Recovery of urinary function after radical prostatectomy: predictors of urinary function on preoperative prostate magnetic resonance imaging.

PURPOSE: We determined whether pelvic soft tissue and bony dimensions on endorectal magnetic resonance imaging influence the recovery of continence after radical prostatectomy, and whether adding significant magnetic resonance imaging variables to a statistical model improves the prediction of continence recovery. MATERIALS AND METHODS: Between 2001 and 2004, 967 men undergoing radical prostatectomy underwent preoperative magnetic resonance imaging. Soft tissue and bony dimensions were retrospectively measured by 2 raters blinded to clinical and pathological data. Patients who received neoadjuvant therapy, who were preoperatively incontinent or had missing followup for continence were excluded from study, leaving 600 patients eligible for analysis. No pad use defined continent. Logistic regression was used to identify variables associated with continence recovery at 6 and 12 months. We evaluated whether the predictive accuracy of a base model was improved by adding independently significant magnetic resonance imaging variables. RESULTS: Urethral length and urethral volume were significantly associated with the recovery of continence at 6 and 12 months. Larger inner and outer levator distances were significantly associated with a decreased probability of regaining continence at 6 or 12 months, but they did not reach statistical significance for other points. Addition of these 4 magnetic resonance imaging variables to a base model including age, clinical stage, prostate specific antigen and comorbidities marginally improved the discrimination (12-month AUC improved from 0.587 to 0.634). CONCLUSIONS: Membranous urethral length, urethral volume, and an anatomically close relation between the levator muscle and membranous urethra on preoperative magnetic resonance imaging are independent predictors of continence recovery after radical prostatectomy. The addition of magnetic resonance imaging variables to a base model improved the predictive accuracy for continence recovery, but the predictive accuracy remains low.

Clinical and histopathological characteristics of familial prostate cancer in Finland.

OBJECTIVE: • To describe clinical and histopathological characteristics of Finnish familial prostate cancer (PCa) through a detailed analysis of cases in families. PATIENTS AND METHODS: • In total, 202 Finnish families with 617 histopathologically confirmed PCa cases of confirmed genealogy were collected. • Complete clinical data, including age and prostate-specific antigen (PSA) at diagnosis, stage, grade and primary treatment, were gathered. The mean (range) number of affected men per family was 3 (2-8). • All the available diagnostic biopsy samples (n= 323) were collected and regraded by the same uropathologist. • A population-based cohort of 3011 hospital district Pirkanmaa PCa patients was used as a control group. RESULTS: • The mean (range) year of diagnosis of PCa was 1993 (1962-2006) and the mean (range) age at diagnosis was 68 (43-98 years). • The median (range) primary PSA level was 12.0 (0.8-11 000) ng/mL. After regrading, the Gleason score was ≤6 in 38%, 7 in 37% and ≥8 in 25% of men. • The subset of familial PCa men diagnosed after 1995 had higher PSA levels (P= 9.9 × 10(-6) ) and an earlier age of onset (P= 1.7 × 10(-6) ) than men in the control group, although there were no differences in cancer-specific survival. CONCLUSIONS: • We observed an earlier age of onset and higher PSA in familial PCa. • However, differences between sporadic and familial or hereditary PCa cannot be truly solved until genetic testing of high-risk genes in addition to family history is used to define PCa families. • We also emphasize that, when histological samples are collected over a longer study period, reanalysis of the samples by the same experienced uropathologist should be considered.

Do pelvic dimensions and prostate location contribute to the risk of experiencing complications after radical prostatectomy?

OBJECTIVE: To assess if pelvic size, such as a narrow, steep pelvis, as well as prostate location in relation to the pelvic anatomy might have an impact on the likelihood of experiencing complications after radical prostatectomy. PATIENTS AND METHODS: In a standardized manner, different bony and soft tissue dimensions on preoperative staging MRI were retrospectively measured in a study cohort of 934 patients undergoing radical prostatectomy. Measurements were defined aimed at assessing pelvic size and prostate location. Medical and surgical complications after radical prostatectomy were meticulously reviewed and grouped into subcategories to assess whether a narrow, steep pelvis and an anatomically deeply situated prostate (which is thought to be more surgically challenging) might be associated with a higher likelihood of postoperative complications. Multivariate Cox regression was performed to assess if dimensions have a significant impact on the likelihood of postoperative complications. RESULTS: While known parameters such as a higher preoperative PSA and presence of comorbidities were associated with an increased risk of experiencing complications after surgical treatment, none of the dimensions assessed on preoperative MRI had a significant impact on the development of any medical or surgical complication. CONCLUSION: We report the largest cohort of patients where pelvic dimensions were evaluated in a standardized manner on preoperative MRI aimed at assessing anatomic factors and their impact on complications after radical prostatectomy. None of the measurements could significantly predict the likelihood of developing medical or surgical complications.

Pelvimetric dimensions do not impact upon nerve sparing or erectile function recovery in patients undergoing radical retropubic prostatectomy.

INTRODUCTION: The impact of unfavorable pelvic anatomy on the likelihood of having a nerve sparing radical retropubic prostatectomy (RRP) and the potential correlation between pelvic dimensions and recovery of erectile function (EF) after RRP have not been previously evaluated. AIM: To determine the impact of different pelvic bony and soft tissue dimensions as well as apical prostate depth on the likelihood of performing bilateral nerve sparing and on recovery of EF after RP. METHODS: Between November 2001 and June 2007, 644 potent men undergoing RRP had preoperative MRI where pelvimetry was performed with bilateral nerve sparing in 504 men. Outcomes including varying degrees of recovery of EF (level 1: normal; level 2: partial erections routinely sufficient for intercourse; level 3: partial erections occasionally sufficient for intercourse) were assessed. Median follow-up was 44.1 (interquartile range: 29.2, 65.3) months. We evaluated independent predictors of performing a bilateral nerve sparing procedure and of recovery of EF using multivariable Cox proportional hazards methods. MAIN OUTCOME MEASURES: Likelihood of performing bilateral nerve sparing as well as recovery of EF after RRP. RESULTS: Patients with higher clinical stage and biopsy Gleason score are less likely to undergo bilateral nerve sparing. Surgeon is also a factor in the likelihood of having bilateral nerve sparing RRP. On multivariate Cox regression analysis, factors predictive of recovery of EF were age, pretreatment erectile function, surgeon, and modified Charlson score. None of the pelvimetric dimensions were significant predictors of any degree of recovery of EF. However, the study is limited by its retrospective nature and by being based on MRI evaluations useful for cancer staging rather than anatomical evaluation of pelvimetric dimensions. CONCLUSIONS: We did not find unfavorable pelvic anatomy to impact the likelihood of performing a nerve sparing procedure or to be predictive of any degree of recovery of EF after RRP.

The depth of the prostatic apex is an independent predictor of positive apical margins at radical prostatectomy.

OBJECTIVE: To determine the effect of a deep and narrow pelvis on apical positive surgical margins (PSM) at radical prostatectomy (RP), controlling for other clinical and pathological variables and surgical approach, i.e. open retropubic (RRP) vs laparoscopic (LRP), as apical dissection is expected to be more challenging at RP with a prostate situated deep in a narrow pelvis. PATIENTS AND METHODS: From July 2003 to January 2005, 512 consecutive patients with preoperative prostate magnetic resonance imaging (MRI) underwent RRP or LRP with no previous radio- or hormonal therapy. An additional 74 patients with preoperative MRI undergoing RP from December 2001 to June 2007 who had an apical PSM were also included, with 586 patients comprising the study population. Bony and soft-tissue pelvic dimensions, including interspinous distance (ISD), bony (BFW) and soft tissue (SW) pelvic width, apical prostate depth (AD) and symphysis pubis angle, were measured on preoperative MRI. The pelvic dimension index (PDI), bony width index (BWI) and soft-tissue width index (SWI) were defined as ISD/AD, BFW/AD and SW/AD, respectively. Multivariate logistic regression was used to assess the effect of pelvic dimensions on apical PSM, controlling for surgical approach and clinical and pathological variables. RESULTS: There was no significant difference in ISD, BFW, SW or symphysis angle between patients with and without apical PSM. The AD was significantly greater in men with an apical PSM and consequently PDI, BWI and SWI were significantly lower in men with an apical PSM. Each of PDI, AD, BWI and SWI was a significant independent predictor of apical PSM, independent of surgical approach, and other clinicopathological variables. The main limitations of the study were that it was retrospective, and the relatively few patients with apical PSM. CONCLUSIONS: Apical prostate depth is an independent risk factor for apical PSM at RP. MRI pelvimetry might allow for preoperative planning of the approach to RP.

Early prostate-specific antigen changes and the diagnosis and prognosis of prostate cancer.

PURPOSE OF REVIEW: To delineate how recent findings on prostate-specific antigen (PSA) can improve prediction of risk, detection, and prediction of clinical endpoints of prostate cancer (PCa). RECENT FINDINGS: The widely used PSA cut-point of 4.0 ng/ml increasingly appears arbitrary, but no cut-point achieves both high sensitivity and high specificity. The accuracy of detecting PCa can be increased by additional predictive factors and a combinations of markers. Evidence implies that a panel of kallikrein markers improves the specificity and reduces costs by eliminating unnecessary biopsies. Large, population-based studies have provided evidence that PSA can be used to predict PCa risk many years in advance, improve treatment selection and patient care, and predict the risk of complications and disease recurrence. However, definitive evidence is currently lacking as to whether PSA screening lowers PCa -specific mortality. SUMMARY: PSA is still the main tool for early detection, risk stratification, and monitoring of PCa. However, PSA values are affected by many technical and biological factors. Instead of using a fixed PSA cut-point, using statistical prediction models and considering the integration additional markers may be able to improve and individualize PCa diagnostics. A single PSA measurement at early middle age can predict risk of advanced PCa decades in advance and stratify patients for intensity of subsequent screening.

PALB2 variants in hereditary and unselected Finnish prostate cancer cases.

BACKGROUND: PALB2 1592delT mutation is associated with increased breast cancer and suggestive prostate cancer (PRCA) risk in Finland. In this study we wanted to assess if any other PALB2 variants associate to increased PRCA risk and clinically describe patients with formerly found PALB2 1592delT mutation. METHODS: Finnish families with two or more PRCA cases (n = 178) and unselected cases (n = 285) with complete clinical data were initially screened for variants in the coding region and splice sites of PALB2. Potentially interesting variants were verified in additional set of unselected cases (n = 463). RESULTS: From our clinically defined sample set we identified total of six variants in PALB2. No novel variants among Finnish PRCA cases were found. Clinical characteristics of the variant carriers, including the previously described family carrying PALB2 1592delT, revealed a trend towards aggressive disease, which also applied to a few non-familial cases. Hypersensitivity to mitomycin C (MMC) of lymphoblasts from individuals from the family with 1592delT revealed haploinsufficiency among carriers with altered genotype. CONCLUSIONS: Though any of the detected PALB2 variants do not associate to PRCA in population level in Finland it cannot be ruled out that some of these variants contribute to cancer susceptibility at individual level.

Germ-line alterations in MSR1 gene and prostate cancer risk.

PURPOSE: The MSR1 gene maps to 8p22-23, a novel susceptibility locus for hereditary prostate cancer (HPC). Mutations in MSR1 have been reported to associate with prostate cancer (PRCA) risk. Here we report a follow-up study from Finland to evaluate the association between PRCA and MSR1 gene. EXPERIMENTAL DESIGN: The youngest affected patient from each of 120 HPC families was initially used for the screening of MSR1 mutations by single-strand conformational polymorphism analysis. Selected variants of MSR1 gene were then screened in 537 unselected PRCA cases and in 480 controls. RESULTS: Among 120 HPC families, five MSR1 sequence variants were identified. The carrier frequencies of the R293X, P275A, and -14743A>G variants were compared between the probands with HPC, unselected PRCA cases, and healthy male blood donors. No significant differences were observed. The odds ratios for R293X, P275A, and -14743A>G mutations were also calculated to estimate the PRCA risk. No significantly elevated or lowered risks for PRCA among these three variants were detected. However, the mean age at diagnosis of the R293X mutation carriers among HPC probands was significantly lower compared with noncarriers (55.4 versus 65.4 years; t test, P = 0.04). The same trend was observed among unselected PRCA cases (65.7 versus 68.7 years; t test, P = 0.37). CONCLUSIONS: Our results do not support a major role for the MSR1 gene in the causation of hereditary or unselected PRCAs but suggest a possible modifying role in cancer predisposition.

Ethnic variation in pelvimetric measures and its impact on positive surgical margins at radical prostatectomy.

OBJECTIVES: We sought to evaluate the ethnic variation in pelvimetry and its impact as a predictor of positive surgical margins (PSM) at radical prostatectomy (RP). METHODS: Preoperative MRI was performed in 482 Caucasian and 103 African American (AA) men undergoing RP without previous treatment from July 2003 to January 2005 and November 2001 to June 2007, respectively. We measured bony and soft tissue dimensions on magnetic resonance imaging (MRI) to evaluate the pelvic inlet, midplane, prostate size, and apical depth. Analysis of covariance was performed to determine the effect of ethnicity on the midpelvic area (MPA). We performed multivariate logistic regression analysis for prediction of overall and site-specific PSM. RESULTS: AA men had a significantly steeper symphysis pubis angle (median, 43.1 vs. 41.3°, respectively, P = .001) and smaller MPA (median, 78.5 vs. 83.9 cm(2), respectively, P = .004). Ethnicity and BMI were found to have a significant effect on MPA. Apical depth of the prostate was identified as a significant independent predictor of apical PSM, with a more pronounced effect in AA men. Pelvimetric measures were not a significant predictor of other sites of PSM. CONCLUSIONS: AA men have a significantly smaller MPA and steeper symphysis angle. The adverse impact of a deep pelvis, as measured by the apical prostatic depth on apical PSM was found to be greater in AA men. Evaluation of pelvic dimensions and prostate parameters in preoperative MRI may add to our understanding of their impact on surgical outcomes.

Incidence of cancer in finnish families with clinically aggressive and nonaggressive prostate cancer.

BACKGROUND: Clinical features of familial prostate cancer (PCa) and other malignancies associated with PCa are poorly described. Using a large family-based data registry of histologically confirmed cancers with a 40-year follow-up, we sought to determine incidence of cancer in Finnish PCa families, separately for clinically aggressive and clinically nonaggressive PCa. METHODS: We calculated standardized incidence ratios (SIR) for 5,523 members of 202 families by dividing the number of observed cancers (altogether 497 cases) by the number of expected cancers. The number of expected cancers is based on the national cancer incidence rates. RESULTS: SIR for overall cancer risk, excluding PCa, for male relatives in clinically nonaggressive families was 0.7 [95% confidence interval (95% CI), 0.6-0.8] and in clinically aggressive families 0.8 (95% CI, 0.6-1.0). The respective SIRs for women were 1.0 (95% CI, 0.8-1.1) and 1.1 (95% CI, 0.8-1.3). The incidence of lung cancer among men was significantly lower than in the general population. The SIR for gastric cancer among women was 1.9 in both clinically nonaggressive and clinically aggressive families. In clinically aggressive families, there was borderline significant excess of cancer of the gallbladder in men and liver cancer in women. CONCLUSIONS: The incidence of non-PCa cancers is not increased in clinically aggressive or clinically nonaggressive PCa families except for stomach cancer among women.

Segregation analysis of 1,546 prostate cancer families in Finland shows recessive inheritance.

Prostate cancer (PCa) is the most frequently diagnosed cancer in men worldwide and is likely to be caused by a number of genes with different modes of inheritance, population frequencies and penetrance. The objective of this study was to assess the familial aggregation of PCa in a sample of 1,546 nuclear families ascertained through an affected father and diagnosed during 1988-1993, from the unique, founder population-based resource of the Finnish Cancer Registry. Segregation analysis was performed for two cohorts of 557 early-onset and 989 late-onset families evaluating residual paternal effects and assuming that age at diagnosis followed a logistic distribution after log-transformation. The results did not support an autosomal dominant inheritance as has been reported in many of the hospital-based prostatectomy series. Instead, it confirmed the existence of hereditary PCa in the Finnish population under a complex model that included a major susceptibility locus with Mendelian recessive inheritance and a significant paternal regressive coefficient that is indicative of a polygenic/multifactorial component. The strengths of our study are the homogenous Finnish population, large epidemiological population-based data, histologically confirmed cancer diagnosis done before the PSA-era in Finland and registry based approach. Our results support the evidence that the inheritance of PCa is controlled by major genes and are in line with the previous linkage studies. Moreover, this is the first time a recessive inheritance is suggested to fit PCa in all data even when divided to early and late-onset cohorts.

Hemochromatosis gene mutations among Finnish male breast and prostate cancer patients.

Hereditary hemochromatosis (HH), the most common genetic disease in northern Europeans, is an autosomal recessive disorder of iron metabolism. The association between hepatocellular carcinoma and HFE homozygosity is well documented, but recently HFE hetero- and homozygosity has also been linked to nonhepatocellular malignancies, including female breast cancer. We hypothesized that C282Y and H63D mutations in the HFE gene could contribute to male breast cancer (MBC) and prostate cancer (PC) susceptibility at the population level in Finland. We screened the 2 major HFE mutations, H63D and C282Y, from 116 MBC cases diagnosed in Finland between 1967 and 1996, 843 consecutive unselected PC cases diagnosed at the Pirkanmaa Hospital District between 1999 and 2001 and 480 anonymous blood donor controls by minisequencing. Our results indicate that the frequencies of the HFE mutations do not significantly differ between MBC and PC patients and the population-based controls. No significantly altered risks for MBC or PC among carriers of the 2 variants were observed. However, HFE mutations were seen twice as often among carriers of a common BRCA2 mutation 9346(-2)A-->G compared with the rest of the MBC cases, indicating that HFE may be an MBC risk modifier gene among BRCA2 mutation carriers. In conclusion, our results indicate a minor role for the HFE mutations C282Y and H63D in the causation of MBC and PC, but carriers of both BRCA2 9346(-2)A-->G and an HFE mutation may be at an increased risk.

Two-locus genome-wide linkage scan for prostate cancer susceptibility genes with an interaction effect.

Prostate cancer represents a significant worldwide public health burden. Epidemiological and genetic epidemiological studies have consistently provided data supporting the existence of inherited prostate cancer susceptibility genes. Segregation analyses of prostate cancer suggest that a multigene model may best explain familial clustering of this disease. Therefore, modeling gene-gene interactions in linkage analysis may improve the power to detect chromosomal regions harboring these disease susceptibility genes. In this study, we systematically screened for prostate cancer linkage by modeling two-locus gene-gene interactions for all possible pairs of loci across the genome in 426 prostate cancer families from Johns Hopkins Hospital, University of Michigan, University of Umeå, and University of Tampere. We found suggestive evidence for an epistatic interaction for six sets of loci (target chromosome-wide/reference marker-specific P< or =0.0001). Evidence for these interactions was found in two independent subsets from within the 426 families. While the validity of these results requires confirmation from independent studies and the identification of the specific genes underlying this linkage evidence, our approach of systematically assessing gene-gene interactions across the entire genome represents a promising alternative approach for gene identification for prostate cancer.

Hereditary prostate cancer in Finland: fine-mapping validates 3p26 as a major predisposition locus.

In a recent genome-wide linkage (GWL) analysis of Finnish families at high risk for prostate cancer, we found two novel putative susceptibility loci at 3p25-p26 and 11q14. Here, we report the fine-mapping of these two critical regions at high resolution with 39 microsatellite markers in 16 families, including multiplex families that were not used in the GWL scan. The maximum multipoint HLOD was 3.39 at 3p26 and 1.42 at 11q14. The highest LOD scores were seen around markers D3S1270 and D3S4559 (alpha=0.89), covering approximately two megabases. The two known genes in this region CHL1 (cell adhesion molecule with homology to L1CAM) and CNTN6 (contactin 6) were screened for exonic mutations in the families showing the strongest linkage, but no disease-segregating sequence variants were observed. The recombination map pointed to a region proximal to the area of best linkage, suggesting that more genes may need to be investigated as candidates. These results provide strong evidence for the existence of a prostate cancer susceptibility gene at 3p26 in Finnish prostate cancer families. This locus has not been strongly linked with hereditary prostate cancer in other populations. However, the mildly positive 3p LOD scores in a recent GWL analysis of patients from the United States suggest that the locus may also be important in other populations.

Androgen receptor CAG polymorphism and prostate cancer risk.

Recent studies have suggested that polymorphisms of the androgen receptor gene ( AR) may influence the risk of prostate cancer (PC) development and progression. Here, we analyzed the length of the CAG repeat of the AR gene in 1363 individuals, including patients with PC, benign prostate hyperplasia (BPH), and population controls. There was a tendency for short CAG repeats to be associated with PC. The Odds Ratio (OR) for PC was 1.47 ( P=0.05) when individuals with short CAG repeats (18). CAG repeat length was not significantly associated with family history, disease stage, grade, age at diagnosis, prostate-specific antigen (PSA) level at diagnosis, or prognosis of the patients. Unexpectedly, short CAG repeats were significantly less common in patients with BPH compared with controls (OR=0.47, P=0.03). Our results suggest that the CAG polymorphism of the AR gene is unlikely to have a major role in the development or progression of PC in the Finnish population. The association of CAG repeats with the risk of BPH warrants further study.

Germline alterations of the RNASEL gene, a candidate HPC1 gene at 1q25, in patients and families with prostate cancer.

The RNASEL gene (2',5'-oligoisoadenylate-synthetase dependent) encodes a ribonuclease that mediates the antiviral and apoptotic activities of interferons. The RNASEL gene maps to the hereditary-prostate-cancer (HPC)-predisposition locus at 1q24-q25 (HPC1) and was recently shown to harbor truncating mutations in two families with linkage to HPC1. Here, we screened for RNASEL germline mutations in 66 Finnish patients with HPC, and we determined the frequency of the changes in the index patients from 116 families with HPC, in 492 patients with unselected prostate cancer (PRCA), in 223 patients with benign prostatic hyperplasia (BPH), and in 566 controls. A truncating mutation, E265X, was found in 5 (4.3%) of the 116 patients from families with HPC. This was significantly higher (odds ratio [OR] =4.56; P=.04) than the frequency of E265X in controls (1.8%). The highest mutation frequency (9.5%) was found in patients from families with four or more affected members. Possible segregation was detected only in a single family. However, the median age at disease onset for E265X carriers was 11 years less than that for noncarriers in the same families. In addition, of the four missense variants found, R462Q showed an association with HPC (OR=1.96; P=.07). None of the variants showed any differences between controls and either patients with BPH or patients with PRCA. We conclude that, although RNASEL mutations do not explain disease segregation in Finnish families with HPC, the variants are enriched in families with HPC that include more than two affected members and may also be associated with the age at disease onset. This suggests a possible modifying role in cancer predisposition. The impact that the RNASEL sequence variants have on PRCA burden at the population level seems small but deserves further study.

Combined genome-wide scan for prostate cancer susceptibility genes.

BACKGROUND: Prostate cancer represents a substantial public health burden worldwide. It is the second leading cause of cancer death among men in the United States. A family history of the disease is among the most well-established risk factors for prostate cancer. Efforts to localize prostate cancer susceptibility alleles by using genetic linkage analysis methods have been hindered by genetic heterogeneity, incomplete penetrance, disease phenocopies, and the lack of DNA samples from parents of individuals with late-onset prostate cancer. METHODS: We performed a combined genome-wide linkage analysis among 426 families from four existing hereditary prostate cancer (HPC) study populations to systematically search for prostate cancer susceptibility genes. To decrease the degree of locus heterogeneity, we analyzed subsets of families with similar clinical and demographic characteristics. Nonparametric multipoint linkage was the primary method of analysis. Results are presented as allele-sharing logarithm of the odds (LOD) scores, and all reported P values are two-sided. RESULTS: The strongest evidence for prostate cancer linkage was found at chromosome region 17q22 (nonparametric multipoint Kong and Cox allele-sharing LOD score = 3.16 at marker D17S787; P =.00007). Stratified analyses revealed several additional chromosomal regions that are likely to segregate prostate cancer susceptibility genes among specific subsets of HPC families, including 15q11 among families with late-onset disease (allele-sharing LOD = 5.57 at marker D15S128; P<.00001) and 4q35 among families with four or more affected family members (allele-sharing LOD = 3.10 at marker D4S1615; P =.00008). CONCLUSION: Fine mapping studies to facilitate identification of prostate cancer susceptibility genes in these linked regions are warranted.