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1.  Impact of intraoperative MRI/TRUS fusion on dosimetric parameters in cT3a prostate cancer patients treated with high-dose-rate real-time brachytherapy 
Purpose
The purpose of this study was to evaluate the impact of intraoperative MRI/TRUS fusion procedure in cT3a prostate cancer patients treated with high-dose-rate (HDR) real-time brachytherapy.
Material and methods
Prostate gland, dominant intraprostatic lesions (DILs), and extracapsular extension (ECE) were delineated in the pre-brachytherapy magnetic resonance images (MRI) of 9 consecutive patients. The pre-implant P-CTVUS (prostate clinical target volume) was defined as the prostate seen in the transrectal ultrasound (TRUS) images. The CTVMR includedthe prostate with the ECE image (ECE-CTV) as defined on the MRI. Two virtual treatment plans were performed based on the MRI/TRUS fusion images, the first one prescribing 100% of the dose to the P-PTVUS, and the second prescribing to the PTVMR. The implant parameters and dose-volume histogram (DVH) related parameters of the prostate, OARs, and ECE were compared between both plans.
Results
Mean radial distance of ECE was 3.6 mm (SD: 1.1). No significant differences were found between prostate V100, V150, V200, and OARs DVH-related parameters between the plans. Mean values of ECE V100, V150, and V200 were 85.9% (SD: 15.1), 18.2% (SD: 17.3), and 5.85% (SD: 7) when the doses were prescribed to the PTVUS, whereas ECE V100, V150, and V200 were 99.3% (SD: 1.2), 45.8% (SD: 22.4), and 19.6% (SD: 12.6) when doses were prescribed to PTVMR (p = 0.028, p = 0.002 and p = 0.004, respectively).
Conclusions
TRUS/MRI fusion provides important information for prostate brachytherapy, allowing for better coverage and higher doses to extracapsular disease in patients with clinical stage T3a.
doi:10.5114/jcb.2014.43299
PMCID: PMC4105645  PMID: 25097555
extracapsular extension; high-dose-rate brachytherapy; MRI/TRUS fusion; prostate cancer
2.  Reevaluating the imaging definition of tumor progression: perfusion MRI quantifies recurrent glioblastoma tumor fraction, pseudoprogression, and radiation necrosis to predict survival 
Neuro-Oncology  2012;14(7):919-930.
INTRODUCTION: Contrast-enhanced MRI (CE-MRI) represents the current mainstay for monitoring treatment response in glioblastoma multiforme (GBM), based on the premise that enlarging lesions reflect increasing tumor burden, treatment failure, and poor prognosis. Unfortunately, irradiating such tumors can induce changes in CE-MRI that mimic tumor recurrence, so called post treatment radiation effect (PTRE), and in fact, both PTRE and tumor re-growth can occur together. Because PTRE represents treatment success, the relative histologic fraction of tumor growth versus PTRE affects survival. Studies suggest that Perfusion MRI (pMRI)–based measures of relative cerebral blood volume (rCBV) can noninvasively estimate histologic tumor fraction to predict clinical outcome. There are several proposed pMRI-based analytic methods, although none have been correlated with overall survival (OS). This study compares how well histologic tumor fraction and OS correlate with several pMRI-based metrics. METHODS: We recruited previously treated patients with GBM undergoing surgical re-resection for suspected tumor recurrence and calculated preoperative pMRI-based metrics within CE-MRI enhancing lesions: rCBV mean, mode, maximum, width, and a new thresholding metric called pMRI–fractional tumor burden (pMRI-FTB). We correlated all pMRI-based metrics with histologic tumor fraction and OS. RESULTS: Among 25 recurrent patients with GBM, histologic tumor fraction correlated most strongly with pMRI-FTB (r = 0.82; P < .0001), which was the only imaging metric that correlated with OS (P<.02). CONCLUSION: The pMRI-FTB metric reliably estimates histologic tumor fraction (i.e., tumor burden) and correlates with OS in the context of recurrent GBM. This technique may offer a promising biomarker of tumor progression and clinical outcome for future clinical trials.
doi:10.1093/neuonc/nos112
PMCID: PMC3379799  PMID: 22561797
glioblastoma; histologic tumor fraction; perfusion MRI; pseudoprogression; radiation necrosis; recurrent; relative cerebral blood volume; survival
3.  Prostate Cancer Detection and Diagnosis: The Role of MR and its Comparison to other Diagnostic Modalities – A Radiologist's Perspective 
NMR in biomedicine  2013;27(1):10.1002/nbm.3002.
It is now universally recognized that many prostate cancers are over-diagnosed and over-treated. The European Randomized Study of Screening for Prostate Cancer (ERSPC) from 2009 evidenced that, to save one man from death of prostate cancer, over 1,400 men had to be screened, and 48 had to undergo treatment. Detection of prostate cancer is traditionally based upon digital rectal examination (DRE) and measuring serum prostate specific antigen (PSA), followed by ultrasound guided biopsy. The primary role of imaging for the detection and diagnosis of prostate cancer has been transrectal ultrasound (TRUS) guidance during biopsy. MRI has traditionally been used primarily for staging disease in men with biopsy proven cancer. It is has a well-established role in detecting T3 disease, planning radiation therapy, especially 3D conformal or intensity modulated external beam radiation therapy (IMRT), and planning and guiding interstitial seed implant or brachytherapy. New advances have now established prostate MRI can accurately characterize focal lesions within the gland, an ability that has led to new opportunities for improved cancer detection and guidance for biopsy. There are two new approaches to prostate biopsy are under investigation both use pre-biopsy MRI to define potential targets for sampling and then the biopsy is performed either with direct real-time MR guidance (in-bore) or MR fusion/registration with TRUS images (out-of-bore). In-bore or out-of-bore MRI-guided prostate biopsies have the advantage of using the MR target definition for accurate localization and sampling of targets or suspicious lesions. The out-of-bore method uses combined MRI/TRUS with fusion software that provided target localization and increases the sampling accuracy for TRUS-guided biopsies by integrating prostate MRI information with TRUS. Newer parameters for each imaging modality such as sonoelastography or shear wave elastography (SWE), contrast enhanced US (CEUS) and MRI-elastography, show promise to further enrich data sets.
doi:10.1002/nbm.3002
PMCID: PMC3851933  PMID: 24000133
4.  Ultrasound-Fluoroscopy Registration for Prostate Brachytherapy Dosimetry 
Medical image analysis  2012;16(7):1347-1358.
Prostate brachytherapy is a treatment for prostate cancer using radioactive seeds that are permanently implanted in the prostate. The treatment success depends on adequate coverage of the target gland with a therapeutic dose, while sparing the surrounding tissue. Since seed implantation is performed under transrectal ultrasound (TRUS) imaging, intraoperative localization of the seeds in ultrasound can provide physicians with dynamic dose assessment and plan modification. However, since all seeds cannot be seen in the ultrasound images, registration between ultrasound and fluoroscopy is a practical solution for intraoperative dosimetry. In this manuscript, we introduce a new image-based nonrigid registration method that obviates the need for manual seed segmentation in TRUS images and compensates for the prostate displacement and deformation due to TRUS probe pressure. First, we filter the ultrasound images for subsequent registration using thresholding and Gaussian blurring. Second, a computationally efficient point-to-volume similarity metric, an affine transformation and an evolutionary optimizer are used in the registration loop. A phantom study showed final registration errors of 0.84 ± 0.45 mm compared to ground truth. In a study on data from 10 patients, the registration algorithm showed overall seed-to-seed errors of 1.7 ± 1.0 mm and 1.5 ± 0.9 mm for rigid and nonrigid registration methods, respectively, performed in approximately 30 seconds per patient.
doi:10.1016/j.media.2012.06.001
PMCID: PMC3448845  PMID: 22784870
Prostate Brachytherapy; Registration; Fluoroscopy; Ultrasound
5.  Prostate volume changes during permanent seed brachytherapy: an analysis of intra-operative variations, predictive factors and clinical implication 
Background
To determine prostate volume (Pvol) changes at 3 different time points during the course of I125 permanent seed brachytherapy (PB). To assess the impact of these changes on acute urinary retention (AUR) and dosimetric outcome.
Methods
We analyzed 149 hormone-naïve patients. Measurements of the prostate volume were done using three-dimensional transrectal ultrasound (3D-TRUS) in the operating room before insertion of any needle (V1), after the insertion of 2 fixation needles with a harpoon (V2) and upon completion of the implant (V3). The quality of the implant was analyzed with the D90 (minimum dose in Grays received by 90% of the prostate volume) at day 30.
Results
Mean baseline prostate volume (V1) was 37.4 ± 9.6 cc. A volume increase of >5% was seen in 51% between V1-V2 (mean = 2.5 cc, p < 0.01), in 42% between V2-V3 (mean = 1.9 cc, p < 0.01) and in 71% between V1-V3 (mean = 4.5 cc, p < 0.01). Pvol changes caused by insertion of the fixation needles were not statistically different than those caused by the implant itself (p = 0.23).
In multivariate linear regression analysis, baseline Pvol is predictive of Pvol changes between V2 and V1 and V3 and V1 but not between V3 and V2. The extent of prostate swelling had an influence on D90. An increase of 10% in prostate volume between V1 and V2 results in an increase of D90 at Day 30 by 11.7%. Baseline Pvol (V1) was the only predictor of the duration of urinary retention in both univariate and multivariate (p = 0.04) regression analysis.
Conclusions
A large part of intraoperative swelling occurs already after the insertion of the fixation needles. This early prostate swelling predicts for D90 but not for AUR.
doi:10.1186/1748-717X-8-177
PMCID: PMC3720214  PMID: 23837971
Prostate; Permanent seed brachytherapy; Intra-operative edema
6.  Selection of Optimal Hyper-Parameters for Estimation of Uncertainty in MRI-TRUS Registration of the Prostate 
Transrectal ultrasound (TRUS) facilitates intra-treatment delineation of the prostate gland (PG) to guide insertion of brachytherapy seeds, but the prostate substructure and apex are not always visible which may make the seed placement sub-optimal. Based on an elastic model of the prostate created from MRI, where the prostate substructure and apex are clearly visible, we use a Bayesian approach to estimate the posterior distribution on deformations that aligns the pre-treatment MRI with intra-treatment TRUS. Without apex information in TRUS, the posterior prediction of the location of the prostate boundary, and the prostate apex boundary in particular, is mainly determined by the pseudo stiffness hyper-parameter of the prior distribution. We estimate the optimal value of the stiffness through likelihood maximization that is sensitive to the accuracy as well as the precision of the posterior prediction at the apex boundary. From a data-set of 10 pre- and intra-treatment prostate images with ground truth delineation of the total PG, 4 cases were used to establish an optimal stiffness hyper-parameter when 15% of the prostate delineation was removed to simulate lack of apex information in TRUS, while the remaining 6 cases were used to cross-validate the registration accuracy and uncertainty over the PG and in the apex.
PMCID: PMC3712120  PMID: 23286120
7.  An MRI-Based Dose-Response Analysis of Urinary Sphincter Dose and Urinary Morbidity after Brachytherapy for Prostate Cancer in a Phase II Prospective Trial 
Brachytherapy  2013;12(3):210-216.
Purpose
To compare dose-volume histogram (DVH) variables for the internal and external urinary sphincters (IUS/EUS) with urinary quality of life after prostate brachytherapy.
Materials and Methods
Subjects were 42 consecutive men from a prospective study of brachytherapy as monotherapy with 125I for intermediate-risk localized prostate cancer. No patient received hormone therapy. Preplanning constraints included prostate V100 >95%, V150 <60%, and V200 <20% and rectal R100 < 1 cm3. Patients completed the EPIC quality of life questionnaire before and 1, 4, 8, and 12 months after implantation, and urinary domain scores were analyzed. All structures including the IUS and EUS were contoured on T2-weighted MRI at day 30, and doses received were calculated from identification of seeds on CT. Spearman's (nonparametric) rank correlation coefficient (ρ) was used for statistical analyses.
Results
Overall urinary morbidity was worst 1 month after the implant. Urinary function declined when the IUS V285 was 0.4% (ρ =–0.32, p=0.04); bother worsened when the IUS V35 was 99% (ρ=–0.31, p=0.05) or the EUS V240 was 63% (ρ=–0.31, p=0.05); irritation increased when the IUS V35 was 95% (ρ=–0.37, p=0.02) and the EUS V265 was 24% (ρ=–0.32, p=0.04); and urgency worsened when the IUS V35 was 99.5% (ρ=–0.38, p=0.02). Incontinence did not correlate with EUS or IUS dose
Conclusions
Doses to the IUS and EUS on MRI/CT predicted worse urinary function, with greater bother, irritative symptoms, and urgency. Incorporating MRI-based DVH analysis into the treatment planning process may reduce acute urinary morbidity after brachytherapy.
doi:10.1016/j.brachy.2012.10.006
PMCID: PMC3891368  PMID: 23466360
Health-related quality of life; Expanded Prostate cancer Index Composite (EPIC) survey; MRI/CT
8.  Variability in MRI vs. ultrasound measures of prostate volume and its impact on treatment recommendations for favorable-risk prostate cancer patients: a case series 
Background
Prostate volume can affect whether patients qualify for brachytherapy (desired size ≥20 mL and ≤60 mL) and/or active surveillance (desired PSA density ≤0.15 for very low risk disease). This study examines variability in prostate volume measurements depending on imaging modality used (ultrasound versus MRI) and volume calculation technique (contouring versus ellipsoid) and quantifies the impact of this variability on treatment recommendations for men with favorable-risk prostate cancer.
Methods
We examined 70 patients who presented consecutively for consideration of brachytherapy for favorable-risk prostate cancer who had volume estimates by three methods: contoured axial ultrasound slices, ultrasound ellipsoid (height × width × length × 0.523) calculation, and endorectal coil MRI (erMRI) ellipsoid calculation.
Results
Average gland size by the contoured ultrasound, ellipsoid ultrasound, and erMRI methods were 33.99, 37.16, and 39.62 mLs, respectively. All pairwise comparisons between methods were statistically significant (all p < 0.015). Of the 66 patients who volumetrically qualified for brachytherapy on ellipsoid ultrasound measures, 22 (33.33%) did not qualify on ellipsoid erMRI or contoured ultrasound measures. 38 patients (54.28%) had PSA density ≤0.15 ng/dl as calculated using ellipsoid ultrasound volumes, compared to 34 (48.57%) and 38 patients (54.28%) using contoured ultrasound and ellipsoid erMRI volumes, respectively.
Conclusions
The ultrasound ellipsoid and erMRI ellipsoid methods appeared to overestimate ultrasound contoured volume by an average of 9.34% and 16.57% respectively. 33.33% of those who qualified for brachytherapy based on ellipsoid ultrasound volume would be disqualified based on ultrasound contoured and/or erMRI ellipsoid volume. As treatment recommendations increasingly rely on estimates of prostate size, clinicians must consider method of volume estimation.
doi:10.1186/1748-717X-9-200
PMCID: PMC4261899  PMID: 25205146
Prostate volume; Favorable-risk prostate cancer; Brachytherapy; Active surveillance; MRI; Ultrasound
9.  Fully Automated Prostate Magnetic Resonance Imaging and Transrectal Ultrasound Fusion via a Probabilistic Registration Metric 
In this work, we present a novel, automated, registration method to fuse magnetic resonance imaging (MRI) and transrectal ultrasound (TRUS) images of the prostate. Our methodology consists of: (1) delineating the prostate on MRI, (2) building a probabilistic model of prostate location on TRUS, and (3) aligning the MRI prostate segmentation to the TRUS probabilistic model. TRUS-guided needle biopsy is the current gold standard for prostate cancer (CaP) diagnosis. Up to 40% of CaP lesions appear isoechoic on TRUS, hence TRUS-guided biopsy cannot reliably target CaP lesions and is associated with a high false negative rate. MRI is better able to distinguish CaP from benign prostatic tissue, but requires special equipment and training. MRI-TRUS fusion, whereby MRI is acquired pre-operatively and aligned to TRUS during the biopsy procedure, allows for information from both modalities to be used to help guide the biopsy. The use of MRI and TRUS in combination to guide biopsy at least doubles the yield of positive biopsies. Previous work on MRI-TRUS fusion has involved aligning manually determined fiducials or prostate surfaces to achieve image registration. The accuracy of these methods is dependent on the reader’s ability to determine fiducials or prostate surfaces with minimal error, which is a difficult and time-consuming task. Our novel, fully automated MRI-TRUS fusion method represents a significant advance over the current state-of-the-art because it does not require manual intervention after TRUS acquisition. All necessary preprocessing steps (i.e. delineation of the prostate on MRI) can be performed offline prior to the biopsy procedure. We evaluated our method on seven patient studies, with B-mode TRUS and a 1.5 T surface coil MRI. Our method has a root mean square error (RMSE) for expertly selected fiducials (consisting of the urethra, calcifications, and the centroids of CaP nodules) of 3.39 ± 0.85 mm.
doi:10.1117/12.2007610
PMCID: PMC3864967  PMID: 24353393
10.  Real-Time Intraoperative CT Assessment of Quality of Permanent Interstitial Seed Implantation for Prostate Cancer 
Urology  2010;76(5):1138-1142.
Objectives
Evaluate real-time kilovoltage cone-beam computed tomography (CBCT) during prostate brachytherapy for intraoperative dosimetric assessment and correcting deficient dose regions.
Methods
Twenty patients were evaluated intraoperatively with a mobile CBCT unit immediately after implantation while still anesthetized. The source-detector system is enclosed into a circular CT-like geometry with a bore that accommodates patients in the lithotomy position. After seed deposition, CBCT scans were obtained, Dosimetry was evaluated and compared to standard postimplantation CT-based assessment. In eight patients deposited seeds were localized in the intraoperative CBCT frame of reference and registered to the intraoperative transrectal ultrasound (TRUS) images. With this information, a second intraoperative plan was generated to ascertain if additional seeds were needed to achieve the planned prescription dose. Final dosimetry was compared with postimplantation scan assessment.
Results
Mean differences between dosimetric parameters from the intraoperative CBCT and post-implant CT scans were <0.5% for V100, D90, and V150 target values. Mean percentage differences for average urethral doses were not significantly different. Differences for D5 (maximum dose) of the urethra were <4%. The dose to 2 cc of the rectum differed by 10% on average. After fusion of implanted seed coordinates from the intraoperative CBCT scans onto the intraoperative TRUS images, dosimetric outcomes were similar to postimplantation CT dosimetric results.
Conclusions
Intraoperative CT-based dosimetric evaluation of prostate permanent seed implantation prior to anesthesia reversal is feasible and may avert misadministration of dose delivery. Dosimetric measurements based on the intraoperative CBCT scans are dependable and correlate well with postimplant diagnostic CT evaluation.
doi:10.1016/j.urology.2010.01.067
PMCID: PMC4049478  PMID: 20430423
Prostate; brachytherapy; dosimetry; image-guidance
11.  Definition of medical event is to be based on the total source strength for evaluation of permanent prostate brachytherapy: A report from the American Society for Radiation Oncology 
Practical Radiation Oncology  2011;1(4):218-223.
Purpose
The Nuclear Regulatory Commission deems it to be a medical event (ME) if the total dose delivered differs from the prescribed dose by 20% or more. A dose-based definition of ME is not appropriate for permanent prostate brachytherapy as it generates too many spurious MEs and thereby creates unnecessary apprehension in patients, and ties up regulatory bodies and the licensees in unnecessary and burdensome investigations. A more suitable definition of ME is required for permanent prostate brachytherapy.
Methods and Materials
The American Society for Radiation Oncology (ASTRO) formed a working group of experienced clinicians to review the literature, assess the validity of current regulations, and make specific recommendations about the definition of an ME in permanent prostate brachytherapy.
Results
The working group found that the current definition of ME in §35.3045 as “the total dose delivered differs from the prescribed dose by 20 percent or more” was not suitable for permanent prostate brachytherapy since the prostate volume (and hence the resultant calculated prostate dose) is dependent on the timing of the imaging, the imaging modality used, the observer variability in prostate contouring, the planning margins used, inadequacies of brachytherapy treatment planning systems to calculate tissue doses, and seed migration within and outside the prostate. If a dose-based definition for permanent implants is applied strictly, many properly executed implants would be improperly classified as an ME leading to a detrimental effect on brachytherapy. The working group found that a source strength-based criterion, of >20% of source strength prescribed in the post-procedure written directive being implanted outside the planning target volume is more appropriate for defining ME in permanent prostate brachytherapy.
Conclusions
ASTRO recommends that the definition of ME for permanent prostate brachytherapy should not be dose based but should be based upon the source strength (air-kerma strength) administered.
doi:10.1016/j.prro.2011.05.001
PMCID: PMC3808748  PMID: 24174998
12.  Current Status of Brachytherapy for Prostate Cancer 
Korean Journal of Urology  2012;53(11):743-749.
Brachytherapy was developed to treat prostate cancer 50 years ago. Current advanced techniques using transrectal ultrasonography were established 25 years ago. Transrectal ultrasound (TRUS) has enabled the prostate to be viewed with improved resolution with the use of modern ultrasound machines. Moreover, the development of software that can provide images captured in real time has improved treatment outcomes. Other new radiologic imaging technologies or a combination of magnetic resonance and TRUS could be applied to brachytherapy in the future. The therapeutic value of brachytherapy for early-stage prostate cancer is comparable to that of radical prostatectomy in long-term follow-up. Nevertheless, widespread application of brachytherapy cannot be achieved for several reasons. The treatment outcome of brachytherapy varies according to the skill of the operator and differences in patient selection. Currently, only three radioactive isotopes are available for use in low dose rate prostate brachytherapy: I-125, Pd-103, and Cs-131; therefore, more isotopes should be developed. High dose rate brachytherapy using Ir-192 combined with external beam radiation, which is needed to verify the long-term effects, has been widely applied in high-risk patient groups. Recently, tumor-selective therapy or focal therapy using brachytherapy, which is not possible by surgical extraction, has been developed to maintain the quality of life in selected cases. However, this new application for prostate cancer treatment should be performed cautiously because we do not know the oncological outcome, and it would be an interim treatment method. This technique might evolve into a hybrid of whole-gland treatment and focal therapy.
doi:10.4111/kju.2012.53.11.743
PMCID: PMC3502731  PMID: 23185664
Brachytherapy; Neoplasms; Prostate
13.  Predicting pubic arch interference in prostate brachytherapy on transrectal ultrasonography-computed tomography fusion images 
Journal of Radiation Research  2012;53(5):753-759.
We investigated the usefulness of the fusion image created by transrectal ultrasonography (TRUS) and large-bore computed tomography (CT) for predicting pubic arch interference (PAI) during prostate seed brachytherapy. The TRUS volume study was performed in 21 patients, followed by large-bore computed tomography of patients in the lithotomy position. Then, we created TRUS-CT fusion images using a radiation planning treatment system. TRUS images in which the prostate outline was the largest were overlaid on CT images with the narrowest pubic arch. PAI was estimated in the right and left arch separately and classified to three grades: no PAI, PAI positive within 5 mm and PAI of >5 mm. If the estimated PAI was more than 5 mm on at least one side of the arch, we judged there to be a significant PAI. Brachytherapy was performed in 18 patients who were evaluated as not having significant PAI on TRUS. Intra-operative PAI was observed in one case, which was also detected with a fusion image. On the other hand, intra-operative PAI was not observed in one case that had been evaluated as having significant PAI with a fusion image. In the remaining three patients, TRUS suggested the presence of significant PAI, which was also confirmed by a fusion image. Intra-operative PAI could be predicted by TRUS-CT fusion imaging, even when it was undetectable by TRUS. Although improvement of the reproducibility of the patients’ position to avoid false-positive cases is warranted, TRUS-CT fusion imaging has the possibility that the uncertainty of TRUS can be supplemented.
doi:10.1093/jrr/rrs020
PMCID: PMC3430429  PMID: 22843359
prostate cancer; brachytherapy; seed implantation; pubic arch interference; fusion image
14.  Progressive transition from pre-planned to intraoperative optimizing seed implant: post implementation analysis 
Purpose
To perform a dosimetric comparison between a pre-planned technique and a pre-plan based intraoperative technique in prostate cancer patients treated with I-125 permanent seed implantation.
Material and methods
Thirty patients were treated with I-125 permanent seed implantation using TRUS guidance. The first 15 of these patients (Arm A) were treated with a pre-planned technique using ultrasound images acquired prior to seed implantation. To evaluate the reproducibility of the prostate volume, ultrasound images were also acquired during the procedure in the operating room (OR). A surface registration was applied to determine the 6D offset between different image sets in arm A. The remaining 15 patients (Arm B) were planned by putting the pre-plan on the intraoperative ultrasound image and then re-optimizing the seed locations with minimal changes to the pre-plan needle locations. Post implant dosimetric analyses included comparisons of V100(prostate), D90(prostate) and V100(rectum).
Results
In Arm A, the 6D offsets between the two image sets were θx=−1.4±4.3; θy=−1.7±2.6; θz=−0.5±2.6; X=0.5±1.8 mm; Y=−1.3±−3.5 mm; Z=−1.6±2.2 mm. These differences alone degraded V100 by 6.4% and D90 by 9.3% in the pre-plan, respectively. Comparing Arm A with Arm B, the pre-plan based intraoperative optimization of seed locations used in the plans for patients in Arm B improved the V100 and D90 in their post-implant studies by 4.0% and 5.7%, respectively. This was achieved without significantly increasing the rectal dose (V100(rectum)).
Conclusions
We have progressively moved prostate seed implantation from a pre-planned technique to a pre-plan based intraoperative technique. In addition to reserving the advantage of cost-effective seed ordering and efficient OR implantation, our intraoperative technique demonstrates increased accuracy and precision compared to the pre-planned technique.
doi:10.5114/jcb.2012.27951
PMCID: PMC3551369  PMID: 23346139
pre-plan; intraoperative planning; seed implant; prostate cancer
15.  Intra-operative Localization of Brachytherapy Implants Using Intensity-based Registration 
Proceedings of SPIE  2009;7261:726139.
In prostate brachytherapy, a transrectal ultrasound (TRUS) will show the prostate boundary but not all the implanted seeds, while fluoroscopy will show all the seeds clearly but not the boundary. We propose an intensity-based registration between TRUS images and the implant reconstructed from uoroscopy as a means of achieving accurate intra-operative dosimetry. The TRUS images are first filtered and compounded, and then registered to the uoroscopy model via mutual information. A training phantom was implanted with 48 seeds and imaged. Various ultrasound filtering techniques were analyzed, and the best results were achieved with the Bayesian combination of adaptive thresholding, phase congruency, and compensation for the non-uniform ultrasound beam profile in the elevation and lateral directions. The average registration error between corresponding seeds relative to the ground truth was 0.78 mm. The effect of false positives and false negatives in ultrasound were investigated by masking true seeds in the uoroscopy volume or adding false seeds. The registration error remained below 1.01 mm when the false positive rate was 31%, and 0.96 mm when the false negative rate was 31%. This fully automated method delivers excellent registration accuracy and robustness in phantom studies, and promises to demonstrate clinically adequate performance on human data as well. Keywords: Prostate brachytherapy, Ultrasound, Fluoroscopy, Registration.
doi:10.1117/12.812447
PMCID: PMC2997743  PMID: 21152376
16.  Initial clinical experience with real-time transrectal ultrasonography-magnetic resonance imaging fusion-guided prostate biopsy 
BJU international  2007;101(7):841-845.
OBJECTIVE
To evaluate the feasibility and utility of registration and fusion of real-time transrectal ultrasonography (TRUS) and previously acquired magnetic resonance imaging (MRI) to guide prostate biopsies.
PATIENTS AND METHODS
Two National Cancer Institute trials allowed MRI-guided (with or with no US fusion) prostate biopsies during placement of fiducial markers. Fiducial markers were used to guide patient set-up for daily external beam radiation therapy. The eligible patients had biopsy-confirmed prostate cancer that was visible on MRI. A high-field (3T) MRI was performed with an endorectal coil in place. After moving to an US suite, the patient then underwent TRUS to visualize the prostate. The US transducer was equipped with a commercial needle guide and custom modified with two embedded miniature orthogonal five-degrees of freedom sensors to enable spatial tracking and registration with MR images in six degrees of freedom. The MRI sequence of choice was registered manually to the US using custom software for real-time navigation and feedback. The interface displayed the actual and projected needle pathways superimposed upon the real-time US blended with the prior MR images, with position data updating in real time at 10 frames per second. The registered MRI information blended to the real-time US was available to the physician who performed targeted biopsies of highly suspicious areas.
RESULTS
Five patients underwent limited focal biopsy and fiducial marker placement with real-time TRUS-MRI fusion. The Gleason scores at the time of enrolment on study were 8, 7, 9, 9, and 6. Of the 11 targeted biopsies, eight showed prostate cancer. Positive biopsies were found in all patients. The entire TRUS procedure, with fusion, took ≈10 min.
CONCLUSION
The fusion of real-time TRUS and prior MR images of the prostate is feasible and enables MRI-guided interventions (like prostate biopsy) outside of the MRI suite. The technique allows for navigation within dynamic contrast-enhanced maps, or T2-weighted or MR spectroscopy images. This technique is a rapid way to facilitate MRI-guided prostate therapies such as external beam radiation therapy, brachytherapy, cryoablation, high-intensity focused ultrasound ablation, or direct injection of agents, without the cost, throughput, or equipment compatibility issues that might arise with MRI-guided interventions inside the MRI suite.
doi:10.1111/j.1464-410X.2007.07348.x
PMCID: PMC2621260  PMID: 18070196
magnetic resonance; ultrasound; prostate cancer; imaging; transrectal
17.  Preimplant factors affecting postimplant CT-determined prostate volume and the CT/TRUS volume ratio after transperineal interstitial prostate brachytherapy with 125I free seeds 
Background
The aim was to identify preimplant factors affecting postimplant prostate volume and the increase in prostate volume after transperineal interstitial prostate brachytherapy with 125I free seeds.
Methods
We reviewed the records of 180 patients who underwent prostate brachytherapy with 125I free seeds for clinical T1/T2 prostate cancer. Eighty-one (45%) of the 180 patients underwent neoadjuvant hormonal therapy. No patient received supplemental external beam radiotherapy. Postimplant computed tomography was undertaken, and postimplant dosimetric analysis was performed. Univariate and multivariate analyses were performed to identify preimplant factors affecting postimplant prostate volume by computed tomography and the increase in prostate volume after implantation.
Results
Preimplant prostate volume by transrectal ultrasound, serum prostate-specific antigen, number of needles, and number of seeds implanted were significantly correlated with postimplant prostate volume by computed tomography. The increase in prostate volume after implantation was significantly higher in patients with neoadjuvant hormonal therapy than in those without. Preimplant prostate volume by transrectal ultrasound, number of needles, and number of seeds implanted were significantly correlated with the increase in prostate volume after implantation. Stepwise multiple linear regression analysis showed that preimplant prostate volume by transrectal ultrasound and neoadjuvant hormonal therapy were significant independent factors affecting both postimplant prostate volume by computed tomography and the increase in prostate volume after implantation.
Conclusions
The results of the present study show that preimplant prostate volume by transrectal ultrasound and neoadjuvant hormonal therapy are significant preimplant factors affecting both postimplant prostate volume by computed tomography and the increase in prostate volume after implantation.
doi:10.1186/1748-717X-5-86
PMCID: PMC2954882  PMID: 20875137
18.  Benefits of a dual sagittal crystal transducer for ultrasound imaging during I-125 seed implantation for permanent prostate brachytherapy 
Purpose
To investigate whether a longer sagittal view and less movement using a dual sagittal crystal probe (DSCP) for trans rectal ultra sound (TRUS) allow for more accurate online-planning in I-125 permanent implant brachytherapy of the prostate, compared to a single sagittal crystal probe (SSCP).
Material and methods
Between March 2008 and March 2010, 50 patients with prostate cancer were consecutively included in the study. The first 25 of these patients had both their pre- and online-planning based on a single sagittal crystal probe (SSCP). The treatment-plans of the other 25 patients were based on a DSCP TRUS. Three weeks after implantation a post-planning was made based on CT. TRUS online and CT post-plan dose-volume histogram (DVH) parameters, D90 and V100, were compared for both groups. Also, the post-plan DVH parameters of SSCP were compared to DSCP. The possible factors that might influence the post-plan D90 and V100 were analysed using Analysis of Variance (ANOVA).
Results
SSCP and DSCP online mean D90 and V100 were significantly larger than post-plan mean D90 and V100 (P < 0.01). The post-plan mean D90 and mean V100 were both non-significantly larger for SSCP based post-plans compared to DSCP based post plans (P = 0.76 and P = 0.68). ANOVA showed significant impact of prostate volume on the post-plan D90 and V100.
Conclusions
The advantages of the dual sagittal crystal probe did not lead to more accurate online planning by investigating DVH-parameters. The only factor found to have influence on the DVH-parameters was the prostate volume.
doi:10.5114/jcb.2012.30680
PMCID: PMC3551381  PMID: 23346143
prostatic neoplasms; brachytherapy; computer assisted radiotherapy planning; transrectal ultrasound; D90; V100
19.  Least Squares for Diffusion Tensor Estimation Revisited: Propagation of Uncertainty with Rician and non-Rician Signals 
NeuroImage  2011;59(4):4032-4043.
Least Squares (LS) and its minimum variance counterpart, Weighted Least Squares (WLS), have become very popular when estimating the Diffusion Tensor (DT), to the point that they are the standard in most of the existing software for diffusion MRI. They are based on the linearization of the Stejskal-Tanner equation by means of the logarithmic compression of the diffusion signal. Due to the Rician nature of noise in traditional systems, a certain bias in the estimation is known to exist. This artifact has been made patent through some experimental set-ups, but it is not clear how the distortion translates in the reconstructed DT, and how important it is when compared to the other source of error contributing to the Mean Squared Error (MSE) in the estimate, i.e. the variance. In this paper we propose the analytical characterization of log-Rician noise and its propagation to the components of the DT through power series expansions. We conclude that even in highly noisy scenarios the bias for log-Rician signals remains moderate when compared to the corresponding variance. Yet, with the advent of Parallel Imaging (pMRI), the Rician model is not always valid. We make our analysis extensive to a number of modern acquisition techniques through the study of a more general Non Central-Chi (nc-χ) model. Since WLS techniques were initially designed bearing in mind Rician noise, it is not clear wether or not they still apply to pMRI. An important finding in our work is that the common implementation of WLS is nearly optimal when nc-χ noise is considered. Unfortunately, the bias in the estimation becomes far more important in this case, to the point that it may nearly overwhelm the variance in given situations. Furthermore, we evidence that such bias cannot be removed by increasing the number of acquired gradient directions. A number of experiments have been conducted that corroborate our analytical findings, while in vivo data have been used to test the actual relevance of the bias in the estimation.
doi:10.1016/j.neuroimage.2011.09.074
PMCID: PMC4039744  PMID: 22015852
Diffusion Tensor; Least Squares; Rician; Non-Central-Chi; Bias
20.  Long Term Results of a Phase II Trial of Ultrasound-Guided Radioactive Implantation of the Prostate for Definitive Management of Localized Adenocarcinoma of the Prostate (RTOG 98-05) 
Purpose
To evaluate the long term effectiveness of transrectal ultrasound (TRUS)-guided permanent radioactive I125 implantation of the prostate for organ confined adenocarcinoma of the prostate compared with historical data of prostatectomy and external beam radiotherapy (EBRT) within a cooperative group setting.
Methods and Materials
Patients accrued to this study had histologically confirmed, locally confined, adenocarcinoma of the prostate clinical stage T1b, T1c, or T2a, no nodal or metastatic disease, prostate specific antigen (PSA) level of ≤ 10 ng/ml and a Gleason score of ≤ 6. All patients underwent TRUS-guided radioactive I125 seed implantation into the prostate. The prescribed dose was 145 Gy to the prostate planning target volume (PTV).
Results
A total of 101 patients from 27 institutions were accrued to this protocol; by design no single institution accrued more than 8 patients. There were 94 eligible patients. The median follow up was 8.1 years (range 0.1 to 9.2 years). After 8 years, 8 patients had protocol-defined biochemical (PSA) failure (cumulative incidence 8.0%), 5 patients had local failure (cumulative incidence 5.5%), and 1 patient had distant failure (cumulative incidence 1.1%; this patient also had biochemical failure and non-prostate cancer related death). The 8-year overall survival (OS) rate was 88%. At last follow up, no patient died of prostate cancer or related toxicities. Three patients had maximum late toxicity of Grade 3 and all were genitourinary (GU). There were no Grade 4 or 5 toxicities observed.
Conclusion
The long term results of this clinical trial have demonstrated that this kind of trial can be successfully completed through the RTOG and that results in terms of biochemical failure and toxicity compare very favorably with other brachytherapy published series as well as surgical and external beam radiotherapy series. Additionally, the prospective, multi-centered design highlights the probably generalizability of the outcomes.
doi:10.1016/j.ijrobp.2010.05.056
PMCID: PMC3132830  PMID: 21470793
Prostate; brachytherapy; low dose rate (LDR)
21.  Narrow safety range of intraoperative rectal irradiation exposure volume for avoiding bleeding after seed implant brachytherapy 
Background & Purpose
Rectal toxicity is less common after 125I seed implant brachytherapy for prostate cancer, and intraoperative rectal dose-volume constraints (the constraint) is still undetermined in pioneering studies. As our constraint failed to prevent grade 2 or 3 rectal bleeding (bled-pts) in 5.1% of patients, we retrospectively explored another constraint for the prevention of rectal bleeding.
Materials and methods
The study population consisted of 197 patients treated with the brachytherapy as monotherapy using real-time intraoperative transrectal ultrasound (US)-guided treatment at a prescribed dose of 145 Gy. Post-implant dosimetry was performed on Day 1 and Day 30 after implantation using computed tomography (CT) imaging. Rectal bleeding toxicity was classified by CTC-AE ver. 3.0 during a mean 29-month (range, 12-48 months) period after implantation. The differences in rV100s were compared among intraoperative, Day 1 and Day 30 dosimetry, and between that of patients with grade 2 or 3 rectal bleeding (the bled-pts) and of the others (the spared-pts). All patients were divided into groups based on provisional rV100s that were increased stepwise in 0.1-cc increments from 0 to 1.0 cc. The difference in the ratios of the bled-pts to the spared-pts was tested by chi-square tests, and their odds ratios were calculated (bled-OR). All statistical analyses were performed by t-tests.
Results
The mean values of rV100us, rV100CT_1, and rV100CT_30 were 0.31 ± 0.43, 0.22 ± 0.36, and 0.59 ± 0.68 cc, respectively. These values temporarily decreased (p = 0.020) on Day 1 and increased (p = 0.000) on Day 30. There was no significant difference in rV100s between the bled-pts and spared-pts at any time of dosimetry. The maximum bled-OR was identified among patients with an rV100us value above 0.1 cc (p = 0.025; OR = 7.8; 95% CI, 1.4-145.8); an rV100CT_1 value above 0.3 cc (p = 0.014; OR = 16.2; 95% CI, 3.9-110.7), and an rV100CT_30 value above 0.5 cc (p = 0.019; OR = 6.3; 95% CI, 1.5-42.3).
Conclusion
By retrospective analysis exploring rV100 as intraoperative rectal dose-volume thresholds in 125I seed implant brachytherapy for prostate cancer, it is proved that rV100 should be less than 0.1 cc for preventing rectal bleeding.
doi:10.1186/1748-717X-7-15
PMCID: PMC3293044  PMID: 22293400
prostate cancer; brachytherapy; dose-volume histogram
22.  Re-implantation of suboptimal prostate seed implantation: technique with intraoperative treatment planning 
Purpose
Post-implant dosimetry following prostate seed implantation (PSI) occasionally reveals suboptimal dosimetric coverage of the gland. Published reports of re-implantation techniques have focused on earlier-generation techniques, including preplanned approaches and stranded seeds. The purpose of this case report is to describe a customizable approach to perform corrective re-implantation using loose seeds and intraoperative planning technique.
Material and methods
This case report describes a 63-year-old male with favorable risk prostate adenocarcinoma receiving PSI. Thirty day post-implant dosimetric evaluation revealed suboptimal coverage of the base of the gland. Using guidance from post-implant CT-images and real-time planning, the patient received a corrective re-implantation with intraoperative planning.
Results
Post-implant dosimetry after re-implantation procedure with intraoperative planning yielded improved target volume coverage that achieved standard dosimetric criteria.
Conclusions
Re-implantation as a salvage treatment technique after sub-optimal PSI is a valid treatment option performed with intraoperative real-time planning.
doi:10.5114/jcb.2012.30684
PMCID: PMC3551375  PMID: 23346147
low-dose-rate brachytherapy; prostate cancer; re-implantation; salvage therapy; seeds
23.  Automatic segmentation of seeds and fluoroscope tracking (FTRAC) fiducial in prostate brachytherapy x-ray images 
C-arm X-ray fluoroscopy-based radioactive seed localization for intraoperative dosimetry of prostate brachytherapy is an active area of research. The fluoroscopy tracking (FTRAC) fiducial is an image-based tracking device composed of radio-opaque BBs, lines, and ellipses that provides an effective means for pose estimation so that three-dimensional reconstruction of the implanted seeds from multiple X-ray images can be related to the ultrasound-computed prostate volume. Both the FTRAC features and the brachytherapy seeds must be segmented quickly and accurately during the surgery, but current segmentation algorithms are inhibitory in the operating room (OR). The first reason is that current algorithms require operators to manually select a region of interest (ROI), preventing automatic pipelining from image acquisition to seed reconstruction. Secondly, these algorithms fail often, requiring operators to manually correct the errors. We propose a fast and effective ROI-free automatic FTRAC and seed segmentation algorithm to minimize such human intervention. The proposed algorithm exploits recent image processing tools to make seed reconstruction as easy and convenient as possible. Preliminary results on 162 patient images show this algorithm to be fast, effective, and accurate for all features to be segmented. With near perfect success rates and subpixel differences to manual segmentation, our automatic FTRAC and seed segmentation algorithm shows promising results to save crucial time in the OR while reducing errors.
doi:10.1117/12.844520
PMCID: PMC3438694  PMID: 22977294
segmentation; localization; C-arm; X-ray; fiducial; prostate brachytherapy
24.  Documenting the location of systematic transrectal ultrasound-guided prostate biopsies: correlation with multi-parametric MRI 
During transrectal ultrasound (TRUS)-guided prostate biopsies, the actual location of the biopsy site is rarely documented. Here, we demonstrate the capability of TRUS-magnetic resonance imaging (MRI) image fusion to document the biopsy site and correlate biopsy results with multi-parametric MRI findings. Fifty consecutive patients (median age 61 years) with a median prostate-specific antigen (PSA) level of 5.8 ng/ml underwent 12-core TRUS-guided biopsy of the prostate. Pre-procedural T2-weighted magnetic resonance images were fused to TRUS. A disposable needle guide with miniature tracking sensors was attached to the TRUS probe to enable fusion with MRI. Real-time TRUS images during biopsy and the corresponding tracking information were recorded. Each biopsy site was superimposed onto the MRI. Each biopsy site was classified as positive or negative for cancer based on the results of each MRI sequence. Sensitivity, specificity, and receiver operating curve (ROC) area under the curve (AUC) values were calculated for multi-parametric MRI. Gleason scores for each multi-parametric MRI pattern were also evaluated. Six hundred and 5 systemic biopsy cores were analyzed in 50 patients, of whom 20 patients had 56 positive cores. MRI identified 34 of 56 positive cores. Overall, sensitivity, specificity, and ROC area values for multi-parametric MRI were 0.607, 0.727, 0.667, respectively. TRUS-MRI fusion after biopsy can be used to document the location of each biopsy site, which can then be correlated with MRI findings. Based on correlation with tracked biopsies, T2-weighted MRI and apparent diffusion coefficient maps derived from diffusion-weighted MRI are the most sensitive sequences, whereas the addition of delayed contrast enhancement MRI and three-dimensional magnetic resonance spectroscopy demonstrated higher specificity consistent with results obtained using radical prostatectomy specimens.
doi:10.1102/1470-7330.2011.0007
PMCID: PMC3080122  PMID: 21450548
Prostate cancer; multi-parametric MR imaging; TRUS/MRI fusion tracking
25.  Documenting the location of systematic transrectal ultrasound-guided prostate biopsies: correlation with multi-parametric MRI 
Cancer Imaging  2011;11(1):31-36.
Abstract
During transrectal ultrasound (TRUS)-guided prostate biopsies, the actual location of the biopsy site is rarely documented. Here, we demonstrate the capability of TRUS-magnetic resonance imaging (MRI) image fusion to document the biopsy site and correlate biopsy results with multi-parametric MRI findings. Fifty consecutive patients (median age 61 years) with a median prostate-specific antigen (PSA) level of 5.8 ng/ml underwent 12-core TRUS-guided biopsy of the prostate. Pre-procedural T2-weighted magnetic resonance images were fused to TRUS. A disposable needle guide with miniature tracking sensors was attached to the TRUS probe to enable fusion with MRI. Real-time TRUS images during biopsy and the corresponding tracking information were recorded. Each biopsy site was superimposed onto the MRI. Each biopsy site was classified as positive or negative for cancer based on the results of each MRI sequence. Sensitivity, specificity, and receiver operating curve (ROC) area under the curve (AUC) values were calculated for multi-parametric MRI. Gleason scores for each multi-parametric MRI pattern were also evaluated. Six hundred and 5 systemic biopsy cores were analyzed in 50 patients, of whom 20 patients had 56 positive cores. MRI identified 34 of 56 positive cores. Overall, sensitivity, specificity, and ROC area values for multi-parametric MRI were 0.607, 0.727, 0.667, respectively. TRUS-MRI fusion after biopsy can be used to document the location of each biopsy site, which can then be correlated with MRI findings. Based on correlation with tracked biopsies, T2-weighted MRI and apparent diffusion coefficient maps derived from diffusion-weighted MRI are the most sensitive sequences, whereas the addition of delayed contrast enhancement MRI and three-dimensional magnetic resonance spectroscopy demonstrated higher specificity consistent with results obtained using radical prostatectomy specimens.
doi:10.1102/1470-7330.2011.0007
PMCID: PMC3080122  PMID: 21450548
Prostate cancer; multi-parametric MR imaging; TRUS/MRI fusion tracking

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