CT based quantitative measures of the stability of fractured metastatically involved vertebrae treated with spine stereotactic body radiotherapy.

Mechanical instability secondary to vertebral metastases can lead to pathologic vertebral compression fracture (VCF) mechanical pain, neurological compromise, and the need for surgical stabilization. Stereotactic body radiation therapy (SBRT) as a treatment for spinal metastases is effective for pain and local tumor control, it has been associated with an increased risk of VCF. This study quantified computed tomography (CT) based stability measures in metastatic vertebrae with VCF treated with spine SBRT. It was hypothesized that semi-automated quantification of VCF based on CT metrics would be related to clinical outcomes. 128 SBRT treated spinal metastases patients were identified from a prospective database. Of these, 18 vertebral segments were identified with a VCF post-SBRT. A semi-automated system for quantifying VCF was developed based on CT imaging before and after SBRT. The system identified and segmented SBRT treated vertebral bodies, calculated stability metrics at single time points and changes over time. In the vertebrae that developed a new (n = 7) or progressive (n = 11) VCF following SBRT, the median time to VCF/VCF progression was 1.74 months (range 0.53-7.79 months). Fractured thoracolumbar vertebrae that went on to be stabilized (cemented and/or instrumented), had greater fractured vertebral body volume progression over time (12%) compared to those not stabilized (0.4%, p < 0.05). Neither the spinal instability neoplastic score (SINS) or any single timepoint stability metrics in post-hoc analyses correlated with future stabilization. This pilot study presents a quantitative semi-automated method assessing fractured thoracolumbar vertebrae based on CT. Increased fractured vertebral body volume progression post-SBRT was shown to predict those patients who were subsequently stabilized, motivating study of methods that assess temporal radiological changes toward augmenting existing clinical management in the metastatic spine.

Prospective evaluation of pretreatment and intratreatment FDG PET-CT SUV stability in primary head and neck cancer.

PURPOSE: To evaluate standardized uptake value (SUV) stability on pretreatment and intratreatment 18-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) in patients undergoing definitive CRT for head and neck cancer (HNC). METHODS: Primary tumor and nodal volumes of interest (VOIs) from HNC patients were contoured on the pretreatment and intratreatment PET-CT by two independent observers. SUV stability was measured with intersection calculations (DICE, overlap fraction, center to center) between the VOIs at threshold levels of 50%, 60%, 70%, 80%, and 90% of the SUV maximum. RESULTS: The mean calculated DICE of the 50%, 60%, 70%, 80%, 90% SUV threshold was 0.53, 0.48, 0.41, 0.28, and 0.12, respectively. The mean calculated overlap fraction was 0.71, 0.65, 0.58, 0.43, and 0.2, respectively. Center-center difference demonstrates spatial variability of 7.8, 8.2, 8.6, 9.5, and 11.2 mm for these SUV subvolumes of interest. CONCLUSIONS: HNC subvolumes defined by SUV thresholding technique in FDG PET-CT imaging do not remain physically stable during (chemo)RT. HIGHLIGHTS: All pretreatment and intratreatment SUV thresholds (50%-90%) overlap indexes are low during the course of (chemo)radiation. Pretreatment and intratreatment center to center variation further corroborates that all FDG threshold volumes do not remain stable during treatment. No difference in SUV threshold stability was seen between p16 positive and negative tumors.

Classification and evaluation strategies of auto-segmentation approaches for PET: Report of AAPM task group No. 211.

PURPOSE: The purpose of this educational report is to provide an overview of the present state-of-the-art PET auto-segmentation (PET-AS) algorithms and their respective validation, with an emphasis on providing the user with help in understanding the challenges and pitfalls associated with selecting and implementing a PET-AS algorithm for a particular application. APPROACH: A brief description of the different types of PET-AS algorithms is provided using a classification based on method complexity and type. The advantages and the limitations of the current PET-AS algorithms are highlighted based on current publications and existing comparison studies. A review of the available image datasets and contour evaluation metrics in terms of their applicability for establishing a standardized evaluation of PET-AS algorithms is provided. The performance requirements for the algorithms and their dependence on the application, the radiotracer used and the evaluation criteria are described and discussed. Finally, a procedure for algorithm acceptance and implementation, as well as the complementary role of manual and auto-segmentation are addressed. FINDINGS: A large number of PET-AS algorithms have been developed within the last 20 years. Many of the proposed algorithms are based on either fixed or adaptively selected thresholds. More recently, numerous papers have proposed the use of more advanced image analysis paradigms to perform semi-automated delineation of the PET images. However, the level of algorithm validation is variable and for most published algorithms is either insufficient or inconsistent which prevents recommending a single algorithm. This is compounded by the fact that realistic image configurations with low signal-to-noise ratios (SNR) and heterogeneous tracer distributions have rarely been used. Large variations in the evaluation methods used in the literature point to the need for a standardized evaluation protocol. CONCLUSIONS: Available comparison studies suggest that PET-AS algorithms relying on advanced image analysis paradigms provide generally more accurate segmentation than approaches based on PET activity thresholds, particularly for realistic configurations. However, this may not be the case for simple shape lesions in situations with a narrower range of parameters, where simpler methods may also perform well. Recent algorithms which employ some type of consensus or automatic selection between several PET-AS methods have potential to overcome the limitations of the individual methods when appropriately trained. In either case, accuracy evaluation is required for each different PET scanner and scanning and image reconstruction protocol. For the simpler, less robust approaches, adaptation to scanning conditions, tumor type, and tumor location by optimization of parameters is necessary. The results from the method evaluation stage can be used to estimate the contouring uncertainty. All PET-AS contours should be critically verified by a physician. A standard test, i.e., a benchmark dedicated to evaluating both existing and future PET-AS algorithms needs to be designed, to aid clinicians in evaluating and selecting PET-AS algorithms and to establish performance limits for their acceptance for clinical use. The initial steps toward designing and building such a standard are undertaken by the task group members.

Differentiating between visual hallucination-free dementia with Lewy bodies and corticobasal syndrome on the basis of neuropsychology and perfusion single-photon emission computed tomography.

INTRODUCTION: Dementia with Lewy bodies (DLB) and Corticobasal Syndrome (CBS) are atypical parkinsonian disorders with fronto-subcortical and posterior cognitive dysfunction as common features. While visual hallucinations are a good predictor of Lewy body pathology and are rare in CBS, they are not exhibited in all cases of DLB. Given the clinical overlap between these disorders, neuropsychological and imaging markers may aid in distinguishing these entities. METHODS: Prospectively recruited case-control cohorts of CBS (n =31) and visual hallucination-free DLB (n =30), completed neuropsychological and neuropsychiatric measures as well as brain perfusion single-photon emission computed tomography and structural magnetic resonance imaging (MRI). Perfusion data were available for forty-two controls. Behavioural, perfusion, and cortical volume and thickness measures were compared between the groups to identify features that serve to differentiate them. RESULTS: The Lewy body with no hallucinations group performed more poorly on measures of episodic memory compared to the corticobasal group, including the delayed and cued recall portions of the California Verbal Learning Test (F (1, 42) =23.1, P <0.001 and F (1, 42) =14.0, P =0.001 respectively) and the delayed visual reproduction of the Wechsler Memory Scale-Revised (F (1, 36) =9.7, P =0.004). The Lewy body group also demonstrated reduced perfusion in the left occipital pole compared to the corticobasal group (F (1,57) =7.4, P =0.009). At autopsy, the Lewy body cases all demonstrated mixed dementia with Lewy bodies, Alzheimer's disease and small vessel arteriosclerosis, while the corticobasal cases demonstrated classical corticobasal degeneration in five, dementia with agyrophilic grains + corticobasal degeneration + cerebral amyloid angiopathy in one, Progressive Supranuclear Palsy in two, and Frontotemporal Lobar Degeneration-Ubiquitin/TAR DNA-binding protein 43 proteinopathy in one. MRI measures were not significantly different between the patient groups. CONCLUSIONS: Reduced perfusion in the left occipital region and worse episodic memory performance may help to distinguish between DLB cases who have never manifested with visual hallucinations and CBS at earlier stages of the disease. Development of reliable neuropsychological and imaging markers that improve diagnostic accuracy will become increasingly important as disease modifying therapies become available.

Dose equivalent rate constants and barrier transmission data for nuclear medicine facility dose calculations and shielding design.

A primary goal of nuclear medicine facility design is to keep public and worker radiation doses As Low As Reasonably Achievable (ALARA). To estimate dose and shielding requirements, one needs to know both the dose equivalent rate constants for soft tissue and barrier transmission factors (TFs) for all radionuclides of interest. Dose equivalent rate constants are most commonly calculated using published air kerma or exposure rate constants, while transmission factors are most commonly calculated using published tenth-value layers (TVLs). Values can be calculated more accurately using the radionuclide's photon emission spectrum and the physical properties of lead, concrete, and/or tissue at these energies. These calculations may be non-trivial due to the polyenergetic nature of the radionuclides used in nuclear medicine. In this paper, the effects of dose equivalent rate constant and transmission factor on nuclear medicine dose and shielding calculations are investigated, and new values based on up-to-date nuclear data and thresholds specific to nuclear medicine are proposed. To facilitate practical use, transmission curves were fitted to the three-parameter Archer equation. Finally, the results of this work were applied to the design of a sample nuclear medicine facility and compared to doses calculated using common methods to investigate the effects of these values on dose estimates and shielding decisions. Dose equivalent rate constants generally agreed well with those derived from the literature with the exception of those from NCRP 124. Depending on the situation, Archer fit TFs could be significantly more accurate than TVL-based TFs. These results were reflected in the sample shielding problem, with unshielded dose estimates agreeing well, with the exception of those based on NCRP 124, and Archer fit TFs providing a more accurate alternative to TVL TFs and a simpler alternative to full spectral-based calculations. The data provided by this paper should assist in improving the accuracy and tractability of dose and shielding calculations for nuclear medicine facility design.

Toward magnetic resonance-only simulation: segmentation of bone in MR for radiation therapy verification of the head.

PURPOSE: To develop a practical method to localize bones in magnetic resonance (MR) images, to create "computed tomography-like" MR images (ctMRI) that could be used for radiation therapy verification, and to generate MR-based digitally reconstructed radiographs (DRR). METHODS AND MATERIALS: Using T1-weighted MR images, an air mask was derived from the manual contouring of all airways within the head and neck region using axial images at 6 anatomic levels. Compact bone, spongy bone, and soft tissue masks were then automatically generated using the statistical data derived from MR intensities and the air mask. ctMRI were then generated by mapping the MR intensities of the voxels within these masks into the CT number ranges of corresponding tissues. MR-based DRRs created from ctMRI were quantitatively evaluated using the co-registered MR and CT head images of 20 stereotactic radiosurgery patients. Ten anatomical points, positioned on the skull segmented using a threshold of 300 HU, in CT and ctMRI, were used to determine the differences in distance between MR-based DRRs and CT-based DRRs, and to evaluate the geometric accuracy of ctMRI and MR-based DRRs. RESULTS: The bony structures were identified on ctMRI and were visible in the MR-based DRRs. From the 20 patient cases, the mean geometric difference and standard deviation between the 10 anatomical points on MR-based and CT-based DRRs was -0.05 ± 0.85 mm, respectively. This included uncertainty in image fusion. The maximum distance difference was 1.88 mm. CONCLUSIONS: A practical method was developed to segment bone from MR images. The ctMRI created can be used for radiation treatment verification when MR-only simulation is performed. MR-based DRRs can be used in place of CT-based DRRs.

Phase I trial to evaluate the tumor and normal tissue uptake, radiation dosimetry and safety of (111)In-DTPA-human epidermal growth factor in patients with metastatic EGFR-positive breast cancer.

The safety, pharmacokinetics, biodistribution and radiation dosimetry of (111)In-DTPA-hEGF, an Auger electron-emitting radiopharmaceutical, were evaluated in a first-in-human trial. Dose escalation was performed in patients with EGFR-positive metastatic breast cancer who had received ≥2 prior courses of systemic treatment. (111)In-DTPA-hEGF (0.25 mg) was administered once intravenously (i.v.). Blood was collected for biochemistry/hematology testing and pharmacokinetic and immunogenicity analyses at selected times post injection (p.i.). Whole body planar images were acquired at 1, 4-6, 24 and 72 h p.i. and SPECT images at 24 and/or 72 h p.i. Macrodosimetry (MIRD) for the whole body and organs was estimated using OLINDA. Correlative radiological imaging was obtained at baseline, 1 and 3 months and then 6 monthly. Toxicity was scored using Common Terminology Criteria for Adverse Events (CTCAE)v2.0. Sixteen patients, median age 47 yr (range, 35-59), received (111)In-DTPA-hEGF as follows: 357-434 MBq (7), 754-805 MBq (3), 1,241-1,527 MBq (3) and 2,030-2,290 MBq (3). Fifteen were evaluable for toxicity. The commonest adverse events (AE) were flushing, chills, nausea, and vomiting occurring during or immediately p.i. One patient experienced Grade 3 thrombocytopenia (attributed to bone marrow infiltration by cancer). There were no other Grade 3 or 4 AEs. Maximum tolerated dose was not reached. Clear accumulation of radiopharmaceutical in at least one known site of disease was observed in 47% of patients. (111)In-DTPA-hEGF was cleared biexponentially from the blood with α-phase T½ of 0.16 ± 0.03 h and ß-phase T½ of 9.41 ± 1.93 h. (111)In-DTPA-hEGF was not immunogenic. The mean radiation dose estimates in mGy/MBq for whole body, liver, kidneys, spleen and thyroid were 0.08, 0.86, 0.74, 0.37 and 0.30, respectively. No objective antitumor responses were observed at the doses studied. In summary, administered amounts of up to 2,290 MBq (0.25 mg) of (111)In-DTPA-hEGF were well tolerated as a single i.v. injection.

Uncertainty in measurements of ¹8F blood concentration and its effect on simplified dynamic PET analysis.

UNLABELLED: The purpose of this study was to assess the accuracy and practicality of well counter- and thyroid probe-based methods, commonly available in nuclear medicine facilities, for measuring the concentration of (18)F-FDG in blood samples. The degree to which the accuracy of such methods influences quantitative analysis of dynamic PET scans was also assessed. METHODS: Thirty-five patients with cancer of the head and neck underwent dynamic PET imaging as part of a study intended to evaluate the utility of quantitative, image-based metrics for assessment of early treatment response. The activity in blood samples from the patients, necessary to provide an estimate of the input function for quantitative analysis, was measured both using a thyroid probe and using a well counter. Three calibration techniques were compared: single-point calibration using a standard solution for the thyroid probe (ProbePoint technique), single-point calibration using a standard solution for the well counter (WellPoint technique), and multiple-point calibration over the full range of expected blood activities for the well counter (WellCurve technique). The WellCurve method was assumed to provide the most accurate estimate of blood activity. The precision of measuring blood volume using a micropipette was also evaluated by obtaining multiple blood samples. Simplified-kinetic-analysis multiple-time-point (SKA-M) uptake rates for the primary tumor were calculated for all 35 patients using PET images and each of the 3 methods for assessing blood concentration. RESULTS: Errors in blood activity measurements ranging from -9.5% to 7.6% were found using the ProbePoint method, whereas the error range was much less (from -1.3% to 0.9%) for the WellPoint method. The precision in blood volume measurements ranged from -6% to 12% in the 10 patients assessed. The errors in blood activity and volume measurements were reflected in the SKA-M measurements in the same range. CONCLUSION: The WellPoint method provides a compromise between accuracy and clinical practicality. Random errors in both blood activity and volume measurements accumulate and may compromise parameters--such as the SKA-M estimate of tumor uptake rate--that depend not only on images but also on blood concentration data.

Phase I trial of intraoperative detection of tumor margins in patients with HER2-positive carcinoma of the breast following administration of 111In-DTPA-trastuzumab Fab fragments.

INTRODUCTION: Our aim was to conduct a Phase I clinical trial to determine the feasibility of intraoperative detection of tumor margins in HER2 positive breast carcinoma using a hand-held γ-probe following administration of (111)In-DTPA-trastuzumab Fab fragments. Accurate delineation of tumor margins is important for preventing local recurrence. METHODS: Six patients with HER2-positive in situ or invasive ductal carcinoma were administered 74MBq (0.5mg) of (111)In-DTPA-trastuzumab Fab fragments and counts in the tumor, surgical cavity wall and en face margins were measured intraoperatively at 72h post-injection using the Navigator or C-Trak γ-probes. Margins were evaluated histologically. Quantitative whole body planar imaging was performed to estimate radiation absorbed doses using OLINDA/EXM software. SPECT imaging of the thorax was performed to evaluate tumor uptake. The pharmacokinetics of elimination from the blood and plasma were determined over 72h. RESULTS: There were no acute adverse reactions from (111)In-DTPA-trastuzumab Fab fragments and no changes in hematological or biochemical indices were found over a 3month period. (111)In-DTPA-trastuzumab Fab fragments exhibited a biphasic elimination from the blood and plasma with t1/2α=11.9h and 7.5h, respectively, and t1/2ß=26.6 and 20.7h, respectively. The radiopharmaceutical accumulated in the liver, spleen and kidneys. SPECT imaging did not reveal tumor in any patient. The mean effective dose was 0.146mSv/MBq (10.8mSv for 74MBq). Counts in excised tumors were low but were higher than in margins. Margins in two patients harboured tumor but this was not correlated with counts obtained using the γ-probes. Surgical cavity counts were high and likely due to detection of γ-photons outside the surgical field. CONCLUSION: We conclude that it was not feasible, at least at the administered amount of radioactivity used in this study, to reliably detect the margins of disease in patients with in situ or invasive ductal carcinoma intraoperatively using a hand-held γ-probe and (111)In-DTPA-trastuzumab Fab fragments due to low uptake in the tumor and involved margins.

Effects of ROI Placement on PET-Based Assessment of Tumor Response to Therapy.

Purpose. Quantitative PET response assessment during therapy requires regions of interest (ROI). Commonly, a fixed-size ROI is placed at the maximum uptake point in the pretreatment study. For intratreatment, the ROI is placed either at the maximum uptake point (ROIpeak) or at the same location as the pretreatment ROI (ROIsame). We have evaluated the effects of the ROI placement on response assessment. Methods. PET scans of 15 head and neck cancer patients were used to evaluate the effects of the two ROI methods on response assessment. Results. The average intratreatment ROIpeak uptake was 13.4% higher than the ROIsame uptake (range -14% to 38%). The average relative change in ROIpeak uptake was 7.9% lower than ROIsame uptake (range -5% to 36%), resulting in ambiguous tumour classification in 19% of the tumours. Conclusion. Quantitative PET response assessment using a fixed-size ROI is sensitive the ROI placement. The difference between ROIpeak and ROIsame could be substantial resulting in ambiguous response assessment. Although the fixed-size ROI is simple to implement, it is also prone to the limitations and should be used with caution. Clinical trial data are necessary to establish reliable thresholds for fixed-size ROI techniques and to evaluate their efficacy for response assessment.

Automatic Segmentation of Lung Carcinoma Using 3D Texture Features in 18-FDG PET/CT.

Target definition is the largest source of geometric uncertainty in radiation therapy. This is partly due to a lack of contrast between tumor and healthy soft tissue for computed tomography (CT) and due to blurriness, lower spatial resolution, and lack of a truly quantitative unit for positron emission tomography (PET). First-, second-, and higher-order statistics, Tamura, and structural features were characterized for PET and CT images of lung carcinoma and organs of the thorax. A combined decision tree (DT) with K-nearest neighbours (KNN) classifiers as nodes containing combinations of 3 features were trained and used for segmentation of the gross tumor volume. This approach was validated for 31 patients from two separate institutions and scanners. The results were compared with thresholding approaches, the fuzzy clustering method, the 3-level fuzzy locally adaptive Bayesian algorithm, the multivalued level set algorithm, and a single KNN using Hounsfield units and standard uptake value. The results showed the DTKNN classifier had the highest sensitivity of 73.9%, second highest average Dice coefficient of 0.607, and a specificity of 99.2% for classifying voxels when using a probabilistic ground truth provided by simultaneous truth and performance level estimation using contours drawn by 3 trained physicians.

Region-Based Partial Volume Correction Techniques for PET Imaging: Sinogram Implementation and Robustness.

Background/Purpose. Limited spatial resolution of positron emission tomography (PET) requires partial volume correction (PVC). Region-based PVC methods are based on geometric transfer matrix implemented either in image-space (GTM) or sinogram-space (GTMo), both with similar performance. Although GTMo is slower, it more closely simulates the 3D PET image acquisition, accounts for local variations of point spread function, and can be implemented for iterative reconstructions. A recent image-based symmetric GTM (sGTM) has shown improvement in noise characteristics and robustness to misregistration over GTM. This study implements the sGTM method in sinogram space (sGTMo), validates it, and evaluates its performance. Methods. Two 3D sphere and brain digital phantoms and a physical sphere phantom were used. All four region-based PVC methods (GTM, GTMo, sGTM, and sGTMo) were implemented and their performance was evaluated. Results. All four PVC methods had similar accuracies. Both noise propagation and robustness of the sGTMo method were similar to those of sGTM method while they were better than those of GTMo method especially for smaller objects. Conclusion. The sGTMo was implemented and validated. The performance of the sGTMo in terms of noise characteristics and robustness to misregistration is similar to that of the sGTM method and improved compared to the GTMo method.

Symmetric geometric transfer matrix partial volume correction for PET imaging: principle, validation and robustness.

Limited spatial resolution of positron emission tomography (PET) often requires partial volume correction (PVC) to improve the accuracy of quantitative PET studies. Conventional region-based PVC methods use co-registered high resolution anatomical images (e.g. computed tomography (CT) or magnetic resonance images) to identify regions of interest. Spill-over between regions is accounted for by calculating regional spread functions (RSFs) in a geometric transfer matrix (GTM) framework. This paper describes a new analytically derived symmetric GTM (sGTM) method that relies on spill-over between RSFs rather than between regions. It is shown that the sGTM is mathematically equivalent to Labbe's method; however it is a region-based method rather than a voxel-based method and it avoids handling large matrices. The sGTM method was validated using two three-dimensional (3D) digital phantoms and one physical phantom. A 3D digital sphere phantom with sphere diameters ranging from 5 to 30 mm and a sphere-to-background uptake ratio of 3-to-1 was used. A 3D digital brain phantom was used with four different anatomical regions and a background region with different activities assigned to each region. A physical sphere phantom with the same geometry and uptake as the digital sphere phantom was manufactured and PET-CT images were acquired. Using these three phantoms, the performance of the sGTM method was assessed against that of the GTM method in terms of accuracy, precision, noise propagation and robustness. The robustness was assessed by applying mis-registration errors and errors in estimates of PET point spread function (PSF). In all three phantoms, the results showed that the sGTM method has accuracy similar to that of the GTM method and within 5%. However, the sGTM method showed better precision and noise propagation than the GTM method, especially for spheres smaller than 13 mm. Moreover, the sGTM method was more robust than the GTM method when mis-registration errors or errors in estimates of PSF occur. The improved robustness was more pronounced for smaller objects. In conclusion, the sGTM method was analytically derived and validated. The noise characteristics and robustness of the sGTM method were better than the conventional GTM method.