Next generation sequencing in adult patients with glioblastoma in Switzerland: a multi-centre decision analysis.

BACKGROUND: Glioblastoma is the most common malignant primary brain tumour in adults and driven by various genomic alterations. Next generation sequencing (NGS) provides timely information about the genetic landscape of tumours and might detect targetable mutations. To date, differences exist in the application and NGS assays used as it remains unclear to what extent these variants may affect clinical decision making. In this survey-based study, we investigated the use of NGS in adult patients with glioblastoma in Switzerland. METHODS: All eight primary care centres for Neuro-Oncology in Switzerland participated in this survey. The NGS assays used as well as the criteria for the application of NGS in newly diagnosed glioblastoma were investigated. Decision trees were analysed for consensus and discrepancies using the objective consensus methodology. RESULTS: Seven out of eight centres perform NGS in patients with newly diagnosed glioblastoma using custom made or commercially available assays. The criteria most relevant to decision making were age, suitability of standard treatment and fitness. NGS is most often used in fitter patients under the age of 60 years who are not suitable for standard therapy, while it is rarely performed in patients in poor general health. CONCLUSION: NGS is frequently applied in glioblastomas in adults in Neuro-Oncology centres in Switzerland despite seldom changing the course of treatment to date.

Bevacizumab plus hypofractionated radiotherapy versus radiotherapy alone in elderly patients with glioblastoma: the randomized, open-label, phase II ARTE trial.

Background: The addition of bevacizumab to temozolomide-based chemoradiotherapy (TMZ/RT â†’ TMZ) did not prolong overall survival (OS) in patients with newly diagnosed glioblastoma in phase III trials. Elderly and frail patients are underrepresented in clinical trials, but early reports suggested preferential benefit in this population. Patients and methods: ARTE was a 2 : 1 randomized, multi-center, open-label, non-comparative phase II trial of hypofractionated RT (40 Gy in 15 fractions) with bevacizumab (10 mg/kg×14 days) (arm A, N = 50) or without bevacizumab (arm B, N = 25) in patients with newly diagnosed glioblastoma aged ≥65 years. The primary objective was to obtain evidence for prolongation of median OS by the addition of bevacizumab to RT. Response was assessed by RANO criteria. Quality of life (QoL) was monitored by the EORTC QLQ-C30/BN20 modules. Exploratory studies included molecular subtyping by 450k whole methylome and gene expression analyses. Results: Median PFS was longer in arm A than in arm B (7.6 and 4.8 months, P = 0.003), but OS was similar (12.1 and 12.2 months, P = 0.77). Clinical deterioration was delayed and more patients came off steroids in arm A. Prolonged PFS in arm A was confined to tumors with the receptor tyrosine kinase (RTK) I methylation subtype (HR 0.25, P = 0.014) and proneural gene expression (HR 0.29, P = 0.025). In a Cox model of OS controlling for established prognostic factors, associations with more favorable outcome were identified for age <70 years (HR 0.52, P = 0.018) and Karnofsky performance score 90%-100% (HR 0.51, P = 0.026). Including molecular subtypes into that model identified an association of the RTK II gene methylation subtype with inferior OS (HR 1.73, P = 0.076). Conclusion: Efficacy outcomes and exploratory analyses of ARTE do not support the hypothesis that the addition of bevacizumab to RT generally prolongs survival in elderly glioblastoma patients. Molecular biomarkers may identify patients with preferential benefit from bevacizumab. Clinical trial registration number: NCT01443676.

Patterns of care in recurrent glioblastoma in Switzerland: a multicentre national approach based on diagnostic nodes.

Despite moderate improvements in outcome of glioblastoma after first-line treatment with chemoradiation recent clinical trials failed to improve the prognosis of recurrent glioblastoma. In the absence of a standard of care we aimed to investigate institutional treatment strategies to identify similarities and differences in the pattern of care for recurrent glioblastoma. We investigated re-treatment criteria and therapeutic pathways for recurrent glioblastoma of eight neuro-oncology centres in Switzerland having an established multidisciplinary tumour-board conference. Decision algorithms, differences and consensus were analysed using the objective consensus methodology. A total of 16 different treatment recommendations were identified based on combinations of eight different decision criteria. The set of criteria implemented as well as the set of treatments offered was different in each centre. For specific situations, up to 6 different treatment recommendations were provided by the eight centres. The only wide-range consensus identified was to offer best supportive care to unfit patients. A majority recommendation was identified for non-operable large early recurrence with unmethylated MGMT promoter status in the fit patients: here bevacizumab was offered. In fit patients with late recurrent non-operable MGMT promoter methylated glioblastoma temozolomide was recommended by most. No other majority recommendations were present. In the absence of strong evidence we identified few consensus recommendations in the treatment of recurrent glioblastoma. This contrasts the limited availability of single drugs and treatment modalities. Clinical situations of greatest heterogeneity may be suitable to be addressed in clinical trials and second opinion referrals are likely to yield diverging recommendations.

Susceptibility changes in meningiomas influence the apparent diffusion coefficient in diffusion-weighted MRI.

INTRODUCTION: Cell-dense tumors may restrict diffusivity which can be measured by diffusion-weighted MRI (DWI), and which is quantified by the apparent diffusion coefficient (ADC). Little is known about diffusivity in meningiomas. These tumors frequently show hemorrhage and calcification which can be demonstrated using susceptibility weighted MRI (SWI). Both DWI and SWI represent T2-derived MRI sequences. Here we investigated ADC variability in meningiomas and analyzed whether susceptibility changes (SWIpos) alter diffusivity. METHODS: We grouped newly diagnosed meningiomas according to the presence (SWIpos) or absence (SWIneg) of susceptibility changes. ADC values were calculated using region-of-interest analysis, and ADC values of SWIpos and SWIneg meningiomas were compared. In addition ADC histograms were created. RESULTS: We retrospectively studied 36 patients (13 WHO grade I, 8 WHO grade II, 15 suspected meningiomas). Thirteen meningiomas (36%) exhibited SWIpos. Global ADC values were higher in SWIpos (1.00 ± 0.15 × 10-3mm(2)/s) compared to SWIneg (0.82 ± 0.09 × 10-3mm(2)/s) tumors (P<0.0001). Meningiomas showing both SWIpos and SWIneg areas caused two separated histogram peaks, whereas homogeneously appearing meningiomas with either SWIposor SWIneg areas showed one peak only. ADC values did not correlate with age or gender, and showed substantial overlap between WHO grade I and II. CONCLUSION: Susceptibility changes (SWIpos) in meningiomas influence measures of diffusivity by increasing ADC values on average by 38%. This shift has to be considered when conclusions on tumor behavior are drawn from DWI. Further studies should address whether ADC changes and histogram patterns can be used to monitor treatment of meningiomas.

Susceptibility and Tumor Size Changes During the Time Course of Standard Treatment in Recurrent Glioblastoma.

BACKGROUND AND PURPOSE: Susceptibility-weighted magnetic resonance imaging (SWI) yields information regarding tumor biology (e.g., hemorrhage) of growing gliomas. SWI changes can also be observed as a consequence of treatment, for example radiation therapy. The aim of our study was to investigate how susceptibility changes occur during the time course after completion of standard treatment in newly diagnosed glioblastoma (GBM). METHODS: Eighteen GBM patients were retrospectively analyzed. After completion of therapy, imaging was performed every 3 months. MRI was analyzed at the following time points: after the third and sixth cycle of adjuvant temozolomide chemotherapy, thereafter in 3 month intervals and at recurrence. The number of SWI positive tumor pixels was quantified and compared with progression as defined by the RANO criteria on T2- and contrast-enhanced T1-weighted MRI sequences (T1-CE). RESULTS: The MRI interval between completion of the sixth chemotherapy cycle and last MRI before progression was 390 ± 292 days. Between the last MRI before progression and at progression a significant increase in SWI positive tumor pixels was observed (P = .012), whereas tumor size remained unchanged (RANO T2: P = .385; RANO T1-CE: P = .165). The number of SWI positive pixels remained unchanged between last MRI before progression until progression (P = .149), whereas RANO T2 and T1-CE showed tumor progression (interval 128 ± 69 days). CONCLUSIONS: SWI positive pixel count increases significantly prior to changes in tumor size (RANO). Our findings may be explained by microbleeds compatible with stimulation of angiogenesis and possibly serve as an early biomarker of tumor progression.

Imaging brain tumor proliferative activity with [124I]iododeoxyuridine.

Iododeoxyuridine (IUdR) uptake and retention was imaged by positron emission tomography (PET) at 0-48 min and 24 h after administration of 28.0-64.4 MBq (0.76-1.74 mCi) of [124I]IUdR in 20 patients with brain tumors, including meningiomas and gliomas. The PET images were directly compared with gadolinium contrast-enhanced or T2-weighted magnetic resonance images. Estimates for IUdR-DNA incorporation in tumor tissue (Ki) required pharmacokinetic modeling and fitting of the 0-48 min dynamically acquired data to correct the 24-h image data for residual, nonincorporated radioactivity that did not clear from the tissue during the 24-h period after IUdR injection. Standard uptake values (SUVs) and tumor:brain activity ratios (Tm:Br) were also calculated from the 24-h image data. The Ki, SUV, and Tm/Br values were related to tumor type and grade, tumor labeling index, and survival after the PET scan. The plasma half-life of [124I]IUdR was short (2-3 min), and the arterial plasma input function was similar between patients (48 +/- 12 SUV*min). Plasma clearance of the major radiolabeled metabolite ([124I]iodide) varied somewhat between patients and was markedly prolonged in one patient with renal insufficiency. It was apparent from our analysis that a sizable fraction (15-93%) of residual nonincorporated radioactivity (largely [124I]iodide) remained in the tumors after the 24-h washout period, and this fraction varied between the different tumor groups. Because the SUV and Tm:Br ratio values reflect both IUdR-DNA incorporated and exchangeable nonincorporated radioactivity, any residual nonincorporated radioactivity will amplify their values and distort their significance and interpretation. This was particularly apparent in the meningioma and glioblastoma multiforme groups of tumors. Mean tumor Ki values ranged between 0.5 +/- 0.9 (meningiomas) and 3.9 +/- 2.3 microl/min/g (peak value for glioblastoma multiforme, GBM). Comparable SUV and Tm:Br values at 24 h ranged from 0.13 +/- 0.03 to 0.29 +/- 0.19 and from 2.0 +/- 0.6 to 6.1 +/- 1.5 for meningiomas and peak GBMs, respectively. Thus, the range of values was much greater for Ki (approximately 8-fold) compared with that for SUV (approximately 2.2-fold) and Tm:Br (approximately 3-fold). The expected relationships between Ki, SUV, and Tm:Br and other measures of tumor proliferation (tumor type and grade, labeling index, and patient survival) were observed. However, greater image specificity and significance of the SUV and Tm:Br values would be obtained by achieving greater washout and clearance of the exchangeable fraction of residual (background) radioactivity in the tumors, i.e., by increased hydration and urinary clearance and possibly by imaging later than 24 h after [124I]IUdR administration.

Reduced glucose metabolism in the frontal cortex and basal ganglia of multiple sclerosis patients with fatigue: a 18F-fluorodeoxyglucose positron emission tomography study.

To investigate the pathophysiology of fatigue in MS, we assessed cerebral glucose metabolism (CMR-Glu) in 47 MS patients using PET and 18F-fluorodeoxyglucose. Applying the Fatigue Severity Scale (FSS), we first compared MS patients with severe fatigue (MS-FAT, n = 19, FSS > 4.9) and MS patients without fatigue (MS-NOF, n = 16, FSS < 3.7) on a pixel-by-pixel basis using Statistical Parametric Mapping (SPM95). Second, we compared FSS values of all 47 patients covering the whole range of this scale with CMRGlu using an analysis of covariance (SPM95). In addition, we determined global CMRGlu by region-of-interest analysis. Sixteen healthy subjects served as control subjects (CON). Global CMRGlu was significantly lower in both MS groups compared with CON (CON 43.3 +/- 6.9 mumol/100 mL/min, MS-FAT 34.7 +/- 4.4, MS-NOF 35.4 +/- 4.5) but was not related to fatigue severity. Comparing the two MS groups, SPM95 analysis revealed predominant CMRGlu reductions bilaterally in a prefrontal area involving the lateral and medial prefrontal cortex and adjacent white matter, in the premotor cortex, putamen, and in the right supplementary motor area of MS-FAT. In addition, there were CMRGlu reductions in the white matter extending from the rostral putamen toward the lateral head of the caudate nucleus. FSS values were inversely related to CMRGlu in the right prefrontal cortex. CMRGlu in the cerebellar vermis and anterior cingulate was relatively higher in MS-FAT than in MS-NOF patients. CMRGlu of both regions showed positive correlations with FSS values. Our data suggest that fatigue in MS is associated with frontal cortex and basal ganglia dysfunction that could result from demyelination of the frontal white matter.

Dexamethasone treatment and plasma glucose levels: relevance for fluorine-18-fluorodeoxyglucose uptake measurements in gliomas.

UNLABELLED: Dexamethasone (DEX) is frequently used in brain tumor management. This study investigated the effect of DEX treatment and plasma glucose levels on 18F-fluorodeoxyglucose (FDG) uptake in patients with malignant gliomas (16 glioblastoma, 3 anaplastic astrocytoma). METHODS: Fifteen DEX-treated patients (mean relative dose 0.23 +/- 0.15 mg(-1) x kg(-1) x day(-1), range 0.07-0.53), four patients not treated with DEX and nine healthy subjects were studied using PET and FDG. PET data obtained from tumors and the contralateral cortex were fitted to a standard two-tissue compartment model. The FDG transport and phosphorylation rates, distribution volume (DV), steady-state accumulation (Ki), deoxyglucose metabolism (R), plasma volume as well as standardized uptake values (SUVs) and tumor-to-brain ratios were determined. In addition, the tumor size was estimated from the maximal area of contrast-enhancing tumor on computed cranial tomography (CCT) scans or MRI. RESULTS: FDG uptake was depressed in the contralateral cortex of patients and was related to tumor size. With increasing relative DEX dose, a decrease in the DV of tumors (linear regression p = 0.021) and in the DV (p = 0.109) and plasma volume (p = 0.010) of contralateral cortex was found. R, Ki and SUVs in tumors and contralateral cortex were not related to the relative DEX dose. With increasing plasma glucose levels, differential decreases in Ki and SUVs in tumors (p = 0.057 and p = 0.733, respectively) and contralateral cortex (p = 0.001 and p = 0.029, respectively) were observed. CONCLUSION: The data suggest that DEX affects FDG uptake in malignant gliomas through interaction with cerebral blood vessels and extracellular space, whereas FDG metabolism in tumors is not influenced substantially. This is of practical importance for patients having serial brain tumor imaging for treatment evaluation because patients may receive different DEX doses at different time points in the course of their disease. By contrast, the plasma glucose level must be considered a confounding variable when SUVs, tumor-to-brain ratios or Ki are used for treatment evaluation.

Differential effect of spinal cord injury and functional impairment on human brain activation.

Reorganization of human brain function after spinal cord injury (SCI) has been shown in electrophysiological studies. However, it is less clear how far changes of brain activation in SCI patients are influenced by the extent of SCI (neuronal lesion) or the consequent functional impairment. Positron emission tomography ([15O]-H2O-PET) was performed during an unilateral hand movement in SCI patients and healthy subjects. SCI patients with paraplegia and normal hand function were compared to tetraplegic patients with impaired hand movements. Intergroup comparison between paraplegic patients and healthy subjects showed an increased activation of contralateral sensorimotor cortex (SMC), contralateral thalamus, ipsilateral superior parietal lobe, and bilateral cerebellum. In contrast to this, tetraplegic patients with impaired upper limb function revealed only a significant activation of supplementary motor area (SMA). Correlational analysis in the tetraplegic patients showed that the strength of hand movement was related to the activation of contralateral SMC. However, the severity of upper limb sensorimotor deficit was related to a reduced activation of contralateral SMA and ipsilateral cerebellum. The findings suggest that in paraplegic patients with normal hand function the spinal neuronal lesion itself induces a reorganization of brain activation unrelated to upper limb function. Compared to this, in tetraplegic patients changes of brain activation are related to the impaired upper limb function. Therefore, in patients with SCI a differential impact of spinal lesion and functional impairment on brain activation can be shown. The effect of impaired afferent feedback and/or increased compensatory use of non-impaired limbs in SCI patients needs further evaluation.

PET in neuro-oncology.

This article reviews possible clinical applications of positron emission tomography (PET) in brain tumor patients. PET allows quantitative assessment of brain tumor pathophysiology and biochemistry. It therefore provides different information about tumors when compared to histological or neuroradiological methods. Common clinical indications for PET comprise tumor delineation and identification of the metabolically most active tumor regions (target for biopsy, differentiation of viable tumor from necrosis). Further, the spatial relation between brain activated e.g., by speech, and the tumor bulk can be explored by activation studies. PET could also aid in the prediction of treatment response by measurement of tumor perfusion or hypoxia. Moreover, PET tracers could identify treatment targets e.g., gene products. The latter topic has not been systematically evaluated in human patients.

Activation of the human brain by monetary reward.

With the purpose of studying neural activation associated with reward processing in humans, we measured regional cerebral blood flow in 10 right-handed healthy subjects performing a delayed go-no go task in two different reinforcement conditions. Correct responses were either rewarded by money or a simple "ok' reinforcer. Behaviour rewarded by money, as compared with the "ok' reinforcement, was most significantly associated with activation of dorsolateral and orbital frontal cortex and also involved the midbrain and thalamus. These results may reflect the processing of reward information, although arousal effects cannot be completely excluded. It is suggested that the observed foci are implicated in the assessment of consequences in goal-directed behaviour which agrees with research in non-human primates.

Intermanual transfer of training: blood flow correlates in the human brain.

In a previous study, we found that relearning of a task with one hand might negatively be influenced by previous, opposite hand training of the analogue task, Thut G., et al., Exp. Brain Res., 108 (1996) 321-327. Drawing of a figure with the right hand, following left hand training, was slower than right hand drawing of an unknown figure. These conditions were termed right hand transfer learning (rTL) and right hand original learning (rOL). The present study aimed to identify the cerebral areas associated with these influences by measuring regional cerebral blood flow (rCBF) in 16 right-handed, healthy subjects during rTL and rOL. Positron emission tomography and statistical parametric mapping were used. Compared with rOL, rTL was associated with increased rCBF in the left medial prefrontal cortex and the right prefrontal convexity. Individual rCBF changes in the area homotopic to the right prefrontal convexity furthermore correlated with individual changes in rTL performance. While the smallest rCBF increases were found in subjects with weakest slowing of rTL relative to rOL, highest rCBF increases were present when rTL slowing dominated. Comparisons between rTL and rOL, however, revealed on average no performance differences. Our data suggest that relearning after previous opposite hand training activates neural mechanisms within the prefrontal convexity which might have an inhibitory function but that inhibition does not have to be the net final behavioral result.

Meningopolyradiculitis (Bannwarth syndrome) as primary manifestation of a centrocytic-centroblastic lymphoma.

A 65-year-old female presented with Bannwarth's syndrome. Symptoms initially responded to antibiotics but soon progressed despite further adequate antibiotic treatment. Consistently absent antibody titres to Borrelia burgdorferi, repeated CSF examinations combined with an extensive search for tumour, revealed leukaemic meningitis secondary to uterine centrocytic-centroblastic lymphoma. The diagnostic steps required to elucidate the aetiology of meningopolyradiculitis, especially when chronic and progressive, are described.

Untreated neuroborreliosis: Bannwarth's syndrome evolving into acute schizophrenia-like psychosis. A case report.

In general, meningopolyradiculitis (Bannwarth's syndrome, stage 2 of neuroborreliosis) follows a predictable monophasic self-limiting course. In contrast, we report the case of a patient with an untreated meningopolyradiculitis which evolved into acute schizophrenia-like psychosis due to persistent infection with Borrelia burgdorferi. The psychosis resolved within 1 week of treatment with ceftriaxone. This case shows that the usually benign monophasic meningopolyradiculitis may progress to severe CNS complications, which may have implications on current pathophysiological beliefs.

Alteration of blood-brain barrier in human brain tumors: comparison of [18F]fluorodeoxyglucose, [11C]methionine and rubidium-82 using PET.

The influence of the blood-brain barrier (BBB) on tracer uptake was investigated in 21 patients with gliomas and meningiomas using PET, [18F]fluorodeoxyglucose (FDG), [18C]methionine (MET) and the K+ analog rubidium-82 (RUB) whose uptake into brain is largely prevented if the BBB is intact. Tracer uptake was quantitated by (1) multiple time graphical plotting providing tracer distribution volume (VD), unidirectional tracer uptake (Ki), and (2) normalized uptake (NU) which is a measure of net tissue radioactivity related to administered activity and body weight. VD, Ki and NU of MET were higher in meningiomas compared to gliomas and were significantly correlated with NU RUB (Spearman rank: p < 0.005 (VD), p < 0.05 (Ki), p < 0.001 (NU)). NU MET correlated with VD (p < 0.001) and Ki (p < 0.005) of MET. For FDG, tumor VD was in the range of contralateral cortex. Ki and NU values of FDG were highest in glioblastomas. NU of FDG correlated significantly with Ki of FDG (p < 0.005) but not with VD. The results suggest, that alteration of MET uptake in tumors is governed by changes of tracer influx across the BBB, whereas FDG uptake is related to tracer metabolism. This makes FDG the appropriate tracer particularly for the differential diagnosis of contrast enhancing lesions in operated and irradiated patients.

Crossed cerebellar diaschisis and brain tumor biochemistry studied with positron emission tomography, [18F]fluorodeoxyglucose and [11C]methionine.

Cerebral gliomas may cause a reduction of glucose metabolism in the cerebellum contralateral to the tumor side (crossed cerebellar diaschisis, CCD). We investigated whether CCD is related to tumor localization, histological grade, size and tumor biochemistry. Cerebellar glucose metabolism was measured in 44 glioma patients and 15 healthy subjects using positron emission tomography and [18F]fluorodeoxyglucose (FDG). CCD was determined by calculating an asymmetry index of cerebellar glucose metabolism. Further, the tumor uptake of FDG and [11C]methionine (MET) was also assessed, and was expressed as ratio of normalized tracer uptake in tumor over contralateral cortex (T/C). Frontal lobe tumors were associated with highest CCD values. For these tumors, CCD was higher in malignant (-11.8+/-9.9%) than in low-grade (-4.3+/-4.1%) gliomas (P=0.010). In addition, frontal lobe tumors showed increasing CCD values with increasing size. In tumors of the parietal or temporal lobe, CCD was less marked or absent. T/C ratios of tumor tracer uptake were higher in malignant than in low-grade gliomas, but were not correlated with CCD. Our data indicate that the magnitude of CCD is mainly determined by tumor localization and size, the latter being associated with tumor grade. These findings raise the question whether CCD provides a measure of expansion or progression particularly in low-grade tumors of the frontal lobe.

[76Br]Bromodeoxyuridine PET in tumor-bearing animals.

5-bromodeoxyuridine (BUdR) provides in vitro measures of tumor cell proliferation. We used positron emission tomography to study tissue and plasma kinetics of [76Br]BUdR in tumor-bearing animals. In order to account for the slow washout of the major plasma metabolite, [76Br]bromide, a mathematical correction for the distribution volume of [76Br]bromide was applied. However, following correction specific tumor tracer retention was low or even zero and did not correlate with independent measures of proliferation. The kinetic characteristics of [76Br]BUdR make this tracer unsuitable for proliferation imaging.

Alterations of cerebral metabolism or perfusion due to lesions of the central nervous system.

Positron emission tomography (PET) provides non-invasive measures of brain physiology and biochemistry in quantitative terms and is frequently applied to the investigation of cerebral blood flow (CBF) and glucose metabolism (CMRGlu) in health and disease. Both CBF and CMRGlu may serve as indicators of regional neuronal activity and may provide tools for functional brain imaging of cerebral plasticity following central nervous system injury. This review will briefly describe the technique currently used to investigate brain function with PET and will summarize results on motor activation in healthy subjects. It will further illustrate how resting brain energy metabolism changes following transverse spinal cord injury. In addition, data from activation studies in stroke patients will be presented which indicate that recovery of motor function is associated with the recruitment of cortical regions of the non-damaged hemisphere and with the extension of activated brain areas adjacent to brain lesions themselves.

Fatty acids as markers of the blood-cerebrospinal fluid barrier function in man.

The blood-cerebrospinal fluid barrier (BCB) function in man is derived from the CSF:serum ratio of albumin (QAlb). In order to study other than BCB protein transport we compared CSF:serum ratios of fatty acids in patients revealing normal and increased QAlb values. Ratios of unsaturated fatty acids, which are involved in inflammation, increased significantly in patients with increased QAlb (p < 0.005). In contrast, CSF:serum ratios of saturated fatty acids increased only slightly. We conclude that characterisation of BCB lipid properties may be of particular interest regarding drug penetration into the CSF and lipid metabolism in inflammation.

Multicentric tumor manifestations of high grade gliomas: independent proliferation or hallmark of extensive disease?

OBJECTIVE: Improvements in microneurosurgical techniques, radiotherapy and chemotherapy for the treatment of high grade gliomas resulted in better local tumor control and longer progression-free survival. Multicentric (MC) lesions located distant from the initial resection area contribute to treatment failure in a growing number of patients. These MC lesions may develop within the course of the disease (metachronous) or may already be present at the time of first tumor manifestation (synchronous). To look for mechanisms and regular patterns behind MC glioma manifestations and to investigate whether they are "a second primary tumor" or the result of continuous diffuse glioblastoma cell invasion, we retrospectively analyzed the initial and all follow-up MR studies of our high grade glioma (HGG) patients. PATIENTS AND METHODS: MR studies of 247 consecutive patients treated for HGG at a single institution were analyzed. MC tumor manifestation was defined as more than one gadolinium enhancing lesion within the brain on MRI without a connecting signal alteration in T2 sequences and/or without a connecting hypointense mass in T1 sequences. The minimal distance to define two solitary lesions was set at >10 mm. According to these specifications 40 patients showed MC tumor manifestations in their MR studies on admission or during treatment of their disease. The MR studies of these cases were retrospectively analyzed for patterns in MC tumor manifestation and progression. Topographical specifications and delay in manifestation were used to explain possible pathways of development. Kaplan Meyer survival graphs for metachronous and synchronous MC disease were calculated. RESULTS: 24 patients showed MC tumor manifestation at the time of admission. 16 cases developed MC manifestation within a follow-up period of 3-57 months. The location of all lesions could be categorized into one of three distinct patterns (white matter, subependymal, intraventricular). The patterns showed individual and location-specific time gaps to metachronous manifestation. Calculated from the time of first tumor diagnosis, the median survival was longer for patients with metachronous MC lesions (353 days, p<0.05) compared to patients with synchronous MC lesions (110 days) or patients without multicentricity (234 days). Patients with metachronous lesions showed a similar survival (72 days) as patients with synchronous MC lesions (110 days) once they developed MC disease. CONCLUSION: The topographical patterns and temporal characteristics of MC disease suggest that all manifestations share common mechanisms such as an active migratory process. Our data therefore do not support the concept of an independent MC development of multiple gliomas.