John M. McGregor

Blood-Brain Barrier Disruption and Intra-Arterial Methotrexate-Based Therapy for Newly Diagnosed Primary CNS Lymphoma: A Multi-Institutional Experience

PURPOSE Primary CNS lymphoma (PCNSL) is confined to the CNS and/or the eyes at presentation and is usually initially treated with intravenous methotrexate-based chemotherapy and whole-brain radiotherapy (WBRT). However, the intact blood-brain barrier (BBB) can limit diffusion of methotrexate into brain and tumor. With BBB disruption (BBBD), enhanced drug delivery to the tumor can be achieved. PATIENTS AND METHODS This report summarizes the multi-institutional experience of 149 newly diagnosed (with no prior WBRT) patients with PCNSL treated with osmotic BBBD and intra-arterial (IA) methotrexate at four institutions from 1982 to 2005. In this series, 47.6% of patients were age > or = 60 years, and 42.3% had Karnofsky performance score (KPS) less than 70 at diagnosis. Results The overall response rate was 81.9% (57.8% complete; 24.2% partial). Median overall survival (OS) was 3.1 years (25% estimated survival at 8.5 years). Median progression-free survival (PFS) was 1.8 years, with 5-year PFS of 31% and 7-year PFS of 25%. In low-risk patients (age < 60 years and KPS > or = 70), median OS was approximately 14 years, with a plateau after approximately 8 years. Procedures were generally well tolerated; focal seizures (9.2%) were the most frequent side effect and lacked long-term sequelae. CONCLUSION This large series of patients treated over a 23-year period demonstrates that BBBD/IA methotrexate-based chemotherapy results in successful and durable tumor control and outcomes that are comparable or superior to other PCNSL treatment regimens.

Cervical spondylotic myelopathy: functional and radiographic long-term outcome after laminectomy and posterior fusion.

OBJECTIVE To evaluate the long-term efficacy of cervical laminectomy with posterior lateral mass fusion/fixation in the treatment of patients with cervical spondylotic myelopathy (CSM). METHOD Twenty-five patients treated for CSM by laminectomy and lateral mass fusion at the Division of Neurosurgery at The Ohio State University between 1989 and 1994 were studied retrospectively. Only patients with longer than 2-year postoperative follow-up durations were included. At follow-up examination, each patient completed an SF36 questionnaire, underwent a physical examination, underwent plain radiography showing the spinal curvature with plate and screw position, and underwent magnetic resonance imaging of the cervical spine, which evaluated dural sac decompression and spinal cord abnormalities. Patient-generated data were used for outcome measurements. RESULTS The mean follow-up duration was 47.5 months. Good outcome was defined by the presence of three criteria: ability to walk unassisted (Grade IIIA or better), ability to write unassisted, and ability to manage buttons and/or zippers unassisted. The inability to meet these criteria was defined as a poor outcome. Two patients (8%) experienced complications that resulted from the surgery. There was no instability or progression to significant kyphosis. Lesions that were hyperintense on magnetic resonance images did not correlate with outcome. Eighty percent of the patients achieved good outcomes, and 76% had improved myelopathy scores. None of the patients had late neurological deterioration. Patients with better neurological statuses at the time of surgery (Grade IIIA or better) were more likely to improve (P < 0.0001); the likelihood of a change in status for those starting with poorer grades (IIIB or worse) was not statistically significant (P < 0.08). CONCLUSION Cervical laminectomy with posterior fusion/fixation proved useful in the treatment of patients with CSM with straight or lordotic spines and multilevel compression. This therapy addresses the dynamic and compressive forces that are important in the pathogenesis of CSM, resulting in minimal complications and possible improvement in long-term outcomes.

Phase IB Study of Gene-Mediated Cytotoxic Immunotherapy Adjuvant to Up-Front Surgery and Intensive Timing Radiation for Malignant Glioma

PURPOSE Despite aggressive therapies, median survival for malignant gliomas is less than 15 months. Patients with unmethylated O(6)-methylguanine-DNA methyltransferase (MGMT) fare worse, presumably because of temozolomide resistance. AdV-tk, an adenoviral vector containing the herpes simplex virus thymidine kinase gene, plus prodrug synergizes with surgery and chemoradiotherapy, kills tumor cells, has not shown MGMT dependency, and elicits an antitumor vaccine effect. PATIENTS AND METHODS Patients with newly diagnosed malignant glioma received AdV-tk at 3 × 10(10), 1 × 10(11), or 3 × 10(11) vector particles (vp) via tumor bed injection at time of surgery followed by 14 days of valacyclovir. Radiation was initiated within 9 days after AdV-tk injection to overlap with AdV-tk activity. Temozolomide was administered after completing valacyclovir treatment. RESULTS Accrual began December 2005 and was completed in 13 months. Thirteen patients were enrolled and 12 completed therapy, three at dose levels 1 and 2 and six at dose level 3. There were no dose-limiting or significant added toxicities. One patient withdrew before completing prodrug because of an unrelated surgical complication. Survival at 2 years was 33% and at 3 years was 25%. Patient-reported quality of life assessed with the Functional Assessment of Cancer Therapy-Brain (FACT-Br) was stable or improved after treatment. A significant CD3(+) T-cell infiltrate was found in four of four tumors analyzed after treatment. Three patients with MGMT unmethylated glioblastoma multiforme survived 6.5, 8.7, and 46.4 months. CONCLUSION AdV-tk plus valacyclovir can be safely delivered with surgery and accelerated radiation in newly diagnosed malignant gliomas. Temozolomide did not prevent immune responses. Although not powered for efficacy, the survival and MGMT independence trends are encouraging. A phase II trial is ongoing.

Surgical treatment of the spontaneous spinal epidural abscess

Seven cases of spontaneous epidural abscess are reviewed. Three patients had posterior abscesses and no evidence of vertebral body osteomyelitis. These patients had excellent outcomes with laminectomies and antibiotics. Because of significant vertebral destruction, two patients with vertebral osteomyelitis required posterior fixation after laminectomy. Two other patients with vertebral osteomyelitis had complete destruction of the vertebral body and required anterior decompression and fusion in addition to posterior fixation. In the four patients with vertebral osteomyelitis, morbidity was high, reflecting their age and significant medical problems. This review supports the contention that medically stable patients with posterior epidural abscesses can be treated with laminectomy and antibiotics with little risk of progressive instability. The proper surgical treatment of anterior epidural abscesses secondary to osteomyelitis requires knowledge about the amount of destruction of the supporting columns, the amount of neural compression secondary to the purulence, and the patients general medical condition.

Quantitative Outcome and Radiographic Comparisons between Laminectomy and Laminotomy in the Treatment of Acquired Lumbar Stenosis

OBJECTIVE The objective of this study was to conduct a comparative quantitative analysis of outcomes, radiographic findings, and magnetic resonance imaging results after laminectomy or laminotomy was performed for patients with lumbar stenosis. Such as analysis had not previously been conducted. METHODS Twenty-six patients with no exclusion criteria who were treated surgically for acquired stenosis at the Division of Neurological Surgery at The Ohio State University from 1990 to 1993 were studied retrospectively. At follow-up examinations, each patient completed a detailed questionnaire that included visual analog scales, functional assessments, and the medical outcome study short form health survey, SF-36. Each patient underwent plain static and dynamic radiography that detailed vertebral body sagittal listhesis and rotation and magnetic resonance imaging that evaluated dural sac compression. RESULTS The mean follow-up duration was 36.7 months. Good outcome was defined by the presence of three criteria: no greater than mild leg pain (Grades 0-4), the ability to walk more than one block without developing lower extremity pain, and the ability to walk without assistance devices. Fifty-eight percent of the patients who had undergone laminectomies and 50% of the patients who had undergone laminotomies had good outcomes. All were judged to have had adequate decompression. The average maximum postoperative listhesis was 17.3 +/- 9.9% in the laminectomy group and 17.6 +/- 12.5% in the laminotomy group. In contrast to some previous studies, pre- or postoperative listhesis was not statistically related to outcome in either group. Patients in each poor outcome category seemed to have worse comorbid medical conditions than did patients in the good outcome category. The SF-36 measurements of poor functioning because of health factors and bodily pain correlated somewhat with poor outcomes in the patients who had undergone laminectomies. In patients who had undergone laminotomies, the only statistically significant finding among the outcome groups was the effect of poor emotional health on activity for the patients with poor outcomes. CONCLUSION This study indicates that laminotomy can adequately decompress lumbar canal stenosis, that laminectomy and laminotomy have the same degree of postoperative listhesis, and that the quantitative outcome of any treatment for lumbar stenosis is dependent not only on surgical factors but also on comorbid physical and psychological factors.

Stereotactic radiosurgery with or without whole brain radiotherapy for patients with a single radioresistant brain metastasis.

Purpose:To examine the outcomes of patients with a single brain metastasis from radioresistant histologies (renal cell carcinoma and melanoma) treated with stereotactic radiosurgery (SRS) with or without whole brain radiotherapy (WBRT). Methods and Materials:We reviewed the medical records of 27 patients treated at our institution between 2000 and 2007 with a single radioresistant brain metastasis. Patients were treated with Gamma Knife based SRS. Tumor histologies included renal cell carcinoma and melanoma. Results:Patients were treated to a median marginal dose was 20 Gy (range, 15–22 Gy). At follow-up intervals ranging from 1.8 to 23.2 months, the radiographic responses were as follows: progression in 7 patients; stable in 5 patients; and shrinkage in 15 patients. Fifteen patients (56%) developed distant brain failure. Seven of the 27 patients were alive at last follow-up. The 3-, 6-, 9-, 12-, and 18-months after SRS local control rates were 82.8%, 77.9%, 69.3%, 69.3%, and 55.4%, respectively. None of the 5 patients who received WBRT developed distant brain failure although the follow-up intervals were short (range, 3.5–13.7 months; median, 5.1 months). WBRT did not appear to affect local control, progression free survival, and overall survival (P = 0.32, 0.87, 0.69). One patient developed worsening of symptoms attributable to SRS. Conclusions:Gamma Knife SRS is a safe and feasible strategy for treatment of patients with a single radioresistant brain metastasis. Radiosurgery alone is a reasonable treatment option, but may carry a greater likelihood of distant brain recurrence.

Gamma Knife radiosurgery for intracranial metastatic melanoma: an analysis of survival and prognostic factors

Objective of this study was to evaluate retrospectively the effectiveness of Gamma Knife radiosurgery for intracranial metastatic melanoma and to identify prognostic factors related to survival. Twenty-six patients with intracranial metastases (72 lesions) from melanoma underwent Gamma Knife radiosurgery. In 14 patients (54%) whole-brain radiotherapy (WBRT) was performed as part of the initial treatment, and in 12 patients (38%) immunotherapy and/or chemotherapy was given after Gamma Knife radiosurgery. The median tumor volume for Gamma Knife radiosurgery treated lesions was 1.72 cm3. The median prescribed radiation dose was 18 Gy (range 8–22 Gy) typically prescribed to the isodose at the tumor margin. Univariate and multivariate analyses were used to determine significant prognostic factors affecting survival. Overall median survival was 6 months after Gamma Knife radiosurgery, and 1-year survival was 25%. The median survival from the onset of brain metastases was 9 months and from the original diagnosis of melanoma was 50 months (range 4–160 months). There were no major acute or late GKS complications. In univariate testing, the Karnofsky score equal to or higher than 90% (P < 0.01, log-rank test), supratentorial localization (P < 0.001, log-rank test), intracranial tumor volume less than 1 cm3 (P < 0.02, log-rank test), and absence of neurological signs or symptoms before Gamma Knife radiosurgery (P < 0.003, log-rank test) were significant favorable factors for survival. In multivariate regression analyses, the most important predictors associated with increased survival were a KPS ≥ 90 (P < 0.023), female sex (P < 0.004), supratentorial localization (P < 0.01), and absence of neurological symptoms (P < 0.008). Radiosurgery is a noninvasive, safe, and effective treatment option for patients with single or multiple intracranial metastases from melanoma. Female sex, Karnofsky score ≥90, supratentorial localization and lack of symptoms before the Gamma Knife radiosurgery were good independent predictors of survival.

Unsanctifying the sanctuary: challenges and opportunities with brain metastases

While the use of targeted therapies, particularly radiosurgery, has broadened therapeutic options for CNS metastases, patients respond minimally and prognosis remains poor. The inability of many systemic chemotherapeutic agents to penetrate the blood-brain barrier (BBB) has limited their use and allowed brain metastases to become a burgeoning clinical challenge. Adequate preclinical models that appropriately mimic the metastatic process, the BBB, and blood-tumor barriers (BTB) are needed to better evaluate therapies that have the ability to enhance delivery through or penetrate into these barriers and to understand the mechanisms of resistance to therapy. The heterogeneity among and within different solid tumors and subtypes of solid tumors further adds to the difficulties in determining the most appropriate treatment approaches and methods of laboratory and clinical studies. This review article discusses therapies focused on prevention and treatment of CNS metastases, particularly regarding the BBB, and the challenges and opportunities these therapies present.

Interpretive risks: the use of the Hopkins Symptom Checklist 90-Revised (SCL 90-R) with brain tumour patients

Patients with brain tumours often report distress. Interpretive problems ensue when measures normed on healthy persons are utilized to quantify distress. This study investigated potentially spurious elevations on the Hopkins Symptom Checklist 90 Revised (SCL 90-R). Responses of 17 patients were obtained prior to aggressive chemotherapy. Traditional interpretation indicated that 47% of the patients endorsed clinical levels of somatization, 53% obsessive-compulsive and 59% psychotic disorders. Elevations were attributable to common consequences of brain tumours, medication and the emotional reaction to prognosis. Conventional interpretation would lead to inappropriate classifications. The majority of SCL 90-R item endorsements were significantly different than those of the norm group. Appropriate interpretation of scores is discussed.

Phase II multicenter study of gene-mediated cytotoxic immunotherapy as adjuvant to surgical resection for newly diagnosed malignant glioma

BACKGROUND Despite aggressive standard of care (SOC) treatment, survival of malignant gliomas remains very poor. This Phase II, prospective, matched controlled, multicenter trial was conducted to assess the safety and efficacy of aglatimagene besadenovec (AdV-tk) plus valacyclovir (gene-mediated cytotoxic immunotherapy [GMCI]) in combination with SOC for newly diagnosed malignant glioma patients. METHODS Treatment cohort patients received SOC + GMCI and were enrolled at 4 institutions from 2006 to 2010. The preplanned, matched-control cohort included all concurrent patients meeting protocol criteria and SOC at a fifth institution. AdV-tk was administered at surgery followed by SOC radiation and temozolomide. Subset analyses were preplanned, based on prognostic factors: pathological diagnosis (glioblastoma vs others) and extent of resection. RESULTS Forty-eight patients completed SOC + GMCI, and 134 met control cohort criteria. Median overall survival (OS) was 17.1 months for GMCI + SOC versus 13.5 months for SOC alone (P = .0417). Survival at 1, 2, and 3 years was 67%, 35%, and 19% versus 57%, 22%, and 8%, respectively. The greatest benefit was observed in gross total resection patients: median OS of 25 versus 16.9 months (P = .0492); 1, 2, and 3-year survival of 90%, 53%, and 32% versus 64%, 28% and 6%, respectively. There were no dose-limiting toxicities; fever, fatigue, and headache were the most common GMCI-related symptoms. CONCLUSIONS GMCI can be safely combined with SOC in newly diagnosed malignant gliomas. Survival outcomes were most notably improved in patients with minimal residual disease after gross total resection. These data should help guide future immunotherapy studies and strongly support further evaluation of GMCI for malignant gliomas. CLINICAL TRIAL REGISTRY ClinicalTrials.gov NCT00589875.