoplásicos/toxicidad , Encéfalo/efectos de los fármacos , Encéfalo/efectos de la radiación , Irradiación Craneana , Traumatismos Experimentales por Radiación/patología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Barrera Hematoencefálica/efectos de los fármacos , Encéfalo/patología , Carboplatino/toxicidad , Quimioterapia Adyuvante , Terapia Combinada , Relación Dosis-Respuesta en la Radiación , Esquema de Medicación , Etopósido/toxicidad , Manitol/farmacología , Metotrexato/toxicidad , Radioterapia Adyuvante , Ratas , Resultado del Tratamiento

RESUMEN

The volume of distribution in tissue (Vt) that can be achieved by direct interstitial infusion of therapeutic agents into brain is limited. The maintenance of a pressure gradient during interstitial infusion to establish fluid convection has been shown to increase the Vt of small, medium, and large molecules. We have used monocrystalline iron oxide nanocompounds, superparamagnetic particles of sizes the same order of magnitude as virions, to investigate the effect of dose, the volume of infusate, and the time of infusion on the distribution of large molecules in rodent brain. Our initial study in rats (n = 6) replicated the results of a previously described report of convection-enhanced delivery in cats. At a constant rate and concentration, the Vt increased in a linear fashion, proportional to the increases in time, volume, and dose. When using a constant rate and a constant concentration, however, it is unclear which variable or variables (dose, volume, infusion time) have the greatest influence on this effect. Therefore, we assessed each variable independently (n = 12). When the iron dose was increased from 5.3 to 26.5 micrograms, there was a three- to fivefold increase in the Vt, depending on the volume and time of infusion (2 Microliters/20 min, 24 microliters/20 min, or 24 microliters/120 min) (P < 0.001). When the volume of infusate was increased from 2 to 24 microliters, at an infusion time of 20 minutes and a dose of either 5.3 or 26.5 micrograms, there was a 43 or 52% decline in the Vt, respectively (P = 0.018). When the time for the infusion of 24 microliters was increased from 20 to 120 minutes, there was a 79% increase in the Vt at a dose of 26.5 micrograms but no change in the Vt at a dose of 5.3 micrograms. The effect associated with infusion time was not significant (P = 0.113). Magnetic resonance imaging was performed to document the distribution of monocrystalline iron oxide nanocompounds in vivo, and histochemical staining for iron was used to document the distribution of monocrystalline iron oxide nanocompounds in tissue sections. The Vt for both methods was calculated by computer image analysis, and the correlation between magnetic resonance and histological volumes was determined (r2 = 0.93). On the basis of this model, we suggest that dose, rather than convection, might be the most important variable in maximizing the Vt and improved distribution might be achieved by administering an increased concentration of agent.

Asunto(s)

Encéfalo/patología , Medios de Contraste/farmacocinética , Hierro/farmacocinética , Imagen por Resonancia Magnética , Óxidos/farmacocinética , Animales , Encéfalo/efectos de los fármacos , Medios de Contraste/administración & dosificación , Convección , Difusión , Relación Dosis-Respuesta a Droga , Óxido Ferrosoférrico , Inyecciones , Hierro/administración & dosificación , Óxidos/administración & dosificación , Ratas , Distribución Tisular

RESUMEN

PURPOSE: To determine if tumor-specific monoclonal antibodies conjugated to superparamagnetic monocrystalline iron oxide nanoparticles can be used to yield specific diagnoses with the use of MR imaging. METHODS: Monoclonal antibodies conjugated to monocrystalline iron oxide nanoparticles were given to nude rats with intracranial tumors either by intravenous injection, intraarterial injection with osmotic blood-brain barrier disruption, or direct intratumoral inoculation. Either L6, a tumor-specific antibody, or P-1.17, a control isotype-matched antibody, was used. Coronal T1-weighted, T2-weighted, and spoiled gradient-recalled acquisition in the steady state images were obtained before, 30 minutes after, 6 hours after, and 24 hours after injection. RESULTS: Intravenous injection of greater than 2 mg of the tumor-specific antibody showed a specific pattern of enhancement of the tumors with the largest concentration of antibody in the area with the greatest density of tumor cells. The control antibody showed nonspecific changes. After intraarterial injection with barrier disruption to increase delivery globally or direct inoculation to increase delivery focally, no specific enhancement pattern was seen. CONCLUSION: Monoclonal antibodies conjugated with monocrystalline iron oxide particles may provide a method to obtain specific diagnoses with the use of MR imaging.

Asunto(s)

Anticuerpos Monoclonales/inmunología , Neoplasias Encefálicas/inmunología , Carcinoma de Células Pequeñas/inmunología , Hierro , Imagen por Resonancia Magnética , Óxidos , Animales , Anticuerpos Monoclonales/administración & dosificación , Barrera Hematoencefálica , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/patología , Carcinoma de Células Pequeñas/diagnóstico , Carcinoma de Células Pequeñas/patología , Medios de Contraste , Epítopos , Femenino , Óxido Ferrosoférrico , Humanos , Inyecciones Intraarteriales , Inyecciones Intravenosas , Hierro/administración & dosificación , Ratones , Trasplante de Neoplasias , Óxidos/administración & dosificación , Ratas , Ratas Desnudas , Trasplante Heterólogo

RESUMEN

PURPOSE: To validate the use of techniques of irreversible compression of images, which can be performed using a block-based discrete cosine transform technique as defined by the Joint Photographic Experts Group, before they can be used in clinical applications, by evaluating the effect of compression on the ability of observers to detect discrete white matter lesions on MR images of the brain. METHODS: Sixty T2- and intermediate-weighted spin-echo images were compressed with varying degrees of coefficient quantization with compression ratios from 1:1 to more than 40:1, randomized, and evaluated by three observers blinded to the degree of compression. RESULTS: No significant difference in the number of lesions detected was apparent until compression ratios reached 40:1, despite a significant subjective loss in perceived image quality at 20:1. Only small (< or = 5 mm) lesions were missed at the highest degree of compression. No significant differences were observed in the detection of confluent periventricular white matter disease at any degree of compression tested. CONCLUSIONS: The use of high degrees of irreversible compression of MR images may be acceptable for diagnostic tasks.

Asunto(s)

Encefalopatías/diagnóstico , Imagen por Resonancia Magnética/métodos , Sistemas de Información Radiológica , Encéfalo/patología , Ventrículos Cerebrales/patología , Humanos , Procesamiento de Imagen Asistido por Computador

RESUMEN

CARBOPLATIN AND ETOPOSIDE have been investigated in preclinical studies and a limited toxicity study in 13 patients; these studies have established carboplatin and etoposide as a tolerable combination when administered with blood-brain barrier disruption. The studies also found a predictable dose-limiting toxicity of myelosuppression. Subsequently, a broad efficacy trial of this regimen was carried out. A total of 34 patients, ranging in age from 7 to 72 years, underwent a combination chemotherapy regimen of carboplatin (200 mg/m2 administered intra-arterially) and etoposide (200 mg/m2 administered intravenously) administered with blood-brain barrier disruption on each of 2 consecutive days every 28 days. The diagnoses included glioblastoma multiforme (n = 3), malignant astrocytoma (n = 8), malignant astrocytoma-oligodendroglioma (n = 1), primitive neuroectodermal tumor (n = 4), disseminated germ cell tumor of the central nervous system (CNS) (n = 6), CNS lymphoma (n = 7), and metastatic carcinoma (n = 5). The major toxicity observed in patients treated with multiple courses of this regimen was the expected reversible myelosuppression and an unexpected, irreversible high-frequency hearing loss. Of these 34 patients, 22 had measurable disease, and 9 radiographic responses (50% or more decrease in enhancing tumors) were observed in these patients. Carboplatin and etoposide with blood-brain barrier disruption is an active regimen in the treatment of malignant astrocytomas and has shown dramatic responses in primitive neuroectodermal tumors and CNS lymphoma. Additionally, the durability of responses in patients with disseminated CNS germ cell tumors is encouraging. However, such therapy is associated with unexpected high-frequency hearing loss; even so, on the basis of the favorable responses in patients with primitive neuroectodermal tumors, germ cell tumors, and lymphomas, the study of this regimen for those tumors is being extended in a multiinstitutional trial that also includes cytoxan to further evaluate the potential enhanced drug delivery.

Asunto(s)

Antineoplásicos/toxicidad , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Barrera Hematoencefálica/efectos de los fármacos , Neoplasias Encefálicas/tratamiento farmacológico , Carboplatino/toxicidad , Etopósido/toxicidad , Adolescente , Adulto , Anciano , Antineoplásicos/administración & dosificación , Astrocitoma/tratamiento farmacológico , Astrocitoma/cirugía , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/cirugía , Carboplatino/administración & dosificación , Niño , Etopósido/administración & dosificación , Femenino , Germinoma/tratamiento farmacológico , Germinoma/cirugía , Glioblastoma/tratamiento farmacológico , Glioblastoma/cirugía , Humanos , Linfoma/tratamiento farmacológico , Linfoma/cirugía , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Tumores Neuroectodérmicos Primitivos/tratamiento farmacológico , Tumores Neuroectodérmicos Primitivos/cirugía , Oligodendroglioma/tratamiento farmacológico , Oligodendroglioma/cirugía , Tomografía Computarizada por Rayos X

RESUMEN

PURPOSE: To establish changes on MR of the brain in a feline model of Sandhoff disease in order to develop standards by which this model may be used in future noninvasive studies. METHODS: Five affected felines and six age-matched, littermate controls were evaluated. T1- and T2-weighted images were obtained once or twice for each of four affected and five control animals at 4 1/2 to 12 weeks of age, for a total of 15 MR examinations. Images were evaluated qualitatively for the pattern of myelination and the size of the ventricular system. After the animals were killed, pathologic specimens of the brain were examined with light and electron microscopy, and pathologic changes were correlated with MR. RESULTS: Compared with control animals, affected animals showed MR evidence of delayed myelination, manifested by white matter signal hypointensity on T1-weighted images and signal hyperintensity on T2-weighted images. This finding was corroborated by histopathologic findings of decreased myelin in the subcortical and internal capsule regions. White matter abnormalities were not detected ultrastructurally in the animals examined. CONCLUSION: Although GM2 gangliosidosis is primarily a neuronal disease, MR imaging can show changes in myelination of white matter tracts that may be secondary to the neuronal damage. This provides a noninvasive method of in vivo monitoring as therapeutic strategies are developed in this animal model.

Asunto(s)

Encefalopatías Metabólicas/patología , Encéfalo/patología , Imagen por Resonancia Magnética , Enfermedad de Sandhoff/patología , Factores de Edad , Animales , Animales Endogámicos , Encefalopatías Metabólicas/genética , Gatos , Aberraciones Cromosómicas/genética , Trastornos de los Cromosomas , Modelos Animales de Enfermedad , Gangliósido G(M2)/metabolismo , Genes Recesivos , Microscopía Electrónica , Vaina de Mielina/patología , Neuronas/patología , Enfermedad de Sandhoff/genética

RESUMEN

PURPOSE: To determine whether osmotic blood-brain barrier disruption is associated with MR abnormalities or cognitive deterioration and, if so, whether the MR findings correlate with cognitive test results. METHODS: Fifteen brain tumor patients who had a complete tumor response (nine central nervous system lymphoma, three germ cell and two astrocytoma, and one primitive neuroectodermal tumor) treated with blood-brain barrier disruption procedures (318 total procedures) with intraarterial chemotherapy were included. MR images were evaluated for the development of white matter hyperintensity, vascular lesions, or atrophy. Cognitive testing was performed to assess deterioration caused by this therapy. RESULTS: In two patients white matter hyperintensity developed, in two small vascular lesions developed, and in one mild atrophy developed. One infarct was asymptomatic and the second one resulted in mild dysesthesia in one upper extremity. No patient showed diminished cognitive function on the posttherapy evaluation. CONCLUSION: In patients undergoing blood-brain barrier disruption with intraarterial chemotherapy, new abnormalities on MR imaging may develop. These patients maintain the same level of cognitive and neurologic function and MR findings do not correlate with the results of cognitive testing.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Barrera Hematoencefálica/efectos de los fármacos , Neoplasias Encefálicas/tratamiento farmacológico , Infusiones Intraarteriales , Imagen por Resonancia Magnética , Pruebas Neuropsicológicas , Equilibrio Hidroelectrolítico/efectos de los fármacos , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Encéfalo/efectos de los fármacos , Encéfalo/patología , Daño Encefálico Crónico/inducido químicamente , Daño Encefálico Crónico/diagnóstico , Neoplasias Encefálicas/diagnóstico , Niño , Femenino , Estudios de Seguimiento , Humanos , Masculino , Manitol/administración & dosificación , Persona de Mediana Edad , Resultado del Tratamiento

RESUMEN

This study characterized agent differential permeability, three-dimensional tumor volume, and survival in an LX-1 human small cell lung carcinoma intracerebral xenograft model in the nude rat. The percent accessible tissue space (distribution volume) and the permeability x capillary surface product for aminoisobutyric acid (M(r) 103), methotrexate (M(r) 454), dextran 10 (M(r) 10,000), and dextran 70 (M(r) 70,000) were measured between 8 and 16 days after inoculation of tumor. Magnetic resonance imaging and histology were used to quantitate intracerebral tumor volume (mm3). Accessible tissue space (ml/g) and permeability x capillary surface product in intracranial tumor, surrounding brain, and subcutaneous tumor decreased with increasing molecular weight of the agent, regardless of the number of days after inoculation. Accessible tissue space in intracranial tumor increased between 8 and 16 days for all agents except dextran 70. There was little change in the subcutaneous tumor or other tissues with time. Tumor volume calculations from imaging studies correlated with volumetric measurements from histological sections (r2 = 98.5%) and illustrated natural tumor progression (9 to 225 mm3). These results provide a basis for therapeutic design based on differential permeability of specific agents and the ability to quantitatively measure brain tumor volume for accessing tumor response.

Asunto(s)

Antineoplásicos/farmacocinética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Carcinoma de Células Pequeñas/metabolismo , Carcinoma de Células Pequeñas/patología , Neoplasias Pulmonares , Animales , Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/mortalidad , Carcinoma de Células Pequeñas/tratamiento farmacológico , Carcinoma de Células Pequeñas/mortalidad , Modelos Animales de Enfermedad , Humanos , Imagen por Resonancia Magnética , Masculino , Trasplante de Neoplasias , Permeabilidad , Ratas , Ratas Desnudas , Tasa de Supervivencia , Factores de Tiempo

RESUMEN

We reviewed 27 patients with congenital anomalies of the sacral spine. There were 16 males and 11 females with a mean follow-up of 81.1 months (range 8-211 months). Fifteen patients had sacral agenesis and 12 had sacral dysgenesis. Fifteen patients had neuroimaging of the spine. Seven patients had conus termination below the L2 vertebral body. Four patients had associated thoracic syringomyelia and 6 patients were identified with caudal or dorsal lipoma. There were only two episodes of neurological deterioration, both in a single patient who had a lipomyelomeningocele, in 182 patient-years of follow-up. Four patients with low lying conus had pre-emptive spinal cord exploration for release of tethering in order to prevent neurological deterioration. Patients with agenesis or dysgenesis of the sacrum should undergo magnetic resonance (MR) imaging of the spine in order to detect spinal cord lesions associated with progressive neurological deterioration. Findings on MR imaging are more likely to correlate with clinical course than findings on skeletal radiography.

Asunto(s)

Anomalías Múltiples/diagnóstico , Defectos del Tubo Neural/diagnóstico , Sacro/anomalías , Anomalías Múltiples/cirugía , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Defectos del Tubo Neural/cirugía , Examen Neurológico , Complicaciones Posoperatorias/diagnóstico , Sacro/patología , Sacro/cirugía , Disrafia Espinal/diagnóstico , Disrafia Espinal/cirugía

RESUMEN

OBJECTIVE: This experiment was done to evaluate the gross neurotoxicity of intravenous Gd-DTPA administered in conjunction with osmotic blood-brain barrier (BBB) disruption and to image a human small cell lung carcinoma intracerebral tumor xenograft before and after osmotic BBB disruption. MATERIALS AND METHODS: Neurotoxicity studies were performed in normal Sprague-Dawley rats following osmotic BBB disruption by the injection of 25% mannitol in the right internal carotid artery and intravenous administration of Gd-DTPA (n = 10). Animals were observed for major neurologic changes such as seizure or substantial motor defects, and after death neuropathologic examination was performed. Human small cell lung carcinoma cells were implanted intracerebrally in athymic nude rats (n = 4). Gadopentetate dimeglumine was injected intravenously and serial T1-weighted images were obtained. Blood-brain barrier disruption was produced in each animal, followed by a second dose of intravenous Gd-DTPA, and imaging studies were repeated. RESULTS: No gross neurologic toxicity was observed. Tumors showed dense enhancement in a small area, and BBB disruption resulted in marked enhancement in most of the gray matter of the right cerebral hemisphere. CONCLUSION: Gadopentetate dimeglumine appears to be safe in doses up to 21 mmol/m2 in conjunction with barrier disruption in rats. A human small cell lung carcinoma intracerebral xenograft provides a useful method to study brain tumors.

Asunto(s)

Barrera Hematoencefálica/fisiología , Neoplasias Encefálicas/diagnóstico , Carcinoma de Células Pequeñas/diagnóstico , Medios de Contraste , Gadolinio , Imagen por Resonancia Magnética , Compuestos Organometálicos , Ácido Pentético/análogos & derivados , Animales , Barrera Hematoencefálica/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/patología , Medios de Contraste/toxicidad , Combinación de Medicamentos , Femenino , Gadolinio/toxicidad , Gadolinio DTPA , Aumento de la Imagen , Procesamiento de Imagen Asistido por Computador , Meglumina/toxicidad , Compuestos Organometálicos/toxicidad , Ósmosis , Ácido Pentético/toxicidad , Ratas , Ratas Desnudas , Ratas Sprague-Dawley , Convulsiones/inducido químicamente

RESUMEN

Delivery of viral particles to the brain is limited by the volume of distribution that can be obtained. Additionally, there is currently no way to non-invasively monitor the distribution of virus following delivery to the central nervous system (CNS). To examine the delivery of virus-sized particles across the blood-brain barrier (BBB), dextran coated, superparamagnetic monocrystalline iron oxide particles, with a hydrodynamic diameter of 20 +/- 4 nm, were delivered to rat brain by direct intracerebral inoculation or by osmotic BBB disruption with hypertonic mannitol. Delivery of these particles was documented by magnetic resonance (MR) imaging and, unexpectedly, neuronal uptake was demonstrated by histochemical staining. Electron microscopy (EM) confirmed iron particle delivery across the capillary basement membrane and localization within CNS parenchymal cells following administration with BBB disruption. This is the first histologic and ultrastructural documentation of the delivery of particles the size of virions across the blood-brain barrier. Additionally, these dextran-coated, iron oxide particles may be useful, in and of themselves, as vectors for diagnostic and/or therapeutic interventions directed at the CNS.

Asunto(s)

Barrera Hematoencefálica/fisiología , Encéfalo/microbiología , Compuestos Férricos/farmacocinética , Vectores Genéticos , Animales , Complejo Hierro-Dextran , Imagen por Resonancia Magnética , Microscopía Electrónica , Neuronas/patología , Tamaño de la Partícula , Ratas

RESUMEN

PURPOSE: To compare CT and radionuclide imaging of osmotic blood-brain barrier disruption. To develop a quantitative method for imaging osmotic blood-brain barrier disruption and to see if iopamidol could be safely given intravenously in conjunction with blood-brain barrier disruption. METHODS: Forty-five blood-brain barrier disruption procedures were imaged with CT and radionuclide scans. The scans were evaluated with visual and quantitative scales. Patients were observed for adverse effects after blood-brain barrier disruption. RESULTS: There was a 4% rate of seizures in this study. There was good agreement between visual CT and radionuclide grading systems. Quantitative methods to grade disruption did not add useful information to visual interpretations. CONCLUSIONS: Nonionic iodine-based contrast medium has a lower incidence of seizures when injected intravenously in conjunction with osmotic blood-brain barrier disruption than ionic contrast material. Contrast-enhanced CT is the preferred method to image disruption because it has better spatial resolution than radionuclide techniques.

Asunto(s)

Barrera Hematoencefálica/fisiología , Neoplasias Encefálicas/diagnóstico por imagen , Adolescente , Adulto , Anciano , Neoplasias Encefálicas/fisiopatología , Femenino , Humanos , Yopamidol , Masculino , Persona de Mediana Edad , Compuestos de Organotecnecio , Ósmosis , Cintigrafía , Azúcares Ácidos , Tomografía Computarizada por Rayos X

RESUMEN

The antemortem diagnosis of syringomyelia in the setting of sacral agenesis has not been reported before. We describe the clinical and neuroimaging features in 3 patients. None has required surgical intervention to date.

Asunto(s)

Sacro/anomalías , Enfermedades de la Médula Espinal/congénito , Enfermedades de la Columna Vertebral/congénito , Siringomielia/fisiopatología , Niño , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Enfermedades de la Médula Espinal/complicaciones , Enfermedades de la Médula Espinal/diagnóstico , Enfermedades de la Columna Vertebral/complicaciones , Enfermedades de la Columna Vertebral/diagnóstico , Siringomielia/complicaciones , Siringomielia/diagnóstico

RESUMEN

Twelve adults (11 male, 1 female), diagnosed as having supratentorial gliomas, were treated with osmotic blood-brain barrier disruption and chemotherapy (intra-arterial methotrexate, 2500 mg/infusion; intravenous Cytoxan, 15 mg/kg/infusion; and oral procarbazine, 100 mg daily x 14 days) prior to radiotherapy. To assess higher cortical function, all patients underwent neuropsychological testing. Volumetric analysis of pretreatment and serial enhanced computerized tomographic scans were recorded. Four of ten patients with enhancing tumor showed radiographic tumor response, defined as 50% reduction of enhancing tumor volume. These four patients received no steroids at the time of maximum tumor response. Osmotic blood-brain barrier disruption and chemotherapy administered prior to radiotherapy can result in significant objective tumor responses with maintenance of cognitive function. It also offers a new and unique means to assess chemosensitivity, which may lead to improved treatment protocols.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Barrera Hematoencefálica/fisiología , Glioma/tratamiento farmacológico , Neoplasias Supratentoriales/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Combinada , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Glioma/radioterapia , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Presión Osmótica , Neoplasias Supratentoriales/radioterapia

RESUMEN

PURPOSE: To describe the MR findings of primary CNS lymphoma. METHODS: MR scans of 20 patients with histologically proved primary CNS lymphoma were reviewed. We evaluated the size, multiplicity, signal intensities, and enhancement characteristics of the lesions. We divided the lesions into an enhancing area referred to as Zone 1 and abnormal signal surrounding this, referred to as Zone 2. RESULTS: Primary CNS lymphoma presented as solitary enhancing lesions in 40% of the patients and multiple lesions in 40%. Thirty-three separate lesions were visible: 58% abutted the ventricular system, 76% showed a homogenous enhancement pattern, and 79% showed marked enhancement. In 64% of the lesions, Zone 1 and Zone 2 showed different signal intensities on T1-weighted images. CONCLUSIONS: Primary CNS lymphoma usually presents as solitary or multiple dense homogenous enhancing lesions that abut an ependymal surface. These lesions can be divided into an enhancing area and an area of surrounding abnormal signal. These two areas often have different signal intensities on unenhanced T2-weighted images. These findings are sufficiently suggestive of the diagnosis of primary CNS lymphoma that a needle biopsy be performed based on these findings and appropriate therapy can then be instituted.

Asunto(s)

Neoplasias del Sistema Nervioso Central/diagnóstico , Linfoma/diagnóstico , Imagen por Resonancia Magnética , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad