Systemic dissemination of glioblastoma: literature review

SUMMARY INTRODUCTION: Glioblastoma (GBM) is the most frequent primary malignant tumor from the central nervous system in adults. However, the presence of systemic metastasis is an extremely rare event. The objective of this study was to review the literature, evaluating the possible biological mechanisms related to the occurrence of systemic metastasis in patients diagnosed with GBM. RESULTS: The mechanisms that may be related to GBM systemic dissemination are the blood-brain barrier breach, often seen in GBM cases, by the tumor itself or by surgical procedures, gaining access to blood and lymphatic vessels, associated with the acquisition of mesenchymal features of invasiveness, resistance to the immune mechanisms of defense and hostile environment through quiescence. CONCLUSIONS: Tumor cells must overcome many obstacles until the development of systemic metastasis. The physiologic mechanisms are not completely clear. Although not fully understood, the pathophysiological understanding of the mechanisms that may be associated with the systemic spread is salutary for a global understanding of the disease. In addition, this knowledge may be used as a basis for a therapy to be performed in patients diagnosed with GBM distant metastasis.

RESUMO INTRODUÇÃO: Glioblastoma (GBM) é o tumor maligno mais comum do sistema nervoso central em adultos. Entretanto, metástase a distância de GBM é um evento extremamente raro. O presente estudo teve o objetivo de realizar uma revisão da literatura para avaliar os possíveis mecanismos biológicos relacionados com a ocorrência de metástase a distância de pacientes com diagnóstico de GBM. RESULTADOS: Os mecanismos que podem estar relacionados com a capacidade de disseminação sistêmica do GBM são a quebra de barreira hematoencefálica (BHE) frequentemente vista em GBM, seja pela doença, seja por procedimentos cirúrgicos, dando acesso aos vasos sanguíneos e linfáticos, associada à aquisição de características mesenquimais de invasividade, resistência aos mecanismos de defesa do sistema imunológico e adaptação a hostilidades dos meios distantes por meio de quiescência. CONCLUSÕES: As células tumorais necessitam vencer diversos obstáculos até a formação de uma metástase distante. Apesar de não totalmente esclarecido, o entendimento fisiopatológico dos mecanismos pelos quais podem estar associados à disseminação sistêmica do GBM é salutar para a compreensão global da doença. Além disso, esse conhecimento pode servir de base para a terapia a ser empregada diante do paciente com diagnóstico de GBM com metástase a distância.

Permeability Parameters Measured with Dynamic Contrast-Enhanced MRI: Correlation with the Extravasation of Evans Blue in a Rat Model of Transient Cerebral Ischemia

OBJECTIVE: The purpose of this study was to correlate permeability parameters measured with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using a clinical 3-tesla scanner with extravasation of Evans blue in a rat model with transient cerebral ischemia. MATERIALS AND METHODS: Sprague-Dawley rats (n = 13) with transient middle cerebral artery occlusion were imaged using a 3-tesla MRI with an 8-channel wrist coil. DCE-MRI was performed 12 hours, 18 hours, and 36 hours after reperfusion. Permeability parameters (K(trans), v(e), and v(p)) from DCE-MRI were calculated. Evans blue was injected after DCE-MRI and extravasation of Evans blue was correlated as a reference with the integrity of the blood-brain barrier. Correlation analysis was performed between permeability parameters and the extravasation of Evans blue. RESULTS: All permeability parameters (K(trans), v(e), and v(p)) showed a linear correlation with extravasation of Evans blue. Among them, K(trans) showed highest values of both the correlation coefficient and the coefficient of determination (0.687 and 0.473 respectively, p < 0.001). CONCLUSION: Permeability parameters obtained by DCE-MRI at 3-T are well-correlated with Evans blue extravasation, and K(trans) shows the strongest correlation among the tested parameters.

Clinical Implications of Sulcal Enhancement on Postcontrast Fluid Attenuated Inversion Recovery Images in Patients with Acute Stroke Symptoms

OBJECTIVE: Hyperintense acute reperfusion marker (HARM) without diffusion abnormalities is occasionally found in patients with an acute stroke. This study was to determine the prevalence and clinical implications of HARM without diffusion abnormalities. MATERIALS AND METHODS: There was a retrospective review of magnetic resonance images 578 patients with acute strokes and identified those who did not have acute infarction lesions, as mapped by diffusion-weighted imaging (DWI). These patients were classified into an imaging-negative stroke and HARM without diffusion abnormalities groups, based on the DWI findings and postcontrast fluid attenuated inversion recovery images. The National Institutes of Health Stroke Scale (NIHSS) scores at admission, 1 day, and 7 days after the event, as well as clinical data and risk factors, were compared between the imaging-negative stroke and HARM without diffusion abnormalities groups. RESULTS: Seventy-seven acute stroke patients without any DWI abnormalities were found. There were 63 patients with an imaging-negative stroke (accounting for 10.9% of 578) and 13 patients with HARM without diffusion abnormalities (accounting for 2.4% of 578). The NIHSS scores at admission were higher in HARM without diffusion abnormalities group than in the imaging-negative stroke group (median, 4.5 vs. 1.0; p < 0.001), but the scores at 7 days after the event were not significantly different between the two groups (median, 0 vs. 0; p = 1). The patients with HARM without diffusion abnormalities were significantly older, compared with patients with an imaging-negative stroke (mean, 73.1 years vs. 55.9 years; p < 0.001). CONCLUSION: Patients with HARM without diffusion abnormalities are older and have similarly favorable short-term neurological outcomes, compared with the patients with imaging-negative stroke.

Blood-brain barrier breakdown and repair following gliotoxic drug injection in the brainstem of streptozotocin-diabetic rats / Ruptura e reparo da barreira hematoencefálica pós-injeção de droga gliotóxica no tronco encefálico ratos diabéticos

Ethidium bromide (EB) causes local astrocytic disappearance, with glia limitans disruption and blood-brain barrier (BBB) breakdown. The aim of this study was to evaluate the BBB integrity after the injection of 0.1 percent EB or 0.9 percent saline solution into the cisterna pontis of Wistar rats submitted or not to the streptozotocin diabetogenic model. Brainstem sections were collected from 24 hours to 31 days post-injection for ultrastructural analysis and glial fibrillary acidic protein immunohistochemical staining. Some animals received colloidal carbon ink by intravenous route at the same periods. In rats injected with EB, results revealed astrocyte disappearance and leakage of carbon particles beginning at 48 hours and persisting for 7 days in non-diabetic rats and for 15 days in the diabetic ones, although, in both groups, several areas remained devoid of astrocytic processes up to 31 days. In rats injected with saline, there was no sign of astrocytic loss or carbon particles leakage.

O brometo de etídio (BE) determina o desaparecimento local de astrócitos, com ruptura da glia limitans e dano na barreira hematoencefálica (BHE). Este estudo visou avaliar a integridade da BHE após injeção de solução de BE a 0,1 por cento ou de salina a 0,9 por cento na cisterna pontis de ratos Wistar submetidos ou não ao modelo diabetogênico da estreptozotocina. Fragmentos do tronco encefálico foram coletados das 24 horas aos 31 dias pós-injeção para estudo ultraestrutural e marcação imuno-histoquímica para proteína glial fibrilar ácida. Alguns animais receberam carvão coloidal por via intravenosa nos mesmos períodos. Nos grupos injetados com BE, os resultados mostraram desaparecimento astrocitário e extravasamento de partículas de carvão nas lesões a partir das 48 horas, persistindo por até sete dias nos animais não diabéticos e 15 dias nos diabéticos, embora, em ambos os grupos, diversas áreas permanecessem destituídas de astrócitos até 31 dias após. Nos ratos injetados com salina, diabéticos ou não, não houve sinal de perda astrocitária nem de extravasamento vascular de carvão.

Contribution of Nitric Oxide Synthase [NOS] Activity in Blood-Brain Barrier Disruption and Edema after Acute Ischemia/ Reperfusion in Aortic Coarctation-Induced Hypertensive Rats

Nitric oxide synthase [NOS] activity is increased during hypertension and cerebral ischemia. NOS inactivation reduces stroke-induced cerebral injuries, but little is known about its role in blood-brain barrier [BBB] disruption and cerebral edema formation during stroke in acute hypertension. Here, we investigated the role of NOS inhibition in progression of edema formation and BBB disruptions provoked by ischemia/reperfusion injuries in acute hypertensive rats. Rats were made acutely hypertensive by aortic coarctation. After 7 days, the rats were randomly selected for the recording of carotid artery pressure, or regional cerebral blood flow [rCBF] using laser Doppler. Ishcemia induced by 60-min middle cerebral artery occlusion [MCAO], followed by 12-h reperfusion. A single i.p. dose of L-NAME [1 mg/kg] was injected before MCAO. After evaluation of neurological disabilities, rats were slaughtered under deep anesthesia to assess cerebral infarction volume, edema, or BBB disruption. A 75-85% reduction in rCBF was occurred during MCAO which returned to pre-occluded levels during reperfusion. Profound neurological disabilities were evidenced after MCAO alongside with severe cerebral infarctions [628 +/- 98 mm[3]], considerable edema [4.05 +/- 0.52%] and extensive BBB disruptions [Evans blue extravasation, 8.46 +/- 2.03 [microg/g]. L-NAME drastically improved neurological disabilities, diminished cerebral infarction [264 +/- 46 mm[3]], reduced edema [1.49 +/- 0.47%] and BBB disruption [2.93 +/- 0.66 microg/g]. The harmful actions of NOS activity on cerebral microvascular integrity are intensified by ischemia/reperfusion injuries during acute hypertension. NOS inactivation by L-NAME preserved this integrity and diminished cerebral edema

Pathogenesis and pathology of brain abscess.

Brain abscess continues to be a serious medical problem with increasing incidence despite advances in diagnostic and surgical methods, and advent of new antibiotics. This is due to increase in immune suppressed individuals, opportunistic pathogens and resistance to antibiotics. The morbidity, mortality and long term sequelae of brain abscess like cognitive impairment and poor neurological outcome are due to persistent release of proinflammatory mediators by activated microglia, astrocytes and infiltrating inflammatory cells, along with disruption of blood brain barrier. Anti-inflammatory drugs along with specific antimicrobial agents help in minimizing damage to the adjacent brain parenchyma. Identification of microorganisms in the aspirated material or the excised specimen help decide the optimal antimicrobial therapy. Prompt examination of smear and meticulous culture techniques to identify aerobes, anerobes, mycobacteria, actinomycetes, parasites and fungi are of utmost importance in choosing antibiotics. Histology complements culture and plays a key role especially in specific infections. Use of appropriate histochemical stains along with tissue reaction helps in diagnosis. The route of spread, the type and virulence of the organism, thickness of the capsule, location and number of abscesses in the brain, and immune status of the host are important determinants of outcome. Identification of microorganisms and insights into pathogenesis allow appropriate therapeutic interventions to improve outcome.