Biomedical subjects

Henry Brem

Publications and source records attributed to Henry Brem.

45 records · Page 3Linked to original sources

PubMed2002

Local drug delivery to the brain.

The controlled local delivery of antineoplastic agents by biodegradable polymers is a technique that allows for exposure of tumor cells to therapeutic doses of an active agent for prolonged periods of time while avoiding high systemic doses associated with debilitating toxicities. The use of polymers for chemotherapy delivery expands the spectrum of available treatment of neoplasms in the central nervous system, and facilitates new approaches for the treatment of malignant gliomas. In this article, we discuss the rationale and history of the development and use of these polymers, and review the various agents that have used this technology to treat malignant brain tumors.

Anhydrides↗

PubMed2002

Polymer delivery of camptothecin against 9L gliosarcoma: release, distribution, and efficacy.

Camptothecin is a potent antineoplastic agent that has shown efficacy against multiple tumor lines in vitro; unfortunately, systemic toxicity has limited its in vivo efficacy. This is the first study to investigate the release, biodistribution, and efficacy of camptothecin from a biodegradable polyanhydride polymer. Tritiated camptothecin was incorporated into biodegradable polymers that were implanted intracranially in 16 male Fischer 344 rats and the animals were followed up to 21 days post-implant. A concentration of 11-45 microg of camptothecin-sodium/mg brain tissue was within a 3 mm radius of the polymer disc, with levels of 0.1 microg at the outermost margin of the rat brain, 7 mm from the site of implantation. These tissue concentrations are within the therapeutic ranges for human and rat glioma lines tested against camptothecin-sodium in vitro. The in vivo efficacy of camptothecin-sodium was evaluated with male Fischer 344 rats implanted intracranially with 9L gliosarcoma and compared with the efficacy of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). The animals were divided into four groups. Group 1 (control) had a median survival of 17 days. Group 2 (3.8% BCNU polymer) had a median survival of 23 days (P = 0.006). Group 3 (20% camptothecin polymer) had a median survival of 25 days (P = 0.023). Group 4 (50% camptothecin polymer) had a median survival of 69 days (P < 0.001). Drug loadings of 20% and 50% camptothecin released intact camptothecin for up to 1000 h in vitro. We conclude that the biodegradable polymer p(CPP: SA) releases camptothecin-sodium, produces tumoricidal tissue levels, results in little or no systemic toxicity, and prolongs survival in a rat glioma model.

Animals↗

PubMed2002

Extreme drug resistance in primary brain tumors: in vitro analysis of 64 resection specimens.

Understanding chemoresistance profiles of brain tumors may aid in more educated selection of chemotherapeutic regimens for clinical trials and patient treatment. Although the literature contains many reports of the application of drug resistance assays, little is known about extreme drug resistance (EDR) in primary brain tumors. We undertook this study to determine chemoresistance profiles for brain tumors. From September 1991 to February 1998, we collected 64 brain tumor specimens from patients admitted to the Johns Hopkins Hospital. Tumors were classified according to the revised World Health Organization system. Brain tumor specimens were tested against 13 different chemotherapeutic agents using an extreme drug resistance assay. Results were reported as percent cell inhibition (PCI) (compared to control cultures). A drug resistance profile (extreme, intermediate, or low) was determined based on statistical comparison to a historical database of tumor specimens tested against the same panel of chemotherapeutic agents. Brain tumor specimens were classified histologically as Grade IV astrocytoma (glioblastoma multiforme, n = 35), Grade II/III astrocytoma (n = 11), oligodendroglioma (n = 6), meningioma (n = 9), hemangiopericytoma (n = 2), and ependymoma (n = 1). A large percentage of glioblastomas displayed extreme drug resistance to paclitaxel (69%, n = 35), SN38 (75%, n = 28), and vincristine (38%, n = 29). The majority of Grade II/III astrocytomas displayed extreme drug resistance to carboplatin (67%, n = 6), cisplatin (60%, n = 10), and paclitaxel (60%, n = 10). In a similar fashion, oligodendrogliomas displayed extreme drug resistance to vincristine (60%, n = 5) and paclitaxel (50% n = 6). Most meningiomas displayed extreme drug resistance to vincristine (75%, n = 8), dacarbazine (63%, n = 8), and 4-HC (50%, n = 8). Through the continued analysis of brain tumor specimens and compilation of data from multiple institutions, chemoresistance profiles could assist in the development of rationale clinical trials and treatment regimens for patients with brain tumors.

Brain Neoplasms↗

PubMed2002

Pericytic-like angiotropism of glioma and melanoma cells.

We have identified in malignant melanoma an angiotumoral complex in which tumor cells occupy a pericytic location along the endothelium of microvessels without evidence of intravasation. We have suggested that this pericytic-like angiotropism could be a marker of an extravascular migration of tumor cells along the abluminal surface of vessels. The extravascular migratory metastasis proposed for melanoma has close analogies with glioma migration. To compare our hypothesis of extravascular migration by melanoma with the migration of glioma cells, we have used the B16 murine melanoma cell line and the GL26 murine glioma cell line in an in vivo murine brain tumor model and in vitro using endothelial cells that have formed capillary-like structures and have been cocultivated with tumor cells. In the brain tumors, a clear progression of glioma and melanoma cells was observed along the abluminal surface of vessels, where they occupied a pericytic location along the periendothelial laminin. In vitro, time-lapse videomicroscopy recorded the migration of tumor cells toward endothelial tubules. After 24 hours, both the melanoma cells and the glioma cells were localized along the external surfaces of the vascular tubules, occupying a pericytic-like location. These similarities between glioma and melanoma support the hypothesis of an extravascular migration of melanoma cells, particularly along the abluminal surface of vessels.

Brain Neoplasms↗

PubMed2002

Ectopic recurrence of craniopharyngioma after an interhemispheric transcallosal approach: case report.

OBJECTIVE AND IMPORTANCE: Ectopic recurrence of a craniopharyngioma is a rare postoperative complication. We present a case of a craniopharyngioma that ectopically recurred along the tract of a previous surgical route. CLINICAL PRESENTATION: A 73-year-old female patient presented 8 years earlier with a suprasellar craniopharyngioma. She underwent a right frontal craniotomy, with an interhemispheric transcallosal approach, for total microsurgical resection of the tumor. No postoperative radiotherapy was administered. Four years after surgery, magnetic resonance imaging studies revealed a well-circumscribed, heterogeneously enhancing, parasagittal mass with significant vasogenic edema in the right frontal lobe. Enlargement of the lesion was noted in subsequent radiological evaluations until 8 years after surgery, when the patient experienced a significant decline in neurocognitive status and the mass was surgically resected. INTERVENTION: Gross total resection of a histologically confirmed craniopharyngioma was achieved. CONCLUSION: To our knowledge, only eight previous case reports described the ectopic recurrence of a craniopharyngioma. Transplantation of tumor cells along the tract of a previous surgical route in six cases and dissemination in cerebrospinal fluid in two cases are presumed to be the primary mechanisms by which these ectopic recurrences occurred. The results of our literature review led us to conclude that total surgical resection, combined with careful inspection and irrigation of the surgical field, is the optimal treatment for preventing ectopic recurrences. Furthermore, it is recommended that, after primary craniopharyngioma resection, patients undergo long-term clinical and radiological follow-up monitoring for the rare development of an ectopically recurring tumor.

Aged↗

PubMed2002

Hypertonic saline ameliorates cerebral edema associated with experimental brain tumor.

Cerebral edema commonly accompanies brain tumors and frequently leads to lethal intracranial compartmental shifts and elevated intracranial pressure. Therapeutic modalities for tumor-associated cerebral edema include diuretics, osmotherapy, and corticosteroids. Recently, hypertonic saline (HS) has received attention as an osmotic agent in the treatment of cerebral edema from diverse causes. The effects of continuous HS infusion in brain tumor-associated edema have not been previously reported. Therefore, we tested the hypothesis that HS given as a continuous intravenous infusion ameliorates tumor-associated edema in a rat model of brain tumor. 9L gliosarcoma, propagated as a solid flank tumor, was implanted intracranially over the left hemisphere in adult female Fischer 344 rats (180-220 g). On day 11 after implantation, rats were divided in a blinded, randomized fashion into groups that received no treatment or continuous infusion of 0.9% saline (NS) (0.3 mL/h) and in a subsequent series that included NS + intravenous furosemide 2.5 mg/kg every six hours, NS + intravenous mannitol 2.5 g/kg every six hours, or continuous infusion 7.5% HS (chloride:acetate 50:50) (0.3 mL/h). Hemispheric water content ipsilateral (IH) and contralateral to tumor implantation was determined at day 13 by wet-to-dry weight ratio after 48 hours of therapy. Ipsilateral hemispheric water content (mean +/- SEM) was significantly increased in rats with intracranial tumor on day 11 (80.3 +/- 0.5%) (n = 7) and day 13 (81.4 +/- 0.3%) (n = 10), as compared to naive weight-matched rats without tumor implant (79.3 +/- 0.1%) (n = 13) (P <.05). After 48 hours of treatment, IH water content was attenuated with continuous HS (n = 15) (79.3 +/- 0.2%), mannitol (n = 14) (80.1 +/- 0.2%), and furosemide (n = 15) (79.9 +/- 0.2%) as compared to NS (n = 7) (80.8 +/- 0.5%). Continuous HS infusion attenuated cerebral edema in the affected hemisphere as well as the contralateral noninjured hemisphere to a larger extent than was observed with furosemide or mannitol. These findings suggest a potential new treatment strategy for tumor-associated cerebral edema.

Animals↗

PubMed2002

Local delivery of mitoxantrone for the treatment of malignant brain tumors in rats.

OBJECT: Mitoxantrone is a drug with potent in vitro activity against malignant brain tumor cell lines; however, its effectiveness as a systemic agent has been hampered by poor central nervous system penetration and dose-limiting myelosuppression. To avoid these problems, we incorporated mitoxantrone into biodegradable polymeric wafers to be used for intracranial implantation, a strategy that has been shown to be safe and successful in the treatment of malignant gliomas. The authors investigated the release kinetics, toxicity, distribution, and efficacy of mitoxantrone delivered from intracranially implanted biodegradable wafers in the treatment of 9L gliosarcoma in Fischer 344 rats. METHODS: Mitoxantrone released from the biodegradable wafer matrix reached therapeutic drug concentrations in the brain for at least 35 days. Only animals with implanted wafers of the highest drug loading dose (20% mitoxantrone by weight) showed signs of significant toxicity. In three separate efficacy experiments, animals treated with mitoxantrone-loaded biodegradable wafers had significantly improved survival compared with control animals. The combined median survival for each treatment group was the following: 0% mitoxantrone wafers, 19 days; 1%, 30 days, p < 0.0001; 5%, 34 days, p < 0.0001; and 10%, 50 days, p < 0.0001. CONCLUSIONS: These findings establish that mitoxantrone delivered from intracranially implanted biodegradable wafers is effective in the treatment of malignant gliomas in rodents and should be considered for future clinical application in humans.

Animals↗

PubMedDate not supplied

Gene therapy for experimental brain tumors using a xenogenic cell line engineered to secrete hIL-2.

Local delivery of cytokines has been shown to have a potent anti-tumor activity against a wide range of malignant brain tumors. In this study, we examined the feasibility and efficacy of using a rat endothelial cell line (NTC-121) transfected with the human interleukin-2 (IL-2) gene in treating experimental murine CNS tumors. The NTC-121 cells were injected intracranially in C57BL/6 mice (N = 10/group) along with non-irradiated, non-transfected B16/F10 (wild type) melanoma cells. Sixty percent of mice treated with IL-2 (p < 0.001 vs. control) were long-term survivors (LTS) of > 120 days. Control animals that received only wild type cells had a median survival of 18 days (range 15-20). Histopathological examination of brains from animals sacrificed at different times showed no tumor growth in the non-irradiated NTC-121 group, moderate (1-2 mm) tumor growth in the irradiated group, and gross tumor invasion (>2 mm) and tissue necrosis in the control group. Moreover, animals treated with IL-2 showed an accumulation of CD8+ T cells around the site of the injected tumor. The use of a xenogenic cell line to deliver hIL-2 stimulates a strong immunologic cytotoxic anti-tumor response that leads to significant prolongation of survival in mice challenged with the B16/F10 intracranial melanoma tumor. Our findings demonstrate that the use of a xenogenic cell line can provide a potent vehicle for the delivery of gene therapy and may therefore represent a new approach for brain tumor therapy.

Animals↗

PubMedDate not supplied

Local delivery of doxorubicin for the treatment of malignant brain tumors in rats.

BACKGROUND: Local delivery of carmustine (BCNU) via biodegradable polymers has been shown to improve survival in patients with glioblastoma multiforme (GBM). In the current study, we hypothesized that local delivery of an anthracycline antibiotic, doxorubicin (DOX), might act to improve the survival of animals bearing experimental intracranial glioma. MATERIALS AND METHODS: Polyanhydride polymers (PCPP-SA), containing either 3% or 5% ADR by weight, were prepared using the mix-melt method. Forty male Fisher 344 rats received an intracranial challenge with a lethal dose of 9L gliosarcoma cells. Five days later, they received DOX or blank polymer. There were a total of four treatment groups: (1) blank polymer; (2) 3% DOX polymer; (3) 5% DOX polymer, and (4) control group with no polymer. RESULTS: Compared to control animals treated with no polymers or blank polymer, animals receiving DOX had significantly extended survival. The median survival for the control group was 21 days vs. 34 days (p < 0.01) for the 3% DOX group and 45 days (p < 0.0001) for the 5% DOX group. CONCLUSION: Doxorubicin, when delivered locally, is an effective monotherapeutic agent against experimental intracranial glioma.

Animals↗