Neuro-oncology

Neurological Disorders And Stroke

Investigators

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Abstract

VHL[unreadable] To gain insights into the natural history of VHL-associated CNS hemangioblastomas, we have reviewed the serial clinical and imaging findings in VHL patients. Data from these studies revealed that hemangioblastomas have multiple periods of tumor growth separated by periods of arrested growth and many untreated tumors may remain the same size for several years and will not require treatment. Furthermore, peritumoral cysts were commonly found with CNS hemangioblastomas and the pace of enlargement for the cysts was much greater than for the hemangioblastoma itself. In fact, by the time symptoms appeared, the majority of the mass effect that produced the symptoms derived from the cyst, rather than the associated hemangioblastoma. Longitudinal imaging and cyst fluid analyses demonstrated that the mechanism that underlies the formation of peritumoral cysts is plasma extravasation through permeable tumor vessels. Subsequently, factors that lead to increased tumor vessel permeability (e.g., radiation) may exacerbate edema and/or cyst propagation, while targeted therapeutic agents that reduce tumor vascular permeability could potentially reduce edema/cyst formation and delay or prevent symptom development. Future findings of this study should lead to the identification of hemangioblastoma properties that will predict symptom formation permitting the treatment of smaller tumors, which should reduce the morbidity associated with waiting to treat larger, symptomatic hemangioblastomas.[unreadable] [unreadable] Previous studies have suggested that the neoplastic cells in hemangioblastomas are developmentally-arrested hemangioblasts. We characterized and expanded tumor cells from resected CNS hemangioblastomas in VHL patients. Consistent with an embryologically-derived hemangioblast, the neoplastic cells demonstrated co-expression of mesodermal markers brachyury, Flk-1 and Scl. The neoplastic cells also expressed hematopoietic stem cell antigens and receptors including CD133, CD34, c-kit, Scl, erythropoietin and erythropoietin receptor. Neoplastic cells (hemangioblasts) were expanded and differentiated into erythrocytic, granulocytic and endothelial progenitors. Deletion of the wild-type VHL allele in the hematopoietic and endothelial progeny confirmed their neoplastic origin. These findings indicate that the neoplastic cells from CNS hemangioblastomas in VHL patients are hemangioblasts derived from embryologically-arrested mesoderm and provide evidence for human tumourigenesis as developmental phenomenon. [unreadable] [unreadable] ELSTs in VHL are associated with hearing loss, tinnitus, vertigo, aural fullness, and/or facial nerve dysfunction. In VHL, ELSTs frequently occur bilaterally and often result in significant neurologic disability, including deafness. Despite the devastating effects of ELSTs and their association with VHL, the underlying pathophysiologic mechanisms of audiovestibular dysfunction associated with ELSTs and the optimal timing of treatment of ELSTs had not been defined. We analyzed the serial imaging, clinical and surgical findings in 35 VHL patients with 38 ELSTs. We found that ELST size was not related to sensorineural hearing loss or vestibulopathy. ELST-associated sensorineural hearing loss and vestibulopathy often occurred suddenly due to tumor-associated intralabyrinthine hemorrhage, or insidiously, consistent with endolymphatic hydrops. Both of these pathophysiologic mechanisms were found with very small tumors that are not associated with otic capsule invasion. These findings suggest that the high incidence of unexplained audiovestibular dysfunction in VHL may in part be explained microscopic ELSTs. Because audiovestibular morbidity is not related to tumor size and is unpredictable, early detection and surgical treatment of ELSTs can reduce audiovestibular morbidity. [unreadable] [unreadable] Brain Metastases[unreadable] Despite the increasing use of immunotherapy in the treatment of systemic melanoma, the effects of this therapy in the management of patients with associated brain metastases is not defined. We analyzed melanoma immunotherapy patients with brain metastases that were surgically resected. Consecutive melanoma immunotherapy patients with brain metastases were included. Patient characteristics, tumor properties, response to immunotherapy and use of adjuvant whole-brain radiation therapy (WBRT) were analyzed. Forty-three patients (median age, 44.5 years) underwent resection of 54 brain metastases. Median metastasis volume was 1.9 cm3. Local and distant brain recurrence rates were similar between WBRT (25.0%, 37.5%; respectively) versus non-WBRT (3.7%, 29.6%) groups for the duration of follow-up (P>0.05). Furthermore, survival from the time of resection of the first brain metastasis was the same between WBRT (mean, 19.0 months) and non-WBRT groups (mean, 18.4 months; P>0.05). Objective systemic response to immunotherapy (n=16) was associated with increased time to recurrence in the brain and survival following first brain metastasis resection (P<0.05). Surgical resection of melanoma brain metastases in immunotherapy patients provides excellent local control with low morbidity. Moreover, these results indicate that adjuvant WBRT in melanoma immunotherapy patients with limited metastatic disease to the brain may be avoided.[unreadable] [unreadable] GBM[unreadable] GBM, the most malignant of the gliomas, are highly aggressive and invasive tumors. Among the phenotypic characteristics associated with malignant GBMs are rapid growth, high glucose consumption, and perivascular infiltration of glioma cells. Aquaporins (AQP) function as a water-selective transport mechanism in cells, and have been proposed as a contributor to brain tumor-associated edema. However, AQPs probably also contribute to pH homeostasis in highly metabolic cells by facilitating the movement of H+ from the inside to the outside of the cell, thus relieving intracellular acidosis. We observed that AQP-1 is absent from normal brain, but markedly and selectively upregulated in GBMs in a perivascular pattern at the tumor periphery. This upregulation occurs exclusively in the glioma cell and not in the endothelial cells of the blood vessels. This pattern of AQP-1 expression in GBMs is of interest because 1) the tumor periphery is also the region of highest glucose consumption, rendering these tumor cells most susceptible to intracellular acidosis, and 2) glioma cell invasion occurs in the perivascular space at the tumor periphery. In cultured glioma cells, we observed that the strongest inducer of AQP-1 was increased glucose consumption. This upregulation probably occurs through activation of a carbohydrate-responsive element (ChoRE) in the AQP-1 gene promoter. Two other proteins, which also have a ChoRE in their gene promoters, are lactate dehydrogenase (LDH) and cathepsin B. These enzymes were also strongly upregulated in glioma cells under the same conditions as AQP-1. This is of interest because, along with AQP-1, LDH contributes to acidification of the medium, and cathepsin B is an acid-dependent protease associated with glioma cell infiltration and spread. In addition to the perivascular staining pattern of AQP-1 described above, immunohistochemical staining of human GBM specimens also revealed increased expression of LDH and cathepsin B in the same glioma cells associated with blood vessels at the tumor periphery. GBMs are known to exhibit high rates of glucose consumption. Increased glucose metabolism at the tumor periphery may provide a scenario by which coincident upregulation of AQP1, LDH, and cathepsin B contributes to acidification of the extracellular milieu, and provides optimal conditions for proteolytic degradation of the extracellular matrix and glioma cell invasion/migration in the perivascular space. Specific upregulation and metabolic consequences of increased AQP1 in gliomas may provide a therapeutic target.