Upfront boost Gamma Knife "leading-edge" radiosurgery to FLAIR MRI-defined tumor migration pathways in 174 patients with glioblastoma multiforme: a 15-year assessment of a novel therapy.

OBJECTIVE Glioblastoma multiforme (GBM) is composed of cells that migrate through the brain along predictable white matter pathways. Targeting white matter pathways adjacent to, and leading away from, the original contrast-enhancing tumor site (termed leading-edge radiosurgery [LERS]) with single-fraction stereotactic radiosurgery as a boost to standard therapy could limit the spread of glioma cells and improve clinical outcomes. METHODS Between December 2000 and May 2016, after an initial diagnosis of GBM and prior to or during standard radiation therapy and carmustine or temozolomide chemotherapy, 174 patients treated with radiosurgery to the leading edge (LE) of tumor cell migration were reviewed. The LE was defined as a region outside the contrast-enhancing tumor nidus, defined by FLAIR MRI. The median age of patients was 59 years (range 22-87 years). Patients underwent LERS a median of 18 days from original diagnosis. The median target volume of 48.5 cm3 (range 2.5-220.0 cm3) of LE tissue was targeted using a median dose of 8 Gy (range 6-14 Gy) at the 50% isodose line. RESULTS The median overall survival was 23 months (mean 43 months) from diagnosis. The 2-, 3-, 5-, 7-, and 10-year actual overall survival rates after LERS were 39%, 26%, 16%, 10%, and 4%, respectively. Nine percent of patients developed treatment-related imaging-documented changes due to LERS. Nineteen percent of patients were hospitalized for management of edema, 22% for resection of a tumor cyst or new tumor bulk, and 2% for shunting to treat hydrocephalus throughout the course of their disease. Of the patients still alive, Karnofsky Performance Scale scores remained stable in 90% of patients and decreased by 1-3 grades in 10% due to symptomatic treatment-related imaging changes. CONCLUSIONS LERS is a safe and effective upfront adjunctive therapy for patients with newly diagnosed GBM. Limitations of this study include a single-center experience and single-institution determination of the LE tumor target. Use of a leading-edge calculation algorithm will be described to achieve a consistent approach to defining the LE target for general use. A multicenter trial will further elucidate its value in the treatment of GBM.

Closed head injury-induced changes in brain pathophysiology assessed with near-infrared structured illumination in a mouse model.

Use of near-infrared (NIR) structured illumination technique has recently received great interest in biomedical research and clinical studies because of its ability to perform wide-field imaging and quantitatively map changes in tissue hemodynamic properties and morphological features in a noncontact and scan-free fashion. We report on the feasibility of using the same to quantitatively monitor and map changes in brain optical properties and physiological parameters pre- and post-closed head injury in a mouse model. Five anesthetized male mice underwent head injury by weight-drop model using a ~50-g cylindrical metal object falling from a height of 90 cm onto the intact scalp. During experiments, NIR structured illumination was projected on the mouse head at two spatial frequencies and six different NIR wavelengths. A CCD camera positioned perpendicular to the head recorded the diffuse-reflected light. Computer analysis performed off-line on the captured data reveals spatiotemporal changes in the distribution of brain tissue absorption and reduced scattering coefficients. Using Beer's law and Mie theory, hemodynamic (hemoglobin, oxygen saturation, and lipids) and morphological (scattering amplitude and power) changes up to 1-h post-trauma were observed in comparison with baseline measurements. Functional maps of different brain properties were also generated. Following injury, we found difference in both brain hemodynamic and morphologic properties with respect to baseline levels, where in some properties, this difference was considered statistically significant. Specifically, a t-test indicates a substantial decrease in oxyhemoglobin (HbO(2)) concentration and tissue oxygen saturation (StO(2)) post-injury (p < 0.01 and p < 0.001, respectively). Overall, our preliminary results demonstrate the potential application of NIR structured illumination technique to track and spatially map changes in intact mouse brain pathophysiological parameters following head injury.

Monitoring hemodynamic and morphologic responses to closed head injury in a mouse model using orthogonal diffuse near-infrared light reflectance spectroscopy.

The authors' aim is to assess and quantitatively measure brain hemodynamic and morphological variations during closed-head injury (CHI) in mice using orthogonal diffuse near-infrared reflectance spectroscopy (o-DRS). CHI is a type of injury to the head that does not penetrate the skull. Usually, it is caused by mechanical blows to the head and frequently occurs in traffic accidents, falls, and assaults. Measurements of brain optical properties, namely absorption and reduced scattering coefficients in the wavelength range from 650 to 1000 nm were carried out by employing different source-detector distance and locations to provide depth sensitivity on an intact scalp over the duration of the whole experiment. Furthermore, alteration in both cortical hemodynamics and morphologic markers, i.e., scattering power and amplitude properties were derived. CHI was induced in anesthetized male mice by a weight-drop model using ∼50 g cylindrical metal falling from a height of 90 cm onto the intact scalp producing an impact of 4500 g cm. With respect to baseline, difference in brain physiological properties was observed following injury up to 1 h post-trauma. Additionally, the reduced scattering spectral shapes followed Mie scattering theory was quantified and clearly shows changes in both scattering amplitude and power from baseline indicating structural variations likely from evolving cerebral edema during CHI. We further demonstrate high correlation between scattering amplitude and scattering power, with more than 20% difference in slope in comparison to preinjury. This result indicates the possibility of using the slope also as a marker for detection of structural changes. Finally, experiments investigating brain function during the first 20 min postinjury were conducted and changes in chromophore concentrations and scattering were observed. Overall, our experiments demonstrate the potential of using the proposed technique as a valuable quantitative noninvasive tool for monitoring brain physiology following CHI injury at the bedside and/or at the field.

Diffuse near-infrared reflectance spectroscopy during heatstroke in a mouse model: pilot study.

Heatstroke, a form of hyperthermia, is a life-threatening condition characterized by an elevated core body temperature that rises above 40°C (104°F) and central nervous system dysfunction that results in delirium, convulsions, or coma. Without emergency treatment, the victim lapses into a coma and death soon follows. The study presented was conducted with a diffuse reflectance spectroscopy (DRS) setup to assess the effects of brain dysfunction that occurred during heatstroke in mice model (n=6). It was hypothesized that DRS can be utilized in small animal studies to monitor change in internal brain tissue temperature during heatstroke injury since it induces a sequence of pathologic changes that change the tissue composition and structure. Heatstroke was induced by exposure of the mice body under general anesthesia, to a high ambient temperature. A type of DRS in which the brain tissue was illuminated through the intact scalp with a broadband light source and diffuse reflected spectra was employed, taking in the spectral region between 650 and 1000 nm and acquired at an angle of 90 deg at a position on the scalp ∼12 mm from the illumination site. The temperature at the onset of the experiment was ∼34°C (rectal temperature) with increasing intervals of 1°C until mouse death. The increase in temperature caused optical scattering signal changes consistent with a structural alteration of brain tissue, ultimately resulting in death. We have found that the peak absorbance intensity and its second derivative at specific wavelengths correlate well with temperature with an exponential dependence. Based on these findings, in order to estimate the influence of temperature on the internal brain tissue a reflectance-temperature index was established and was seen to correlate as well with measured temperature. Overall, results indicate variations in neural tissue properties during heatstroke and the feasibility to monitor and assess internal temperature variations using DRS. Although several approaches have described the rise in temperature and its impact on tissue, to the best of our knowledge no information is available describing the ability to monitor temperature during heatstroke with DRS. The motivation of this study was to successfully describe this ability.

Glioma cell growth inhibition following photochemical internalization enhanced non-viral PTEN gene transfection.

BACKGROUND AND OBJECTIVE: One of many limitations for cancer gene therapy is the inability of the therapeutic gene to transfect a sufficient number of tumor cells. Photochemical internalization (PCI) is a photodynamic therapy-based approach for improving the delivery of macromolecules and genes into the cell cytosol. The utility of PCI for the delivery of the GFP reporter gene on the same plasmid as a tumor suppressor gene (PTEN) was investigated in monolayers of U251 human glioma cells and muticell U87 glioma spheroids. MATERIALS AND METHODS: U251 monolayers or U87 spheroids were incubated in AlPcS(2a) and non-viral vector polyplexes for 18 hours. In all cases, light treatment was performed with a diode laser at a wavelength of 670 nm. The non-viral transfection agents, branched polyethylenimine (bPEI), or protamine sulfate (PS), were used with the plasmid constructs GFP/PTEN or GFP. RESULTS: PS/GFP polyplexes were much less toxic to the glioma cells compared to bPEI/GFP polyplexes but were highly inefficient at gene transfection if used alone. PCI resulted in a 5- to 10-fold increase in GFP protein expression compared to controls. PCI-bPEI/PTEN or PCI-PS/PTEN transfection of either U251 monolayers or U87 spheroids significantly inhibited their growth. but had no effect on MCF-7 cells containing a wild-type PTEN gene. In addition PCI-GFP transfection of gliomas cells had no effect on their growth pattern. CONCLUSIONS: Collectively, the results suggest that AlPcS(2a) -mediated PCI can be used to enhance cell growth inhibition via transfection of tumor suppressor genes in glioma cells containing mutant PTEN genes.

Photochemical internalization of bleomycin for glioma treatment.

We study the use of photochemical internalization (PCI) for enhancing chemotherapeutic response to malignant glioma cells in vitro. Two models are studied: monolayers consisting of F98 rat glioma cells and human glioma spheroids established from biopsy-derived glioma cells. In both cases, the cytotoxicity of aluminum phthalocyanine disulfonate (AlPcS2a)-based PCI of bleomycin was compared to AlPcS(2a)-photodynamic therapy (PDT) and chemotherapy alone. Monolayers and spheroids were incubated with AlPcS(2a) (PDT effect), bleomycin (chemotherapy effect), or AlPcS(2a)+bleomycin (PCI effect) and were illuminated (670 nm). Toxicity was evaluated using colony formation assays or spheroid growth kinetics. F98 cells in monolayer/spheroids were not particularly sensitive to the effects of low radiant exposure (1.5 J/cm(2) @ 5 mW/cm(2)) AlPcS(2a)-PDT. Bleomycin was moderately toxic to F98 cells in monolayer at relatively low concentrations-incubation of F98 cells in 0.1 µg/ml for 4 h resulted in 80% survival, but less toxic in human glioma spheroids respectively. In both in vitro systems investigated, a significant PCI effect is seen. PCI using 1.5 J/cm(2) together with 0.25 µg/ml bleomycin resulted in approximately 20% and 18% survival of F98 rat glioma cells and human glioma spheroids, respectively. These results show that AlPcS(2a)-mediated PCI can be used to enhance the efficacy of chemotherapeutic agents such as bleomycin in malignant gliomas.

Photochemical internalization-mediated delivery of chemotherapeutic agents in human breast tumor cell lines.

Breast-conservation surgery (BCS) is now utilized in patients with stage I and II invasive breast cancer. However, positive surgical margins are associated with recurrence, and therefore some form of localized postoperative therapy (radiation/chemotherapy) is necessary to eliminate remaining cancer cells. Existing modalities have significant treatment-limiting side effects; therefore, alternative forms of localized therapy need to be explored. We studied the ex vivo effects of photochemical internalization (PCI) using 4 chemotherapeutic agents: cisplatin, cisplatin analog [D prostanoid, DP], doxorubicin, and bleomycin) on 3 breast cancer cell lines: MCF-7, MDA-MB-435, and MDA-MB-231. Illumination was carried out using a 670-nm diode laser at 5 mW/cm2 following incubation in the photosensitizer with aluminum phthalocyanine disulfonate. Toxicity was investigated using colony-forming assays and the mechanism of cell death was determined using Annexin flow-cytometry. We found that toxicity of DP and bleomycin was significantly enhanced by PCI compared with drug alone but was unchanged for cisplatin and doxorubicin. PCI treatment caused a decrease in the percentage of viable cells, predominantly by enhancing apoptosis. The action was synergistic across all 3 cell lines tested for DP and bleomycin. Thus, with appropriate delivery devices and choice of chemotherapeutic agents, PCI holds the promise of enhancing tumor cell toxicity surrounding the cavity of BCS resection sites and thereby decreasing local recurrence.

The sacral hiatus approach for drainage of anterior lumbo-sacral epidural abscesses. A case report and technical note.

Lumbosacral epidural abscesses are managed either conservatively with IV antibiotics or with open surgery, particularly in the presence of acute neurological symptoms. Their location makes it difficult for image-guided interventional approaches either for biopsy or evacuation. We report the sacral hiatus and canal as a corridor for image-guided minimally invasive abscess of lumbosacral epidural abscess for aspiration. A 56-year-old man presented to the emergency department complaining of six weeks of worsening low back pain. MRI of the patient's lumbosacral spine showed osteomyelitis involving his L5, S1 vertebrae, L5-S1 discitis, as well as an anterior epidural abscess extending from L4-5 disc space to the S2 vertebral level. Blood cultures grew out gram-positive cocci. For drainage, a 5-French micropuncture kit was utilized to access the hiatus. Under fluoroscopic guidance a microwire was then advanced along the sacral canal. An 18-gauge needle curved to approximate the contours of the sacral canal was then advanced over the guidewire. Once anatomic access was established 2 ml of thick purulent material was aspirated. The patient tolerated the procedure well, and no focal nerve root symptoms were noted following the procedure. Image-guided aspiration of lumbosacral epidural abscesses can thus be carried out in a safe and effective manner using a sacral hiatus approach.

Cerebral edema following photodynamic therapy using endogenous and exogenous photosensitizers in normal brain.

BACKGROUND AND OBJECTIVE: Failure of treatment for high-grade gliomas is usually due to local recurrence at the site of surgical resection indicating that a more aggressive form of local therapy such as photodynamic therapy (PDT) could be of benefit. The increase in brain edema following PDT using endogenous and exogenous photosensitizers was compared in terms of animal survival, MR imaging, and histopathological changes in normal brain. MATERIALS AND METHODS: Fischer rats were exposed to increasing laser light treatment following intraperitoneal injection of either the photosensitizers 5-aminolevulinic acid (ALA) or aluminum phthalocyanine disulfonate (AlPcS2a). Light treatment was applied either via an optical fiber inserted directly into the brain parenchyma or through a fiber applied to the surface of the intact skull. Edema development was followed by T2-weighted MR imaging. RESULTS: ALA and AlPcS2a PDT resulted in a fluence dependent increase in cerebral edema and mortality. AlPcS2a PDT showed significant edema and mortality even at low fluences following interstitial light delivery, which was reduced with surface illumination. The mechanism of edema was determined to be vasogenic by response to steroid therapy and confirmed on histological images. CONCLUSIONS: T2 and contrast enhanced T1 MRI scanning proved to be a highly effective and noninvasive modality in following the development of the edema reaction and the degree and time course of blood-brain barrier dysfunction thus allowing the use of fewer animals. ALA mediated PDT induced a lower edema reaction than that observed with the photosensitizer AlPcS2a.

EFEMP1 suppresses malignant glioma growth and exerts its action within the tumor extracellular compartment.

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.

Primary leptomeningeal plasmablastic lymphoma.

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.

Neuroendovascular optical coherence tomography imaging and histological analysis.

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.

Safety and feasibility of intraarterial eptifibatide as a revascularization tool in acute ischemic stroke.

OBJECT: Experience with the use of platelet glycoprotein (GP) IIb-IIIa inhibitor eptifibatide in patients with ischemic stroke is limited. The authors report the off-label use of intraarterial eptifibatide during endovascular ischemic stroke revascularization procedures for reocclusion after documented recanalization or formed fresh thrombi in distal vessels that were inaccessible to endovascular devices. METHODS: Patients who received intraarterial eptifibatide were identified from a prospectively collected database of patients in whom endovascular revascularization for acute ischemic stroke was attempted between 2005 and 2008. Data were analyzed retrospectively. The intraarterial eptifibatide dose was a single-bolus dose of 180 µg/kg body weight. Primary outcome measures were angiographic recanalization (Thrombolysis in Myocardial Infarction Grade 2 or 3), symptomatic intracranial hemorrhage rate, overall mortality rate, and favorable 3-month modified Rankin Scale score (≤ 2). RESULTS: The study included 35 patients (mean age 62 years, range 18-85 years). The median presenting National Institutes of Health Stroke Scale score was 13. Two patients received intravenous tissue plasminogen activator before endovascular therapy. The median time from symptom onset to therapy initiation was 230 minutes (range 90-1370 minutes). Twelve patients (34%) received intraarterial tissue plasminogen activator without mechanical measures. Mechanical revascularization measures used were Merci retriever in 19 (54%), Penumbra device in 1 (3%), balloon angioplasty in 15 (43%), and stent placement in 22 (63%) patients. The mean dose of intraarterial eptifibatide was 11.6 mg (range 5-16.6 mg). Partial-to-complete recanalization (Thrombolysis in Myocardial Infarction Grade 2 or 3) was achieved in 27 patients (77%). Postprocedure intracranial hemorrhage occurred in 13 patients (37%), causing symptoms in 5 (14%). In the 5 symptomatic intracranial hemorrhage cases, all patients but one presented more than 8 hours after symptom onset and all received intraarterial recombinant tissue plasminogen activator. The median discharge National Institutes of Health Stroke Scale score was 7 (range 0-17). At 3 months postprocedure, 21 patients (60%) had a modified Rankin Scale score ≤ 2, and 8 patients (23%) had died. CONCLUSIONS: Adjunctive intraarterial eptifibatide is a feasible option for salvage of reocclusion and thrombolysis of distal inaccessible thrombi during endovascular stroke revascularization. Its safety and efficacy need to be studied further in larger, multicenter, controlled studies.

PAX6 suppression of glioma angiogenesis and the expression of vascular endothelial growth factor A.

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.

Safety, effectiveness, and practicality of endovascular therapy within the first 3 hours of acute ischemic stroke onset.

OBJECTIVE: This study assesses the safety, effectiveness, and practicality of endovascular therapy for ischemic stroke within the first 3 hours of symptom onset. METHODS: A retrospective chart review (January 2000-July 2008) was performed of 94 consecutive patients who had endovascular therapy within 3 hours after acute ischemic stroke onset. Endovascular therapy was administered in patients in whom intravenous (IV) thrombolysis failed or was contraindicated. Outcome measures analyzed were recanalization rate, intracranial hemorrhage (ICH) rate, procedural complications, modified Rankin Scale score, National Institutes of Health Stroke Scale (NIHSS) score, and mortality rate. RESULTS: The study included 41 male and 53 female patients with a mean age of 68 years (age range, 13-98 years). The mean NIHSS score at the time of admission was 14.7. Eight-three patients had anterior circulation ischemic events, and 11 had posterior circulation ischemic events. The cause was determined to be arterioembolic in 21 patients (22%), cardioembolic in 45 (48%), arterial dissection in 2, left-to-right cardiac shunt in 1, and unknown in 25 (27%). Endovascular interventions included intra-arterial (IA) pharmacological thrombolysis (n = 44), mechanical thrombolysis (Merci Retrieval System, intracranial or extracranial stent, microwire) (n = 79), and intracranial or extracranial angioplasty (n = 32) in various combinations. The mean time from stroke onset to angiogram was 72 minutes. Thirteen patients received a half dose (n = 8) or full dose (n = 5) of IV thrombolysis (tissue plasminogen activator [tPA]) in conjunction with endovascular therapy. Twenty-two patients received IA or IV adjunctive glycoprotein IIb/IIIa inhibitor (eptifibatide). Partial-to-complete recanalization (Thrombolysis in Myocardial Infarction scale score of 2 or 3) was achieved in 62 of 89 of patients (70%) presenting with significant occlusion (Thrombolysis in Myocardial Infarction scale score of 0 or 1). Postprocedure symptomatic ICH occurred in 5 patients (5.3%), which was purely subarachnoid hemorrhage in 3 patients. Of these, 2 received IA tPA in conjunction with Merci Retrieval System passes; the others each received IA tPA, mechanical thrombectomy (guidewire), or extracranial angioplasty. The total mortality rate including procedural mortality, progression of disease, and other comorbidities was 26.6%. Sixteen patients (17%) were discharged home, 49 (52%) to rehabilitation, and 4 (4%) to long-term care facilities. Overall, 36.7% had a modified Rankin Scale score of 2 or less at discharge. The mean NIHSS score at discharge was 6.5, representing an overall 8-point improvement on the NIHSS. CONCLUSION: Endovascular therapy within the first 3 hours of stroke symptom onset in patients in whom IV tPA therapy is contraindicated or fails is safe, effective, and practical. The risk of symptomatic ICH is low and should be viewed relative to the poor prognosis in this group of patients.

The effects of ultra low fluence rate single and repetitive photodynamic therapy on glioma spheroids.

BACKGROUND AND OBJECTIVE: Achieving local control of gliomas with photodynamic therapy (PDT) requires the delivery of adequate light fluences to depths of 1-2 cm in the resection margin where the majority of local recurrences originate. This is clinically impractical with current single-shot, intraoperative PDT treatments due to the length of time required to deliver adequate fluences. Multiple or extended treatment protocols would therefore seem to be required. The response of human glioma spheroids to 5-aminolevulinic acid (ALA)-mediated PDT using single or, repetitive light delivery protocols was investigated at both low and ultra low fluence rates. STUDY DESIGN/MATERIALS AND METHODS: Human glioma spheroids (400 microm diameter) were subjected to sub-threshold light fluence (1.5, 3, or 6 J cm(-2)) ALA-PDT consisting of four light delivery schemes: single treatment given over either 1 or 24 hours, repetitive treatment given either as four 1 hour light treatments separated by a 4 day interval, or 24 hours light delivery, consisting of four 24 hours treatments separated by a 3 day interval. Treatment efficacy was evaluated using a growth assay. In some cases, confocal microscopy was used to image cell viability. RESULTS: The repetitive and single light treatment protocols were most effective when delivered at ultra low (microW cm(-2)) fluence rates. In all cases, growth inhibition was light dose-dependent. The repetitive ultra low fluence rate treatment (1.5 J cm(-2); irradiance = 17 microW cm(-2)) light delivery protocol was the most effective resulting in total growth inhibition during the 2-week observation period. CONCLUSION: Ultra low light fluence rate ALA-PDT results in significant spheroid growth inhibition. Repeated administration of ALA was required during repetitive and/or protracted single PDT treatment protocols. The existence of a lower fluence rate limit, below which the efficacy of threshold light fluences diminish was not found in these studies. Lasers Surg. Med. 41:578-584, 2009. (c) 2009 Wiley-Liss, Inc.

Imaging cortical absorption, scattering, and hemodynamic response during ischemic stroke using spatially modulated near-infrared illumination.

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.

Primary leptomeningeal oligodendrogliomatosis.

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.

Motexafin gadolinium enhances the efficacy of aminolevulinic acid mediated-photodynamic therapy in human glioma spheroids.

Photodynamic therapy (PDT) has been investigated as a postoperative treatment in patients with high grade gliomas. The purpose of this in vitro investigation was to determine whether motexafin gadolinium (MGd), a known radiation sensitizer, could potentiate the effects of 5-aminolevulinic acid (ALA)-PDT. Human glioma (ACBT) spheroids (250 microm diameter) were incubated in 5-aminolevulinic acid (ALA) with and without MGd and irradiated with 635 nm light for a total light fluence of 6, 12, or 18 J cm(-2) delivered at a fluence rate of 5 mW cm(-2). Spheroid growth was monitored for a period of 4 weeks following each treatment. In another set of experiments, 400-500 microm diameter ACBT spheroids were implanted into a gel collagen matrix and subjected to ALA-PDT (fluence: 3 or 6 J cm(-2)), MGd, or a combination of ALA-PDT and MGd. The migration distance of surviving glioma cells in each treatment group was recorded over a 5-day period. The results showed that MGd interacted with PDT in a synergistic manner resulting in greater cytotoxicity than that achievable with either treatment modality alone. The degree of synergism was shown to increase with increasing light fluence. At the highest light fluence investigated (18 J cm(-2)), the percentage of spheroids demonstrating growth 4 weeks following exposure to MGd, ALA-PDT, or MGd + ALA-PDT was 100%, 75%, and 15%, respectively. The results of cell migration studies revealed that the combination of PDT and MGd produced a significant inhibitory effect on glioma cell migration: the addition of MGd resulted in an approximately three times reduction in migration distance compared with PDT alone. Overall, the results suggest that MGd can potentiate both the cytotoxic and migration inhibitory effects of ALA-PDT and hence, this combined therapeutic approach has the potential to extend treatment volumes in patients with malignant gliomas.