Glioblastoma spheroids produce infiltrative gliomas in the rat brainstem.

PURPOSE: Diffuse intrinsic pontine glioma (DIPG) is universally fatal without proven therapy other than radiation therapy for palliation. Representative animal models will play an essential role in the preclinical stage of future therapy development. To address the shortage of representative models, we created a novel infiltrative brainstem glioma model in rats based on glioblastoma spheroids. METHODS: Cells dissociated from glioblastoma spheroids grown from surgical specimens were implanted into the brainstem of NIH nude rats. Animals were serially assessed clinically and radiographically with magnetic resonance imaging (MRI). Tumors were further characterized using histology, immunohistochemistry, and cytogenetics. RESULTS: Tumor generation was successful in all animals receiving glioblastoma spheroid cells. The rats survived 17-25 weeks before severe symptoms developed. The tumors showed as diffuse hyperintense lesions on T2-weighted images. Histologically, they demonstrated cellular heterogeneity, and infiltrative and invasive features, with cells engorging vascular structures. The tumors were shown to comprise immature human origin glial tumor cells, with human epidermal growth factor receptor (EGFR) gene amplification and gain. CONCLUSIONS: This study showed that cells from glioblastoma spheroids produced infiltrative gliomas in rat brainstem. The rat brainstem gliomas are radiographically and histologically accurate compared to DIPG. These tumors develop over several months that would allow sequential clinical and radiographic assessments of therapeutic interventions. This study demonstrated in principle the feasibility of developing patient-specific animal models based on putative cancer stem cells from biopsy or resection samples.

Comparison of navigated versus non-navigated pedicle screw placement in 260 patients and 1434 screws: screw accuracy, screw size, and the complexity of surgery.

OBJECTIVE: Computer 3D navigation (3D NAV) techniques in spinal instrumentation can theoretically improve screw placement accuracy and reduce injury to critical neurovascular structures, especially in complex cases. In this series, we analyze the results of 3D NAV in pedicle screw placement accuracy, screw outer diameter, and case complexity in comparison with screws placed with conventional lateral fluoroscopy. METHODS: Pedicle screws placed in the cervical, thoracic, or lumbar spine using either standard lateral fluoroscopy or 3D NAV using isocentric fluoroscopy were retrospectively analyzed. The accuracy of each individual screw was graded on a 4-tiered classification system. Screw and pedicle diameter measurements were also made in both cohorts, and case complexity was compared between the 2 cohorts. Complex cases were defined as deformity surgery, re-do cases, and minimally invasive surgery. RESULTS: A total of 708 screws were placed under 3D NAV guidance and 726 screws were placed without stereotaxy. Eighty-eight percent of 3D NAV-guided pedicle screws were graded nonbreach versus 82% of cases with lateral fluoroscopy (P<0.001). The ratio of screw/pedicle diameter was significantly larger in the 3D NAV cohort (0.71 vs. 0.63, P<0.05). Seventy-six percent of 3D NAV cases had a predefined aspect of complexity, whereas 44% of non-3D NAV cases met criteria to be labeled complex (P<0.001). Reoperation occurred less frequently in 3D NAV cases than fluoroscopy alone. CONCLUSIONS: The use of 3D NAV was associated with improved screw placement accuracy, improved screw-to-pedicle diameter measurements, and was used in cases with a higher degree of surgical complexity. We conclude that 3D NAV is a valuable tool in current spinal instrumentation, especially for more complex surgeries.

B7-H3, a potential therapeutic target, is expressed in diffuse intrinsic pontine glioma.

Diffuse intrinsic pontine glioma (DIPG) is a brain cancer with a median survival of only 1 year. Lack of molecular characterization of this tumor impedes the development of novel therapies. Membrane protein B7-H3, aka CD276, involved in interactions with host defenses in certain cancers, has been shown to be over-expressed in the majority of malignant neuroectodermal tumors including adult high-grade glioma. Targeting B7-H3 with a monoclonal antibody has demonstrated safety and efficacy in the salvage treatment of stage IV childhood neuroblastoma, another neuroectodermal tumor. It thus stands to reason that B7-H3 might serve as a therapeutic target in DIPG. B7-H3 immunoreactivity was determined in DIPG and non-diffuse brainstem glioma specimens with immunohistochemistry. In addition, B7-H3 mRNA expression was evaluated with microarrays in another set of specimens. All of the nine (100 %) DIPG specimens were shown to be B7-H3 immunoreactive. In the non-diffuse brainstem glioma group, none of the eight WHO grade I specimens showed B7-H3 immunoreactivity and nine of the 24 WHO grade II specimens (37.5 %) showed B7-H3 immunoreactivity. The association between histological grade and B7-H3 immunoreactivity was statistically highly significant. B7-H3 mRNA expression was also significantly higher in DIPG samples than in normal brain and juvenile pilocytic astrocytoma (WHO grade I) specimens. In summary, B7-H3 is over-expressed in DIPG. Given the need for novel treatment in this disease, antibody-based immunotherapy against B7-H3 in DIPG warrants further investigation.

The value of intraoperative electrocorticography in surgical decision making for temporal lobe epilepsy with normal MRI.

PURPOSE: We hypothesized that acute intraoperative electrocorticography (ECoG) might identify a subset of patients with magnetic resonance imaging (MRI)-negative temporal lobe epilepsy (TLE) who could proceed directly to standard anteromesial resection (SAMR), obviating the need for chronic electrode implantation to guide resection. METHODS: Patients with TLE and a normal MRI who underwent acute ECoG prior to chronic electrode recording of ictal onsets were evaluated. Intraoperative interictal spikes were classified as mesial (M), lateral (L), or mesial/lateral (ML). Results of the acute ECoG were correlated with the ictal-onset zone following chronic ECoG. Onsets were also classified as "M,""L," or "ML." Positron emission tomography (PET), scalp-EEG (electroencephalography), and Wada were evaluated as adjuncts. KEY FINDINGS: Sixteen patients fit criteria for inclusion. Outcomes were Engel class I in nine patients, Engel II in two, Engel III in four, and Engel IV in one. Mean postoperative follow-up was 45.2 months. Scalp EEG and PET correlated with ictal onsets in 69% and 64% of patients, respectively. Wada correlated with onsets in 47% of patients. Acute intraoperative ECoG correlated with seizure onsets on chronic ECoG in all 16 patients. All eight patients with "M" pattern ECoG underwent SAMR, and six (75%) experienced Engel class I outcomes. Three of eight patients with "L" or "ML" onsets (38%) had Engel class I outcomes. SIGNIFICANCE: Intraoperative ECoG may be useful in identifying a subset of patients with MRI-negative TLE who will benefit from SAMR without chronic implantation of electrodes. These patients have uniquely mesial interictal spikes and can go on to have improved postoperative seizure-free outcomes.

Interstitial infusion of erlotinib in the rodent brain.

A critical need exists for the development of novel forms of treatment for high-grade glioma. Molecular characterization of high-grade glioma has shown overexpression of the epidermal growth factor receptor, antagonists to which, including erlotinib, may prevent tumor growth. Interstitial infusion is a mode of local delivery which bypasses the blood-brain barrier and utilizes a pressure-dependent gradient to enhance drug uniformity and volume of distribution. Interstitial infusion of erlotinib was performed to the striatum of 12 rats in increasing, therapeutic doses. No evidence of clinical or histopathologic toxicity was found. In this experimental study we demonstrate that interstitial infusion of erlotinib is safe in the rodent brain, and may have potential applicability for the treatment of high-grade glioma.

Increased sensitivity to traumatic axonal injury on postconcussion diffusion tensor imaging scans in National Football League players by using premorbid baseline scans.

OBJECTIVE: Statistical challenges exist when using diffusion tensor imaging (DTI) to assess traumatic axonal injury (TAI) in individual concussed athletes. The authors examined active professional American football players over a 6-year time period to study potential TAI after concussion and assess optimal methods to analyze DTI at the individual level. METHODS: Active American professional football players recruited prospectively were assessed with DTI, conventional MRI, and standard clinical workup. Subjects underwent an optional preseason baseline scan and were asked to undergo a scan within 5 days of concussion during gameplay. DTI from 25 age- and sex-matched controls were obtained. Both semiautomated region-of-interest analysis and fully automated tract-based spatial statistics (TBSS) were used to examine DTI at individual and group levels. Statistical differences were assessed comparing individual DTI data to baseline imaging versus a normative database. Group-level comparisons were also performed to determine if longer exposure to professional-level play or prior concussion cause white matter microstructural integrity changes. RESULTS: Forty-nine active professional football players were recruited into the study. Of the 49 players, 7 were assessed at baseline during the preseason and after acute concussion. An additional 18 players were assessed after acute concussion only. An additional 24 players had only preseason baseline assessments. The results suggest DTI is more sensitive to suspected TAI than conventional MRI, given that 4 players demonstrated decreased fractional anisotropy (FA) in multiple tracts despite normal conventional MRI. Furthermore, the data suggest individual assessment of DTI data using baseline premorbid imaging is more sensitive than typical methods of comparing data to a normative control group. Among all subjects with baseline data, 1 reduced FA tract (± 2.5 standard deviations) was found using the typical normative database reference versus 10 statistically significant (p < 0.05) reduced FA tracts when referencing internal control baseline data. All group-level comparisons were statistically insignificant (p > 0.05). CONCLUSIONS: Baseline premorbid DTI data for individual DTI analysis provides increased statistical sensitivity. Specificity using baseline imaging also increases because numerous potential etiologies for reduced FA may exist prior to a concussion. These data suggest that there is a high potential for false-positive and false-negative assessment of DTI data using typical methods of comparing an individual to normative groups given the variability of FA values in the normal population.

Endoscopic resection of solid intraventricular brain tumors.

OBJECT: Endoscopic removal of intraventricular brain tumors is well established for cystic tumors such as colloid cysts. Aspiration followed by removal or ablation of the membranous wall is possible given the constituent features of these tumors. It is generally expected that endoscopic removal of solid brain tumors from the intraventricular compartment would impose additional technical demands. In this paper, the feasibility and safety of endoscopic removal of solid intraventricular brain tumors is evaluated. METHODS: Eighty-one patients who underwent endoscopic management of an intraventricular brain tumor were identified from a prospective database. Of these patients, seven underwent attempted endoscopic surgical removal of a solid primary brain tumor. Patient selection, surgical technique, procedure-related morbidity, and extent of removal were reviewed. Five patients underwent complete resection of a solid intraventricular brain tumor, a treatment option that was based on intraoperative assessment and confirmed by postoperative imaging. No patient experienced any procedure-related morbidity. Of the individuals in whom a total endoscopic resection was successful, there has been no symptomatic or radiological evidence of recurrence (mean follow up 20 months). Maximum tumor diameter ranged from 0.5 to 1.8 cm for patients who underwent complete resection, whereas maximum tumor diameter measured 2.4 and 2.5 cm in the two patients in whom a subtotal excision was performed. CONCLUSIONS: In select patients, complete endoscopic removal of solid intraventricular brain tumors is possible and safe. Factors that influence the ability of a surgeon to perform a complete endoscopic resection include tumor size, composition, and vascularity. The procedure requires careful patient selection, the use of refined endoscopic instrumentation, and a disciplined surgical technique.

Novel low-grade glioneuronal neoplasm presenting in an octogenarian: case report and review of the literature.

Glioneuronal neoplasms are rare tumors that typically affect patients in the first three decades of life. Since the publication of the World Health Organization (WHO) 2000 classification of tumors, further variants of these tumors have been reported. We present an 83-year-old gentleman who presented with a history of ataxia and weight loss. MRI and CT scan revealed a ring-enhancing bihemispheric lesion in the premotor cortex consistent with a malignant primary brain tumor crossing the corpus collosum. The patient underwent a sterotactic biopsy with drainage of the cystic component. Histopathologic studies revealed a mixed glioneuronal tumor with benign characteristics. A craniotomy was performed and the tumor was resected. Postoperatively, the patient has been followed with serial MRI scans with no evidence of disease recurrence at 27 months. Glioneuronal tumors are extremely uncommon in the octogenarian population, however, it is important to include them in the differential diagnosis of intracerebral masses. They are histopathologically quite heterogeneous, and in this report we present a novel subtype. Radiographically, these lesions can mimic more aggressive primary brain tumors.

Neuroendoscopic resection of posterior third ventricular ependymoma. Case report.

The practice of neuroendoscopy in the definitive management of cystic tumors and hydrocephalus has been well established. Resection of solid intraventricular tumors by a primary endoscopic technique, however, has rarely been demonstrated. The authors present the case of a 31-year-old woman in whom endoscopic resection of a posterior third ventricular ependymoma was successfully accomplished. Metastatic workup yielded no sites of dissemination, adjuvant radiation therapy was deferred, and the patient has been without radiographic evidence of disease after 6 months of follow up. Endoscopic resection of solid tumors appears feasible in select patients and warrants further evaluation.

Hemorrhagic sequelae from intracranial neuroendoscopic procedures for intraventricular tumors.

OBJECT: Concern regarding the ability to accomplish adequate hemostasis during intracranial neuroendoscopy is often cited as a potential obstacle for primary endoscopic tumor management. In this study, the rate of clinically significant hemorrhage encountered as a result of endoscopic surgery for an intraventricular brain tumor is examined. METHODS: A total of 86 patients underwent an endoscopic biopsy procedure or resection of an intraventricular tumor. Recognized hemorrhagic sequelae occurred at a rate of 3.5% per patient. Visual obscuration due to the presence of intraventricular bleeding necessitated aborting the procedure before completion of the objective in two cases. There was a hemorrhagic event resulting in relevant morbidity in one patient, who suffered a bilateral diencephalic stroke after attempted tumor biopsy sampling. CONCLUSIONS: The low hemorrhagic complication rate described in this series counters the misconception surrounding ineffective hemostasis during intracranial endoscopy for tumors and provides further evidence that this minimally invasive approach is a safe alternative to some conventional intracranial approaches.

The potential of theragnostic ¹²4I-8H9 convection-enhanced delivery in diffuse intrinsic pontine glioma.

BACKGROUND: Reasons for failure in prior human glioma convection-enhanced delivery (CED) clinical trials remain unclear. Concentration-dependent volume of distribution (Vd) measurement of CED-infused agents in the human brain is challenging and highlights a potential technical shortcoming. Activity of iodine isotope 124 ((124)I ) in tissue can be directly measured in vivo with high resolution via PET. With the potential therapeutic utility of radioimmunotherapy, we postulate (124)I conjugated to the antiglioma monoclonal antibody 8H9 may serve as a "theragnostic" agent delivered via CED to diffuse intrinsic pontine glioma. METHODS: Fifteen rats underwent CED of 0.1-1.0 mCi of (131)I-8H9 to the pons for toxicity evaluation. Six additional rats underwent CED of 10 µCi of (124)I-8H9 to the pons for dosimetry, with serial microPET performed for 1 week. Two primates underwent CED of gadolinium-albumin and 1.0 mCi of (124)I-8H9 to the pons for safety and dosimetry analysis. Serial postoperative PET, blood, and CSF radioactivity counts were performed. RESULTS: One rat (1.0 mCi (131)I-8H9 infusion) suffered toxicity necessitating early sacrifice. PET analysis in rats yielded a pontine absorbed dose of 37 Gy/mCi. In primates, no toxicity was observed, and absorbed pontine dose was 3.8 Gy/mCi. Activity decreased 10-fold with 48 h following CED in both animal models. Mean Vd was 0.14 cc(3) (volume of infusion [Vi] to Vd ratio = 14) in the rat and 6.2 cc(3) (Vd/Vi = 9.5) in primate. CONCLUSION: The safety and feasibility of (124)I dosimetry following CED via PET is demonstrated, establishing a preclinical framework for a trial evaluating CED of (124)I-8H9 for diffuse intrinsic pontine glioma.

Volumetric response to radiosurgery for brain metastasis varies by cell of origin.

OBJECT: The aim of this study was to evaluate the imaging response of brain metastases after radiosurgery and to correlate the response with tumor type and patient survival. METHODS: The authors conducted a retrospective review of patients who had undergone Gamma Knife radiosurgery for brain metastases from non-small cell lung cancer (NSCLC), breast cancer, or melanoma. The imaging volumetric response by tumor type was plotted at 3-month intervals and classified as a sustained decrease in tumor volume (Type A), a transient decrease followed by a delayed increase in tumor volume (Type B), or a sustained increase in tumor volume (Type C). These imaging responses were then compared with patient survival and tumor type. RESULTS: Two hundred thirty-three patients with metastases from NSCLC (96 patients), breast cancer (98 patients), and melanoma (39 patients) were eligible for inclusion in this study. The patients with NSCLC were most likely to exhibit a Type A response; those with breast cancer, a Type B response; and those with melanoma, a Type C response. Among patients with NSCLC, the median overall survival was 11.2 months for those with a Type A response (76 patients), 8.6 months for those with a Type B response (6 patients), and 10.5 months for those with a Type C response (14 patients). Among patients with breast cancer, the median overall survival was 16.6 months in those with a Type A response (65 patients), 18.1 months in those with a Type B response (20 patients), and 7.5 months in those with a Type C response (13 patients). For patients with melanoma, the median overall survival was 5.2 months in those with a Type A response (26 patients) and 6.7 months in those with a Type C response (13 patients). None of the patients with melanoma had a Type B response. The imaging response was significantly associated with survival only in patients with breast cancer. CONCLUSIONS: The various types of imaging responses of metastatic brain tumors after stereotactic radiosurgery depend in part on tumor type. However, the type of response only correlates with survival in patients with breast cancer.

Motor function after stereotactic radiosurgery for brain metastases in the region of the motor cortex.

OBJECT: The authors sought to better define the clinical response of patients who underwent stereotactic radiosurgery (SRS) for brain metastases located in the region of the motor cortex. METHODS: A retrospective analysis was performed in 2026 patients with brain metastasis who underwent SRS with the Gamma Knife between 2002 and 2012, and multiple factors that affect motor function before and after SRS were evaluated. Ninety-four patients with tumors ≥ 1.5 cm in diameter located in or adjacent to the motor strip were identified, including 2 patients with bilateral motor strip metastases. RESULTS: Motor function improved after SRS in 30 (31%) of 96 cases, remained stable in 48 (50%), and worsened over time in 18 (19%) instances. Forty-seven patients had no motor weakness prior to radiosurgery; 10 (22%) developed new Grade 3/5-4/5 weakness. Thirty (68%) of 44 patients with ≥ 3/5 pre-SRS weakness improved, 6 (14%) remained stable, and 8 (18%) worsened. Three of 5 patients with < 3/5 pre-SRS motor function improved. Motor deficits prior to SRS did not correlate with a worse outcome; however, worse outcomes were associated with larger tumor volumes. The median tumor volume in patients whose function improved or remained stable was 5.3 cm(3), but it was 9.2 cm(3) in patients who worsened (p < 0.05). Tumor volumes > 9 cm(3) were associated with a higher risk of worsening motor function. Adverse radiation effects occurred in 5 patients. CONCLUSIONS: Most intact patients with brain metastases in or adjacent to motor cortex maintained neurological function after SRS, and most patients with symptomatic motor weakness remained stable or improved. Larger tumor volumes were associated with less satisfactory outcomes.

Predicting tumor control after resection bed radiosurgery of brain metastases.

BACKGROUND: Stereotactic radiosurgery (SRS) to the resection bed of a brain metastasis is an important treatment option. OBJECTIVE: To identify factors associated with tumor progression after SRS of the resection bed of a brain metastasis and to evaluate patterns of failure for patients who eventually had tumor progression. METHODS: We performed a retrospective analysis of 120 patients who underwent tumor bed radiosurgery after an initial gross total resection. The mean imaging follow-up time was 55 weeks. The median margin dose was 16 Gy. Forty-seven patients (39.2%) underwent whole-brain radiation therapy before or shortly after SRS. RESULTS: Local tumor control was achieved in 103 patients (85.8%). Progression-free survival was 96% at 6 months, 87% at 12 months, and 74% at 24 months. Recurrence most commonly occurred deep in the cavity (65%) outside the planned treatment volume (PTV) margin (53%). PTV, cavity diameter, and a margin dose < 16 Gy significantly correlated with local failure. For patients with PTVs ≥ 8.0 cm, local progression-free survival declined to 93% at 6 months, 83% at 12 months, and 65% at 24 months. Development or progression of distant metastases occurred in 40% of patients. Whole-brain radiation therapy was not associated with improved local control. CONCLUSION: Resection bed SRS for brain metastases provided excellent local control. The cavity PTV is predictive of tumor control. Because failure usually occurs outside the PTV, inclusion of a judicious 2- to 3-mm margin beyond the area of postoperative enhancement may be prudent.

Subarachnoid dissemination of intraventricular tumors following simultaneous endoscopic biopsy and third ventriculostomy.

OBJECT: Endoscopic biopsy with concomitant third ventriculostomy (ETV) is a well-established diagnostic and therapeutic maneuver in patients presenting with noncommunicating hydrocephalus resulting from a tumor of the pineal region or posterior third ventricle. Fenestration of the floor of the third ventricle theoretically provides a conduit for the subarachnoid dissemination of an intraventricular tumor. The aim of this study was to ascertain the rate of leptomeningeal dissemination following this surgical procedure. METHODS: The authors conducted a review of all patients for whom an ETV and simultaneous endoscopic biopsy procedure or tumor resection had been performed at their institutions between 1995 and 2008. Patients were divided into high or low risk groups by leptomeningeal metastatic potential based on pathology. All available postoperative clinical and radiographic data, including MR imaging of the brain and spinal cord, as well as CSF sampling were evaluated when available. A review of the literature was then conducted to establish rates of distant leptomeningeal dissemination for comparative purposes. RESULTS: Thirty-two patients satisfied the criteria for study inclusion. Pathology revealed that 22 had a high risk for leptomeningeal dissemination. New leptomeningeal disease (1 yolk sac tumor and 1 pineoblastoma) occurred in 2 patients. The median clinical and brain MR imaging follow-ups overall were 34 (range 2-103 months) and 38 months (range 1-94 months), respectively. Follow-up MR imaging of the spine was performed in 12 patients (median 7 months postoperation), and CSF was analyzed in 15 patients (median 1 month postoperation). A Kaplan-Meier survival analysis predicted a 2-year metastasis-free survival of 94.7% for high-risk patients. Baseline rates of dissemination when ETV was not performed were in general between 8 and 24% for various high-risk pathologies according to a literature review. CONCLUSIONS: The rate of leptomeningeal metastasis of tumors in this biopsy and ETV study was not increased when compared with rates from large series in the literature.

Interstitial infusion of glioma-targeted recombinant immunotoxin 8H9scFv-PE38.

Monoclonal antibodies have the potential to target therapy for high-grade gliomas. Monoclonal antibody 8H9 is specific for membrane protein B7H3 and is reactive with most human high-grade gliomas. We tested the 8H9scFv-PE38 recombinant Pseudomonas immunotoxin in a preclinical model of high-grade glioma. The half maximal inhibitory concentration (IC(50)) of 8H9scFv-PE38 in vitro was determined using glioblastoma cell lines U87 and U251. Maximum tolerated infusion dose of 8H9scFv-PE38 following interstitial infusion to the striatum and pons was defined using athymic rats. Maximum tolerated infusion dose of 8H9scFv-PE38 or PBS control were interstitially delivered to athymic rats xenografted with U87 in the striatum or brain stem. Radiographic response and survivals were measured and compared between treatment groups. The in vitro IC(50) of 8H9scFv-PE38 for U87 was 1,265 ng/mL and, for U251, 91 ng/mL. The maximum tolerated infusion doses of interstitially infused 8H9scFv-PE38 to the striatum and brain stem were 0.75 and 1.8 mug, respectively. For rats harboring intracranial U87 xenografts, infusion of 8H9scFv-PE38 increased mean survival (striatum, 43.4 versus 24.6 days; brain stem, 80.6 versus 45.5 days; n = 28 total) and produced three long-term survivors past 120 days. None of the 14 placebo-treated animals survived >54 days. Tumors also showed volumetric response to infusion of 8H9scFv-PE38 by magnetic resonance imaging. Interstitial infusion of 8H9scFv-PE38 shows potential for the treatment of hemispherical and brain stem glioma. Mol Cancer Ther; 9(4); 1039-46. (c)2010 AACR.

Giant cell tumor of the spine.

Giant cell tumors are benign but locally aggressive neoplasms that typically affect the extremities. When involving the spine, the tumors occur predominantly in the sacrum. Gross total resection of the tumor with wide margins yields good results in terms of survival. However, it carries a significant potential for morbidity and disability. Subtotal resection with adjuvant radiation carries a risk for recurrence or, more concerning, sarcomatous malignant transformation. Endovascular tumor embolizations have also been attempted to control unresectable tumors, and have been performed with moderate degrees of success. Outcomes are analyzed outcomes following surgery, radiation therapy, and tumor embolization.

Intraparenchymal and intratumoral interstitial infusion of anti-glioma monoclonal antibody 8H9.

OBJECTIVE: Interstitial infusion, a form of local delivery that bypasses the blood-brain barrier, has been shown to afford high regional concentrations of a therapeutic molecule while avoiding systemic exposure. The distribution of monoclonal antibodies administered via interstitial infusion has not been characterized, and this is salient in light of the potential sequestration by epitopes expressed by targeted tissue. Interstitial delivery of murine immunoglobulin G1 monoclonal antibody (MAb) 8H9 was investigated in a rodent model for the potential treatment of infiltrative gliomas. METHODS: MAb 8H9 was infused in varying concentrations and volumes into previously untreated animals and into an immunoreactive U87 xenograft to evaluate distributive potential. Previously untreated animals and athymic rats bearing U87 xenografts underwent variable infusions into the striatum or grafted tumor, respectively. Animals were sacrificed at multiple time points, and the volume of 8H9 distribution was determined using a new semiautomated technique. RESULTS: Increasing both the volume and dose of 8H9 infusion increased the volume of distribution. Distribution was significantly greater at 24 hours after infusion than at 1 hour. Interstitial infusion of MAb 8H9 resulted in a positive relationship between the volume of distribution and either the infusion volume or infusion dose. No significant difference in the volume of distribution was seen between antibodies in naïve striatum and U87 xenografts. Antibody distribution was effectively augmented by convection and diffusion after delivery. CONCLUSION: Finally, intratumoral interstitial infusion of a reactive MAb has been performed similarly to delivery to a normal brain. This finding is encouraging from a therapeutic standpoint, given the clinical need to affect large domains of these infiltrative tumors.

Correlation of endoscopic biopsy with tumor marker status in primary intracranial germ cell tumors.

We retrospectively analyzed the results of eight patients who underwent endoscopic biopsy of a newly diagnosed primary intracranial germ cell tumor (GCT), and correlated tumor pathology with serum and cerebrospinal fluid (CSF) tumor markers and treatment outcome in order to determine the reliability of GCT sampling by this method. A biopsy diagnosis was made in each patient, and the tumor histology correlated with tumor marker measurements for all six patients diagnosed with germinoma and for one with a yolk sac tumor. One biopsy revealed only mature teratoma, an inconclusive result since the patient's serum and CSF tumor markers were elevated. No morbidity was experienced as a result of the operative procedure. Five of six patients diagnosed with germinoma responded completely to radiation therapy and are without evidence of disease, while one suffered a likely germinoma recurrence and was subsequently successfully retreated. We conclude that endoscopic biopsy of marker-negative germ cell tumors is a safe, reliable method of establishing a diagnosis of germinoma. However, endoscopic biopsy may fail to yield an accurate diagnosis in cases of malignant non-germinomatous tumor. We would thus conclude that when primary germ cell tumor is considered, endoscopic tumor biopsy is recommended in patients with a negative biochemical analysis, but not suggested for patients presenting with elevated tumor markers.