✓ Previously these authors and others demonstrated frequent homozygous deletions of the chromosome 9p—localized class I interferon (IFN) gene cluster in glioblastoma tumors and cell lines. To investigate the biological effects of class I IFN gene transfer and constitutive expression in glioblastoma cells devoid of this gene cluster, the authors have developed a stable IFN “transfectant” of the cell line U118. The expression of IFNα protein in the U118 transfectant clone is associated with decreased levels of DNA synthesis exhibited by cultures of transfected cells, reduced colony-forming ability in soft agar, and loss of tumorigenicity in athymic nude mice. To address the molecular consequences of constitutive IFNα synthesis, they examined the expression of four genes whose transcription has been shown to be responsive to IFN-mediated signal transduction and could be important to the observed antiproliferative and antitumor effects. Northern blot analysis revealed that changes in the levels of messenger (m)RNA for two of these genes, c-myc and mhc class I, are minor. However, mRNAs for oligoadenylate synthetase (OAS) as well as double-stranded RNA-activated protein kinase (PKR), which are not expressed in parental U118 cells, were constitutively express ed in IFNα transfectants. These results indicate a differential responsiveness among these four genes to constitutive IFNα expression, and suggest that the suppression of U118-transformed phenotypes by IFNα transfection may be mediated by the induction of specific IFN response genes thought to have a negative growth-regulatory function.
Ju He, Jeffrey J. Olson, A. Jonas Ekstrand, Andrei Serbanescu, Jing Yang, Margaret K. Offermann and C. David James
James B. Stubbs, Roger H. Frankel, Karl Schultz, Ian Crocker, Dirck Dillehay and Jeffrey J. Olson
Object. The objectives of this study were to evaluate the safety and performance of a new brachytherapy applicator in the treatment of resected brain tumors in a canine model.
Methods. The brachytherapy applicator is an inflatable balloon catheter that is implanted in the resection cavity remaining after a brain tumor has been debulked. After implantation the balloon is inflated with Iotrex, a sterile solution containing organically bound iodine-125. The low-energy photons emitted by the iodine-125 deposit a therapeutic radiation dose across short distances from the surface of the balloon. After delivery of a prescribed radiation dose to the targeted volume, the radioactive fluid is retrieved and the catheter removed.
Small resections of the right frontal lobe were performed in large dogs. Magnetic resonance (MR) images were obtained and used to assess tissue response and to measure the conformance between the resection cavity wall and the balloon surface. In four animals a dose ranging from 36 to 59 Gy was delivered. Neurological status and histological characteristics of the brain were assessed in all dogs.
Implantation and explantation as well as inflation and deflation of the device were easily accomplished and well tolerated. The device was easily visualized on MR images, which demonstrated the expected postsurgical changes. The resection cavity and the balloon were highly conformal (range 93–100%). Histological changes to the cavity margin were consistent with those associated with surgical trauma. Additionally, radiation-related changes were observed at the margins of the resection cavity in dogs in which the brain was irradiated.
Conclusions. This balloon catheter and 125I radiotherapy solution system can safely and reliably deliver radiation to the margins of brain cavities created by tumor resection. Results of this study showed that intracranial pressure changes due to balloon inflation and deflation were unremarkable and characteristic of the imaging properties and radiation safety profile of the device prior to its clinical evaluation. Clinically relevant brachytherapy (adequate target volume and total dose) was accomplished in all four animals subjected to treatment.
Stephen B. Tatter, Edward G. Shaw, Mark L. Rosenblum, Kastytis C. Karvelis, Lawrence Kleinberg, Jon Weingart, Jeffrey J. Olson, Ian R. Crocker, Steven Brem, James L. Pearlman, Joy D. Fisher, Kathryn A. Carson, Stuart A. Grossman and other members of The New Approaches to Brain Tumor Therapy Central Nervous System Consortium
Object. In this study the authors evaluated the safety and performance of the GliaSite Radiation Therapy System (RTS) in patients with recurrent malignant brain tumors who were undergoing tumor resection.
Methods. The GliaSite is an inflatable balloon catheter that is placed in the resection cavity at the time of tumor debulking. Low-dose-rate radiation is delivered with an aqueous solution of organically bound iodine-125 (Iotrex [sodium 3-(125I)-iodo-4-hydroxybenzenesulfonate]), which are temporarily introduced into the balloon portion of the device via a subcutaneous port. Adults with recurrent malignant glioma underwent resection and GliaSite implantation. One to 2 weeks later, the device was filled with Iotrex for 3 to 6 days, following which the device was explanted. Twenty-one patients with recurrent high-grade astrocytomas were enrolled in the study and received radiation therapy. There were two end points: 1) successful implantation and delivery of brachytherapy; and 2) safety of the device.
Implantation of the device, delivery of radiation, and the explantation procedure were well tolerated. At least 40 to 60 Gy was delivered to all tissues within the target volume. There were no serious adverse device-related events during brachytherapy. One patient had a pseudomeningocele, one patient had a wound infection, and three patients had meningitis (one bacterial, one chemical, and one aseptic). No symptomatic radiation necrosis was identified during 21.8 patient-years of follow up. The median survival of previously treated patients was 12.7 months (95% confidence interval 6.9–15.3 months).
Conclusions. The GliaSite RTS performs safely and efficiently. It delivers a readily quantifiable dose of radiation to tissue at the highest risk for tumor recurrence.
Salah G. Aoun, Sonja E. Stutzman, Phuong-Uyen N. Vo, Tarek Y. El Ahmadieh, Mohamed Osman, Om Neeley, Aaron Plitt, James P. Caruso, Venkatesh Aiyagari, Folefac Atem, Babu G. Welch, Jonathan A. White, H. Hunt Batjer and Daiwai M. Olson
Cerebral vasospasm causing delayed cerebral ischemia (DCI) is a source of significant morbidity after subarachnoid hemorrhage (SAH). Transcranial Doppler is used at most institutions to detect sonographic vasospasm but has poor positive predictive value for DCI. Automated assessment of the pupillary light reflex has been increasingly used as a reliable way of assessing pupillary reactivity, and the Neurological Pupil Index (NPi) has been shown to decrease hours prior to the clinical manifestation of ischemic injury or herniation syndromes. The aim of this study was to investigate the role of automated pupillometry in the setting of SAH, as a potential adjunct to TCD.
Our analysis included patients that had been diagnosed with aneurysmal SAH and admitted to the neuro–intensive care unit of the University of Texas Southwestern Medical Center between November 2015 and June 2017. A dynamic infrared pupillometer was used for all pupillary measurements. An NPi value ranging from 3 to 5 was considered normal, and from 0 to 2.9 abnormal. Sonographic vasospasm was defined as middle cerebral artery velocities greater than 100 cm/sec with a Lindegaard ratio greater than 3 on either side on transcranial Doppler. Most patients had multiple NPi readings daily and we retained the lowest value for our analysis. We aimed to study the association between DCI and sonographic vasospasm, and DCI and NPi readings.
A total of 56 patients were included in the final analysis with 635 paired observations of daily TCD and NPi data. There was no statistically significant association between the NPi value and the presence of sonographic vasospasm. There was a significant association between DCI and sonographic vasospasm, χ2(1) = 6.4112, p = 0.0113, OR 1.6419 (95% CI 1.1163–2.4150), and between DCI and an abnormal decrease in NPi, χ2(1) = 38.4456, p < 0.001, OR 3.3930 (95% CI 2.2789–5.0517). Twelve patients experienced DCI, with 7 showing a decrease of their NPi to an abnormal range. This change occurred > 8 hours prior to the clinical decline 71.4% of the time. The NPi normalized in all patients after treatment of their vasospasm.
Isolated sonographic vasospasm does not seem to correlate with NPi changes, as the latter likely reflects an ischemic neurological injury. NPi changes are strongly associated with the advent of DCI and could be an early herald of clinical deterioration.
Eva M. Wu, Tarek Y. El Ahmadieh, Benjamin Kafka, James P. Caruso, Om J. Neeley, Aaron R. Plitt, Salah G. Aoun, Daiwai Olson, Robert A. Ruchinskas, C. Munro Cullum, Babu G. Welch, H. Hunt Batjer and Jonathan A. White
Objective assessment tests are commonly used to predict the response to ventriculoperitoneal (VP) shunting in patients with normal pressure hydrocephalus (NPH). Whether subjective reports of improvement after a lumbar drain (LD) trial can predict response to VP shunting remains controversial. The goal in this study was to compare clinical characteristics, complication rates, and shunt outcomes of objective and subjective LD responders who underwent VP shunt placement.
This was a retrospective review of patients with NPH who underwent VP shunt placement after clinical improvement with the LD trial. Patients who responded after the LD trial were subclassified into objective LD responders and subjective LD responders. Clinical characteristics, complication rates, and shunt outcomes between the 2 groups were compared with chi-square test of independence and t-test.
A total of 116 patients received a VP shunt; 75 were objective LD responders and 41 were subjective LD responders. There was no statistically significant difference in patient characteristics between the 2 groups, except for a shorter length of stay after LD trial seen with subjective responders. The complication rates after LD trial and VP shunting were not significantly different between the 2 groups. Similarly, there was no significant difference in shunt response between objective and subjective LD responders. The mean duration of follow-up was 1.73 years.
Reports of subjective improvement after LD trial in patients with NPH can be a reliable predictor of shunt response. The currently used objective assessment scales may not be sensitive enough to detect subtle changes in symptomatology after LD trial.
Tarek Y. El Ahmadieh, Eva M. Wu, Benjamin Kafka, James P. Caruso, Om J. Neeley, Aaron Plitt, Salah G. Aoun, Daiwai M. Olson, Robert A. Ruchinskas, C. Munro Cullum, Samuel Barnett, Babu G. Welch, H. Hunt Batjer and Jonathan A. White
A short-term lumbar drain (LD) trial is commonly used to assess the response of normal pressure hydrocephalus (NPH) patients to CSF diversion. However, it remains unknown whether the predictors of passing an LD trial match the predictors of improvement after ventriculoperitoneal shunting. The aim of this study was to examine outcomes, complication rates, and associations between predictors and outcomes after an LD trial in patients with NPH.
The authors retrospectively reviewed the records of 254 patients with probable NPH who underwent an LD trial between March 2008 and September 2017. Multivariate regression models were constructed to examine predictors of passing the LD trial. Complications associated with the LD trial procedure were recorded.
The mean patient age was 77 years and 56.7% were male. The mean durations of gait disturbance, cognitive decline, and urinary incontinence were 29 months, 32 months, and 28 months, respectively. Of the 254 patients, 30% and 16% reported objective and subjective improvement after the LD trial, respectively. Complications included a sheared LD catheter, meningitis, lumbar epidural abscess, CSF leak at insertion site, transient lower extremity numbness, slurred speech, refractory headaches, and hyponatremia. Multivariate analyses using MAX-R revealed that a prior history of stroke predicted worse outcomes, while disproportionate subarachnoid spaces (uneven enlargement of supratentorial spaces) predicted better outcomes after the LD trial (r2 = 0.12, p < 0.05).
The LD trial is generally safe and well tolerated. The best predictors of passing the LD trial include a negative history of stroke and having disproportionate subarachnoid spaces.