Primary leptomeningeal oligodendrogliomas (PLOs) are rare intracranial malignancies where tumors grow in the subarachnoid space without an obvious connection to the brain or spinal cord parenchyma. Adding to the three previously reported cases of PLO with no parenchymal involvement we report a fourth case of the same in this paper in a 50-year-old woman presenting with unrelenting headaches. CT scan of her head revealed hydrocephalus and MRI revealed diffuse enhancement of her leptomeninges throughout her brain and spine, prominent over the basilar region. Biopsy obtained using a frameless stereotactic biopsy showed sharply defined cell borders, clear cytoplasm, and rounded nuclei consistent with an oligodendroglioma. Our case suggests that PLO can mimic diffuse forms of granulomatous meningitis and should be suspected in patients that clinically and radiographically present like granulomatous meningitis but without blood or CSF markers for the same.

Lymphomas that develop in human immunodeficiency virus (HIV) infected patients are predominantly aggressive B-cells lymphomas. The most common HIV-associated lymphomas include Burkitt lymphoma, diffuse large B-cell lymphoma (that often involves the CNS), primary effusion lymphoma, and plasmablastic lymphoma (PBL). Of these, PBL is relatively uncommon and displays a distinct affinity for presentation in the oral cavity. In this manuscript we report a previously undescribed primary leptomeningeal form of PBL in a patient with acquired immunodeficiency syndrome. A 40-year-old HIV positive man presented with acute onset confusion, emesis, and altered mental status. Lumbar puncture showed numerous nucleated cells with atypical plasmocyte predominance. CSF flowcytometry showed kappa restriction with CD8 and CD38 positivity and negative lymphocyte markers, while the MRI showed diffuse leptomeningeal enhancement. As the extensive systemic work-up failed to reveal any disease outside the brain, an en bloc diagnostic brain and meningeal biopsy was performed. The biopsy specimen showed sheets of plasmacytoid cells with one or more large nuclei, prominent nuclear chromatin, scattered mitoses, and abundant cytoplasm, highly suggestive of plasmablastic lymphoma. HIV-associated malignancies have protean and often confusing presentations, which pose diagnostic difficulties posed to the practicing neurological-surgeons. Even in cases where an infectious cause is suspected for the meningeal enhancement, neoplastic involvement should be considered, and cytology and flow-cytometry should be routinely ordered on the CSF samples.

The authors report on the feasibility of clinical neuroendovascular optical coherence tomography (OCT) imaging as well as its efficacy and safety by comparing findings with histology in animal, cadaveric and clinical studies. Catheter-based in vivo endovascular OCT imaging was carried out intracranially in four patients, three in the anterior circulation and one in the posterior circulation (vertebral artery). The neuroendovascular OCT device was delivered to the desired location using groin access and standard endovascular procedures. In vivo findings were reproduced using ex vivo OCT imaging in corresponding animal and human (cadaveric) harvested tissue segments with findings matched by histology. OCT images correlated well with the images obtained after histologic sectioning, and visualized in vivo the laminar vascular structure. Satisfactory imaging findings were obtained with no complications. Neuroendovascular OCT imaging is thus feasible for clinical use and can detect with high resolution the structure of arterial segments. Understanding OCT imaging in non-diseased arteries is important in establishing baseline findings necessary for interpreting pathologic processes. This allows neuroendovascular optical biopsies of vascular tissue to be obtained without the need for excision and processing, and potentially allows prophylactic interventions against stroke and other cerebrovascular disease before they become symptomatic. © 2011 Copyright SPIE - The International Society for Optical Engineering.

Background

Intravascular optical coherence tomography (OCT) is a recently developed optical imaging technique that provides high-resolution cross-sectional in situ images from intact tissue based on tissue reflectance of near-infrared or infrared light.

Objective

To report on the feasibility of neuroendovascular OCT imaging and compare the neuroendovascular OCT findings with histology in nondiseased vessels in an animal, cadaveric, and clinical study.

Methods

Catheter-based in vivo endovascular OCT imaging was performed in the common carotid arteries of 2 pigs and in the intracranial carotid arteries of 3 patients. The endovascular OCT device was delivered to the desired location via groin access and using standard endovascular procedures. Images were obtained via rotational and translational scanning using external motors. In vivo findings were reproduced using ex vivo OCT imaging in corresponding animal and human (cadaveric) harvested tissue segments. These segments underwent histological examination for comparison.

Results

The structural compositions of the OCT-imaged segments of the common carotid arteries in pigs as well as the petrous and cavernous intracranial carotid arteries in patients were visualized at high resolution (8 μm). The in vivo images were identical to those obtained ex vivo, demonstrating the imaging capabilities of the endovascular OCT device. The OCT images correlated well with the images obtained after histological sectioning and visualized in vivo the laminar vascular structure.

Conclusion

Neuroendovascular OCT imaging is feasible for clinical use and can detect with high resolution the structure of arterial segments. Understanding OCT imaging in nondiseased arteries is important in establishing baseline findings necessary for interpreting pathological processes. This allows neuroendovascular optical biopsies of vascular tissue to be obtained without the need for excision and processing.

We describe a technique that uses spatially modulated near-infrared (NIR) illumination to detect and map changes in both optical properties (absorption and reduced scattering parameters) and tissue composition (oxy- and deoxyhemoglobin, total hemoglobin, and oxygen saturation) during acute ischemic injury in the rat barrel cortex. Cerebral ischemia is induced using an open vascular occlusion technique of the middle cerebral artery (MCA). Diffuse reflected NIR light (680 to 980 nm) from the left parietal somatosensory cortex is detected by a CCD camera before and after MCA occlusion. Monte Carlo simulations are used to analyze the spatial frequency dependence of the reflected light to predict spatiotemporal changes in the distribution of tissue absorption and scattering properties in the brain. Experimental results from seven rats show a 17+/-4.7% increase in tissue concentration of deoxyhemoglobin and a 45+/-3.1, 23+/-5.4, and 21+/-2.2% decrease in oxyhemoglobin, total hemoglobin concentration and cerebral tissue oxygen saturation levels, respectively, 45 min following induction of cerebral ischemia. An ischemic index (I(isch)=ctHHbctO(2)Hb) reveals an average of more then twofold contrast after MCAo. The wavelength-dependence of the reduced scattering (i.e., scatter power) decreased by 35+/-10.3% after MCA occlusion. Compared to conventional CCD-based intrinsic signal optical imaging (ISOI), the use of structured illumination and model-based analysis allows for generation of separate maps of light absorption and scattering properties as well as tissue hemoglobin concentration. This potentially provides a powerful approach for quantitative monitoring and imaging of neurophysiology and metabolism with high spatiotemporal resolution.

We reported that PAX6 suppresses glioblastoma cell growth in vivo and anchorage-independent growth without significant alteration of cell proliferation in vitro, suggesting that PAX6 may alter the tumor microenvironment. Because we found that PAX6 downregulates expression of the gene encoding vascular endothelial growth factor A (VEGFA) in glioma cells, we used a subcutaneous xenograft model to verify PAX6 suppression of VEGFA-induced angiogenesis based on CD31-immunostaining of endothelial cells. The results showed a significant reduction of VEGFA at the transcription level in PAX6-transfected cells in xenografts and PAX6 has a suppressive effect on the microvascular amplification typically seen in glioblastoma. We showed that PAX6 suppression of VEGFA expression requires its DNA binding-domain. The C-terminal truncation mutant of PAX6, however, did not show the dominant negative function in regulating VEGFA expression that it showed previously in regulating MMP2 expression. In the glioma cell line U251HF, we further determined that blocking the PI3K/Akt signaling pathway with either adenoviral-mediated PTEN expression or LY294002 enhanced PAX6-mediated suppression of VEGFA in an additive manner; thus, PAX6-mediated suppression of VEGFA is not via the canonical pathway through HIF1A. These two VEGFA-regulatory pathways can also be similarly modulated in another malignant glioma cell line, U87, but not in LN229 where the basal VEGFA level is low and PTEN is wild-type. PAX6 suppression of VEGFA appears to be blocked in LN229. In conclusion, our data showed that PAX6 can initiate in glioma cells a new signaling pathway independent of PI3K/Akt-HIF1A signaling to suppress VEGFA expression.

Abstract Purpose There are conflicting reports regarding the function of EFEMP1 in different cancer types. In this study, we sought to evaluate the role of EFEMP1 in malignant glioma biology. Experimental Design Real-time qRT-PCR was used to quantify EFEMP1 expression in 95 glioblastoma multiforme (GBM). Human high-grade glioma cell lines and primary cultures were engineered to express ectopic EFEMP1, a small hairpin RNA of EFEMP1, or treated with exogenous recombinant EFEMP1 protein. Following treatment, growth was assayed both in vitro and in vivo (subcutaneous (s.c.) and intracranial (i.c.) xenograft model systems). Results Cox regression revealed that EFEMP1 is a favorable prognostic marker for patients with GBM. Over-expression of EFEMP1 eliminated tumor development and suppressed angiogenesis, cell proliferation, and VEGFA expression, while the converse was true with knock-down of endogenous EFEMP1 expression. The EFEMP1 suppression of tumor onset time was nearly restored by ectopic VEGFA expression; however, overall tumor growth rate remained suppressed. This suggested that inhibition of angiogenesis was only partly responsible for EFEMP1's impact on glioma development. In glioma cells that were treated by exogenous EFEMP1 protein or over-expressed endogenous EFEMP1, the EGFR level was reduced and AKT signaling activity attenuated. Mixing of EFEMP1 protein with cells prior to s.c. and i.c. implantations or injection of the protein around the established s.c. xenografts, both significantly suppressed tumorigenicity. Conclusions Overall, our data reveals that EEFEMP1 suppresses glioma growth in vivo, both by modulating the tumor extracellular microenvironment and by altering critical intracellular oncogenic signaling pathways.