Predictive value of diffusion MRI-based parametric response mapping for prognosis and treatment response in glioblastoma.

BACKGROUND: Early detection of treatment response is important for the management of patients with malignant brain tumors such as glioblastoma to assure good quality of life in relation to therapeutic efficacy. AIM: To investigate whether parametric response mapping (PRM) with diffusion MRI may provide prognostic information at an early stage of standard therapy for glioblastoma. MATERIALS AND METHODS: This prospective study included 31 patients newly diagnosed with glioblastoma WHO grade IV, planned for primary standard postoperative treatment with radiotherapy 60Gy/30 fractions with concomitant and adjuvant Temozolomide. MRI follow-up including diffusion and perfusion weighting was performed at 3 T at start of postoperative chemoradiotherapy, three weeks into treatment, and then regularly until twelve months postoperatively. Regional mean diffusivity (MD) changes were analyzed voxel-wise using the PRM method (MD-PRM). At eight and twelve months postoperatively, after completion of standard treatment, patients were classified using conventional MRI and clinical evaluation as either having stable disease (SD, including partial response) or progressive disease (PD). It was assessed whether MD-PRM differed between patients having SD versus PD and whether it predicted the risk of disease progression (progression-free survival, PFS) or death (overall survival, OS). A subgroup analysis was performed that compared MD-PRM between SD and PD in patients only undergoing diagnostic biopsy. MGMT-promotor methylation status (O6-methylguanine-DNA methyltransferase) was registered and analyzed with respect to PFS, OS and MD-PRM. RESULTS: Of the 31 patients analyzed: 21 were operated by resection and ten by diagnostic biopsy. At eight months, 19 patients had SD and twelve had PD. At twelve months, ten patients had SD and 20 had PD, out of which ten were deceased within twelve months and one was deceased without known tumor progression. Median PFS was nine months, and median OS was 17 months. Eleven patients had methylated MGMT-promotor, 16 were MGMT unmethylated, and four had unknown MGMT-status. MD-PRM did not significantly predict patients having SD versus PD neither at eight nor at twelve months. Patients with an above median MD-PRM reduction had a slightly longer PFS (P = 0.015) in Kaplan-Maier analysis, as well as a non-significantly longer OS (P = 0.099). In the subgroup of patients only undergoing biopsy, total MD-PRM change at three weeks was generally higher for patients with SD than for patients with PD at eight months, although no tests were performed. MGMT status strongly predicted both PFS and OS but not MD-PRM change. CONCLUSION: MD-PRM at three weeks was not demonstrated to be predictive of treatment response, disease progression, or survival. Preliminary results suggested a higher predictive value in non-resected patients, although this needs to be evaluated in future studies.

Cause of death in autopsy-confirmed dementia disorders.

BACKGROUND AND PURPOSE: Dementia disorders predispose for lethal complications and decrease life expectancy. A more profound knowledge regarding end-stage conditions in dementia could therefore ameliorate treatment and care of these patients. METHODS: Autopsy reports on 207 deceased individuals with clinically diagnosed neurocognitive disorder/dementia and on 200 neurocognitively healthy individuals of the same age range were studied. Autopsy results, especially cause of death, were compared between the dementia and the control groups. RESULTS: The two most frequent causes of death in the dementia population were pneumonia (34.3%) and acute myocardial infarction (30.4%). This result differed from that of the control group, in which acute myocardial infarction (42.5%) accounted for most events of deaths, followed by circulatory failure (12.5%). The leading cause of death varied amongst dementia subtypes. Further, in Alzheimer's disease pneumonia was more frequent in severe/advanced cases whilst acute myocardial infarction was more common in milder cases. CONCLUSIONS: Cause of death differed between the demented and the general population of the same age and between subtypes of dementia. Alzheimer's disease severity was reflected in different final conditions. The findings have relevance for the final stage care and treatment in dementia disorders.

A cortical microvascular structure in vascular dementia, Alzheimer's disease, frontotemporal lobar degeneration and nondemented controls: a sign of angiogenesis due to brain ischaemia?

AIMS: We observed a microvascular structure in the cerebral cortex that has not, to our knowledge, been previously described. We have termed the structure a 'raspberry', referring to its appearance under a bright-field microscope. We hypothesized that raspberries form through angiogenesis due to some form of brain ischaemia or hypoperfusion. The aims of this study were to quantify raspberry frequency within the cerebral cortex according to diagnosis (vascular dementia, Alzheimer's disease, frontotemporal lobar degeneration and nondemented controls) and brain regions (frontal, temporal, parietal and occipital cortices, regardless of diagnosis). MATERIALS AND METHODS: In each of 10 age-matched subjects per group, a 20-mm section of the cerebral cortex was examined in haematoxylin-and-eosin-stained sections of the frontal, temporal and parietal, and/or occipital lobes. Tests were performed to validate the haematoxylin-and-eosin-based identification of relative differences between the groups, and to investigate inter-rater variability. RESULTS: Raspberry frequency was highest in subjects with vascular dementia, followed by those with frontotemporal lobar degeneration, Alzheimer's disease and last, nondemented controls. The frequency of raspberries in subjects with vascular dementia differed from that of all other groups at a statistically significant level. In the cerebral lobes, there was a statistically significant difference between the frontal and occipital cortices. CONCLUSIONS: We believe the results support the hypothesis that raspberries are a sign of angiogenesis in the adult brain. It is pertinent to discuss possible proangiogenic stimuli, including brain ischaemia (such as mild hypoperfusion due to a combination of small vessel disease and transient hypotension), neuroinflammation and protein pathology.

SIRT1 is increased in affected brain regions and hypothalamic metabolic pathways are altered in Huntington disease.

AIMS: Metabolic dysfunction is involved in modulating the disease process in Huntington disease (HD) but the underlying mechanisms are not known. The aim of this study was to investigate if the metabolic regulators sirtuins are affected in HD. METHODS: Quantitative real-time polymerase chain reactions were used to assess levels of SIRT1-3 and downstream targets in post mortem brain tissue from HD patients and control cases as well as after selective hypothalamic expression of mutant huntingtin (HTT) using recombinant adeno-associated viral vectors in mice. RESULTS: We show that mRNA levels of the metabolic regulator SIRT1 are increased in the striatum and the cerebral cortex but not in the less affected cerebellum in post mortem HD brains. Levels of SIRT2 are only increased in the striatum and SIRT3 is not affected in HD. Interestingly, mRNA levels of SIRT1 are selectively increased in the lateral hypothalamic area (LHA) and ventromedial hypothalamus (VMH) in HD. Further analyses of the LHA and VMH confirmed pathological changes in these regions including effects on SIRT1 downstream targets and reduced mRNA levels of orexin (hypocretin), prodynorphin and melanin-concentrating hormone (MCH) in the LHA and of brain-derived neurotrophic factor (BDNF) in the VMH. Analyses after selective hypothalamic expression of mutant HTT suggest that effects on BDNF, orexin, dynorphin and MCH are early and direct, whereas changes in SIRT1 require more widespread expression of mutant HTT. CONCLUSIONS: We show that SIRT1 expression is increased in HD-affected brain regions and that metabolic pathways are altered in the HD hypothalamus.

The influence of late displacement in distal radius fractures on function, grip strength, range of motion and quality of life.

Late displacement of distal radius fractures, still in acceptable radiological position after 1-2 weeks, occurs in approximately one-third of cases. The aim of this study was to investigate the influence of late displacement on the functional outcome and quality of life at 1 year in non-operatively treated distal radius fractures. One hundred and seventy five unilateral conservatively treated distal radius fractures with minimal displacement after 10-14 days were finally evaluated in the study. Follow-up included radiographs at 3 months and clinical examination 1 year after the fracture. Final radiographic parameters, grip strength, range of motion, QuickDASH, EQ-5D and pain visual analogue scale were evaluated with multivariate analysis. Late displacement occurred in 28% of the cases and was associated with loss of grip strength and range of motion. No significant differences were seen in the outcome questionnaires. LEVEL OF EVIDENCE: II.

Cartilage oligomeric matrix protein contributes to the development and metastasis of breast cancer.

Cartilage oligomeric matrix protein (COMP) is a soluble pentameric protein expressed in cartilage and involved in collagen organization. Tissue microarrays derived from two cohorts of patients with breast cancer (n=122 and n=498) were immunostained, revealing varying expression of COMP, both in the tumor cells and surrounding stroma. High levels of COMP in tumor cells correlated, independently of other variables, with poor survival and decreased recurrence-free survival. Breast cancer cells, MDA-MB-231, stably expressing COMP were injected into the mammary fat pad of SCID (CB-17/Icr-Prkdcscid/Rj) mice. Tumors expressing COMP were significantly larger and were more prone to metastasize as compared with control, mock-transfected, tumors. In vitro experiments confirmed that COMP-expressing cells had a more invasive phenotype, which could in part be attributed to an upregulation of matrix metalloprotease-9. Furthermore, microarray analyses of gene expression in tumors formed in vivo showed that COMP expression induced higher expression of genes protecting against endoplasmic reticulum stress. This observation was confirmed in vitro as COMP-expressing cells showed better survival as well as a higher rate of protein synthesis when treated with brefeldin A, compared with control cells. Further, COMP-expressing cells appeared to undergo a metabolic switch, that is, a Warburg effect. Thus, in vitro measurement of cell respiration indicated decreased mitochondrial metabolism. In conclusion, COMP is a novel biomarker in breast cancer, which contributes to the severity of the disease by metabolic switching and increasing invasiveness and tumor cell viability, leading to reduced survival in animal models and human patients.

Cortical comminution in distal radial fractures can predict the radiological outcome: a cohort multicentre study.

This paper investigates whether cortical comminution and intra-articular involvement can predict displacement in distal radius fractures by using a classification that includes volar comminution as a separate parameter. A prospective multicentre study involving non-operative treatment of distal radius fractures in 387 patients aged between 15 and 74 years (398 fractures) was conducted. The presence of cortical comminution and intra-articular involvement according to the Buttazzoni classification is described. Minimally displaced fractures were treated with immobilisation in a cast while displaced fractures underwent closed reduction with subsequent immobilisation. Radiographs were obtained after reduction, at 10 to 14 days and after union. The outcome measure was re-displacement or union. In fractures with volar comminution (Buttazzoni type 4), 96% (53 of 55) displaced. In intra-articular fractures without volar comminution (Buttazzoni 3), 72% (84 of 117) displaced. In extra-articular fractures with isolated dorsal comminution (Buttazzoni 2), 73% (106 of 145) displaced while in non-comminuted fractures (Buttazzoni 1), 16 % (13 of 81 ) displaced. A total of 32% (53 of 165) of initially minimally displaced fractures later displaced. All of the initially displaced volarly comminuted fractures re-displaced. Displacement occurred in 31% (63 of 205) of fractures that were still in good alignment after 10 to 14 days. Regression analysis showed that volar and dorsal comminution predicted later displacement, while intra-articular involvement did not predict displacement. Volar comminution was the strongest predictor of displacement.

von Economo neurones are selectively targeted in frontotemporal dementia.

BACKGROUND: von Economo neurones (VEN) are bipolar neurones located in the anterior cingulate cortex (ACC) and the frontoinsular cortex (FI), areas affected early in behavioural variant frontotemporal dementia (bvFTD), in which VEN may constitute a selectively vulnerable cellular population. AIM: A previous study has shown a selective loss of VEN in FTD above other neurones in the ACC of FTD. The aim of this study was to confirm this finding in a larger cohort, using a different methodology, and to examine VEN loss in relation to neuropathological severity and molecular pathology. METHODS: VEN and neighbouring neurones (NN) were quantified in layers Va and Vb of the right dorsal ACC in 21 cases of bvFTD, 10 cases of Alzheimer's disease (AD) and 10 non-demented controls (NDC). RESULTS: A marked VEN reduction was seen in all FTD cases. In the neuropathologically early cases of FTD (n = 13), VEN/10,000 NN was significantly reduced by 53% compared with NDC (P < 0.001) and 41% compared with AD (P = 0.019), whereas AD patients showed a non-significant 30% reduction of VEN/10,000 NN compared with NDC. VEN reduction was present in all protein pathology subgroups. DISCUSSION: In conclusion, this study confirms selective sensitivity of VEN in FTD and suggests that VEN loss is an early event in the neurodegenerative process.

Neuron-specific enolase correlates with other prognostic markers after cardiac arrest.

OBJECTIVE: Therapeutic hypothermia (TH) is a recommended treatment for survivors of cardiac arrest. Prognostication is complicated since sedation and muscle relaxation are used and established indicators of a poor prognosis are lacking. This prospective, observational study describes the pattern of commonly used prognostic markers in a hypothermia-treated cohort of cardiac arrest patients with prolonged coma. METHODS: Among 111 consecutive patients, 19 died, 58 recovered, and 34 were in coma 3 days after normothermia (4.5 days after cardiac arrest), defined as prolonged coma. All patients were monitored with continuous amplitude-integrated EEG and repeated samples of neuron-specific enolase (NSE) were collected. In patients with prolonged coma, somatosensory evoked potentials (SSEP) and brain MRI were performed. A postmortem brain investigation was undertaken in patients who died. RESULTS: Six of the 17 patients (35%) with NSE levels <33 µg/L at 48 hours regained the capacity to obey verbal commands. By contrast, all 17 patients with NSE levels >33 failed to recover consciousness. In the >33 NSE group, all 10 studied with MRI had extensive brain injury on diffusion-weighted images, 12/16 lacked cortical responses on SSEP, and all 6 who underwent autopsy had extensive severe histologic damage. NSE levels also correlated with EEG pattern, but less uniformly, since 11/17 with NSE <33 had an electrographic status epilepticus (ESE), only one of whom recovered. A continuous EEG pattern correlated to NSE <33 and awakening. CONCLUSIONS: NSE correlates well with other markers of ischemic brain injury. In patients with no other signs of brain injury, postanoxic ESE may explain a poor outcome.

Differential degeneration of the locus coeruleus in dementia subtypes.

OBJECTIVE: Neuronal loss in the locus coeruleus (LC) is common in Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). The aims of the present study were to investigate LC degeneration in different dementia disorders including vascular dementia (VaD) and frontotemporal lobar degeneration (FTLD), to compare LC degeneration with severity of pathology in AD and DLB/PDD, to further evaluate the usefulness of a previously presented scoring system and to examine the predictive value of macroscopic assessment of the LC. METHODS: A horizontal mid-level section of the pons was examined in 200 neuropathologically examined cases with clinical dementia. A previous macroscopic assessment of the LC was performed in 149 of the cases. RESULTS: Cases with DLB/ PDD and AD presented with the highest microscopic LC degeneration scores, with significant differences compared to combined AD + VaD, in turn with a higher score than VaD, FTLD and other dementia disorders. Interrater agreement (weighted kappa;) for LC degeneration scoring was 0.83 - 0.91. DLB/ PDD, AD and AD + VaD were the diagnoses for 85% of the cases with macroscopic LC depigmentation. CONCLUSION: LC degeneration, which may be macroscopically noted, often indicates synuclein and/or Alzheimer pathology among demented. When clinical information is scarce or inconsistent, a macroscopic assessment of the LC may facilitate focusing of the subsequent neuropathological investigation. Also, the semiquantitative scoring system is a reliable tool for histological assessment of LC degeneration.

Comparison of four neuropathological scales for Alzheimer's disease.

OBJECTIVE: There are several neuropathological scales for staging of Alzheimer pathology. The system proposed by Braak and Braak is based on the topographic distribution of neurofibrillary tangles and neuropil threads, while that of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) is based on the quantity of neocortical neuritic plaques. A combination of the Braak and CERAD staging scales was recommended by the National Institute on Aging and Reagan Institute (NIA-RI). The Poly-Pathology Alzheimer's Disease assessment, nine areas (PPAD9) is a staging system based on the extent of neuronal degeneration, microvacuolization, cytoarchitectural disorder and gliosis, in addition to neurofibrillary tangles and neuritic plaques, in nine cerebral regions. The aim of the present study was to critically compare these four neuropathological staging scales. METHODS: We assessed the Alzheimer pathology, using the four scales, in 43 patients with various dementia disorders, with focus on concordance and differences between the staging systems. RESULTS: Comparing the staging systems, the Spearman's rho value for PPAD9 vs. Braak was 0.65, for PPAD9 vs. CERAD 0.72, for PPAD9 vs. NIA-RI 0.67, and for Braak vs. CERAD 0.46. CONCLUSION: The correlation between the neuropathological staging systems was suboptimal, and we conclude that the choice of staging system affects the evaluation of Alzheimer pathology, and hence the final diagnosis.

Apoptosis-inducing factor mediates dopaminergic cell death in response to LPS-induced inflammatory stimulus: evidence in Parkinson's disease patients.

We show that intranigral lipopolysaccharide (LPS) injection, which provokes specific degeneration of DA neurons, induced caspase-3 activation in the rat ventral mesencephalon, which was mostly associated with glial cells. In contrast, nigral DA neurons exhibited AIF nuclear translocation in response to LPS. A significant decrease of the Bcl-2/Bax ratio in nigral tissue after LPS injection was observed. We next developed an in vitro co-culture system with the microglial BV2 and the DA neuronal MN9D murine cell lines. The silencing of caspase-3 or AIF by small interfering RNAs exclusively in the DA MN9D cells demonstrated the key role of AIF in the LPS-induced death of DA cells. In vivo chemical inhibition of caspases and poly(ADP-ribose)polymerase-1, an upstream regulator of AIF release and calpain, proved the central role of the AIF-dependent pathway in LPS-induced nigral DA cell death. We also observed nuclear translocation of AIF in the ventral mesencephalon of Parkinson's disease subjects.

Intraepidermal nerve fibre density at wrist level in diabetic and non-diabetic patients.

AIMS: Myelinated nerve fibre pathology has been demonstrated at wrist level in diabetic patients. We examined if quantification of intra-epidermal nerve fibre density (IENFD) in hairy and glabrous skin at wrist level could detect signs of subclinical small nerve fibre neuropathy. METHODS: In 35 diabetic patients who were age and gender matched with 31 non-diabetic patients, punch biopsies were obtained in conjunction with surgical carpal tunnel release. Biopsies were immunostained with anti-protein gene product (PGP) 9.5. The IENFD was quantified using manual counting by light microscopy. RESULTS: We could not demonstrate significant differences in IENFD between diabetic or non-diabetic patients. Additionally, no differences were found between patients with Type 1 and Type 2 diabetes or in diabetic patients with and without neurophysiologic signs of mild peripheral neuropathy. However, the IENFD was significantly higher in hairy skin compared with glabrous skin. Furthermore, the IENFD was significantly higher in females than in males and correlated with age, but not with duration of diabetes or glycated haemoglobin (HbA(1c)). CONCLUSIONS: In mild neuropathy no difference in IENFD at the wrist level could be detected between diabetic and non-diabetic patients. Independent of diabetes, we found IENFD to be higher in hairy skin compared with glabrous skin and higher in females than in males. These results must be taken into consideration when assessing small nerve fibre pathology in the upper extremity.

Cause of death in patients with dementia disorders.

BACKGROUND: Investigations on cause of death may provide valuable information about life expectancy and on conditions of terminal dementia care, which perhaps can be ameliorated. METHODS: The autopsy reports were studied on all patients (n = 524; 55.3% females; median age 80 years) with a clinically and neuropathologically diagnosed dementia disorder who underwent a complete autopsy at the University Hospital in Lund, Sweden, during 1974-2004. RESULTS: The two most common causes of death were bronchopneumonia (38.4%) and ischaemic heart disease (23.1%), whilst neoplastic diseases were uncommon (3.8%). In a general population of elderly studied for comparison, bronchopneumonia accounted for 2.8%, ischaemic heart disease for 22.0%, and neoplasm for 21.3% of the deaths. Amongst the demented patients, circulatory and respiratory system diseases were the causes of death in 23.2% and 55.5% of the Alzheimer patients, respectively, whilst the corresponding figures were 54.8% and 33.1% for the patients with vascular dementia. CONCLUSIONS: In patients with dementia, pneumonia as the immediate cause of death may reflect a terminal stage in which patient care and feeding is difficult to manage well. Knowledge about what actually causes death is of value in the terminal care of patients with dementia disorders.

Different assessments of immunohistochemically stained Ki-67 and hTERT in glioblastoma multiforme yield variable results: a study with reference to survival prognosis.

OBJECTIVE: To investigate a marker of tumor proliferation, Ki-67, and telomerase expression in glioblastoma multiforme and to compare the results of different mainly quantitative assessments, in relation to age and survival rates. METHODS: Immunohistochemical stainings of Ki-67 and hTERT were evaluated in 39 formaldehyde-fixed, paraffin-embedded surgical samples of glioblastoma multiforme diagnosed during 2004, comprising all specimens with sufficient amount of vital tissue sent to the Department of Pathology during this year. Ki-67 counting and hTERT evaluation was assessed on whole tumor sections and on selected areas within each section. Age and length of survival were analyzed in relation to these parameters. RESULTS: We found that different methods of evaluating the stained sections yielded different results regarding Ki-67, but less marked differences for hTERT. With Ki-67 counting on whole sections (non-selected areas), we found a statistically significant correlation with length of survival. There was no corresponding information in the hTERT assessment. We could also confirm a significant inverse correlation between age and length of survival, as previously published. CONCLUSION: Our data demonstrate that different methods of Ki-67 evaluation may give markedly dissimilar results. The significant correlation found between survival and one but not with two other methods of Ki-67 assessment, implicate the value of standardized quantification methods. Our data indicate a possible prognostic use of immunohistochemical Ki-67 proliferation index in glioblastoma multiforme.

Abdominal aortic aneurysm and the impact of infectious burden.

OBJECTIVES: Little is known about the biological processes causing aortic aneurysm rupture. Chronic Chlamydophila pneumoniae infection has been suggested as a possible contributing factor to the development and expansion of abdominal aortic aneurysm (AAA). The importance of infection in AAA may be related to the previous pathogen burden, that is, the number of significant titres of antibodies against infectious pathogens rather than to single infectious agents. The aim of this study was to examine the relationship between infectious burden and AAA rupture. METHODS: In a case-control study, 119 patients with abdominal aortic aneurysm and 36 matched controls without aneurysm were prospectively investigated for specific IgG class antibodies against C. pneumoniae, Helicobacter pylori, Cytomegalovirus, and Herpes simplex virus. RESULTS: Patients with ruptured AAA have similar levels of pathogen burden as patients with nonruptured electively operated AAA, small AAA, and controls without aneurysm. CONCLUSION: The present study fails to demonstrate a connection between infectious burden and abdominal aortic aneurysm rupture.

Tracing anthropogenic nuclear activity with (129)I in lake sediment.

This study reports the first data of (129)I fallout in Scandinavia, covering the last 80 years. The investigation is based on sediment sections from a lake in central Sweden. In addition to analysis of (129)I, a combination of several radionuclides ((210)Pb, (137)Cs and (14)C) was used to establish an accurate chronology of the sediment profile. The concentration of (129)I exhibits an increasing trend ( approximately 10(7) to approximately 10(9)atoms/g) during the last 40 years, suggesting a significant atmospheric input from the nuclear reprocessing facilities in Sellafield (UK) and La Hague (France). A peak corresponding to fallout from the Chernobyl accident (1986) is clearly distinguishable, whereas the impact of fallout from the nuclear weapons' tests since the early 1950s is not distinguished.

Genetic intratumour heterogeneity in high-grade brain tumours is associated with telomere-dependent mitotic instability.

Glioblastoma multiforme (GBM) and other high-grade brain tumours are typically characterized by complex chromosome abnormalities and extensive intratumour cytogenetic heterogeneity. The mechanisms behind this diversity have been little explored. In this study, we analysed the pattern of chromosome segregation at mitosis in 20 brain tumours. We found an abnormal segregation of chromatids at mitosis through anaphase bridging (10-25% of anaphase cells) in all 10 GBMs. Anaphase bridging was also found in two medulloblastomas (7-15%), one anaplastic astrocytoma (17%) and one oligodendroglioma (6%). These tumours showed a relatively high degree of cytogenetic complexity and heterogeneity. In contrast, cell division abnormalities were not found in low-grade brain tumours with less complex karyotypes, including two pilocytic astrocytomas and two ependymomas. Further analysis of two GBMs by fluorescence in situ hybridization with telomeric repeat probes revealed excessive shortening of TTAGGG repeats, indicating dysfunctional protection of chromosome ends. In xenografts established from these GBMs, there was a gradual reduction in cytogenetic heterogeneity through successive passages as the proportion of abnormally short telomeres was reduced and the frequency of anaphase bridges decreased from >25% to 0. However, bridging could be reintroduced in late-passage xenograft cells by pharmacological induction of telomere shortening, using a small-molecule telomerase inhibitor. Telomere-dependent abnormal segregation of chromosomes at mitosis is thus a common phenomenon in high-grade brain tumours and may be one important factor behind cytogenetic intratumour diversity in GBM.

Dynamic susceptibility contrast-enhanced perfusion magnetic resonance (MR) imaging combined with contrast-enhanced MR imaging in the follow-up of immunogene-treated glioblastoma multiforme.

PURPOSE: To assess the value of the combined use of dynamic susceptibility contrast-enhanced perfusion magnetic resonance imaging (MRI) and conventional contrast-enhanced MRI for the follow-up of treatment of glioblastoma multiforme (GBM). MATERIAL AND METHODS: 79 examinations were performed in six surgically and immunogene-treated patients and two surgically treated patients. Ratios of the relative cerebral blood volume (rCBV) in lesions and in the contralateral normal-appearing white matter were calculated. The regions with elevated rCBV were compared with those with contrast enhancement. Tissue specimens from surgical biopsies and autopsies were studied histopathologically. RESULTS: The lesion-to-normal rCBV ratios were high in the tumors prior to operation (7.3 to 18.2) as well as in the recurrent tumors (1.6 to 13.2). The volumes of the regions with elevated rCBV were similar to those with contrast enhancement in 63 of the 79 examinations. However, in 11 of 79 examinations, the regions with high rCBV were smaller than the regions with contrast enhancement ("mismatch"). In two samples from the immunogene-treated patients this was correlated with the histopathological finding of malignant tumor with numerous proliferating GBM vessels with multiple minimal lumina, sometimes thrombotized or ruptured. These vessels may have increased permeability with contrast enhancement not accompanied by increased microvascular volume. CONCLUSION: 1) Elevated rCBV on perfusion MRI corresponding to the contrast-enhancing lesion supports the diagnosis of recurrent malignant tumor. 2) A mismatch showing a volume of rCBV elevation smaller than that of contrast enhancement can be seen in particularly aggressive tumor growth and is thus not always a sign of reactive non-tumor changes. 3) The combination of perfusion MRI and conventional contrast MRI provides useful information in the follow-up of glioblastoma multiforme treatment.

Tumor extension in high-grade gliomas assessed with diffusion magnetic resonance imaging: values and lesion-to-brain ratios of apparent diffusion coefficient and fractional anisotropy.

PURPOSE: To determine whether the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) can distinguish tumor-infiltrated edema in gliomas from pure edema in meningiomas and metastases. MATERIAL AND METHODS: Thirty patients were studied: 18 WHO grade III or IV gliomas, 7 meningiomas, and 5 metastatic lesions. ADC and FA were determined from ROIs placed in peritumoral areas with T2-signal changes, adjacent normal appearing white matter (NAWM), and corresponding areas in the contralateral healthy brain. Values and lesion-to-brain ratios from gliomas were compared to those from meningiomas and metastases. RESULTS: Values and lesion-to-brain ratios of ADC and FA in peritumoral areas with T2-signal changes did not differ between gliomas, meningiomas, and metastases (P = 0.40, P = 0.40, P = 0.61, P = 0.34). Values of ADC and FA and the lesion-to-brain ratio of FA in the adjacent NAWM did not differ between tumor types (P = 0.74, P = 0.25, and P = 0.31). The lesion-to-brain ratio of ADC in the adjacent NAWM was higher in gliomas than in meningiomas and metastases (P = 0.004), but overlapped between tumor types. CONCLUSION: Values and lesion-to-brain ratios of ADC and FA in areas with T2-signal changes surrounding intracranial tumors and adjacent NAWM were not helpful for distinguishing pure edema from tumor-infiltrated edema when data from gliomas, meningiomas, and metastases were compared.