Diagnostic Accuracy of PET, SPECT, and Arterial Spin-Labeling in Differentiating Tumor Recurrence from Necrosis in Cerebral Metastasis after Stereotactic Radiosurgery.

BACKGROUND AND PURPOSE: Radiographic assessment of cerebral metastasis after stereotactic radiosurgery remains a major challenge in neuro-oncology. It is often difficult to distinguish tumor progression from radiation necrosis in this setting using conventional MR imaging. The objective of this study was to compare the diagnostic sensitivity and specificity of different functional imaging modalities for detecting tumor recurrence after stereotactic radiosurgery. MATERIALS AND METHODS: We retrospectively reviewed patients treated between 2007 and 2010 and identified 14 patients with cerebral metastasis who had clinical or radiographic progression following stereotactic radiosurgery and were imaged with arterial spin-labeling, FDG-PET, and thallium SPECT before stereotactic biopsy. Diagnostic accuracy, specificity, sensitivity, positive predictive value, and negative predictive value were calculated for each imaging technique by using the pathologic diagnosis as the criterion standard. RESULTS: Six patients (42%) had tumor progression, while 8 (58%) developed radiation necrosis. FDG-PET and arterial spin-labeling were equally sensitive in detecting tumor progression (83%). However, the specificity of arterial spin-labeling was superior to that of the other modalities (100%, 75%, and 50%, respectively). A combination of modalities did not augment the sensitivity, specificity, positive predictive value, or negative predictive value of arterial spin-labeling. CONCLUSIONS: In our series, arterial spin-labeling positivity was closely associated with the pathologic diagnosis of tumor progression after stereotactic radiosurgery. Validation of this finding in a large series is warranted.

Expression of cellular adhesion molecule 'OPCML' is down-regulated in gliomas and other brain tumours.

The four GPI-anchored cell adhesion molecules that exemplify the IgLON family are most highly expressed in the nervous system and associate to form up to six different heterodimeric 'Diglons' that can modify cell adhesion and inhibit axon migration. Recently, two members, OPCML and LSAMP, were identified as putative tumour suppressor genes in ovarian and renal carcinomas respectively. In this study, we investigated OPCML expression in nonneoplastic brain tissue and 35 brain tumours (18 glioblastoma multiformes, five anaplastic gliomas, five meningiomas, six metastases and one medulloblastoma) and four glioma cell lines using quantitative reverse transcriptase polymerase chain reaction (RT-PCR). OPCML was highly expressed in cerebellum, less so in cerebral cortex, frontal lobe and meninges and was significantly reduced or absent in 83% of brain tumours and all cell lines compared with nonneoplastic whole brain. Two OPCML splice variants have been identified in humans, termed alpha1 and alpha2, but the latter has not been demonstrated in human neural tissues. Using PCR with specific primers, nonneoplastic brain and 3/6 of tested brain tumours expressed both splice variants, whereas the remaining brain tumours only expressed the alpha2 variant. Hypermethylation of the alpha1 OPCML promoter, associated with down-regulation of expression in ovarian tumours, did not correlate with expression levels in the subset of brain tumours tested, implying transcription of OPCML from an alternative promoter or a different mechanism of down-regulation. This study demonstrates that OPCML down-regulation occurs in the majority of brain tumours tested, warranting further investigation of OPCML and other IgLONs in the development and progression of brain tumours.

Genetic and metabolic predictors of chemosensitivity in oligodendroglial neoplasms.

The -1p/-19q genotype predicts chemosensitivity in oligodendroglial neoplasms, but some with intact 1p/19q also respond and not all with 1p/19q loss derive durable benefit from chemotherapy. We have evaluated the predictive and prognostic significance of pretherapy (201)Tl and (18)F-FDG SPECT and genotype in 38 primary and 10 recurrent oligodendroglial neoplasms following PCV chemotherapy. 1p/19q loss was seen in 8/15 OII, 6/15 OAII, 7/7 OIII, 3/11 OAIII and was associated with response (Fisher-Exact: P=0.000) and prolonged progression-free (log-rank: P=0.002) and overall survival (OS) (log-rank: P=0.0048). Response was unrelated to metabolism, with tumours with high or low metabolism showing response. Increased (18)F-FDG or (201)Tl uptake predicted shorter progression-free survival (PFS) in the series (log-rank: (201)Tl P=0.0097, (18)F-FDG P=0.0170) and in cases with or without the -1p/-19q genotype. Elevated metabolism was associated with shorter OS in cases with intact 1p/19q (log-rank: (18)F-FDG P=0.0077; (201)Tl P=0.0004) and shorter PFS in responders (log-rank: (18)F-FDG P=0.005; (201)Tl P=0.0132). (201)Tl uptake and 1p/19q loss were independent predictors of survival in multivariate analysis. In this initial study, (201)Tl and (18)F-FDG uptake did not predict response to PCV, but may be associated with poor survival following therapy irrespective of genotype. This may be clinically useful warranting further study.

Clinical use of genotype to predict chemosensitivity in oligodendroglial tumors.

BACKGROUND: The -1p/-19q genotype has been associated with prolonged survival and chemosensitivity in oligodendroglial neoplasms, but the predictive and prognostic significance of genotype in the routine clinic is not established. METHODS: The authors investigated allelic imbalance in 1p36, 19q13, 17p13, 10p12-15, and 10q22-26 and p53 mutation in a cohort representative of clinical practice at their center (50 primary, 26 recurrent cases) given PCV chemotherapy between 2000 and 2003 and compared with response and outcome following PCV. RESULTS: 1p/19q loss was found in 12/19 OII, 10/23 OAII, 11/13 OIII, and 6/21 OAIII. Response, seen in 92% with 1p/19q loss, was associated with the -1p/-19q genotype (Fisher exact: p < 0.001) regardless of WHO grade or whether primary or recurrent. 1p/19q loss was an independent prognostic factor associated with longer progression-free (PFS) and overall survival (OS) (Cox regression: PFS and OS p < 0.001), with greater impact on PFS than OS in primary tumors, and OS at recurrence. 17p13 loss and p53 mutation were associated with poor prognosis in recurrent tumors and chromosome 10 loss was associated with short PFS and OS in primary tumors. Histologic subtype did not influence outcome in tumors of equivalent genotype. Genotype had greater association with response and outcome than conventional clinical factors. A total of 29% with intact 1p/19q and a variety of genetic or clinicopathologic characteristics responded in association with increased PFS and OS. CONCLUSIONS: The -1p/-19q genotype predicted response and favorable outcome following PCV chemotherapy corroborating genetic analysis to guide routine clinical management. However, some cases with intact 1p/19q also had clinical benefit.

MRS of oligodendroglial tumors: correlation with histopathology and genetic subtypes.

BACKGROUND: Oligodendroglial neoplasms with combined loss of chromosomes 1p and 19q may have a good prognosis and respond to procarbazine-lomustine (CCNU)-vincristine (PCV) chemotherapy. OBJECTIVE: To determine whether single voxel magnetic resonance spectroscopy (SV-MRS) obtained through routine clinical practice distinguishes between histopathologic and genetic subtypes of oligodendroglial tumors. METHODS: Forty-eight patients with oligodendroglial tumors (19 oligodendrogliomas and 29 oligoastrocytomas) underwent molecular genetic analysis to determine allelic imbalance in chromosomes 1p36 and 19q13. SV-MRS was obtained pretherapy to determine tumor metabolite ratios. RESULTS: Grade III oligodendroglial tumors had higher choline (Mann-Whitney; p = 0.002), methyl lipid (Mann-Whitney; p = 0.002), and combined methylene lipid and lactate ratios (Mann-Whitney; p < 0.001) than grade II tumors. Lactate did not distinguish between tumor types (Fisher exact test; p = 0.342) or grade (Fisher exact test; p = 0.452). There were no significant associations when tumors were analyzed according to histopathology or genetic subtypes. CONCLUSION: As a noninvasive diagnostic tool used in routine clinical practice, SV-MRS has the potential benefit of determining oligodendroglial tumor grade but not subtypes classified by histopathology or molecular genetics. MRS may be useful for determining the timing of therapy but is unlikely to predict chemosensitivity.

Interstitial radiosurgery in the treatment of gelastic epilepsy due to hypothalamic hamartomas.

The authors evaluated a new stereotactic radiosurgical approach in seven patients with gelastic epilepsy due to hypothalamic hamartomas. Stereotactic implantation of 125I-seeds into the hamartoma was feasible in six patients. At follow-up at least 1 year after interstitial radiotherapy, two patients had become seizure-free within 2 months, and two others had only persisting auras. There were no major perioperative or postoperative side effects.

Stereotactic volumetric resection of gliomas.

The aim of stereotactic volumetric resection of intrinsic brain tumors at the time of design of the method was a most radical and complete resection of all tumor tissue while reducing morbidity by using minimally invasive approaches. This should also using the precision and accuracy of stereotaxis allow for resection of deep-seated tumors previously believed to be unresectable. Numerous retrospective studies have been performed and have shown that radical resection is feasible using this methodology and even so in eloquent brain areas. Whereas in malignant gliomas there is no proof of increased survival or time-to-progression after stereotactic volumetric resection quite favourable results have been obtained in deep-seated low grade gliomas. What the actual role of this modality is in comparison to other forms of local treatment of circumscribed CNS lesions remains to be open in view of the lack of comparative studies.

Interstitial stereotactic radiosurgery.

Stereotactic radiosurgery by means of interstitial application of either radionuclides or radiation devices has been used extensively in primary and secondary brain tumors. A few centers have gained sufficient expertise and clinical data to scientifically evaluate this treatment modality. Interstitial stereotactic radiosurgery is limited to circumscribed lesions with a diameter of 3.5 cm or less. The radiobiology of interstitial radiosurgery is quite well elaborated as to doses, dose rates and effects on vascular physiology. Efficacy in low grade gliomas is well documented by several European centers using 125-J sources. Different modes of implantation have been used and evaluated including single fraction treatment using a miniature linear accelerator (Photoelectron). In malignant gliomas interstitial radiosurgery has been investigated in a prospective, randomised, controlled trial and not shown to be effective. Steretactic interstitial radiosurgery is a powerful treatment option in circumscribed CNS tumors like some low grade gliomas and metastasis but does play no major role in the treatment of malignant glioma.

Immunogene therapy of recurrent glioblastoma multiforme with a liposomally encapsulated replication-incompetent Semliki forest virus vector carrying the human interleukin-12 gene--a phase I/II clinical protocol.

Glioblastoma multiforme (GBM) is an incurable brain tumor resistant to standard treatment modalities such as surgery, radiation, and chemotherapy. Since recurrent GBM tends to develop predominantly within the infiltrative rim surrounding the primary tumor focus, novel therapy strategies need in addition to focal tumor destruction to target this somewhat diffuse area. This is a phase I/II clinical study in adult patients with recurrent GBM which is aimed at evaluating biological safety, maximum tolerated dose, and antitumor efficacy of a genetically modified replication-disabled Semliki forest virus vector (SFV) carrying the human interleukin 12 (IL-12) gene and encapsulated in cationic liposomes (LSFV-IL12). The vector will be administered in doses of 1 x 10(7)-1 x 10(9) infectious particles by continuous intratumoral infusion, thus exploiting the advantages of convection-enhanced drug delivery in the brain. The present protocol is also designed to investigate systemic and local immune response and to identify factors predicting tumor response to LSFV-IL12 therapy, such as volume of extracellular space of the tumor, volume of contrast enhancing lesion, and immune status of the patients. SFV, an insect alphavirus, infects mitotic and non-mitotic cells and triggers apoptosis in tumor cells within 48-72 h. Preclinical work with the LSFV-IL12 vector in breast and prostate cancer animal models demonstrated its biosafety and some antitumor efficacy. An ongoing phase I clinical study in patients with melanoma and renal cell carcinoma seems also to confirm the biosafety of intravenously administered vectors. This protocol will be the first study of SFV-IL12 therapy of human recurrent GBM.

Comment on "Kullback-Leibler and renormalized entropies: applications to electroencephalograms of epilepsy patients".

In a recent paper Quian Quiroga et al. [R. Quian Quiroga et al., Phys. Rev. E 62, 8380 (2000)] found renormalized entropy, formerly introduced as a complexity measure for the different regimes of a dynamical system, to be closely related to the standard Kullback-Leibler entropy. They assure this finding by reanalyzing electroencephalographic data of epilepsy patients, previously examined by exclusive use of renormalized entropy [K. Kopitzki et al., Phys. Rev. E 58, 4859 (1998)]. We argue that the general considerations undertaken by the authors and the experimental results do not justify this conclusion.

The effects of continuous and single-dose radiation on choline uptake in organotypic tissue slice cultures of rabbit hippocampus.

The objective of the present study was to determine the time-dependent course of choline uptake in mature organotypic slice cultures of rabbit hippocampal formation and to assess the effects of continuous and single high-dose irradiation on choline uptake in cultivated slices in vitro. Transverse slices of hippocampus were dynamically incubated in a cerebrospinal fluid-like culture medium for 72 h. To study the changes in choline uptake longitudinally, the slice cultures were processed with 0.1 microM [3H]-choline, and tritium accumulation was counted. Two different gamma irradiation sources (125I seeds and a clinical 60Co source) were used as representative models of interstitial radiosurgery and other radiosurgical techniques. A total dose of approximately 6000 cGy was delivered to the brain slices in one session or in a continuous, relatively low-dose rate fashion, and their effects on high-affinity choline uptake were examined. In another set of experiments with 125I, 5 microM hemicholinium-3 was used in choline uptake procedures as a competitive high-affinity choline uptake inhibitor. The results can be summarized as follows: (1) in the control group of the hippocampal tissue culture, there was a significant increase in tritium accumulation values from 0 to 48 h and a decrease thereafter; (2) continuous 125I irradiation caused a highly significant depression of the accumulation of tritium compared to that observed in the control group throughout its application for 72 h; (3) there was no significant change in the accumulation of tritium in the slices after single high-dose rate irradiation with a 60Co source; and (4) 5 microM hemicholinium significantly depressed the accumulation of tritium in both the control and the 125I-irradiated groups, and there was no longer a difference between 125I-irradiated and control groups when both groups were treated with hemicholinium. These results demonstrate that the delivery of continuous but relatively low-dose rate gamma irradiation is more efficacious than single high-dose external irradiation on high-affinity choline uptake in hippocampal nervous tissue. The results also indicate that continuous irradiation specifically affected the high-affinity energy-dependent choline uptake mechanism, whereas nonspecific choline uptake did not seem to be disturbed.

Immediate and long term outcome after infrathalamic and thalamic lesioning for intractable Tourette's syndrome.

OBJECTIVE: The surgical treatment of intractable Tourette's syndrome is controversial. Experience with 17 consecutive patients treated between 1970 and 1998 is reviewed and the efficacy and safety of surgical treatment is assessed. METHODS: These patients were retrospectively reclassified into subtypes according to the protocol of the Tourette's Syndrome Study Group. One patient was excluded from the study. Ventriculography based stereotactic zona incerta (ZI) and ventrolateral/ lamella medialis thalamotomy (VL/LM) were performed on all patients. The preoperative, postoperative, and late tic severities were assessed by the tic severity rating scale. The median follow up of 11 patients (65%) was 7 years (range 3.5-17 years) and six patients were lost to long term follow up. RESULTS: Median age was 23 years (range 11-40) at the time of surgery. Median duration of illness was 14 years (range 3-33). The mean preoperative motor and vocal tic severities were estimated to be 4.44 (SD 0.63) and 3.81 (SD 0.66), respectively. Unilateral ZI lesioning and VL/LM lesioning selected by asymmetry of symptoms provide an effective control of tic severity (p motor and vocal<0.001). In attenuation of contralateral symptoms, a second surgical intervention in the relevant side could reduce tic severity sufficiently (p motor<0.01; p vocal<0.005). Transient complications occurred in 68% of patients. Only one permanent complication was registered in six patients followed up after unilateral surgery. Two out of five patients followed up after bilateral surgery had disabling side effects of surgery. CONCLUSIONS: ZI and VL/LM lesioning provide a significant long term reduction of tic severity in intractable Tourette's syndrome. Adequate selection of the side of first intervention might prevent the patient from increased risk of bilateral surgery.

Early effects of PRS-irradiation for 9L gliosarcoma: characterization of interphase cell death.

We characterized the interphase cell death of 9L gliosarcoma after high-dose-rate, low-energy photon irradiation using the Photon Radiosurgery System (PRS), a novel device for interstitial radiotherapy. Within 24 hours after irradiation with a dose of 18 Gray, 22.0% of cells underwent metabolic cell death, whereas dead cells in controls stayed less than 5.0% (p<0.005). In the majority of sensitive cells, loss of membrane integrity preceded the lethal morphological changes. The response was dose-dependent over the range of 9-18 Gray, but saturation was obtained over 18 Gray. On the other hand, a significant (p < 0.01) increase in the number of TUNEL-positive cells with apoptotic morphology was detected 6-24 hours after irradiation, but the fraction remained 1.9-2.1% of the population and was independent of the doses between 9 and 25 Gray. Apoptotic cells were rarely observed in the control cells (0.3-0.6%). Our data indicate that single high-dose irradiation induces both necrotic and apoptotic interphase cell death in 9L gliosarcoma, but rapid cell death mostly occurs through the non-apoptotic pathway.

[Neuronavigation. Computer-assisted neurosurgery]. / Neuronavigation. Computerassistierte Neurochirurgie.

The use of stereotactic methods for the resection of subcortical lesions is heavily advocated in clinical neurosurgery introducing the term "neuronavigation". Though being an unequivocally elegant technique for the localisation and delineation of pathological lesions in the central nervous system neuronavigation has not been validated by any prospective randomized controlled trial. The method is prone to significant errors as to the intraoperative localisation based upon preoperative three-dimensional images. The maximum error can be up to 2.6 cm depending on the extent of the so-called brain shift. In comparison classical frame based stereotaxy has a mean error of +/- 1 mm and remains the gold standard for the exact three-dimensional localisation of a given lesion. The value of neuronavigation is evident for small deep seated vascular lesions. For metastatic tumors or skull base tumors the usefulness is rather marginal because alternative therapies are available with proven and equivalent efficacy and reduced morbidity on one hand, and because of the anatomy of the tumor which makes neuronavigation unnecessary. For the currently most common application of neuronavigation, i.e. surgery of gliomas, no significant improvements of therapeutic results can be expected from neuronavigation. The biology of gliomas limits any mechanical approaches.

Vascular endothelial growth factor expression, vascular volume, and, capillary permeability in human brain tumors.

OBJECTIVE: Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen and a potent inducer of vascular permeability. In this study, we determined whether expression of VEGF is correlated with in vivo measurements of the capillary permeability and vascular volume of primary human brain tumors. METHODS: Tumor samples (seven glioblastomas, one anaplastic astrocytoma, two low-grade astrocytomas, one pilocytic astrocytoma, and three primary cerebral lymphomas) were stereotactically obtained from 14 patients. A semiquantitative polymerase chain reaction was used to quantify the relative expression of VEGF messenger ribonucleic acid in the tumors. VEGF protein was demonstrated in tissue sections by immunohistochemical techniques. A two-compartment dynamic computed tomographic method was used to quantitatively measure the aforementioned parameters in the regions from which the biopsies were obtained. RESULTS: In glial tumors, there was significant correlation of VEGF messenger ribonucleic acid levels with capillary permeability (P < 0.05) and vascular volume (P < 0.01). Although all primary cerebral lymphomas showed considerable increases in capillary permeability and vascular volume, VEGF expression was only slightly upregulated in these tumors. CONCLUSION: Our findings are consistent with the hypothesis that VEGF may be responsible for endothelial cell proliferation and vascular permeability in glial tumors. This relationship has implications for clinical applications, i.e., assessment of delivery of water-soluble drugs, treatment of edema, and antiangiogenesis therapy based on inhibition of VEGF function.