Evaluation of minimally invasive excisional brain biopsy and intracranial brachytherapy catheter placement in dogs

Rebecca A. Packer Departments of Veterinary Clinical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.
Basic Medical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.

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Lynetta J. Freeman Departments of Veterinary Clinical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.

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Margaret A. Miller Comparative Pathobiology, School of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.

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Amy E. Fauber Departments of Veterinary Clinical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.

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Wallace B. Morrison Departments of Veterinary Clinical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.

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Abstract

Objective—To evaluate a technique for minimally invasive excisional brain biopsy and intracranial brachytherapy catheter placement in dogs.

Animals—5 healthy adult female dogs.

Procedures—Computed tomographic guidance was used to plan a biopsy trajectory to a selected area of brain with reference to a localizer grid. The procedure was performed through a 1-cm skin incision and 6-mm burr hole by use of a 9-gauge biopsy device. Five cylindrical samples (3 to 4 mm in diameter and 7 to 12 mm in length) were removed over 5 cycles of the vacuum-assisted tissue excision system, leaving approximately a 2-cm3 resection cavity. A balloon-tipped intracranial brachytherapy catheter was placed through the burr hole into the resection cavity, expanded with saline (0.9% NaCl) solution, and explanted 7 days later.

Results—4 of 5 dogs survived the procedure. The fifth died because of iatrogenic brain damage. Neurologic deficits were unilateral and focal. Twenty-four hours after surgery, all surviving dogs were ambulatory, 2 dogs exhibited ipsiversive circling, 4 had contralateral proprioceptive deficits, 3 had contralateral menace response deficits, 2 had a reduced contralateral response to noxious nasal stimulation, and 1 had dull mentation with intermittent horizontal nystagmus and ventrolateral strabismus. Neurologic status improved throughout the study period. Histologic quality of biopsy specimens was excellent.

Conclusions and Clinical Relevance—This technique enabled histologic diagnosis from high-quality biopsy specimens obtained through a minimally invasive technique and has potential applications for multimodal treatment of deep brain tumors in dogs.

Abstract

Objective—To evaluate a technique for minimally invasive excisional brain biopsy and intracranial brachytherapy catheter placement in dogs.

Animals—5 healthy adult female dogs.

Procedures—Computed tomographic guidance was used to plan a biopsy trajectory to a selected area of brain with reference to a localizer grid. The procedure was performed through a 1-cm skin incision and 6-mm burr hole by use of a 9-gauge biopsy device. Five cylindrical samples (3 to 4 mm in diameter and 7 to 12 mm in length) were removed over 5 cycles of the vacuum-assisted tissue excision system, leaving approximately a 2-cm3 resection cavity. A balloon-tipped intracranial brachytherapy catheter was placed through the burr hole into the resection cavity, expanded with saline (0.9% NaCl) solution, and explanted 7 days later.

Results—4 of 5 dogs survived the procedure. The fifth died because of iatrogenic brain damage. Neurologic deficits were unilateral and focal. Twenty-four hours after surgery, all surviving dogs were ambulatory, 2 dogs exhibited ipsiversive circling, 4 had contralateral proprioceptive deficits, 3 had contralateral menace response deficits, 2 had a reduced contralateral response to noxious nasal stimulation, and 1 had dull mentation with intermittent horizontal nystagmus and ventrolateral strabismus. Neurologic status improved throughout the study period. Histologic quality of biopsy specimens was excellent.

Conclusions and Clinical Relevance—This technique enabled histologic diagnosis from high-quality biopsy specimens obtained through a minimally invasive technique and has potential applications for multimodal treatment of deep brain tumors in dogs.

Conventional craniotomy procedures in veterinary patients do not facilitate resection of deep brain tumors without damage to overlying brain tissue. Although conventional stereotactic brain biopsy methods may spare extratumoral tissue, they do not allow for rapid resection of large tumors. Therefore, less invasive techniques are needed for biopsy and resection of deep brain tumors to reduce procedural duration, collateral tissue damage, and adverse effects associated with the surgical approach.

Current glioma treatment options in humans involve invasive surgery deep within brain tissue and aggressive chemotherapy and external beam radiation protocols that usually result in poor long-term outcomes, particularly for patients with high-grade gliomas.1–3 Treatment options for veterinary patients with gliomas are often limited by the tissue trauma induced by invasive surgical approaches that require dissection through normal brain tissue to access deep tumors. As a result, definitive treatment for veterinary patients with gliomas is often limited to external beam radiation therapy and chemotherapy. For these reasons, less invasive treatment methods for deep brain tumors are needed to minimize adverse effects without sacrificing outcome.

Minimally invasive stereotactic brain biopsy procedures are available for veterinary patients; however, none are used for tumor resection because of the small-gauge needles that preclude efficient tissue resection and compromise biopsy specimen quality.4–12 Neuroendoscopic procedures for brain tumor biopsy and resection in animals have been reported, but available instrumentation limits the ability to perform efficient endoscopic resection of tumor tissue because only small tissue specimens can be excised with each passing of the biopsy forceps.12,13 For this reason, application of minimally invasive tumor resection and endoscopic neurosurgery to date has largely been limited to ventriculostomy procedures, CSF diversion procedures, or trans-sphenoidal and hypothalamic surgeries in which only small volumes of tumor tissue needed to be removed.14–18 An ultrasonic aspirator tip was recently adapted for neuroendoscopic resection19; however, reported use was limited to resection of pituitary adenomas and evacuation of third ventricle hematomas, and the aspirator does not obtain biopsy specimens.

Newer minimally invasive excisional biopsy techniques have been developed for other organ systems20,21 but have not been tested for the brain. An excisional brain biopsy technique yet to be evaluated in nonhuman animals is an adaptation of the stereotactic, image-guided technique used for excisional biopsy of benign breast tumors in humans through the use of a vacuum-assisted biopsy and tissue removal system.20,21,a This minimally invasive breast biopsy system has been used in > 1.7 million breast biopsy procedures in humans and has the potential to be used for excisional biopsy of brain tissue.20,21 The purpose of the study reported here was to develop a minimally invasive technique for the diagnosis and treatment (ie, excision) of deep brain tumors in dogs that would minimize trauma to the healthy brain tissue external to the tumor.

Materials and Methods

Animals—Five healthy adult female Beagles from the same breeder were used in the study. The dogs weighed between 10.0 and 12.2 kg and ranged in age from 2 years 9 months to 8 years. All were judged clinically normal on the basis of physical and neurologic examinations. Animals were housed in individual runs for the duration of the study and cared for according to the principles outlined in the National Institutes of Health Guide for the Care and Use of Laboratory Animals. The study protocol was approved by the Purdue University Institutional Animal Care and Use Committee.

Study protocol—Dogs were treated according to the following general timeline. On day 0, each dog was anesthetized for CT scan of the head to establish coordinates for the biopsy and tissue resection procedures. The dogs were then taken to surgery for tissue resection and intracranial catheter placement. Computed tomography was performed immediately after the procedure to confirm appropriate placement of the balloon-tipped catheter. The catheter balloon was then deflated. On day 7, the dogs were sedated, and the catheter balloon was inflated with sterile saline (0.9% NaCl) solution to represent 125I (radioisotope of iodine) instillation. On day 14, the dogs were anesthetized for catheter deflation and removal. Each dog was then monitored for an additional 14 days. The study period ended on day 28, at which time dogs were euthanized and pathological evaluation occurred.

Anesthetic and treatment protocol—Dogs received glycopyrrolate (0.01 mg/kg) in combination with acepromazine maleate (0.02 to 0.05 mg/kg) and butorphanol tartrate (0.2 to 0.4 mg/kg), all administered IM. Anesthesia was induced by IV injection of 2.5% sodium pentothal (15 mg/kg), and dogs were endotracheally intubated. Anesthesia was maintained with 1% to 2% isoflurane in oxygen. All dogs received cefazolin sodium (22 mg/kg, IV) preoperatively and every 2 hours throughout the anesthetic period. All dogs also received mannitol (1 g/kg, IV), administered over 20 minutes, at the beginning of the surgical biopsy procedure. Mannitol was not administered during the catheter removal procedure on day 14.

On day 7, the dogs were sedated with medetomidine hydrochloride (5 μg/kg, IV) and butorphanol (0.2 mg/kg, IV) for the balloon inflation procedure; sedation was later reversed with atipamezole hydro-chloride (5 mg/mL) at a volume equal to that of the medetomidine.

Biopsy apparatus—The biopsy apparatus consists of a craniotomy stand to stabilize the dog's head in position, 2 localizer grids, and 2 angle guides, in mirrored symmetry, to accommodate right- or left-sided approaches (Figure 1). The animal's upper dental arcade rests on the adjustable cross pins. A localizer grid attaches to the craniotomy stand by sliding into a rigid slot and is secured in place with threaded pins. This localizer grid is positioned in firm contact with the animal's head. The angle guide indicates the angle of the animal's head relative to the biopsy grid. For lesions in the left hemisphere, there is 1 angle guide ranging from 0° to 90° axially from dorsal midline to the left; for lesions in the right hemisphere, there is another angle guide ranging from 0° to 90° axially from dorsal mid-line to the right.

Figure 1—
Figure 1—

Photographs of the craniotomy stand used for minimally invasive excisional brain biopsy and intracranial brachytherapy catheter placement in dogs, with the localizer grid in place for right-sided biopsy. A—Front of the apparatus. B—Back of the apparatus. C—Close-up view of the angle guide for right-sided positioning. D—For the procedures, the dog's head was positioned as shown and could be rotated axially to accommodate variable angles of biopsy trajectory. The dog's upper dental arcade rested on adjustable cross pins (also visible in panel B).

Citation: American Journal of Veterinary Research 72, 1; 10.2460/ajvr.72.1.109

The apparatus includes a needle guide, which is a small plastic insert that fits into a square of the biopsy grid and contains 9 circular channels. These channels accommodate the biopsy introducer, which secures the probe snugly in place at the appropriate trajectory and depth. The biopsy probe fits through the introducer so that the entire apparatus remains securely positioned during the entire procedure.

The biopsy system also involves use of a localizer worksheet,a adapted from the human breast biopsy system, with 2 grid diagrams: the CT-planning grid, which is oriented to the CT images and used for planning the biopsy, and the table-patient grid, which is oriented relative to the patient as if table-side for the biopsy procedure. Worksheets are depicted specifically for left- or right-sided biopsy approaches.

Determination of biopsy site—Dogs were positioned in sternal recumbency, with the head secured in the craniotomy stand. Each head was shaved and prepared for surgery by use of standard aseptic technique. The sterile right-sided localizer grid was attached to the craniotomy stand and placed in contact with the aseptically prepared area of the dog's head (against the skin overlying the frontalis, interscutularis, and temporal musculature). The center point of a mock lesion approximately 2 cm3 in dimension was arbitrarily targeted in the right frontal-parietal region of the brain on transverse CT images. This volume was chosen to approximate excision of a tumor and to create a sufficient cavity for brachytherapy catheter placement.

Determination of the biopsy site was performed as follows. In step 1, the ideal angle trajectory for the biopsy path was determined from the transverse CT images and selected to penetrate the least amount of healthy brain tissue en route to the mock lesion (Figure 2). The angle guide on the craniotomy stand was set according to the trajectory calculated from the CT images. In step 2, a fiducial was placed in 1 square of the grid away from the lesion location so as to not interfere with the aseptically prepared area of interest. This location was recorded on the grid diagram labeled Patient View on the biopsy worksheet and was transferred to the Image View grid diagram. In step 3, additional CT images were acquired with the grid in place and with the head positioned at the appropriate angle relative to the grid, as determined from step 1. These additional CT images were used to determine the intended biopsy site in the rostral-caudal and lateral directions by use of the localizer worksheet while cross-referencing the mock lesion location to the grid on the scout images.

Figure 2—
Figure 2—

Illustration of the biopsy targeting procedure and associated worksheet (top) for minimally invasive excisional brain biopsy and intracranial brachytherapy catheter placement in dogs. The blue lines on the CT images are used to determine the site of intended biopsy and are generated by standard imaging software to cross-reference transverse CT images (bottom right) to lateral scout CT images (bottom left). The fiducial is represented by the blue F on the grid diagram and lateral scout CT image. The blue line on the transverse CT image is used to determine the biopsy depth and the location of the intended biopsy site according to the appropriate numbered row on the localizer grid by use of the Image View grid diagram. In this example, row 2 corresponds to the appropriate biopsy location (numbered row highlighted in yellow). The blue line on the lateral scout CT image is used to determine the biopsy location according to the appropriate lettered row on the localizer grid by use of the Image View grid diagram. In this example, row D corresponds to the appropriate biopsy location (lettered row highlighted in yellow). The intersection of these 2 rows corresponds to the specific grid square to be used for the biopsy procedure. In this example, square D2 corresponds to the appropriate biopsy grid square. The Needle Guide diagram is used to determine the specific location within the selected biopsy square. In this example, channel c3 corresponds to the appropriate location of the biopsy introducer and cannula (indicated by the blue circle). The specific biopsy localization point (blue circle) is then transferred from the point D2/c3 on the Image View grid and Needle Guide diagrams to the corresponding D2/c3 location on the Patient View grid (red square) and Needle Guide (red star) diagrams.

Citation: American Journal of Veterinary Research 72, 1; 10.2460/ajvr.72.1.109

In subsequent steps, biopsy site determination required standard imaging software to provide cross-referenced lines between orthogonal images. In step 4, the transverse CT image acquired at the center of the lesion was viewed. Bearing in mind the angle trajectory calculated in step 1, a line was drawn to determine the depth from the skin-grid interface to the center of the lesion (the biopsy depth gauge is standardized to the interface of the skin grid). When drawn correctly, this line should be perpendicular to the grid. In step 5, the same transverse CT image and same line drawn in step 4 were used to determine the numbered row (ie, rows 1 through 5) of the biopsy grid that corresponded to the biopsy tool entry point. In step 6, while the same transverse CT image that was centered within the lesion was viewed, the slice was cross-referenced to the lateral CT scout image. The lateral CT scout image was used to determine the lettered row (ie, rows A through I) corresponding to the center of the lesion. In step 7, the intersection of these lettered and numbered rows was used to assign the biopsy trajectory to a specific square on the CT-planning grid worksheet.

In step 8, once the appropriate grid square was identified, the needle guide diagram on the worksheet was used to select the appropriate guide from the 9 channels (a-1 through c-3). In step 9, the same cross-referenced lines on orthogonal images (ie, the lateral scout CT image and the transverse CT slice at the center of the lesion) were used to determine whether the line on the lateral scout image, previously determined to be in row D of the localizer grid in our example, corresponded with the rostral (row c of the needle guide), middle (row b of the needle guide), or caudal (row a of the needle guide) lettered row of the needle guide (Figure 2). It also had to be established whether the angle trajectory on the transverse CT image, previously determined to be in row 2 of the localizer grid in our example, corresponded with the dorsal (row 3 of the needle guide), middle (row 2 of the needle guide), or ventral (row 1 of the needle guide) numbered row of the needle guide. Finally, in step 10, this location of the biopsy grid (square D2) and the needle guide location (channel c3) on the Image View grid diagram on the worksheet were transferred to the Patient View grid diagram portion of the worksheet for use during the actual biopsy procedure.

Surgical procedure—Surgical biopsy and resection were performed immediately following the biopsy site determination procedure. Each dog remained positioned in the craniotomy stand in sternal recumbency with the head angled in relationship to the localizer grid according to measurements. Sterile surgical drapes were placed over each dog, with an access hole cut in the drape over the appropriate grid square as determined during planning. The grid remained in place during the entire surgical procedure and was only removed prior to securing the catheter in place and closing the incision.

A 1-cm skin incision was made through the appropriate square on the grid by use of a No. 11 scalpel blade (Figure 3). The subcutaneous tissue was bluntly dissected to expose the temporal fascia. A 6-mm skin biopsy punch was used to remove a core of temporalis muscle to expose the periosteum of the cranium. A 6-mm burr hole in the parietal bone was made with an electric drill with a 6-mm-diameter burr to accommodate the 9–gauge biopsy device. The needle guide was inserted into the appropriate grid square, and the biopsy tool introducer was placed through the appropriate channel of the needle guide to the predetermined depth and trajectory according to the planning parameters. The introducer cannula was removed from the introducer sheath, and the biopsy probe was inserted to the appropriate depth. The automated tissue excision system with built-in irrigation and suctiona was then used to excise the targeted brain tissue.

Figure 3—
Figure 3—

Illustration of the surgical procedure used for minimally invasive excisional brain biopsy and intracranial brachytherapy catheter placement in dogs. A—An incision is created through the appropriate square on the localizer grid. B—A punch biopsy tool is used to remove temporalis muscle and allow access to the calvarium. C—A burr hole is created with a high-speed drill. A thoracotomy port is used as a shield to protect adjacent tissue from damage. D—The needle guide and introducer are placed. E—The biopsy device is introduced through the needle guide. F—Biopsy specimens are obtained. The device can be rotated as needed to remove tissue through use of a pedal to control the duration of tissue collection.

Citation: American Journal of Veterinary Research 72, 1; 10.2460/ajvr.72.1.109

Once the biopsy probe was in the correct location, samples were obtained by automated vacuum suction to pull tissue through the lateral aperture of the probe and sever the tissue sample. The automated suction gently pulls the tissue into the sterile collection chamber for storage. This collection chamber has a cylindrical mesh insert that can be removed, emptied, and replaced aseptically during the procedure, as needed for submission of tissue cultures or for intraoperative evaluation of frozen sections.

By rotation of the shaft of the biopsy probe, sequential biopsy specimens (and tissue removal) were obtained around a 360° circumference. This resulted in a cylindrical cavity up to 1.5 cm in diameter and up to 1.2 cm long (with the potential for 2-cm length depending on which of 2 aperture sizes is used), without repositioning the biopsy probe.

Five cylindrical samples were removed over 5 cycles of the vacuum-assisted tissue excision system in an attempt to create a 2-cm3 resection cavity. With such a system, the surgeon can guide the tissue excision by rotating the probe so that the aperture faces the tissue of interest. Real-time feedback via CT or MRI can be used during the biopsy and resection procedure; the system is MRI compatible.

After tissue excision, the grid was backed away from the dog and removed by a technician using aseptic technique, maintaining the sterile surgical field and surgical drapes. A balloon-tipped catheterb was placed through the burr-hole craniotomy defect, advanced to the depth of the resection cavity according to the measurements on the catheter cannula, and secured in place.

Closure was routine, and 2-0 polypropylenec was used to secure the catheter to the temporalis musculature with 2 friction sutures. The catheter tubing was coiled subcutaneously under the platysma muscle and dorsal to the temporalis fascia. The access port was secured with 2-0 polypropylene suture to the temporalis fascia by use of the 3 tacking holes. The platys-ma muscle was sutured with 3-0 polydioxanoned in a simple continuous pattern. The skin was sutured with 3-0 polydioxanone in a simple continuous pattern. After surgery, CT scans were performed with the balloon inflated to confirm balloon location within the excision cavity. The balloon was then deflated after placement was confirmed.

Recovery and monitoring procedures (days 1 through 28)—Serial neurologic examinations were performed on all dogs every 12 hours for the first 72 hours after the biopsy procedure and every 24 hours thereafter for the duration of the 28–day study period. All neurologic examinations were performed by the same board-certified neurologist (RAP), except for 1 day on which the neurologic examinations were performed by a board-certified surgeon (AEF). Mentation, rectal temperature, heart rate, and respiratory rate were monitored in each dog every 12 hours throughout the study period. Body weight was recorded daily as well.

After the biopsy procedure, dogs recovered from anesthesia and were monitored continuously by direct observation, with an observer in attendance for the first 48 hours. Attitude, mentation, and seizure activity were monitored continuously during this time. Heart rate; respiratory rate; pupil size, symmetry, and responsiveness to light; and indirect blood pressure were monitored hourly for the first 24 hours after the biopsy procedure, then every 4 hours for the next 24 hours. Rectal temperature was monitored hourly until the dogs reached their typical rectal temperature and then every 4 hours throughout the 48-hour postoperative period.

During the first 48 hours after biopsy, dogs received constant rate IV infusions of morphine (0.05 to 0.1 mg/kg/h) and lidocaine (20 μg/kg/h) in saline solution for pain control. After 12 to 24 hours, all dogs appeared comfortable and received carprofen (2.2 mg/kg, SC, q 12 h for 2 to 3 days) for continued analgesia. Dogs were monitored for any of the following indications of pain or discomfort: increased heart rate, increased respiration rate, restlessness or agitation, and vocalization.

After the initial 48-hour postoperative monitoring period, all dogs were continuously monitored via video surveillance for the remainder of the study in addition to the direct monitoring already described. The surveillance system used was specifically selected for its output quality and was of sufficient resolution to allow detection of tremors and seizure activity. All dogs were housed in individual runs with individual surveillance cameras. The surveillance tapes were reviewed in their entirety for each dog, and any seizure activity or other adverse events were recorded.

Catheter balloon inflation (day 7)—Seven days after biopsy and catheter placement, the dogs were sedated as described earlier. The catheter balloon was in-fated with 1.5 mL of saline solution administered over 1 minute to simulate the volume of 125I that the brachytherapy catheter would contain for brachytherapy treatment. The balloon was left inflated for 7 days in accordance with the duration of brachytherapy.

Catheter balloon deflation and explantation (day 14)—After the 7-day dwell time, the dogs were anesthetized as described for the biopsy procedure. The catheter balloon was deflated, and the catheter was removed. Dogs recovered from anesthesia and were monitored continuously by an observer in attendance for 12 hours afterward. Thereafter, all dogs were continuously monitored via surveillance cameras.

Day 28—At the endpoint of the study, dogs were humanely euthanized with sodium pentobarbital (0.22 to 0.44 mL/kg, IV) in accordance with recommendations from the 2000 AVMA Panel on Euthanasia.22 After euthanasia, the brain was removed and submitted for gross and histologic evaluation.

Biopsy specimen and postmortem brain assessment—The biopsy specimens from all 5 dogs were fixed by immersion in neutral-buffered 10% formalin, weighed after fixation (all submitted tissue, including brain and clotted blood, was included), placed in a biopsy cassette, photographed, processed routinely, and embedded en masse in paraffin for histologic examination. The rest of the brain was collected from each dog, fixed by immersion in formalin, weighed after formalin fixation, sliced transversely, and photographed.

After macroscopic photography, slices of brain from each dog that included the biopsy defect and catheter trajectory were submitted for routine histologic processing. Paraffin sections (5 μm thick) of the biopsy specimens and brain slices were stained with H&E. Image analysis was performed with imaging softwaree to determine the area of brain tissue in histologic sections. Blood clots were not included in the image analysis. Selected postmortem brain sections from each dog were also stained with Masson trichrome stain for fibrous collagen and evaluated immunohistochemically for expression of GFAP23 to identify astrocytes. An avidinbiotin immunoperoxidase technique with no antigen retrieval was used for GFAP detection on dewaxed and rehydrated 5-μm-thick paraffin sections. Rabbit poly-clonal antibodyf diluted at 1:1,000 was applied to the slides of paraffin sections and incubated for 30 minutes at room temperature (approx 21°C). Immunohistochemical labeling was detected with diaminobenzidine as the chromogen. Slides were counterstained with Mayer hematoxylin. Nonimmune rabbit serumf replaced the primary antibody for the negative reagent control sample. Histologic examination was performed to evaluate the quality of the biopsy specimens and the tissue response (at day 28) to the procedure-induced injury.

Data collection—Incidence was recorded for any neurologic deficits evident during the study period. The duration of these deficits and the time of their resolution were also recorded and described. Total anesthesia duration was calculated as the time from induction to extubation, including planning, patient transport, procedure, and recovery time. Total procedure duration was calculated as the time from skin incision to skin closure for the biopsy, excision, and catheter placement procedure.

Accuracy of the excisional biopsy procedure was estimated by use of transparencies of the transverse CT images. The preoperative (planning) CT image from each dog was superimposed over the corresponding postoperative CT image to determine the degree of overlap between the mock lesion and the biopsy cavity or the inflated catheter balloon, which was situated in the biopsy cavity. The degree of overlap was described as centered when the mock lesion was superimposed over the center point of the biopsy cavity or the inflated balloon of the brachytherapy catheter; as offset when the mock lesion was superimposed with the biopsy cavity or inflated balloon, but not located on the center point; or as peripheral when the mock lesion and biopsy cavity or inflated balloon did not overlap.

Statistical analysis—Data were summarized descriptively and are reported as mean ± SD.

Results

Procedure feasibility—Total procedure duration for the biopsy, excision, and catheter placement procedures decreased from 80 minutes for the first of the 5 dogs to 25 minutes for the last dog (Table 1). Total anesthesia duration varied because of the variation in time necessary for performing CT scans and planning the biopsy, including 1 instance of CT mechanical failure, and ranged from 1 hour 35 minutes to 4 hours 5 minutes.

Table 1—

Body weight, procedure durations, and neurologic status in healthy Beagles that underwent minimally invasive excisional brain biopsy and intracranial brachytherapy catheter placement (day 0).

Dog No.Total surgery duration (min)Total anesthesia duration (min)Neurologic status 24 hours after surgeryNeurologic status during recoveryNeurologic deficits 28 days after surgery
180220Ambulatory, ipsiversive circling, dull mentation, contralateral proprioceptive deficits, contralateral menace response deficit, reduced response to noxious nasal stimulation contralaterally, intermittent horizontal nystagmus, intermittent ventrolateral strabismusNystagmus and strabismus resolved by day 5; mentation was restored by day 15; deficits in menace and noxious nasal responses became intermittent by day 15; circling and proprioceptive deficits became intermittent by day 17All residual deficits were intermittent and included contralateral proprioceptive deficits, contralateral menace response deficits, and decreased response to noxious nasal stimulation contralaterally
255210Ambulatory, normal gait, contralateral proprioceptive deficits, intermittent deficits in contralateral menace response and response to noxious nasal stimulationDeficits in menace and noxious nasal stimulation responses resolved by day 16Contralateral proprioceptive deficits
355245*Died postoperativelyNANA
43595Ambulatory, normal gait, intermittent contralateral menace response deficitIntermittent delayed proprioception in contralateral pelvic limb was detected once on day 2; contralateral reduced response to noxious nasal stimulation was detected once on day 19Intermittent contralateral menace response deficit
525145Ambulatory, ipsiversive circling, mild hemiparesis, contralateral proprioceptive deficitsCircling became less consistent and hemiparesis improved by day 4; proprioception was intermittently normal by day 16Intermittent contralateral proprioceptive deficits and intermittent circling in either direction

*Recovery from anesthesia was prolonged in this dog.

Scanning time was prolonged because of CT machine downtime.

NA = Not applicable.

All neurologic findings are reported as compared with findings in a clinically normal dog. Contralateral refers to the side opposite that of the biopsy site. Total anesthesia duration was calculated as the time from induction to extubation, including planning, patient transport, procedure, and recovery time. Total procedure duration was calculated as the time from skin incision to skin closure for the biopsy, excision, and catheter placement procedures.

Procedure accuracy—When preoperative and postoperative CT images were superimposed, the site of the mock lesion (preoperative image) appeared to correspond with site of the biopsy cavity (postoperative image) in all 5 dogs. The center point of the mock lesion was centered within the biopsy cavity in 3 dogs and offset, but still within the biopsy cavity, in 2 dogs.

Adverse effects—All dogs were neurologically normal prior to the study. One dog died within 12 hours after the biopsy procedure. All 4 surviving dogs had postsurgical neurologic deficits that improved by the end of the 28-day study period. Those dogs reattained their presurgical functional quality of life (defined as alert mentation, usual interactions with people and the environment, usual ambulatory ability, usual appetite, and no apparent signs of pain or disorientation), with minimal residual deficits. Although the 4 surviving dogs were ambulatory after 24 hours, neurologic deficits were observed including persistent or intermittent proprioceptive deficits contralateral to the biopsy site (n = 4), contralateral deficits in the menace response (3), decreased contralateral response to noxious nasal stimulation (2), ipsiversive circling (2), dull mentation (1), and intermittent horizontal nystagmus (fast phase to the right) and intermittent right-sided ventrolateral strabismus (1; Table 1). Most deficits improved noticeably over the first 1 to 2 weeks of the study. At the end of the study, 4 dogs had their usual normal mentation, 3 had their gait restored (1 dog continued to circle intermittently with no directional preference), 3 had proprioceptive deficits contralateral to the biopsy site, 2 had a contralateral menace response deficit, and 1 had a contralateral decreased response to noxious nasal stimulation.

All dogs tolerated the procedure with minimal signs of pain, which had been controlled with analgesics. The catheter inflation and deflation-explantation procedures did not result in any additional signs of pain; there was no worsening of existing neurologic deficits, and no additional neurologic deficits were detected after these procedures.

One dog (dog 2) had muscle spasms in the cervical spinal musculature and hyperesthesia on deep palpation of the cervical spinal musculature on day 9 of the study. These signs resolved with carprofen administration (2.2 mg/kg, SC, q 12 h for 7 days). At the end of the study, postmortem examination confirmed an inter-vertebral disk protrusion at C6–C7.

In the dog that died 12 hours after the biopsy procedure (dog 3; approx 4 hours after recovery from anesthesia), the surgeon had deviated from the biopsy protocol after burr-hole placement. The surgeon attempted to probe the margins of the burr hole in the cranium with a small nerve root retractor to become oriented to its depth but inadvertently passed the instrument through the burr hole (without contacting the bony margins) and into brain tissue, resulting in damage to thalamic tissue. Thalamic damage was confirmed via postmortem examination.

Biopsy specimen quality—Histologic quality was excellent for all biopsy specimens. The cylindrical specimens were 3 to 4 mm in maximal diameter (mean ± SD value, 3.8 ± 0.4 mm). Excluding for fragmented specimens, specimens were 9.8 ± 2.3 mm in length. Other specimen dimensions were also summarized (Table 2).

Table 2—

Weights and dimensions of biopsy specimens and brains from healthy Beagles that underwent minimally invasive excisional brain biopsy and intracranial brachytherapy catheter placement.

DogBody weight (kg)Biopsy specimen weight in formalin (g)Brain weight in formalin (g)Total weight in formalin (g)Biopsy specimen length (mm)Biopsy specimen diameter (mm)Biopsy specimen area (cm2)
110.81.076.077.01041.49
212.23.972.476.3830.87
310.00.784.485.1742.22
410.20.872.773.51242.43
512.02.079.781.71242.24
Mean ± SD value1.7 ± 1.377.0 ± 5.178.7 ± 4.69.8 ± 2.33.8 ± 0.41.85 ± 0.65

Distortion of biopsy tissue or fraying of the edges of the specimens was minimal, even in the smaller fragments. The only artifacts detected were hemorrhagic material (generally microscopic in size, uncommon, and more common in the white matter than in gray) and dark neurons (an artifact characteristic of brain tissue that was handled before fixation24). The dark-neuron artifact was minimal or not even noticeable in most biopsy specimens.

Postmortem evaluation—Brains collected at necropsy and fixed in formalin had a mean weight of 77.0 ± 5.1 g. The dog that died within 12 hours after the biopsy procedure (dog 3) was the smallest dog at body weight of 10.0 kg but had the heaviest brain (84.4 g). Upon gross examination of the formalin-fixed brain, a hemorrhagic tract of friable parenchyma extended from a 1-cm-diameter cavitated defect (entry site) in the lateral aspect of the right parietal lobe across the brain through the basal nuclei and thalamus and almost penetrated the ventral aspect of the left pyriform lobe. Histologically, hemorrhage into brain parenchyma appeared more extensive in dog 3 than in the other dogs. In addition, a higher degree of perivascular and perineuronal space, as well as a generalized fine spongiotic appearance to the neuropil and patchy vacuolation of cerebral white matter, suggested that edema contributed to increased brain weight.

In the 4 dogs that survived 4 weeks after the biopsy procedure, brain tissue superficial (external) to the biopsy cavity was minimally disrupted, and there was negligible inflammation with minimal collateral damage to adjacent tissue (Figure 4). Histologically, the biopsy cavity appeared as a space 3 to 5 mm in maximal dimension, bordered by a < 1-mm- to 2-mm-wide zone of necrosis (Figure 5). Immunohistochemical detection of GFAP (Figure 6) accentuated the increased number, size, and prominence of cellular processes of astrocytes in cerebrocortical tissue around the biopsy cavity, compared with characteristics in tissue farther from that site. The astrocytosis and astrogliosis were less apparent around the biopsy cavity or catheter tract in cerebral white matter, but the zone of necrosis in the white matter appeared wider than that in gray matter, with loss of nearly all brain parenchyma so that only the vasculature remained. The vessels had hypertrophied, crowded endothelial cells and perivascular cuffing by lymphocytes and histiocytes. The space between vessels was filled by gitter cells and lightly scattered erythrocytes. Peripheral to the zone of necrosis in cerebral cortex, the only apparent histologic change was dispersal of Nissl substance in neuronal somata and hypertrophy of astrocytes, which had abundant hyaline cytoplasm and an eccentric nucleus. White matter peripheral to the zone of liquefactive necrosis had patchy spongiosis with swollen axons or spheroids and hypertrophied astrocytes.

Figure 4—
Figure 4—

Photograph of transverse sections of formalin-fixed brain tissue from a healthy Beagle (dog 5) that underwent a minimally invasive excisional brain biopsy procedure. Sections were obtained from the region at the center of the biopsy defect. Notice the cavity created by the biopsy device. Tissue external to the cavity is minimally disrupted, and the cavity is created internal to the surface of the brain. Scale units in millimeters.

Citation: American Journal of Veterinary Research 72, 1; 10.2460/ajvr.72.1.109

Figure 5—
Figure 5—

Photomicrographs of brain tissue of a healthy Beagle (dog 1) that underwent a minimally invasive excisional brain biopsy procedure. A—At the biopsy site in the cerebral cortex, gray matter is disrupted at the edge of the biopsy defect (left), and numerous hypertrophied astrocytes (arrows) and lightly scattered erythrocytes are present in adjacent gray matter. Bar = 50 μm. B—In the cerebral cortex, 1 mm away from the edge of the biopsy defect, the gray matter is intact, and hypertrophied (gemistocytic) astrocytes (arrow) are few. Bar = 50 μm. C—Cerebral white matter at the edge of the biopsy defect has evidence of disintegration (left), consisting mainly of macrophages (gitter cells) and vessels with hypertrophied endothelial cells. Adjacent tissue (right) has axonal degeneration with dilated myelin sheaths and swollen (or absent) axons. Bar = 100 μm. D—In this image, cerebral white matter 1 mm from the edge of the biopsy defect is intact with only focal axonal degeneration (arrows). Bar = 100 μm. H&E stain for all.

Citation: American Journal of Veterinary Research 72, 1; 10.2460/ajvr.72.1.109

Figure 6—
Figure 6—

Photomicrographs of immunohistochemically stained brain tissue obtained from healthy Beagles (dog 1 and dog 5) that underwent a minimally invasive excisional brain biopsy procedure. A—At the biopsy site in the cerebral cortex of dog 1, there is increased density of hypertrophied astrocytes that form a glial scar-like formation around the biopsy defect, but fibrosis is not evident. The astrocytosis-astrogliosis is particularly prominent just beneath the pia mater in the glia limitans (arrow). The leptomeninges (top left) appear to be reflected from the biopsy defect. Notice a decrease in prominence of astrocytes away from the biopsy defect (left). Staining included the avidin-biotin immunoperoxidase technique for GFAP, diaminobenzidine chromogen, and Mayer hematoxylin counterstain. H&E stain; bar = 250 μm. B—At the biopsy site in the cerebral cortex of dog 5, the leptomeninges are in contact with the biopsy defect. Fibrous tissue (blue) thickens the pia mater, bridges the biopsy defect in the plane of section, and extends into the underlying cerebral cortex. Masson trichrome stain; bar = 250 μm.

Citation: American Journal of Veterinary Research 72, 1; 10.2460/ajvr.72.1.109

In all surviving dogs, a narrow tract of necrosis was evident along the catheter trajectory and extended from the biopsy cavity to the lateral ventricle, where ependymal lining was focally disrupted. In dogs 2 and 5, there was superficial proliferation of fibroblasts in continuity with the leptomeninges. This was associated with deposition of fibrous collagen, which stained blue with Masson trichrome stain. In these 2 dogs with fibrosis, the leptomeninges had been displaced into the biopsy defect, whereas in the other 2 surviving dogs (without apparent fibrosis), the leptomeninges had been reflected from the biopsy defect. In all 4 dogs, the response to injury was confined to a narrow band around the biopsy or catheter defect, with tissue just 1 or 2 mm away appearing nearly normal histologically.

Discussion

In this study, a stereotactic tissue resection system was used for excisional biopsy and to aid placement of an intracranial brachytherapy catheter to develop a multimodal technique for minimally invasive brain tumor treatment. In theory, this combination of techniques offers the potential advantage for brain tumors in dogs to be diagnosed, excised, and treated via brachytherapy entirely in a minimally invasive manner, with efficient tissue resection, shorter treatment duration, and a reduction in adverse effects associated with the procedures.

The biopsy and excision system used in our study has several advantages, compared with other biopsy methods: the ability to perform excisional rather than incisional biopsy, a shorter procedure duration and more rapid tissue excision than with other minimally invasive methods of tissue resection via small-aperture biopsy instrumentation, the ability to remove tissue in an asymmetric pattern, and the larger size of biopsy specimens obtained.

The duration of the biopsy and resection portion of the procedure described in this report shortened consistently with surgeon experience throughout the study. The short procedure duration confirmed the device's capability for rapid tissue resection. Unlike other methods of brain biopsy, the biopsy device used in our study can excise large volumes of tissue in minutes, facilitating gross total tumor resection. The rate of tissue removal must be controlled by the surgeon because the device's capability for tissue removal is much more rapid than that desired for safe brain tumor resection. The variation in anesthesia duration we observed reflected the time needed for biopsy planning (ie, slower in the first 2 dogs), prolonged recovery from anesthesia (dog 3), and technical difficulties (brief malfunction of the CT scanner for dog 5). There was no consistent relationship between the duration of anesthesia and outcome, although the small sample size precluded reliable performance of statistical analysis.

The ability to remove tissue asymmetrically with respect to the trajectory of the biopsy probe is a unique advantage of the system reported here. When a lesion is irregularly shaped and asymmetric, or when the probe trajectory is not in the center of the lesion, the surgeon can control the position of the aperture such that tissue can be removed asymmetrically as desired. To facilitate this, the resection device is compatible with magnetic resonance imaging, so resection could be performed serially with image guidance during tissue removal. Although this would increase the duration of the procedure, such intraoperative serial imaging would reduce inaccuracy in lesion targeting caused by a shift in the brain's location as tissue is resected (brain shift).

Brain shift is a widely recognized problem in microsurgical procedures that involve preoperative imaging for neuronavigation. Several factors can cause brain shift, most notably opening of the cranial vault, removal of tumor tissue, brain swelling, gravitational forces, and administration of diuretics.25 In 1 study,25 the amount of brain shift that occurred during microsurgical removal of supratentorial tumors ranged from 0.8 to 14.3 mm intraoperatively and from 2.4 to 15.2 mm by the end of tumor removal. Factors that can influence the degree of brain shift included the degree of midline shift present prior to resection, tumor volume, and the size of the craniotomy.25 Although the size of the craniotomy site (burr hole) in the technique used in our study was minimal, compared with that in open surgical approaches, the volume of tissue resected with this excisional biopsy technique was much greater than that with typical stereotactic biopsy. As a result, the excisional biopsy technique reported here may be more prone to brain shift than conventional stereotactic, incisional biopsy techniques.

An important and practical advantage of the biopsy system we used, compared with conventional open surgical approaches, is that deep parenchymal tumors such as gliomas can be approached with minimal disruption of healthy brain tissue peripheral to the tumor and with minimal effects to adjacent tissue. Further, the device described here acquires high-quality biopsy specimens with minimal tissue distortion or artifact. During the procedure, all resected tissue was stored in a collection chamber for later retrieval, and tissue samples could have been easily retrieved from the collection chamber at any point during the procedure to allow for evaluation of intraoperative frozen sections or for tissue culture. The tissue collection chamber we used can be easily replaced for continued resection while maintaining aseptic technique.

The balloon-tipped catheters were inserted into the biopsy cavity to mimic intracranial catheter placement that could be used for brachytherapy with liquid 125I. The rationale for including brachytherapy catheter placement in this study was that brachytherapy has the potential to reduce exposure of surrounding healthy tissue to radiation by delivering the radiation dose locally to the site of interest.26–28 This tissue-sparing effect is achieved by diffusion of radioactive isotope into tissue adjacent to the biopsy cavity, with diffusion distance being a function of dosage.26 Use of brachytherapy also avoids the prolonged hospitalization and repeated anesthesia associated with external beam radiation therapy. Compared with open surgical placement of intracranial catheters, a minimally invasive technique for implantation of such catheters has the potential to further minimize the adverse effects associated with brachytherapy.

The technical aspects of intracranial brachytherapy catheter implantation in our study were uncomplicated. The inflation and deflation-explantation procedures were well tolerated, and none of the dogs developed new neurologic deficits after these events. The inflation procedure was performed with dogs sedated to allow for a controlled rate of inflation gradually over 1 minute. The deflation and explantation procedure was performed concurrently with dogs anesthetized and was a quick and simple procedure with rapid recovery.

Although we found the technique of minimally invasive brain biopsy to be valuable, several limitations exist. In animals in which the tumors are well demarcated and noninvasive (eg, many feline meningiomas or choroid plexus tumors), this technique is unlikely to be superior to open surgical procedures that would facilitate satisfactory tumor removal with preservation of healthy surrounding tissue by allowing full visibility of tumor margins. Additionally, the minimally invasive approach limits detection and control of hemorrhage. The brain of each study dog was examined grossly at removal for postmortem evaluation, and gross hemorrhage in surrounding brain parenchyma was not apparent. Although dog 3 did have evidence of hemorrhage in the biopsy and catheter tract, there was no localized accumulation of blood that would have caused a mass effect and compression or herniation of the brain. It is possible that the balloon placement helped prevent clinically important hemorrhage perioperatively and that hemorrhage might have been likely to occur if this resection technique had been used independently, without use of a brachytherapy catheter.

The adverse effects observed with the biopsy procedure used here may not apply to diseased dogs because healthy dogs were used in the study and functional brain tissue was removed rather than tumor tissue. If one presumes that excision of functional tissue would result in greater neurologic deficits than would occur with removal of dysfunctional tumor tissue, then the adverse effects we detected may be greater than those that might develop in diseased dogs. The converse might also be true; removal of healthy tissue may cause less hemorrhage than removal of tumor tissue, and the remaining brain tissue may be more adaptable to surgical trauma than that of dogs with preexisting neurologic deficits. In that situation, the effects detected in our study might be less severe than those that might develop in dogs with tumors.

Although a fifth of the dogs in our study died, this proportion may not be a reliable reflection of the true mortality rate associated with the technique used because the death of 1 dog could be attributed to surgeon error and inexperience rather than to the technique itself. It is important to consider that the depth gauge on the biopsy localization grid was, in fact, accurate and should have prevented this accident had the surgeon adhered to the biopsy protocol. As reported in the results of postmortem evaluation of the brain, the thalamic damage in the dog that died in the immediate postoperative period was deep to the resection cavity. The biopsy device was advanced only to the maximal depth of the resection cavity, and thus, the deeper thalamic damage could have occurred only as a result of probing during deviation from the biopsy protocol because that was the only other occurrence in which any instrument was advanced through the burr hole.

All 4 surviving dogs had some neurologic deficits as a direct result of the procedure. The initial severity of residual deficits 24 hours after the biopsy was performed varied; however, all 4 dogs were capable of activities indicative of quality of life (ie, ambulating, eating, drinking, and being alert to and interactive with their environment) by the end of the study. Any residual deficits present at the end of the study period would have been unlikely to be noticed by an untrained observer because they were apparent only during neurologic examination and included contralateral deficits in conscious proprioceptive placing of limbs (these deficits were not apparent during ambulation), menace response, and response to noxious nasal stimulation.

The intermittent spontaneous horizontal nystagmus with fast phase toward the right (ie, toward the lesion) and ventrolateral strabismus of the right eye in dog 1 could not be explained by means of conventional neuroanatomic localization given the cerebral lesion created. When the dog was examined at necropsy, there were no postmortem findings that would suggest vestibular damage as the origin of spontaneous nystagmus. Although epileptic nystagmus has been reported as a form of epilepsy with a seizure focus in the temporo-parieto-occipital region of the brain, unlike that observed in dog 1, the fast phase of nystagmus during such seizures is contralateral to the side of the lesion.29 Additionally, epileptic nystagmus is often accompanied by other manifestations of seizure activity (eg, tonic head movements or loss of consciousness).29 No motor activity of the head or any other areas of the face or body were present in dog 1 during these episodes of nystagmus that would have indicated the typical characteristics of epileptic nystagmus as described in the literature. In monkeys, experimentally induced posterior parietal lesions can cause transient nystagmus with the fast phase toward the side of the parietal lesion.30 That phenomenon may be a more likely explanation for the nystagmus observed in dog 1, given the known location of the lesion and lack of associated motor activity. The experimentally induced nystagmus in the primate study30 resolved within the first week after surgery. Similarly, the nystagmus observed in dog 1 resolved on day 5 after biopsy.

In dog 2, the episode of localized muscle spasms and hyperesthesia that were evident during deep palpation of the cervical spinal musculature were characteristic of nerve root signature due to protrusion of a cervical intervertebral disk. Although intervertebral disk protrusion at C6–C7 was confirmed on postmortem examination, a central pain syndrome could not be entirely ruled out. No evidence of spinal cord compression was apparent on neurologic examination prior to the study, although moving and positioning the dog when anesthetized may have exacerbated a previously subclinical spinal cord lesion.

The intermittent circling exhibited by dog 4 at the end of the study could not be explained by a focal, unilateral lesion because the circling occurred in either direction. Given the excitable and agitated nature the dog displayed when examined prior to the study, this circling might have been behavioral in origin.

Mortality rates associated with other brain tumor resection techniques are lower than that reported here. Those associated clinically or temporally with open craniotomy resections were 5% in a study31 of canine brain tumors and 6.4% in a study32 of canine meningiomas treated with surgery alone or surgery and radiation therapy. In another study13 involving 39 dogs that underwent endoscopic-assisted brain tumor resection after open craniotomy, 4 (10%) dogs were excluded from the study because of surgery-related deaths. These surgical mortality rates are similar to those in dogs undergoing stereotactic biopsy in which fatal complications occurred in 3 of 41 (7%) patients.8 One could argue that death in all the aforementioned situations was a result of the brain disease rather than the treatment technique because it is difficult to distinguish between those variables. A more accurate assessment of adverse effects and the mortality rate associated with our biopsy technique would require clinical application.

Although our technique could be used to acquire a single 9-gauge incisional biopsy specimen, this was not done in the study reported here, and therefore, we cannot separate the overall adverse effects we observed from those that might have developed had only a single incisional specimen been collected. Morbidity rates associated with conventional stereotactic biopsy devices used in dogs vary from 12% (5/41)8 or 26% (6/23)10 to 50% (2/4)7; mortality rates (including animals euthanized at owner request because of deteriorating neurologic status after biopsy) vary from 0% (0/4)7 to 7% (3/41)8 or 9% (2/23).10 Although dogs in 2 of the aforementioned studies8,10 deteriorated in neurologic condition, the ultimate cause of deterioration could not be determined because it was not possible to separate the influence of primary disease progression from procedural effect.

Excisional accuracy could not be assessed quantitatively in the present study because of software limitations that precluded CT-based direct comparisons before and after biopsy and because of federal restrictions regarding location of the surgical procedure that precluded performing the biopsy in the CT suite and maintaining identical positioning during scanning. This would not be a factor in dogs with brain tumors in which the biopsy procedure could be performed aseptically within the CT or magnetic resonance imaging suite to allow for intraoperative imaging. Because the dogs in our study had no preexisting brain lesion, the brain could not be also evaluated histologically at necropsy for residual lesional tissue. However, accuracy was evaluated qualitatively by comparing preoperative with postoperative CT images, and the center of the mock lesion corresponded to the biopsy cavity in postoperative CT images for all 5 dogs. Because of the lack of mathematical coordinates, the accuracy of this technique could not be exactly gauged and cannot be compared with the accuracy of other stereotactic techniques.

The minimally invasive excisional biopsy technique used in the study reported here was an efficient, simple method of targeting and resecting brain tissue for the purpose of tumor excision and biopsy in healthy dogs. Large volumes of tissue could be removed within minutes and safely collected in the sterile collection chamber of the device. Biopsy specimens were of excellent quality, and the surrounding tissue was minimally affected by the biopsy procedure or insertion of the brachytherapy catheter. This technique should be explored further as a potential treatment for brain tumors and would be particularly useful for intraparenchymal tumors for which conventional approaches would require dissection through healthy tissue to access the tumor.

ABBREVIATIONS

CT

Computed tomography

GFAP

Glial fibrillary acidic protein

MRI

Magnetic resonance imaging

a.

ATEC, Suros Surgical Systems, Hologic Inc, Indianapolis, Ind.

b.

GliaSite, Proxima Therapeutics Inc, Alpharetta, Ga.

c.

Prolene, Ethicon Inc, Somerville, NJ.

d.

PDS, Ethicon Inc, Somerville, NJ.

e.

Image J Analysis, Research Services Branch, National Institute of Health, Bethesda, Md.

f.

Dako, Carpenteria, Calif.

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