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PubMed2003

Variation of the relaxographic "shutter-speed" for transcytolemmal water exchange affects the CR bolus-tracking curve shape.

Contrast reagents (CRs) may enter the tissue interstitium for a period after a vascular bolus injection. As the amount of interstitial CR increases, the longitudinal relaxographic NMR "shutter-speed" (T(-1)) for the equilibrium transcytolemmal water exchange process increases. The quantity T(-1) is given by |r(1o)[CR(o)] + R(1o0) - R(1i)| (where r(1o) and [CR(o)] represent the interstitial (extracellular) CR relaxivity and concentration, respectively, and R(1o0) and R(1i) are the extra- and intracellular (1)H(2)O relaxation rate constants, respectively, in the absence of exchange). The increase of T(-1) with [CR(o)] causes the kinetics of the water exchange equilibrium to appear to decrease. Here, analytical theory for two-site-exchange processes is combined with that for pharmacokinetic CR delivery, extraction, and distribution in a method termed BOLus Enhanced Relaxation Overview (BOLERO(Copyright )). The shutter-speed effect alters the shape of the bolus-tracking (B-T) time-course. It is shown that this is mostly accounted for by the inclusion of only one additional parameter, which measures the mean intracellular lifetime of a water molecule. Simulated and real data demonstrate that the effect of shutter-speed variation on pharmacokinetic parameters can be very significant: neglecting this effect can lead to an underestimation of the parameter values by 50%. This phenomenon can be heterogeneous. Within a tiny gliosarcoma implanted in the rat brain, the interstitial CR in the tumor core never rises to a level sufficient to cause apparent slowing of the exchange process. However, within the few microns needed to reach the proliferating rim, this occurs to a significant degree. Thus, even relative pharmacokinetic quantities can be incorrectly represented in a parametric map that neglects this effect. The BOLERO analysis shows promise for in vivo vascular phenotyping in pathophysiology. It also includes a provision for approximating the separation of the perfusion and permeability contributions to CR extravasation.

Animals↗
PubMed2003

Amide proton transfer (APT) contrast for imaging of brain tumors.

In this work we demonstrate that specific MR image contrast can be produced in the water signal that reflects endogenous cellular protein and peptide content in intracranial rat 9L gliosarcomas. Although the concentration of these mobile proteins and peptides is only in the millimolar range, a detection sensitivity of several percent on the water signal (molar concentration) was achieved. This was accomplished with detection sensitivity enhancement by selective radiofrequency (RF) labeling of the amide protons, and by utilizing the effective transfer of this label to water via hydrogen exchange. Brain tumors were also assessed by conventional T(1)-weighted, T(2)-weighted, and diffusion-weighted imaging. Whereas these commonly-used approaches yielded heterogeneous images, the new amide proton transfer (APT) technique showed a single well-defined region of hyperintensity that was assigned to brain tumor tissue.

Amides↗
PubMed1995

BSH distributions in the canine head and a human patient using 11B MRI.

A 3D projection reconstruction (3DPR) method was used to obtain in vivo 11B images in a large canine brain tumor model and in a human infused with borocaptate sodium (BSH). Studies were performed in dogs with and without gliosarcomas implanted and grown to a size of 2-3 cm. The 3DPR method demonstrates a signal-to-noise ratio (SNR) that allows qualitative kinetic studies of the boron compound in normal and tumor tissue of the head. The measurements indicate initial uptake of the BSH compound in tumor to be less than that in muscle with no uptake in normal brain tissue. Moreover, uptake of BSH in tissue was found to lag the boron concentration in blood with delays that depend on tissue type. In addition, the first human boron images were obtained on a patient who underwent surgical resection and volumetric debulking of a large (7 cm) glioblastoma multiforme. BSH was readily taken up in residual tumor tissue, while diffusion into the resection volume was slower.

Animals↗
PubMed2006

Proton and sodium MRI assessment of emerging tumor chemotherapeutic resistance.

The ultimate goal of any cancer therapy is to target the elimination of neoplastic cells. Although newer therapeutic strategies are in constant development, therapeutic assessment has been hampered by the inability to assess, rapidly and quantitatively, efficacy in vivo. Diffusion imaging and, more recently, sodium MRI have demonstrated their distinct abilities to detect therapy-induced alterations in tumor cellularity, which has been demonstrated to be indicative of therapeutic efficacy. More importantly, both imaging modalities detect tumor response much earlier than traditional methodologies that rely on macroscopic volumetric changes. In this study, the correlation between tumor sodium and diffusion was further tested to demonstrate the sensitivity of sodium imaging to gauge tumor response to therapy by using a 9L rat gliosarcoma treated with varying doses of BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea]. This orthotopic model has been demonstrated to display variability in response to BCNU therapy where initial insult has been shown to lead to drug-resistance. In brief, a single 26.6 mg/kg BCNU dose yielded dramatic responses in both diffusion and sodium MRI. However, a second equivalent BCNU dose yielded a much smaller change in diffusion and sodium, suggesting a drop in tumor sensitivity to BCNU. The MRI responses of animals treated with 13.3 mg/kg BCNU were much lower and similar responses were observed after the initial and secondary applications of BCNU. Furthermore, these results were further validated using volumetric measurements of the tumor and also ex vivo determination of tumor sensitivity to BCNU. Overall, these experiments demonstrate the sensitivity and applicability of sodium and diffusion MRI as tools for dynamic assessment of tumor response to therapy.

Animals↗
PubMed2000

Phase I study of adenoviral delivery of the HSV-tk gene and ganciclovir administration in patients with current malignant brain tumors.

Between December 1996 and September 1998, 13 patients with advanced recurrent malignant brain tumors (9 with glioblastoma multiforme, 1 with gliosarcoma, and 3 with anaplastic astrocytoma) were treated with a single intratumoral injection of 2 x 10(9), 2 x 10(10), 2 x 10(11), or 2 x 10(12) vector particles (VP) of a replication-defective adenoviral vector bearing the herpes simplex virus thymidine kinase gene driven by the Rous sarcoma virus promoter (Adv.RSVtk), followed by ganciclovir (GCV) treatment. The VP to infectious unit ratio was 20:1. Our primary objective was to determine the safety of this treatment. Injection of Adv.RSVtk in doses <==2 x 10(11) VP, followed by GCV, was safely tolerated. Patients treated with the highest dose, 2 x 10(12) VP, exhibited central nervous system toxicity with confusion, hyponatremia, and seizures. One patient is living and stable 29.2 months after treatment. Two patients survived >25 months before succumbing to tumor progression. Ten patients died within 10 months of treatment, 9 from tumor progression and 1 with sepsis and endocarditis. Neuropathologic examination of postmortem tissue demonstrated cavitation at the injection site, intratumoral foci of coagulative necrosis, and variable infiltration of the residual tumor with macrophages and lymphocytes.

Adenoviridae↗
PubMed1993

Effect of hemoglobin solution on the response of intracranial and subcutaneous 9L tumors to antitumor alkylating agents.

The 9L gliosarcoma growing subcutaneously in the hind leg of the Fisher 344 rat contains major areas of severe (< 5 mmHg) hypoxia, making up about 49% of the tumor. Intravenous administration of an ultrapurified polymerized bovine hemoglobin solution (8 ml/kg) along with normal air breathing reduces the percentage of severe hypoxia to about 24% and increases oxygenation throughout the tumor. Coadministration of the hemoglobin solution increased the tumor growth delay of subcutaneously implanted 9L tumors treated with carmustine (BCNU), cyclophosphamide, or ifosfamide but did not significantly change the tumor growth delay produced by cisplatin (CDDP). Coadministration of the hemoglobin solution with each of the four antitumor alkylating agents resulted in a near doubling of the percentage of increase in life span in animals bearing intracranial tumors treated with the combination as compared with animals treated with the drugs alone. Increases in serum blood urea nitrogen (BUN) and creatinine levels in treated animals returned to normal by 11 days posttreatment. Major changes in liver enzymes occurred with the combination of cyclophosphamide and the hemoglobin solution at 4 days posttreatment; however, these values returned to the levels in the untreated control animals within 1 week thereafter. These results indicate that further exploration of the use of hemoglobin solutions in cancer therapy is warranted.

Animals↗
PubMed1994

The 9L rat brain tumor model for pre-clinical investigation of radiation-chemotherapy interactions.

The rat 9L gliosarcoma brain tumor model has been used for more than thirty years to investigate a variety of potential therapeutic agents, combinations, schedules, and approaches that might be applicable to the management of high-grade malignant brain tumors in man. When tumor cells are implanted intracerebrally, a solid tumor grows until its mass results in the death of the animal, typically between 20 and 30 days postinoculation. Radiation therapy (either single or fractionated doses) is effective at prolonging survival in a dose-dependent manner. Numerous cancer chemotherapeutic agents, by a variety of doses, schedules, and routes of delivery, have demonstrated therapeutic efficacy in the 9L model. The combination of radiation and agents such as AZQ, BCNU, bleomycin, and cis-platinum has resulted in prolongation of survival that is significantly better than either agent used alone, without exceeding the tolerance of critical normal tissues. These pre-clinical data suggest that combining standard fractionated radiation therapy with appropriate concomitant cytotoxic chemotherapeutic agents might benefit patients with high-grade brain tumors.

Animals↗
PubMed1994

In vivo measurement of tumor blood oxygenation by near-infrared spectroscopy: immediate effects of pentobarbital overdose or carmustine treatment.

Near-infrared (NIR) spectroscopy was used to measure blood oxygen saturation (SO2) in vivo, in normal rat brain and in subcutaneously-implanted rat 9L gliosarcoma. Changes in cranial and tumor blood SO2 were measured during lethal pentobarbital overdose. After sacrifice, SO2 of cranial blood fell rapidly to a mean of 5.0% of the pre-sacrifice values, whereas SO2 of tumor blood stabilized at a mean of 72.4% of the pre-sacrifice values. This suggests that oxygen consumption by tumor is very low compared to brain. Cranial blood had a higher SO2 than tumor blood before sacrifice (p = 0.03), and a lower SO2 after sacrifice (p = 0.02). The magnitude of the change in SO2 after sacrifice was greater in normal brain than in tumor (p = 0.02), showing that brain tissue uses a greater proportion of the oxygen in ischemic blood than does tumor tissue. To determine the effect of carmustine (BCNU) treatment on tumor and cranial blood SO2, we compared BCNU-treated rats with sham-treated rats. Continuous NIR measurements before and immediately following treatment (ie. over 30-60 min) showed that tumor blood SO2 tended to increase after BCNU treatment, whereas SO2 tended to decrease following sham-treatment. The difference in SO2 between treated and control tumors was significant at 60 min (p = 0.02). Thus BCNU treatment can potentially result in immediate increases in tumor oxygenation. The increase in treated tumor blood SO2 occurred despite the fact that there was no change in cranial blood SO2 even at day 4 following treatment. Tumor blood SO2 was inversely correlated with tumor size (p = 0.001), confirming that blood is more poorly oxygenated in large tumors.

Animals↗
PubMed1995

Internalization of microbubbles by tumor cells in vivo and in vitro.

Lipid-coated microbubbles (LCM) administered intravenously (i.v.) to rats bearing brain tumor, specifically enhance tumor visualization by ultrasound [1]. In order to understand the basis for this observation, we have examined the interactions of LCM with glioblastoma (C6) and gliosarcoma (9L) tumor cells in vivo and in vitro. LCM and LCM labeled with the fluorescent lipophilic dye 3,3'-dioctadecyloxacarbocyanine perchlorate (diO) were administered to rats bearing brain tumor. LCM and diO-labeled LCM were found principally at the tumor site with no evidence of label in the surrounding normal brain tissue. Analysis of the tumor by confocal laser scanning microscopy revealed that labeled LCM were inside the tumor cells. Similar analysis of LCM interactions with C6 and 9L cells in culture showed that LCM first adsorb at the surface of the cells, and with time became localized inside the cells. Binding and internalization proceeded faster at 37 degrees C than at room temperature (RT). Staining of live cells with N-(3-((2,4-dinitrophenyl)amino)propyl)-N-(3-aminopropyl) methylamine dihydrochloride (DAMP), a dye that recognizes acidic compartments, showed that the majority of internalized LCM was associated with compartments containing DAMP. If the same uptake mechanism were operative in vivo, it would indicate that a portion of LCM bypasses the reticuloendothelial system and become endocytosed directly by tumor cells.

Animals↗
PubMed1995

Monocyte chemoattractant protein-1 (MCP-1) gene transduction: an effective tumor vaccine strategy for non-intracranial tumors.

Recently, there has been renewed interest in the concept of tumor vaccines using genetically engineered tumor cells expressing a variety of cytokines to increase their immunogenicity. Human MCP-1 (JE) is a potent chemoattractant and activator of monocytes and T lymphocytes and thus a good candidate gene for a tumor vaccine. We therefore evaluated the efficacy of vaccines consisting of irradiated tumor cells transduced with the murine MCP-1 gene in the syngeneic 9L gliosarcoma brain tumor model. 9L cell lines stably expressing murine MCP-1 (9L-JE) and control cell lines expressing neomycin 3' phosphotransferase (9L-Neo) were generated by infection with a Moloney murine leukemia retroviral vector. Fisher 344 rats were immunized with intradermal injections of 5 x 10(5) or 2 x 10(6) irradiated (5000 cGy) 9L-JE, 9L-Neo, and wild-type 9L (9L-WT) cells. Two weeks later immunized and non-immunized animals were challenged with various doses of intradermal (5 x 10(6)-5 x 10(7) or intracerebral (2 x 10(4)-5 x 10(5) 9L-WT cells. Intradermal tumors grew in all non-immunized animals. No tumors grew in animals immunized with irradiated 9L-JE or 9L-Neo cells and challenged with inocula of fewer than 5 x 10(5) 9L-WT cells. With higher inocula up to 10(7) cells, tumors appeared in all the animals, but subsequently regressed in the immunized animals. Tumors in animals immunized with 9L-JE were always smaller than tumors in the other groups. In addition, only the 9L-JE vaccine protected against tumor inocula of 5 x 10(7) cells. Thus vaccination with MCP-1-expressing cells was able to protect animals against at least a 100-fold larger number of challenge tumor cells than vaccination with control cells. In contrast to studies with intradermal tumors, immunization with 9L-JE and 9L-Neo produced only minimal protection against intracerebral tumors. There was no significant difference between the 9L-JE and 9L-Neo vaccines in intracerebral challenge. This study suggests that tumor vaccines expressing cytokine genes such as MCP-1 can increase the antitumor response. However, the protective effect of these vaccines appears to be largely limited to intradermal tumors rather than intracerebral tumors.

Animals↗
PubMed2000

Glial cell line-derived neurotrophic factor (GDNF) and its receptor (GFR-alpha 1) are strongly expressed in human gliomas.

Glial cell line-derived neurotrophic factor (GDNF), a sequence-related factor of the transforming growth factor-beta family, has been identified as a potent neurotrophic factor for a variety of neuronal cell populations. At present, it is still unknown whether human gliomas in vivo are also capable of producing GDNF. We studied the expression of GDNF in 14 human glioblastomas, 1 gliosarcoma and 5 astrocytomas. Using an enzyme-linked immunosorbent assay, the amount of GDNF was quantified in human gliomas and compared to GDNF-expression in C6 glioma cells, mouse fibroblasts and normal human and rat brain. Mean concentration of GDNF in gliomas was 937 +/- 140 pg GDNF/g tissue (n = 20). C6 cells revealed the highest expression levels of 2,837 +/- 813 pg/g, whereas mouse 3T3 fibroblasts showed no detectable GDNF protein. Mean GDNF tissue levels in normal human and rat brain were significantly lower. Using reverse transcriptase-polymerase chain reaction, GDNF mRNA was detected in human gliomas and in rat C6 cells. Immunohistochemistry revealed strong GDNF- and GDNF receptor-alpha 1-expressing tumor cells in human glioma tissue. These results show that glial tumors, even in the most dedifferentiated form of glioblastoma, express GDNF at concentrations up to five times higher compared to normal human brain. This overexpression of GDNF may be of biological relevance for proliferation of glial tumors in humans.

Adult↗
PubMed2003

Radiotherapy in supratentorial gliomas. A study of 821 cases.

PURPOSE: Analysis of the results of radiotherapy in a large group of cerebral gliomas with identification of prognostic factors and the outcome with respect to different decades of treatment. PATIENTS AND METHODS: Two decades (1979-1999) of radiotherapy in supratentorial astrocytic and oligodendroglial tumors (n = 821) at the University Hospital Groningen were retrospectively evaluated. Prognostic factors for survival were analyzed. Two decades of radiotherapy treatment were compared with respect to radiotherapy dose and treatment-field design. RESULTS: Glioblastoma multiforme, including gliosarcoma, was the most frequent supratentorial glioma (n = 442) with a poor survival, i.e., median survival time (MST) 7 months, especially in patients > 50 years of age and with poor performance. Patients with good performance were selected for radiotherapy with an optimum dose of 60 Gy local-field irradiation. However, in patients with poor prognosis, no radiotherapy was applied or a shorter treatment scheme was given. Anaplastic astrocytomas (n = 131) were treated in the same way as glioblastoma multiforme. Over time, a decrease in radiation dose (from 60 to 45 Gy) and from whole brain irradiation to local-field treatment was observed, following the literature. In low-grade gliomas, prognostic factors for survival were age, performance, and extent of resection. Gemistocytic astrocytoma (n = 15) had an inferior survival compared to astrocytoma (MST 46 vs. 54 months), but a superior survival compared to anaplastic astrocytoma (MST 10 months). The presence of an oligodendroglial component in a glioma implied a superior survival compared to the astrocytic gliomas. The inherent biology of the glioma is reflected by the study of recurrent tumors with progression to higher grades of malignancy in 32-40% and by the histology of recurrent oligodendroglial tumors. In comparing two decades of radiotherapy in gliomas, no differences in survival were observed despite the technological improvements. However, reduction in long-term side effects was not evaluated, especially in low-grade gliomas which were treated in the second decade of the study with local fields only and a reduced radiotherapy dose using computerized three-dimensional (3-D) planning. CONCLUSION: Radiotherapy does not cure cerebral glioma. Prognostic factors for survival are histopathologic classification and grading, age, and patient performance. Technological improvements do not improve survival, but possibly reduce late effects.

Adolescent↗
PubMed2006

A novel brainstem tumor model: functional and histopathological characterization.

INTRODUCTION: Diffuse pontine gliomas remain a challenging and frustrating disease to treat. The survival rates for these high-grade brainstem tumors (BSTs) is dismal and optimal therapy has yet to be determined. The development of a satisfactory brainstem tumor model is necessary for testing new therapeutic paradigms that may prolong survival. MATERIALS AND METHODS: We report the surgical technique, functional testing, and histopathological features of a novel brainstem tumor model in rats. Female Fischer 344 rats (n=45) were randomized to receive an injection of either 3 microl of 9L gliosarcoma cells (100,000 cells, n=), 3 microl of F98 glioma cells (100,000 cells, n=10), or 3 microl of medium (Dulbecco's modified eagle medium) into the pontine tegmentum. Using a cannulated guide screw system, implanted in the skull of the animal, we injected each group at coordinates 1.4 mm right of the sagittal and 1.0 mm anterior of the lambdoid sutures, at a depth of 7.0 mm from the dura. The head was positioned 5 degrees from horizontal before injection. The rats were post-operatively evaluated for neurological deficits using an automated test. Kaplan-Meier curves were generated for survival and disease progression, and brains were processed postmortem for histopathology. RESULTS AND DISCUSSION: 9L and F98 tumor cells grew in 100% of animals injected and resulted in a statistically significant mean onset of hemiparesis of 16.5+/-0.56 days (P=0.001, log-rank test), compared to animals in the control group which lacked neurological deficits by day 60. The animals with tumor cells implanted demonstrated significant deterioration of function on the automated rod testing. Animals in the control group showed no functional or pathological signs of tumor. Progression to hemiparesis was consistent in all tumor-injected animals, with predictable onset of symptoms occurring approximately 17 days post-surgery. The histopathological characteristics of the 9L and F98 BSTs were comparable to those of aggressive human BSTs. CONCLUSION: The establishment of this animal tumor model will facilitate the testing of new therapeutic paradigms for the treatment of BSTs.

Animals↗
PubMed2006

Lactacystin exhibits potent anti-tumor activity in an animal model of malignant glioma when administered via controlled-release polymers.

Lactacystin, a proteasome-inhibitor, has been shown to induce apoptosis of experimental gliomas in vitro. However, its systemic toxicity prevents further clinical use. To circumvent this problem, lactacystin can be delivered intratumorally. We tested the efficacy of lactacystin incorporated into controlled-release polymers for treating experimental gliomas. 9L-gliosarcoma and F98-glioma cell lines were treated with lactacystin (10-100 microg/ml) for 72 h in vitro. Cell-viability was measured with MTT-assays. Toxicity of lactacystin/polycarboxyphenoxypropane-sebacic-acid (pCPP : SA) polymers was tested in vivo using Fischer-344 rats intracranially implanted with lactacystin polymers loaded from 0.1 to 2% lactacystin by weight. The efficacy of 1, 1.3, 1.5 and 1.7% lactacystin/pCPP : SA polymers was determined in Fischer-344 rats intracranially challenged with 9L and treated either simultaneously or 5 days after tumor implantation. Lactacystin was cytotoxic in 9L cells, causing a 16 +/- 8% growth inhibition at 10-microg/ml that increased to 78 +/- 4% at 100-microg/ml. Similarly, lactacystin inhibited growth of F98 by 18 +/- 8% at 10-microg/ml and 74 +/- 2% at 100-microg/ml in vitro. Polymers released lactacystin for 21 days and intracranial implantation in rats neither generate local nor systemic toxicity at doses lower than 2%. Treatment with lactacystin/pCPP : SA polymers with loading concentrations of 1.0, 1.3, and 1.5% prolonged survival of animals intracranially challenged with 9L when polymers where inserted in the day of tumor implantation. In conclusion, lactacystin exhibits potent cytotoxic-activity against 9L and F98 in vitro, it can be efficiently incorporated and delivered using controlled-release polymers, and at the proposed concentrations lactacystin polymers are safe for CNS delivery and prolong survival in the 9L model.

Acetylcysteine↗
PubMed1994

Intracarotid infusion of bradykinin selectively increases blood-tumor permeability in 9L and C6 brain tumors.

This study investigated the effects of bradykinin on blood-tumor barrier (BTB) permeability in transplanted 9L gliosarcomas (9L) and C6 gliomas (C6) in rats. Permeability, expressed as the unidirectional transfer constant, Ki (microliter/g/min), was measured by quantitative autoradiography. Tracers used to examined permeability included radiolabeled alpha-aminoisobutyric acid ([14C]AIB), sucrose ([14C]sucrose) and dextran ([14C]dextran). Intracarotid infusion of bradykinin (10 mg/kg/min) significantly increased the BTB permeability in both 9L and C6 tumors to [14C]AIB and [14C]sucrose, but did not increase permeability to [14C]dextran. Blood-brain barrier (BBB) permeability in normal (non-tumor) brain was not significantly increased to any of the tracers by intracarotid bradykinin infusion. Ki values for [14C]AIB, [14C]sucrose and [14C]dextran of 9L tumors in the bradykinin group versus control group were 41.6 +/- 12.6 vs. 24.8 +/- 6.30 (P < 0.02), 17.5 +/- 9.34 vs. 9.05 +/- 4.36 (P < 0.05), and 3.90 +/- 2.59 vs. 2.42 +/- 1.76, respectively (mean +/- S.D.). Ki values to [14C]AIB, [14C]sucrose and [14C]dextran of C6 tumors in the bradykinin group versus control group were 41.4 +/- 19.0 vs. 19.5 +/- 11.4 (P < 0.01), 18.0 +/- 8.88 vs. 7.06 +/- 3.05 (P < 0.01), and 4.07 +/- 1.45 vs. 2.27 +/- 1.26, respectively (mean +/- S.D.). Intracarotid infusion of bradykinin did not significantly increase the blood volume in tumor or brain tissue despite its known vasodilative effect. Intracarotid infusion of bradykinin may be a useful technique for selective delivery of compounds to brain tumors.

Aminoisobutyric Acids↗
PubMed1994

Selective ablation of rat brain tumors by boron neutron capture therapy.

PURPOSE: Damage to the surrounding normal brain tissue limits the amount of radiation that can be delivered to intracranial tumors. Boron neutron capture therapy (BNCT) is a binary treatment that allows selective tumor irradiation. This study evaluates the damage imparted to the normal brain during BNCT or x-irradiation. METHODS AND MATERIALS: The brains of rats with implanted 9L gliosarcomas were examined 1 year after tumor-curative doses of either 250 kV X rays or BNCT. Histopathologic techniques included hematoxylin and eosin staining, horseradish peroxidase perfusion, and electron microscopy. RESULTS: Longterm X ray survivors showed extensive cortical atrophy, loss of neurons, and widespread leakage of the blood-brain barrier (BBB), particularly around the tumor scar. In contrast, the brains and the BBB of longterm BNCT survivors appeared relatively normal under both light- and electron-microscopic examination. Intact blood vessels were observed running directly through the avascular, collagenous tumor scar. CONCLUSION: The selective therapeutic effect of BNCT is evident in comparison to x-irradiation. Both groups of animals showed no evidence of residual tumor at 1 year. However, with x-irradiation there is no therapeutic ratio and tumor eradication severely injures the remaining brain parenchyma. These observations indicate a substantial therapeutic gain for BNCT.

Animals↗
PubMed1995

Stereotactic radiosurgery as an adjunct to surgery and external beam radiotherapy in the treatment of patients with malignant gliomas.

PURPOSE: To evaluate the efficacy and toxicity of a stereotactic radiosurgery boost as part of the primary management of a minimally selected population of patients with malignant gliomas. METHODS AND MATERIALS: Between June, 1991 and January, 1994 a stereotactic radiosurgery boost was given to 30 patients after completion of fractionated external beam radiotherapy. The study population consisted of 22 males and 8 females, with a range in age at treatment from 5 to 74 years (median: 54 years). Tumor volume ranged from 2.1 to 115.5 cubic centimeters (cc) (median: 24 cc). Histology included 17 with glioblastoma multiforme, 10 with anaplastic astrocytoma, 1 with a mixed anaplastic astrocytoma-oligodendroglioma, and 2 with a gliosarcoma. A complete resection was performed in 9 (30%) patients, while 18 (60%) underwent a subtotal resection, and 3 (10%) received a biopsy only. Fractionated radiation dose ranged from 44 to 62 Gy, with a median of 59.4 Gy. Prescribed stereotactic radiosurgery dose ranged from 0.5 to 18 Gy (median: 10 Gy), and the volume receiving the prescription dose ranged from 2.1 to 158.7 cc (median: 46 cc). The volume of tumor receiving the prescription dose ranged from 70-100% (median: 100%). One to four (median: 2) isocenters were used, and collimator size ranged from 12.5 to 50 mm (median size: 32.5 mm). The median minimum stereotactic radiosurgery dose was 70% of the prescription dose and the median maximum dose was 200% of the prescription dose. RESULTS: With a minimum follow-up of 1 year from radiosurgery, 7 (23%) of the patients are still living and 22 (73%) have died of progressive disease. One patient died of a myocardial infarction 5 months after stereotactic radiosurgery. Follow-up for living patients ranged from 12 to 45 months, with a median of 30 months. The 1- and 2-year disease-specific survival from the date of diagnosis is 57 [95% confidence interval (CI) 39 to 74%] and 25% (95% CI 9 to 41%), respectively (median survival: 13.9 months). No significant acute or late toxicity has been observed. CONCLUSION: Stereotactic radiosurgery provides a safe and feasible technique for dose escalation in the primary management of unselected malignant gliomas. Longer follow-up and a randomized prospective trial is required to more thoroughly evaluate the role of radiosurgery in the primary management of malignant gliomas.

Adolescent↗
PubMed1995

Fluorescence localization in tumour and normal brain after intratumoral injection of haematoporphyrin derivative into rat brain tumour.

In the intracerebral 9L rat gliosarcoma, the spatial distribution of the photosensitizer haematoporphyrin derivative (HpD) was studied after intratumoral injection. The fluorescence volume was measured in histological sections from 10 min up to 5 days after injection. Complete sensitization of the tumours could not be achieved by slow stereotactical injection of 4 mm3 HpD (mean HpD fluorescence volume, 13 +/- 11 mm3). Larger parts of the tumour could be loaded with HpD (39 +/- 23 mm3, p = 0.0001) by increasing the injection velocity and the volume to 50 mm3. Again, complete sensitization of the tumours was not achieved during a time scale of 5 days after intratumoral injection. Although the fluorescence volume did not change significantly with time, it was influenced by the injection site within the tumour. Injection of HpD within 1 mm from the tumour border resulted in significantly smaller fluorescence volumes in the tumour than injection into the tumour centre. Large injection volumes caused an increased leakage of HpD to normal brain, leading to the loss of selectivity of photosensitizer content and the occurrence of dark toxicity of normal brain while the tumours still appeared vital.

Animals↗