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1.  A comparison of preplan MRI and preplan CT-based prostate volume with intraoperative ultrasound-based prostate volume in real-time permanent brachytherapy 
Radiation Oncology Journal  2011;29(3):199-205.
The present study compared the difference between intraoperative transrectal ultrasound (iTRUS)-based prostate volume and preplan computed tomography (CT), preplan magnetic resonance imaging (MRI)-based prostate volume to estimate the number of seeds needed for appropriate dose coverage in permanent brachytherapy for prostate cancer.
Materials and Methods
Between March 2007 and March 2011, among 112 patients who underwent permanent brachytherapy with 125I, 60 image scans of 56 patients who underwent preplan CT (pCT) or preplan MRI (pMRI) within 2 months before brachytherapy were retrospectively reviewed. Twenty-four cases among 30 cases with pCT and 26 cases among 30 cases with pMRI received neoadjuvant hormone therapy (NHT). In 34 cases, NHT started after acquisition of preplan image. The median duration of NHT after preplan image acquisition was 17 and 21 days for cases with pCT and pMRI, respectively. The prostate volume calculated by different modalities was compared. And retrospective planning with iTRUS image was performed to estimate the number of 125I seed required to obtain recommended dose distribution according to prostate volume.
The mean difference in prostate volume was 9.05 mL between the pCT and iTRUS and 6.84 mL between the pMRI and iTRUS. The prostate volume was roughly overestimated by 1.36 times with pCT and by 1.33 times with pMRI. For 34 cases which received NHT after image acquisition, the prostate volume was roughly overestimated by 1.45 times with pCT and by 1.37 times with pMRI. A statistically significant difference was found between preplan image-based volume and iTRUS-based volume (p < 0.001). The median number of wasted seeds is approximately 13, when the pCT or pMRI volume was accepted without modification to assess the required number of seeds for brachytherapy.
pCT-based volume and pMRI-based volume tended to overestimate prostate volume in comparison to iTRUS-based volume. To reduce wasted seeds and cost of the brachytherapy, we should take the volume discrepancy into account when we estimate the number of 125I seeds for permanent brachytherapy.
PMCID: PMC3429903  PMID: 22984671
Brachytherapy; Prostate cancer; Prostate volume
2.  Incidence of seed migration to the chest, abdomen, and pelvis after transperineal interstitial prostate brachytherapy with loose 125I seeds 
The aim was to determine the incidence of seed migration not only to the chest, but also to the abdomen and pelvis after transperineal interstitial prostate brachytherapy with loose 125I seeds.
We reviewed the records of 267 patients who underwent prostate brachytherapy with loose 125I seeds. After seed implantation, orthogonal chest radiographs, an abdominal radiograph, and a pelvic radiograph were undertaken routinely to document the occurrence and sites of seed migration. The incidence of seed migration to the chest, abdomen, and pelvis was calculated. All patients who had seed migration to the abdomen and pelvis subsequently underwent a computed tomography scan to identify the exact location of the migrated seeds. Postimplant dosimetric analysis was undertaken, and dosimetric results were compared between patients with and without seed migration.
A total of 19,236 seeds were implanted in 267 patients. Overall, 91 of 19,236 (0.47%) seeds migrated in 66 of 267 (24.7%) patients. Sixty-nine (0.36%) seeds migrated to the chest in 54 (20.2%) patients. Seven (0.036%) seeds migrated to the abdomen in six (2.2%) patients. Fifteen (0.078%) seeds migrated to the pelvis in 15 (5.6%) patients. Seed migration occurred predominantly within two weeks after seed implantation. None of the 66 patients had symptoms related to the migrated seeds. Postimplant prostate D90 was not significantly different between patients with and without seed migration.
We showed the incidence of seed migration to the chest, abdomen and pelvis. Seed migration did not have a significant effect on postimplant prostate D90.
PMCID: PMC3206434  PMID: 21974959
Brachytherapy; 125I; Migration; Prostate cancer; Seed
3.  Case series analysis of post-brachytherapy prostate edema and its relevance to post-implant dosimetry. Post-implant prostate edema and dosimetry 
We evaluated the post-operative pattern of prostate volume (PV) changes following prostate brachytherapy (PB) and analyzed variables which affect swelling.
Material and methods
Twenty-nine patients treated with brachytherapy (14) or combined brachytherapy and external beam radiotherapy modality (15) underwent pre- and post-implant computed tomography (CT). Prostate volume measurements were done on post-operative days 1, 9, 30, and 60. An observer performed 139 prostate volume (PV) measurements. We analyzed the influence of pre-implant PV, number of needles and insertion attempts, number and activity of seeds, Gleason score, use of hormonal therapy and external beam radiation therapy on the extent of edema. We computed a volume correction factor (CF) to account for dosimetric changes between day 1 and day 30. Using the calculated CF, the dose received by 90% (D90) of the prostate on day 30 (D90Day30) was obtained by dividing day 1 (D90Day1) by the CF.
The mean PV recorded on post-operative day 1 was 67.7 cm3, 18.8 cm3 greater than average pre-op value (SD 15.6 cm3). Swelling returned to pre-implant volume by day 30. Seed activity, treatment modality, and Gleason score were significant variables. The calculated CF was 0.76. After assessment using the CF, the mean difference between estimated and actual D90Day30 was not significant.
We observed maximum prostate size on post-operative day 1, returning to pre-implant volume by day 30. This suggests that post-implant dosimetry should be obtained on or after post-operative day 30. If necessary, day 30 dosimetry can be estimated by dividing D90Day1 by a correction factor of 0.76.
PMCID: PMC3552628  PMID: 23349648
prostate brachytherapy; post-implant dosimetry; computed brachytherapy
4.  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
5.  Comparison between preoperative and real-time intraoperative planning 125I permanent prostate brachytherapy: long-term clinical biochemical outcome 
The purpose of the study is to evaluate the long-term clinical outcome through biochemical no evidence of disease (bNED) rates among men with low to intermediate risk prostate cancer treated with two different brachytherapy implant techniques: preoperative planning (PP) and real-time planning (IoP).
From June 1998 to July 2011, 1176 men with median age of 67 years and median follow-up of 47 months underwent transperineal ultrasound-guided prostate 125I-brachytherapy using either PP (132) or IoP (1044) for clinical T1c-T2b prostate adenocarcinoma Gleason <8 and prostate-specific antigen (PSA) <20 ng/ml. Men with Gleason 7 received combination of brachytherapy, external beam radiation and 6-month androgen deprivation therapy (ADT). Biological effective dose (BED) was calculated using computerized tomography (CT)-based dosimetry 1-month postimplant. Failure was determined according to the Phoenix definition.
The 5- and 7-year actuarial bNED rate was 95% and 90% respectively. The 7-year actuarial bNED was 67% for the PP group and 95% for the IoP group (P < 0.001). Multivariate Cox regression analyses identified implant technique or BED, ADT and PSA as independent prognostic factors for biochemical failure.
Following our previous published results addressing the limited and disappointing outcomes of PP method when compared to IoP based on CT dosimetry and PSA kinetics, we now confirm the long-term clinical, bNED rates clear cut superiority of IoP implant methodology.
PMCID: PMC3904193  PMID: 24341548
Prostate cancer; Brachytherapy; Implant technique; Biochemical failure
6.  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
7.  Long-term tumor control after brachytherapy for base-of-prostate cancer 
To evaluate the outcomes of patients presenting with cancer at the base of the prostate after brachytherapy as monotherapy.
Material and methods
We retrospectively reviewed the medical records of all patients who had undergone transperineal ultrasound-guided implantation with 125I or 103Pd seeds as monotherapy between March 1998 and December 2006, at our institution. A minimum follow-up interval of 2 years was required for inclusion in our analysis. Dosimetry was assessed using computed tomography 30 days after the implant. Treatment failure was defined as the appearance of biopsy-proved tumor after seed implantation, radiographic evidence of metastases, receipt of salvage therapy, or elevation of the prostate-specific antigen level beyond the nadir value plus 2 ng/mL.
With a median follow-up interval of 89 months (range 25–128 months), all 52 of the identified patients had no evidence of disease progression or biochemical failure. The mean number of cores sampled at the prostate base was 2.84 (median 2); Gleason scores assigned at central review were 6-8 in all patients. Of the 30 patients (58%) for whom dosimetric data were available at day 30, the median V100 values of the right and left base were 92.0% and 93.5%, respectively, and the median D90 values of the right and left base were 148 Gy and 151 Gy, respectively.
Permanent prostate brachytherapy as monotherapy results in a high probability of disease-free survival for men with cancer at the base of the prostate.
PMCID: PMC3551361  PMID: 23346126
prostate cancer; monotherapy; sector analysis
8.  Sexual Function and the use of Medical Devices or Drugs to Optimize Potency after Prostate Brachytherapy 
Prospective evaluation of sexual outcomes after prostate brachytherapy with iodine-125 seeds as monotherapy at a tertiary cancer care center.
Methods and Materials
Subjects were 129 men with prostate cancer with I-125 seed implants (prescribed dose, 145 Gy) without supplemental hormonal or external beam radiation therapy. Sexual function, potency, and bother were prospectively assessed at baseline and at 1, 4, 8, and 12 months using validated quality-of-life self-assessment surveys. Postimplant dosimetry values, including dose to 10% of the penile bulb (D10), D20, D33, D50, D75, D90, and penile-volume receiving 100% of the prescribed dose (V100) were calculated.
At baseline, 56% of patients recorded having optimal erections; at 1 year, 62% of patients with baseline erectile function maintained optimal potency, 58% of whom with medically prescribed sexual aids or drugs. Variables associated with pretreatment-to-posttreatment decline in potency were time after implant (p=0.04) and age (p=0.01). Decline in urinary function may have been related to decline in potency. At 1 year, 69% of potent patients younger than 70 years maintained optimal potency, whereas 31% of patients over 70 maintained optimal potency (p=0.02). Diabetes was related to a decline in potency (p=0.05), but neither smoking nor hypertension were. For patients with optimal potency at baseline, mean sexual bother scores had declined significantly at 1 year (p<0.01). Sexual potency, sexual function, and sexual bother scores failed to correlate with any dosimetric variable tested.
Erections firm enough for intercourse can be achieved at 1 year after treatment, but most men will require medical aids to optimize potency. Although younger men were better able to maintain erections firm enough for intercourse than older men, there was no correlation between potency, sexual function, or sexual bother and penile bulb dosimetry.
PMCID: PMC3891366  PMID: 22300559
erectile dysfunction; radiation therapy; brachytherapy; prostate cancer; sexual aids; sexual function; penile rehabilitation
9.  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.
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).
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.
PMCID: PMC3293044  PMID: 22293400
prostate cancer; brachytherapy; dose-volume histogram
10.  Treatment of Prostatic Abscess: Case Collection and Comparison of Treatment Methods 
Korean Journal of Urology  2012;53(12):860-864.
Prostatic abscess is an uncommon urologic disease but has a high mortality rate if not treated properly. Furthermore, diagnosis and proper treatment of prostatic abscesses remains a challenge for physicians. Therefore, we compared data on conservative treatments, transurethral resection of prostatic abscess, and transrectal ultrasound (TRUS)-guided needle aspiration in 52 cases over a 10-year period.
Materials and Methods
The records of 52 patients diagnosed with prostatic abscess by computed tomography at Gangnam Severance Hospital between January 2000 and September 2010 were retrospectively reviewed. All patients were discharged when their leukocytosis had normalized and they had been free of fever for 2 days. Multivariate regression analysis was done to determine independent risk factors for the length of hospitalization.
At the time of diagnosis, the average age of the 52 patients was 61.3 years (range, 33 to 81 years), the average volume of the prostate was 56.3 ml (range, 21 to 223 ml), the average prostate-specific antigen was 18.54 ng/ml (range, 2.0 to 57.0 ng/ml), and the average abscess size was 3.8 cm (range, 2.1 to 5.5 cm). All patients were treated with parenteral antibiotics during their hospital stay with intravenous antibiotics (fluoroquinolone monotherapy or 3rd-generation cephalosporin in combination with an aminoglycoside). Of 52 patients, 22 had diabetes mellitus (42.3%), 19 had hypertension (36.5%), and 7 (13.5%) had paraplegia due to spinal cord injury. The most common symptoms were fever (47, 90.4%), perineal discomfort (43, 82.7%), dysuria (40, 76.9%), and urinary retention (29, 55.8%). Prostatic abscesses were treated by conservative treatment (11 cases), transurethral resection of prostatic abscess (23 cases), and TRUS-guided needle aspiration (18 cases). The average hospitalization stay was 17.5 days (range, 6 to 39 days); that of conservative treatment patients was 19.1 days (range, 9 to 39 days). Patients treated by transurethral resection of prostatic abscess and TRUS-guided needle aspiration stayed 10.2 days (range, 6 to 15 days) and 23.25 days (range, 18 to 34 days), respectively. Of the 18 cases who underwent needle aspiration, prostatic abscesses recurred in 4 cases (22.2%) within 1 month after patient discharge. The 2 patients subjected to conservative treatment died due to sepsis. We found no independent factors that affected the average hospitalization period.
Patients with prostatic abscess treated by transurethral resection of the prostate had a significantly shorter hospitalization length compared with needle aspiration.
PMCID: PMC3531640  PMID: 23301131
Abscess; Prostate; Transurethral resection of prostate
11.  Evaluation of the dosimetric impact of loss and displacement of seeds in prostate low-dose-rate brachytherapy 
To analyze the seed loss and displacement and their dosimetric impact in prostate low-dose-rate (LDR) brachytherapy while utilizing the combination of loose and stranded seeds.
Material and methods
Two hundred and seventeen prostate cancer patients have been treated with LDR brachytherapy. Loose seeds were implanted in the prostate center and stranded seeds in the periphery of the gland. Patients were imaged with transrectal ultrasound before implant and with computerized tomography/magnetic resonance imaging (CT/MR) one month after implant. The seed loss and displacement had been analyzed. Their impact on prostate dosimetry had been examined. The seed distribution beyond the prostate inferior boundary had been studied.
The mean number of seeds per patient that were lost to lung, pelvis/abdomen, urine, or unknown destinations was 0.21, 0.13, 0.03, and 0.29, respectively. Overall, 40.1% of patients had seed loss. Seed migration to lung and pelvis/abdomen occurred in 15.5% and 10.5% of the patients, respectively. Documented seed loss to urine was found in 3% of the patients while 20% of patients had seed loss to unknown destinations. Prostate length difference between pre-plan and post-implant images was within 6 mm in more than 98% of cases. The difference in number of seeds inferior to prostate between pre-plan and post-implant dosimetry was within 7 seeds for 93% of patients. At time of implant, 98% of seeds, inferior to prostate, were within 5 mm and 100% within 15 mm, and in one month post-implant 83% within 9 mm and 96.3% within 15 mm. Prostate post-implant V100, D90, and rectal wall RV100 for patients without seed loss were 94.6%, 113.9%, and 0.98 cm3, respectively, as compared to 95.0%, 114.8%, and 0.95 cm3 for the group with seed loss.
Seed loss and displacement have been observed to be frequent. No correlation between seed loss and displacement and post-plan dosimetry has been reported.
PMCID: PMC4499516  PMID: 26207108
brachytherapy; dosimetry; LDR; prostate cancer; seeds
12.  Prostate cancer (early) 
BMJ Clinical Evidence  2006;2006:1805.
Prostate cancer is the sixth most common cancer in the world, and 85% of cases are diagnosed in men over the age of 65 years. In men with well to moderately differentiated prostate cancer that remains within the capsule, clinical progression-free survival is 70% at 5 years, and 40% at 10 years.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for early prostate cancer? We searched: Medline, Embase, The Cochrane Library and other important databases up to February 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 25 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding hormone therapy to external beam radiation therapy, or to brachytherapy; adding neoadjuvant hormone therapy to surgery alone, or to surgery plus adjuvant hormone therapy; brachytherapy alone; external beam radiation therapy alone; hormone therapy plus standard care; immediate hormone therapy; radical prostatectomy; and watchful waiting.
Key Points
Prostate cancer is the sixth most common cancer in the world and 85% of cases are diagnosed in men over the age of 65 years. Subclinical prostate cancer is thought to be very common and increases with age, with an estimated prevalence of 30% in men aged 30-39 years, increasing to over 75% in men aged over 85 years.Risk factors include black ethnic origin, family history of prostate cancer and diet.In men with well to moderately differentiated prostate cancer that remains within the capsule, clinical progression free survival is 70% at 5 years and 40% at 10 years.Age adjusted mortality rates for prostate cancer do not seem to be affected by national PSA screening and treatment rates.
This review focuses on clinically localised disease that has not extended beyond the prostate capsule (TNM classification system T0, T1, T2, and American Urologic Staging system stages A and B).
Radical prostatectomy may reduce mortality compared with watchful waiting in men with clinically localised prostate cancer, but the benefits in quality adjusted life expectancy seem to be moderate. Radical prostatectomy may reduce overall and prostate cancer mortality and metastasis, but increases the risk of urinary and sexual dysfunction.
The benefits of external beam radiation therapy (EBRT) or brachytherapy compared with watchful waiting or radical prostatectomy are unknown. EBRT increases the risk of erectile dysfunction and toxicity to the surrounding tissues. Long term survival after EBRT depends on pre-treatment PSA level and tumour differentiation.
Hormone therapy may be used as neoadjuvant therapy before surgery or radiotherapy, concurrently with radiation therapy, or as an adjuvant to other treatments or usual care. Evidence of benefit from hormone therapy in early prostate cancer is very limited. Neoadjuvant hormone therapy may improve biochemical free survival when used with EBRT, but not when given before surgery plus adjuvant hormonal therapy. Immediate hormone therapy in men with clinically localised prostate cancer may reduce disease progression but may not reduce overall mortality, although few adequate studies have been found. Adjuvant hormonal therapy may reduce disease progression but may not improve overall survival compared with placebo.Hormone therapy is associated with increased rates of gynaecomastia and breast pain.
PMCID: PMC2907626  PMID: 19454100
13.  Use of Micro-Computed Tomography to Nondestructively Characterize Biomineral Coatings on Solid Freeform Fabricated Poly (L-Lactic Acid) and Poly (ɛ-Caprolactone) Scaffolds In Vitro and In Vivo 
Biomineral coatings have been extensively used to enhance the osteoconductivity of polymeric scaffolds. Numerous porous scaffolds have previously been coated with a bone-like apatite mineral through incubation in simulated body fluid (SBF). However, characterization of the mineral layer formed on scaffolds, including the amount of mineral within the scaffolds, often requires destructive methods. We have developed a method using micro-computed tomography (μ-CT) scanning to nondestructively quantify the amount of mineral in vitro and in vivo on biodegradable scaffolds made of poly (L-lactic acid) (PLLA) and poly (ɛ-caprolactone) (PCL). PLLA and PCL scaffolds were fabricated using an indirect solid freeform fabrication (SFF) technique to achieve orthogonally interconnected pore architectures. Biomineral coatings were formed on the fabricated PLLA and PCL scaffolds after incubation in modified SBF (mSBF). Scanning electron microscopy and X-ray diffraction confirmed the formation of an apatite-like mineral. The scaffolds were implanted into mouse ectopic sites for 3 and 10 weeks. The presence of a biomineral coating within the porous scaffolds was confirmed through plastic embedding and μ-CT techniques. Tissue mineral content (TMC) and volume of mineral on the scaffold surfaces detected by μ-CT had a strong correlation with the amount of calcium measured by the orthocresolphthalein complex-one (OCPC) method before and after implantation. There was a strong correlation between OCPC pre- and postimplantation and μ-CT measured TMC (R2=0.96 preimplant; R2=0.90 postimplant) and mineral volume (R2=0.96 preimplant; R2=0.89 postimplant). The μ-CT technique showed increases in mineral following implantation, suggesting that μ-CT can be used to nondestructively determine the amount of calcium on coated scaffolds.
PMCID: PMC3662384  PMID: 23134479
14.  Application of an interstitial and biodegradable balloon system for prostate-rectum separation during prostate cancer radiotherapy: a prospective multi-center study 
Background and purpose
Rectal toxicity presents a significant limiting factor in prostate radiotherapy regimens. This study evaluated the safety and efficacy of an implantable and biodegradable balloon specifically designed to protect rectal tissue during radiotherapy by increasing the prostate–rectum interspace.
Patients and methods
Balloons were transperineally implanted, under transrectal ultrasound guidance, into the prostate–rectum interspace in 27 patients with localized prostate cancer scheduled to undergo radiotherapy. Patients underwent two simulations for radiotherapy planning--the first simulation before implant, and the second simulation seven days post implant. The balloon position, the dimensions of the prostate, and the distance between the prostate and rectum were evaluated by CT/US examinations 1 week after the implant, weekly during the radiotherapy period, and at 3 and 6 months post implant. Dose-volume histograms of pre and post implantation were compared. Adverse events were recorded throughout the study period.
Four of 27 patients were excluded from the evaluation. One was excluded due to a technical failure during implant, and three patients were excluded because the balloon prematurely deflated. The balloon status was evaluated for the duration of the radiotherapy period in 23 patients. With the balloon implant, the distance between the prostate and rectum increased 10-fold, from a mean 0.22 ± 0.2 cm to 2.47 ± 0.47 cm. During the radiotherapy period the balloon length changed from 4.25 ± 0.49 cm to 3.81 ± 0.84 cm and the balloon height from 1.86 ± 0.24 cm to 1.67 ± 0.22 cm. But the prostate-rectum interspace distance remained constant from beginning to end of radiotherapy: 2.47 ± 0.47 cm and 2.41 ± 0.43 cm, respectively. A significant mean reduction in calculated rectal radiation exposure was achieved. The implant procedure was well tolerated. The adverse events included mild pain at the perineal skin and in the anus. Three patients experienced acute urinary retention which resolved in a few hours following conservative treatment. No infections or thromboembolic events occurred during the implant procedure or during the radiotherapy period.
The transperineal implantation of the biodegradable balloon in patients scheduled to receive radiotherapy was safe and achieved a significant and constant gap between the prostate and rectum. This separation resulted in an important reduction in the rectal radiation dose. A prospective study to evaluate the acute and late rectal toxicity is needed.
PMCID: PMC3643836  PMID: 23618548
Implantable biodegradable balloon; Prostate-rectum separation; Prostate radiotherapy
15.  Technical and dosimetric aspects of iodine-125 seed reimplantation in suboptimal prostate implants 
The British Journal of Radiology  2013;86(1026):20130058.
Brachytherapy employing iodine-125 seeds is an established treatment for low-risk prostate cancers. Post-implant dosimetry (PID) is an important tool for identifying suboptimal implants. The aim of this work was to improve suboptimal implants by a subsequent iodine-125 seed top-up (reimplantation), based on the PID results.
Of 255 patients treated between 2009 and 2012, 6 were identified as having received suboptimal implants and were scheduled for seed top-up. Needle configurations and the number of top-up seeds were determined based on post-implant CT images as well as a reimplantation treatment plan. An average of 14 seeds per patient were implanted during each top-up. Dosimetric outcome was assessed via target parameters and doses received by organs at risk.
All six patients had a successful top-up, with a 67% increase in the mean dose delivered to 90% of the prostate volume and a 40% increase in the volume that receives 100% of the prescribed dose. However, the final dosimetric assessment was based on the same seed activity, as the planning system does not account for the decay of the initially implanted seeds. Although physical dosimetry is not influenced by different seed activities (doses are calculated to infinity), the radiobiological implications might be slightly different from the situation when optimal implantation is achieved with one treatment only.
Seed reimplantation in suboptimal prostate implants is feasible and leads to successful clinical outcomes.
Advances in knowledge:
Suboptimal prostate implants can occur for various reasons. This work shows that seed reimplantation as salvage therapy can lead to an optimal dosimetric outcome with manageable normal tissue effects.
PMCID: PMC3664978  PMID: 23520225
16.  Effect of Prostatitis on Lower Urinary Tract Symptoms: Retrospective Analysis of Prostate Biopsy Tissue 
Korean Journal of Urology  2012;53(2):109-113.
Most patients, even some urologists, assume that prostate volume is the most important prognostic factor for lower urinary tract symptoms (LUTS). In some cases, however, prostatic inflammation is a more important factor in LUTS than is prostate volume. For this reason, comparison of the impact on LUTS of inflammation and prostate volume is an attractive issue.
Materials and Methods
From January 2000 to May 2009, 1,065 men aged between 47 and 91 years (who underwent transrectal ultrasound-guided prostate needle biopsy and transurethral prostatectomy) were retrospectively investigated. Components such as age, serum prostate-specific antigen (PSA) level, prostate volume, and the presence of prostatitis were investigated through independent-sample t-tests, chi-square tests, and univariate and multivariate analyses.
Chi-square tests between prostatitis, prostate volume, serum PSA, and severe LUTS showed that prostate volume (R=0.173; p=0.041) and prostatitis (R=0.148; p<0.001) were related to LUTS. In particular, for a prostate volume under 50 ml, prostatitis was a stronger risk factor than was prostate volume. Among the multivariate predictors, prostatitis (odds ratio [OR]: 1.945; p<0.001) and prostate volume (OR, 1.029; p<0.001) were found to be aggravating factors of LUTS.
For patients with prostate volume less than 50 ml, prostatitis was found to be a more vulnerable factor for LUTS. For those with prostate volume over 50 ml, on the other hand, the volume itself was a more significant risk factor than was prostatitis. In conclusion, the presence of prostatitis is one of the risk factors for LUTS with increased prostate volume.
PMCID: PMC3285705  PMID: 22379590
Inflammation; Prostate; Prostatic hyperplasia
17.  Preoperative treatment planning with intraoperative optimization can achieve consistent high-quality implants in prostate brachytherapy 
Advances in brachytherapy treatment planning systems have allowed the opportunity for brachytherapy to be planned intraoperatively as well as preoperatively. The relative advantages and disadvantages of each approach have been the subject of extensive debate, and some contend that the intraoperative approach is vital to the delivery of optimal therapy. The purpose of this study was to determine whether high-quality permanent prostate implants can be consistently achieved using a preoperative planning approach that allows for, but does not necessitate, intraoperative optimization. To achieve this purpose, we reviewed the records of 100 men with intermediate-risk prostate cancer who had been prospectively treated with brachytherapy monotherapy between 2006 and 2009 at our institution. All patients were treated with iodine-125 stranded seeds; the planned target dose was 145 Gy. Only 8 patients required adjustments to the plan on the basis of intraoperative findings. Consistency and quality were assessed by calculating the correlation coefficient between the planned and implanted amounts of radioactivity and by examining the mean values of the dosimetric parameters obtained on preoperative and 30 days postoperative treatment planning. The amount of radioactivity implanted was essentially identical to that planned (mean planned radioactivity, 41.27 U vs. mean delivered radioactivity, 41.36 U; R2 = 0.99). The mean planned and day 30 prostate V100 values were 99.9% and 98.6%, respectively. The mean planned and day 30 prostate D90 values were 186.3 Gy and 185.1 Gy, respectively. Consistent, high-quality prostate brachytherapy treatment plans can be achieved using a preoperative planning approach, mostly without the need for intraoperative optimization. Good quality assurance measures during simulation, treatment planning, implantation, and postimplant evaluation are paramount for achieving a high level of quality and consistency.
PMCID: PMC3935513  PMID: 22560295
prostate cancer; brachytherapy; iodine-125
18.  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) 
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).
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.
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.
PMCID: PMC3132830  PMID: 21470793
Prostate; brachytherapy; low dose rate (LDR)
19.  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
20.  Transperineal prostate brachytherapy, using I-125 seed with or without adjuvant androgen deprivation, in patients with intermediate-risk prostate cancer: study protocol for a phase III, multicenter, randomized, controlled trial 
BMC Cancer  2010;10:572.
The optimal protocol for 125I-transperineal prostatic brachytherapy (TPPB) in intermediate-risk prostate cancer (PCa) patients remains controversial. Data on the efficacy of combining androgen-deprivation therapy (ADT) with 125I-TPPB in this group remain limited and consequently the guidelines of the American Brachytherapy Society (ABS) provide no firm recommendations.
Seed and Hormone for Intermediate-risk Prostate Cancer (SHIP) 0804 is a phase III, multicenter, randomized, controlled study that will investigate the impact of adjuvant ADT following neoadjuvant ADT and 125I-TPPB. Prior to the end of March, 2011, a total of 420 patients with intermediate-risk, localized PCa will be enrolled and randomized to one of two treatment arms. These patients will be recruited from 20 institutions, all of which have broad experience of 125I-TPPB. Pathological slides will be centrally reviewed to confirm patient eligibility. The patients will initially undergo 3-month ADT prior to 125I-TPPB. Those randomly assigned to adjuvant therapy will subsequently undergo 9 months of adjuvant ADT. All participants will be assessed at baseline and at the following intervals: every 3 months for the first 24 months following 125I-TPPB, every 6 months during the 24- to 60-month post-125I-TPPB interval, annually between 60 and 84 months post-125I-TPPB, and on the 10th anniversary of treatment.
The primary endpoint is biochemical progression-free survival (BPFS). Secondary endpoints are overall survival (OS), clinical progression-free survival, disease-specific survival, salvage therapy non-adaptive interval, acceptability (assessed using the international prostate symptom score [IPSS]), quality of life (QOL) evaluation, and adverse events. In the correlative study (SHIP36B), we also evaluate biopsy results at 36 months following treatment to examine the relationship between the results and the eventual recurrence after completion of radiotherapy.
These two multicenter trials (SHIP0804 & SHIP36B) are expected to provide crucial data regarding the efficacy, acceptability and safety of adjuvant ADT. SHIP36B will also provide important information about the prognostic implications of PSA levels in intermediate-risk PCa patients treated with 125I-TPPB.
Trial registration
NCT00664456, NCT00898326, JUSMH-BRI-GU05-01, JUSMH-TRIGU0709
PMCID: PMC2984426  PMID: 20964826
To compare the toxicity and biochemical outcomes of intensity-modulated radiation therapy (IMRT) and 125I transperineal permanent prostate seed implant (125I) for patients with low-risk prostate cancer.
Methods and Materials
Between 1998 and 2004, a total of 374 low-risk patients (prostate-specific antigen < 10 ng/ml, T1c–T2b, Gleason score of 6 or less, and no neoadjuvant hormones) were treated at Fox Chase Cancer Center (216 IMRT and 158 125I patients). Median follow-up was 43 months for IMRT and 48 months for 125I. The IMRT prescription dose ranged from 74–78 Gy, and 125I prescription was 145 Gy. Acute and late gastrointestinal (GI) and genitourinary (GU) toxicity was recorded by using a modified Radiation Therapy Oncology Group scale. Freedom from biochemical failure was defined by using the Phoenix definition (prostate-specific antigen nadir + 2.0 ng/ml).
Patients treated by using IMRT were more likely to be older and have a higher baseline American Urological Association symptom index score, history of previous transurethral resection of the prostate, and larger prostate volumes. On multivariate analysis, IMRT was an independent predictor of lower acute and late Grade 2 or higher GU toxicity and late Grade 2 or higher GI toxicity. Three-year actuarial estimates of late Grade 2 or higher toxicity were 2.4% for GI and 3.5% for GU by using IMRT compared with 7.7% for GI and 19.2% for GU for 125I, respectively. Four-year actuarial estimates of freedom from biochemical failure were 99.5% for IMRT and 93.5% for 125I (p = 0.09).
The IMRT and 125I produce similar outcomes, although IMRT appears to have less acute and late toxicity.
PMCID: PMC2763097  PMID: 18207665
Prostate cancer; Radiation therapy; IMRT; Brachytherapy; Toxicity
22.  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
23.  [18F]fluoroethylcholine-PET/CT imaging for radiation treatment planning of recurrent and primary prostate cancer with dose escalation to PET/CT-positive lymph nodes 
At present there is no consensus on irradiation treatment volumes for intermediate to high-risk primary cancers or recurrent disease. Conventional imaging modalities, such as CT, MRI and transrectal ultrasound, are considered suboptimal for treatment decisions. Choline-PET/CT might be considered as the imaging modality in radiooncology to select and delineate clinical target volumes extending the prostate gland or prostate fossa. In conjunction with intensity modulated radiotherapy (IMRT) and imaged guided radiotherapy (IGRT), it might offer the opportunity of dose escalation to selected sites while avoiding unnecessary irradiation of healthy tissues.
Twenty-six patients with primary (n = 7) or recurrent (n = 19) prostate cancer received Choline-PET/CT planned 3D conformal or intensity modulated radiotherapy. The median age of the patients was 65 yrs (range 45 to 78 yrs). PET/CT-scans with F18-fluoroethylcholine (FEC) were performed on a combined PET/CT-scanner equipped for radiation therapy planning.
The majority of patients had intermediate to high risk prostate cancer. All patients received 3D conformal or intensity modulated and imaged guided radiotherapy with megavoltage cone beam CT. The median dose to primary tumours was 75.6 Gy and to FEC-positive recurrent lymph nodal sites 66,6 Gy. The median follow-up time was 28.8 months.
The mean SUVmax in primary cancer was 5,97 in the prostate gland and 3,2 in pelvic lymph nodes. Patients with recurrent cancer had a mean SUVmax of 4,38. Two patients had negative PET/CT scans. At 28 months the overall survival rate is 94%. Biochemical relapse free survival is 83% for primary cancer and 49% for recurrent tumours. Distant disease free survival is 100% and 75% for primary and recurrent cancer, respectively. Acute normal tissue toxicity was mild in 85% and moderate (grade 2) in 15%. No or mild late side effects were observed in the majority of patients (84%). One patient had a severe bladder shrinkage (grade 4) after a previous treatment with TUR of the prostate and seed implantation.
FEC-PET/CT planning could be helpful in dose escalation to lymph nodal sites of prostate cancer.
PMCID: PMC3095991  PMID: 21529377
24.  Does prostate size impact upon perioperative outcomes associated with photoselective vaporization of the prostate using the 180W lithium triborate laser? 
Urology Annals  2015;7(1):17-20.
Photoselective vaporization of the prostate (PVP) has been widely adopted as a surgical treatment for lower urinary tract symptoms due to benign prostatic hyperplasia (BPH). Recently, a high-powered 180 W lithium triborate (LBO) laser has become commercially available and there is relatively little information on the impact of this very high-powered laser on perioperative outcomes. Even more so is the impact of the laser on outcomes according to prostate size.
The objective of this study was to evaluate perioperative outcomes after PVP with the 180W laser, relative to prostate size.
Patients and Methods:
A prospectively maintained institutional ethics approved database was retrospectively reviewed. Subjects were analyzed according to transrectal ultrasound and categorized into groups namely 0-39 mL, 40-79 mL, 80-120 mL and >120 mL. Perioperative measures included energy utilized, length of operation, duration catheterization, post operative length of stay (POLOS), Clavien-Dindo adverse events and number discharged home within 24 hours catheter free.
With increasing prostate size, there was a statistically significant increase in energy utilization and operation time (P < 0.01 between groups). Duration of catheterization, POLOS, incidence of Grade 3 and above Clavien-Dindo adverse events and discharge home catheter free within 24 hours was not statistically significant across groups.
Prostate volume impacts upon energy utilized with PVP surgery. Prostate volume does not influence duration of catheterization or POLOS. Clavien-Dindo Grade 3 or greater adverse events were low and do not appear to be influenced by prostate size. The ability to be discharged home catheter free within 24 hours likewise does not appear to be influenced by prostate size.
PMCID: PMC4310110  PMID: 25657537
Benign prostatic hyperplasia; laser prostatectomy; photoselective vaporization prostate
25.  Systematic overview of the evidence for brachytherapy in clinically localized prostate cancer 
Brachytherapy (permanent implantation of radioactive seeds) has emerged as an alternative to existing standard therapy with radical prostatectomy or external beam radiotherapy in the treatment of clinically localized (T1 and T2) prostate cancer. The Genitourinary Cancer Disease Site Group of the Cancer Care Ontario Practice Guidelines Initiative examined the role of brachytherapy in treating clinically localized prostate cancer.
A systematic review of articles published from 1988 to April 1999, retrieved through a search of MEDLINE and CANCERLIT databases, was combined with a consensus interpretation of the evidence in the context of conventional practice.
Although there were no randomized trials comparing brachytherapy with standard treatment, evidence was available from 13 case series and 3 cohort studies. Rates of freedom from biochemical failure (biochemically no evidence of disease [bNED]) varied considerably from one series to another and were highly dependent on tumour stage, grade and pretreatment serum prostate-specific antigen (PSA) levels. Results in patients with favourable tumours (T1 or T2 tumour, Gleason score of 6 or lower, serum PSA level of 10 ng/mL [μg/L] or less) were comparable to those in patients undergoing radical prostatectomy. Acute urinary retention was reported in 1%–14% of patients. Long-term sequelae occurred in less than 5% of patients and included urinary incontinence, cystitis, urethral strictures and proctitis. Sexual potency was maintained after implantation in 86%–96% of patients.
At present, there is insufficient evidence to recommend the use of brachytherapy over current standard therapy for localized prostate cancer. Brachytherapy using transrectal ultrasound guidance for seed implantation is promising in terms of freedom from biochemical failure in selected patients with early-stage prostate cancer. Brachytherapy is currently available outside of clinical trials, but whenever possible patients should be asked to participate in randomized trials comparing brachytherapy and current standard therapy. Brachytherapy should be available to selected patients (those with T1c or T2a tumours, a Gleason score of 6 or lower and a serum PSA level of 10 μg/L or less), after discussion of the available data and potential adverse effects.
PMCID: PMC80925  PMID: 11314451

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