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1.  Reviewer acknowledgement 2013 
BMC Medical Physics  2014;14:1.
Contributing Reviewers
The editors of BMC Medical Physics would like to thank all our reviewers who have contributed to the journal in Volume 13 (2013).
doi:10.1186/1756-6649-14-1
PMCID: PMC3896715  PMID: 24433296
2.  Real-time prostate motion assessment: image-guidance and the temporal dependence of intra-fraction motion 
BMC Medical Physics  2013;13:4.
Background
The rapid adoption of image-guidance in prostate intensity-modulated radiotherapy (IMRT) results in longer treatment times, which may result in larger intrafraction motion, thereby negating the advantage of image-guidance. This study aims to qualify and quantify the contribution of image-guidance to the temporal dependence of intrafraction motion during prostate IMRT.
Methods
One-hundred and forty-three patients who underwent conventional IMRT (n=67) or intensity-modulated arc therapy (IMAT/RapidArc, n=76) for localized prostate cancer were evaluated. Intrafraction motion assessment was based on continuous RL (lateral), SI (longitudinal), and AP (vertical) positional detection of electromagnetic transponders at 10 Hz. Daily motion amplitudes were reported as session mean, median, and root-mean-square (RMS) displacements. Temporal effect was evaluated by categorizing treatment sessions into 4 different classes: IMRTc (transponder only localization), IMRTcc (transponder + CBCT localization), IMATc (transponder only localization), or IMATcc (transponder + CBCT localization).
Results
Mean/median session times were 4.15/3.99 min (IMATc), 12.74/12.19 min (IMATcc), 5.99/5.77 min (IMRTc), and 12.98/12.39 min (IMRTcc), with significant pair-wise difference (p<0.0001) between all category combinations except for IMRTcc vs. IMATcc (p>0.05). Median intrafraction motion difference between CBCT and non-CBCT categories strongly correlated with time for RMS (t-value=17.29; p<0.0001), SI (t-value=−4.25; p<0.0001), and AP (t-value=2.76; p<0.0066), with a weak correlation for RL (t-value=1.67; p=0.0971). Treatment time reduction with non-CBCT treatment categories showed reductions in the observed intrafraction motion: systematic error (Σ)<0.6 mm and random error (σ)<1.2 mm compared with ≤0.8 mm and <1.6 mm, respectively, for CBCT-involved treatment categories.
Conclusions
For treatment durations >4-6 minutes, and without any intrafraction motion mitigation protocol in place, patient repositioning is recommended, with at least the acquisition of the lateral component of an orthogonal image pair in the absence of volumetric imaging.
doi:10.1186/1756-6649-13-4
PMCID: PMC3849088  PMID: 24059584
Prostate cancer; Real-time motion tracking; Intrafraction variation; Treatment margin; Treatment time
3.  Predictions of CD4 lymphocytes’ count in HIV patients from complete blood count 
BMC Medical Physics  2013;13:3.
Background
HIV diagnosis, prognostic and treatment requires T CD4 lymphocytes’ number from flow cytometry, an expensive technique often not available to people in developing countries. The aim of this work is to apply a previous developed methodology that predicts T CD4 lymphocytes’ value based on total white blood cell (WBC) count and lymphocytes count applying sets theory, from information taken from the Complete Blood Count (CBC).
Methods
Sets theory was used to classify into groups named A, B, C and D the number of leucocytes/mm3, lymphocytes/mm3, and CD4/μL3 subpopulation per flow cytometry of 800 HIV diagnosed patients. Union between sets A and C, and B and D were assessed, and intersection between both unions was described in order to establish the belonging percentage to these sets. Results were classified into eight ranges taken by 1000 leucocytes/mm3, calculating the belonging percentage of each range with respect to the whole sample.
Results
Intersection (A ∪ C) ∩ (B ∪ D) showed an effectiveness in the prediction of 81.44% for the range between 4000 and 4999 leukocytes, 91.89% for the range between 3000 and 3999, and 100% for the range below 3000.
Conclusions
Usefulness and clinical applicability of a methodology based on sets theory were confirmed to predict the T CD4 lymphocytes’ value, beginning with WBC and lymphocytes’ count from CBC. This methodology is new, objective, and has lower costs than the flow cytometry which is currently considered as Gold Standard.
doi:10.1186/1756-6649-13-3
PMCID: PMC3847222  PMID: 24034560
CBC; CD4; HIV; Predictions; Sets theory
4.  Dose mapping sensitivity to deformable registration uncertainties in fractionated radiotherapy – applied to prostate proton treatments 
BMC Medical Physics  2013;13:2.
Background
Calculation of accumulated dose in fractionated radiotherapy based on spatial mapping of the dose points generally requires deformable image registration (DIR). The accuracy of the accumulated dose thus depends heavily on the DIR quality. This motivates investigations of how the registration uncertainty influences dose planning objectives and treatment outcome predictions.
A framework was developed where the dose mapping can be associated with a variable known uncertainty to simulate the DIR uncertainties in a clinical workflow. The framework enabled us to study the dependence of dose planning metrics, and the predicted treatment outcome, on the DIR uncertainty. The additional planning margin needed to compensate for the dose mapping uncertainties can also be determined. We applied the simulation framework to a hypofractionated proton treatment of the prostate using two different scanning beam spot sizes to also study the dose mapping sensitivity to penumbra widths.
Results
The planning parameter most sensitive to the DIR uncertainty was found to be the target D95. We found that the registration mean absolute error needs to be ≤0.20 cm to obtain an uncertainty better than 3% of the calculated D95 for intermediate sized penumbras. Use of larger margins in constructing PTV from CTV relaxed the registration uncertainty requirements to the cost of increased dose burdens to the surrounding organs at risk.
Conclusions
The DIR uncertainty requirements should be considered in an adaptive radiotherapy workflow since this uncertainty can have significant impact on the accumulated dose. The simulation framework enabled quantification of the accuracy requirement for DIR algorithms to provide satisfactory clinical accuracy in the accumulated dose.
doi:10.1186/1756-6649-13-2
PMCID: PMC3701614  PMID: 23768107
Radiotherapy; Adaptive radiotherapy; Dose tracking; Dose mapping; Dose accumulation; Dose accumulation accuracy; Deformable image registration; Non-rigid image registration; Protons
5.  The 2D Hotelling filter - a quantitative noise-reducing principal-component filter for dynamic PET data, with applications in patient dose reduction 
BMC Medical Physics  2013;13:1.
Background
In this paper we apply the principal-component analysis filter (Hotelling filter) to reduce noise from dynamic positron-emission tomography (PET) patient data, for a number of different radio-tracer molecules. We furthermore show how preprocessing images with this filter improves parametric images created from such dynamic sequence.
We use zero-mean unit variance normalization, prior to performing a Hotelling filter on the slices of a dynamic time-series. The Scree-plot technique was used to determine which principal components to be rejected in the filter process. This filter was applied to [11C]-acetate on heart and head-neck tumors, [18F]-FDG on liver tumors and brain, and [11C]-Raclopride on brain. Simulations of blood and tissue regions with noise properties matched to real PET data, was used to analyze how quantitation and resolution is affected by the Hotelling filter. Summing varying parts of a 90-frame [18F]-FDG brain scan, we created 9-frame dynamic scans with image statistics comparable to 20 MBq, 60 MBq and 200 MBq injected activity. Hotelling filter performed on slices (2D) and on volumes (3D) were compared.
Results
The 2D Hotelling filter reduces noise in the tissue uptake drastically, so that it becomes simple to manually pick out regions-of-interest from noisy data. 2D Hotelling filter introduces less bias than 3D Hotelling filter in focal Raclopride uptake. Simulations show that the Hotelling filter is sensitive to typical blood peak in PET prior to tissue uptake have commenced, introducing a negative bias in early tissue uptake. Quantitation on real dynamic data is reliable. Two examples clearly show that pre-filtering the dynamic sequence with the Hotelling filter prior to Patlak-slope calculations gives clearly improved parametric image quality. We also show that a dramatic dose reduction can be achieved for Patlak slope images without changing image quality or quantitation.
Conclusions
The 2D Hotelling-filtering of dynamic PET data is a computer-efficient method that gives visually improved differentiation of different tissues, which we have observed improve manual or automated region-of-interest delineation of dynamic data. Parametric Patlak images on Hotelling-filtered data display improved clarity, compared to non-filtered Patlak slope images without measurable loss of quantitation, and allow a dramatic decrease in patient injected dose.
doi:10.1186/1756-6649-13-1
PMCID: PMC3636030  PMID: 23574799
6.  Multiscale forward electromagnetic model of uterine contractions during pregnancy 
BMC Medical Physics  2012;12:4.
Background
Analyzing and monitoring uterine contractions during pregnancy is relevant to the field of reproductive health assessment. Its clinical importance is grounded in the need to reliably predict the onset of labor at term and pre-term. Preterm births can cause health problems or even be fatal for the fetus. Currently, there are no objective methods for consistently predicting the onset of labor based on sensing of the mechanical or electrophysiological aspects of uterine contractions. Therefore, modeling uterine contractions could help to better interpret such measurements and to develop more accurate methods for predicting labor. In this work, we develop a multiscale forward electromagnetic model of myometrial contractions during pregnancy. In particular, we introduce a model of myometrial current source densities and compute its magnetic field and action potential at the abdominal surface, using Maxwell’s equations and a four-compartment volume conductor geometry. To model the current source density at the myometrium we use a bidomain approach. We consider a modified version of the Fitzhugh-Nagumo (FHN) equation for modeling ionic currents in each myocyte, assuming a plateau-type transmembrane potential, and we incorporate the anisotropic nature of the uterus by designing conductivity-tensor fields.
Results
We illustrate our modeling approach considering a spherical uterus and one pacemaker located in the fundus. We obtained a travelling transmembrane potential depolarizing from −56 mV to −16 mV and an average potential in the plateau area of −25 mV with a duration, before hyperpolarization, of 35 s, which is a good approximation with respect to the average recorded transmembrane potentials at term reported in the technical literature. Similarly, the percentage of myometrial cells contracting as a function of time had the same symmetric properties and duration as the intrauterine pressure waveforms of a pregnant human myometrium at term.
Conclusions
We introduced a multiscale modeling approach of uterine contractions which allows for incorporating electrophysiological and anatomical knowledge of the myometrium jointly. Our results are in good agreement with the values reported in the experimental technical literature, and these are potentially important as a tool for helping in the characterization of contractions and for predicting labor using magnetomyography (MMG) and electromyography (EMG).
doi:10.1186/1756-6649-12-4
PMCID: PMC3605117  PMID: 23126570
7.  The study of radiosensitivity in left handed compared to right handed healthy women 
BMC Medical Physics  2012;12:3.
Background
Radiosensitivity is an inheriting trait that mainly depends on genetic factors. it is well known in similar dose of ionizing radiation and identical biological characteristics 9–10 percent of normal population have higher radiation response. Some reports indicate that distribution of breast cancer, immune diseases including autoimmune diseases as example lupus, Myasthenia Gravies and even the rate of allergy are more frequent in left handed individuals compared to right handed individuals. The main goal of the present study is determination of radiosensitivity in left handed compared to right handed in healthy women by cytokinesis blocked micronuclei [CBMN] assay.
5 ml peripheral fresh blood sample was taken from 100 healthy women including 60 right handed and 40 left handed. The age of participants was between 20–25 old years and they had been matched by sex. After blood sampling, blood samples were divided to 2 groups including irradiated and non-irradiated lymphocytes that irradiated lymphocytes were exposed to 2 Gy CO-60 Gama rays source then chromosomal aberrations was analyzed by CBMN [Cytokinesis Blocked Micronuclei Assay].
Results
Our results have shown radiosensitivity index [RI] in left-handers compared to right-handers is higher. Furthermore, the mean MN frequency is elevated in irradiated lymphocytes of left-handers in comparison with right-handers.
Conclusion
Our results from CBMN assay have shown radiosensitivity in the left handed is higher than right handed women but more attempts need to prove this hypothesis.
doi:10.1186/1756-6649-12-3
PMCID: PMC3531301  PMID: 22920225
8.  Comparison of the dosimetries of 3-dimensions Radiotherapy (3D-RT) with linear accelerator and intensity modulated radiotherapy (IMRT) with helical tomotherapy in children irradiated for neuroblastoma 
BMC Medical Physics  2012;12:2.
Background
Intensity modulated radiotherapy is an efficient radiotherapy technique to increase dose in target volumes and decrease irradiation dose in organs at risk. This last objective is mainly relevant in children. However, previous results suggested that IMRT could increase low dose, factor of risk for secondary radiation induced cancer. This study was performed to compare dose distributions with 3D-radiotherapy (3D-RT) and IMRT with tomotherapy (HT) in children with neuroblastoma. Seven children with neuroblastoma were irradiated. Treatment plans were calculated for 3D-RT, and for HT. For the volume of interest, the PTV-V95% and conformity index were calculated. Dose constraints of all the organs at risk and integral dose were compared.
Results
The conformity index was statistically better for HT than for 3D-RT. PTV-V95% constraint was reached in 6 cases with HT compared to 2 cases with 3D-RT. For the ipsilateral kidney of the tumor, the V12 Gy constraint was reached for 3 patients with both methods. The values were lower with HT than with 3D-RT in two cases and higher in one case. The threshold was not reached for one patient with either technique, but the value was lower with HT than with 3D-RT. For the contralateral kidney of the tumors, the V12 Gy constraint was reached for all patients with both methods. The values were lower with HT than with 3D-RT in 5 of 7 children, equal in one patient and higher in one patient. The organ-at-risk volumes receiving low doses were significantly lower with 3D-RT but larger for the highest doses, compared to those irradiated with HT. The integral doses were not different.
Conclusions
IMRT with HT allows a better conformity treatment, a more frequently acceptable PTV-V95% than 3D-RT and, concomitantly, a better shielding of the kidneys. The integral doses are comparable between both techniques but consideration of differences in dose distribution between the two techniques, for the organs at risk, has to be taken in account when validating treatment.
doi:10.1186/1756-6649-12-2
PMCID: PMC3598555  PMID: 22742393
Neuroblastoma; IMRT; 3D-RT; Tomotherapy; Dosimetry
9.  Navigator channel adaptation to reconstruct three dimensional heart volumes from two dimensional radiotherapy planning data 
BMC Medical Physics  2012;12:1.
Background
Biologically-based models that utilize 3D radiation dosimetry data to estimate the risk of late cardiac effects could have significant utility for planning radiotherapy in young patients. A major challenge arises from having only 2D treatment planning data for patients with long-term follow-up. In this study, we evaluate the accuracy of an advanced deformable image registration (DIR) and navigator channels (NC) adaptation technique to reconstruct 3D heart volumes from 2D radiotherapy planning images for Hodgkin's Lymphoma (HL) patients.
Methods
Planning CT images were obtained for 50 HL patients who underwent mediastinal radiotherapy. Twelve image sets (6 male, 6 female) were used to construct a male and a female population heart model, which was registered to 23 HL "Reference" patients' CT images using a DIR algorithm, MORFEUS. This generated a series of population-to-Reference patient specific 3D deformation maps. The technique was independently tested on 15 additional "Test" patients by reconstructing their 3D heart volumes using 2D digitally reconstructed radiographs (DRR). The technique involved: 1) identifying a matching Reference patient for each Test patient using thorax measurements, 2) placement of six NCs on matching Reference and Test patients' DRRs to capture differences in significant heart curvatures, 3) adapting the population-to-Reference patient-specific deformation maps to generate population-to-Test patient-specific deformation maps using linear and bilinear interpolation methods, 4) applying population-to-Test patient specific deformation to the population model to reconstruct Test-patient specific 3D heart models. The percentage volume overlap between the NC-adapted reconstruction and actual Test patient's true heart volume was calculated using the Dice coefficient.
Results
The average Dice coefficient expressed as a percentage between the NC-adapted and actual Test model was 89.4 ± 2.8%. The modified NC adaptation technique made significant improvements to the population deformation heart models (p = 0.01). As standard evaluation, the residual Dice error after adaptation was comparable to the volumetric differences observed in free-breathing heart volumes (p = 0.62).
Conclusions
The reconstruction technique described generates accurate 3D heart models from limited 2D planning data. This development could potentially be used to retrospectively calculate delivered dose to the heart for historically treated patients and thereby provide a better understanding of late radiation-related cardiac effects.
doi:10.1186/1756-6649-12-1
PMCID: PMC3398341  PMID: 22257738
10.  Preclinical multimodality phantom design for quality assurance of tumor size measurement 
BMC Medical Physics  2011;11:1.
Background
Evaluation of changes in tumor size from images acquired by ultrasound (US), computed tomography (CT) or magnetic resonance imaging (MRI) is a common measure of cancer chemotherapy efficacy. Tumor size measurement based on either the World Health Organization (WHO) criteria or the Response Evaluation Criteria in Solid Tumors (RECIST) is the only imaging biomarker for anti-cancer drug testing presently approved by the United States Food and Drug Administration (FDA). The aim of this paper was to design and test a quality assurance phantom with the capability of monitoring tumor size changes with multiple preclinical imaging scanners (US, CT and MRI) in order to facilitate preclinical anti-cancer drug testing.
Methods
Three phantoms (Gammex/UTHSCSA Mark 1, Gammex/UTHSCSA Mark 2 and UTHSCSA multimodality tumor measurement phantom) containing tumor-simulating test objects were designed and constructed. All three phantoms were scanned in US, CT and MRI devices. The size of test objects in the phantoms was measured from the US, CT and MRI images. RECIST, WHO and volume analyses were performed.
Results
The smaller phantom size, simplified design and better test object CT contrast of the UTHSCSA multimodality tumor measurement phantom allowed scanning of the phantom in preclinical US, CT and MRI scanners compared with only limited preclinical scanning capability of Mark 1 and Mark 2 phantoms. For all imaging modalities, RECIST and WHO errors were reduced for UTHSCSA multimodality tumor measurement phantom (≤1.69 ± 0.33%) compared with both Mark 1 (≤ -7.56 ± 6.52%) and Mark 2 (≤ 5.66 ± 1.41%) phantoms. For the UTHSCSA multimodality tumor measurement phantom, measured tumor volumes were highly correlated with NIST traceable design volumes for US (R2 = 1.000, p < 0.0001), CT (R2 = 0.9999, p < 0.0001) and MRI (R2 = 0.9998, p < 0.0001).
Conclusions
The UTHSCSA multimodality tumor measurement phantom described in this study can potentially be a useful quality assurance tool for verifying radiologic assessment of tumor size change during preclinical anti-cancer therapy testing with multiple imaging modalities.
doi:10.1186/1756-6649-11-1
PMCID: PMC3206432  PMID: 21958653
11.  Theoretical generalization of normal and sick coronary arteries with fractal dimensions and the arterial intrinsic mathematical harmony 
BMC Medical Physics  2010;10:1.
Background
Fractal geometry is employ to characterize the irregular objects and had been used in experimental and clinic applications. Starting from a previous work, here we made a theoretical research based on a geometric generalization of the experimental results, to develop a theoretical generalization of the stenotic and restenotic process, based on fractal geometry and Intrinsic Mathematical Harmony.
Methods
Starting from all the possibilities of space occupation in box-counting space, all arterial prototypes differentiating normality and disease were obtained with a computational simulation. Measures from 2 normal and 3 re-stenosed arteries were used as spatial limits of the generalization.
Results
A new methodology in animal experimentation was developed, based on fractal geometric generalization. With this methodology, it was founded that the occupation space possibilities in the stenotic process are finite and that 69,249 arterial prototypes are obtained as a total.
Conclusions
The Intrinsic Mathematical Harmony reveals a supra-molecular geometric self-organization, where the finite and discrete fractal dimensions of arterial layers evaluate objectively the arterial stenosis and restenosis process.
doi:10.1186/1756-6649-10-1
PMCID: PMC2954867  PMID: 20846449
12.  Differential radio-sensitivities of human chromosomes 1 and 2 in one donor in interphase- and metaphase-spreads after 60Co γ-irradiation 
Background
Radiation-induced chromosome aberrations lead to a plethora of detrimental effects at cellular level. Chromosome aberrations provide broad spectrum of information ranging from probability of malignant transformation to assessment of absorbed dose. Studies mapping differences in radiation sensitivities between human chromosomes are seldom undertaken. Consequently, health risk assessment based on radio-sensitivities of individual chromosomes may be erroneous. Our efforts in this article, attempt to demonstrate differences in radio-sensitivities of human chromosome-1 and/or -2, both in interphase and metaphase spreads.
Methods
Upon blood collection, dosimetry and irradiation were performed. Lymphocytes were isolated after whole-blood irradiation with 60Co γ-rays in the dose range of 0–5 Gy for both interphase, and metaphase aberration studies. Induction of premature chromosome condensation in interphase cells was accomplished using a phosphatase inhibitor, calyculin-A. Metaphase spreads were harvested from short-term peripheral blood lymphocyte cultures following colcemid arrest and using an automated metaphase harvester and spreader. Aberration analysis in both interphase and metaphase spreads were done using FISH.
Results
In interphase, aberrant cell and aberration frequency involving chromosome 1 and/or 2 increased linearly with radiation dose. In metaphase, aberrations increased in a linear-quadratic manner with dose. Our studies ascertain that chromosome-2 is more radio-sensitive than chromosome-1 in both interphase and metaphase stages, albeit the DNA content of chromosome-2 is lesser than chromosome-1 by almost 10 million base pairs.
Conclusion
Differences in radio-sensitivities of chromosomes have implications in genetic damage, chromosome organization, and chromosome function. Designing research experiments based on our vital findings may bring benefit to radiation-induced risk assessment, therapeutics and development of chromosome specific biomarkers.
doi:10.1186/1756-6649-9-6
PMCID: PMC2704179  PMID: 19531236
13.  Prognostic implication of late gadolinium enhancement on cardiac MRI in light chain (AL) amyloidosis on long term follow up 
Background
Light chain amyloidosis (AL) is a rare plasma cell dyscrasia associated with poor survival especially in the setting of heart failure. Late gadolinium enhancement (LGE) on cardiac MRI was recently found to correlate with myocardial amyloid deposition but the prognostic role is not established. The aim is to determine the prognostic significance of LGE in AL by comparing long term survival of AL patients with and without LGE.
Methods
Twenty nine consecutive patients (14 females; 62 ± 11 years) with biopsy-proven AL undergoing cardiac MRI with gadolinium as part of AL workup were included. Survival was prospectively followed 29 months (median) following MRI and compared between those with and without LGE by Kaplan-Meier and log-rank analyses.
Results
LGE was positive in 23 subjects (79%) and negative in 6 (21%). Left ventricular ejection fraction was 66 ± 17% in LGE-positive and 69 ± 12% in LGE-negative patients (p = 0.8). Overall 1-year mortality was 36%. On follow-up, 14/23 LGE-positive and none of LGE-negative patients died (log rank p = 0.0061). Presenting New York Heart Association heart failure class was also associated with poor survival (p = 0.0059). Survival between two LGE groups stratified by heart failure class still showed a significant difference by a stratified log-rank test (p = 0.04).
Conclusion
Late gadolinium enhancement is common and is associated with poor long-term survival in light chain amyloidosis, even after adjustment for heart failure class presentation. The prognostic significance of late gadolinium enhancement in this disease may be useful in patient risk-stratification.
doi:10.1186/1756-6649-9-5
PMCID: PMC2686669  PMID: 19416541
14.  Average arterial input function for quantitative dynamic contrast enhanced magnetic resonance imaging of neck nodal metastases 
Background
The present study determines the feasibility of generating an average arterial input function (Avg-AIF) from a limited population of patients with neck nodal metastases to be used for pharmacokinetic modeling of dynamic contrast-enhanced MRI (DCE-MRI) data in clinical trials of larger populations.
Methods
Twenty patients (mean age 50 years [range 27–77 years]) with neck nodal metastases underwent pretreatment DCE-MRI studies with a temporal resolution of 3.75 to 7.5 sec on a 1.5T clinical MRI scanner. Eleven individual AIFs (Ind-AIFs) met the criteria of expected enhancement pattern and were used to generate Avg-AIF. Tofts model was used to calculate pharmacokinetic DCE-MRI parameters. Bland-Altman plots and paired Student t-tests were used to describe significant differences between the pharmacokinetic parameters obtained from individual and average AIFs.
Results
Ind-AIFs obtained from eleven patients were used to calculate the Avg-AIF. No overall significant difference (bias) was observed for the transfer constant (Ktrans) measured with Ind-AIFs compared to Avg-AIF (p = 0.20 for region-of-interest (ROI) analysis and p = 0.18 for histogram median analysis). Similarly, no overall significant difference was observed for interstitial fluid space volume fraction (ve) measured with Ind-AIFs compared to Avg-AIF (p = 0.48 for ROI analysis and p = 0.93 for histogram median analysis). However, the Bland-Altman plot suggests that as Ktrans increases, the Ind-AIF estimates tend to become proportionally higher than the Avg-AIF estimates.
Conclusion
We found no statistically significant overall bias in Ktrans or ve estimates derived from Avg-AIF, generated from a limited population, as compared with Ind-AIFs.
However, further study is needed to determine whether calibration is needed across the range of Ktrans. The Avg-AIF obtained from a limited population may be used for pharmacokinetic modeling of DCE-MRI data in larger population studies with neck nodal metastases. Further validation of the Avg-AIF approach with a larger population and in multiple regions is desirable.
doi:10.1186/1756-6649-9-4
PMCID: PMC2679707  PMID: 19351382
15.  Bone turnover markers are correlated with total skeletal uptake of 99mTc-methylene diphosphonate (99mTc-MDP) 
Background
Skeletal uptake of 99mTc labelled methylene diphosphonate (99mTc-MDP) is used for producing images of pathological bone uptake due to its incorporation to the sites of active bone turnover. This study was done to validate bone turnover markers using total skeletal uptake (TSU) of 99mTc-MDP.
Methods
22 postmenopausal women (52–80 years) volunteered to participate. Scintigraphy was performed by injecting 520 MBq of 99mTc-MDP and taking whole body images after 3 minutes, and 5 hours. TSU was calculated from these two images by taking into account the urinary loss and soft tissue uptake. Bone turnover markers used were bone specific alkaline phosphatase (S-Bone ALP), three different assays for serum osteocalcin (OC), tartrate resistant acid phosphatase 5b (S-TRACP5b), serum C-terminal cross-linked telopeptides of type I collagen (S-CTX-I) and three assays for urinary osteocalcin (U-OC).
Results
The median TSU of 99mTc-MDP was 23% of the administered activity. All bone turnover markers were significantly correlated with TSU with r-values from 0.52 (p = 0.013) to 0.90 (p < 0.001). The two resorption markers had numerically higher correlations (S-TRACP5b r = 0.90, S-CTX-I r = 0.80) than the formation markers (S-Total OC r = 0.72, S-Bone ALP r = 0.66), but the difference was not statistically significant. TSU did not correlate with age, weight, body mass index or bone mineral density.
Conclusion
In conclusion, bone turnover markers are strongly correlated with total skeletal uptake of 99mTc-MDP. There were no significant differences in correlations for bone formation and resorption markers. This should be due to the coupling between formation and resorption.
doi:10.1186/1756-6649-9-3
PMCID: PMC2674029  PMID: 19331678
16.  Repeatability of regional myocardial blood flow calculation in 82Rb PET imaging 
Background
We evaluated the repeatability of the calculation of myocardial blood flow (MBF) at rest and pharmacological stress, and calculated the coronary flow reserve (CFR) utilizing 82Rb PET imaging. The aim of the research was to prove high repeatability for global MBF and CFR values and good repeatability for regional MBF and CFR values. The results will have significant impact on cardiac PET imaging in terms of making it more affordable and increasing its use.
Methods
12 normal volunteers were imaged at rest and during pharmacological stress, with 2220 MBq of 82Rb each. A GE Advance PET system was used to acquire dynamic 50-frame studies. MBF was calculated with a 2-compartmental model using a modified PMOD program (PMOD; University Hospital Zurich, Zurich, Switzerland). Two differential equations, describing a 2-compartmental model, were solved by numerical integration and using Levenberg-Marquardt's method for fitting data. The PMOD program defines 16 standard segments and calculates myocardial flow for each segment, as well as average septal, anterior, lateral, inferior and global flow. Repeatability was evaluated according to the method of Bland and Altman.
Results
Global rest and stress MBF, as well as global CFR, showed very good repeatability. No significant differences were found between the paired resting global MBF (0.63 ± 0.13 vs. 0.64 ± 0.13 mL/min/g; mean difference, -1.0% ± 2.6%) and the stress global MBF (1.37 ± 0.23 vs. 1.37 ± 0.24; mean difference, 0.1% ± 2.3%). Global CFR was highly reproducible (2.25 ± 0.56 vs. 2.22 ± 0.54, P = not statistically significant; mean difference, 1.3% ± 14.3%). Repeatability coefficients for global rest MBF were 0.033 (5.2%) and stress MBF 0.062 (4.5%) mL/min/g. Regional rest and stress MBF and CFR have shown good reproducibility. The average per sector repeatability coefficients for rest MBF were 0.056 (8.5%) and stress MBF 0.089 (6.3%) mL/min/g, and average repeatability coefficient for CFR was 0.25 (10.6%).
Conclusion
The results of the study show that software calculation of MBF and CFR with 82Rb myocardial PET imaging is highly repeatable for global values and has good repeatability for regional values.
doi:10.1186/1756-6649-9-2
PMCID: PMC2646684  PMID: 19178700
17.  Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields) 
Background
The present study explores the efficacy and toxicity of combining a new, non-toxic, cancer treatment modality, termed Tumor Treating Fields (TTFields), with chemotherapeutic treatment in-vitro, in-vivo and in a pilot clinical trial.
Methods
Cell proliferation in culture was studied in human breast carcinoma (MDA-MB-231) and human glioma (U-118) cell lines, exposed to TTFields, paclitaxel, doxorubicin, cyclophosphamide and dacarbazine (DTIC) separately and in combinations. In addition, we studied the effects of combining chemotherapy with TTFields in an animal tumor model and in a pilot clinical trial in recurrent and newly diagnosed GBM patients.
Results
The efficacy of TTFields-chemotherapy combination in-vitro was found to be additive with a tendency towards synergism for all drugs and cell lines tested (combination index ≤ 1). The sensitivity to chemotherapeutic treatment was increased by 1–3 orders of magnitude by adjuvant TTFields therapy (dose reduction indexes 23 – 1316). Similar findings were seen in an animal tumor model. Finally, 20 GBM patients were treated with TTFields for a median duration of 1 year. No TTFields related systemic toxicity was observed in any of these patients, nor was an increase in Temozolomide toxicity seen in patients receiving combined treatment. In newly diagnosed GBM patients, combining TTFields with Temozolomide treatment led to a progression free survival of 155 weeks and overall survival of 39+ months.
Conclusion
These results indicate that combining chemotherapeutic cancer treatment with TTFields may increase chemotherapeutic efficacy and sensitivity without increasing treatment related toxicity.
doi:10.1186/1756-6649-9-1
PMCID: PMC2647898  PMID: 19133110
18.  Multiple window spatial registration error of a gamma camera: 133Ba point source as a replacement of the NEMA procedure 
Background
The accuracy of multiple window spatial resolution characterises the performance of a gamma camera for dual isotope imaging. In the present study we investigate an alternative method to the standard NEMA procedure for measuring this performance parameter.
Methods
A long-lived 133Ba point source with gamma energies close to 67Ga and a single bore lead collimator were used to measure the multiple window spatial registration error. Calculation of the positions of the point source in the images used the NEMA algorithm. The results were validated against the values obtained by the standard NEMA procedure which uses a liquid 67Ga source with collimation.
Results
Of the source-collimator configurations under investigation an optimum collimator geometry, consisting of a 5 mm thick lead disk with a diameter of 46 mm and a 5 mm central bore, was selected. The multiple window spatial registration errors obtained by the 133Ba method showed excellent reproducibility (standard deviation < 0.07 mm). The values were compared with the results from the NEMA procedure obtained at the same locations and showed small differences with a correlation coefficient of 0.51 (p < 0.05). In addition, the 133Ba point source method proved to be much easier to use. A Bland-Altman analysis showed that the 133Ba and the 67Ga Method can be used interchangeably.
Conclusion
The 133Ba point source method measures the multiple window spatial registration error with essentially the same accuracy as the NEMA-recommended procedure, but is easier and safer to use and has the potential to replace the current standard procedure.
doi:10.1186/1756-6649-8-6
PMCID: PMC2615416  PMID: 19068107
19.  Influence of increased target dose inhomogeneity on margins for breathing motion compensation in conformal stereotactic body radiotherapy 
Background
Breathing motion should be considered for stereotactic body radiotherapy (SBRT) of lung tumors. Four-dimensional computer tomography (4D-CT) offers detailed information of tumor motion. The aim of this work is to evaluate the influence of inhomogeneous dose distributions in the presence of breathing induced target motion and to calculate margins for motion compensation.
Methods
Based on 4D-CT examinations, the probability density function of pulmonary tumors was generated for ten patients. The time-accumulated dose to the tumor was calculated using one-dimensional (1D) convolution simulations of a 'static' dose distribution and target probability density function (PDF). In analogy to stereotactic body radiotherapy (SBRT), different degrees of dose inhomogeneity were allowed in the target volume: minimum doses of 100% were prescribed to the edge of the target and maximum doses varied between 102% (P102) and 150% (P150). The dose loss due to breathing motion was quantified and margins were added until this loss was completely compensated.
Results
With the time-weighted mean tumor position as the isocentre, a close correlation with a quadratic relationship between the standard deviation of the PDF and the margin size was observed. Increased dose inhomogeneity in the target volume required smaller margins for motion compensation: margins of 2.5 mm, 2.4 mm and 1.3 mm were sufficient for compensation of 11.5 mm motion range and standard deviation of 3.9 mm in P105, P125 and P150, respectively. This effect of smaller margins for increased dose inhomogeneity was observed for all patients. Optimal sparing of the organ-at-risk surrounding the target was achieved for dose prescriptions P105 to P118. The internal target volume concept over-compensated breathing motion with higher than planned doses to the target and increased doses to the surrounding normal tissue.
Conclusion
Treatment planning with inhomogeneous dose distributions in the target volume required smaller margins for compensation of breathing induced target motion with the consequence of lower doses to the surrounding organs-at-risk.
doi:10.1186/1756-6649-8-5
PMCID: PMC2637830  PMID: 19055768
20.  Metabolism of no-carrier-added 2-[18F]fluoro-L-tyrosine in rats 
Background
Several fluorine-18 labelled fluoroamino acids have been evaluated as tracers for the quantitative assessment of cerebral protein synthesis in vivo by positron emission tomography (PET). Among these, 2-[18F]fluoro-L-tyrosine (2-[18F]Tyr) has been studied in mice at a low specific activity. Its incorporation into proteins is fast and metabolism via other pathways is limited. The present in vivo study was carried out in normal awake rats using no-carrier-added 2-[18F]Tyr. Under normal physiological conditions, we have studied the incorporation into proteins and the metabolism of the tracer in different brain areas.
Methods
No-carrier-added 2-[18F]Tyr was administered to awake rats equipped with chronic arterial and venous catheters. The time course of the plasma activity was studied by arterial blood sampling. The biodistribution of the activity in the main organs was studied at the end of the experiment. The distribution of radioactive species in plasma and brain regions was studied by acidic precipitation of the proteins and HPLC analysis of the supernatant.
Results
The absolute uptake of radioactivity in brain regions was homogenous. In awake rats, no-carrier-added 2-[18F]Tyr exhibits a fast and almost quantitative incorporation into the proteins fractions of cerebellum and cortex. In striatum, this incorporation into proteins and the unchanged fraction of the tracer detected by HPLC could be lower than in other brain regions.
Conclusion
This study confirms the potential of 2-[18F]fluoro-L-tyrosine as a tracer for the assessment of the rate of protein synthesis by positron emission tomography. The observed metabolism suggests a need for a correction for the appearance of metabolites, at least in plasma.
doi:10.1186/1756-6649-8-4
PMCID: PMC2606674  PMID: 18990255
21.  NEOadjuvant therapy monitoring with PET and CT in Esophageal Cancer (NEOPEC-trial) 
Background
Surgical resection is the preferred treatment of potentially curable esophageal cancer. To improve long term patient outcome, many institutes apply neoadjuvant chemoradiotherapy. In a large proportion of patients no response to chemoradiotherapy is achieved. These patients suffer from toxic and ineffective neoadjuvant treatment, while appropriate surgical therapy is delayed. For this reason a diagnostic test that allows for accurate prediction of tumor response early during chemoradiotherapy is of crucial importance. CT-scan and endoscopic ultrasound have limited accuracy in predicting histopathologic tumor response. Data suggest that metabolic changes in tumor tissue as measured by FDG-PET predict response better. This study aims to compare FDG-PET and CT-scan for the early prediction of non-response to preoperative chemoradiotherapy in patients with potentially curable esophageal cancer.
Methods/design
Prognostic accuracy study, embedded in a randomized multicenter Dutch trial comparing neoadjuvant chemoradiotherapy for 5 weeks followed by surgery versus surgery alone for esophageal cancer. This prognostic accuracy study is performed only in the neoadjuvant arm of the randomized trial. In 6 centers, 150 consecutive patients will be included over a 3 year period. FDG-PET and CT-scan will be performed before and 2 weeks after the start of the chemoradiotherapy. All patients complete the 5 weeks regimen of neoadjuvant chemoradiotherapy, regardless the test results. Pathological examination of the surgical resection specimen will be used as reference standard. Responders are defined as patients with < 10% viable residual tumor cells (Mandard-score).
Difference in accuracy (area under ROC curve) and negative predictive value between FDG-PET and CT-scan are primary endpoints. Furthermore, an economic evaluation will be performed, comparing survival and costs associated with the use of FDG-PET (or CT-scan) to predict tumor response with survival and costs of neoadjuvant chemoradiotherapy without prediction of response (reference strategy).
Discussion
The NEOPEC-trial could be the first sufficiently powered study that helps justify implementation of FDG-PET for response-monitoring in patients with esophageal cancer in clinical practice.
Trial registration
ISRCTN45750457
doi:10.1186/1756-6649-8-3
PMCID: PMC3301128  PMID: 18671847
22.  A computerized Infusion Pump for control of tissue tracer concentration during Positron Emission Tomography in vivo Pharmacokinetic/Pharmacodynamic measurements 
Background
A computer controlled infusion pump (UIPump) for regulation of target tissue concentration of radioactive compounds was developed for use in biological research and tracer development for PET.
Methods
Based on observed tissue or plasma kinetics after a bolus injection of the tracer an algorithm calculates the infusion needed to obtain a specified target kinetic curve. A computer feeds this infusion scheme into an infusion pump connected to an animal via a venous catheter. The concept was validated using [11C]Flumazenil administrated to Sprague-Dawley rats where the whole brain distribution and kinetic of the tracer was measured over time using a microPET-scanner. The accuracy and precision of the system was assessed by producing steady-state levels of the tracer and by mimicking kinetics after oral administration.
Results
Various kinetic profiles could be generated, including rapid achievement of constant levels, or step-wise increased levels. The resulting tissue curves had low deviation from the target curves according to the specified criteria: AUC (%): 4.2 ± 2.8, Maximal deviation (%): 13.6 ± 5.0 and R2: 0.95 ± 0.02.
Conclusion
The UIPump-system is suitable for use in PET-research for assessment of PK/PD properties by simulation of different tracer tissue kinetics in vivo.
doi:10.1186/1756-6649-8-2
PMCID: PMC2430701  PMID: 18513382
23.  Perfusion scanning using 99mTc-HMPAO detects early cerebrovascular changes in the diabetic rat 
Background
99mTc-HMPAO is a well-established isotope useful in the detection of regional cerebral blood flow. Diabetes gives rise to arterial atherosclerotic changes that can lead to significant end organ dysfunction, prominently affecting perfusion to the heart, kidneys, eyes and brain. In the current study, we investigated the role of 99mTc-HMPAO cerebral perfusion scans in detecting early vascular changes in the diabetic brain.
Methods
Cerebral perfusion studies were performed on both control and streptozotocin-(STZ) induced diabetic male Wistar rats. Rat brain imaging using a gamma camera was performed for each group 0.5, 2, 4, and 24 hours post 99mTc-HMPAO injection. Data processing for each cerebral perfusion scan was performed by drawing a region of interest (ROI) circumferentially around the brain (B). Background (BKG) due to signal from the soft tissue of each rat was subtracted. Brain 99mTc-HMPAO uptake minus background counts (net brain counts; NBC) were then compared between the two groups.
Results
The NBC (mean ± SD) for the STZ group were statistically significantly higher (p = 0.0004) than those of the control group at each of the time points studied.
Conclusion
99mTc-HMPAO brain scan may be useful in the detection of early atherosclerotic changes in the diabetic rat brain.
doi:10.1186/1756-6649-8-1
PMCID: PMC2322850  PMID: 18559077

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