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Rafael J. Tamargo, Jonathan I. Epstein and Henry Brem

✓ Three human glioma cell lines (TE-671 medulloblastoma, U-87 MG glioblastoma, and U-373 MG glioblastoma) were transplanted to the quadrigeminal cistern of the brain in 37 newborn Sprague-Dawley rats and to the subcutaneous space in 30 of their siblings. Two of the three gliomas (the TE-671 medulloblastoma and the U-87 MG glioblastoma) grew both intracranially and subcutaneously. The U-373 MG glioblastoma did not grow in either site. The resulting tumors expressed unique morphological features characteristic of their tissue of origin. The newborn rat represents a model for the heterologous transplantation of human gliomas, providing a biological window for the study of these lesions.

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Rafael J. Tamargo, Allen K. Sills Jr., Carla S. Reinhard, Michael L. Pinn, Donlin M. Long and Henry Brem

✓ 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 µg 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.

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Stuart A. Grossman, Carla Reinhard, O. Michael Colvin, Mark Chasin, Robert Brundrett, Rafael J. Tamargo and Henry Brem

✓ The local concentration and distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) within normal brain tissue were studied following surgical implantation of biodegradable polymer containing BCNU in New Zealand White rabbits. Cylindrical discs of poly(bis(p-carboxyphenoxy)-propane:sebacic acid) copolymer in a 20:80 formulation were made containing [3H]-inulin or [3H]-BCNU labeled in the methylene hydrogens of the chloroethyl groups. These were implanted in the brains of 56 New Zealand White rabbits. The animals were sacrificed 3, 7, 14, or 21 days later and the brains were rapidly removed, frozen, and prepared for quantitative autoradiography. Autoradiographs from coronal sections bisecting the polymer were analyzed to determine both the proportion of the brain section exposed to the tracer and the local drug concentrations as a function of distance from the polymer. Tritiated BCNU was also injected directly into the brains of eight additional rabbits, and local brain concentrations were studied over time.

The results of this study demonstrate that approximately 50% of the area of the brain sections was exposed to radiolabeled compound 3 days after BCNU-polymer implantation, 15% at 7 days, and less than 10% at 14 and 21 days. Polymer discs containing 600 µg BCNU generated 6 mM concentrations of BCNU in brain tissue 10 mm from the polymer at 3 and 7 days. Pharmacological studies demonstrated that approximately 25% of the tritium label was associated with intact BCNU 3 days following polymer implantation. Radiolabeled inulin delivered by polymer remained dispersed throughout the ipsilateral hemisphere for 14 days. Direct injection of [3H]-BCNU into brain parenchyma resulted in widely distributed tracer at 1 and 3 hours with rapid disappearance thereafter. It is concluded that local delivery of BCNU to brain tissue with this polymeric drug delivery system results in sustained high local concentrations of BCNU which may be of value in the treatment of patients with brain tumors.

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Henry Brem, Rafael J. Tamargo, Alessandro Olivi, Michael Pinn, Jon D. Weingart, Moody Wharam and Jonathan I. Epstein

✓ Sustained drug delivery by biodegradable polymer devices can increase the therapeutic efficacy of drugs by producing high local tissue concentrations over extended periods of time. It has been shown previously that implantation of controlled-release polymers impregnated with the nitrosourea carmustine (BCNU) extended the period of survival in rats bearing the 9L glioma compared with similar rats treated with systemically administered BCNU. This study evaluated the effect on the monkey brain of interstitial delivery of BCNU by the biodegradable polyanhydride copolymer poly[bis(p-carboxyphenoxy)propane]anhydride (PCPP) and sebacic acid (SA) in a 20:80 formulation (PCPP:SA). The effect of combining interstitial BCNU with radiation therapy was also evaluated. Eighteen male cynomologus monkeys were randomly assigned to one of four groups: a control group; a group with implantation of empty polymer; a group with implantation of BCNU-loaded polymer; and a group with implantation of empty polymer in the right hemisphere and BCNU-loaded polymer in the left hemisphere, followed by irradiation. The effects were evaluated radiologically and histologically at specified times. A local reaction by the brain to the polymer was found, which was greater when the polymer contained BCNU. Local cerebral edema was observed radiographically on postoperative Day 14 and had resolved by Day 72. Histologically, a subacute cellular inflammatory response was seen on postoperative Day 16, which had changed to a chronic inflammatory response by Day 72. In the group with radiation therapy administered to the hemisphere bearing BCNU-loaded polymer, only localized pathological changes were detected. In all animals, brain distant from the polymer implantation site was normal. No neurological or general deleterious effects were seen in any of the animals. It is concluded that the interstitial delivery of BCNU by the polyanhydride polymer PCPP:SA is safe in the primate brain and that concomitant radiation therapy did not lead to any adverse effects. These experimental findings are important to an understanding of the clinical effects of PCPP:SA implants in treating brain diseases.

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Neil R. Miller, Lee H. Monsein, Gerard M. Debrun, Rafael J. Tamargo and Haring J. W. Nauta

✓ The authors describe the method and results of treatment of 12 consecutive patients with carotid-cavernous sinus fistulas (CCFs). Treatment was by embolization via a transvenous approach through the superior ophthalmic vein (SOV). The CCFs (two direct and 10 dural) had previously been treated unsuccessfully or, for mechanical reasons, could not be treated by the standard techniques of endoarterial balloon occlusion, particle or glue embolization of feeding vessels from one or both external carotid arteries, or transvenous occlusion of the fistula via the ipsilateral inferior petrosal sinus. All 12 patients were successfully treated either by advancement of a detachable balloon catheter through the ipsilateral SOV into the cavernous sinus with subsequent inflation and detachment of the balloon (11 patients) or by introduction of multiple thrombogenic coils into the fistula via the ipsilateral SOV (one patient).

All patients had complete resolution of symptoms and signs after successful occlusion of the CCF. There were no intraoperative complications; however, one patient required postoperative embolization of a residual posteriorly draining fistula via the ipsilateral external carotid artery, and another developed a persistent abducens nerve paresis that eventually required surgical correction. Ten (83.3%) of the 12 patients underwent cerebral angiography 3 to 6 months after surgery, and none showed evidence of a recurrent fistula. Similarly, none of the 12 patients developed recurrent symptoms and signs suggesting recurrence of the fistula during a follow-up period that ranged from 6 months to 10 years (mean 64 months). It is concluded that the transvenous approach to the cavernous sinus through the SOV is a safe and effective treatment of both direct and dural CCFs that are not amenable to transarterial or other transvenous approaches.

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Eric M. Oshiro, David A. Rini and Rafael J. Tamargo

In patients with bilateral supratentorial aneurysms, surgical clipping of all aneurysms via a unilateral approach would obviate the need for a second operation. The authors conducted a microsurgical study in human cadaver heads to examine the contralateral exposure for four common aneurysm sites in the anterior circulation: the ophthalmic artery (OA) origin, the posterior communicating artery (PCoA) origin, the internal carotid artery (ICA) termination, and the middle cerebral artery (MCA) bifurcation. Frontotemporal craniotomies were performed in 16 cadavers to evaluate the corridor for exposure of these sites from the contralateral side. Morphometric data, including lengths and diameters of major arterial segments and optic nerves, were documented for anatomical correlation.

In this study, the contralateral OA origin was successfully exposed in 62% of specimens, the PCoA origin in 50%, the ICA bifurcation in 100%, and the MCA bifurcation in 62%. Exposure of the OA origin and, in some cases, the PCoA, required incision of the falciform ligament and mobilization of the contralateral optic nerve. Exposure of the MCA bifurcation was dependent on the length of the M1 segment, with successful exposure only when this segment was shorter than 14 mm. Implications for the contralateral approach to aneurysms at these sites are discussed and the microsurgical corridors for exposure are described.

For correlation with the anatomical study, a brief clinical review of patients with bilateral supratentorial aneurysms treated at The Johns Hopkins Hospital between 1992 and 1995 is presented. Guidelines for the contralateral approach to aneurysms are discussed with reference to the anatomical study and the clinical review.

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Eric M. Oshiro, David A. Rini and Rafael J. Tamargo

✓ In patients with bilateral supratentorial aneurysms, surgical clipping of all aneurysms via a unilateral approach would obviate the need for a second operation. The authors conducted a microsurgical study in human cadaver heads to examine the contralateral exposure for four common aneurysm sites in the anterior circulation: the ophthalmic artery (OA) origin, the posterior communicating artery (PCoA) origin, the internal carotid artery (ICA) termination, and the middle cerebral artery (MCA) bifurcation. Frontotemporal craniotomies were performed in 16 cadavers to evaluate the corridor for exposure of these sites from the contralateral side. Morphometric data, including lengths and diameters of major arterial segments and optic nerves, were documented for anatomical correlation.

In this study, the contralateral OA origin was successfully exposed in 62% of specimens, the PCoA origin in 50%, the ICA bifurcation in 100%, and the MCA bifurcation in 62%. Exposure of the OA origin and, in some cases, the PCoA, required incision of the falciform ligament and mobilization of the contralateral optic nerve. Exposure of the MCA bifurcation was dependent on the length of the M1 segment, with successful exposure only when this segment was shorter than 14 mm. Implications for the contralateral approach to aneurysms at these sites are discussed and the microsurgical corridors for exposure are described.

For correlation with the anatomical study, a brief clinical review of patients with bilateral supratentorial aneurysms treated at The Johns Hopkins Hospital between 1992 and 1995 is presented. Guidelines for the contralateral approach to aneurysms are discussed with reference to the anatomical study and the clinical review.

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Raymond I. Haroun, Daniele Rigamonti and Rafael J. Tamargo

✓ Although the recurrent artery of Heubner is one of the best known cerebral arteries, little has been written in the neurosurgical or anatomical literature about its discovery. The artery is of primary importance to cerebrovascular surgeons, who identify it during clipping of anterior communicating artery aneurysms. Johann Otto Leonhardt Heubner (1843–1926), who described this artery in 1872, is better known as the father of German pediatrics. He was appointed to the first professorship in Germany exclusively devoted to pediatrics at the Charité Children's Clinic of Berlin University. Although he initially studied internal medicine in Leipzig under Carl Reinhold August Wunderlich and Ernst Leberecht Wagner, his early research involved anatomical studies of the circulation of the brain, from which he described syphilitic endarteritis (Heubner's disease). Finding morphological studies inconclusive, he turned to more physiological experiments. Together with the physiologist Max Rubner, Heubner performed important studies on energy metabolism in infancy, creating the notion of the nutrition quotient. In this article the authors review Heubner's life and scientific discoveries.

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William B. Borden and Rafael J. Tamargo

✓ George J. Heuer was a pioneer in neurosurgery at The Johns Hopkins Hospital in the early 20th century; he trained under Harvey Cushing and acted as a mentor to Walter Dandy. In his early career, Heuer focused on research and clinical work in the field of neurosurgery and temporarily led the neurosurgery section at Johns Hopkins. One of his most important contributions to neurosurgery was the modern frontotemporal craniotomy. This elegant craniotomy, which initially was used to approach chiasmal tumors, developed into the modern frontosphenotemporal craniotomy, which neurosurgeons use to approach numerous tumors as well as most aneurysms. Although Dandy is frequently credited with inventing this operation, his article detailing the new approach clearly attributes its origin to Heuer, who was serving in World War I when the new technique was presented.

Although he had hoped to lead the neurosurgical section at Johns Hopkins permanently, he returned from military service to find that Dandy had been appointed to this position. Heuer subsequently advanced to a distinguished career in general surgery as the chairman of surgery at two institutions, and was known for his contributions to surgical education. Throughout his academic years, Heuer continued to operate on the nervous system and to perform spinal cord and peripheral nerve surgery. He played an important role along with Cushing and Dandy in the creation of neurosurgery as a specialty, but he is rarely given credit for this accomplishment. The authors describe Heuer's contributions to neurosurgery as well as his distinguished surgical career.

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Roberto C. Heros