Germline mutations and sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk.

Deletions on human chromosome 8p22-23 in prostate cancer cells and linkage studies in families affected with hereditary prostate cancer (HPC) have implicated this region in the development of prostate cancer. The macrophage scavenger receptor 1 gene (MSR1, also known as SR-A) is located at 8p22 and functions in several processes proposed to be relevant to prostate carcinogenesis. Here we report the results of genetic analyses that indicate that mutations in MSR1 may be associated with risk of prostate cancer. Among families affected with HPC, we identified six rare missense mutations and one nonsense mutation in MSR1. A family-based linkage and association test indicated that these mutations co-segregate with prostate cancer (P = 0.0007). In addition, among men of European descent, MSR1 mutations were detected in 4.4% of individuals affected with non-HPC as compared with 0.8% of unaffected men (P = 0.009). Among African American men, these values were 12.5% and 1.8%, respectively (P = 0.01). These results show that MSR1 may be important in susceptibility to prostate cancer in men of both African American and European descent.

Pretreatment prostate-specific antigen velocity is associated with freedom from biochemical recurrence of prostate cancer after low-dose-rate prostate brachytherapy alone.

PURPOSE: This report examines the relationship between pretreatment prostate-specific antigen (PSA) velocity (PSAV) and freedom from biochemical recurrence (FFBR) in men with prostate cancer treated with low-dose-rate prostate brachytherapy (LDRPB). METHODS AND MATERIALS: This is a report of 51 men treated with LDRPB between 1997 and 1999. INCLUSION CRITERIA: two or more evaluable PSA values >3 months apart and <18 months before treatment. PSAV is calculated using a linear regression equation. All patients had biopsy confirmed, clinically localized prostate cancer. All men were treated with (125)I LDRPB. The prescription dose was 144Gy. Biochemical failure is determined from PSA values over time using the ASTRO Consensus Definition. FFBR is estimated using Kaplan-Meier method. Pretreatment variables analyzed include percentage positive biopsy cores, D(90), risk group, and PSAV. All p values are two-sided. RESULTS: The median followup is 60 months. The median pretreatment PSA is 6.5, 75% of men were Stage T1c, and 88% had Gleason score > or =6; 10% developed evidence of biochemical recurrence at a median of 13 months (range, 6-36). The 6-year estimate of FFBR is 90% for the entire cohort. On univariate analysis, pretreatment PSAV and risk group are associated with FFBR. The 6-year estimate of FFBR in patients with a PSAV <2 ng/mL/yr is 100% vs. 80% (95% confidence interval: 64-96%) when the pretreatment PSAV is > or =2 ng/mL/yr before LDRPB (p = 0.017). CONCLUSIONS: Pretreatment PSAV is a predictor of FFBR after LDRPB in this population of men with prostate cancer. Men with a pretreatment PSAV > or =2 ng/mL/yr may warrant more aggressive treatment.

Deficient nucleotide excision repair capacity enhances human prostate cancer risk.

Prostate cancer (CaP) is the most commonly diagnosed non-skin cancer and the second leading cause of cancer death in American men. The etiology of CaP is not fully understood. Because most of the DNA adducts generated by some CaP-related carcinogens, including polycyclic aromatic hydrocarbons, heterocyclic amines, and pesticides, are removed by the nucleotide excision repair (NER) pathway, we pilot tested the hypothesis that CaP is associated with deficient NER capacity (NERC), measured by a plasmid-based host reactivation assay. Using cryopreserved lymphocytes collected in an ongoing, clinic-based case-control study, our results showed that the mean NERC was significantly lower (P = 0.03) in 140 cases (mean +/- SD, 8.06 +/- 5.17) than in 96 controls (9.64 +/- 5.49). There was a significant association between below-median NERC and CaP risk: odds ratio (OR), 2.14; 95% confidence interval (CI), 1.19-3.86, after adjustment for age, race/ethnicity, smoking history, benign prostatic hyperplasia, and family history. This association was stronger in younger (<60 years of age) subjects (OR, 3.98; 95% CI, 1.13-14.02) compared with older (> or = 60) subjects (OR, 1.74; 95% CI, 0.90-3.37). When we stratified NERC values by quartiles of controls, there was a significant dose-dependent association between lower NERC and elevated CaP risk (p (test for linear trend), 0.01). Compared with the highest quartile of NERC as the referent group, the adjusted ORs for the 75th, 50th, and 25th quartiles were: 1.09 (95% CI, 0.46-2.59); 1.81 (95% CI, 0.77-4.27); and 2.63 (95% CI, 1.17-5.95), respectively. This pilot study is the first direct evidence associating deficient NERC with human CaP risk.

Dosimetry and cancer control after low-dose-rate prostate brachytherapy.

PURPOSE: To describe the relationship between two commonly used dosimetric quantifiers (dose received by 90% of the prostate [D(90)] and volume receiving 100% of dose [V(100)]) and biochemical disease-free survival (bDFS) in a cohort of men treated with low-dose-rate prostate brachytherapy (LDRPB). METHODS AND MATERIALS: The information in this report concerned the first 63 men treated with LDRPB alone at our institution between September 1997 and September 1998. All men had histologically confirmed, clinically localized prostate cancer. All men were treated with(125)I. The prescription dose was 144 Gy according to the Task Group 43 formalism. LDRPB was performed jointly by a radiation oncologist and urologist. Dosimetric quantifiers (D(90), V(100)) were calculated from a CT scan performed 1 month after LDRPB. Biochemical recurrence was defined according to the American Society for Therapeutic Radiology and Oncology consensus definition. Biochemical relapse-free survival (bRFS) was estimated using the product-limit method. D(90) and V(100) were examined as putative covariates for bRFS using the proportional hazards regression method. All p values are two-sided. RESULTS: The median follow-up for the entire cohort was 62 months. The median D(90) was 122 Gy (range, 57-171Gy), and in 16 (25%) of 63 patients, the calculated D(90) was >140 Gy. The median V(100) was 81% (range, 51-97%). Nine men developed evidence of biochemical relapse at a median of 19 months (range, 6-38 months). The 5-year estimate of bRFS was 85% (95% confidence interval, 80-90%). The 5-year estimates of bRFS according to D(90) were as follows: D(90) > or =140 Gy, 86%; D(90) <140 Gy, 84% (p = not statistically significant). No threshold value of D(90) was predictive of the 5-year estimates of bRFS until the D(90) was <80 Gy (D(90) > or =80 Gy, 89%; D(90) <80 Gy, 50%; p = 0.02). The 5-year estimates of bRFS according to V(100) were as follows: V(100) > or =85%, 87%; V(100) <85%, 84% (p = not statistically significant). No threshold value of V(100) was predictive of the 5-year estimates of BRFS unless the dosimetry was particularly poor. The 5-year BRFS was 89% if the V(100) was > or =65% compared with 40% if the V(100) was <65% (p = 0.006). CONCLUSION: The dosimetric or quantifiers described in this report did not predict for bRFS after LDRPB unless the dosimetry was very poor. This finding is not in complete agreement with those of previous reports. Possible reasons for this observation are (1) the study in underpowered, (2) inherent measurement error, (3) dosimetric quantifiers are poor surrogates of the dose received by the cancer, and (4) length of follow-up. Additional work in the area of quality assessment after LDRPB is required.

Dosimetric quantifiers for low-dose-rate prostate brachytherapy: is V(100) superior to D(90)?

PURPOSE: The purpose of the present report is to describe the relationship between two dosimetric quantifiers (V(100) and D(90)) and freedom from biochemical recurrence (FFBR) in a cohort of men treated with low-dose-rate prostate brachytherapy (LDRPB) alone. METHODS AND MATERIALS: One hundred three men were treated with LDRPB alone between September 1997 and December 1999. All men had histologically confirmed clinically localized prostate cancer. Fifty-nine percent of the cohort had low-risk disease (defined as PSA<10, Gleason <7, and T stage /=10, Gleason>/=7, or T stage T2b). The prescription dose was 144Gy according to the Task Group 43 formalism. LDRPB was performed jointly by a radiation oncologist and a urologist. Dosimetric quantifiers (D(90), V(100)) were calculated from a CT scan performed 1 month after LDRPB. Biochemical recurrence was defined according to the ASTRO Consensus Definition. FFBR was estimated using the product-limit method. Disease-specific and treatment variables were examined as putative covariates for FFBR using the proportional hazards regression method. Univariate and multivariate methods were used. All p values are two sided. RESULTS: The median followup for the entire cohort is 61 months. The median followup of patients at risk for biochemical failure is 66 months. The median D(90) is 129Gy (range 47-221Gy), and the median V(100) is 86% (range 51-99%). Thirteen men have developed evidence of biochemical relapse at a median of 25 months (range 6-42 months). The 5-year estimate of FFBR for the entire cohort is 87% (95% CI 80-94%). On univariate analysis, disease-specific variables found to be significantly associated with FFBR included pretreatment PSA and percent positive biopsies. When considered as a continuous variable, each of the dosimetric quantifiers was associated with FFBR (V(100): p=0.007; D(90): p=0.05). D'Amico risk group classification is highly predictive of FFBR after LDRPB (HR 5.68, p=0.003). Multivariate analysis indicated that each dosimetric quantifier was independently associated with FFBR, but due to the high degree of correlation (Pearson correlation coefficient 0.94, p<0.0001) between the dosimetric quantifiers both could not be included simultaneously in the model. In the two models explored, V(100) was at least as good as D(90) in predicting FFBR. CONCLUSIONS: Dosimetric quantifiers (V(100) and D(90)) are independent predictors of FFBR after treatment with LDRPB alone. In our experience, V(100) seems to be at least equivalent (and perhaps superior) to D(90) for predicting FFBR.

Surgical Staging of Carcinoma of the Prostate.

Surgical staging (bilateral pelvic lymphadenectomy) has become a widely used and accepted procedure over the past eight years. It's utility is recognized by surgeons and radiotherapists alike. Approximately 15 to 20% of patients with small, palpable prostate cancer nodules (Stage B,) have (+) pelvic lymph nodes; over 30% of patients with larger but still intracapsular involvement (Stage B2 ) have (+) nodes. Over 50% of patients with localized capsular penetration (Stage C) have (+) nodes. Poorly-differentiated tumors metastasize to nodes with greater frequency than do well-differentiated tumors. The complication rate appears to be acceptable with lymphocele formation, thromboembolic phenomena, wound infections, and lymphedema being some of the more common problems. Operative mortality due to pelvic lymphadenectomy is extremely rare. Multiple positive nodes are a bad prognostic sign, whereas one or two nodes with minimal tumor volume are much less ominous. Little data is available on the therapeutic efficacy of a thorough pelvic lymphadenectomy in combination with radical prostatectomy or radiotherapy in terms of 10 or 15 year survival. Such data should become available in the next few years.

Radioactive sources embedded in suture are associated with improved postimplant dosimetry in men treated with prostate brachytherapy.

BACKGROUND AND PURPOSE: Reports using the retropubic and transperineal technique of prostate brachytherapy suggest that adequate radiation doses are required for good clinical results with I-125. After 3 years of using loose sources (LS), radioactive sources embedded in suture (SES) were introduced into our prostate brachytherapy technique. The purpose of the present report is to determine whether dosimetric quantifiers of implant adequacy were affected by the use of SES. MATERIALS AND METHODS: Between September 1999 and April 2000, 20 patients were treated with prostate brachytherapy alone with a preplanned, preloaded needle technique using LS. Between May 2000 and February 2001, 20 patients were treated with prostate brachytherapy alone with a preplanned, preloaded needle technique using SES. Dosimetric quantifiers (DQ) of implant adequacy were calculated using a computed tomography scan performed 1 month following prostate brachytherapy. DQ were compared between patients treated with LS and patients treated with SES. RESULTS: The demographic characteristics were similar for each group. Men treated with SES had slightly smaller prostate glands compared to men treated with LS. The mean total activity and activity per seed were similar for each group but the activity per unit volume was slightly higher for the SES group. Patients treated with SES were found to have significantly improved DQ compared to patients treated with LS. The mean V100 for patients treated with SES was 94.10% compared to 86.54% in those patients treated with LS (P<0.001). CONCLUSIONS: In our experience using preplanning and preloaded needles, the use of SES is associated with improved postimplant DQ.

Radiation dose to the neurovascular bundles or penile bulb does not predict erectile dysfunction after prostate brachytherapy.

PURPOSE: To examine the relationship between calculated doses to the neurovascular bundles (NVBs) and the penile bulb (PB) and the development of erectile dysfunction (ED) after low-dose-rate prostate brachytherapy (LDRPB) alone. METHODS AND MATERIALS: Between September 1997 and June 1999, 84 men were treated with LDRPB alone. Inclusion criteria for this study were (1) no ED according to a self-administered questionnaire before PB, (2) treatment with PB alone (125I; 144 Gy), (3) postimplant CT scan of the prostate 1 month after PB, and (4) minimum of 24 months of continuous follow-up. Fifty men met all inclusion criteria. ED was assessed by a self-administered questionnaire completed before and at each follow-up visit after LDRPB. Radiation doses to the NVB and PB were calculated on the basis of axial postimplant CT images. Multiple variables (patient-related and dosimetric quantifiers) that may predict for the development of ED were examined by univariate analysis. RESULTS: Thirty of the 50 men (60%) were potent at last follow-up. The only patient-related variable that predicted for the development of ED was patient age (<65 vs. >65 years; p=0.03). The calculated mean maximum doses to the NVB and PB were 684 Gy (range, 195-1277 Gy) and 498 Gy (range, 44-971 Gy), respectively. The mean calculated doses to 50% of the NVB and PB were 158 Gy (range, 76-240 Gy) and 43 Gy (range, 19-101 Gy), respectively. The calculated mean maximum, mean minimum, and mean doses to 50% of the NVB or PB did not differ between those men who developed ED and those men who did not develop ED. None of the dosimetric variables examined predicted the development of ED after LDRPB. CONCLUSIONS: In our experience, higher calculated doses to the NVB or PB are not associated with ED after LDRPB.

Financial and educational costs of the residency interview process for urology applicants.

OBJECTIVES: To investigate the financial and educational costs of the urology residency interview process, we performed a survey of the applicants to the 2006 urology match. METHODS: All applicants registered for the 2006 urology match were invited to participate. In January 2006 prior to the match, an anonymous online survey containing 8 questions on the financial and educational costs of the interview process was distributed via email. RESULTS: Survey response rate was 61% (287/468). The median educational debt of the applicants was $125,000 (IQR 65,000 to 160,000). Respondents reported having a median 12 interviews (IQR 8 to 15) with urology residencies and spending a median 20 days (IQR 14 to 30) on the interview trail. The total cost of the interview process was a median $4000 (IQR 2000 to 5200) with a median expense per interview of $330 (IQR 211 to 455). Applicants reported that travel expenses accounted for a median 60% of overall interview expenses, whereas the remainder of the expense was accounted for by lodging (25%), food (10%) and clothing (5%). The money to cover these interview-related expenses was obtained primarily by loans. Forty-six percent of the applicants reported that skipping medical school clerkships and classes for urology interviews was "not at all detrimental" to their medical education, whereas 1% reported that it was "greatly detrimental." CONCLUSIONS: The financial cost of the interview process for urology applicants is substantial, although the educational cost appears to be limited. Efforts to reduce the financial impact of the interview process should be initiated at both a regional and national level.

A simple model predicts freedom from biochemical recurrence after low-dose rate prostate brachytherapy alone.

OBJECTIVE: The objective of this study was to describe a simple model that predicts freedom from biochemical recurrence (FFBR) in men with prostate cancer after treatment with low-dose rate prostate brachytherapy (LDRPB) alone. MATERIALS AND METHODS: One hundred thirty-two men were treated with LDRPB alone between September 1997 and April 2001. Sixty-four percent of men had low-risk disease (prostate-specific antigen [PSA] <10, Gleason <7, and T stage or =10, Gleason > or =7, or T stage T2b). The dosimetric quantifier D90 was calculated from a computed tomography scan performed 1 month after LDRPB. The percent positive biopsies (PPB) were determined for all patients. FFBR was estimated using the product limit method. All P values are 2-sided. RESULTS: The median follow-up is 65 months. The median D90 is 138 Gy (range, 47-221 Gy). Fourteen men have developed evidence of biochemical relapse at a median of 27 months (range, 6-42 months). The 5-year FFBR rate for the entire cohort is 88%. On univariate analysis, variables found to be associated with FFBR included: PSA, Gleason score, T stage, risk group, PPB, and D90. Multivariate analysis indicated that D90, PPB, and risk group were independently associated with FFBR. Patients were categorized based on the following 3 adverse prognostic factors: D90 <140 Gy, PPB > or =50%, and intermediate-risk group. Group 1 (0 factors, n = 30), group 2 (1 factor, n = 72), and group 3 (> or =2 factors, n = 30) patients had 5-year FFBR rates of 100% (+/-0%), 92% (+/-6%), and 67% (+/-18%) (P < 0.0001). CONCLUSIONS: We have developed a simple, robust model based on implant quality and disease factors that predicts FFBR in men with prostate cancer treated with LDRPB alone.

Percentage of positive biopsies associated with freedom from biochemical recurrence after low-dose-rate prostate brachytherapy alone for clinically localized prostate cancer.

OBJECTIVES: To examine the relationship between the percentage of positive biopsies (PPBs) and freedom from biochemical recurrence (FFBR) in men treated with low-dose-rate prostate brachytherapy (LDRPB) alone. The PPBs has been associated with FFBR in men treated with radical prostatectomy and external beam radiotherapy for prostate cancer. METHODS: This report concerns 108 men treated with LDRPB alone between November 1997 and December 1999. All patients had clinically localized prostate cancer confirmed by biopsy. All men were treated with iodine-125 to 144 Gy. FFBR was estimated using the product-limit method. Putative covariates for FFBR, including T stage, Gleason score, pretreatment prostate-specific antigen level, minimal dose received by 90% of the target volume, and PPBs, were examined using the proportional hazards regression model. RESULTS: The median follow-up was 61 months. Of the 108 men, 13 developed evidence of biochemical relapse at a median of 25 months. The 5-year estimate of FFBR was 87% (95% confidence interval 81% to 93%) for the entire cohort. On univariate analysis, prostate-specific antigen, T stage, minimal dose received by 90% of the target volume, and PPBs were associated with FFBR. In the multivariate model, the PPBs was the only variable that predicted for FFBR (P = 0.002). The 5-year estimate of FFBR was 95% for patients with less than 50% PPB disease versus 63% in patients with more than 50% PPB disease (P < 0.0001). CONCLUSIONS: The PPBs is an important independent predictor of FFBR after LDRPB alone. The FFBR after LDRPB in the group of patients with more than 50% PPBs was poor.

What makes a medical student avoid or enter a career in urology? Results of an international survey.

PURPOSE: To recruit the best and brightest medical students, it is crucial to understand what causes a medical student to pursue or avoid a career in urology. We performed a survey of 2 cohorts of residency applicants to elucidate these determinants. MATERIALS AND METHODS: All 410 applicants to the 2003-2004 United States urology residency match and all 624 individuals who applied to a Boston-area emergency medicine (EM) residency program were invited to participate in the study. The on-line survey for the urology applicants asked the research question "What caused you to pursue the specialty of urology?" The EM applicant survey asked the research question "What caused you NOT to pursue a career in a surgical subspecialty, such as urology?" Qualitative responses were analyzed for themes by 2 researchers and independently coded. RESULTS: Sixty percent (248 of 410) of urology applicants and 40% (252 of 624) of EM applicants completed the survey. Thematic coding of the qualitative responses yielded an inter-rater agreement of 89% to 94%. Positive determinants cited by urology applicants included the mix of medicine/surgery, the diversity of urological procedures, and clinical exposure to the field. Negative determinants cited by EM applicants included the narrowness of the specialty, an unattractive lifestyle, and the demands of a surgical residency. No significant correlations were noted between themes cited and participants' genders, degrees or medical school nationalities. CONCLUSIONS: Ensuring that medical students have clinical exposure to urology, receive appropriate mentorship, and develop realistic perceptions of the specialty may substantially facilitate recruitment.

Results of the 5 region prostate biopsy method: the repeat biopsy population.

PURPOSE: The decision to repeat prostate biopsy in a patient in whom the first biopsy did not detect prostate cancer poses a challenge to urologists. Many published series show a low yield on repeat biopsy using standard techniques. We reviewed our data on the 5 region prostate biopsy method to evaluate its yield in the repeat biopsy population. MATERIALS AND METHODS: A total of 125 repeat transrectal ultrasound guided prostate needle biopsy sessions were done in 110 patients for standard indications using the 5 region method. Pathological findings were reviewed and the yield of the additional regions was analyzed. RESULTS: Patients were categorized with respect to the initial biopsy technique. In those who underwent 1 and more than 1 previous sextant biopsy the relative increase in yield of the 5 region technique over the standard sextant technique was 31% and 33%, respectively. In the cohort that underwent previous 5 region biopsy the relative increase in yield of the 5 region technique over the standard sextant technique was 38%. CONCLUSIONS: In the setting of repeat biopsy the 5 region method results in an increased yield over the sextant method. It is true in patients who have previously undergone biopsies with the sextant or 5 region technique.

Prostate biopsy: indications and technique.

PURPOSE: The last decade has seen numerous modifications in the way prostate cancer is diagnosed. We review the current indications for and methods of prostate biopsy. MATERIALS AND METHODS: The English language literature was reviewed regarding major indications for and methods of prostate biopsy. Pertinent peer reviewed articles were collated and analyzed. RESULTS: The most widely accepted indication for prostate biopsy is a prostate specific antigen (PSA) value of greater than 4.0 ng./ml. However, some investigators advocate prostate biopsy for men with a PSA value in the 2.5 to 4.0 ng./ml. range, believing that use of this parameter results in detection of a greater number of cases of curable disease. Age specific PSA range, percent free PSA and presence of prostatic intraepithelial neoplasia or atypia are all considered to be relative indications for prostate biopsy. The current literature describes a trend toward increasing the number of cores obtained and the sites biopsied beyond those of the standard sextant technique. The additional cores in many series are obtained from more lateral regions of the gland. CONCLUSIONS: Although several criteria are used as indications for initial prostate biopsy, all are based on PSA level and/or abnormal digital rectal examination. Future improvements in currently used prostate cancer markers may result in better selection of cases to biopsy. There is no universally accepted technique of prostate gland biopsy. The current literature supports use of more extensive biopsy techniques to increase the likelihood of prostate cancer detection.

Cancer control after low-dose-rate prostate brachytherapy performed by a multidisciplinary team with no previous prostate brachytherapy experience.

OBJECTIVES: To describe the biochemical disease-free survival observed in the first cohort men treated by a multidisciplinary team of clinicians with no previous experience in low-dose-rate prostate brachytherapy (LDRPB). METHODS: The information in this report concerns the first 63 men treated with LDRPB alone at our institution between September 1997 and September 1998. All men had histologically confirmed, clinically localized prostate cancer. All men were treated with iodine 125 according to published methods. The prescription dose was 144 Gy according to the Task Group 43 formalism. LDRPB was performed jointly by a radiation oncologist and urologist. Three definitions of biochemical recurrence were used: the American Society for Therapeutic Radiology and Oncology consensus definition; prostate-specific antigen level greater than 0.4 ng/mL at last follow-up; and prostate-specific antigen level greater than 0.2 ng/mL at last follow-up. Biochemical relapse-free survival was estimated using the product-limit method. Putative covariates for biochemical relapse-free survival were examined using the proportional hazards regression model. All P values are two-sided. RESULTS: The median follow-up for the entire cohort was 62 months. Of the 63 men, 45 (71%) had more than 60 months of follow-up. The median pretreatment prostate-specific antigen level was 6.68 ng/mL (range 1.1 to 23), and most men (44 of 63; 70%) had nonpalpable disease. The institutionally assigned Gleason score was less than 7 in 54 men (86%). Nine men developed evidence of biochemical relapse at a median of 19 months (range 6 to 38). The 5-year estimate of biochemical relapse-free survival was 85% (95% confidence interval 80% to 90%), 80% (95% confidence interval 74% to 86%), and 70% (95% confidence interval 64% to 76%) according to the three definitions given above. CONCLUSIONS: The biochemical results achieved in the first cohort of men treated with LDRPB by a previously inexperienced multidisciplinary team of clinicians are similar to the results reported from centers with extensive LDRPB experience.