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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.
Purpose
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.
Results
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.
Conclusion
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.
doi:10.3857/roj.2011.29.3.199
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 
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1748-717X-6-130
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 
Purpose
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.
Results
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.
Conclusions
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.
doi:10.5114/jcb.2012.29363
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 
Background
To determine prostate volume (Pvol) changes at 3 different time points during the course of I125 permanent seed brachytherapy (PB). To assess the impact of these changes on acute urinary retention (AUR) and dosimetric outcome.
Methods
We analyzed 149 hormone-naïve patients. Measurements of the prostate volume were done using three-dimensional transrectal ultrasound (3D-TRUS) in the operating room before insertion of any needle (V1), after the insertion of 2 fixation needles with a harpoon (V2) and upon completion of the implant (V3). The quality of the implant was analyzed with the D90 (minimum dose in Grays received by 90% of the prostate volume) at day 30.
Results
Mean baseline prostate volume (V1) was 37.4 ± 9.6 cc. A volume increase of >5% was seen in 51% between V1-V2 (mean = 2.5 cc, p < 0.01), in 42% between V2-V3 (mean = 1.9 cc, p < 0.01) and in 71% between V1-V3 (mean = 4.5 cc, p < 0.01). Pvol changes caused by insertion of the fixation needles were not statistically different than those caused by the implant itself (p = 0.23).
In multivariate linear regression analysis, baseline Pvol is predictive of Pvol changes between V2 and V1 and V3 and V1 but not between V3 and V2. The extent of prostate swelling had an influence on D90. An increase of 10% in prostate volume between V1 and V2 results in an increase of D90 at Day 30 by 11.7%. Baseline Pvol (V1) was the only predictor of the duration of urinary retention in both univariate and multivariate (p = 0.04) regression analysis.
Conclusions
A large part of intraoperative swelling occurs already after the insertion of the fixation needles. This early prostate swelling predicts for D90 but not for AUR.
doi:10.1186/1748-717X-8-177
PMCID: PMC3720214  PMID: 23837971
Prostate; Permanent seed brachytherapy; Intra-operative edema
5.  Comparison between preoperative and real-time intraoperative planning 125I permanent prostate brachytherapy: long-term clinical biochemical outcome 
Background
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).
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1748-717X-8-288
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.
Objectives
Evaluate real-time kilovoltage cone-beam computed tomography (CBCT) during prostate brachytherapy for intraoperative dosimetric assessment and correcting deficient dose regions.
Methods
Twenty patients were evaluated intraoperatively with a mobile CBCT unit immediately after implantation while still anesthetized. The source-detector system is enclosed into a circular CT-like geometry with a bore that accommodates patients in the lithotomy position. After seed deposition, CBCT scans were obtained, Dosimetry was evaluated and compared to standard postimplantation CT-based assessment. In eight patients deposited seeds were localized in the intraoperative CBCT frame of reference and registered to the intraoperative transrectal ultrasound (TRUS) images. With this information, a second intraoperative plan was generated to ascertain if additional seeds were needed to achieve the planned prescription dose. Final dosimetry was compared with postimplantation scan assessment.
Results
Mean differences between dosimetric parameters from the intraoperative CBCT and post-implant CT scans were <0.5% for V100, D90, and V150 target values. Mean percentage differences for average urethral doses were not significantly different. Differences for D5 (maximum dose) of the urethra were <4%. The dose to 2 cc of the rectum differed by 10% on average. After fusion of implanted seed coordinates from the intraoperative CBCT scans onto the intraoperative TRUS images, dosimetric outcomes were similar to postimplantation CT dosimetric results.
Conclusions
Intraoperative CT-based dosimetric evaluation of prostate permanent seed implantation prior to anesthesia reversal is feasible and may avert misadministration of dose delivery. Dosimetric measurements based on the intraoperative CBCT scans are dependable and correlate well with postimplant diagnostic CT evaluation.
doi:10.1016/j.urology.2010.01.067
PMCID: PMC4049478  PMID: 20430423
Prostate; brachytherapy; dosimetry; image-guidance
7.  Long-term tumor control after brachytherapy for base-of-prostate cancer 
Purpose
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.
Results
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.
Conclusion
Permanent prostate brachytherapy as monotherapy results in a high probability of disease-free survival for men with cancer at the base of the prostate.
doi:10.5114/jcb.2011.26468
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 
Purpose
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.
Results
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.
Conclusions
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.
doi:10.1016/j.ijrobp.2011.11.004
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.
Results
The mean values of rV100us, rV100CT_1, and rV100CT_30 were 0.31 ± 0.43, 0.22 ± 0.36, and 0.59 ± 0.68 cc, respectively. These values temporarily decreased (p = 0.020) on Day 1 and increased (p = 0.000) on Day 30. There was no significant difference in rV100s between the bled-pts and spared-pts at any time of dosimetry. The maximum bled-OR was identified among patients with an rV100us value above 0.1 cc (p = 0.025; OR = 7.8; 95% CI, 1.4-145.8); an rV100CT_1 value above 0.3 cc (p = 0.014; OR = 16.2; 95% CI, 3.9-110.7), and an rV100CT_30 value above 0.5 cc (p = 0.019; OR = 6.3; 95% CI, 1.5-42.3).
Conclusion
By retrospective analysis exploring rV100 as intraoperative rectal dose-volume thresholds in 125I seed implant brachytherapy for prostate cancer, it is proved that rV100 should be less than 0.1 cc for preventing rectal bleeding.
doi:10.1186/1748-717X-7-15
PMCID: PMC3293044  PMID: 22293400
prostate cancer; brachytherapy; dose-volume histogram
10.  Treatment of Prostatic Abscess: Case Collection and Comparison of Treatment Methods 
Korean Journal of Urology  2012;53(12):860-864.
Purpose
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.
Results
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.
Conclusions
Patients with prostatic abscess treated by transurethral resection of the prostate had a significantly shorter hospitalization length compared with needle aspiration.
doi:10.4111/kju.2012.53.12.860
PMCID: PMC3531640  PMID: 23301131
Abscess; Prostate; Transurethral resection of prostate
11.  Prostate cancer (early) 
Clinical Evidence  2006;2006:1805.
Introduction
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).
Results
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.
Conclusions
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
12.  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.
doi:10.1089/ten.tec.2012.0495
PMCID: PMC3662384  PMID: 23134479
13.  Effect of Prostatitis on Lower Urinary Tract Symptoms: Retrospective Analysis of Prostate Biopsy Tissue 
Korean Journal of Urology  2012;53(2):109-113.
Purpose
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.
Results
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.
Conclusions
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.
doi:10.4111/kju.2012.53.2.109
PMCID: PMC3285705  PMID: 22379590
Inflammation; Prostate; Prostatic hyperplasia
14.  Technical and dosimetric aspects of iodine-125 seed reimplantation in suboptimal prostate implants 
The British Journal of Radiology  2013;86(1026):20130058.
Objective:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
doi:10.1259/bjr.20130058
PMCID: PMC3664978  PMID: 23520225
15.  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.
doi:10.1016/j.meddos.2012.03.001
PMCID: PMC3935513  PMID: 22560295
prostate cancer; brachytherapy; iodine-125
16.  Long Term Results of a Phase II Trial of Ultrasound-Guided Radioactive Implantation of the Prostate for Definitive Management of Localized Adenocarcinoma of the Prostate (RTOG 98-05) 
Purpose
To evaluate the long term effectiveness of transrectal ultrasound (TRUS)-guided permanent radioactive I125 implantation of the prostate for organ confined adenocarcinoma of the prostate compared with historical data of prostatectomy and external beam radiotherapy (EBRT) within a cooperative group setting.
Methods and Materials
Patients accrued to this study had histologically confirmed, locally confined, adenocarcinoma of the prostate clinical stage T1b, T1c, or T2a, no nodal or metastatic disease, prostate specific antigen (PSA) level of ≤ 10 ng/ml and a Gleason score of ≤ 6. All patients underwent TRUS-guided radioactive I125 seed implantation into the prostate. The prescribed dose was 145 Gy to the prostate planning target volume (PTV).
Results
A total of 101 patients from 27 institutions were accrued to this protocol; by design no single institution accrued more than 8 patients. There were 94 eligible patients. The median follow up was 8.1 years (range 0.1 to 9.2 years). After 8 years, 8 patients had protocol-defined biochemical (PSA) failure (cumulative incidence 8.0%), 5 patients had local failure (cumulative incidence 5.5%), and 1 patient had distant failure (cumulative incidence 1.1%; this patient also had biochemical failure and non-prostate cancer related death). The 8-year overall survival (OS) rate was 88%. At last follow up, no patient died of prostate cancer or related toxicities. Three patients had maximum late toxicity of Grade 3 and all were genitourinary (GU). There were no Grade 4 or 5 toxicities observed.
Conclusion
The long term results of this clinical trial have demonstrated that this kind of trial can be successfully completed through the RTOG and that results in terms of biochemical failure and toxicity compare very favorably with other brachytherapy published series as well as surgical and external beam radiotherapy series. Additionally, the prospective, multi-centered design highlights the probably generalizability of the outcomes.
doi:10.1016/j.ijrobp.2010.05.056
PMCID: PMC3132830  PMID: 21470793
Prostate; brachytherapy; low dose rate (LDR)
17.  Prostate Cancer Detection and Diagnosis: The Role of MR and its Comparison to other Diagnostic Modalities – A Radiologist's Perspective 
NMR in biomedicine  2013;27(1):10.1002/nbm.3002.
It is now universally recognized that many prostate cancers are over-diagnosed and over-treated. The European Randomized Study of Screening for Prostate Cancer (ERSPC) from 2009 evidenced that, to save one man from death of prostate cancer, over 1,400 men had to be screened, and 48 had to undergo treatment. Detection of prostate cancer is traditionally based upon digital rectal examination (DRE) and measuring serum prostate specific antigen (PSA), followed by ultrasound guided biopsy. The primary role of imaging for the detection and diagnosis of prostate cancer has been transrectal ultrasound (TRUS) guidance during biopsy. MRI has traditionally been used primarily for staging disease in men with biopsy proven cancer. It is has a well-established role in detecting T3 disease, planning radiation therapy, especially 3D conformal or intensity modulated external beam radiation therapy (IMRT), and planning and guiding interstitial seed implant or brachytherapy. New advances have now established prostate MRI can accurately characterize focal lesions within the gland, an ability that has led to new opportunities for improved cancer detection and guidance for biopsy. There are two new approaches to prostate biopsy are under investigation both use pre-biopsy MRI to define potential targets for sampling and then the biopsy is performed either with direct real-time MR guidance (in-bore) or MR fusion/registration with TRUS images (out-of-bore). In-bore or out-of-bore MRI-guided prostate biopsies have the advantage of using the MR target definition for accurate localization and sampling of targets or suspicious lesions. The out-of-bore method uses combined MRI/TRUS with fusion software that provided target localization and increases the sampling accuracy for TRUS-guided biopsies by integrating prostate MRI information with TRUS. Newer parameters for each imaging modality such as sonoelastography or shear wave elastography (SWE), contrast enhanced US (CEUS) and MRI-elastography, show promise to further enrich data sets.
doi:10.1002/nbm.3002
PMCID: PMC3851933  PMID: 24000133
18.  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.
Background
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.
Methods/Design
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.
Discussion
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
doi:10.1186/1471-2407-10-572
PMCID: PMC2984426  PMID: 20964826
19.  A COMPARISON OF ACUTE AND CHRONIC TOXICITY FOR MEN WITH LOW-RISK PROSTATE CANCER TREATED WITH INTENSITY-MODULATED RADIATION THERAPY OR 125I PERMANENT IMPLANT 
Purpose
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).
Results
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).
Conclusions
The IMRT and 125I produce similar outcomes, although IMRT appears to have less acute and late toxicity.
doi:10.1016/j.ijrobp.2007.10.019
PMCID: PMC2763097  PMID: 18207665
Prostate cancer; Radiation therapy; IMRT; Brachytherapy; Toxicity
20.  [18F]fluoroethylcholine-PET/CT imaging for radiation treatment planning of recurrent and primary prostate cancer with dose escalation to PET/CT-positive lymph nodes 
Background
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.
Methods
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.
Results
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.
Conclusions
FEC-PET/CT planning could be helpful in dose escalation to lymph nodal sites of prostate cancer.
doi:10.1186/1748-717X-6-44
PMCID: PMC3095991  PMID: 21529377
21.  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.
Introduction:
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.
Objectives:
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.
Results:
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.
Conclusions:
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.
doi:10.4103/0974-7796.148579
PMCID: PMC4310110  PMID: 25657537
Benign prostatic hyperplasia; laser prostatectomy; photoselective vaporization prostate
22.  Systematic overview of the evidence for brachytherapy in clinically localized prostate cancer 
Background
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.
Methods
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.
Results
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.
Interpretation
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
23.  Metabolic syndrome and prostate abnormalities in male subjects of infertile couples 
Asian Journal of Andrology  2014;16(2):295-304.
No previous study has evaluated systematically the relationship between metabolic syndrome (MetS) and prostate-related symptoms and signs in young infertile men. We studied 171 (36.5 ± 8.3-years-old) males of infertile couples. MetS was defined based on the National Cholesterol Education Program Third Adult Treatment Panel. All men underwent hormonal (including total testosterone (TT) and insulin), seminal (including interleukin-8 (IL-8), seminal plasma IL-8 (sIL-8)), scrotal and transrectal ultrasound evaluations. Because we have previously assessed correlations between MetS and scrotal parameters in a larger cohort of infertile men, here, we focused on transrectal features. Prostate-related symptoms were assessed using the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) and the International Prostate Symptom Score (IPSS). Twenty-two subjects fulfilled MetS criteria. In an age-adjusted logistic ordinal model, insulin levels increased as a function of MetS components (Wald = 29.5, P < 0.0001) and showed an inverse correlation with TT (adjusted r = -0.359, P< 0.0001). No association between MetS and NIH-CPSI or IPSS scores was observed. In an age-, TT-, insulin-adjusted logistic ordinal model, an increase in number of MetS components correlated negatively with normal sperm morphology (Wald = 5.59, P< 0.02) and positively with sIL-8 levels (Wald = 4.32, P < 0.05), which is a marker of prostate inflammation, with prostate total and transitional zone volume assessed using ultrasound (Wald = 17.6 and 12.5, both P < 0.0001), with arterial peak systolic velocity (Wald = 9.57, P = 0.002), with texture nonhomogeneity (hazard ratio (HR) = 1.87 (1.05–3.33), P < 0.05), with calcification size (Wald = 3.11, P < 0.05), but not with parameters of seminal vesicle size or function. In conclusion, in males of infertile couples, MetS is positively associated with prostate enlargement, biochemical (sIL8) and ultrasound-derived signs of prostate inflammation but not with prostate-related symptoms, which suggests that MetS is a trigger for a subclinical, early-onset form of benign prostatic hyperplasia.
doi:10.4103/1008-682X.122341
PMCID: PMC3955344  PMID: 24435050
infertile men; interleukin-8; metabolic syndrome; prostate-related symptoms and signs; semen analysis; transrectal ultrasound
24.  Prospective multi-center dosimetry study of low-dose Iodine-125 prostate brachytherapy performed after transurethral resection 
Purpose
To evaluate in a multicenter setting the ability of centers to perform pre-implant permanent prostate brachytherapy planning, fulfilling dosimetric goals and constraints based on the Groupe de Curiethérapie-European Society for Radiotherapy and Oncology guidelines in the setting of implantation after prior prostate transurethral resection (TURP).
Material and methods
A reference transrectal ultrasound image set of the prostate gland from a patient who had undergone TURP was used. Contouring of the prostate, clinical target volume and organs at risk was performed by the coordinating center. Goals and constraints regarding the dosimetry were defined.
Results
Seventeen of twenty-five centers invited to participate were able to import the Digital Imaging and Communications in Medicine-images into their planning computer and plan the implant using the defined guidelines. All centers were able to plan treatment, and achieve the recommended objectives and constraints. However, sector analysis has shown a risk of under-dosage in the anterior part of the prostate.
Conclusions
Correct pre-implantation planning with adherence to protocol guidelines and in compliance with defined dosimetric constraints seems feasible in a post-TURP setting, at least on a theoretical basis. A prospective study evaluating the outcome of prostate brachytherapy performed after TURP can therefore be undertaken with an expectation of a correct dosimetry in the multicenter setting.
doi:10.5114/jcb.2013.36174
PMCID: PMC3708148  PMID: 23878549
brachytherapy; permanent seed implant; prostate cancer; transurethral resection; TURP
25.  A Prospective Study of Plasma Vitamin D Metabolites, Vitamin D Receptor Polymorphisms, and Prostate Cancer 
PLoS Medicine  2007;4(3):e103.
Background
Vitamin D insufficiency is a common public health problem nationwide. Circulating 25-hydroxyvitamin D3 (25[OH]D), the most commonly used index of vitamin D status, is converted to the active hormone 1,25 dihydroxyvitamin D3 (1,25[OH]2D), which, operating through the vitamin D receptor (VDR), inhibits in vitro cell proliferation, induces differentiation and apoptosis, and may protect against prostate cancer. Despite intriguing results from laboratory studies, previous epidemiological studies showed inconsistent associations of circulating levels of 25(OH)D, 1,25(OH)2D, and several VDR polymorphisms with prostate cancer risk. Few studies have explored the joint association of circulating vitamin D levels with VDR polymorphisms.
Methods and Findings
During 18 y of follow-up of 14,916 men initially free of diagnosed cancer, we identified 1,066 men with incident prostate cancer (including 496 with aggressive disease, defined as stage C or D, Gleason 7–10, metastatic, and fatal prostate cancer) and 1,618 cancer-free, age- and smoking-matched control participants in the Physicians' Health Study. We examined the associations of prediagnostic plasma levels of 25(OH)D and 1,25(OH)2D, individually and jointly, with total and aggressive disease, and explored whether relations between vitamin D metabolites and prostate cancer were modified by the functional VDR FokI polymorphism, using conditional logistic regression. Among these US physicians, the median plasma 25(OH)D levels were 25 ng/ml in the blood samples collected during the winter or spring and 32 ng/ml in samples collected during the summer or fall. Nearly 13% (summer/fall) to 36% (winter/spring) of the control participants were deficient in 25(OH)D (<20 ng/ml) and 51% (summer/fall) and 77% (winter/spring) had insufficient plasma 25(OH)D levels (<32 ng/ml). Plasma levels of 1,25(OH)2D did not vary by season. Men whose levels for both 25(OH)D and 1,25(OH)2D were below (versus above) the median had a significantly increased risk of aggressive prostate cancer (odds ratio [OR] = 2.1, 95% confidence interval [CI] 1.2–3.4), although the interaction between the two vitamin D metabolites was not statistically significant (pinteraction = 0.23). We observed a significant interaction between circulating 25(OH)D levels and the VDR FokI genotype (pinteraction < 0.05). Compared with those with plasma 25(OH)D levels above the median and with the FokI FF or Ff genotype, men who had low 25(OH)D levels and the less functional FokI ff genotype had increased risks of total (OR = 1.9, 95% CI 1.1–3.3) and aggressive prostate cancer (OR = 2.5, 95% CI 1.1–5.8). Among men with plasma 25(OH)D levels above the median, the ff genotype was no longer associated with risk. Conversely, among men with the ff genotype, high plasma 25(OH)D level (above versus below the median) was related to significant 60%∼70% lower risks of total and aggressive prostate cancer.
Conclusions
Our data suggest that a large proportion of the US men had suboptimal vitamin D status (especially during the winter/spring season), and both 25(OH)D and 1,25(OH)2D may play an important role in preventing prostate cancer progression. Moreover, vitamin D status, measured by 25(OH)D in plasma, interacts with the VDR FokI polymorphism and modifies prostate cancer risk. Men with the less functional FokI ff genotype (14% in the European-descent population of this cohort) are more susceptible to this cancer in the presence of low 25(OH)D status.
Results of this study by Haojie Li and colleagues suggest that vitamin D deficiency is common among men in the US, and that vitamin D status and genetic variation in theVDR gene affect prostate cancer risk.
Editors' Summary
Background.
Prostate cancer occurs when cells in the prostate gland (part of the male reproductive system) accumulate genetic changes that allow them to grow into a disorganized mass of cells. Patients whose disease is diagnosed when these cells are still relatively normal can survive for many years, but for patients with aggressive cancers—ones containing fast-growing cells that can migrate around the body—the outlook is poor. Factors that increase prostate cancer risk include increasing age, having a family history of prostate cancer, and being African American. Also, there are hints that some environmental or dietary factors affect prostate cancer risk. One of these factors is vitamin D, of which high levels are found in seafood and dairy products, but which can also be made naturally by the body—more specifically, by sunlight-exposed skin. One reason researchers think vitamin D might protect against prostate cancer is that this cancer is more common in sun-starved northern countries (where people often have a vitamin D deficiency) than in sunny regions. Prostate cancer is also more common in African American men than in those of European descent (when exposed to the same amount of sunlight, individuals with darker skin make less vitamin D than those with lighter skin). Once in the human body, vitamin D is converted into the vitamin D metabolite 25-hydroxyvitamin D3 (25[OH]D) and then into the active hormone 1,25 dihydroxyvitamin D3 (1,25[OH]2D). This binds to vitamin D receptors (VDRs) and inhibits cell proliferation and migration.
Why Was This Study Done?
The effect of 1,25(OH)2D on cells and the observation that related chemicals slow prostate cancer growth in rodents suggest that vitamin D protects against prostate cancer. But circulating levels of vitamin D metabolites in human male populations do not always reflect how many men develop prostate cancer. This lack of correlation may partly be because different forms of the VDR gene exist. One area of variation in the VDR gene is called the FokI polymorphism. Because everyone carries two copies of the VDR gene, individuals may have a FokI FF, FokI Ff, or FokI ff genotype. The f variant (or allele) codes for a receptor that is less responsive to 1,25(OH)2D than the receptor encoded by the FokI F allele. So levels of vitamin D sufficient to prevent cancer in one person may be insufficient in someone with a different FokI genotype. In this study, the researchers have investigated how levels of 25(OH)D and 1,25(OH)2D in combination with different VDR FokI alleles are influencing prostate cancer risk.
What Did the Researchers Do and Find?
The researchers identified 1,066 men who developed prostate cancer between enrollment into the US Physicians' Health Study in 1982 and 2000, and 1,618 cancer-free men of the same ages and smoking levels as “controls.” They measured vitamin D metabolite levels in many of the blood samples taken from these men in 1982 and determined their FokI genotype. Two-thirds of the men had insufficient blood levels of vitamin D metabolites in the winter/spring; almost one-third had a vitamin D deficiency. Men whose blood levels of both metabolites were below average were twice as likely to develop aggressive prostate cancer as those in whom both levels were above average. Compared with men with high blood levels of 25(OH)D and the FokI FF or Ff genotype, men with low 25(OH)D levels and the FokI ff genotype were 2.5 times as likely to develop aggressive prostate cancer. However, men with the ff genotype were not at higher risk if they had sufficient 25(OH)D levels. Among men with the ff genotype, sufficient 25(OH)D levels might therefore protect against prostate cancer, especially against the clinically aggressive form.
What Do These Findings Mean?
These findings confirm that many US men have suboptimal levels of circulating vitamin D. This vitamin is essential for healthy bones, so irrespective of its effects on prostate cancer, vitamin D supplements might improve overall health. In addition, this large and lengthy study reveals an association between low levels of the two vitamin D metabolites and aggressive prostate cancer that is consistent with vitamin D helping to prevent the progression of prostate cancer. It also indicates that the VDR FokI genotype modifies the prostate cancer risk associated with different blood levels of vitamin D. Together, these results suggest that improving vitamin D status through increased exposure to sun and vitamin D supplements might reduce prostate cancer risk, particularly in men with the FokI ff genotype. Because the study participants were mainly of European descent, the researchers caution that these results may not apply to other ethnic groups and note that further detailed studies are needed to understand fully how vitamin D affects prostate cancer risk across the population.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040103.
MedlinePlus encyclopedia has pages on prostate cancer and on vitamin D
Information for patients and physicians is available from the US National Cancer Institute on prostate cancer and on cancer prevention
The Prostate Cancer Foundation's information on prostate cancer discusses the effects of nutrition on the disease
Patient information on prostate cancer is available from Cancer Research UK
Cancerbackup also has patient information on prostate cancer
doi:10.1371/journal.pmed.0040103
PMCID: PMC1831738  PMID: 17388667

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