A phase II trial of arsenic trioxide and temozolomide in combination with radiation therapy for patients with malignant gliomas.

Standard treatment for GBM is radiation (RT) and temozolomide (TMZ). Arsenic trioxide (ATO) is synergistic with RT based on several mechanisms of action previously identified, however not tested herein. The MTD of ATO, RT and TMZ was determined in a Phase I trial. We now present the combined Phase I/II data. Patients with newly diagnosed malignant gliomas were eligible for treatment. Patients were treated with RT (60 GY), TMZ (75 mg/m2 daily × 42 days) and ATO 0.20 mg/kg daily in week 1 then twice a week ×5 weeks, after completing RT they were treated with TMZ 5/28 for up to 12 months. MRIs were performed every 8 weeks. A total of 42 patients were enrolled in both the Phase I and II trials for this study treatment. Of the 42 enrolled patients (24 M and 18 W) the median age was 54 (24-80) and median KPS 90 (60-100). 28 patients had a GBM and 14 had anaplastic glioma (AG). All patients completed RT/TMZ/ATO and went on to maintenance TMZ. Median number of post RT cycles of TMZ was 4 (0-12). Median PFS was 7 m for GBM and 75 m for AG and median OS was 17 m for GBM and NR for AG. Best response was CR in 2, SD in 28, PR in 5 and PD in 7. There were no unexpected adverse events. Grade 3 toxicities likely attributable to ATO included prolonged Qtc (n = 1), elevated liver enzymes (n = 2 for ALT/n = 1 for AST) and elevated bilirubin (n = 1). Adding ATO to RT and TMZ is feasible with no increased side effects. The addition of arsenic did not improve overall survival in the GBM patients as compared to historic data. MGMT status was analyzed in 20 of the 42 patients where tissue was available for retrieval and MGMT testing.

A phase II trial evaluating the effects and intra-tumoral penetration of bortezomib in patients with recurrent malignant gliomas.

One resistance mechanism in malignant gliomas (MG) involves nuclear factor-κB (NF-κB) activation. Bortezomib prevents proteasomal degradation of NF-κB inhibitor α (NFKBIA), an endogenous regulator of NF-κB signaling, thereby limiting the effects of NF-κB on tumor survival and resistance. A presurgical phase II trial of bortezomib in recurrent MG was performed to determine drug concentration in tumor tissue and effects on NFKBIA. Patients were enrolled after signing an IRB approved informed consent. Treatment was bortezomib 1.7 mg/m(2) IV on days 1, 4 and 8 and then surgery on day 8 or 9. Post-operatively, treatment was Temozolomide (TMZ) 75 mg/m(2) PO on days 1-7 and 14-21 and bortezomib 1.7 mg/m(2) on days 7 and 21 [1 cycle was (1) month]. Ten patients were enrolled (8 M and 2 F) with 9 having surgery. Median age and KPS were 50 (42-64) and 90 % (70-100). The median cycles post-operatively was 2 (0-4). The trial was stopped as no patient had a PFS-6. All patients are deceased. Paired plasma and tumor bortezomib concentration measurements revealed higher drug concentrations in tumor than in plasma; NFKBIA protein levels were similar in drug-treated vs. drug-naïve tumor specimens. Nuclear 20S proteasome was less in postoperative samples. Postoperative treatment with TMZ and bortezomib did not show clinical activity. Bortezomib appears to sequester in tumor but pharmacological effects on NFKBIA were not seen, possibly obscured due to downregulation of NFKBIA during tumor progression. Changes in nuclear 20S could be marker of bortezomib effect on tumor.

Impact of fiducial arrangement and registration sequence on target accuracy using a phantom frameless stereotactic navigation model.

Modern frameless stereotactic techniques utilize scalp fiducial markers for registration. Anecdotal reports from surgeons indicate a variety of methods for improving accuracy using different fiducial arrangements and registration sequences. The few published studies on registration accuracy do not provide a simple and systematic method for determining target accuracy. Nine different arrangements of ten fiducial markers were attached to a model. Ten separate markers were designated as targets for evaluation of registration accuracy. We systematically registered each of the arrangements over multiple trials, in one of four sequences, and then measured the targets. The target coordinates were compared against the established target values, and a root-mean-square deviation (RMSD) was derived. A systematic multivariate analysis determined the effects of different variables on the RMSD. We found no correlation between the "Registration Accuracy" provided by Medtronic (Medtronic Navigation, Louisville, CO, USA) and our RMSD representing targeting accuracy (R=0.008). RMSD did vary for different fiducial arrangements. We found no significant difference between the various sequences of fiducial arrangement. Thus, regardless of fiducial arrangement, registration sequence has no impact on accuracy. Fiducial arrangements distributed optimally across the skull, however, allowed for significantly improved accuracy. Further studies are required to determine which different arrangements of fiducials are relevant for specific procedures.

Diffusion abnormalities of the corpus callosum in patients receiving bevacizumab for malignant brain tumors: suspected treatment toxicity.

Bevacizumab has been reported to cause diffusion restriction in the tumor bed of patients with malignant gliomas. This study evaluated prolonged diffusion restriction, in the corpus callosum (CC), of patients with malignant brain tumors treated with bevacizumab. We retrospectively reviewed our database of patients treated with bevacizumab for malignant brain tumors looking for those with restricted diffusion in the CC. CC ADC ratio measurements were obtained prior to and following treatment. Correlation was made with biopsy (n = 3) and MR perfusion (n = 7) and PET (n = 4). The temporal evolution of these changes relative to therapy was examined with mixed effects regression analysis. Nine patients (eight malignant gliomas, one malignant meningioma) out of 146 patients were found to have developed areas of diffusion restriction in the CC. These areas tended to enlarge and coalesce over serial MRIs and persisted for up to 22 months. Hypoperfusion was demonstrated in MR perfusion in 7/7. PET was hypometabolic in all 4. Biopsy of the CC showed no tumor in 3/3. ADC ratio measurements indicated a significant overall effect of time (F(16,60) = 11.2; p < 0.0001), consistent with persistent diffusion restriction over the measured time periods. Bevacizumab causes prolonged diffusion restriction in the CC. The negative MR perfusion, FDG PET and histopathology suggest this is a toxicity of bevacizumab and not active tumor. Awareness of these changes can assist in patient care.

A phase II trial of PTK787/ZK 222584 in recurrent or progressive radiation and surgery refractory meningiomas.

When surgery and radiation are no longer treatment options, salvage systemic therapy has been used for recurrent meningiomas with little compelling evidence to suggest effectiveness. Patients with surgery and radiation refractory recurrent meningiomas were treated with the oral multifunctional tyrosine kinase inhibitor PTK787/ZK 222584 (PTK787) at a dose of 500 mg twice a day. Each treatment cycle was 4 weeks with MRI done every 8 weeks. Twenty-five patients (14 men; 11 women) with a median age of 59 years and KPS of 80 were treated. Meningioma WHO Grade was I in 2 patients, II in 14 patients and III in 8 patients; 1 patient had a hemangiopericytoma. All patients had prior surgery, external beam radiation therapy or radiosurgery and 11 patients prior systemic chemotherapy. Median number of cycles of PTK 787 administered was 4 (range <1-22). Best response in the 22 evaluable patients was stable disease in 15 (68.2 %). Predominant PTK787 related toxicities included fatigue (60 %), hypertension (24 %) and elevated transaminases (24 %). Grade II patients had a progression free survival (PFS)-6 of 64.3 %, a median PFS of 6.5 months and an overall survival (OS) of 26.0 months; grade III patients had a PFS-6 of 37.5 %, median PFS of 3.6 months and OS 23 months. PTK787 was modestly toxic at the dose of 500 mg administered twice per day. Activity as determined by PFS-6 suggests that targeting PDGF/VEGF pathway warrants further investigation.

Concordance of patient and caregiver reports in evaluating quality of life in patients with malignant gliomas and an assessment of caregiver burden.

BACKGROUND: Given the neurocognitive impairment experienced by many patients with malignant gliomas, caregiver reports can be critical in assessing the quality of life (QOL) of these patients. In this study, we explored whether assessment of patient QOL by the primary caregiver shows concordance with the patient's self-reported QOL, and we quantified the burden faced by caregivers. METHODS: QOL of 45 patients was evaluated by both the patient and primary caregiver on 3 or more separate occasions using the Functional Assessment of Cancer Therapy-Brain (FACT-Br) instrument, and concordance between the 2 reports was evaluated. Caregiver burden was measured using the Caregiver Quality of Life Index-Cancer (CQOL-C) instrument. RESULTS: Overall, good concordance was observed between the patient and caregiver FACT-Br reports (intraclass correlation coefficient = 0.74). Patient-reported FACT-Br scores were 4.75 (95% CI, 1.44-8.05) points higher than paired caregiver reports on the 200-point scale (P = .008); however, this difference did not achieve clinical significance. Caregiver burden, as measured by the CQOL-C, was significantly greater among caregivers in this study than those previously reported for caregivers of patients with lung, breast, or prostate cancer (P < .001). CONCLUSIONS: Despite minor discrepancies in caregiver assessments of patient QOL relative to patient self-reports, our results suggest that the caregiver assessments can serve as adequate proxies for patient reports. Our results also illustrate the particularly heavy burden faced by caregivers of patients with malignant glioma. Further research into both of these areas is warranted.

Phase I study of arsenic trioxide and temozolomide in combination with radiation therapy in patients with malignant gliomas.

To evaluate the toxicity and maximum tolerated dose (MTD) of arsenic trioxide (ATO) in combination with temozolomide (TMZ) and radiation therapy (RT) in malignant gliomas. A 3 + 3 dose escalation study was performed in patients with newly diagnosed glioblastoma, anaplastic astrocytoma (AA), and anaplastic oligoastrocytoma (AOA). All patients received RT 59-61 Gy in 28-33 fractions, TMZ for 42 days, and ATO 1-2 h prior to RT for 5 days during the first week, then twice weekly until completing RT. Dose levels (DL) were: (1) TMZ 60 mg/m(2)/ATO 0.2 mg/kg; (2) TMZ 75 mg/m(2)/ATO 0.2 mg/kg; (3) TMZ 75 mg/m(2)/ATO 0.25 mg/kg. Dose-limiting toxicity (DLT) was defined as grade 3 non-hematologic toxicity or grade 4 toxicity of any type from enrollment until 3 weeks after finishing RT. 17 patients (13 glioblastoma, 4 AA/AOA) were accrued. Median age was 52 (range 25-80). Median KPS was 90 %. DLT's occurred at DL 2 (grade 4 transaminase elevation) and DL 3 (grade 4 neutropenia and grade 3 QTc prolongation). The MTD of TMZ 75 mg/m(2)/ATO 0.2 mg/kg was safe and well tolerated. A phase II study evaluating the efficacy of this combination is underway.

True aneurysm on the posterior meningeal artery associated with a dural arteriovenous fistula: case report.

BACKGROUND: We report an unusual case of a true dural aneurysm arising from the posterior meningeal artery that fed a symptomatic dural arteriovenous fistula located at the right transverse-sigmoid sinus junction. CLINICAL PRESENTATION: A 29-year-old right-handed white woman presented with aneurysmal dilatation of hypertrophied posterior meningeal artery feeding a partially treated dural arteriovenous fistula. INTERVENTION: The aneurysm, which measured approximately 3 mm in width and 5 mm in length, was located in the intracranial space with a thin-walled dome projecting toward the cerebellum. Its afferent and efferent vessels were identified, secured, and the lesion was excised en bloc. CONCLUSION: A thorough evaluation of all diagnostic studies should be performed for patients with vascular malformations to help identify these or other unusual lesions that may aid in the risk stratification process and management plan.

A phase 2 trial of single-agent bevacizumab given in an every-3-week schedule for patients with recurrent high-grade gliomas.

BACKGROUND: The authors evaluated a 3-week schedule of bevacizumab in patients with recurrent high-grade glioma (HGG). METHODS: Patients received bevacizumab 15 mg/kg every 3 weeks and were evaluated every 6 weeks until tumor progression. Tissue correlates were used to quantify tumor content of vascular endothelial growth factor A (VEGFA) and vascular endothelial growth factor receptor-2 (VEGFR2). RESULTS: Of 61 patients who were treated (35 men and 26 women; median age, 52 years; age range, 21-78 years), 50 patients had glioblastoma multiforme (GBM), and 11 patients had anaplastic glioma (AG). The median number of previous chemotherapies was 2 (range, 1-5 previous chemotherapies), and 16 patients had received ≥3 previous chemotherapies. The median number of bevacizumab doses was 4 (range, 1-20 doses), and 45% of patients received >5 doses. The toxicities observed were primarily grade 1 and 2, and the most common were fatigue, hypertension, and headache. One grade 2 intratumoral bleed and 1 bowel perforation were reported. For patients with GBM, the 6-month progression-free survival rate was 25%, the median time to tumor progression was 10.8 weeks, and the median overall survival was 25.6 weeks. The best response included a partial response in 15 patients (24.5%) and stable disease in 31 patients (50.8%) patients; radiographic recurrence patterns included increased changes in fluid attenuation inversion recovery (24%) and multifocal recurrence (20%). The median survival after bevacizumab failure was 10 weeks. The ratio of tumor VEGFA/VEGFR2 was increased in patients aged >55 years; an increased VEGFA/VEGFR2 ratio was correlated nonsignificantly with decreased survival (P = .052). CONCLUSIONS: An every-3-week schedule of bevacizumab had antitumor activity and was relatively nontoxic for patients with recurrent HGG. The predictive value of VEGFA/VEGFR2 in tumor will require validation in a larger patient cohort.

Use of Conivaptan (Vaprisol) for hyponatremic neuro-ICU patients.

BACKGROUND: Hyponatremia is common in neurocritical care and is associated with poor outcome, but the optimal treatment is not known. We wished to test the hypothesis that for neurocritical care patients with severe hyponatremia (Na < 130 mmol/l) or hyponatremia (Na < 135 mmol/l) with depressed Glasgow Coma Scale (GCS) that conivaptan use would lead to increased serum sodium compared to usual care. METHODS: We prospectively screened 249 neurocritical care patients with hyponatremia for a prospective, randomized pilot (goal N = 20) trial. Study interventions were usual care, or usual care plus conivaptan 20 mg IV as a bolus followed by 20 mg IV over 24 h, the lower FDA-approved dose. Patients were prospectively followed for changes in serum and urine electrolytes and clinical examinations with a blinded examiner. This study is registered at www.clinicaltrials.gov (NCT00727090). RESULTS: Despite the prevalence of hyponatremia, recruitment was difficult, and the study was terminated after six patients were enrolled, three in each group. Most hyponatremia in screened but non-randomized patients was transient or not associated with depressed GCS. Conivaptan led to higher serum sodium compared to usual care. The change in serum sodium from baseline, the pre-specified endpoint, was significantly different between groups at six (7.0 +/- 1.7 vs. -0.6 +/- 2.1 mmol/l, P = 0.008), 24 (9.7 +/- 3.2 vs. 0 +/- 1.0 mmol/l), and 36 h (8.0 +/- 5.6 vs. -1.7 +/- 2.1 mmol/l, P = 0.05). There were no apparent differences in clinical examination as a result of treatment. Adverse events were similar, and all randomized patients completed the protocol. CONCLUSIONS: Despite an inclusive protocol, most patients were not candidates for conivaptan therapy for hyponatremia. The role of conivaptan in the Neuro-ICU remains to be defined.

High-grade dural arteriovenous fistula simulating a bilateral thalamic neoplasm.

Dural arteriovenous fistulae (dAVF) provide a diagnostic challenge and must be part of a broad differential in pursuit of a difficult diagnosis or unusual presentation. This case report demonstrates an initially misguided diagnosis of bilateral thalamic neoplasm and demonstrates the importance of continued pursuit until the correct diagnosis is obtained. Moreover, to our knowledge, this is the first reported case of a dAVF simulating a bilateral thalamic neoplasm. We present a patient with a provisional diagnosis of bilateral thalamic neoplasm based on clinical history and an advanced imaging workup including MR spectroscopy. Subsequent biopsy suggested venous congestion, hypoxia, and edema without neoplasia. Routine post-operative CT the following day revealed suggestion of dAVF due to the presence of residual contrast from prior unrelated abdominal CT. Cerebral angiography eventually revealed a Cognard grade IIb dAVF. Trans-arterial Onyx embolization resulted in a dramatic clinical and radiographic improvement. This case highlights an unusual presentation and challenging diagnosis of a dAVF and the importance of pursuing the correct diagnosis.

Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project.

Rituximab improves outcomes for persons with lymphoproliferative disorders and is increasingly used to treat immune-mediated illnesses. Recent reports describe 2 patients with systemic lupus erythematosus and 1 with rheumatoid arthritis who developed progressive multifocal leukoencephalopathy (PML) after rituximab treatment. We reviewed PML case descriptions among patients treated with rituximab from the Food and Drug Administration, the manufacturer, physicians, and a literature review from 1997 to 2008. Overall, 52 patients with lymphoproliferative disorders, 2 patients with systemic lupus erythematosus, 1 patient with rheumatoid arthritis, 1 patient with an idiopathic autoimmune pancytopenia, and 1 patient with immune thrombocytopenia developed PML after treatment with rituximab and other agents. Other treatments included hematopoietic stem cell transplantation (7 patients), purine analogs (26 patients), or alkylating agents (39 patients). One patient with an autoimmune hemolytic anemia developed PML after treatment with corticosteroids and rituximab, and 1 patient with an autoimmune pancytopenia developed PML after treatment with corticosteroids, azathioprine, and rituximab. Median time from last rituximab dose to PML diagnosis was 5.5 months. Median time to death after PML diagnosis was 2.0 months. The case-fatality rate was 90%. Awareness is needed of the potential for PML among rituximab-treated persons.

Multiple brain abscesses due to Actinomyces species.

We report a case of multiple brain abscesses due to Actinomyces species in a 35-year-old immunocompetent man who presented with a 2-month history of headache, diplopia, fever, and weight loss. Despite receipt of broad-spectrum antibiotics for over a month, he continued to have headaches and diplopia. He subsequently underwent right anterior temporal lobectomy and evacuation of abscesses. The diagnosis was aided by identification of sulfur granule on histopathological examination of cerebral cavitary lesion and Gram-positive filamentous rods seen on tissue-Gram stain.

Immunotherapeutic treatment strategies for primary brain tumors.

OPINION STATEMENT: Primary brain tumors account for a minor fraction of cancer diagnoses made worldwide and remain one of the most difficult to treat. Despite ongoing efforts to improve the quality of life and overall survival of these patients, current multimodality therapy has achieved only modest gains; the median survival is approximately 14 months among patients with the deadliest form of primary brain tumor, glioblastoma multiforme. Although the brain has been long considered an immunologically privileged organ, there is increased awareness of and appreciation for the complex interplay between the nervous system and the immune system in the setting of many disease states, including neoplastic. Although the concept of harnessing the specificity, activity, and memory of the immune system toward the treatment of brain tumors has been in existence for several decades and the neuro-oncology literature holds many publications that once promised of a breakthrough, only recently has a strategy emerged that addresses many of the limitations identified through past failures. It is with cautious optimism that the authors review the past and discuss the present status of immunotherapy and its role in the management of patients with primary brain tumors.

Generation of embryonic stem cells: limitations of and alternatives to inner cell mass harvest.

Embryonic stem (ES) cells are pluripotent cells derived from the inner cell mass of the early mammalian embryo. Because of their plasticity and potentially unlimited capacity for self-renewal, ES cells have generated tremendous interest both as models for developmental biology and as possible tools for regenerative medicine. This excitement has been attenuated, however, by scientific, political, and ethical considerations. In this article the authors describe somatic cell nuclear transfer and transcription-induced pluripotency, 2 techniques that have been used in attempts to circumvent the need to derive ES cells by the harvest of embryonic tissue.

Characterization of malignant brain tumor using elastic light scattering spectroscopy.

We report a pilot study designed to test elastic light-scattering (ELS) spectroscopy for characterizing normal, tumor, and tumor-infiltrated brain tissues. ELS spectra were measured from 393 sites on 36 ex vivo tissue specimen obtained from 29 patients. We employed and compared the performances of three methods of spectral classification for tissue characterization, including spectral slope analysis, principle component analysis (PCA), and artificial neural network (ANN) classification. The ANN classifier yielded the best correlation between spectral pattern and histopathological diagnosis, with a typical sensitivity of 80% and specificity of 93% for differentiating tumor from normal brain tissues. We also demonstrate that all three classification methods discriminate between tumor and normal tissue and have the potential to identify and quantitatively characterize tumor-infiltrated brain tissues.

Adult presentation of spinal dysraphism and tandem diastematomyelia.

BACKGROUND CONTEXT: Diastematomyelia is a split-cord malformation often accompanied by other cord or column anomalies. PURPOSE: To report on an adult patient with diastematomyelia and discuss the embryological basis and related developmental sequelae of this split-cord malformation. STUDY DESIGN: Case report. METHODS: A summary of the management of a 54-year-old woman with recent clinical symptomatology related to an undiagnosed split-cord malformation is presented with accompanying literature review. RESULTS: A rare adult presentation of diastematomyelia with accompanying intradural extramedullary epidermoid tumor was repaired with resection of the soft-tissue mass and excision of the fibro-osseous septum. CONCLUSION: Initial presentation of diastematomyelia is rarely seen in adults; accompanying pathology includes scoliosis, tethered cord, and intradural tumors. Effective treatment involves identification of the primary pathology.