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Biomedical subjects

H Brem

Publications and source records attributed to H Brem.

At least 109 records · Page 6Linked to original sources
PubMed1992

Vascular expression of glucose transporter in experimental brain neoplasms.

Vascular abnormalities in brain neoplasms are important to tumor biology and therapy. Glucose transporter (GLUT1) expression is a differentiated property of normal cerebral microvessels typically associated with expression of the blood-brain barrier. We investigated the relationship of GLUT1 expression to other vascular characteristics in F98, 9L, and C6 gliomas and Walker 256 carcinomas implanted into adult rat brains. The percentages of microvessels with immunohistochemically detectable GLUT1 were 95.5 +/- 3.9 in F98, 60.9 +/- 3.9 in 9L, 45.4 +/- 5.6 in C6, and 1.2 +/- 0.3 in Walker 256 (mean +/- SEM). The percentage of GLUT1-positive vessels in F98 was not statistically different from that in normal brain. GLUT1 expression was not dependent on restricted permeability as all tumors were highly permeable to Evans blue. GLUT1 expression was unrelated to vascular density, vascular morphology, and parenchymal GFAP expression. The expression of GLUT1, a marker of cerebral endothelial differentiation, is a newly described property of glial tumor vessels that may have diagnostic and prognostic significance.

Animals↗
PubMed1991

Angiogenesis inhibition by minocycline.

We describe a new inhibitor of angiogenesis, minocycline, a semisynthetic tetracycline antimicrobial with anticollagenase properties. Minocycline was incorporated into controlled release polymers and tested in the rabbit cornea against neovascularization in the presence of the VX2 carcinoma. Inhibition by minocycline was shown to be comparable to that of the combination of heparin and cortisone, a potent inhibitor of angiogenesis. Minocycline decreased tumor-induced angiogenesis by a factor of 4.5, 4.4, and 2.9 at 7, 14, and 21 days, respectively. At the end of the experiment, whereas the corneas with empty polymers had large, invasive, exophytic tumors, none of the corneas with minocycline had such vascular masses. Recently, studies of agents that disrupt collagen synthesis and deposition have yielded several new angiogenesis inhibitors. We suggest that investigation of agents that disrupt collagenolysis may similarly identify other angiogenesis inhibitors and further clarify the mechanisms of angiogenesis.

Animals↗
PubMed1991

A new technique for explantation and in vitro cultivation of chicken embryos.

A technique is described for explanting and cultivating chicken embryos in plastic drinking cups which have been modified with plastic wrap to reproduce the geometry and dimensions of the egg shell. Successful explantation rates of 97% are possible with a double-window technique, and survivability in cups exceeds that achievable in other in vitro systems (i.e., petri dishes). Long-term survival to the 21st day of incubation is seen routinely. This system with cups is less expensive than that with petri dishes, and simpler than that with plastic wrap/tripods. Thus, this new method of in vitro cultivation of chicken embryos improves upon explantation rate, survivability and system design, and has a wide range of applications in developmental biology, angiogenesis, cancer, and pharmacology research.

Animals↗
PubMed1991

Solitary, isolated metastasis from Ewing's sarcoma to the brain: case report.

We report a case of a 30-year-old woman who developed an intraparenchymal cerebral metastasis from a Ewing's sarcoma of the chest wall diagnosed and treated 3 years earlier and in apparent remission at the time of the neurological presentation (seizures). The case was complicated by a spontaneous preoperative intratumoral hemorrhage that occurred the morning of the scheduled surgical resection and caused a left dense hemiparesis. The tumor and the hematoma were removed. The patient improved after surgical intervention and a postoperative course of cranial irradiation followed by systemic chemotherapy was given. Nineteen months after treatment the patient remains disease-free from the clinical and radiological standpoint.

Adult↗
PubMed1991

Interstitial chemotherapy with drug polymer implants for the treatment of recurrent gliomas.

Malignant gliomas have been difficult to treat with chemotherapy. The most effective agent, BCNU (carmustine), has considerable systemic toxicity and a short half-life in serum. To obviate these problems, a method has been developed for the local sustained release of chemotherapeutic agents by their incorporation into biodegradable polymers. Implantation of the drug-impregnated polymer at the tumor site allows prolonged local exposure with minimal systemic exposure. In this Phase I-II study, 21 patients with recurrent malignant glioma were treated with BCNU released interstitially by means of a polyanhydride biodegradable polymer implant. Up to eight polymer wafers were placed in the resection cavity intraoperatively, upon completion of tumor debulking. The polymer releases the therapeutic drug for approximately 3 weeks. Three increasing concentrations of BCNU were studied; the treatment was well tolerated at all three levels. There were no adverse reactions to the BCNU wafer treatment itself. The average survival period after reoperation was 65 weeks for the first dose group, 64 weeks for the second dose group, and 32 weeks for the highest dose group. The overall mean survival time was 48 weeks from reoperation and 94 weeks from the original operation. The overall median survival times were 46 weeks postimplant and 87 weeks from initial surgery. Eighteen (86%) of 21 patients lived more than 1 year from the time of their initial diagnosis and eight (38%) of 21 patients lived more than 1 year after intracranial implantation of the polymer. Frequent hematology, blood chemistry, and urinalysis tests did not reveal any systemic effect from this interstitial chemotherapy. Since the therapy is well tolerated and safe, a placebo-controlled clinical trial has been started. The trial will measure the effect of the second treatment dose on survival of patients with recurrent malignant glioma.

Brain Neoplasms↗
PubMed1991

Interstitial delivery of dexamethasone in the brain for the reduction of peritumoral edema.

Controlled-release polymers have facilitated the interstitial delivery of drugs within the central nervous system. In the present study, dexamethasone was incorporated into ethylene-vinyl acetate polymers, which were then implanted adjacent to a 9L gliosarcoma in the brain of Fischer 344 rats. The effect of interstitial delivery of dexamethasone on peritumoral edema was assessed and compared to the effect of dexamethasone delivered systemically. Eighty-five rats underwent intracranial implantation of the 9L gliosarcoma. Five days later, the animals were randomly assigned to one of four treatment groups: Group 1 received intracranial implantation of controlled-release polymers containing dexamethasone; Group 2 received intraperitoneal implantation of controlled-release polymers containing dexamethasone; Group 3 received serial intraperitoneal injections of dexamethasone; and Group 4 received sham treatment. The animals were sacrificed 3 days after initiation of therapy and their brains were removed for measurement of the water content (edema) in the tumor-bearing and contralateral hemispheres. Brain and plasma samples were analyzed by reverse-phase high-performance liquid chromatography to determine the tissue and plasma concentrations of dexamethasone. Measurement of the release kinetics of dexamethasone from the ethylene-vinyl acetate polymers in an in vitro system showed that the drug was released in a controlled, tapering fashion. During the first 3 days of controlled release in vitro, 330 micrograms of a total content of 7.5 mg of dexamethasone was released into the medium. Analysis of tissue for drug levels demonstrated, however, that the interstitial delivery of this fractional amount of dexamethasone within the brain resulted in levels 19 times higher than those achieved by administering the full dose of 7.5 mg systemically over a 3-day period. Conversely, the systemic administration of dexamethasone resulted in plasma levels 16 times higher than those measured in the interstitial delivery of dexamethasone in the brain. Brain-water content determinations showed that the interstitial controlled release of the fractional amount of dexamethasone within the brain was as effective in controlling peritumoral edema as systemic administration of the full dose by serial intraperitoneal injections. The study demonstrates the following: 1) controlled-release polymeric carriers deliver biologically active dexamethasone in a sustained fashion; 2) very high concentrations of dexamethasone in brain tissue can be achieved using interstitial polymer-mediated drug delivery while minimizing plasma concentrations of this drug which are sometimes associated with serious systemic side effects; and 3) peritumoral brain edema can be effectively treated by the interstitial delivery of dexamethasone directly within the tumor bed.

Animals↗
PubMed1991

Multidrug resistance gene (MDR1) expression in human brain tumors.

Multidrug resistance for many types of cancer outside the central nervous system (CNS) has been found to be due to the overexpression of the multidrug resistance gene MDR1, of which the gene-product P-glycoprotein acts as a membrane-bound efflux pump for many anticancer drugs. To examine whether brain tumors overexpress the MDR1 gene, 25 brain-tumor specimens were subjected to Northern blot analysis: 10 gliomas, eight meningiomas, three schwannomas, one malignant lymphoma, and three tumors metastatic to the brain. Ten fresh-frozen autopsy specimens of various parts of normal brain were also analyzed. Blots were hybridized with 32P-labeled Chinese hamster complementary deoxyribonucleic acid (cDNA) and 32P-labeled human MDR1 cDNA. The MDR1 gene messenger ribonucleic acid (mRNA) was detected in two tumors using the Chinese hamster probe (one sphenoid wing meningioma and one metastatic prostate tumor) and in one CNS lymphoma using the human probe. Intact mRNA could not be extracted from the fresh-frozen autopsy specimens of normal brain. Seventeen tumors were examined for P-glycoprotein by immunohistochemical staining using murine monoclonal antibody C219: eight gliomas, eight meningiomas, and one craniopharyngioma. The neoplastic cells from two gliomas and three meningiomas and the blood vessels within six gliomas and two meningiomas stained positively for P-glycoprotein. Seven of 10 normal brain specimens stained positively for P-glycoprotein in blood vessels but no specimen demonstrated staining of parenchymal cells. This study demonstrates that the MDR1 gene can be detected in normal brain, and in malignant, benign, and metastatic lesions. P-glycoprotein can be present in tumor blood vessels even when it is not seen in neoplastic cells. Although the role of P-glycoprotein in tumor blood vessels needs to be further examined and more clearly defined, drug resistance in malignant primary brain tumors may result from characteristics not solely of neoplastic cells but also tumor vasculature.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Magnetic resonance imaging diagnosis of an intracranial metastasis of adenocarcinoma of the prostate: case report.

Adenocarcinoma of the prostate is the second most common cancer of American males over age fifty. However, the reported instances of cerebral metastases have been exceedingly rare and are usually diagnosed at postmortem. This report describes an unusual case of brain metastasis from an occult adenocarcinoma of the prostate confirmed by craniotomy and tumor resection.

Adenocarcinoma↗
PubMed1990

Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth.

Neovascularization is critical for the growth of tumours and is a dominant feature in a variety of angiogenic diseases such as diabetic retinopathy, haemangiomas, arthritis and psoriasis. Recognition of the potential therapeutic benefit of controlling unabated capillary growth has led to a search for safe and effective angiogenesis inhibitors. We report here the synthesis of a family of novel inhibitors that are analogues of fumagillin, a naturally secreted antibiotic of Aspergillus fumigatus fresenius. We first isolated this fungus from a contaminated culture of capillary endothelial cells. Purified fumagillin inhibited endothelial cell proliferation in vitro and tumour-induced angiogenesis in vivo; it also inhibited tumour growth in mice, but prolonged administration was limited because it caused severe weight loss. Synthesis of fumagillin analogues yielded potent angiogenesis inhibitors ('angioinhibins') which suppress the growth of a wide variety of tumours with relatively few side-effects.

Animals↗
PubMed1990

The glucose transporter and blood-brain barrier of human brain tumors.

The glucose transporter of the human brain has been localized to endothelial cells expressing the blood-brain barrier, but little is known regarding its mechanism of induction or whether its expression is exclusively linked with restricted vascular permeability. We investigated glucose transporter expression by vessels in human astrocytic tumors and pulmonary metastases to the brain using immunohistochemical techniques. Vessels in 9 of 10 low-grade astrocytomas and 8 of 10 anaplastic astrocytomas were positive for glucose transporter. Glioblastoma vessels were transporter-positive in only 2 of 10 specimens. Vessels in all three metastatic tumors were negative for the glucose transporter. The decrease in transporter expression observed in higher-grade tumors occurred independently of increases in vascular permeability. In low-grade astrocytomas and glioblastomas transporter expression and contrast enhancement were inversely related, but vessels in 6 of 9 anaplastic astrocytomas were transporter-positive despite contrast enhancement. These findings suggest that separate mechanisms induce the glucose transporter and the permeability restrictions of the human blood-brain barrier. They also have potential implications for the therapy and prognosis of astroglial neoplasms.

Adult↗
PubMed1990

Growth inhibition of the 9L glioma using polymers to release heparin and cortisone acetate.

Malignant gliomas are difficult to treat systemically because of exclusion of many chemotherapeutic agents by the blood brain barrier. Furthermore, as opposed to other neoplasms, malignant gliomas recur locally, at the site of original presentation. These tumors are remarkably vascular and hence may be more dependent on angiogenesis for continued growth than other tumors. The inhibition of tumor angiogenesis can control tumor growth by preventing the exponential vascular growth phase. We report the inhibition of the growth of the 9L glioma by the localized, controlled release of known angiogenesis inhibitors administered in a biodegradable polyanhydride polymer matrix. In the presence of heparin and cortisone and of cortisone alone there was a 4.5- and 2.3-fold reduction, respectively, in the growth of the 9L glioma. We compared these results to the inhibition of tumor neovascularization in the rabbit cornea by the localized delivery of the same agents. In the rabbit cornea model, the local release of heparin and cortisone and of cortisone alone resulted in a 2.5- and 2.0-fold reduction, respectively, in the angiogenesis response evoked by the VX2 carcinoma. This study introduces two new potential therapeutic modalities for the treatment of malignant gliomas: the use of the combination of heparin and cortisone as antineoplastic agents and the use of polymeric carriers for the local delivery of such agents in the central nervous system.

Animals↗
PubMed1990

The use of endoscopy to treat bronchobiliary fistula caused by choledocholithiasis.

Bronchobiliary fistula is a rare disorder consisting of the formation of a passageway between the biliary ducts and the bronchial tree. We describe an 87-yr-old woman who had a bronchobiliary fistula secondary to obstruction caused by multiple common bile duct stones. The diagnosis was confirmed by the presence of bile in the sputum and transhepatic cholangiography. Successful stone extraction with balloon and basket techniques and endoscopic sphincterotomy decompressed the biliary tract and was followed by healing of the bronchobiliary fistula without surgical intervention, which has heretofore been considered the only successful means of treatment.

Aged↗
PubMed1990

Polymers to treat brain tumours.

Brain tumours are difficult to treat by conventional methods. A biodegradable polymer, poly-[bis(p-carboxyphenoxy)propane sebacic acid] with a nitrosourea, carmustine, has been demonstrated to be biocompatible in the brains of experimental animals and to release drugs in a predictable sustained manner. Carmustine impregnated in polymers appears to be more effective than when delivered by standard methods. A Phase I clinical study has demonstrated the safety of this approach in treating brain tumours and a Phase III placebo-controlled study is currently underway. Other applications of the polymer in the treatment of brain diseases are discussed.

Animals↗
PubMed1990

Modern treatment of brain tumors.

Although there has been enormous improvement in the safety and accuracy of our diagnostic approaches and in the precision and safety of our surgical techniques, the long-term survival of patients with malignant brain tumors remains dismal. With an increased understanding of the fundamental biologic characteristics of brain tumors, we should be able to improve the outlook for these patients.

Brain Neoplasms↗
PubMed1989

Controlled delivery of 1,3-bis(2-chloroethyl)-1-nitrosourea from ethylene-vinyl acetate copolymer.

1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) has been found to be an effective chemotherapeutic agent against brain tumors. However, because it has a very short half-life in plasma, the exposure of neoplastic cells to BCNU is very brief. The delivery of BCNU may be enhanced by using controlled release polymers. We measured the release of BCNU from ethylene-vinyl acetate copolymer (EVAc) into blood, phosphate buffer, and brain tissue. BCNU-EVAc cylinders that weighed 60 mg were implanted in the peritoneum of rats, and BCNU was detected in blood for 6 days. Studies carried out in vitro showed that BCNU was released from EVAc at a decreasing rate for 195 h. BCNU-EVAc cylinders that weighed 15 mg were implanted either intracranially (i.c.) or i.p. in Fischer 344 rats. Controlled release of BCNU from the i.c. BCNU-EVAc implants was observed over 9 days, with peak drug levels of 49.6 micrograms/g of brain tissue in the implanted hemisphere. The BCNU levels in the contralateral hemisphere and the peripheral circulation were much lower and were detectable for only 1 day. By contrast, peak BCNU levels in the brain from the i.p. BCNU-EVAc implants were 2.7-3.0 micrograms/g for only 12 h, accompanied by peak BCNU levels in blood of 1.0 micrograms/ml tapering over 1 day. These results demonstrate the controlled release of intact BCNU from EVAc in vitro and in vivo. Furthermore, the i.c. implants resulted in localized, prolonged, high levels of the drug in the implanted hemisphere. Hence, the i.c. controlled delivery of BCNU may be more efficacious for the treatment of localized brain tumors.

Animals↗
PubMed1989

Brain biocompatibility of a biodegradable, controlled-release polymer in rats.

We report the biocompatibility in the rat brain of a controlled-release, biodegradable polymer, the polyanhydride poly-[bis(p-carboxyphenoxy)propane-sebacic acid] copolymer (PCPP-SA) in a 20:80 formulation. The biodegradable polyanhydride can be used for drug delivery directly into the brain, circumventing the difficulties posed by the blood-brain barrier and avoiding the consequences of having to administer toxic doses systematically to reach therapeutic doses in the central nervous system. The tissue reaction in the presence of PCPP-SA was compared to that seen with other standard neurosurgical implants. Fifty-six adult Sprague-Dawley rats were assigned to one of seven groups and underwent bilateral frontal lobe implantation of PCPP-SA (42 hemispheres), Surgicel (oxidized regenerated cellulose) (35 hemispheres), or Gelfoam (absorbable gelatin sponge) (35 hemispheres). None of the animals showed any behavioral changes or neurological deficits suggestive of either systemic or localized toxicity from the biodegradable polyanhydride, all surviving to the scheduled data of sacrifice. PCPP-SA evoked a well localized inflammatory reaction, comparable to that of Surgicel, which resolved as the PCPP-SA polymer degraded over five weeks. The biodegradable polyanhydride has been shown in this study to be nontoxic and biocompatible in the rat brain, when compared to standard neurosurgical implants.

Animals↗