Immunolocalization of cathepsin B in human glioma: implications for tumor invasion and angiogenesis

1995 ◽  
Vol 83 (2) ◽  
pp. 285-290 ◽  
Author(s):  
Tom Mikkelsen ◽  
Pei-Sha Yan ◽  
Khang-Loon Ho ◽  
Mansoureh Sameni ◽  
Bonnie F. Sloane ◽  
...  
Keyword(s):  
Cathepsin B ◽  
Tumor Invasion ◽  
Malignant Gliomas ◽  
Neuronal Cell ◽  
Immunohistochemical Analysis ◽  
Normal Brain ◽  
Glial Tumor ◽  
Content Type ◽  
Neuronal Cell Bodies ◽  
Fine Print

✓ The poor prognosis of patients with malignant gliomas is at least partially due to the invasive nature of these tumors. In this study, the authors investigated the possibility that the cysteine protease cathepsin B (CB) is a participant in the process of glial tumor cell invasion. To accomplish this, an immunohistochemical analysis was made of the localization of antibodies to CB in biopsies of five specimens of normal brain, 16 astrocytomas, 33 anaplastic astrocytomas, and 33 glioblastomas multiforme. Staining was scored according to the percentage of positive cells and the intensity of the stain, graded from 0 to 3+. Staining for CB was not seen in any of five samples of normal brain except for occasional neuronal cell bodies and microglia. Only five (31%) of 16 astrocytomas showed a small percentage of positive cells (0.01%–3%) that were stained in a light, diffuse cytoplasmic pattern (1+). Twenty-nine (87.8%) of 33 anaplastic astrocytomas showed positive light, granular staining in 2% to 40% of cells. In anaplastic astrocytoma, the staining within a tumor was heterogeneous with intensities of 1+ (17%), 1+ to 2+ (29%), or 2+ (55%). In contrast, all 33 (100%) glioblastomas were positive in 10% to 90% of cells. The staining was present in a coarse, granular pattern with an intensity of 2+ (12%) or 3+ (88%). Tumor cells infiltrating into brain adjacent to malignant gliomas stained positively in 26 cases that could be evaluated for glioblastoma multiforme; these invading cells frequently followed penetrating blood vessels as typical “secondary structures of Scherer.” Moderate to intense CB staining associated with endothelial proliferation in high-grade tumors was also observed, especially in regions of tumor infiltration into adjacent normal brain. These results provide evidence consistent with the hypothesis that CB is functionally significant in the process of tumor invasion and angiogenesis in the clinical progression of the malignant phenotype in astrocytomas.

Immunohistochemical determination of the sympathetic pathway in the orbit via the cranial nerves in humans

2004 ◽  
Vol 101 (6) ◽  
pp. 1037-1044 ◽  
Author(s):  
Susumu Oikawa ◽  
Kyutaro Kawagishi ◽  
Kumiko Yokouchi ◽  
Nanae Fukushima ◽  
Tetsuji Moriizumi
Keyword(s):  
Cranial Nerve ◽  
Cranial Nerves ◽  
Neuronal Cell ◽  
Immunohistochemical Analysis ◽  
Orbital Cavity ◽  
Content Type ◽  
Neuronal Cell Bodies ◽  
Proximal Site ◽  
Fine Print

Object. The present study was undertaken to elucidate the extent and precise distribution of the postganglionic sympathetic fibers in the cranial nerves projecting to the orbit and to reconstruct sympathetic routes in the orbit in humans. For this purpose, the authors made an immunohistochemical determination of the sympathetic fibers by using an antibody against norepinephrine-synthetic enzyme, tyrosine hydroxylase (TH). Methods. Specimens containing the orbit and the cavernous sinus were obtained from formalin-fixed human cadavers. First, it was confirmed that the superior cervical ganglion contained strongly immunostained TH-positive neuronal cell bodies and fibers. After careful dissection of the cranial nerves projecting to the orbit, different segments of each cranial nerve were processed for immunohistochemical analysis for TH. All of the intraorbital cranial nerves contained TH-positive sympathetic fibers, although the amounts were very different in each cranial nerve. At the proximal site of the common tendinous ring, TH-positive fibers were found mainly in the abducent and trochlear nerves. At the distal site of this ring, TH-positive fibers were lost or markedly reduced in number in the abducent and trochlear nerves and were distributed mostly in the ophthalmic and oculomotor nerves. Among the cranial nerves projecting to the orbit, the ophthalmic nerve and its bifurcated nerves—frontal, lacrimal, and nasociliary—contained numerous TH-positive fibers. Conclusions. The authors conclude that the postganglionic sympathetic fibers are distributed to all cranial nerves projecting to the orbit and that the ophthalmic nerve provides a major sympathetic route in the orbital cavity in humans.

Radiation-induced intracranial malignant gliomas

1989 ◽  
Vol 71 (1) ◽  
pp. 77-82 ◽  
Author(s):  
Scott Shapiro ◽  
John Mealey ◽  
Carl Sartorius
Keyword(s):  
Central Nervous System ◽  
Radiation Necrosis ◽  
External Beam Radiotherapy ◽  
Malignant Gliomas ◽  
Interstitial Brachytherapy ◽  
External Beam ◽  
Glial Tumor ◽  
Content Type ◽  
Radiation Induced ◽  
Fine Print

✓ The authors present seven cases of malignant gliomas that occurred after radiation therapy administered for diseases different from the subsequent glial tumor. Included among these seven are three patients who were treated with interstitial brachytherapy. Previously reported cases of radiation-induced glioma are reviewed and analyzed for common characteristics. Children receiving central nervous system irradiation appear particularly susceptible to induction of malignant gliomas by radiation. Interstitial brachytherapy may be used successfully instead of external beam radiotherapy in previously irradiated, tumor-free brain, and thus may reduce the risk of radiation necrosis.

Polysialylated neural cell adhesion molecules expressed in human pituitary tumors and related to extrasellar invasion

2003 ◽  
Vol 98 (5) ◽  
pp. 1084-1093 ◽  
Author(s):  
Jacqueline Trouillas ◽  
Laurent Daniel ◽  
Marie-Paule Guigard ◽  
Soutsakhone Tong ◽  
Joanny Gouvernet ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Tumor Invasion ◽  
Pituitary Tumors ◽  
Immunohistochemical Analysis ◽  
Neural Cell ◽  
Ki 67 ◽  
Content Type ◽  
Neural Cell Adhesion Molecules ◽  
Neural Cell Adhesion ◽  
Fine Print

Object. Pituitary adenomas are usually benign tumors; however, some behave aggressively and metastasize. Until now, no specific marker of aggressive behavior or malignancy has been found. The polysialylated neural cell adhesion molecule (NCAM), which is highly expressed in embryonic tissues such as the brain and pituitary, is detected in some neuronal and neuroendocrine tumors. Because polysialylation has been implicated in the regulation of cell growth and migration, polysialylated NCAM expression has been considered as a prognostic marker in such tumors. Methods. In the present study, the authors analyzed polysialylated NCAM expression in 82 pituitary tumors from humans: 49 secreting adenomas, 32 nonfunctioning adenomas, and one growth hormone and prolactin—secreting carcinoma associated with acromegaly and spinal and liver metastases. Based on immunohistochemical analyses, the tumors were classified as somatotropic (22 tumors), prolactinoma (14 tumors), corticotropic (17 tumors), and gonadotropic or so-called null cell adenomas (28 tumors). Assessment of polysialylated NCAM was performed using three different methods (immunohistochemical analysis, Western blot analysis, and enzyme-linked immunosorbent assay) with a specific mouse monoclonal immunoglobulin M (Men B) that recognizes polysialic acid on NCAM. Tumoral NCAM expression was also evaluated with the aid of immunohistochemical analysis. Using this method, NCAM and polysialylated NCAM were studied in six healthy pituitaries. In addition, corrrelations were investigated using three statistical methods (chi-square test, nonparametric Mann—Whitney U-test, and principal component analysis) to compare tumoral polysialylated NCAM expression and seven parameters (tumor size and type, intrasphenoidal or cavernous sinus invasion, Ki-67 index, mitoses, and patient age and sex). Neural cell adhesion molecules were expressed in the healthy anterior pituitary and in all tumors. In contrast, polysialylated NCAM was not found in the healthy pituitary gland, but was expressed in 46.3% of typical pituitary tumors and in 85% of the tumors selected as highly aggressive, including one carcinoma and three tumors with histological characteristics that raised suspicion of malignancy. There was no significant correlation between polysialylated NCAM expression and tumor size, tumor type, Ki-67 index, mitoses, or patient age and sex. In contrast, the expression of polysialylated NCAM, which was sensitive to endoneuraminidase-N treatment, was strongly correlated with tumor invasion (p < 0.0001). Conclusions. In pituitary tumors in humans, expression of polysialylated NCAM is strongly related to tumor invasion and confirms the clinical diagnosis of aggressiveness.

scholarly journals Apoptosis of T lymphocytes invading glioblastomas multiforme: a possible tumor defense mechanism

2002 ◽  
Vol 96 (3) ◽  
pp. 580-584 ◽  
Author(s):  
Vladimir V. Didenko ◽  
Hop N. Ngo ◽  
Candace Minchew ◽  
David S. Baskin
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Fas Ligand ◽  
Defense Mechanism ◽  
Malignant Gliomas ◽  
Immunohistochemical Analysis ◽  
Content Type ◽  
Morphological Criteria ◽  
Fine Print

Object. The goal of this study was to investigate whether apoptosis occurs in T lymphocytes that invade Fas ligand (FasL)—expressing glioblastomas multiforme (GBMs) and if its induction could be mediated by Fas. Methods. Apoptotic T lymphocytes were detected in GBMs by using detection of cell-type markers combined with active caspase-3 immunohistochemical analysis, a recently introduced apoptosis-specific in situ ligation assay, as well as by examining morphological criteria. Apoptotic T cells expressed Fas and were localized in the vicinity or in direct contact with FasL-expressing tumor cells. The T lymphocytes were undergoing apoptosis in spite of Bcl-2 expression. Expression of Bax was also detected in dying T cells, which can explain the absence of the protective effect of Bcl-2, because Bax inhibits Bcl-2 death-repressor activity. Conclusions. On the basis of the data presented in this paper, the authors suggest that GBM cells that express FasL can induce apoptosis in invading immune cells. This phenomenon may play an important role in these tumors' maintenance of immune privilege and evasion of immune attacks. Awareness of this phenomenon should be helpful for the development of novel strategies for treatment of malignant gliomas.

Neutron interstitial brachytherapy for malignant gliomas: a pilot study

1988 ◽  
Vol 68 (1) ◽  
pp. 67-72 ◽  
Author(s):  
Roy A. Patchell ◽  
Yosh Maruyama ◽  
Phillip A. Tibbs ◽  
J. Lawrence Beach ◽  
Richard J. Kryscio ◽  
...  
Keyword(s):  
Radiation Necrosis ◽  
Malignant Gliomas ◽  
Survival Rates ◽  
Neutron Radiation ◽  
Photon Radiation ◽  
Normal Brain ◽  
External Beam ◽  
Content Type ◽  
Original Tumor ◽  
Fine Print

✓ Fifty-six patients with malignant glioma were treated with implantation of the neutron-emitting element californium-252 (252Cf) within 2 weeks after surgical debulking of the tumor. Implantation was performed using computerized tomography-guided placement of afterloading catheters, and the 252Cf sources were removed after approximately 300 neutron rads were delivered. Patients then received 6000 to 7000 conventional photon rads by external beam. The total photon-equivalent dose to the tumor ranged from 8100 to 9100 rads. The median survival time was 10 months, with 18- and 24-month survival rates of 28% and 19%, respectively. The results of reoperation or autopsy showed that patients had recurrence of the tumor but that radiation necrosis was restricted to the area of the original tumor. Serious complications occurred in five patients (9%) and consisted of wound infections in three, cerebral edema in one, and radiation necrosis beyond the original tumor margin in one. Previous studies using external-beam neutron radiation have shown that neutrons are capable of totally eradicating malignant gliomas; however, in most cases, unacceptable widespread radiation necrosis has resulted. Neutron implants are a logical way to increase the dose to the tumor and decrease the dose to normal brain. Interstitial neutron radiation can be given safely with 252Cf, and the survival results achieved by radiation alone using relatively low doses of interstitial neutron radiation from 252Cf implants plus conventional photon radiation were equal to the results attained with any currently available conventional therapy.

A comparative study on the pharmacokinetics and biodistribution of boronated porphyrin (BOPP) and sulfhydryl boron hydride (BSH) in the RG2 rat glioma model

1995 ◽  
Vol 83 (1) ◽  
pp. 86-92 ◽  
Author(s):  
Crister P. Ceberg ◽  
Arne Brun ◽  
Stephen B. Kahl ◽  
Myoung Seo Koo ◽  
Bertil R. R. Persson ◽  
...  
Keyword(s):  
Body Weight ◽  
Tumor Cells ◽  
Brain Tissue ◽  
Malignant Gliomas ◽  
Normal Brain ◽  
Boron Hydride ◽  
Content Type ◽  
Rat Glioma ◽  
Glioma Model ◽  
Fine Print

✓ Boron neutron capture therapy is a treatment modality for cancer that depends on the specific uptake of boron by the tumor cells. The infiltrative growth of malignant gliomas requires that boron reach and accumulate in migrating cells outside the margin of the tumor; thus, it is important that the biodistribution of new boron compounds is also studied in the surrounding healthy brain tissue. This study is undertaken in the present work, in which the biodistribution and pharmacokinetics of sulfhydryl boron hydride (BSH) and boronated porphyrin (BOPP) in the RG2 rat glioma model are investigated. This model mimics the characteristics of human glioma with cells migrating into the surrounding brain. The animals were infused intravenously with either BSH (25 µg or 175 µg of boron per gram of body weight) or BOPP (12 µg of boron per gram body weight). For the low dose of BSH, the maximum tumor—boron content was 8 ppm at approximately 9 hours after the infusion with a tumor-to-blood ratio of 0.6. At the higher dose, the corresponding figures were 15 ppm after 12 hours with a tumor-to-blood ratio of 0.5. For BOPP, a tumor—boron concentration of 81 ppm was achieved 24 hours after the infusion and sustained in that range for at least 72 hours. The tumor-to-blood ratio at 24 hours was slightly above 6, but continued to increase as the blood was cleared. These results indicate that both compounds are spread into the normal brain tissue following the same pathways as the migrating tumor cells and in this way can be taken up even in distant tumor cell foci.

The deposition of Hg203-chlormerodrin in experimental brain tumors

1971 ◽  
Vol 35 (3) ◽  
pp. 303-308 ◽  
Author(s):  
Tatsuya Kobayashi ◽  
Louis Bakay ◽  
Joseph C. Lee
Keyword(s):  
Brain Tumors ◽  
Tumor Cells ◽  
Normal Brain ◽  
Intracranial Tumors ◽  
Electron Microscopic ◽  
Electron Microscopic Autoradiography ◽  
Content Type ◽  
Meningeal Tumors ◽  
Vacuolar System ◽  
Fine Print

✓ The deposition of Hg203-chlormerodrin was studied in intracranial tumors in mice induced by implantation of 20-methyl cholanthrene by tissue assay, as well as light microscopic and electron microscopic autoradiography. The investigations were carried out in astrocytomas, glioblastomas, and meningeal tumors. The chlormerodrin content of the tumors exceeded that of normal brain with a significant tumor/brain ratio ranging from 5.8 to 22.5. It was found that the chlormerodrin molecule becomes rapidly incorporated in the tumor cells, with a preference for that portion of the cytoplasm associated with the vacuolar system.

Administration of interleukin-12 and -18 enhancing the antitumor immunity of genetically modified dendritic cells that had been pulsed with Semliki Forest virus—mediated tumor complementary DNA

2002 ◽  
Vol 97 (5) ◽  
pp. 1184-1190 ◽  
Author(s):  
Ryuya Yamanaka ◽  
Naoki Yajima ◽  
Naoto Tsuchiya ◽  
Junpei Honma ◽  
Ryuichi Tanaka ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Antitumor Immunity ◽  
Semliki Forest Virus ◽  
Malignant Gliomas ◽  
Glioma Cells ◽  
Antitumor Effects ◽  
Content Type ◽  
Immunogene Therapy ◽  
Fine Print

Object. Immunogene therapy for malignant gliomas was further investigated in this study to improve its therapeutic efficacy. Methods. Dendritic cells (DCs) were isolated from bone marrow and pulsed with phosphate-buffered saline or Semliki Forest virus (SFV)—mediated 203 glioma complementary (c)DNA with or without systemic administration of interleukin (IL)-12 and IL-18 to treat mice bearing the 203 glioma. To study the immune mechanisms involved in tumor regression, the authors investigated tumor growth of an implanted 203 glioma model in T cell subset—depleted mice and in interferon (IFN) γ—neutralized mice. To examine the protective immunity produced by tumor inoculation, a repeated challenge of 203 glioma cells was given by injecting the cells into the left thighs of surviving mice and the growth of these cells was monitored. The authors demonstrated that the combined administration of SFV-cDNA, IL-12, and IL-18 produced significant antitumor effects against the growth of murine glioma cells in vivo and also can induce specific antitumor immunity. The synergic effects of the combination of SFV-cDNA, IL-12, and IL-18 in vivo were also observed to coincide with markedly augmented IFNγ production. The antitumor effects of this combined therapy are mediated by CD4+ and CD8+ T cells and by NK cells. These results indicate that the use of IL-18 and IL-12 in DC-based immunotherapy for malignant glioma is beneficial. Conclusions. Immunogene therapy combined with DC therapy, IL-12, and IL-18 may be an excellent candidate in the development of a new treatment protocol. The self-replicating SFV system may therefore provide a novel approach for the treatment of malignant gliomas.

Thymidine kinase activation of ganciclovir in recurrent malignant gliomas: a gene-marking and neuropathological study

2000 ◽  
Vol 92 (5) ◽  
pp. 804-811 ◽  
Author(s):  
Griffith R. Harsh ◽  
Thomas S. Deisboeck ◽  
David N. Louis ◽  
John Hilton ◽  
Michael Colvin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Enzymatic Activity ◽  
Thymidine Kinase ◽  
Tumor Cells ◽  
Malignant Gliomas ◽  
Retroviral Vectors ◽  
Content Type ◽  
Tumor Bed ◽  
Immunohistochemical Evidence ◽  
Fine Print

Object. The gene therapy paradigm of intratumoral activation of ganciclovir (GCV) following transduction of tumor cells by retroviral vectors bearing the thymidine kinase (tk) gene has produced dramatic remissions of malignant gliomas in animal models. In human trials, although the technique has been deemed safe, little antitumor effect has been demonstrated. To evaluate the basis of this inefficacy in human gliomas, the authors conducted a gene-marking trial involving neuropathological and biochemical studies of treated tumor specimens.Methods. Five patients with malignant recurrent gliomas underwent stereotactic biopsy sampling and intratumoral implantation procedures with three aliquots of 106 vector-producing cells (VPCs) in columns. After 5 days, the tumor was resected and the tumor bed reimplanted with VPCs, and a course of GCV was given. Patients received clinical and radiological follow up for 6 months. Tumor specimens were analyzed neuropathologically and for tk gene expression by anti-TK immunohistochemistry and TK enzymatic activity.Four patients tolerated the treatment well but experienced tumor progression. The other developed an abscess after the second operation and died. Increased TK enzymatic activity was demonstrated in the one tumor specimen analyzed. Immunohistochemical evidence of tk gene expression was limited to VPCs. Transduction of tumor cells was not seen. Viable tumor cells were seen near VPCs containing TK. The lymphocytic immune response was mild.Conclusions. Except for the risk of infection inherent in reoperation, this tk—GCV paradigm was both feasible and safe. Pathological studies indicated that limited dissemination of VPCs and vector from the infusion site and failure to transduce tumor cells with the tk gene are major barriers to efficacy.

Quantification and pharmacokinetics of blood-brain barrier disruption in humans

1996 ◽  
Vol 85 (6) ◽  
pp. 1056-1065 ◽  
Author(s):  
Bernhard Zünkeler ◽  
Richard E. Carson ◽  
Jeff Olson ◽  
Ronald G. Blasberg ◽  
Hetty Devroom ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Normal Brain ◽  
Content Type ◽  
Barrier Disruption ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Brain Barrier Disruption ◽  
Fine Print

✓ Hyperosmolar blood-brain barrier disruption (HBBBD), produced by infusion of mannitol into the cerebral arteries, has been used in the treatment of brain tumors to increase drug delivery to tumor and adjacent brain. However, the efficacy of HBBBD in brain tumor therapy has been controversial. The goal of this study was to measure changes in vascular permeability after HBBBD in patients with malignant brain tumors. The permeability (K1) of tumor and normal brain blood vessels was measured using rubidium-82 and positron emission tomography before and repeatedly at 8- to 15-minute intervals after HBBBD. Eighteen studies were performed in 13 patients, eight with glioblastoma multiforme and five with anaplastic astrocytoma. The HBBBD increased K1 in all patients. Baseline K1 values were 2.1 ± 1.4 and 34.1 ± 22.1 µl/minute/ml (± standard deviation) for brain and tumor, respectively. The peak absolute increases in K1 following HBBBD were 20.8 ± 11.7 and 19.7 ± 10.7 µl/minute/ml for brain and tumor, corresponding to percentage increases of approximately 1000% in brain and approximately 60% in tumor. The halftimes for return of K1 to near baseline for brain and tumor were 8.1 ± 3.8 and 4.2 ± 1.2 minutes, respectively. Simulations of the effects of HBBBD made using a very simple model with intraarterial methotrexate, which is exemplary of drugs with low permeability, indicate that 1) total exposure of the brain and tumor to methotrexate, as measured by the methotrexate concentration-time integral (or area under the curve), would increase with decreasing infusion duration and would be enhanced by 130% to 200% and by 7% to 16%, respectively, compared to intraarterial infusion of methotrexate alone; and 2) exposure time at concentrations above 1 µM, the minimal concentration required for the effects of methotrexate, would not be enhanced in tumor and would be enhanced by only 10% in brain. Hyperosmolar blood-brain barrier disruption transiently increases delivery of water-soluble compounds to normal brain and brain tumors. Most of the enhancement of exposure results from trapping the drug within the blood-brain barrier, an effect of the very transient alteration of the blood-brain barrier by HBBBD. Delivery is most effective when a drug is administered within 5 to 10 minutes after disruption. However, the increased exposure and exposure time that occur with methotrexate, the permeability of which is among the lowest of the agents currently used clinically, are limited and the disproportionate increase in brain exposure, compared to tumor exposure, may alter the therapeutic index of many drugs.

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