Clinical implementation of magnetic resonance imaging simulation for radiation oncology planning: 5 year experience.

PURPOSE: Integrating magnetic resonance (MR) into radiotherapy planning has several advantages. This report details the clinical implementation of an MR simulation (MR-planning) program for external beam radiotherapy (EBRT) in one of North America's largest radiotherapy programs. METHODS AND MATERIALS: An MR radiotherapy planning program was developed and implemented at Sunnybrook Health Sciences Center in 2016 with two dedicated wide-bore MR platforms (1.5 and 3.0 Tesla). Planning MR was sequentially implemented every 3 months for separate treatment sites, including the central nervous system (CNS), gynecologic (GYN), head and neck (HN), genitourinary (GU), gastrointestinal (GI), breast, and brachial plexus. Essential protocols and processes were detailed in this report, including clinical workflow, optimized MR-image acquisition protocols, MR-adapted patient setup, strategies to overcome risks and challenges, and an MR-planning quality assurance program. This study retrospectively reviewed simulation site data for all MR-planning sessions performed for EBRT over the past 5 years. RESULTS: From July 2016 to December 2021, 8798 MR-planning sessions were carried out, which corresponds to 25% of all computer tomography (CT) simulations (CT-planning) performed during the same period at our institution. There was a progressive rise from 80 MR-planning sessions in 2016 to 1126 in 2017, 1492 in 2018, 1824 in 2019, 2040 in 2020, and 2236 in 2021. As a result, the relative number of planning MR/CT increased from 3% of all planning sessions in 2016 to 36% in 2021. The most common site of MR-planning was CNS (49%), HN (13%), GYN (12%), GU (12%), and others (8%). CONCLUSION: Detailed clinical processes and protocols of our MR-planning program were presented, which have been improved over more than 5 years of robust experience. Strategies to overcome risks and challenges in the implementation process are highlighted. Our work provides details that can be used by institutions interested in implementing an MR-planning program.

Skull phantom-based methodology to validate MRI co-registration accuracy for Gamma Knife radiosurgery.

PURPOSE: Target localization, for stereotactic radiosurgery (SRS) treatment with Gamma Knife, has become increasingly reliant on the co-registration between the planning MRI and the stereotactic cone-beam computed tomography (CBCT). Validating image registration between modalities would be particularly beneficial when considering the emergence of novel functional and metabolic MRI pulse sequences for target delineation. This study aimed to develop a phantom-based methodology to quantitatively compare the co-registration accuracy of the standard clinical imaging protocol to a representative MRI sequence that was likely to fail co-registration. The comparative methodology presented in this study may serve as a useful tool to evaluate the clinical translatability of novel MRI sequences. METHODS: A realistic human skull phantom with fiducial marker columns was designed and manufactured to fit into a typical MRI head coil and the Gamma Knife patient positioning system. A series of "optimized" 3D MRI sequences-T1 -weighted Dixon, T1 -weighted fast field echo (FFE), and T2 -weighted fluid-attenuated inversion recovery (FLAIR)-were acquired and co-registered to the CBCT. The same sequences were "compromised" by reconstructing without geometric distortion correction and re-collecting with lower signal-to-noise-ratio (SNR) to simulate a novel MRI sequence with poor co-registration accuracy. Image similarity metrics-structural similarity (SSIM) index, mean squared error (MSE), and peak SNR (PSNR)-were used to quantitatively compare the co-registration of the optimized and compromised MR images. RESULTS: The ground truth fiducial positions were compared to positions measured from each optimized image volume revealing a maximum median geometric uncertainty of 0.39 mm (LR), 0.92 mm (AP), and 0.13 mm (SI) between the CT and CBCT, 0.60 mm (LR), 0.36 mm (AP), and 0.07 mm (SI) between the CT and T1 -weighted Dixon, 0.42 mm (LR), 0.23 mm (AP), and 0.08 mm (SI) between the CT and T1 -weighted FFE, and 0.45 mm (LR), 0.19 mm (AP), and 1.04 mm (SI) between the CT and T2 -weighted FLAIR. Qualitatively, pairs of optimized and compromised image slices were compared using a fusion image where separable colors were used to differentiate between images. Quantitatively, MSE was the most predictive and SSIM the second most predictive metric for evaluating co-registration similarity. A clinically relevant threshold of MSE, SSIM, and/or PSNR may be defined beyond which point an MRI sequence should be rejected for target delineation based on its dissimilarity to an optimized sequence co-registration. All dissimilarity thresholds calculated using correlation coefficients with in-plane geometric uncertainty would need to be defined on a sequence-by-sequence basis and validated with patient data. CONCLUSION: This study utilized a realistic skull phantom and image similarity metrics to develop a methodology capable of quantitatively assessing whether a modern research-based MRI sequence can be co-registered to the Gamma Knife CBCT with equal or less than equal accuracy when compared to a clinically accepted protocol.

Accuracy and precision of apparent diffusion coefficient measurements on a 1.5 T MR-Linac in central nervous system tumour patients.

BACKGROUND AND PURPOSE: MRI linear accelerators (MR-Linacs) may allow treatment adaptation to be guided by quantitative MRI including diffusion-weighted imaging (DWI). The aim of this study was to evaluate the accuracy and precision of apparent diffusion coefficient (ADC) measurements from DWI on a 1.5 T MR-Linac in patients with central nervous system (CNS) tumours through comparison with a diagnostic scanner. MATERIALS AND METHODS: CNS patients were treated using a 1.5 T Elekta Unity MR-Linac. DWI was acquired during MR-Linac treatment and on a Philips Ingenia 1.5 T. The agreement between the two scanners on median ADC over the gross tumour/clinical target volumes (GTV/CTV) and in brain regions (white/grey matter, cerebrospinal fluid (CSF)) was computed. Repeated scans were used to estimate ADC repeatability. Daily changes in ADC over the GTV of high-grade gliomas were characterized from MR-Linac scans. RESULTS: DWI from 59 patients was analyzed. MR-Linac ADC measurements showed a small bias relative to Ingenia measurements in white matter, grey matter, GTV, and CTV (bias: -0.05 ± 0.03, -0.08 ± 0.05, -0.1 ± 0.1, -0.08 ± 0.07 µm2/ms). ADC differed substantially in CSF (bias: -0.5 ± 0.3 µm2/ms). The repeatability of MR-Linac ADC over white/grey matter was similar to previous reports (coefficients of variation for median ADC: 1.4%/1.8%). MR-Linac ADC changes in the GTV were detectable. CONCLUSIONS: It is possible to obtain ADC measurements in the brain on a 1.5 T MR-Linac that are comparable to those of diagnostic-quality scanners. This technical validation study adds to the foundation for future studies that will correlate brain tumour ADC with clinical outcomes.

Chemical exchange saturation transfer MRI in central nervous system tumours on a 1.5 T MR-Linac.

PURPOSE: To describe the implementation and initial results of using Chemical Exchange Saturation Transfer (CEST) for monitoring patients with central nervous system (CNS) tumours treated using a 1.5 tesla MR-guided radiotherapy system. METHODS: CNS patients were treated with up to 30 fractions (total dose up to 60 Gy) using a 1.5 T Elekta Unity MR-Linac. CEST scans were obtained in 54 subjects at one or more time points during treatment. CEST metrics, including the amide magnetization transfer ratio (MTRAmide), nuclear Overhauser effect (NOE) MTR (MTRNOE) and asymmetry, were quantified in phantoms and CNS patients. The signal was investigated between tumour and white matter, across time, and across disease categories including high- and low-grade tumours. RESULTS: The gross tumour volume (GTV) exhibited lower MTRAmide and MTRNOE and higher asymmetry compared to contralateral normal appearing white matter. Signal changes in the GTV during fractionated radiotherapy were observed. There were differences between high- and low-grade tumours, with higher CEST asymmetry associated with higher grade disease. CONCLUSION: CEST MRI using a 1.5 T MR-Linac was demonstrated to be feasible for in vivo imaging of CNS tumours. CEST images showed tumour/white-matter contrast, temporal CEST signal changes, and associations with tumour grade. These results show promise for the eventual goal of using metabolic imaging to inform the design of adaptive radiotherapy protocols.

Measurement of surface dose in an MR-Linac with optically stimulated luminescence dosimeters for IMRT beam geometries.

PURPOSE: This study aims to measure the surface dose on an anthropomorphic phantom for intensity-modulated radiation therapy (IMRT) plans treated in a 1.5 T magnetic resonance (MR)-Linac. Previous studies have used Monte Carlo programs to simulate surface dose and have recognized high surface dose as a potential limiting factor for the MR-Linac; however, to our knowledge surface dose measurement for clinical plans has not yet been published. Given the novelty of the MR-Linac, it is important to perform in vivo measurements of a potentially dose-limiting factor such as surface dose when moving forward for clinical use. METHODS: Optically stimulated luminescence dosimeters (OSLDs) were used on an anthropomorphic phantom. Intensity-modulated radiation therapy plans were generated to treat a near-surface breast tumor in the phantom. The tumor was treated with 2, 3, 5, 7, and 9 beam IMRT plans with a 1.5 T MR-Linac using a 7-MV photon beam. The plans were generated in a Monte Carlo treatment planning system (TPS) capable of modeling magnetic field effects. The surface dose was sampled in seven locations on the surface surrounding the planning target volume (PTV), and in two different OSLD configurations with the dosimeters measuring water equivalent depths of 0.16 and 0.64 mm. The TPS was used to estimate the doses at the OSLD locations. In addition, MR images were taken of a pork belly with and without an OSLD placed anteriorly placed to determine the effect of an OSLD on image fidelity. RESULTS: For the 3, 5, 7, and 9-beam configurations, surface doses were approximately half that of the prescription dose to the simulated tumor, although the magnitude of the skin dose relative to the prescription is certainly also dependent on individual patient anatomy. The general trend for both TPS and measurements was that the greater the number of beams, the lower the skin doses and dose readings; also, with increasing numbers of beams, doses at shallow depths become lower relative to deeper depths. The MR images showed that the presence of the OSLD did not induce clinically relevant geometric distortions or intensity differences. CONCLUSIONS: To our knowledge, this study is the first of its kind to experimentally measure the surface dose in an MR-Linac for IMRT plans. This study has explored the use of OSLDs to measure in vivo surface dose in a clinical setting. OSLDs may be used to measure skin dose clinically when there are concerns of skin radiation burns and near-surface toxicity. Optically stimulated luminescence dosimeters are promising devices for in vivo surface dosimetry in an MR-Linac.

Quantitative MRI Biomarkers of Stereotactic Radiotherapy Outcome in Brain Metastasis.

About 20-40% of cancer patients develop brain metastases, causing significant morbidity and mortality. Stereotactic radiation treatment is an established option that delivers high dose radiation to the target while sparing the surrounding normal tissue. However, up to 20% of metastatic brain tumours progress despite stereotactic treatment, and it can take months before it is evident on follow-up imaging. An early predictor of radiation therapy outcome in terms of tumour local failure (LF) is crucial, and can facilitate treatment adjustments or allow for early salvage treatment. In this study, an MR-based radiomics framework was proposed to derive and investigate quantitative MRI (qMRI) biomarkers for the outcome of LF in brain metastasis patients treated with hypo-fractionated stereotactic radiation therapy (SRT). The qMRI biomarkers were constructed through a multi-step feature extraction/reduction/selection framework using the conventional MR imaging data acquired from 100 patients (133 lesions), and were applied in conjunction with machine learning techniques for outcome prediction and risk assessment. The results indicated that the majority of the features in the optimal qMRI biomarkers characterize the heterogeneity in the surrounding regions of tumour including edema and tumour/lesion margins. The optimal qMRI biomarker consisted of five features that predict the outcome of LF with an area under the curve (AUC) of 0.79, and a cross-validated sensitivity and specificity of 81% and 79%, respectively. The Kaplan-Meier analyses showed a statistically significant difference in local control (p-value < 0.0001) and overall survival (p = 0.01). Findings from this study are a step towards using qMRI for early prediction of local failure in brain metastasis patients treated with SRT. This may facilitate early adjustments in treatment, such as surgical resection or salvage radiation, that can potentially improve treatment outcomes. Investigations on larger cohorts of patients are, however, required for further validation of the technique.

Single-Fraction Stereotactic Radiosurgery Versus Hippocampal-Avoidance Whole Brain Radiation Therapy for Patients With 10 to 30 Brain Metastases: A Dosimetric Analysis.

PURPOSE: To compare normal tissue dosimetry between hippocampal-avoidance whole brain radiation therapy (HA-WBRT) and stereotactic radiosurgery (SRS) in patients with 10 to 30 brain metastases, and to describe a novel SRS strategy we term Spatially Partitioned Adaptive RadiosurgEry (SPARE). METHODS AND MATERIALS: A retrospective review identified SRS treatment plans with >10 brain metastases located >5 mm from the hippocampi. Our Gamma Knife Icon (GKI) SPARE (GKI-Spr) technique treats multiple metastases with single-fraction SRS partitioned over consecutive days while limiting the total treatment time to ≤60 minutes per day. Hippocampal and normal brain dosimetry were compared among GKI-Spr, single-fraction single-day GKI (GKI-Sfr), and 30 Gy in 10 fractions HA-WBRT. Dose metrics were converted to equivalent dose in 2 Gy fractions. RESULTS: Ten cases were analyzed. Compared with HA-WBRT, GKI-Spr significantly reduced the median equivalent dose in 2 Gy fractions hippocampal maximum point dose, mean dose, and dose to 40% of the hippocampi (D40%) by 86%, 93%, and 93%, respectively, and similarly for GKI-Sfr by 81%, 92%, and 91%, respectively. The normal brain median mean dose was reduced by 95% with GKI-Spr and 94% with GKI-Sfr. Compared with GKI-Sfr, GKI-Spr further reduced all normal brain and hippocampal dose metrics (P ≤ .014). CONCLUSIONS: GKI yields superior hippocampal and normal brain dosimetry compared with HA-WBRT, and GKI-Spr results in further dosimetric advantages.

MRI commissioning of 1.5T MR-linac systems - a multi-institutional study.

BACKGROUND: Magnetic Resonance linear accelerator (MR-linac) systems represent a new type of technology that allows for online MR-guidance for high precision radiotherapy (RT). Currently, the first MR-linac installations are being introduced clinically. Since the imaging performance of these integrated MR-linac systems is critical for their application, a thorough commissioning of the MRI performance is essential. However, guidelines on the commissioning of MR-guided RT systems are not yet defined and data on the performance of MR-linacs are not yet available. MATERIALS & METHODS: Here we describe a comprehensive commissioning protocol, which contains standard MRI performance measurements as well as dedicated hybrid tests that specifically assess the interactions between the Linac and the MRI system. The commissioning results of four MR-linac systems are presented in a multi-center study. RESULTS: Although the four systems showed similar performance in all the standard MRI performance tests, some differences were observed relating to the hybrid character of the systems. Field homogeneity measurements identified differences in the gantry shim configuration, which was later confirmed by the vendor. CONCLUSION: Our results highlight the importance of dedicated hybrid commissioning tests and the ability to compare the machines between institutes at this very early stage of clinical introduction. Until formal guidelines and tolerances are defined the tests described in this study may be used as a practical guideline. Moreover, the multi-center results provide initial bench mark data for future MR-linac installations.

Clinical Image Coregistration Variability on a Dedicated Radiosurgery Unit.

BACKGROUND: On a new dedicated radiosurgery unit enabling frameless treatments, a cone-beam computed tomography (CBCT) can be used for stereotactic definition. Since magnetic resonance imaging (MRI) is used to delineate target, reproducible MRI-to-CBCT coregistration is vital for accurate target localization. OBJECTIVE: To evaluate reproducibility of image coregistration in patient images. METHODS: Three types of coregistration (source-to-target) were analyzed: (1) MRI-to-CT; (2) MRI-to-CBCT; and (3) CT-to-CBCT. For each patient (n = 15), each coregistration type was independently performed 5 to 30 times (total: 465 coregistrations). Each coregistration yielded a transformation matrix, which was subsequently applied to transform every point in the source image to stereotactic coordinates. Two metrics were measured: (1) target registration error (TRE): mean distance between the registered position of each target point and the average registration position of that point; (2) compound registration error (CRE): mean spatial difference between stereotactic coordinates using (A) MRI-to-CT-to-CBCT and (B) MRI-to-CBCT. RESULTS: The median (range) of TRE was 0.11 mm (0.06-0.22 mm), 0.17 mm (0.10-0.36 mm), and 0.12 mm (0.08-0.21 mm) for MRI-to-CT, MRI-to-CBCT, and CT-to-CBCT, respectively. The TRE for MRI-to-CBCT was statistically higher than the other 2 methods (P < .01). The median (range) of CRE was 0.44 mm (0.22-0.59 mm). The maximum point CRE between patients ranged from 0.37-1.15 mm when considering all MRI points, but reduced to 0.31-0.90 mm within the central 16 cm. The CRE varied across the image volume, and typically was minimized near the center. CONCLUSION: The variation in image coregistration is within 0.2 mm, indicating a high degree of reproducibility. The CRE varies throughout the head but is submillimeter in the central 16 cm region.

Performance characterization of an integrated cone-beam CT system for dedicated gamma radiosurgery.

PURPOSE: This work describes the performance characterization of a cone-beam CT-guided radiosurgery device, the Gamma Knife® Icon™. METHODS: The performance tests have been categorized into: (a) image quality and mechanical integrity; (b) image coregistration fidelity; (c) adaptive treatment delivery quality; (d) high definition motion management performance characterization; (e) software communication performance testing of the integrated cone-beam CT (CBCT) system. RESULTS: All image quality performance characterization satisfied or exceeded manufacturer specifications. The image quality and mechanical stability of the CBCT system over a 3-month period was within tolerance with negligible (<0.1°) detector tilt angle. The CBCT definition of the stereotactic space had a measured average discrepancy of 0.15-0.16 mm in x, y, and z directions. On average, the high definition motion management system performance was within 0.05 mm with a residual offset of 0.15 mm when large displacements in a given direction were taken. The adaptive treatment delivery component as measured with CBCT coregistration of daily setups against reference setup images was accurate to within 0.2°. Comprehensive end-to-end testing showed a total uncertainty of better than 0.2 mm in positioning and 0.4% in dosimetry for treatment of centrally located lesions. CONCLUSIONS: A set of system performance characterization tests spanning all aspects of the Gamma Knife Icon are presented. Overall, the system performance was in line with manufacturer specifications.

Investigation of irradiated volume in linac-based brain hypo-fractionated stereotactic radiotherapy.

BACKGROUND: Emerging techniques such as brain hypo-fractionated radiotherapy (HF-RT) involve complex cases with limited guidelines for plan quality and normal tissue tolerances. The purpose of the present study was to statistically parameterize irradiated volume independently of dose prescription, or margin to determine what spread in achievable irradiated volume one may expect for a given case. METHODS: We defined EXT as the total tissue within the external contour of the patient (including the target) and we defined BMP as the contour of the brain minus PTV. Irradiated volumes of EXT and BMP at specific doses (i.e. 50, 60%, etc., of the prescribed dose) were extracted from 135 single-target HF-RT clinical cases, each planned with a single-arc, homogeneous (SAHO) approach in which target maximum dose (Dmax) was constrained to <130% of the prescribed dose. Irradiated volumes were subsequently measured for cases involving 2 targets (N = 29), 3 targets (N = 7) and >3 targets (N = 10) to investigate the effect of target number. We also examined the effect of shape complexity. A series of best fit curves with confidence and prediction intervals were generated for irradiated volume versus total target volume and the resulting model was subsequently validated on a subsequent set of 23 consecutive prospective cases not originally used in curve-fitting. A subset of 30 HF-RT cases were re-planned with a well-published four-arc, heterogeneous (FAHE) radiosurgery planning approach (Dmax could exceed 130%) to demonstrate how technique affects irradiated volume. RESULTS: For SAHO, strong correlation (R2 > 0.98) was found for predicting irradiated volumes. For a given total target volume, irradiated-volume increased by a range of 1.4-2.9× for >3 versus single-targets depending on isodose level. Shape complexity had minor impact on irradiated volume. There was no statistical difference in irradiated volumes between validation and input data (p > 0.2). The FAHE-generated irradiated volumes yielded curves and prediction and confidence bands that agreed well with published data indicating that the proposed approach is feasible for cross-institutional comparisons. CONCLUSIONS: A description of irradiated volume for linac-based HF-RT is proposed based on population data. We have demonstrated that the proposed approach is feasible for inter and intra-institutional comparisons.

A realistic phantom for validating MRI-based synthetic CT images of the human skull.

PURPOSE: To introduce a new realistic human skull phantom for the validation of synthetic CT images of cortical bone from ultra-short echo-time (UTE) sequences. METHODS: A human skull of an adult female was utilized as a realistic representation of skull cortical bone. The skull was stabilized in a special acrylic container and was filled with contrast agents that have T1 and T2 relaxation times similar to human brain. The phantom was MR scanned at 3T with UTE and T2 -weighted sequences, followed by CT. A clustering approach was developed to extract the cortical bone signal from MR images. T2∗ maps of the skull were calculated. Synthetic CT images of the bone were compared to cortical bone signal extracted from CT images and confounding factors, such as registration errors, were analyzed. RESULTS: Dice similarity coefficient (DSC) of UTE-detected cortical bone was 0.84 and gradually decreased with decreasing number of spokes. DSC did not significantly depend on echo-time. Registration errors were found to be significant confounding factors, with 25% decrease in DSC for consistent 2 mm error at each axis. CONCLUSION: This work introduced a new realistic human skull phantom, specifically for the evaluation and analysis of synthetic CT images of cortical bone.

Measurement of time delays in gated radiotherapy for realistic respiratory motions.

PURPOSE: Gated radiotherapy is used to reduce internal motion margins, escalate target dose, and limit normal tissue dose; however, its temporal accuracy is limited. Beam-on and beam-off time delays can lead to treatment inefficiencies and/or geographic misses; therefore, AAPM Task Group 142 recommends verifying the temporal accuracy of gating systems. Many groups use sinusoidal phantom motion for this, under the tacit assumption that use of sinusoidal motion for determining time delays produces negligible error. The authors test this assumption by measuring gating time delays for several realistic motion shapes with increasing degrees of irregularity. METHODS: Time delays were measured on a linear accelerator with a real-time position management system (Varian TrueBeam with RPM system version 1.7.5) for seven motion shapes: regular sinusoidal; regular realistic-shape; large (40%) and small (10%) variations in amplitude; large (40%) variations in period; small (10%) variations in both amplitude and period; and baseline drift (30%). Film streaks of radiation exposure were generated for each motion shape using a programmable motion phantom. Beam-on and beam-off time delays were determined from the difference between the expected and observed streak length. RESULTS: For the system investigated, all sine, regular realistic-shape, and slightly irregular amplitude variation motions had beam-off and beam-on time delays within the AAPM recommended limit of less than 100 ms. In phase-based gating, even small variations in period resulted in some time delays greater than 100 ms. Considerable time delays over 1 s were observed with highly irregular motion. CONCLUSIONS: Sinusoidal motion shapes can be considered a reasonable approximation to the more complex and slightly irregular shapes of realistic motion. When using phase-based gating with predictive filters even small variations in period can result in time delays over 100 ms. Clinical use of these systems for patients with highly irregular patterns of motion is not advised due to large beam-on and beam-off time delays.

Robust method for 3D arterial spin labeling in mice.

Arterial spin labeling is a versatile perfusion quantification methodology, which has the potential to provide accurate characterization of cerebral blood flow (CBF) in mouse models. However, a paucity of physiological data needed for accurate modeling, more stringent requirements for gradient performance, and strong artifacts introduced by magnetization transfer present special challenges for accurate CBF mapping in the mouse. This article describes robust mapping of CBF over three-dimensional brain regions using amplitude-modulated continuous arterial spin labeling. To provide physiological data for CBF modeling, the carotid artery blood velocity distribution was characterized using pulsed-wave Doppler ultrasound. These blood velocity measurements were used in simulations that optimize inversion efficiency for parameters meeting MRI gradient duty cycle constraints. A rapid slice positioning algorithm was developed and evaluated to provide accurate positioning of the labeling plane. To account for enhancement of T(1) due to magnetization transfer, a binary spin bath model of magnetization transfer was used to provide a more accurate estimate of CBF. Finally, a study of CBF was conducted on 10 mice with findings of highly reproducible inversion efficiency (mean ± standard-error-of-the-mean, 0.67 ± 0.03), statistically significant variation in CBF over 12 brain regions (P < 0.0001) and a mean ± standard-error-of-the-mean whole brain CBF of 219 ± 6 mL/100 g/min.

Measurement of cerebral blood volume in mouse brain regions using micro-computed tomography.

Micro-computed tomography (micro-CT) is an X-ray imaging technique that can produce detailed 3D images of cerebral vasculature. This paper describes the development of a novel method for using micro-CT to measure cerebral blood volume (CBV) in the mouse brain. As an application of the methodology, we test the hypotheses that differences in CBV exist over anatomical brain regions and that high energy demanding primary sensory regions of the cortex have locally elevated CBV, which may reflect a vascular specialization. CBV was measured as the percentage of tissue space occupied by a radio-opaque silicon rubber that fills the vasculature. To ensure accuracy of the CBV measurements, several innovative refinements were made to standard micro-CT specimen preparation and analysis procedures. Key features of the described method are vascular perfusion under controlled pressure, registration of the micro-CT images to an MRI anatomical brain atlas and re-scaling of micro-CT intensities to CBV units with selectable exclusion of major vessels. Histological validation of the vascular perfusion showed that the average percentage of vessels filled was 93+/-3%. Comparison of thirteen brain regions in nine mice revealed significant differences in CBV between regions (p<0.0001) while cortical maps showed that primary visual and auditory areas have higher CBV than primary somatosensory areas.

Time response of interstitial fluid pressure measurements in cervix cancer.

Increased interstitial fluid pressure (IFP) is a common finding in malignant tumors as a result of the abnormal tumor vasculature and a lack of functional lymphatics. A recent clinical study by Milosevic et al. [Cancer Res. 61 (2001) 6400] reported a link between elevated IFP and survival in patients with cancer of the cervix. Patients with high IFP were more likely to have recurrence of tumors even after radiotherapy and were also more likely to die of progressive disease, independent of other prognostic factors. In this complementary study, using human data, we analyze 152 cervical tumor pressure IFP measurements from 42 patients with clinically diagnosed cancer of the cervix, randomly selected from the sample of 102 patients involved in the original study. We propose a simple biophysical model, based on flow through porous media, to explain the time response of the measured pressure curves in human cervical tumors. The response of IFP was governed by a time-constant tau(IFP) = 14 +/- 1 s averaged over multiple tumor sites. Interstitial hydraulic conductivity was computed to be approximately equal to 4.3 x 10(-6) cm(2)/mm Hgs.