Association between PSA kinetics and cancer-specific mortality in patients with localised prostate cancer: analysis of the placebo arm of the SPCG-6 study

BackgroundThe prognostic value of prostate-specific antigen (PSA) kinetics in untreated prostate cancer (PCa) patients is debatable. We investigated the association between PSA doubling time (PSAdt), PSA velocity (PSAvel) and PSAvel risk count (PSAvRC) and PCa mortality in a cohort of patients with localised PCa managed on watchful waiting.Patients and methodsPatients with clinically localised PCa managed observationally, who were randomised to and remained on placebo for minimum 18 months in the SPCG-6 study, were included. All patients survived at least 2 years and had a minimum of three PSA determinations available. The prognostic value of PSA kinetics was analysed and patients were stratified according to their PSA at consent: ≤10, 10.1–25, and >25 ng/ml. Cumulative incidences of PCa-specific mortality were estimated with the Aalen-Johansen method.ResultsTwo hundred and sixty-three patients were included of which 116, 76 and 71 had a PSA at consent ≤10, 10.1–25, and >25 ng/ml, respectively. Median follow-up was 13.6 years. For patients with PSA at consent between 10.1 and 25 ng/ml, the 13-year risks of PCa mortality were associated with PSA kinetics: PSAdt ≤3 years: 62.0% versus PSAdt >3 years: 16.3% (Gray's test: P < 0.0001), PSAvel ≥2 ng/ml/year: 48.0% versus PSAvel <2 ng/ml/year: 11.0% (Gray's test: P = 0.0008), and PSAvRC 2: 45.0% versus 0–1: 3.8% (Gray's test: P = 0.001). In contrast, none of the PSA kinetics were significantly associated with changes of 13-year risks of PCa mortality in patients with PSA at consent ≤10 or >25 ng/ml.ConclusionWe found that magnitude changes in 13-year risks of PCa mortality that can be indicated by PSA kinetics depend on PSA level in patients with localised PCa who were managed observationally. Our results question PSA kinetics as surrogate marker for PCa mortality in patients with low and high PSA values.Clinical trial numberNCT00672282.     

The risk of prostate cancer for men on aspirin,statin or antidiabetic medications

BackgroundA decreased risk of prostate cancer (PCa) has been suggested in men taking aspirin, statins and metformin, although the evidence has been conflicting. We estimated the association between prescribed medications, prostate specific antigen (PSA) levels and the risk of either any PCa or high-grade PCa.MethodsThis population-based cohort study included 185,667 men having a first recorded PSA test and 18,574 men having a first prostate biopsy in Stockholm County, Sweden for the period 2007–2012. Detailed clinical information including PSA levels, biopsy results, comorbidities and educational level were obtained from population-based registers. High-grade prostate cancer was defined as a Gleason score of seven or higher. Differences in PSA levels by medication status were estimated using linear regression on log PSA values. PCa risk was estimated using multivariate logistic regression.ResultsCompared with men who were not on medication, the PSA level at the first PSA test was lower among men using 75 mg/dose aspirin (−3.9% change in PSA concentration; 95% confidence interval (CI): −5.8 to −2.1), statin (−4.6%; 95% CI: −6.2 to −2.9), metformin (−14%; 95% CI: −17 to −12) and insulin (−16%; 95% CI: −18 to −14). Men using any statins had an increased risk of both high-grade PCa (odds ratio (OR) 1.25; 95% CI: 1.10–1.42) and PCa of any grade (OR 1.16; 95% CI 1.04–1.29). There were no significant associations between aspirin or any antidiabetic medication and the risk of PCa.ConclusionWe found no protective effect of aspirin, statins or antidiabetics in terms of risk for any PCa or high-grade PCa. Use of any statins was associated with an elevated risk of being diagnosed with high-grade prostate cancer.     

Serum inflammatory markers in relation to prostate cancer severity and death in the Swedish AMORIS study

Inflammation is a well‐documented driver of cancer development and progression. However, little is known about its role in prostate carcinogenesis. Thus, we examined the association of C‐reactive protein (CRP), haptoglobin, albumin and white blood cells (WBC) with prostate cancer (PCa) severity (defined by PCa risk category and clinicopathological characteristics) and progression (defined by PCa death). We selected 8,471 Swedish men with newly diagnosed PCa who had exposure measurements taken approximately 14 years prior to diagnosis. We calculated odds ratio (OR) and 95% confidence interval (CI) for the associations between the inflammatory markers and PCa severity using logistic regression, while Cox proportional hazard regression was used for the associations with overall and PCa death. Serum CRP levels were associated with increased odds of high risk and metastatic PCa, and high PSA levels (≥20 µg/L) (OR: 1.29; 95% CI: 1.06–1.56, 1.32; 1.05–1.65 and 1.51; 1.26–1.81, respectively). Similarly, higher haptoglobin levels were associated with increased odds of metastatic PCa, high PSA level and possibly high grade PCa (1.38; 1.10–1.74, 1.50; 1.17–1.93 and 1.25; 1.00–1.56, respectively). Albumin was positively associated with Gleason 4 + 3 tumour (1.38; 1.02–1.86) and overall death (HR_{unit increase in log}: 1.60; 95% CI: 1.11–2.30), but inversely associated with high risk PCa and high PSA levels (≥20 µg/L) (0.71; 0.56–0.89 and 0.72; 0.5 9–0.90). WBC was associated with increased odds of T3–T4 PCa. Except for albumin, none of these markers were associated with PCa death or overall death. Systemic inflammation as early as 14 years prior to diagnosis may influence prostate cancer severity.     

Molecular forms of prostate‐specific antigen in serum with concentrations of total prostate‐specific antigen <4 μg/L: Are they useful tools for early detection and screening of prostate cancer?

Molecular forms of prostate-specific antigen (PSA) improve the differentiation between benign prostatic hyperplasia (BPH) and prostate cancer (PCa) in men with total PSA concentrations between 4 and 10 microg/l. To evaluate the diagnostic utility of free PSA (fPSA) and complexed PSA forms for identification of men with PCa in the low PSA range of <4 microg/l, total PSA (tPSA), alpha(1)-antichymotrypsin complexed PSA (PSA-ACT) and fPSA (Roche Elecsys [ES] system) as well as tPSA and complexed PSA (cPSA) (Bayer Immuno 1 system) were measured in archival serum samples from 31 untreated patients with PCa, 66 patients with BPH, and 90 men without prostatic disease. The median ratios of fPSA/tPSA, PSA-ACT/tPSA and cPSA/tPSA were significantly different between patients with BPH and PCa (27.2 vs. 19.4%, 64 vs. 88%, 77.2 vs. 88.2%, p < 0.05). No associations between PSA forms and tumor stage and grade were found. Analysis of the receiver operating characteristic curves showed that these ratios could discriminate better between BPH and PCa patients than determination of the analytes tPSA, fPSA, cPSA and PSA-ACT alone. The use of one of the ratios would have eliminated roughly half of the unnecessary biopsies in this study. The ratios should be considered as potential tools to increase the selectivity of PCa detection at low PSA concentration. The ratios fPSA/tPSA and cPSA/tPSA can be determined using commercially available assays so that one of these ratios could be preferred instead of PSA-ACT determination. The ratios could be useful in assessing the risk of PCa in the individual and therefore in deciding on prostate biopsy for final diagnosis.     

Prognostic significance of epithelial/stromal caveolin‐1 expression in prostatic hyperplasia,high grade prostatic intraepithelial hyperplasia and prostatic carcinoma and its correlation with microvessel density

Caveolin-1 may play a role in cancer development and progression. The aim was to record the expression and localization of caveolin-1 in benign prostatic hyperplasia (BPH), high grade prostatic intraepithelial neoplasia (HGPIN) and prostatic carcinoma (PCa). Microvessel density was evaluated with CD34 immunostain. Correlations with known prognostic factors of PCa were recorded. Immunohistochemical expression of caveolin-1 and the MVD was evaluated in 65 cases; BPH (25), HGPIN (20) and PCa (20). Stromal caveolin-1expression was significantly higher in BPH than HGPIN and PCca. There was significant inverse relation between stromal caveolin-1 expression and extension to lymph node and seminal vesicle in carcinoma cases. Epithelial caveolin-1 was significantly higher in carcinomas than in BPH and HGPIN. Epithelial expression in carcinoma was significantly associated with preoperative PSA, Gleason score and lymph node extension. MVD was significantly higher in PCa than in BPH and HGPIN. There were significant relations between MVD and preoperative PSA, Gleason score, lymph node and seminal vesicle extension. Stromal caveolin-1 was associated with low MVD while epithelial caveolin-1 with high MVD. Conclusions: Caveolin-1 plays an important role in prostatic carcinogenesis and metastasis. Stromal expression of caveolin-1 in PCa is lowered in relation to BPH and HGPIN. In PCa; stromal caveolin-1 was associated with good prognostic parameters. Epithelial caveolin-1 is significantly increased in PCa than BPH and HGPIN. It is associated with clinically aggressive disease. Caveolin-1 may play a role in angiogenesis.     

Informed decision making on PSA testing for the detection of prostate cancer: An evaluation of a leaflet with risk indicator

BackgroundPopulation-based screening for prostate cancer (PCa) remains controversial. To help men making informed decisions about prostate specific antigen (PSA) screening a risk indicator (www.uroweb.org) was developed. This risk indicator is embedded in a leaflet that informs men about the pros and cons of PCa screening and enables calculation of the individual risk of having a biopsy detectable PCa.AimTo assess the effect of providing a leaflet including individualized risk estimation on informed decision making of men, i.e. knowledge about PCa and PSA screening, attitude towards undergoing a PSA test and intention to have a PSA test.MethodsAn intervention study among 2000 men, aged 55–65 years, randomly selected from the population registry of the city of Dordrecht, the Netherlands, in 2008. Men were sent a questionnaire on knowledge of PCa, attitude and intention to have a PSA test. Men without a history of (screening for) PCa were sent the leaflet and Questionnaire 2 within 2 weeks after returning Questionnaire 1. Validated health and anxiety measures were used.ResultsOne thousand and twenty seven of 2000 men completed Questionnaire 1 (51%), of whom 298 were excluded due to a history of (screening for) PCa. Of the 729 remaining men, 601 completed Questionnaire 2 as well. At the second assessment significantly more men met the requirements of informed decision making (15% versus 33%, p < 0.001), more men had relevant knowledge (284/601, 50% versus 420/601, 77%, p < 0.001) and the intention to have a PSA test had increased (p < 0.001).ConclusionsProviding information on PCa screening combined with individualized risk estimation enhanced informed decision making and may be used for shared decision making on PSA screening of physicians and patients.     

Surgical excision versus observation as initial management of desmoid tumors: A population based study

SynopsisDesmoid tumors can be safely managed with watchful waiting, including either observation alone or tamoxifen/NSAIDs. Surgery at first presentation can be associated with significant treatment burden.BackgroundImmediate surgery was historically recommended for desmoid tumors. Recently, watchful waiting, (tamoxifen/NSAIDs or observation alone), has been advocated.MethodsAll diagnoses of desmoid tumor within the Alberta Cancer Registry from August 2004 to September 2015 were identified. Patients with FAP were excluded. Demographics, tumor characteristics and treatment and outcome data were collected. Outcomes were compared between immediate surgery and watchful waiting. The effect of abdominal wall site on progression and recurrence and the effect of microscopic margin on recurrence were assessed with Fisher's exact test.ResultsWe identified 111 non-FAP patients. Median follow-up was 35 months from diagnosis. 74% were female. Mean age was 42. Fifty (45%) underwent watchful waiting, of whom 21(42%) progressed, with median PFS of 10 months. Fifty-three (48%) underwent resection at presentation, of whom 8 (15%) recurred, with median disease-free survival of 22 months.Abdominal wall lesions were equally represented in both groups, and equally likely to progress on watchful waiting (50% vs 39%, p = 0.53), but there was a trend toward decreased recurrence after surgery. (5% vs 23%, p = 0.08).Microscopic margin had no effect on recurrence (14% of margin negative vs 20% of margin positive, p = 1.0).ConclusionsWatchful waiting was successful in 58% of patients, and a further 28% only required one aggressive treatment thereafter, for a total of 86%. Surgery had a favorable recurrence rate (15%), but some recurrences were associated with significant treatment burden. Treatment should be tailored to individual patients in a multidisciplinary setting. A trial of observation appears warranted in most patients.Recurrence rate was not affected by positive margins.     

Prostate Specific Antigen,Mean Platelet Volume,and Platelet Distribution Width in Combination to Discriminate Prostate Cancer from Benign Prostate Hyperplasia

Background: Prostate cancer (PCa) represents the second most commonly diagnosed malignancy and the sixthleading cause for cancer related death among men worldwide. Although use of the prostate specific antigen (PSA) asa diagnostic marker has improved the detection and management of PCa, low specificity and sensitivity has limited itsclinical efficacy. Moreover, elevated PSA is frequently observed in benign prostate hyperplasia (BPH). Mean plateletvolume (MPV) and platelet distribution width (PDW) are commonly used indicators of platelet activation. The purposeof current study was to investigate the ability of PSA, MPV, and PDW individually or in combination, to differentiatePCa from BPH. Materials and Methods: This study included 100 patients with PCa and 108 patients with BPH. Wecollected all participants’ clinical and laboratory characteristics. The benefit of adding MPV and PDW to a modelwith only PSA was evaluated as an increased in the area under the curve (AUC) obtained by receiver operating curve(ROC). Results: PCa patients had reduced MPV and elevated PSA and PDW levels compared to BPH patients. Singlebiomarkers had AUC values ranging from 0.683 for PDW to 0.865 for PSA. Moreover, the combination of PSA, MPV,and PDW increased the AUC to 0.935 (0.892-0.964) (p<0.0001), significantly higher than those of any single marker.Conclusions: The combined use of PSA, MPV, and PDW may be clinically useful in distinguishing between PCa andBPH.     

Diagnostic Efficacy of PSMA and PSCA mRNAs Combined to PSA in Prostate Cancer Patients

Background: Serum Prostate-specific antigen (PSA) has been used for screening and diagnosis of prostate cancer (PCa) but it is burdened by its low accuracy, creating a need for reliable diagnostic markers. Despite prostate-specific membrane antigen (PSMA) and prostate stem cell antigen (PSCA) being widely expressed in the tissue of PCa, no definite conclusion regarding their use as clinical biomarkers due to their lacking organ specificity. Therefore, this study aimed to evaluate the peripheral blood levels of PSMA and PSCA mRNAs and examine their diagnostic significance as non-invasive integrated markers.Materials and Methods: 125 subjects were enrolled in this study. They were divided into 25 healthy controls, 25 BPH patients, and 75 PCa patients. The expression levels of PSMA and PSCA were determined using quantitative RT- PCR, in addition to measuring serum PSA.Results: Levels of PSMA and PSCA were over-expressed in PCa patients compared to controls and BPH patients and were found to be associated with increased susceptibility to PCa. Moreover, the diagnostic values of PSMA and PSCA to distinguish PCa patients from BPH patients and controls were inferior to that of PSA. However, the combination of PSMA and PSCA with PSA enhanced the efficacy of the latter.Conclusion: This study suggests that these genes were associated with malignant susceptibility. Concerning the duality of PSMA-PSA or PSCA-PSA, this implies the significance of their investigation together in peripheral blood of prostate patients.     

Progression of prostate cancer: diagnostic and prognostic utility of prostate-specific antigen, alpha2-macroglobulin, and their complexes

We previously reported cases of advanced prostate cancer (PCa) in which serum alpha2-macroglobulin (alpha2M) levels were markedly decreased to less than approximately 50 mg/dl whereas serum prostate-specific antigen (PSA) levels were remarkably increased. These cases were not complicated with disseminated intravascular coagulation (DIC). In this study, we measured serum PSA and alpha2M in 108 patients with either benign prostatic hyperplasia (BPH) or PCa to elucidate the relationship between PSA, i.e. the serum protease derived from the prostatic tissue, and alpha2M, i.e. the protease inhibitor that was the most abundantly contained in serum. alpha2M was determined by ELISA, total PSA and PSA-alpha1-antichymotrypsin (PSA-ACT) by EIA, and free-PSA by RIA in 44 patients with untreated BPH and 64 patients with untreated PCa. The ready association of alpha2M and PSA was assessed using Western blotting to identify complexes of the two. Levels of total serum PSA correlated positively with those of PSA-ACT in PCa (r = 0.99, p < 0.001), and both levels increased with advancing stage of disease. In contrast, the serum-free PSA/total PSA ratio (free/total PSA) and alpha2M levels decreased as the disease progressed. However, only the free/total PSA ratio attained significant difference for localized cancer in stage T1,2 versus BPH (p < 0.05). In stage M1b PCa, in which serum PSA levels were very high, there was a negative correlation between the total PSA and alpha2M values (r = -0.57, p < 0.05). In addition, serum alpha2M levels tended to decrease with progression of PCa. Serum total PSA levels correlated tightly with serum PSA-ACT levels. It is suggested that PSA is usually complexed with ACT in the serum. Free/total PSA was useful for differential diagnosis between early cancer and BPH. Levels of serum alpha2M of less than 50 mg/dl in PCa patients may indicate a possibility of bone metastases.     

游离前列腺特异性抗原与总前列腺特异性抗原比值在前列腺癌鉴别诊断中的应用

 目的 探讨游离前列腺特异性抗原（fPSA）与总前列腺特异性抗原（tPSA）比值在前列腺癌（PCa）鉴别诊断中的意义。方法 采用电化学免疫发光技术对86例前列腺良性增生（BPH）45例PCa患者和60例健康男性体检者（正常对照组）血清fPSA和tPSA同时进行测定，并计算出fPSA／tPSA，进行统计分析。结果 BPH、PCa组tPSA水平明显高于正常对照组（P＜0.05）。PCa组和BPH组的血清tPSA差异亦有统计学意义，但当tPSA在4.0 ~ 10.0 μg／L范围时，PCa组血清fPSA／tPSA比值却明显低于BPH组（P＜0.01）。把fPSA／tPSA比值划分成8个区间，当fPSA／tPSA比值15 ％作为诊断灰区PCa诊断的临界值时，诊断的敏感性、特异性、阳性预测值、阴性预测值及正确诊断指数分别为72.8 %、67.5 %、62.5 %、82.2 %、50.2 %。结论 当血清tPSA处于诊断灰区时，联合检测fPSA／tPSA比值可明显提高tPSA对PCa早期诊断的特异性。     

A novel expressed prostatic secretion (EPS)-urine metabolomic signature for the diagnosis of clinically significant prostate cancer

Objective:Significant efforts are currently being made to identify novel biomarkers for the diagnosis and risk stratification of prostate cancer (PCa). Metabolomics can be a very useful approach in biomarker discovery because metabolites are an important read-out of the disease when characterized in biological samples. We aimed to determine a metabolomic signature which can accurately distinguish men with clinically significant PCa from those affected by benign prostatic hyperplasia (BPH).Methods:We first performed untargeted metabolomics using ultrahigh-performance liquid chromatography tandem mass spectrometry on expressed prostatic secretion urine (EPS-urine) from 25 patients affected by BPH and 25 men with clinically significant PCa (defined as Gleason score ≥ 3 + 4). Diagnosis was histologically confirmed after surgical treatment. The EPS-urine metabolomic approach was then applied to a larger, prospective cohort of 92 consecutive patients undergoing multiparametric magnetic resonance imaging for clinical suspicion of PCa prior to biopsy.Results:We established a novel metabolomic signature capable of accurately distinguishing PCa from benign tissue. A metabolomic signature was associated with clinically significant PCa in all subgroups of the Prostate Imaging Reporting and Data System (PI-RADS) classification (100% and 89.13% of accuracy when the PI-RADS was in range of 1–2 and 4–5, respectively, and 87.50% in the more critical cases when the PI-RADS was 3).Conclusions:A combination of metabolites and clinical variables can effectively help in identifying PCa patients that might be overlooked by current imaging technologies. Metabolites from EPS-urine should help in defining the diagnostic pathway of PCa, thus improving PCa detection and decreasing the number of unnecessary prostate biopsies.     

Negative Biopsy Histology in Men With PI-RADS Score 5 in Daily Clinical Practice: Incidence of Granulomatous Prostatitis

IntroductionThe purpose of this study was to evaluate the biopsy histology of men who underwent transperineal multi-parametric magnetic resonance imaging (mpMRI)/transrectal ultrasound fusion biopsy for Prostate Imaging Reporting and Data System (PI-RADS) score 5 lesions.Patients and MethodsFrom January 2016 to June 2019, 105 men with PI-RADS score 5 underwent mpMRI/transrectal ultrasound fusion biopsy combined with systematic prostate biopsy. All the patients underwent a 3.0 Tesla pelvic mpMRI for the first time before prostate biopsy. In detail, the detection rate for clinically significant prostate cancer (PCa) and the follow-up of the patients without proven diagnosis of PCa has been reported.ResultsIn 91 (86.7%) of 105 patients, a stage T1c PCa was diagnosed, and 89 (84.5%) of 105 of them were classified as clinically significant PCa. Among the 16 (15.5%) of 105 patients with absence of cancer, 5 (31.5%) of 16 had an aspecific granulomatous prostatitis, 1 (6.2%) of 16 had a specific granulomatous prostatitis secondary to prostatic Mycobacterium Tubercolosis, and 10 (62.3%) of 16 had a diagnosis of normal parenchyma. The 6 patients with granulomatous prostatitis underwent specific antibiotic therapy followed by laboratory (ie, semen and urine cultures) and clinical evaluation. Six months from prostate biopsy, none of the 16 patients underwent repeat prostate biopsy because prostate-specific antigen (PSA) (15/16 cases) plus PSA density significantly decreased; in addition, in all the cases the initial PI-RADS score 5 was downgraded at mpMRI revaluation to PI-RADS score ≤ 3.ConclusionThe reduction of PSA plus PSA density values and the downgrading of PI-RADS score to ≤ 3 allow avoiding a repeated prostate biopsy in men with initial mpMRI PI-RADS score 5 lesion and negative biopsy histology.     

Value of free-to-total prostate-specific antigen ratio for detection and staging of prostate cancer

Background. We aimed to evaluate the clinical usefulness of measurement of the free-to-total (F/T) ratio of prostate-specific antigen (PSA) for the differentiation of prostate cancer from benign prostate hyperplasia (BPH) and for the staging of prostate cancer. Values for PSA density (PSAD) and PSAD adjusted to the transition zone volume (PSAD-T) were also evaluated in patients with mildly elevated PSA levels (4.1–10 ng/ml). Methods. Total and free PSA and the F/T ratio were determined in 80 men with prostate cancer and 48 men BPH before treatment. PSA levels were measured with a chemiluminescent enzyme immunoassay. Results. Patients with prostate cancer had a significantly lower F/T ratio than those with BPH. A cut-off value of 14% for the F/T ratio provided a positive predictive value of 81.6% and a negative predictive value of 65.4%. The F/T ratio did not differ between patients with clinically localized and metastatic prostate cancer. In patients with a PSA value of 4.1–10 ng/ml, a cut-off value of 14% for the F/T ratio provided a sensitivity of 66.7% and a specificity of 76.2%. Sixty percent of the missed cancer in patients with an F/T value of 14% or more could be rescued using the PSAD value. Conclusion. Measurement of the F/T PSA ratio has good sensitivity and specificity in distinguishing prostate cancer from BPH, especially in patients with a PSA level of 4.1–10 ng/ml. However, compared with serum PSA level, the F/T PSA ratio is not valuable for the clinical staging of prostate cancer. Received: June 23, 1999 / Accepted: September 22, 1999     

Association of Obesity and Diabetes With Prostate Cancer Risk Groups in a Multiethnic Population

IntroductionObesity and diabetes mellitus (DM) have been associated with prostate cancer (PCa) risk, but data examining their combined effects on aggressive PCa are sparse, particularly among non-Hispanic Black and Hispanic men. We investigated the associations of obesity and DM in relation to National Comprehensive Cancer Network (NCCN) PCa risk groups in a racially-diverse patient population.Patients and MethodsWe abstracted demographic and clinical data from men who underwent radical prostatectomy at our institution between 2005 and 2019. Patients were classified into three NCCN PCa risk-groups: low, intermediate and high-risk. Logistic regression models were used to examine the independent and combined associations of body mass index (BMI)/obesity and DM with risks of intermediate and high-risk PCa, adjusting for age and race/ethnicity.ResultsA total of 1303 men with PCa (average age 60 ± 6.9 years) were analyzed. The majority were non-Hispanic Black (N = 493, 38%) or Hispanic (N = 407, 31%). The prevalence of obesity (BMI ≥ 30 kg/m²) and DM was 29.3% (N = 382) and 28.3% (N = 369), respectively. In multivariate analyses, obesity was independently associated with an odds ratio (OR) = 2.21 of high-risk PCa (95% CI: 1.28-3.81), while DM was associated with an OR = 1.49 (95% CI: 1.05-2.11) of intermediate-risk PCa. Compared to non-obese men without diabetes, men with BMI ≥ 30 and DM had increased risks of both intermediate (OR = 1.93; 95% CI 1.12-3.43) and high-risk PCa (OR = 2.40; 95% CI 1.22-4.73). Interestingly, most of the association of high-risk PCa was driven by obesity.ConclusionIn this multiethnic population both obesity and DM were independently associated with intermediate- and high-risk PCa; however, most of the association for high-risk cancer was driven by obesity. Our results corroborate findings that obesity increases the risk of aggressive PCa; however, results regarding DM need to be confirmed in other large multiethnic populations.     

General and abdominal obesity trajectories across adulthood,and risk of prostate cancer: results from the PROtEuS study,Montreal, Canada

Purpose

Greater body fatness is a probable cause of advanced prostate cancer (PCa). Body fat distribution and timing of exposure may be relevant. We investigated associations between body size trajectories and PCa incidence in a population-based case–control study in Montreal, Canada.

Methods

Cases (n?=?1,931), aged?≤?75 years, were diagnosed with PCa in 2005–2009; 1,994 controls were selected from the electoral list. Interviews were conducted to assess body mass index (BMI) and Stunkard’s silhouette at ages 20, 40, 50, 60 years, and before interview. Current waist and hip circumferences were measured, and a predictive model estimated waist circumference in the past. BMI and waist circumference trajectories were determined to identify subgroups. Logistic regression estimated odds ratios (OR) and 95% confidence intervals (CI) for the association between anthropometric indicators and PCa.

Results

Subjects with a current BMI?≥?30 kg/m² had a lower risk of overall PCa (OR 0.71, 95% CI 0.59–0.85). Associations with adult BMI followed similar trends for less and more aggressive tumors, with stronger inverse relationships in early adulthood. Contrastingly, current waist circumference?≥?102 cm was associated with elevated risk of high-grade PCa (OR 1.33, 95% CI 1.03–1.71). Men with increasing BMI or waist circumference adult trajectories had a lower risk of PCa, especially low-grade, than those in the normal-stable range. This was especially evident among men in the obese-increase group for BMI and waist circumference.

Conclusion

Abdominal obesity increased the risk of aggressive PCa. The inverse relationship between body size trajectories and PCa may reflect PSA hemodilution, lower detection, and/or a true etiological effect.

     

The prognostic significance of combined ERG and androgen receptor expression in patients with prostate cancer managed by androgen deprivation therapy

ERG and androgen receptor (AR) are known to function cooperatively in prostate cancer (PCa) progression. However, the prognostic value of combined ERG and AR expression and potential pathways are not well characterized. We assessed ERG and AR protein expression by immunohistochemistry in a cohort of 312 men with PCa diagnosed by transurethral resection of the prostate (TURP). Patients were divided into those with no prior hormonal treatment (designated as PCa/AdvPCa) vs. those with castrate-resistant PCa (CRPC) undergoing channel TURP to relieve obstructive symptoms. The expression status was correlated with various clinical-pathological parameters. The Swedish watchful-waiting cohort was used for validation and characterization of potential gene signatures associated with ERG and AR.   Patients with combined ERG-positive/AR high expression profile demonstrated higher rates of PCa-specific mortality (PCSM) compared with patients with ERG-negative/AR low in patients with no prior treatment (n = 90, P = 0.032), but this was attenuated in the overall cohort which included the CRPC subgroup (n = 125, P = 0.096). The prognostic significance to PCSM was validated in the Swedish watchful waiting cohort in univariate (HR: 3.3; 95% CI: 1.9–5.6, P = 4.25E−5) and multivariate analysis (HR: 2; 95% CI: 0.97–4.1, P = 0.057), which included Gleason score. ERG/AR overexpression status characterized 152 genes signatures including WNT, PI3K/AKT and chemokine signaling pathways known to be deregulated in PCa. In conclusion, combined ERG/AR overexpression signifies a class of patients at highest-risk of PCSM with specific key genetic alteration likely responsible for disease progression. The prognostic value of combined ERG/AR overexpression and its associated genes should be further investigated as potential prognostic and therapeutic targets in prostate cancer progression.     

Clarifying uncertainty regarding detection and treatment of early-stage prostate cancer

Detection and treatment of prostate cancer can theoretically identify and cure a potentially disabling and deadly disease. However, controversy exists primarily because of the absence of randomized controlled trials (RCTs) documenting that these strategies improve survival and quality of life. In the absence of definitive information from RCTs, patients seek information and recommendations from many sources. Physicians have an opportunity to help patients and their families sort through the vast array of conflicting and confusing information. Rather then recommending for or against routine prostate-specific antigen (PSA) testing, physicians should provide men who are interested in prostate cancer testing, 50 years of age and older, and have a life expectancy of at least 10 to 15 years, with balanced information about the potential benefits and established harms of screening, diagnosis, and treatment. Validated informational materials can effectively and efficiently promote shared decision making. For early prostate cancer detection, the minimum information should include: the likelihood that prostate cancer will be diagnosed, possibilities of false-positive and false-negative results, anxiety associated with a positive test, and uncertainty regarding whether screening reduces the risk for death from prostate cancer. For men with localized prostate cancer, acceptable treatment options include radical prostatectomy, radiation therapy, cryotherapy, early androgen-suppression therapy, and watchful waiting. These are all considered acceptable options because data do not provide clear-cut evidence for the superiority of any 1 treatment. The only RCT comparing surgery to watchful waiting, though of relatively small size and conducted before PSA testing, showed no difference in survival after 23 years of follow-up. Watchful waiting does not remove prostate cancer, may miss an opportunity to cure or delay disease progression, and may lead to increased patient anxiety. However, watchful waiting avoids the harmful side effects of early intervention and does provide palliative therapy if and when symptomatic disease progression occurs. Furthermore, intervention is not necessary in the vast majority of men because most prostate cancers do not cause mortality or serious morbidity. Therefore, quality of life in many men treated with watchful waiting is superior to those treated with early intervention. For the minority of men with prostate cancer likely to cause disability or death, early intervention options may not be effective. Although commonly used in other countries, watchful waiting is rarely recommended in the United States. The opportunity exists to resolve the confusion, close the gaps in knowledge, and enhance prostate cancer care by conducting RCTs. Until these RCTs are completed, physicians can assist patients by providing a balanced presentation of the known risks and potential but unproven benefits of detection and treatment options and incorporating patient preferences into health care decisions.