Craig Winter

Computational fluid dynamic analysis of intracranial aneurysmal bleb formation

BACKGROUND The management of unruptured aneurysms is controversial, with the decision to treat influenced by aneurysm characteristics including size and morphology. Aneurysmal bleb formation is thought to be associated with an increased risk of rupture. OBJECTIVE To correlate computational fluid dynamic (CFD) indices with bleb formation. METHODS Anatomic models were constructed from 3-dimensional rotational angiography data in 27 patients with cerebral aneurysms harboring a single bleb. Additional models representing the aneurysm before bleb formation were constructed by digitally removing the bleb. We characterized hemodynamic features of models both with and without the blebs using CFDs. Flow structure, wall shear stress (WSS), pressure, and oscillatory shear index (OSI) were analyzed. RESULTS There was a statistically significant association between bleb location at or adjacent to the point of maximal WSS (74%, P = .019), irrespective of rupture status. Aneurysmal blebs were related to the inflow or outflow jet in 89% of cases (P < .001), whereas 11% were unrelated. Maximal wall pressure and OSI were not significantly related to bleb location. The bleb region attained a lower WSS after its formation in 96% of cases (P < .001) and was also lower than the average aneurysm WSS in 86% of cases (P < .001). CONCLUSION Cerebral aneurysm blebs generally form at or adjacent to the point of maximal WSS and are aligned with major flow structures. Wall pressure and OSI do not contribute to determining bleb location. The measurement of WSS using CFD models may potentially predict bleb formation and thus improve the assessment of rupture risk in unruptured aneurysms.

Glioma surgical aspirate: a viable source of tumor tissue for experimental research

Brain cancer research has been hampered by a paucity of viable clinical tissue of sufficient quality and quantity for experimental research. This has driven researchers to rely heavily on long term cultured cells which no longer represent the cancers from which they were derived. Resection of brain tumors, particularly at the interface between normal and tumorigenic tissue, can be carried out using an ultrasonic surgical aspirator (CUSA) that deposits liquid (blood and irrigation fluid) and resected tissue into a sterile bottle for disposal. To determine the utility of CUSA-derived glioma tissue for experimental research, we collected 48 CUSA specimen bottles from glioma patients and analyzed both the solid tissue fragments and dissociated tumor cells suspended in the liquid waste fraction. We investigated if these fractions would be useful for analyzing tumor heterogeneity, using IHC and multi-parameter flow cytometry; we also assessed culture generation and orthotopic xenograft potential. Both cell sources proved to be an abundant, highly viable source of live tumor cells for cytometric analysis, animal studies and in-vitro studies. Our findings demonstrate that CUSA tissue represents an abundant viable source to conduct experimental research and to carry out diagnostic analyses by flow cytometry or other molecular diagnostic procedures.

Papillary tumour of the pineal region

Papillary tumour of the pineal region (PTRR) is one of the new tumour entities to be included in the latest World Health Organization classification of central nervous system tumours. We report two illustrative patients, a 25-year-old female who presented following a head injury sustained from a fall due to gait disturbances, and a 42-year-old man who presented with headaches. Histology of both cases showed distinct papillary growth patterns with lining of the papillae by multi-layered cuboidal to columnar cells, prominent perivascular rosette and focal true rosette formation. Immunohistochemistry exhibited strong cytokeratin immunoreactivity in addition to CD56, focal S100, glial fibrillary acidic protein and neuron specific enolase positivity which supported a diagnosis of PTPR in both patients. Postoperatively, both patients underwent courses of adjuvant radiation therapy. One patient reported local recurrence of the tumour 23 months after surgery. While PTPR may have been misdiagnosed in the past, clear and consistent characteristics are beginning to be elucidated in the published reports and literature, which have been reviewed. As a relatively new distinct clinicopathological entity, prognostic data are limited and guidelines for treatment protocols are still being investigated in view of its propensity for local recurrence.

Frontal Executive Impairment Associated With Paraneoplastic Cerebellar Degeneration: A Case Study

Paraneoplastic cerebellar degeneration (PCD) is a rare cause of profound cerebellar dysfunction. Degenerative disorders of the cerebellum can cause cognitive and behavioral changes but the neuropsychological and behavioral sequelae of PCD are not well described. In this article, we detail selective frontal-executive disturbance, psychomotor slowing and affective change in a patient with PCD in whom there is no apparent extracerebellar involvement. The pattern of deficits suggests that PCD may be clinically dissociable from other forms of paraneoplastic encephalitis and correspond closely with the recently proposed “cerebellar-affective syndrome.” The results underline the importance of the cerebellum in regulating cognitive function.

Early prediction of treatment response in advanced gliomas with 18F-DOPA positron-emission tomography

The Editor Current Oncology August 27, 2013 Imaging markers that enable prediction of survival are of interest for aiding clinical decision-making for patients with advanced glioma. However, current imaging methods based on the use of contrast-enhanced magnetic resonance imaging (mri) and 18F-fludeoxyglucose positron-emission tomography (pet) applied in the early stages after treatment are not strongly correlated with patient outcome. In conjunction with mri, amino-acid pet tracers have shown promise for this application, including variations in l-[methyl-11C]-methionine uptake1 and 3′-dexoy-3′-[18F] fluorothymidine (flt)2 uptake, and volume variations of regions with high flt and 6-[18F] fluoro-l-dopa (18F-dopa)3 uptake. Uptake of flt is predictive of survival in recurrent advanced glioma, even when chemotherapy renders mri unreliable2. However, previous serial assessments have typically considered global uptake within the tumour1,2,4, even though treatment failure frequently occurs locally within areas of existing abnormality5. The hypothesis explored here is that poor patient survival is directly related to the extent of the most treatment-resistant cluster of malignant cells exhibiting persistent metabolic activity. Apart from the use of 18F-dopa as an early surrogate marker, a key difference between this study and previous work is the longitudinal comparison of metabolic activity within focal peritumoural regions. The study enrolled 9 patients (7 men; age range: 52–71 years), summarized in Table i, with histopathologically confirmed high-grade brain tumour (World Health Organization grade iv). The institutional ethics review board approved the study, and patients provided informed written consent. Patients received mri and 18F-dopa pet scans at two time points: a baseline immediately before tumour resection, and a follow-up at 12 weeks after resection. The post-resection interval consisted of 2 weeks’ recovery, a 6-week course of chemoradiotherapy (external-beam radiotherapy of 60 Gy in 30 fractions or 40 Gy in 15 fractions, with concurrent temozolomide), and 4 weeks’ recovery to minimize potential treatment-induced variations in metabolism. (Figure 1 provides a schematic outline.) The pet intensities were normalized to the ipsilateral cerebellum and reported as standardized uptake value ratios. One patient did not receive chemoradiotherapy. Table I Values extracted from each dataset Figure 1 Timing of magnetic resonance imaging (mri) and 18F-dopa positron-emission tomography (fdopa). Both modalities were used at two time points: once before surgery and once 12 weeks after surgery. Chemo-rt = chemoradiation therapy. After rigid registration, the most metabolically active voxel in each post-treatment tumour was selected from the pet image. Using nearby anatomic features from the fused mri, the corresponding location was selected on the pre-surgery image under the guidance of experienced specialists (PT, MF, RLJ, CW, AC) blinded to the pre-treatment pet image and patient outcome. The mean 18F-dopa uptake within a 1-cm radius sphere centred on each landmark was calculated before computing the difference between baseline and follow-up. The 1-cm radius traded off the typical statistical variation in pet intensities and potential inaccuracies in spatial correspondences with the size of metabolically active regions. A Cox proportional hazards analysis model was used to evaluate the relationship between variations in 18Fdopa uptake and survival. Survival times, plotted in Figure 2 as a function of change in 18F-dopa uptake, ranged from less than 30 weeks to more than 110 weeks. At last report, 3 patients remained alive. Variations in 18F-dopa uptake ranged from less than −50% to more than +20%. The results, summarized in Table ii, demonstrate that a decrease in 18F-dopa uptake is a predictor of extended survival. For interest, the selected regions in each patient are shown in Figures 3–5. A Cox proportional hazards model fitted the data closely (r = 0.65), and showed that the hazard to the patient declined by 10.3% with each 1% decrease in local 18F-dopa uptake. The null hypothesis—that changes in 18F-dopa are not related to survival—was rejected with some significance (p < 0.032). Figure 2 Plot of survival versus local change in the spherical region centred on the point of greatest metabolism after treatment. A value of 0% (dotted line) indicates no change in 18F-dopa uptake. Chemo-rt = chemoradiation therapy. aPatient was alive at last ... Table II Statistics extracted from all patients Figure 3 The spherical region of interest (green circles) superimposed on the 18F-dopa positron-emission tomography (pet) and contrast-enhanced magnetic resonance imaging (mri) images for patients 1–3 at baseline and follow-up. Baseline images were acquired ... Figure 5 The spherical region of interest (green circles) superimposed on the 18F-dopa positron-emission tomography (pet) and contrast-enhanced magnetic resonance (mr) images for patients 7–9 at baseline and follow-up. Baseline images were acquired before ... Figure 4 The spherical region of interest (green circles) superimposed on the 18F-dopa positron-emission tomography (pet) and contrast-enhanced magnetic resonance (mr) images for patients 4–6 at baseline and follow-up. Baseline images were acquired before ... A second model, incorporating age and sex, was compared with the first using analysis of variance (Table iii). The comparison showed that the models largely overlapped (p > 0.7), and consecutive increases for log likelihood (4.74 for change in local 18F-dopa, 0.24 for age, and 0.23 for sex) indicated that age and sex had a more limited influence on the results. Finally, global 18F-dopa uptake (mean over the entire tumour) was compared with survival. Compared with local 18F-dopa, global 18F-dopa was less correlated with survival (5.2% decline in hazard for 1% decrease in uptake), had a poorer fit (r = 0.33), and was less significant (p < 0.1). Table III Crudea analysis of variance that considers additional effects of age and sex The more significant correlation between 18F-dopa variations locally within tumours (rather than globally), supports the hypothesis that patient survival might be linked to focal points of treatment failure within peritumoural colonies of malignant cells that exhibit enhanced amino-acid uptake after therapy. Hence, variations in 18F-dopa are potentially indicative of a genetic predisposition in certain tumours toward treatment sensitivity, with the resulting delay before disease progression leading to extended survival. These results motivate for the use of 18F-dopa–based response criteria as endpoint markers and extend the concept of using 18F-dopa–based response criteria to as early as 12 weeks after surgery. Earlier prediction of response could potentially enable early transfer to palliative care if appropriate, early enrolment of patients into therapeutic trials for recurrent tumour, and rapid screening of new therapeutic agents.

Blood–brain barrier dysfunction following traumatic brain injury: correlation of Ktrans (DCE-MRI) and SUVR (99mTc-DTPA SPECT) but not serum S100B

Abstract Objective: Damage to the blood–brain barrier (BBB) is an important secondary mechanism that occurs following traumatic brain injury (TBI) and may provide a potential therapeutic target to improve patient outcome. For such a progress to be realised, an accurate assessment of BBB compromise needs to be established. Methods: Fourteen patients with TBI were prospectively recruited. Post-traumatic BBB dysfunction was assessed using dynamic contrast-enhanced MRI (DCE-MRI), single-photon emission computerised tomography (SPECT) and serum S100B levels. Results: A statistically significant correlation between standardised uptake value ratio (SUVR) calculated from 99mTc-DTPA SPECT and Ktrans (a volume transfer constant) from DCE-MRI was found for those eight patients who had concurrent scans. The positive correlation persisted when the data were corrected for patient age, number of days following trauma and both parameters combined. We found no statistically significant correlation between either of the imaging modalities and concurrent serum S100B levels. Discussion: The correlation of SPECT with DCE-MRI suggests that either scan may be used to assess post-traumatic BBB damage. We could not support serum S100B to be an accurate measure of BBB damage when sampled a number of days following injury but the small number of patients, the heterogeneity in TBI patients and the delay following injury makes any firm conclusions regarding S100B and BBB difficult.

Joint factor and kinetic analysis of dynamic FDOPA PET scans of brain cancer patients

Kinetic analysis is an essential tool of Positron Emission Tomography image analysis. However it requires a pure tissue time activity curve (TAC) in order to calculate the system parameters. Pure tissue TACs are particularly difficult to obtain in the brain as the low resolution of PET means almost all voxels are a mixture of tissues. Factor analysis explicitly accounts for mixing but is an underdetermined problem that can give arbitrary results. A joint factor and kinetic analysis is proposed whereby factor analysis explicitly accounts for mixing of tissues. Hence, more meaningful parameters are obtained by the kinetic models, which also ensure a less ambiguous solution to the factor analysis. The method was tested using a cylindrical phantom and the 18F-DOPA data of a brain cancer patient.

Elevated plasma S100B levels in high altitude hypobaric hypoxia do not correlate with acute mountain sickness

Abstract Objectives: Ascent to high altitude may result in a hypobaric hypoxic brain injury. The development of acute mountain sickness (AMS) is considered a multifactorial process with hypoxia-induced blood–brain barrier (BBB) dysfunction and resultant vasogenic oedema cited as one potential mechanism. Peripheral S100B is considered a biomarker of BBB dysfunction. This study aims to investigate the S100B release profile secondary to hypoxic brain injury and comment on BBB disturbance and AMS. Methods: A prospective field study of 12 subjects who ascended Mt Fuji (3700 m) was undertaken. Results: The mean baseline plasma S100B level was 0·11 μg/l (95% CI 0·09–0·12), which increased to 0·22 μg/l (95% CI 0·17–0·27) at the average of three high altitude levels (2590, 3700, and 2590 m on descent) (P < 0·001). The mean level for the seven subjects who experienced AMS rose from 0·10 to 0·19 μg/l compared to 0·12 to 0·25 μg/l for the five subjects who did not develop AMS (P  =  0·33). Conclusion: Ascending to 3700 m resulted in elevated plasma S100B levels but this was not associated with AMS.

Incidence and outcome of subarachnoid haemorrhage in the general and emergency department populations in Queensland from 2010 to 2014

To determine: (i) incidence and outcome of subarachnoid haemorrhage (SAH) in the general population; and (ii) proportions of SAH in both the general ED population and in ED patients presenting with headache.

Assessing local outcomes in heterogeneous gliomas

Tumours are known to be heterogeneous, yet typical treatment plans consider them as a single unit. This may influence treatment outcomes. However, treatment cannot be customised to intra-tumour variation without a method to establish outcomes at an intra-tumour scale. This work proposes a method to both assess and measure outcomes locally within tumours. Methods: Four patients were scanned at two post-surgery time points using contrast enhanced MRI and 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-DOPA) PET. The shell of active tumour tissue is divided into a set of small subregions at both time points. Local outcome is measured from changes in subregion volume over time. The utility of the proposed approach is evaluated by measuring the correlation between PET uptake and documented growth. Correlation with overall survival time was also examined. Results: Local outcomes were heterogeneous and evidence of a positive correlation between local 18F-DOPA uptake and local progression was observed. Conclusions: Given that intra-tumour outcomes are heterogeneous the consistently positive correlation between FDOPA uptake and progression, local analysis of tumours could prove useful for treatment planning.