History of Women in Neurosurgery (WINS).

In 2020, the Women in Neurosurgery (WINS) organization, a joint section of the AANS and Congress of Neurological Surgeons, celebrated 30 years since its inception. In this paper, the authors explore the history of WINS from its beginnings through its evolution over the past three decades. The achievements of the group are highlighted, as well as the broader achievements of the women in the neurosurgical community over this time period.

Laser interstitial thermal therapy followed by minimal-access transsulcal resection for the treatment of large and difficult to access brain tumors.

OBJECTIVE Laser interstitial thermal therapy (LITT), sometimes referred to as "stereotactic laser ablation," has demonstrated utility in a subset of high-risk surgical patients with difficult to access (DTA) intracranial neoplasms. However, the treatment of tumors larger than 10 cm3 is associated with suboptimal outcomes and morbidity. This may limit the utility of LITT in dealing with precisely those large or deep tumors that are most difficult to treat with conventional approaches. Recently, several groups have reported on minimally invasive transsulcal approaches utilizing tubular retracting systems. However, these approaches have been primarily used for intraventricular or paraventricular lesions, and subtotal resections have been reported for intraparenchymal lesions. Here, the authors describe a combined approach of LITT followed by minimally invasive transsulcal resection for large and DTA tumors. METHODS The authors retrospectively reviewed the results of LITT immediately followed by minimally invasive, transsulcal, transportal resection in 10 consecutive patients with unilateral, DTA malignant tumors > 10 cm3. The patients, 5 males and 5 females, had a median age of 65 years. Eight patients had glioblastoma multiforme (GBM), 1 had a previously treated GBM with radiation necrosis, and 1 had a melanoma brain metastasis. The median tumor volume treated was 38.0 cm3. RESULTS The median tumor volume treated to the yellow thermal dose threshold (TDT) line was 83% (range 76%-92%), the median tumor volume treated to the blue TDT line was 73% (range 60%-87%), and the median extent of resection was 93% (range 84%-100%). Two patients suffered mild postoperative neurological deficits, one transiently. Four patients have died since this analysis and 6 remain alive. Median progression-free survival was 280 days, and median overall survival was 482 days. CONCLUSIONS Laser interstitial thermal therapy followed by minimally invasive transsulcal resection, reported here for the first time, is a novel option for patients with large, DTA, malignant brain neoplasms. There were no unexpected neurological complications in this series, and operative characteristics improved as surgeon experience increased. Further studies are needed to elucidate any differences in survival or quality of life metrics.

Depths and grids in brain tumors: implantation strategies, techniques, and complications.

Patients with intracranial mass lesions are at increased risk of intractable epilepsy even after tumor resection due to the potential epileptogenicity of lesional and perilesional tissue. Risk factors for tumoral epilepsy include tumor location, histology, and extent of tumor resection. In epilepsy that occurs after tumor resection, the epileptogenic zone often does not correspond precisely with the area of abnormality on imaging, and seizures often arise from a relatively restricted area despite widespread changes on imaging. Invasive monitoring via subdural grids and/or depth electrodes can therefore be helpful to delineate areas of eloquence and localize the epileptogenic zone for subsequent resection. Subdural grids offer excellent contiguous coverage of superficial cortex and allow resection using the same craniotomy, facilitating understanding of anatomic relationships. Depth electrodes offer superior coverage of deep structures, are easier to use in cases where a previous craniotomy is present, are not associated with anatomic distortion due to brain shift, and may be associated with a lower complication rate. We review the biology of focal postoperative epilepsy and invasive diagnostic strategies for the surgical evaluation of medically refractory epilepsy in patients who have undergone resection of intracranial mass lesions.

Targeted radioimmunotherapy: the role of ¹³¹I-chTNT-1/B mAb (Cotara) for treatment of high-grade gliomas.

The prognosis for patients with malignant gliomas remains poor, and novel treatment paradigms are needed. Radioimmunotherapeutic drugs have been studied in clinical trials as adjuncts to treatment for these tumors. One such agent is (131)I-chTNT-1/B mAb (Cotara(®)), a compound locally delivered to the tumor site through convection-enhanced delivery. It is a genetically engineered chimeric monoclonal antibody that binds to the DNA-histone H1 complex, and carries (131)I, which locally delivers its radioactive payload to kill adjacent tumor cells. Clinical experience with Cotara is emerging; completed Phase I and II trials with a total of 51 patients helped to define dosing regimens for the drug. A recent Phase II dose-confirmation trial with Cotara for patients with glioblastoma multiforme at first relapse has demonstrated promising overall survival results of 41 weeks. This review explores the clinical experience of radioimmunotherapy and describes the role of Cotara for treatment of patients with malignant gliomas.

Cervical schwannoma with acute worsening and intratumoral hemorrhage.

BACKGROUND: Primary spinal tumors are rare and include schwannomas. In the cervical region, these lesions can cause pain, radiculopathy, and/or myelopathy. CASE DESCRIPTION: A 53-year-old male presented with 9 months of chronic neck pain and left upper extremity radiculopathy/myelopathy. The MRI revealed an intradural extramedullary C6-C7 left-sided mass with foraminal extension. Following a C5-C7 laminectomy with C5-T2 instrumented fusion, the diagnosis of schwannoma with evidence of recent hemorrhage was confirmed by biopsy. Three weeks postoperatively, the patient was pain free, no longer taking opioids, and neurologically intact. Although the MRI 6 months later showed no tumor, the MRI 15 months later documented a recurrent enhancing C6-C7 lesion. The patient elected to be treated with external beam radiotherapy and remained asymptomatic. CONCLUSION: A 53-year-old underwent resection of a cervical C6-C7 schwannoma with intratumoral hemorrhage. Fifteen months following C5-C7 laminectomy with C5-T2 fusion, the tumor recurred and required external beam radiation therapy.

Images in Spine: A Rare Abnormal Bony Fusion.

Klippel-Feil syndrome (KFS) is characterized by failed segmentation of the cervical spine leading to inappropriately fused vertebral bodies. A 64-year-old male with a previous L5-S1 decompression presented with significant neck pain with radiation into the entire right upper extremity and hand. Imaging demonstrated fusion of the vertebral bodies at C2-3, C4-6, and C7-T1 with associated disc bulges at C3-4 and C6-7. Common presentation of KFS includes significant spondylosis and cervical myeloradiculopathy in addition to the classic triad of short neck, low posterior hairline, and restricted neck motion. We present exemplary images of this rare condition to aid clinicians in future diagnoses.

Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on the Role of Chemotherapy in the Management of Adults With Newly Diagnosed Metastatic Brain Tumors.

QUESTION 1: Should patients with brain metastases receive chemotherapy in addition to whole brain radiotherapy (WBRT) for the treatment of their brain metastases? TARGET POPULATION: This recommendation applies to adult patients with newly diagnosed brain metastases amenable to both chemotherapy and radiation treatment. RECOMMENDATIONS: Level 1: Routine use of chemotherapy following WBRT for brain metastases is not recommended. Level 3: Routine use of WBRT plus temozolomide is recommended as a treatment for patients with triple negative breast cancer. QUESTION 2: Should patients with brain metastases receive chemotherapy in addition to stereotactic radiosurgery (SRS) for the treatment of their brain metastases? RECOMMENDATIONS: Level 1: Routine use of chemotherapy following SRS is not recommended. Level 2: SRS is recommended in combination with chemotherapy to improve overall survival and progression free survival in lung adenocarcinoma patients. QUESTION 3: Should patients with brain metastases receive chemotherapy alone? RECOMMENDATION: Level 1: Routine use of cytotoxic chemotherapy alone for brain metastases is not recommended as it has not been shown to increase overall survival.Please see the full-text version of this guideline (https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter_5) for the target population of each recommendation.

Survival in Patients with High-Grade Spinal Meningioma: An Analysis of the National Cancer Database.

OBJECTIVE: To report baseline demographics and examine for differences in survival for patients with World Health Organization (WHO) grade II and III spinal meningioma. METHODS: The National Cancer Database was queried for patients diagnosed with WHO grade II or grade III spinal meningioma between 2004 and 2015. Cases with histopathological confirmation were included. Descriptive statistics were calculated and stratified by tumor type. Facility type, 30-day readmission, and 90-day mortality were also examined. Crude and adjusted Cox proportional hazards regression models were used to evaluate for differences in survival. RESULTS: A total of 287 patients with WHO grade II or grade III spinal meningioma (white, n = 237; black, n = 32; Asian and Pacific Islander, n = 11; unknown race, n = 7) were identified. The mean patient age was 56.4 years, and the majority were female (70%; n = 201). Almost one-half of the patients were treated in an academic/research program (45.3%; n = 130,). Those with WHO grade III lesions received the earliest treatment, at a mean of 10.8 days following diagnosis. The proportion of patients with unplanned 30-day readmission following surgery was 4.2% (n = 12). Two patients died within 90 days of surgery. Multivariable analysis demonstrated no differences in survival for patients with WHO grade II or grade III lesions (hazard ratio, 2.01; 95% confidence interval, 0.89-4.52; P = 0.09). CONCLUSIONS: No difference in overall survival was identified between patients with WHO grade II or III spinal meningioma, although a trend was seen toward worse survival for patients with WHO grade III lesions.

Association of cancer center type with treatment patterns and overall survival for patients with sacral and spinal chordomas: an analysis of the National Cancer Database from 2004 to 2015.

OBJECTIVE: Chordomas of the spine and sacrum are a rare but debilitating cancer and require complex multidisciplinary care. Studies of other such rare cancers have demonstrated an association of high-volume and/or multidisciplinary centers with improved outcomes and survival. Such an association has been proposed for chordomas, but evidence to support this claim is lacking. The authors performed a study to investigate if treatment facility type is associated with patterns of care and survival for patients with spinal and sacral chordomas by assessing records from a US-based cancer database. METHODS: In this observational retrospective cohort study, the authors identified 1266 patients from the National Cancer Database with vertebral column or sacral chordomas diagnosed between 2004 and 2015. The primary study outcome was overall survival, and secondary outcomes included odds of receiving treatment and time to treatment, defined as radiation therapy, surgery, and/or any treatment, including surgery, radiation therapy, chemotherapy, or participation in clinical trials. The results were adjusted for age, sex, race/ethnicity, level of education, income, and Charlson/Deyo score. RESULTS: Of the 1266 patients identified, the mean age at diagnosis was 59.70 years (SD 16.2 years), and the patients were predominantly male (n = 791 [62.50%]). Patients treated at community cancer programs demonstrated an increased risk of death (HR 1.98, 95% CI 1.13-3.47, p = 0.018) when compared to patients treated at academic/research programs (ARPs). The median survival was longest for those treated at ARPs (131.45 months) compared to community cancer programs (79.34 months, 95% CI 48.99-123.17) and comprehensive community cancer programs (CCCPs) (109.34 months, 95% CI 84.76-131.45); 5-year survival rates were 76.08%, 52.71%, and 61.57%, respectively. Patients treated at community cancer programs and CCCPs were less likely to receive any treatment compared to those treated at ARPs (OR 6.05, 95% CI 2.62-13.95, p < 0.0001; OR 3.74, 95% CI 2.23-6.28, p < 0.0001, respectively). Patients treated at CCCPs and community cancer programs were less likely to receive surgery than those treated at ARPs (OR 2.69, 95% CI 1.82-3.97, p = 0.010; OR = 2.64, 95% CI 1.22-5.71, p = 0.014, respectively). Patients were more likely to receive any treatment (OR 0.59, 95% CI 0.40-0.87, p = 0.007) and surgery (OR 0.58, 95% CI 0.38-0.88, p < 0.0001) within 30 days at a CCCP compared to an ARP. There were no differences in odds of receiving radiation therapy or time to radiation by facility type. CONCLUSIONS: Clinical care at an ARP is associated with increased odds of receiving treatment that is associated with improved overall survival for patients with spinal and sacral chordomas, suggesting that ARPs provide the most comprehensive specialized care for patients with this rare and devastating oncological disease.

Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on the Role of Whole Brain Radiation Therapy in Adults With Newly Diagnosed Metastatic Brain Tumors.

TARGET POPULATION: Adult patients (older than 18 yr of age) with newly diagnosed brain metastases. QUESTION: If whole brain radiation therapy (WBRT) is used, is there an optimal dose/fractionation schedule? RECOMMENDATIONS: Level 1: A standard WBRT dose/fractionation schedule (ie, 30 Gy in 10 fractions or a biological equivalent dose [BED] of 39 Gy10) is recommended as altered dose/fractionation schedules do not result in significant differences in median survival or local control. Level 3: Due to concerns regarding neurocognitive effects, higher dose per fraction schedules (such as 20 Gy in 5 fractions) are recommended only for patients with poor performance status or short predicted survival. Level 3: WBRT can be recommended to improve progression-free survival for patients with more than 4 brain metastases. QUESTION: What impact does tumor histopathology or molecular status have on the decision to use WBRT, the dose fractionation scheme to be utilized, and its outcomes? RECOMMENDATIONS: There is insufficient evidence to support the choice of any particular dose/fractionation regimen based on histopathology. Molecular status may have an impact on the decision to delay WBRT in subgroups of patients, but there is not sufficient data to make a more definitive recommendation. QUESTION: Separate from survival outcomes, what are the neurocognitive consequences of WBRT, and what steps can be taken to minimize them? RECOMMENDATIONS: Level 2: Due to neurocognitive toxicity, local therapy (surgery or SRS) without WBRT is recommended for patients with ≤4 brain metastases amenable to local therapy in terms of size and location. Level 2: Given the association of neurocognitive toxicity with increasing total dose and dose per fraction of WBRT, WBRT doses exceeding 30 Gy given in 10 fractions, or similar biologically equivalent doses, are not recommended, except in patients with poor performance status or short predicted survival. Level 2: If prophylactic cranial irradiation (PCI) is given to prevent brain metastases for small cell lung cancer, the recommended WBRT dose/fractionation regimen is 25 Gy in 10 fractions, and because this can be associated with neurocognitive decline, patients should be told of this risk at the same time they are counseled about the possible survival benefits. Level 3: Patients having WBRT (given for either existing brain metastases or as PCI) should be offered 6 mo of memantine to potentially delay, lessen, or prevent the associated neurocognitive toxicity. QUESTION: Does the addition of WBRT after surgical resection or radiosurgery improve progression-free or overall survival outcomes when compared to surgical resection or radiosurgery alone? RECOMMENDATIONS: Level 2: WBRT is not recommended in WHO performance status 0 to 2 patients with up to 4 brain metastases because, compared to surgical resection or radiosurgery alone, the addition of WBRT improves intracranial progression-free survival but not overall survival. Level 2: In WHO performance status 0 to 2 patients with up to 4 brain metastases where the goal is minimizing neurocognitive toxicity, as opposed to maximizing progression-free survival and overall survival, local therapy (surgery or radiosurgery) without WBRT is recommended. Level 3: Compared to surgical resection or radiosurgery alone, the addition of WBRT is not recommended for patients with more than 4 brain metastases unless the metastases' volume exceeds 7 cc, or there are more than 15 metastases, or the size or location of the metastases are not amenable to surgical resection or radiosurgery.The full guideline can be found at: https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter_3.

Reduction of cerebrospinal fluid rhinorrhea after vestibular schwannoma surgery by reconstruction of the drilled porus acusticus with hydroxyapatite bone cement.

OBJECT: Cerebrospinal fluid (CSF) rhinorrhea remains a significant cause of morbidity after resection of vestibular schwannomas (VSs), with rates of rhinorrhea after this procedure reported to range between 0 and 27%. The authors investigated whether reconstruction of the drilled posterior wall of the porus acusticus with hydroxyapatite cement (HAC) would decrease the incidence of postoperative CSF rhinorrhea. METHODS: A prospective observational study of 130 consecutive patients who underwent surgery for reconstruction of the posterior wall of the drilled porus acusticus with HAC was conducted between October 2002 and September 2005. All patients underwent a retrosigmoid transmeatal approach for VS resection and were followed up to document cases of CSF rhinorrhea, incisional CSF leak, meningitis, or rhinorrhea-associated meningitis. A cohort of 150 patients with VSs who were treated with the same surgical approach but without HAC reconstruction served as a control group. RESULTS: The authors found that HAC reconstruction of the porus acusticus wall significantly reduced the rate of postoperative CSF rhinorrhea in their patients. In the patients treated with HAC, rhinorrhea developed in only three patients (2.3%) compared with 18 patients (12%) in the control group. This was a statistically significant finding (p = 0.002, odds ratio = 5.8). CONCLUSIONS: The use of HAC in the reconstruction of the drilled posterior wall of the porus acusticus, occluding exposed air cells, greatly reduces the risk of CSF rhinorrhea.

Primary spinal intradural extramedullary lymphoma: A novel management strategy.

Primary spinal intradural extramedullary lymphoma remains a very rare entity in spinal oncology. In this case report, we present the first treatment of a PSIEL diagnosed by cytopathologic analysis alone followed by urgent radio- and chemotherapy in the literature. At 18-month follow-up, our patient was ambulatory with near total imaging resolution of the lesion. In conclusion, surgical excision or biopsy may not be necessary when suspicion for PSIEL exists, and may delay prompt medical and radiation treatment due to necessity for wound healing. Further research into the management of extramedullary lymphoma treatment strategies is warranted.

The role of positron emission tomography and computed tomography fusion in the management of early-stage and advanced-stage primary head and neck squamous cell carcinoma.

OBJECTIVE: To evaluate the role of positron emission tomography and computed tomography (PET-CT) fusion in the management of early-stage and advanced-stage primary head and neck squamous cell cancer. DESIGN: Retrospective analysis, with a blinded evaluation of clinical data and formation of a treatment plan. SETTING: Single tertiary academic medical institution. Patients Thirty-six patients with previously untreated head and neck squamous cell carcinoma who underwent staging CT or magnetic resonance imaging of the neck prior to undergoing PET-CT as part of their initial diagnostic evaluation between July 2000 and January 2005. MAIN OUTCOME MEASURES: Confirmation or alteration of the treatment plan with the addition of the PET-CT information compared with traditional clinical and radiological data alone for early-stage and advanced-stage disease. When available, histopathological results were correlated with the PET-CT findings. RESULTS: Among the 36 patients, PET-CT provided additional information that confirmed the treatment plan in 25 patients (69%) and altered the treatment plan in 11 patients (31%). Six of 11 patients in the altered-treatment group had their tumors upstaged. Four of 8 patients with early-stage tumors had their treatment plan altered, compared with 7 of 28 patients with advanced-stage disease. Among 18 patients who underwent a surgical intervention for their primary tumor, PET-CT identified the primary tumor in all 18 patients and, based on histopathological findings, correctly staged the regional nodal disease in 9 of 16 patients who had their nodal disease addressed. CONCLUSION: The use of PET-CT is important in the initial treatment planning of early-stage and advanced-stage head and neck squamous cell carcinoma.

Controlled release of lipopolysaccharide in the subarachnoid space of rabbits induces chronic vasospasm in the absence of blood.

OBJECTIVE: Leukocyte-endothelial cell interactions appear to play a role in the development of vasospasm after SAH. Using a purely inflammatory protein, LPS, we evaluated the effect of inflammation on the development of chronic vasospasm in the absence of blood and compared it to SAH-induced vasospasm in rabbits. METHODS: Lipopolysaccharide was incorporated into EVAc polymers to produce 20% LPS/EVAc polymers (wt/wt). Rabbits (n = 23) were randomized to 4 experimental groups: (1) empty polymer (n = 6), (2) SAH (n = 5), (3) 0.7 mg/kg polymeric LPS dose (n = 6), and (4) 1.4 mg/kg polymeric LPS dose (n = 6). Blood and polymers were inserted into the cisterna magna. The rabbits were killed 3 days postoperatively, and the basilar arteries were harvested for morphometric analysis. Clinical response and lumen patencies were analyzed using ANOVA and a post hoc Newman-Keuls Multiple Comparisons test. RESULTS: Significant narrowing of the basilar artery was observed by insertion of 20% LPS/EVAc polymers into the subarachnoid space at a polymeric dose of 1.4 mg/kg (actual dose, 66 microg kg(-1) d(-1)) (75.4% +/- 4.2%; P < .01) and by SAH (80.3% +/- 8.1%; P < .01) as compared with the empty polymer group. A trend toward narrowing was observed in the 0.7 mg/kg polymeric LPS dose group (actual dose, 33 microg kg(-1) d(-1)) (85.2% +/- 2.6%; P > .05). Symptoms associated with SAH were noted in 50% of the rabbits in the 0.7 mg/kg LPS group and in 100% of rabbits in the 1.4 mg/kg LPS group. CONCLUSION: Controlled release of LPS into the subarachnoid space of rabbits produced chronic vasospasm in a dose-dependent manner. At a polymeric dose of 1.4 mg/kg, LPS-induced vasospasm was equivalent to that induced by SAH. This suggests that LPS and SAH may induce vasospasm through similar mechanisms and provides further evidence that inflammation plays a central role in the etiology of chronic vasospasm.

Hemorrhagic thoracic schwannoma presenting with intradural hematoma and acute paraplegia after spinal manipulation therapy.

Hemorrhagic conversion of spinal schwannomas represents a rare occurrence; also rare is the development of a spinal intradural hematoma after spinal manipulation therapy. We report a unique presentation of paraplegia in a patient who underwent spinal manipulation therapy and was found to have a hemorrhagic thoracic schwannoma at time of surgery in the setting of anti-platelet therapy use. In patients with spinal schwannomas, tumor hemorrhage is a rare occasion, which can be considered in the setting of additive effects of spinal manipulation therapy and antiplatelet therapy.

Extraneural Glioblastoma Multiforme Vertebral Metastasis.

Glioblastoma multiforme (GBM) is the most common malignant central nervous system tumor; however, extraneural metastasis is uncommon. Of those that metastasize extraneurally, metastases to the vertebral bodies represent a significant proportion. We present a review of 28 cases from the published literature of GBM metastasis to the vertebra. The mean age at presentation was 38.4 years with an average overall survival of 26 months. Patients were either asymptomatic with metastasis discovered at autopsy or presented with varying degrees of pain, weakness of the extremities, or other neurologic deficits. Of the cases that included the time to spinal metastasis, the average time was 26.4 months with a reported survival of 10 months after diagnosis of vertebral metastasis. A significant number of patients had no treatments for their spinal metastasis, although the intracranial lesions were treated extensively with surgery and/or adjuvant therapy. With increasing incremental gains in the survival of patients with GBM, clinicians will encounter patients with extracranial metastasis. As such, this review presents timely information concerning the presentation and outcomes of patients with vertebral metastasis.

Dendritic cell immunotherapy for solid tumors: evaluation of the DCVax® platform in the treatment of glioblastoma multiforme.

DCVax(®) (Northwest Biotherapeutics, Inc., MD, USA) is a platform technology for delivering dendritic cell based therapeutic vaccines for a variety of cancers, including glioblastoma multiforme (GBM). DCVax(®)-L, one of the implementations of the DCVax platform, provides personalized active immunotherapy composed of autologous dendritic cells pulsed with autologous whole tumor lysate. Clinical trials with DCVax-L for GBM included previous Phase I/II clinical trials and an ongoing Phase III trial. Preliminary reports of patient outcomes after administration of the DCVax-L vaccine provide a promising therapeutic paradigm for patients with both initially diagnosed and recurrent GBM. Here we evaluate the current literature and clinical experience with the DCVax platform, with a particular focus on GBM treatment.

Extracranial metastasis of gliobastoma: Three illustrative cases and current review of the molecular pathology and management strategies.

Glioblastoma (GBM) is the most common and the most malignant primary brain tumor in adults, accounting for ~12-15% of all intracranial neoplasms. Despite advances in surgical, medical and radiation therapies, the mortality of GBM remains high, with a median survival ranging between 40 and 70 weeks. Similar to other primary brain tumors, the extracranial metastasis of GBM is extremely rare, occurring in <2% of patients. To demonstrate the clinical characteristics of this rare tumor, we herein present three cases of extracranial GBM metastasis: One to the lungs, which represents the longest reported survival of lung metastases from GBM to date; the second to the soft tissue of the posterior neck; and the third to the lumbar intradural space. Unlike tumors elsewhere, there are unique barriers in the brain that prevent the hematogenous and lymphatic spread of intracranial tumors, such as the dura mater and the thickened basement membrane of the blood vessels. In addition, central nervous system tumor cells lack extracellular matrix proteins required to invade surrounding connective tissue, a prerequisite for tumor dissemination. In this study, we aimed to investigate the different possible mechanisms underlying the extracranial metastasis of GBM and determine the biomolecular and genetic characteristics differentiating GBMs that metastasize from those that do not. We also reviewed the role of systemic chemotherapy and bevacizumab in the treatment of disseminated GBMs. Early identification and differentiation of these tumors may enable patients to benefit from surgical resection, radiation and combination chemotherapy prior to developing other comorbidities from metastatic disease, which may translate into prolonged survival with an acceptable quality of life.

Delayed onset of paresis in rats with experimental intramedullary spinal cord gliosarcoma following intratumoral administration of the paclitaxel delivery system OncoGel.

OBJECT: Treatment options for anaplastic or malignant intramedullary spinal cord tumors (IMSCTs) remain limited. Paclitaxel has potent cytotoxicity against experimental intracranial gliomas and could be beneficial in the treatment of IMSCTs, but poor CNS penetration and significant toxicity limit its use. Such limitations could be overcome with local intratumoral delivery. Paclitaxel has been previously incorporated into a biodegradable gel depot delivery system (OncoGel) and in this study the authors evaluated the safety of intramedullary injections of OncoGel in rats and its efficacy against an intramedullary rat gliosarcoma. METHODS: Safety of intramedullary OncoGel was tested in 12 Fischer-344 rats using OncoGel concentrations of 1.5 and 6.0 mg/ml (5 µl); median survival and functional motor scores (Basso-Beattie-Bresnahan [BBB] scale) were compared with those obtained with placebo (ReGel) and medium-only injections. Efficacy of OncoGel was tested in 61 Fischer-344 rats implanted with an intramedullary injection of 9L gliosarcoma containing 100,000 cells in 5 µl of medium, and randomized to receive OncoGel administered on the same day (in 32 rats) or 5 days after tumor implantation (in 29 rats) using either 1.5 mg/ml or 3.0 mg/ml doses of paclitaxel. Median survival and BBB scores were compared with those of ReGel-treated and tumor-only rats. Animals were killed after the onset of deficits for histopathological analysis. RESULTS: OncoGel was safe for intramedullary injection in rats in doses up to 5 µl of 3.0 mg/ml of paclitaxel; a dose of 5 µl of 6.0 mg/ml caused rapid deterioration in BBB scores. OncoGel at concentrations of 1.5 mg/ml and 3.0 mg/ml paclitaxel given on both Day 0 and Day 5 prolonged median survival and preserved BBB scores compared with controls. OncoGel 1.5 mg/ml produced 62.5% long-term survivors when delivered on Day 0. A comparison between the 1.5 mg/ml and the 3.0 mg/ml doses showed higher median survival with the 1.5 mg/ml dose on Day 0, and no differences in median survival or BBB scores after treatment on Day 5. CONCLUSIONS: OncoGel is safe for intramedullary injection in rats in doses up to 5 µl of 3.0 mg/ml, prolongs median survival, and increases functional motor scores in rats challenged with an intramedullary gliosarcoma at the doses tested. This study suggests that locally delivered chemotherapeutic agents could be of temporary benefit in the treatment of malignant IMSCTs under experimental settings.

Convection-enhanced delivery of 131I-chTNT-1/B mAB for treatment of high-grade adult gliomas.

INTRODUCTION: Despite treatment advances for malignant gliomas in adults, prognosis remains poor, largely due to the infiltrative and heterogeneous biology of these tumors. Response to adjuvant therapy is not always uniform and the blood-brain barrier prevents the majority of chemotherapeutics from adequately reaching primary tumor sites. These obstacles necessitate development of novel delivery methods and agents. AREAS COVERED: (131)I-chTNT-1/B mAB (Cotara) is a genetically engineered chimeric monoclonal antibody that binds to the DNA-histone H1 complex. It carries (131)I, which delivers sufficient energy to kill adjacent tumor cells. Through convection-enhanced delivery (CED) it provides radioimmunotherapy directly to the resection cavity. We review the pharmacology and clinical experience with (131)I-chTNT-1/B mAB, detailing results of completed Phase I and II trials. EXPERT OPINION: Novel agents and therapeutic modalities, such as (131)I-chTNT-1/B mAB, are of interest for treatment of malignant glioma, for which the prognosis continues to be dismal. (131)I-chTNT-1/B mAB targets tumor cells and radioisotope labeling allows radiation delivery to the tumor with sharp fall-off. Data from Phase I and II trials of CED delivery of (131)I-chTNT-1/B mAB shows it is well tolerated. Phase II trial data suggests it could be promising therapeutically, though conclusions about efficacy require further trials and clinical experience. The compound is currently in a Phase II trial for dose confirmation in patients with malignant gliomas.