Osseous Pseudoprogression in Vertebral Bodies Treated with Stereotactic Radiosurgery: A Secondary Analysis of Prospective Phase I/II Clinical Trials.

BACKGROUND AND PURPOSE: Osseous pseudoprogression on MR imaging can mimic true progression in lesions treated with spine stereotactic radiosurgery. Our aim was to describe the prevalence and time course of osseous pseudoprogression to assist radiologists in the assessment of patients after spine stereotactic radiosurgery. MATERIALS AND METHODS: A secondary analysis of 2 prospective trials was performed. MRIs before and after spine stereotactic radiosurgery were assessed for response. "Osseous pseudoprogression" was defined as transient growth in signal abnormality centered at the lesion with a sustained decline on follow-up MR imaging that was not attributable to chemotherapy. RESULTS: From the initial set of 223 patients, 37 lesions in 36 patients met the inclusion criteria and were selected for secondary analysis. Five of the 37 lesions (14%) demonstrated osseous pseudoprogression, and 9 demonstrated progressive disease. There was a significant association between single-fraction therapy and the development of osseous pseudoprogression (P = .01), and there was a significant difference in osseous pseudoprogression-free survival between single- and multifraction regimens (P = .005). In lesions demonstrating osseous pseudoprogression, time-to-peak size occurred between 9.7 and 24.4 weeks after spine stereotactic radiosurgery (mean, 13.9 weeks; 95% CI, 8.6-19.1 weeks). The peak lesion size was between 4 and 10 mm larger than baseline. Most lesions returned to baseline size between 23 and 52.4 weeks following spine stereotactic radiosurgery. CONCLUSIONS: Progression on MR imaging performed between 3 and 6 months following spine stereotactic radiosurgery should be treated with caution because osseous pseudoprogression may be seen in more than one-third of these lesions. Single-fraction spine stereotactic radiosurgery may be associated with osseous pseudoprogression. The possibility of osseous pseudoprogression should be incorporated into the prospective criteria for assessment of local control following spine stereotactic radiosurgery.

Total en bloc lumbar spondylectomy. Case report.

The authors describe a technique for total en bloc spondylectomy that can be used for lesions involving the lumbar spine. The technique involves a combined anterior-posterior approach and takes into account the unique anatomy of the lumbar spine. This technique allows for the en bloc resection of lumbar vertebral tumors, thus optimizing outcome while minimizing the risk of neurological injury. The technique is described in detail with the aid of neuroimaging studies, photographs of gross pathological specimens, and illustrations, and a discussion of other authors' experiences is provided for comparison.

Prevention and reversal of experimental posthemorrhagic vasospasm by the periadventitial administration of nitric oxide from a controlled-release polymer.

OBJECTIVE: Despite improvements in the care of patients with aneurysmal subarachnoid hemorrhage, delayed cerebral vasospasm remains a major cause of morbidity and death. There is now evidence that a decrease in the local availability of nitric oxide (NO) plays a role in delayed cerebral vasospasm. We evaluated a controlled-release polymer containing the NO donor (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA/NO) for the treatment of chronic posthemorrhagic vasospasm in the rat femoral artery model. METHODS: The release kinetics of ethylene/vinyl acetate copolymers loaded with 20% (w/w) DETA/NO were determined in vitro. Chronic vasospasm was induced in the left femoral artery of adult male Fischer 344 rats (n = 35) by exposure to autologous blood. At 1, 3, or 7 days after blood exposure, either a 5-mg polymer loaded with 20% (w/w) DETA/NO or an empty 5-mg polymer was placed in the periadventitial space next to the left femoral artery. At the same time, an empty 5-mg polymer was placed next to the right femoral artery. On the 8th day after blood exposure (at the peak of vasospasm in this model), rats were transcardially perfused with 4% paraformaldehyde, and the left and right femoral arteries were removed for histological processing and morphometric analyses. Vasospasm was expressed as the percent lumen patency of the treated left artery, compared with the control right artery. RESULTS: The in vitro release kinetics demonstrated that the 20% DETA/NO-loaded polymers released up to 15% of their total drug load during a 9-day period. DETA/NO treatments initiated at 1, 3, or 7 days after blood deposition all significantly inhibited vasospasm, compared with control values (94.6 +/- 7.2% versus 67.6 +/- 5.8%, 104.6 +/- 5.5% versus 64.9 +/- 1.7%, and 102.4 +/- 5.1% versus 73.6 +/- 1.4%, respectively; mean +/- standard error of the mean percent lumen patency; P < 0.001). No adverse effects of treatment were observed. CONCLUSION: The diazeniumdiolate NO donor DETA/NO can be effectively released from ethylene/vinyl acetate polymers. Administration of DETA/NO into the periadventitial space can prevent the development of chronic posthemorrhagic vasospasm in the rat femoral artery and can reverse established vasospasm. No adverse effects of DETA/NO were observed in this model.

Simultaneous anterior-posterior approach to the thoracic and lumbar spine for the radical resection of tumors followed by reconstruction and stabilization.

OBJECT: Thoracic or lumbar spine malignant tumors involving both the anterior and posterior columns represent a complex surgical problem. The authors review the results of treating patients with these lesions in whom surgery was performed via a simultaneous anterior-posterior approach. METHODS: The hospital records of 26 patients who underwent surgery via simultaneous combined approach for thoracic and lumbar spinal tumors at our institution from July 1994 to March 2000 were reviewed. Surgery was performed with the patients in the lateral decubitus position for the procedure. The technical details are reported. The mean survival determined by Kaplan-Meier analysis was 43.4 months for the 15 patients with primary malignant tumors and 22.5 months for the 11 patients with metastatic spinal disease. At 1 month after surgery, 23 (96%) of 24 patients who complained of pain preoperatively reported improvements (p < 0.001, Wilcoxon signed-rank test), and eight (62%) of 13 patients with preoperative neurological deficits were functionally improved (p = 0.01). There were nine major complications, five minor complications, and no deaths within 30 days of surgery. Two patients (8%) later underwent surgery for recurrent tumor. CONCLUSIONS: The simultaneous anterior-posterior approach is a safe and feasible alternative for the exposure tumors of the thoracic and lumbar spine that involve both the anterior and posterior columns. Advantages of the approach include direct visualization of adjacent neurovascular structures, the ability to achieve complete resection of lesions involving all three columns simultaneously (optimizing hemostasis), and the ability to perform excellent dorsal and ventral stabilization in one operative session.

O6-benzylguanine potentiates the antitumor effect of locally delivered carmustine against an intracranial rat glioma.

Local delivery of carmustine (BCNU) via biodegradable polymers prolongs survival against experimental brain tumors and in human clinical trials. O6-benzylguanine (O6-BG), a potent inhibitor of the DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGT), has been shown to reduce nitrosourea resistance and, thus, enhance the efficacy of systemic BCNU therapy in a variety of tumor models. In this report, we demonstrate that O6-BG can potentiate the activity of BCNU delivered intracranially via polymers in rats challenged with a lethal brain tumor. Fischer 344 rats received a lethal intracranial challenge of 100,000 F98 glioma cells (F98 cells have significant AGT activity, 328 fmol/mg protein). Five days later, animals receiving an i.p. injection of O6-BG (50 mg/kg) 2 h prior to BCNU polymer (3.8% BCNU by weight) implantation had significantly improved survival (n = 7; median survival, 34 days) over animals receiving either O6-BG alone (n = 7; median survival, 22 days; P = 0.0002) or BCNU polymer alone (n = 8; median survival, 25 days; P = 0.0001). Median survival for the control group (n = 8) was 23.5 days. Moreover, there was no physical, behavioral, or pathological evidence of treatment-related toxicity. These findings suggest that O6-BG can potentiate the effects of interstitially delivered BCNU and, for tumors expressing significant AGT, may be necessary for the BCNU to provide a meaningful therapeutic benefit. Given the clinical use of BCNU polymers against malignant gliomas, concurrent treatment with O6-BG may provide an important addition to our therapeutic armamentarium.

Paracrine delivery of IL-12 against intracranial 9L gliosarcoma in rats.

OBJECT: Interleukin-12 (IL- 12) has potential for the treatment of tumors because it can stimulate an antitumor immune response and possesses antiangiogenic properties. In the study reported here, the authors investigated the therapeutic role of locally delivered IL-12 in a malignant brain tumor model. METHODS: After genetically engineering 9L gliosarcoma cells to express IL-12 (9L-IL12 cells), the authors used these cells as a source of locally delivered cytokine. First, they investigated the behavior of these cells, which were implanted with the aid of stereotactic guidance into the rat brain, by using serial magnetic resonance imaging and histopathological examination. Second, they assessed the antitumor efficacy of proliferating, as well as nonproliferating (irradiated), 9L-IL12 cells by implanting these cells in animals challenged by wild-type 9L gliosarcoma (9Lwt) cells. The IL-12 expression in brain regions injected with 9L-IL12 was confirmed by reverse transcription-polymerase chain reaction. Last, the authors explored whether animals treated with 9L-IL12 cells developed an antitumor immunological memory by rechallenging the survivors with a second injection of 9Lwt cells. The authors demonstrated that local delivery of IL-12 into the rat brain by genetically engineered cells significantly prolongs survival time in animals challenged intracranially with a malignant glioma. CONCLUSIONS: These findings support continued efforts to refine local delivery systems of IL-12 in an attempt to bring this therapy to clinical trials.

Late-onset facial nerve degeneration after vestibular schwannoma surgery: incidence, putative mechanisms, and prevention.

Delayed facial nerve dysfunction after vestibular schwannoma surgery is a poorly understood phenomenon that has been reported to occur in 15 to 29% of patients undergoing microsurgery. It is a condition characterized by spontaneous deterioration of facial nerve function in a patient who has otherwise normal or near-normal facial function in the immediate postoperative period. This delayed paralysis is generally reported to occur in the first few days postsurgery, with the majority of patients eventually recovering their immediate postoperative facial function. However, infrequently, it can also occur more than 1 week after surgery (so-called late-onset facial nerve palsy). The authors reviewed facial nerve outcome in 611 patients who underwent microsurgery between 1973 and 1994. The facial nerve was anatomically preserved in 596 patients (97.5%), and 90% of patients had House-Brackmann[6] Grade 1 or 2 function 1 year after surgery. Late-onset facial dysfunction was seen in 13 patients (2.1%). All of these had significant deterioration in facial nerve function between 1 and 4 weeks postoperatively, and all showed improvement by 1 year. In this study, the focus on these patients who developed late-onset facial palsy. The incidence, treatment strategies, and outcomes will be discussed with emphasis on possible pathophysiological mechanisms that contribute to this relatively rare condition.

Coherent network oscillations by olfactory interneurons: modulation by endogenous amines.

1. The procerebral (PC) lobe of the terrestrial mollusk Limax maximus contains a highly interconnected network of local olfactory interneurons that receives direct axonal projections from the two pairs of noses. This olfactory processing network generates a 0.7-Hz oscillation in its local field potential (LFP) that is coherent throughout the network. The oscillating LFP is modulated by natural odorants applied to the neuroepithelium of the superior nose. 2. Two amines known to be present in the PC lobe, dopamine and serotonin, increase the frequency of the PC lobe oscillation and alter its waveform. 3. Glutamate, another putative neurotransmitter known to be present in the lobe, suppresses the PC lobe oscillation by a quisqualate-type receptor and appears to be used by one of the two classes of neurons in the PC lobe to generate the basic LFP oscillation. 4. The known activation of second messengers in Limax PC lobe by dopamine and serotonin together with their effects on the oscillatory rhythm suggest the hypothesis that these amines augment mechanisms mediating synaptic plasticity in the olfactory network, similar to hypothesized effects of amines in vertebrate olfactory systems. 5. The use of a distributed network of interneurons showing coherent oscillations may relate to the highly developed odor recognition and odor learning ability of Limax.

Cultured olfactory interneurons from Limax maximus: optical and electrophysiological studies of transmitter-evoked responses.

1. The olfactory processing network in the procerebral (PC) lobe of the terrestrial mollusk Limax maximus exhibits a coherent oscillation of local field potential that is modulated by odor input. To understand the cellular basis of this oscillation, we developed a cell culture preparation of isolated PC neurons and studied the responses of isolated cells to stimulation with neurotransmitters known to be present in the PC lobe. 2. The distribution of PC soma diameters suggests at least two different populations of neurons. Approximately 95% of isolated cells had soma diameters of 7-8 microns, with the remaining cells having larger diameters (10-15 microns). 3. Extracellular measurements of action potentials and optical measurements of intracellular calcium concentrations in fura-2-loaded cells were made. Serotonin and dopamine excited PC neurons and promoted transitions from steady to bursty activity. Both amines elicited increases in intracellular calcium, presumably concomitant with the increase in action-potential frequency. 4. Glutamate suppressed action-potential firing and reduced intracellular calcium. This effect was seen most clearly when glutamate was applied to cells excited by high potassium medium. Quisqualate is an effective glutamate agonist in this system, whereas kainate is not. 5. Combined with anatomic and biochemical data and with studies of the effects of these neurotransmitters on the oscillating local field potential of the intact PC network, the data from isolated PC neurons are consistent with the hypothesis that dopamine and serotonin modulate network dynamics, whereas glutamate is involved in generating the basic oscillation of local field potential in the PC. 6. The optical studies of fura-2-loaded cells showed that several treatments that increase the rate of action-potential production lead to elevations in intracellular calcium. Optical studies of intracellular calcium may be useful for multisite measurements of activity in the intact, oscillating PC lobe network.