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1.  Dosimetry of permanent interstitial prostate brachytherapy for an interoperative procedure, using O-arm based CT and TRUS 
The aim of this report is dosimetric evaluation for an intraoperative fusion computed tomography (CT) as a superior predictor of 1-month CT based dosimetry in comparison to transrectal ultrasound (TRUS) in permanent interstitial prostate brachytherapy.
Material and methods
Data of 65 patients treated with seed implantation were analyzed. All procedures has been performed with patients in the lithotomy position inside the O-arm system. An end-fine probe is used as a landmark to fuse TRUS and O-arm-based CT images. There was no difference in the patient's position, probe position, and timing of image acquisition between the two imaging modalities. Dose-volume histogram (DVH) parameters such as the dose to 90% of prostate volume (D90) has been analyzed.
The area under the curve of the receiver operating characteristic tended to be larger on fusion CT than on TRUS for most DVH parameters (71.85% vs. 59.59% for D90; p = 0.07). Significant relationships between fusion CT and 1-month CT were confirmed using Pearson's correlation coefficients for most DVH parameters (R = 0.48, p < 0.01 for D90), although the relationship between TRUS and 1-month CT was poor. Large dose reduction (35 Gy for D90) was seen from TRUS to fusion CT, especially in patients with high body weight and small prostate volume.
Intraoperative fusion CT appears to have higher predictive power for 1-month CT-based dosimetry than TRUS. A prospective trial using fusion CT-based planning is warranted.
PMCID: PMC4793069  PMID: 26985192
brachytherapy; intraoperative CT; low dose rate; O-arm system; prostate cancer
2.  Impact of intraoperative MRI/TRUS fusion on dosimetric parameters in cT3a prostate cancer patients treated with high-dose-rate real-time brachytherapy 
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.
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).
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.
PMCID: PMC4105645  PMID: 25097555
extracapsular extension; high-dose-rate brachytherapy; MRI/TRUS fusion; prostate cancer
3.  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.
PMCID: PMC3379799  PMID: 22561797
glioblastoma; histologic tumor fraction; perfusion MRI; pseudoprogression; radiation necrosis; recurrent; relative cerebral blood volume; survival
4.  Role of Pre-operative Magnetic Resonance Imaging in the Surgical Management of Early Stage Breast Cancer 
Annals of surgical oncology  2014;21(11):3473-3480.
To examine the role of pre-operative magnetic resonance imaging (pMRI) on time to surgery and rates of re-operation and contralateral prophylactic mastectomy (CPM) using a population-based study of New Jersey breast cancer (BC) patients.
The study included 289 African-American and 320 white women who participated in the Breast Cancer Treatment Disparity Study and underwent breast surgery for newly diagnosed early stage BC between 2005 and 2010. Patients were identified through rapid case ascertainment by the New Jersey State Cancer Registry. Association between pMRI and time to surgery was examined using linear regression, and with re-operation and CPM using binomial regression.
Half (49.9%) of the study population received pMRI, with higher use for whites compared to African-Americans (62.5% versus 37.5%). After adjusting for potential confounders, patients with pMRI than those without, experienced significantly longer time to initial surgery (geometric mean= 38.7 days; 95% confidence interval: 34.8, 43.0 versus 26.5 days; 95% confidence interval: 24.3, 29.0), significantly higher rate of CPM (relative risk [RR]= 1.82; 95% confidence interval: 1.06, 3.12), and non-significant lower rate of re-operation (RR= 0.76; 95% confidence interval [CI]: 0.54, 1.08).
pMRI was associated with significantly increased time to surgery and higher rate of CPM, but it did not affect the rate of re-operation. Physicians and patients should consider these findings when making surgical decisions based on pMRI findings.
PMCID: PMC4440653  PMID: 24912611
5.  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.
PMCID: PMC3448845  PMID: 22784870
Prostate Brachytherapy; Registration; Fluoroscopy; Ultrasound
6.  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.
PMCID: PMC3851933  PMID: 24000133
7.  Predictors of prostate volume reduction following neoadjuvant cytoreductive androgen suppression 
Limited duration cytoreductive neoadjuvant hormonal therapy (NHT) is used prior to definitive radiotherapeutic management of prostate cancer to decrease prostate volume. The purpose of this study is to examine the effect of NHT on prostate volume before permanent prostate brachytherapy (PPB), and determine associated predictive factors.
Material and methods
Between June 1998 and April 2012, a total of 1,110 patients underwent PPB and 207 patients underwent NHT. Of these, 189 (91.3%) underwent detailed planimetric transrectal ultrasound before and after NHT prior to PPB. Regression analysis was used to assess predictors of absolute and percentage change in prostate volume after NHT.
The median duration of NHT was 4.9 months with inter quartile range (IQR), 4.2-6.6 months. Prostate-specific antigen (PSA) reduced by a median of 97% following NHT. The mean prostate volume before NHT was 62.5 ± 22.1 cm3 (IQR: 46-76 cm3), and after NHT, it was 37.0 ± 14.5 cm3 (IQR: 29-47 cm3). The mean prostate volume reduction was 23.4 cm3 (35.9%). Absolute prostate volume reduction was positively correlated with initial volume and inversely correlated with T-stage, Gleason score, and NCCN risk group. In multivariate regression analyses, initial prostate volume (p < 0.001) remained as a significant predictor of absolute and percent prostate volume reduction. Total androgen suppression was associated with greater percent prostate volume reduction than luteinizing hormone releasing hormone agonist (LHRHa) alone (p = 0.001).
Prostate volume decreased by approximately one third after 4.9 months of NHT, with total androgen suppression found to be more efficacious in maximizing cytoreduction than LHRHa alone. Initial prostate volume is the greatest predictor for prostate volume reduction.
PMCID: PMC5116454  PMID: 27895677
brachytherapy; neoadjuvant hormonal therapy; prostate cancer; volume
8.  Prostate volume estimations using magnetic resonance imaging and transrectal ultrasound compared to radical prostatectomy specimens 
We sought to evaluate the accuracy of prostate volume estimates in patients who received both a preoperative transrectal ultrasound (TRUS) and magnetic resonance imaging (MRI) in relation to the referent pathological specimen post-radical prostatectomy.
Patients receiving both TRUS and MRI prior to radical prostatectomy at one academic institution were retrospectively analyzed. TRUS and MRI volumes were estimated using the prolate ellipsoid formula. TRUS volumes were collected from sonography reports. MRI volumes were estimated by two blinded raters and the mean of the two was used for analyses. Pathological volume was calculated using a standard fluid displacement method.
Three hundred and eighteen (318) patients were included in the analysis. MRI was slightly more accurate than TRUS based on interclass correlation (0.83 vs. 0.74) and absolute risk bias (higher proportion of estimates within 5, 10, and 20 cc of pathological volume). For TRUS, 87 of 298 (29.2%) prostates without median lobes differed by >10 cc of specimen volume and 22 of 298 (7.4%) differed by >20 cc. For MRI, 68 of 298 (22.8%) prostates without median lobes differed by >10 cc of specimen volume, while only 4 of 298 (1.3%) differed by >20 cc.
MRI and TRUS prostate volume estimates are consistent with pathological volumes along the prostate size spectrum. MRI demonstrated better correlation with prostatectomy specimen volume in most patients and may be better suited in cases where TRUS and MRI estimates are disparate. Validation of these findings with prospective, standardized ultrasound techniques would be helpful.
PMCID: PMC5110405  PMID: 27878049
9.  A New CT Prostate Segmentation for CT-Based HDR Brachytherapy 
High-dose-rate (HDR) brachytherapy has become a popular treatment modality for localized prostate cancer. Prostate HDR treatment involves placing 10 to 20 catheters (needles) into the prostate gland, and then delivering radiation dose to the cancerous regions through these catheters. These catheters are often inserted with transrectal ultrasound (TRUS) guidance and the HDR treatment plan is based on the CT images. The main challenge for CT-based HDR planning is to accurately segment prostate volume in CT images due to the poor soft tissue contrast and additional artifacts introduced by the catheters. To overcome these limitations, we propose a novel approach to segment the prostate in CT images through TRUS-CT deformable registration based on the catheter locations. In this approach, the HDR catheters are reconstructed from the intra-operative TRUS and planning CT images, and then used as landmarks for the TRUS-CT image registration. The prostate contour generated from the TRUS images captured during the ultrasound-guided HDR procedure was used to segment the prostate on the CT images through deformable registration. We conducted two studies. A prostate-phantom study demonstrated a submillimeter accuracy of our method. A pilot study of 5 prostate-cancer patients was conducted to further test its clinical feasibility. All patients had 3 gold markers implanted in the prostate that were used to evaluate the registration accuracy, as well as previous diagnostic MR images that were used as the gold standard to assess the prostate segmentation. For the 5 patients, the mean gold-marker displacement was 1.2 mm; the prostate volume difference between our approach and the MRI was 7.2%, and the Dice volume overlap was over 91%. Our proposed method could improve prostate delineation, enable accurate dose planning and delivery, and potentially enhance prostate HDR treatment outcome.
PMCID: PMC4376020  PMID: 25821388
Prostate; CT; segmentation; transrectal ultrasound (TRUS); ultrasound-guided; HDR; brachytherapy
10.  Prostate volume changes during permanent seed brachytherapy: an analysis of intra-operative variations, predictive factors and clinical implication 
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.
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.
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.
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.
PMCID: PMC3720214  PMID: 23837971
Prostate; Permanent seed brachytherapy; Intra-operative edema
11.  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
12.  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.
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.
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
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.
PMCID: PMC3891368  PMID: 23466360
Health-related quality of life; Expanded Prostate cancer Index Composite (EPIC) survey; MRI/CT
13.  Comparison of implant quality between intraoperatively built custom-linked seeds and loose seeds in permanent prostate brachytherapy using sector analysis 
Journal of Radiation Research  2016;57(4):393-399.
We compared the implant quality of intraoperatively built custom-linked (IBCL) seeds with loose seeds in permanent prostate brachytherapy. Between June 2012 and January 2015, 64 consecutive prostate cancer patients underwent brachytherapy with IBCL seeds (n = 32) or loose seeds (n = 32). All the patients were treated with 144 Gy of brachytherapy alone. Brachytherapy was performed using a dynamic dose calculation technique. Computed tomography/magnetic resonance imaging fusion-based dosimetry was performed 1 month after brachytherapy. Post-implant dose–volume histogram (DVH) parameters, prostate sector dosimetry, operation time, seed migration, and toxicities were compared between the IBCL seed group and the loose seed group. A sector analysis tool was used to divide the prostate into six sectors (anterior and posterior sectors at the base, mid-gland, and apex). V100 (95.3% vs 89.7%; P = 0.014) and D90 (169.7 Gy vs 152.6 Gy; P = 0.013) in the anterior base sector were significantly higher in the IBCL seed group than in the loose seed group. The seed migration rate was significantly lower in the IBCL seed group than in the loose seed group (6% vs 66%; P < 0.001). Operation time per seed was significantly longer in the IBCL seed group than in the loose seed group (1.31 min vs 1.13 min; P = 0.003). Other post-implant DVH parameters and toxicities did not differ significantly between the two groups. Our study showed more dose coverage post-operatively in the anterior base prostate sector and less seed migration in IBCL seed implantation compared with loose seed implantation.
PMCID: PMC4973643  PMID: 26976125
prostate cancer; brachytherapy; intraoperatively built custom-linked seeds; dosimetry; sector analysis; seed migration
14.  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.
PMCID: PMC3864967  PMID: 24353393
15.  A Trimodality Comparison of Volumetric Bone Imaging Technologies. Part I: Short-term Precision and Validity 
In vivo peripheral quantitative computed tomography (pQCT) and peripheral magnetic resonance imaging (pMRI) modalities can measure apparent bone microstructure at resolutions 200 μm or higher. However, validity and in vivo test-retest reproducibility of apparent bone microstructure have yet to be determined on 1.0 T pMRI (196 μm) and pQCT (200 μm). This study examined 67 women with a mean age of 74 ± 9 yr and body mass index of 27.65 ± 5.74 kg/m2, demonstrating validity for trabecular separation from pMRI, cortical thickness, and bone volume fraction from pQCT images compared with high-resolution pQCT (hr-pQCT), with slopes close to unity. However, because of partial volume effects, cortical and trabecular thickness of bone derived from pMRI and pQCT images matched hr-pQCT more only when values were small. Short-term reproducibility of bone outcomes was highest for bone volume fraction (BV/TV) and densitometric variables and lowest for trabecular outcomes measuring microstructure. Measurements at the tibia for pQCT images were more precise than at the radius. In part I of this 3-part series focused on trimodality comparisons of precision and validity, it is shown that pQCT images can yield valid and reproducible apparent bone structural outcomes, but because of longer scan time and potential for more motion, the pMRI protocol examined here remains limited in achieving reliable values.
PMCID: PMC5094893  PMID: 25129405 CAMSID: cams6086
MRI; pQCT; segmentation; short-term precision; validity
16.  Variability in MRI vs. ultrasound measures of prostate volume and its impact on treatment recommendations for favorable-risk prostate cancer patients: a case series 
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.
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.
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.
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.
PMCID: PMC4261899  PMID: 25205146
Prostate volume; Favorable-risk prostate cancer; Brachytherapy; Active surveillance; MRI; Ultrasound
17.  Real-Time Intraoperative CT Assessment of Quality of Permanent Interstitial Seed Implantation for Prostate Cancer 
Urology  2010;76(5):1138-1142.
Evaluate real-time kilovoltage cone-beam computed tomography (CBCT) during prostate brachytherapy for intraoperative dosimetric assessment and correcting deficient dose regions.
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.
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.
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.
PMCID: PMC4049478  PMID: 20430423
Prostate; brachytherapy; dosimetry; image-guidance
18.  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.
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.
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.
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.
PMCID: PMC3808748  PMID: 24174998
19.  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.
PMCID: PMC3502731  PMID: 23185664
Brachytherapy; Neoplasms; Prostate
20.  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.
PMCID: PMC3430429  PMID: 22843359
prostate cancer; brachytherapy; seed implantation; pubic arch interference; fusion image
21.  Progressive transition from pre-planned to intraoperative optimizing seed implant: post implementation analysis 
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).
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)).
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.
PMCID: PMC3551369  PMID: 23346139
pre-plan; intraoperative planning; seed implant; prostate cancer
22.  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.
PMCID: PMC2997743  PMID: 21152376
23.  Accuracy evaluation of a 3D-printed individual template for needle guidance in head and neck brachytherapy 
Journal of Radiation Research  2016;57(6):662-667.
To transfer the preplan for the head and neck brachytherapy to the clinical implantation procedure, a preplan-based 3D-printed individual template for needle insertion guidance had previously been designed and used. The accuracy of needle insertion using this kind template was assessed in vivo. In the study, 25 patients with head and neck tumors were implanted with 125I radioactive seeds under the guidance of the 3D-printed individual template. Patients were divided into four groups based on the site of needle insertion: the parotid and masseter region group (nine patients); the maxillary and paranasal region group (eight patients); the submandibular and upper neck area group (five patients); and the retromandibular region group (six patients). The distance and angular deviations between the preplanned and placed needles were compared, and the complications and time required for needle insertion were assessed. The mean entrance point distance deviation for all 619 needles was 1.18 ± 0.81 mm, varying from 0.857 ± 0.545 to 1.930 ± 0.843 mm at different sites. The mean angular deviation was 2.08 ± 1.07 degrees, varying from 1.85 ± 0.93 to 2.73 ± 1.18 degrees at different sites. All needles were manually inserted to their preplanned positions in a single attempt, and the mean time to insert one needle was 7.5 s. No anatomical complications related to inaccurately placed implants were observed. Using the 3D-printed individual template for the implantation of 125I radioactive seeds in the head and neck region can accurately transfer a CT-based preplan to the brachytherapy needle insertion procedure. Moreover, the addition of individual template guidance can reduce the time required for implantation and minimize the damage to normal tissues.
PMCID: PMC5137284  PMID: 27422928
3D-printed; individual template; brachytherapy; head and neck
24.  Initial clinical experience with real-time transrectal ultrasonography-magnetic resonance imaging fusion-guided prostate biopsy 
BJU international  2007;101(7):841-845.
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.
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.
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.
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.
PMCID: PMC2621260  PMID: 18070196
magnetic resonance; ultrasound; prostate cancer; imaging; transrectal
25.  Single fraction multimodal image guided focal salvage high-dose-rate brachytherapy for recurrent prostate cancer 
We present a novel method for treatment of locally recurrent prostate cancer (PCa) following radiation therapy: focal, multimodal image guided high-dose-rate (HDR) brachytherapy.
Material and methods
We treated two patients with recurrent PCa after primary (#1) or adjuvant (#2) external beam radiation therapy. Multiparametric magnetic resonance imaging (mpMRI), choline, positron emission tomography combined with computed tomography (PET/CT), or prostate-specific membrane antigen (PSMA)-PET combined with CT identified a single intraprostatic lesion. Positron emission tomography or magnetic resonance imaging – transrectal ultrasound (MRI-TRUS) fusion guided transperineal biopsy confirmed PCa within each target lesion. We defined a PET and mpMRI based gross tumor volume (GTV). A 5 mm isotropic margin was applied additionally to each lesion to generate a planning target volume (PTV), which accounts for technical fusion inaccuracies. A D90 of 18 Gy was intended in one fraction to each PTV using ultrasound guided HDR brachytherapy.
Six month follow-up showed adequate prostate specific antygen (PSA) decline in both patients (ΔPSA 83% in patient 1 and ΔPSA 59.3% in patient 2). Follow-up 3-tesla MRI revealed regressive disease in both patients and PSMA-PET/CT showed no evidence of active disease in patient #1. No acute or late toxicities occurred.
Single fraction, focal, multimodal image guided salvage HDR brachytherapy for recurrent prostate cancer is a feasible therapy for selected patients with single lesions. This approach has to be evaluated in larger clinical trials.
PMCID: PMC4965505  PMID: 27504134
HDR brachytherapy; multimodal imaging; recurrent prostate cancer; salvage therapy

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