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This article discusses the use of intraoperative computed tomography (CT) during neurosurgery. This intraoperative CT scanner is integrated with an image-guided surgery system. The authors' intent is to present information on how these technologies are implemented in the operating room and to describe the improvements in surgical accuracy. Two case studies demonstrate the workflow during spinal procedures and the advantages for the surgeons and patients.

The critical role of angiogenesis in the growth of solid tumors, including neoplasms of the central nervous system, has provided the impetus for research leading to the discovery of inhibitors of tumor neovascularization. The therapeutic potential of systemically administered antiangiogenic drugs for brain tumors, however, is limited by a variety of anatomic and physiologic barriers to drug delivery. Implantable controlled-release polymers for local drug administration directly into the tumor parenchyma have therefore been developed to achieve therapeutic concen-trations of these drugs within the brain while minimizing systemic toxicity. With use of these polymers, successfull antiangiogenic therapy for treatment of experimental intracranial malignancies has been achieved. This has been demonstrated with a variety of otherwise unrelated drugs – including the angiostatic steroids, tetracycline derivatives, and amiloride – which modulate collagenase activity, and thus, basement membrane and interstitial matrix metabolism. Controlled‐release polymers provide a clinically practicable method of achieving sustained antian-giogenic therapy which can be readily used in combination with other treatment modalities such as cytoreductive surgery, radiation, and cytotoxic chemotherapy.

Two approaches for improving the interstitial administration of carmustine (BCNU) using 3.8% loaded poly(carboxyphenoxypropane-sebacic acid), an implantable biodegradable anhydride which significantly prolongs survival in patients with recurrent malignant gliomas, were evaluated. First, increasing the ratio of carboxyphenoxypropane (CPP) to sebacic acid (SA) in the polymer increases its hydrolytic stability, thus prolonging its half-life in vivo, and extending the period of drug release. A second approach is to increase the dose of drug loaded into the polymer. This study evaluated the relative merits of these two approaches by comparing release kinetics, safety, and efficacy of escalating BCNU does in polymers with 20:80 and 50:50 ratios of CPP to SA. At the highest dose tested, the 50:50 polymer released BCNU 2.5 times as long in vitro as the 20:80 polymer. Both formulations were nontoxic in rat brains for all BCNU doses tested except 32%. The 20:80 and 50:50 polymers were equally effective in the rat intracranial 9L-glioma model. A dose-response relationship for BCNU was observed (hazard ratio 0.8354 for each mg/kg increase, P < 0.001). The two highest loading doses of BCNU improved survival 40-fold (P < 0.001). The 20% BCNU-loaded 20:80 polymer achieved the best balance of toxicity and antitumor efficacy, yielding a 75% long-term survival rate. Further evaluation of this polymer in monkeys suggests that it might be used with acceptable toxicity. This study establishes that a dose-escalation strategy for improving BCNU controlled-release polymers is more effective than adjusting the ratio of CPP to SA to prolong drug release.

A young patient surviving four years after treatment for primary intracerebral small-cell osteosarcoma is reported. This 16-year-old girl presented with headaches, visual disturbance, and papilledema and was found to have a large, heavily calcified mass in the left parietal lobe. A gross total resection of the tumor was performed and pathologic analysis revealed a small-cell osteosarcoma. Thoracic computerized tomography (CT) scans and a complete bone scan showed no other lesions. The patient received adjuvant chemotherapy and radiotherapy. She continues to do well with no evidence of metastases or local recurrence 4 years after her initial presentation. The clinical, radiographic, surgical, pathologic, and immunohistochemical features of this case, along with therapeutic interventions and outcome, are presented.

OBJECTIVE : A frameless stereotactic system (the Viewing Wand ; Elekta Instruments, Atlanta, GA) has been developed for use with preoperative computed tomography, magnetic resonance imaging, and positron emission tomography as an adjunct for surgical planning and intraoperative navigation. This clinical study was designed to evaluate the safety, efficacy, and accuracy of the Viewing Wand in a variety of intracranial procedures. METHODS : We used this system in 250 patients undergoing a wide range of neurosurgical procedures from July 1990 to July 1994, to assess its clinical usefulness and safety. In a subset of 45 neurosurgical patients studied between March 1993 and March 1994, a battery of objective accuracy measurements was obtained before and during surgery. RESULTS : In this series, there were no instances of adverse outcomes attributable to the use of this system. A comparison of two alternative patient-image registration techniques established that the fiducial-fit method was slightly more accurate than the surface-fit method (geometric means = 2.51 and 3.03 mm, respectively). The clinical accuracy achieved with magnetic resonance imaging was nearly equivalent to that with computed tomography. CONCLUSIONS : On the basis of this clinical series, recommendations are made regarding preoperative scanning parameters, registration techniques, and methods for reestablishing registration if needed during the course of surgery. The primary clinical benefits of the wand in this series were improved intraoperative navigation and surgical safety. For most cases, the wand was also useful in planning the location and size of the scalp incision, craniotomy, or corticotomy, as well as the extent of surgical resection.

Therapy of brain tumors has been limited by lack of effective methods of drug delivery. Systemic administration often fails to achieve therapeutic concentrations of drugs within intracranial tumors despite toxic systemic levels. This article discusses new methods for delivering therapeutic agents to brain tumors, including intra-arterial, intrathecal, intraventricular, and interstitial administration techniques.

✓ This study was designed to explore the question of whether minocycline, a semisynthetic tetracycline shown to inhibit tumor-induced angiogenesis, could control the growth of the rat intracranial 9L gliosarcoma. Minocycline was tested alone and in combination with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in vivo. Treatment was started at the time of intracranial implantation of 9L gliosarcoma into male Fischer 344 rats, 5 days later, or after tumor resection. Minocycline was delivered locally with a controlled-release polymer or systemically by intraperitoneal injection. Systemic minocycline did not extend survival time. Local treatment with minocycline by a controlled-release polymer implanted at the time of tumor implantation extended median survival time by 530% (p < 0.001) compared to treatment with empty polymer. When treatment was begun 5 days after tumor implantation, minocycline delivered locally or systemically had no effect on survival. However, after tumor resection, treatment with locally delivered minocycline resulted in a 43% increase in median survival time (p < 0.002) compared to treatment with empty polymer. Treatment with a combination of minocycline delivered locally in a controlled-release polymer and systemic BCNU 5 days after tumor implantation resulted in a 93% extension of median survival time compared to BCNU alone (p < 0.002). In contrast, treatment with a combination of systemic minocycline and BCNU did not increase survival time compared to systemic BCNU alone. These results demonstrate that minocycline affects tumor growth when delivered locally and suggest that minocycline may be a clinically effective modulator of intracranial tumor growth when used in combination with a chemotherapeutic agent and surgical resection.

✓ Retrograde thrombosis of feeding arteries is a potentially catastrophic complication occasionally reported following resection of arteriovenous malformations (AVM's). No successful therapy for this condition, which causes postoperative stroke, has previously been reported. A case of retrograde thrombosis of the left middle cerebral artery immediately following resection of a parietal AVM is reported in a patient with a retained intra-arterial catheter from preoperative embolization. The administration of urokinase within 4 hours of surgery resulted in dramatic clinical and angiographic improvement without hemorrhagic complications. While urokinase is considered highly experimental in this setting, this case demonstrates that thrombolytic agents should be viewed as therapeutic options worthy of further investigation.

OBJECTIVE: L-buthionine sulfoximine (BSO) inhibits glutathione synthesis and may modulate tumor resistance to some alkylating agents, but it has not been proven effective in the treatment of intracranial neoplasms. To evaluate this drug for the treatment of brain tumors, we studied the use of BSO for potentiating the antineoplastic effect of 4-hydroxyperoxycyclophosphamide (4-HC) in the rat 9L glioma model. METHODS: The survival of male Fischer 344 rats with intracranial 9L gliomas was measured after implantation of controlled-release polymers containing one of the following: no drug, BSO, 4-HC, or both BSO and 4-HC. The efficacy of intracranial 4-HC treatment was assessed with and without serial systemic intraperitoneal BSO injections. Tissue glutathione levels were measured in the brains, tumors, and livers of animals treated with intraperitoneal injections or local delivery of BSO. RESULTS: The median survival of animals treated with intracranial polymers containing 4-HC was 2.3 times greater than that of controls. This survival benefit was doubled by local delivery of BSO. In contrast, systemic BSO therapy did not improve survival time. In animals that were treated systemically, both liver and tumor glutathione levels were significantly lower than they were in control animals. In the locally treated animals, glutathione levels were reduced in the brain tumor but not in the liver. CONCLUSION: These results demonstrate that local but not systemic delivery of BSO enhances the antineoplastic effect of 4-HC in this rat 9L glioma model. In addition, because local delivery of BSO within the brain did not deplete glutathione levels systemically, this method of treatment may be safer than systemic administration of BSO.

Objective Because decision making in the daily practice of neurosurgery requires judgments about changes in the volume of spatially complex three-dimensional objects, we sought a simple, rapid, and accurate method for extracting this information from standard computed tomographic (CT) scans. Methods Volume measurements were made by using a transparent template to overlay a grid of regularly-spaced points over CT scans of randomly selected patients with hydrocephalus or malignant gliomas. The volume of an object appearing on a scan is the product of the sum of points that fell on the object, the area associated with each point, and the distance between scan slices. This method is known as the Cavalieri Direct Estimator. We assessed the potential clinical applicability of this technique by measuring interobserver correlation for ventricular volume measurements in hydrocephalic patients, correlating brain tumor volume measurements with those obtained using the ISG Allegro system (ISG Technologies, Inc., Mississauga, Ontario) (a three-dimensional reconstruction software package), and measuring the time required for volumetric analyses. Results Tumor volume estimates using this method correlated highly (r = 0.999) with those made by the ISG Allegro System. Interobserver correlation for ventricular volume estimates was also high (r = 0.968). We found that the time required for application of this technique to CT scans ranged from 4 to 10 minutes. Conclusions We conclude that the Cavalieri Direct Estimator can be easily applied to acquire volume measurements from standard CT scans and requires only a few minutes and no additional expense, making it ideal for daily use in clinical practice.

The exponential growth of solid tumors depends upon induction of new vessel growth, a process mediated by diffusable angiogenic factors produced by tumor cells. By inhibiting angiogenesis, it is now possible to modulate tumor growth and metastasis in laboratory animals. The first described inhibitor of angiogenesis was a protein derived from cartilage. Other important classes of antiangiogenic agents include angiostatic steroids combined with heparin or heparin derivatives, and the synthetic derivatives of fumigallin. As the mechanisms of action of these and other angiostatic agents are being elucidated, it is becoming apparent that many modulators of collagen metabolism inhibit angiogenesis and may offer clinically useful anticancer treatments. Minocycline and other tetracycline derivatives with anticollagenase properties have been shown to be potent inhibitors of angiogenesis. These agents, when administered with other standard cancer therapies, help prolong survival in laboratory animals with solid tumors. Further studies of these biologic response modifiers of tumor progression are under way in the hope that they will offer effective new treatments for cancer in humans.