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The study was conducted to assess the possible impact of spine deformity in patients with idiopathic scoliosis (IS) on tibial nerve somatosensory evoked potentials (t-SSEPs) and the influence of spine correction upon postoperative SSEP recordings. In 61 consecutive patients undergoing 64 spinal instrumentations, 129 pre- and postoperative SSEPs were analyzed. The degree of spine deformity was assessed by the pre-operative Cobb angle of the major scoliotic curve. In a control group, reference values of t-SSEP latencies were established with respect to body height. In a cohort study, IS patients were compared with healthy controls with respect to t-SSEP latency, amplitude, configuration and interside difference. The results of the analysis showed that preoperative-body-height-corrected t-SSEP latencies were prolonged in 61% of patients, with a pathological interside difference in 23.4% of them. The impairment of t-SSEPs was not related to the extent of spine deformity as assessed by the Cobb angle. Even without occurrence of postoperative neurological deficits, postoperative t-SSEPs showed significantly increased latencies without changes in t-SSEP configuration. The prolongation of t-SSEP latencies was related to the surgical procedure (combined ventro-dorsal approach), but not to the extent of spine correction, level of instrumentation, or number of fused segments. The analysis of preoperative t-SSEPs was of no predictive value for intra- or postoperative neurological complications. t-SSEPs are significantly affected in IS patients, although these patients show no obvious clinical neurological deficits. The extent of t-SSEP impairment is not related to the severity of scoliosis. Even in clinically uneventful surgery, the postoperative t-SSEPs can be deteriorated depending on the surgical approach. This indicates a subclinical impact of spine surgery upon spinal cord function.

Unlabelled: Locoregional administration may yield higher tumor drug concentrations compared with intravenous injection and may reduce the risk of systemic adverse effect. Furthermore, in the case of brain tumors, it may circumvent limited drug delivery imposed by the blood-brain barrier. We used PET to study the retention and spatial distribution of iododeoxyuridine (IUdR), which has been used as a DNA-targeting radiosensitizing drug and which can be charged with therapeutic nuclides., Methods: Locoregional (resection cavity, tumor) instillation of 5-19 MBq (124)I-IUdR was achieved in 7 postoperative patients with malignant gliomas through a reservoir implanted in the skull. Patients were scanned with PET during the first hour and at 2, 24, and 48 h after (124)I-IUdR instillation. (124)I-IUdR metabolism was measured in the reservoir fluid in the presence or absence of a degradation inhibitor (5'-butyryl-IUdR [butyryl-IUdR]). Region-of-interest analysis was applied to calculate intratumoral retention (K(local)) of (124)I-IUdR from the PET images after a 24-h washout phase using an autoradiographic method., Results: At 24 h, radioactivity concentration in the reservoir was approximately 1% of the concentration 5 min after tracer instillation. The major metabolite of (124)I-IUdR in the reservoir was (124)I-iodouracil. (124)I-IUdR degradation could be partially inhibited by butyryl-IUdR. In the plasma, radioactivity peaked between 2 and 6 h. The area of tissue radioactivity increased with time up to 3-fold compared with the initial distribution. Tumor (124)I-IUdR retention (K(local)) ranged from 0.006 to 0.017 micro L/g/min, which is substantially lower compared with the IUdR-DNA incorporation reported recently after intravenous injection of (124)I-IUdR (K(i), 3.9 +/- 2.3 micro L/g/min, where K(i) is the DNA incorporation rate of (124)I-IUdR after intravenous tracer injection)., Conclusion: Although a single injection of (124)I-IUdR resulted in radioactivity distribution over the tumor, retention at 24 h was substantially lower compared with intravenous injection of (124)I-IUdR. Slow diffusion after locoregional administration, in contrast to fast delivery via tumor capillaries after intravenous injection, may account for our findings, resulting in a low amount of drug incorporation into DNA before degradation and washout from tissue.

Study Design: To evaluate a potential protective effect of increased creatine levels in spinal cord injury (SCI) in an animal model., Objectives: Acute SCI initiates a series of cellular and molecular events in the injured tissue leading to further damage in the surrounding area. This secondary damage is partly due to ischemia and a fatal intracellular loss of energy. Phospho-creatine in conjunction with the creatine kinase isoenzyme system acts as a potent intracellular energy buffer. Oral creatine supplementation has been shown to elevate the phospho-creatine content in brain and muscle tissue, leading to neuroprotective effects and increased muscle performance., Setting: Zurich, Switzerland., Methods: Twenty adult rats were fed for 4 weeks with or without creatine supplemented nutrition before undergoing a moderate spinal cord contusion., Results: Following an initial complete hindlimb paralysis, rats of both groups substantially recovered within 1 week. However, creatine fed animals scored 2.8 points better than the controls in the BBB open field locomotor score (11.9 and 9.1 points respectively after 1 week; P=0.035, and 13 points compared to 11.4 after 2 weeks). The histological examination 2 weeks after SCI revealed that in all rats a cavity had developed which was comparable in size between the groups. In creatine fed rats, however, a significantly smaller amount of scar tissue surrounding the cavity was found., Conclusions: Thus creatine treatment seems to reduce the spread of secondary injury. Our results favour a pretreatment of patients with creatine for neuroprotection in cases of elective intramedullary spinal surgery. Further studies are needed to evaluate the benefit of immediate creatine administration in case of acute spinal cord or brain injury.

Principles: Intramedullary spinal cord tumours are rare. The long-term results depend on their varying natural histories and the surgical approach. Less extensive tumour resection avoids greater postoperative neurological impairment without a negative impact on postoperative outcome., Methods: Twenty-seven patients who underwent a total of 34 surgical interventions (including 7 reoperations) were clinically and radiologically reinvestigated. Histology revealed 19 glial, 4 nonglial and 4 miscellaneous tumours., Results: Postoperative long-term clinical follow-up (mean 62 months postoperatively) in 25 patients revealed functional improvement in 2 cases, stable conditions in 17 and deterioration in 6. Although there was residual tumour on MRI in 19 of the 22 patients reexamined, stable radiological studies were seen in 15 cases. Despite the high percentage of partial resections or biopsies, good long-term clinical results were found in 19 patients (70%)., Conclusion: The long-term outcome depends on tumour biology and the type of surgery. For low-grade astrocytomas we propose partial resection without incurring the risk of major postoperative neurological deficits, with semi-annual and, after 5 years, annual follow-up. Despite the fact that ependymomas are amenable to complete surgical resection, this was achieved in only one of six cases in this series. Postoperative MRI follow-up of intramedullary tumours must be protracted, as most of these tumours are slow-growing. An increase in the extent and intensity of contrast enhancement of the tumours was defined as tumour recurrence or progressive tumour growth.

P16 and P14ARF are two tumor suppressors encoded by the locus ink4a-arf which is frequently deleted in human tumors. Recent experiments performed with mouse embryonic fibroblasts have shown that P14ARF is an upstream regulator of the P53 pathway. This raises the question as to whether in human tumors the loss of p14arf and mutation of p53 are mutually exclusive events which segregate with genetic alterations at other loci. To examine this question we performed a multigenic analysis on 29 gliomas. We analysed p53 and p14arf in relation with five other genetic loci encoding the most frequently mutated genes in human gliomas: cdkn2a, mdm2, egfr, pten and the chromosomal regions 10q23.3 and 10q25-26. Our study shows for the first time that p53 mutations and p14arf deletions appear mutually exclusive in human glioblastoma, suggesting that they may be functionally redundant in glioma tumorigenesis. The P53 pathway is, therefore, disrupted in 81.8% of malignant gliomas (WHO grades III and IV), either by mutation of the p53 gene (31.8%) or by p14arf deletion (54.5%). These tumors further showed MDM2 overexpression (9.1%), egfr oncogene amplification/egfr overexpression (50%), pten mutations (27.3%) and loss of heterozygosity (LOH) at the chromosomal regions 10q23.3 (86.4%) and 10q25-26 (100%). These alterations did not segregate with p53 mutations or p14arf deletions, while p14arf and cdkn2a were always deleted.

Human gliomas, especially of low-grade type, have been shown to express high-affinity somatostatin receptor type 2 (J-C. Reubi et al., Am. J. Pathol, 134: 337-344, 1989). We enrolled seven low-grade and four anaplastic glioma patients in a pilot study using the diffusible peptidic vector 90Y-labeled DOTA0-D-Phe1-Tyr3-octreotide (DOTATOC) for receptor targeting. The radiopharmakon was locoregionally injected into a stereotactically inserted Port-a-cath. DOTATOC competes specifically with somatostatin binding to somatostatin receptor type 2 in the low nanomolar range as shown by a displacement curve of 125I-[Tyr3]-octreotide in tumor tissue sections. Diagnostic (111)In-labeled DOTATOC-scintigraphy following local injection displayed homogeneous to nodular intratumoral vector distribution. The cumulative activity of regionally injected peptide-bound 90Y amounted to 370-3300 MBq, which is equivalent to an effective dose range between 60 +/- 15 and 550 +/- 110 Gy. Activity was injected in one to four fractions according to tumor volumes; 1110 MBq of 90Y-labeled DOTATOC was the maximum activity per single injection. We obtained six disease stabilizations and shrinking of a cystic low-grade astrocytoma component. The only toxicity observed was secondary perifocal edema. The activity:dose ratio (MBq:Gy) represents a measure for the stability of peptide retention in receptor-positive tissue and might predict the clinical course. We conclude that SR-positive human gliomas, especially of low-grade type, can be successfully targeted by intratumoral injection of the metabolically stable small regulatory peptide DOTATOC.

We analyzed the biodistribution of the 111In-labelled murine anti-tenascin-C MAb BC-2 after intralesional injection in 15 glioblastoma patients. The activated ligand DTPA was conjugated via the isothiocyanato-benzyl group onto BC-2. Conjugates were labelled with 111In, displaying immunoreactivity greater than 90% and labelling efficiency of 99 +/- 1%. In contrast to i.v. injections, excellent tumor uptake was obtained by direct intralesional injection of conjugates that showed only slow systemic release. In serum, conjugates were found to be intact; in urine, only low-molecular-weight decay products were detected. In 8 patients, outflow from the site of injection into systemic circulation was low; daily activity in the serum and urine was found to be below 2% of the total injected radioactivity; most of the injected activity was retained within the tumor, resulting in effective half-lives of 58 +/- 5 hr. In contrast, higher outflow up to 10% of regionally injected 111In-DTPA-BC-2 MAb into systemic circulation resulted in considerable shortening of the effective half-lives to 20 to 40 hr in 7 patients. This outflow was found to correlate with tumor size and blood/brain barrier disruption. In one patient, HPLC analysis of tumor cyst fluid 3 and 6 days after intralesional injection revealed conjugates to be intact and allowed the estimate of about 70% of the total injected 111In-DTPA-BC-2 to be confined to tumor tissue. We conclude that different outflow patterns can be observed following locoregional injection of 111In-DTPA-BC-2, leading to considerable variations in the effective half-lives of isotopes within the tumor, requiring adjustment of the radiation dose in therapeutic trials.

History and Clinical Findings: A 73-year-old woman was admitted because of vertigo of recent onset with a tendency to fall down and progressive hearing impairment with tinnitus over the last 2 years. Neurological examination also revealed right recurrent nerve paresis, facial hemispasm and lingual atrophy, pointing to a lesion involving cranial nerves VII, VIII, IX, X and XII. She was found to have spontaneous nystagmus to the left, due to peripheral vestibular function deficit, without otoscopic abnormalities. She was in atrial fibrillation with a blood pressure of 140/80 mm Hg. The suspected cause was a hormonally active glomus jugulare tumour with intermittent hypertension and involvement of several cranial nerves., Investigations: Repeatedly measured plasma and urinary catecholamine concentration was normal. Neuroradiology showed a contrast-rich lesion close to the jugular vein and the hypoglossal nerve, as well as a tumour in the left retromandibular fossa with displacement of the left internal carotid artery. The suspected cause of these findings was a neurologically asymptomatic left carotid body tumour with multiple cranial nerve deficits (VII, VIII, IX and XII) due to their compression at the base of the skull. No abnormal catecholamine activity could be demonstrated., Treatment and Course: After complete excision of the right carotid body there were no further hypertensive crises. Later on the left carotid body tumour was embolised because it had continued to grow., Conclusion: The repeated hypertensive crises were probably caused by absent blood pressure regulation, the result of destruction of the afferent fibres. This destruction was due to compression of the hypoglossal nerve by the right jugular glomus, at the same time as the contralateral carotid body had been destroyed by tumour.