Bile CXC Motif Chemokine 10 Levels Correlate With Anti-donor Cytotoxic T Cell Responses After Liver Transplantation

Background

CXC motif chemokine 10 (CXCL10), known as interferon-γ−induced protein 10, is an inflammatory cytokine secreted by various cells in response to interferon-γ. CXCR3, the receptor of CXCL10, is predominantly expressed on activated T, B, natural killer, and dendritic cells, as well as macrophages. CXCR3 promotes chemotaxis upon binding CXCL10. Serum CXCL10 levels have recently attracted attention as a post-transplantation biomarker for graft rejection. However, the correlation between the degree of T cell response to allostimulation and CXCL10 levels remains unclear. In this study, we investigated the serum and bile CXCL10 levels of patients who underwent living donor liver transplantation (LDLT) and compared them with the T cell responses to allostimulation.

Patients and Methods

Between February 2009 and August 2012, 41 patients underwent LDLT at Hiroshima University Hospital. Serum and bile CXCL10 levels were measured weekly for 4 weeks after surgery, while the T cell responses to allostimulation were evaluated using a mixed lymphocyte reaction with an intracellular carboxyfluorescein diacetate succinimidyl ester−labeling technique that we regularly use to monitor the immune response to anti-donor and anti−third-party stimulation after liver transplantation. The stimulation index (SI) and CD25 expression of the CD4+ and CD8+ T cell subsets in response to allostimulation were then analyzed using flow cytometry.

Results

Serum CXCL10 levels were significantly correlated with the SI values for CD8+ T cells in response to both types of allostimulation. Bile CXCL10 levels were significantly correlated with CD25 expression of CD8+ T cell subsets, especially in response to anti-donor stimulation. Patients with higher bile CXCL10 levels suffered from severe acute cellular rejection that was refractory to steroid pulse.

Conclusion

Measurements of bile CXCL10 levels could predict anti-donor cytotoxic T cell responses in liver transplant recipients.     

Hedgehog signalling in androgen independent prostate cancer

Objectives

Androgen-deprivation therapy effectively shrinks hormone-naïve prostate cancer, both in the prostate and at sites of distant metastasis. However prolonged androgen deprivation generally results in relapse and androgen-independent tumour growth, which is inevitably fatal. The molecular events that enable prostate cancer cells to proliferate in reduced androgen conditions are poorly understood. Here we investigate the role of Hedgehog signalling in androgen-independent prostate cancer (AIPC).

Methods

Activity of the Hedgehog signalling pathway was analysed in cultured prostate cancer cells, and circulating prostate tumour cells were isolated from blood samples of patients with AIPC.

Results

AIPC cells were derived through prolonged culture in reduced androgen conditions, modelling hormone therapy in patients, and expressed increased levels of Hedgehog signalling proteins. Exposure of cultured AIPC cells to cyclopamine, which inhibits Hedgehog signalling, resulted in inhibition of cancer cell growth. The expression of the Hedgehog receptor PTCH and the highly prostate cancer–specific gene DD3^PCA3 was significantly higher in circulating prostate cancer cells isolated from patients with AIPC compared with samples prepared from normal individuals. There was an association between PTCH and DD3^PCA3 expression and the length of androgen-ablation therapy.

Conclusions

Our data are consistent with reports implicating overactivity of Hedgehog signalling in prostate cancer and suggest that Hedgehog signalling contributes to the androgen-independent growth of prostate cancer cells. As systemic anti-Hedgehog medicines are developed, the Hedgehog pathway will become a potential new therapeutic target in advanced prostate cancer.     

The Evolving Role of Oestrogens and Their Receptors in the Development and Progression of Prostate Cancer

Context

Oestrogens were proven effective in the hormonal treatment of advanced prostate cancer (PCa) >60 yr ago and are still used as second-line hormonal therapy. Paradoxically, oestrogens might also be involved in the development and progression of PCa.

Objective

To examine mechanisms of how oestrogens may affect prostate carcinogenesis and tumour progression.

Evidence acquisition

Recent data obtained from animal, experimental, and clinical studies were reviewed.

Evidence synthesis

The human prostate is equipped with a dual system of oestrogen receptors (oestrogen receptor alpha [ERα], oestrogen receptor beta [ERβ]) that undergoes profound remodelling during PCa development and tumour progression. In high-grade prostatic intraepithelial neoplasia (HGPIN), the ERα is upregulated and most likely mediates carcinogenic effects of estradiol as demonstrated in animal models. Preliminary clinical studies with the ERα antagonist toremifene have identified the ERα as a promising target for PCa prevention. The partial loss of the ERβ in HGPIN indicates that the ERβ acts as a tumour suppressor. The ERβ is generally retained in hormone-naïve PCa but is partially lost in castration-resistant disease. The progressive emergence of the ERα and the oestrogen-regulated progesterone receptor (PR) during PCa progression and hormone-refractory disease suggests that these tumours can use oestrogens and progestins for their growth. The TMPRSS2-ERG gene fusion recently reported as a potentially aggressive molecular subtype of PCa is regulated by ER-dependent signalling. TMPRSS2-ERG expression has been found to be increased by ERα agonist (oestrogens) and decreased by ERβ agonists.

Conclusions

Oestrogens and their receptors are implicated in PCa development and tumour progression. There is significant potential for the use of ERα antagonists and ERβ agonists to prevent PCa and delay disease progression. Tumours equipped with the pertinent receptors are potential candidates for this new therapeutic approach.     

Multicenter European External Validation of a Prostate Health Index–based Nomogram for Predicting Prostate Cancer at Extended Biopsy

Background

External validation of a prediction tool is mandatory to assess the tool's accuracy and generalizability within different patient cohorts.

Objective

To externally validate a previously developed Prostate Health Index (PHI)–based nomogram for predicting the presence of prostate cancer (PCa) at biopsy.

Design, setting, and participants

The study population consisted of 883 patients who were scheduled for a prostate biopsy at one of five European tertiary care centers. Total prostate-specific antigen (tPSA), free prostate-specific antigen (fPSA), and [−2]pro–prostate-specific antigen (p2PSA) levels were determined. The fPSA-to-tPSA ratio (%fPSA), p2PSA, and PHI ([p2PSA / fPSA] × √tPSA) were calculated.

Intervention

Extended initial and repeat prostate biopsy.

Outcome measurements and statistical analysis

Logistic regression models were fitted to test the predictors of PCa and to determine their predictive accuracy. A calibration plot was used to evaluate the extent of overestimation or underestimation between nomogram predictions and observed PCa rate. Decision curve analysis (DCA) provided an estimate of the net benefit obtained by using the PHI-based nomogram.

Results and limitations

Of 833 patients, 365 (41.3%) were diagnosed with PCa at extended prostate biopsy. In accuracy analyses, PHI was the most informative predictor of PCa (0.68), outperforming tPSA (0.51) and %fPSA (0.64). The predictive accuracy of the previously developed nomogram was 75.2% (95% confidence interval, 71.4–78.1). Calibration of the nomogram was good in patients at a low to intermediate predicted probability of PCa, while calibration was suboptimal, with a tendency to overestimate the presence of PCa, in high-risk patients. Finally, DCA demonstrated that the use of the PHI-based nomogram resulted in the highest net benefit. The main limitation of the study is the fact that only Caucasian patients were included.

Conclusions

At external validation, the previously developed PHI-based nomogram confirmed its ability to determine the presence of PCa at biopsy. These findings provide further evidence supporting the potential role of the nomogram in the biopsy decision pathway for European men with suspected PCa.

Patient summary

In the current study, we externally validated a Prostate Health Index–based nomogram to predict the presence of prostate cancer (PCa) at biopsy. This tool may help clinicians determine the need for a prostate biopsy in European patients with suspected PCa.     

Sarcosine in Urine after Digital Rectal Examination Fails as a Marker in Prostate Cancer Detection and Identification of Aggressive Tumours

Background

Sarcosine in urine was recently suggested to be a promising tool in prostate cancer (PCa) diagnostics.

Objective

To reevaluate sarcosine as a potential biomarker for early PCa detection and for prediction of tumour aggressiveness.

Design, setting, and participants

Sarcosine was measured in urine samples from 106 PCa patients and 33 patients with no evidence of malignancy (NEM), confirmed by 8–12 core prostate biopsies, after standardised digital rectal examination, as well as from 12 healthy men and women. The results were related to the clinicopathologic data on prostate volume, tumour stage, Gleason score, and prostate specific antigen (PSA).

Measurements

Sarcosine in urine was determined by gas chromatography-mass spectrometry using a commercial amino acid assay and was normalised to urine creatinine. Nonparametric statistical tests and receiver operating characteristics (ROC) analyses were performed to assess the diagnostic performance.

Results and limitations

The median sarcosine-creatinine ratio in urine was 13% lower in PCa than in NEM patients. Sarcosine values were not associated with tumour stage (pT2 vs pT3) or grade (Gleason score <7 vs ≥7). ROC analyses proved that the discrimination between PCa and NEM patients was not improved by sarcosine in comparison with total PSA, but it was significantly worse than the percent free PSA. The higher proportion of PCa than NEM patients can be considered a limitation of this study.

Conclusions

Sarcosine in urine after rectal digital examination cannot be considered as a suitable marker to differentiate between patients with and without PCa.     

Overexpression of ELAV-like protein HuR is associated with increased COX-2 expression in atrophy, high-grade prostatic intraepithelial neoplasia, and incidental prostate cancer in cystoprostatectomies

Background

The human ELAV-like protein HuR regulates the stability of several mRNA targets, including that of cyclooygenase-2 (COX-2). Their expression in prostatic carcinogenesis is uncertain.

Objective

To analyze HuR and COX-2 expression in cystoprostatectomies (CyPs) with incidental prostate cancer and compare their expression with those in radical prostatectomies (RPs) with clinically detected cancer.

Design, setting, and participants

HuR and COX-2 were immunohistochemically evaluated in normal-looking epithelium (NEp), atrophy, high-grade prostatic intraepithelial neoplasia (HGPIN), and prostate carcinoma (PCa) in 20 CyPs and 20 RPs, both types of specimens with pT2a Gleason score 6 PCa.

Measurements

At least 1000 cells were counted in contiguous 400X microscopic fields in each case, separately for NEp, atrophy, HGPIN, and PCa.

Results and limitations

There was an increase in the percentage of secretory cells with cytoplasmic HuR staining from NEp to atrophy, HGPIN, and PCa. The mean percentages in NEp, atrophy, and HGPIN adjacent to PCa were greater than away from cancer, both in the CyP and RPs. There was a trend towards a reduced nuclear HuR expression in atrophy, HGPIN, and PCa, compared to NEp. COX-2 staining was seen in the cytoplasm of the basal and secretory cells. There was a reduction in the mean proportion of positive basal cells and progressive increase in the percentage of positive secretory cells from atrophy to HGPIN and PCa, compared to NEp. Cytoplasmic HuR overexpression was correlated with COX-2 expression. There was no difference in HuR and COX-2 expression between cancers with tumour volume <0.5 ccm or >0.5 ccm.The limitations of this study were the small number of cases investigated and lack of a control group without cancer.

Conclusions

The secretory cells showed shift in HuR staining from nuclear in NEp to cytoplasmic in PCa. This is associated with a parallel shift in COX-2 expression from basal to secretory cells.     

CXCR4 Expression Predicts Patient Outcome and Recurrence Patterns after Hepatic Resection for Colorectal Liver Metastases

Background

The purpose of this study was to determine if the expression of the chemokine receptors, CXCR4 and CCR7, and the chemokine ligand, CXCL12, in completely resected colorectal cancer hepatic metastases are predictive of disease-specific survival, recurrence-free survival and patterns of recurrence.

Methods

Immunohistochemical analysis of CXCR4, CCR7 and CXCL12 expression within resected hepatic metastases was performed and correlated with clinicopathological variables, disease-specific survival, recurrence-free survival and patterns of recurrence.

Results

Seventy-five patients who underwent partial hepatectomy with curative intent were studied. CXCR4 expression (hazard ratio [HR] 3.6, 95% confidence interval [95% CI] 1.4–9.1) and clinical risk score >2 (HR 2.3, 95% CI 1.1–4.7) were independently associated with disease-specific survival by multivariate analysis. The 5-year estimated disease-specific survival rates for positive and negative CXCR4 tumor expression were 44 and 77%, respectively (P = 0.005). CXCR4 expression (HR 2.2, 95% CI 1.2–4.2) and clinical risk score >2 (HR 1.9, 95% CI 1.1–3.4) were independently associated with recurrence-free survival by multivariate analysis. The five year estimated recurrence-free survival rates for positive and negative CXCR4 tumor expression were 20 and 50%, respectively (P = 0.004). Neither CXCL12 nor CCR7 expression in tumors predicted disease-specific survival or recurrence-free survival. Forty-nine patients (65%) developed recurrent disease after initial hepatectomy. Negative CXCR4 tumor expression was associated with favorable recurrence patterns amenable to salvage resection and/or ablation.

Conclusions

Negative CXCR4 expression in resected colorectal cancer hepatic metastases is independently associated with improved disease-specific and recurrence-free survival and favorable patterns of recurrence.

     

Validation of the contemporary epstein criteria for insignificant prostate cancer in European men

Objectives

The Epstein criteria represent the most widely used scheme for prediction of clinically insignificant prostate cancer (PCa). However, they were never validated in European men. We assessed the rate of unfavorable prostate cancer (Gleason 7–10 or non–organ-confined disease) in a cohort of 366 men who fulfilled the Epstein clinically insignificant PCa criteria.

Methods

Between 1996 and 2006, 2580 men underwent radical prostatectomy at a single academic European institution. Of those, 366 fulfilled the contemporary Epstein clinically insignificant PCa criteria. Analyses targeted the rate of pathologically unfavorable prostate cancer, defined as either Gleason sum 7–10 or non–organ-confined disease, or a combination of these characteristics in patients with clinically insignificant PCa.

Results

Gleason 7–10 prostate cancer at radical prostatectomy was found in 88 patients (24%) with clinically insignificant PCa. In addition, 30 (34.1%) of the 88 patients harboured non–organ-confined disease. Consequently, the contemporary Epstein criteria for clinically insignificant PCa were inaccurate in 24% of patients.

Conclusions

The Epstein clinical insignificant PCa criteria may underestimate the true nature of prostate cancer in as many as 24% of European patients. Therefore, caution is advised when treatment decisions are based solely on these criteria.     

Effect of dutasteride on prostate biopsy rates and the diagnosis of prostate cancer in men with lower urinary tract symptoms and enlarged prostates in the Combination of Avodart and Tamsulosin trial

Background

A 23% relative risk reduction (RRR) in prostate cancer (PCa) was shown in men receiving dutasteride in the 4-yr Reduction by Dutasteride of Prostate Cancer Events study, in whom biopsies were protocol dependent.

Objective

Our aim was to explore PCa risk reduction in men with benign prostatic hyperplasia (BPH) from the Combination of Avodart and Tamsulosin (CombAT) study, in which biopsies were undertaken for cause.

Design, setting, and participants

CombAT was a 4-yr randomized double-blind parallel group study in 4844 men ≥50 yr of age with clinically diagnosed moderate to severe BPH, International Prostate Symptom Score ≥12, prostate volume ≥30 ml, and serum prostate-specific antigen (PSA) 1.5–10 ng/ml. Men underwent annual PSA measurement and digital rectal examination (DRE), and prostate biopsies were performed for cause.

Intervention

All patients took tamsulosin 0.4 mg/d, dutasteride 0.5 mg/d, or a combination of both.

Measurements

The primary end point was incidence of PCa. Secondary end points included postbaseline prostate biopsy rates and Gleason score of cancers.

Results and limitations

Dutasteride (alone or in combination with tamsulosin) was associated with a 40% RRR of PCa diagnosis compared with tamsulosin monotherapy (95% confidence interval, 16–57%; p = 0.002) and a 40% reduction in the likelihood of biopsy. There were similar reductions in low- and high-grade Gleason score cancers. The biopsy rate in the groups receiving dutasteride trended toward a higher diagnostic yield (combination: 29%, dutasteride: 28%, tamsulosin: 24%). One limitation was the lack of a standardized approach to PCa diagnosis and grading.

Conclusions

Dutasteride, alone or in combination with tamsulosin, significantly reduced the relative risk of PCa diagnosis in men with BPH undergoing annual DRE and PSA screening. Consistent with the increased usefulness of PSA for PCa detection, men receiving dutasteride had a numerically lower biopsy rate and higher yield of PCa on biopsy.

Trial registration

Clinicaltrials.gov identifier: NCT00090103 (http://www.clinicaltrials.gov/ct2/show/NCT00090103).     

Prospective Study of Diagnostic Accuracy Comparing Prostate Cancer Detection by Transrectal Ultrasound–Guided Biopsy Versus Magnetic Resonance (MR) Imaging with Subsequent MR-guided Biopsy in Men Without Previous Prostate Biopsies

Background

The current diagnosis of prostate cancer (PCa) uses transrectal ultrasound–guided biopsy (TRUSGB). TRUSGB leads to sampling errors causing delayed diagnosis, overdetection of indolent PCa, and misclassification. Advances in multiparametric magnetic resonance imaging (mpMRI) suggest that imaging and selective magnetic resonance (MR)–guided biopsy (MRGB) may be superior to TRUSGB.

Objective

To compare the diagnostic efficacy of the magnetic resonance imaging (MRI) pathway with TRUSGB.

Design, setting, and participants

A total of 223 consecutive biopsy-naive men referred to a urologist with elevated prostate-specific antigen participated in a single-institution, prospective, investigator-blinded, diagnostic study from July 2012 through January 2013.

Intervention

All participants had mpMRI and TRUSGB. Men with equivocal or suspicious lesions on mpMRI also underwent MRGB.

Outcome measurements and statistical analysis

The primary outcome was PCa detection. Secondary outcomes were histopathologic details of biopsy and radical prostatectomy specimens, adverse events, and MRI reader performance. Sensitivity, specificity, negative predictive values (NPVs), and positive predictive values were estimated and basic statistics presented by number (percentage) or median (interquartile range).

Results and limitations

Of 223 men, 142 (63.7%) had PCa. TRUSGB detected 126 cases of PCa in 223 men (56.5%) including 47 (37.3%) classed as low risk. MRGB detected 99 cases of PCa in 142 men (69.7%) with equivocal or suspicious mpMRI, of which 6 (6.1%) were low risk. The MRGB pathway reduced the need for biopsy by 51%, decreased the diagnosis of low-risk PCa by 89.4%, and increased the detection of intermediate/high-risk PCa by 17.7%. The estimated NPVs of TRUSGB and MRGB for intermediate/high-risk disease were 71.9% and 96.9%, respectively. The main limitation is the lack of long follow-up.

Conclusions

We found that mpMRI/MRGB reduces the detection of low-risk PCa and reduces the number of men requiring biopsy while improving the overall rate of detection of intermediate/high-risk PCa.

Patient summary

We compared the results of standard prostate biopsies with a magnetic resonance (MR) image–based targeted biopsy diagnostic pathway in men with elevated prostate-specific antigen. Our results suggest patient benefits of the MR pathway. Follow-up of negative investigations is required.     

High incidence of prostate cancer detected by saturation biopsy after previous negative biopsy series

Objectives

We explored the yield of saturation biopsy and developed a nomogram predicting the probability of prostate cancer (PCa) on the basis of saturation biopsy.

Materials and methods

Between 2001 and 2004, saturation biopsies (average of 24 cores) were performed in 161 men with persistently elevated prostate specific antigen (PSA) level (median, 9 ng/ml). All had at least two previously negative, eight-core biopsy sessions. PCa predictors on saturation biopsy were integrated within multivariate nomograms.

Results

PCa detection was 41% (n = 66 of 161). PSA density and transition zone volume were the most significant predictors of PCa on saturation biopsy. The accuracy of the nomogram with the best performance characteristics was 72%.

Conclusions

Saturation biopsy may be indicated in men with a persistent suspicion of PCa. High-risk individuals can be identified accurately with our nomogram.     

A Calculator for Prostate Cancer Risk 4 Years After an Initially Negative Screen: Findings from ERSPC Rotterdam

Background

Inconclusive test results often occur after prostate-specific antigen (PSA)–based screening for prostate cancer (PCa), leading to uncertainty on whether, how, and when to repeat testing.

Objective

To develop and validate a prediction tool for the risk of PCa 4 yr after an initially negative screen.

Design, setting, and participants

We analyzed data from 15 791 screen-negative men aged 55–70 yr at the initial screening round of the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer.

Outcome measurements and statistical analysis

Follow-up and repeat screening at 4 yr showed either no PCa, low-risk PCa, or potentially high-risk PCa (defined as clinical stage >T2b and/or biopsy Gleason score ≥7 and/or PSA ≥10.0 ng/ml). A multinomial logistic regression analysis included initial screening data on age, PSA, digital rectal examination (DRE), family history, prostate volume, and having had a previous negative biopsy. The 4-yr risk predictions were validated with additional follow-up data up to 8 yr after initial screening.

Results and limitations

Positive family history and, especially, PSA level predicted PCa, whereas a previous negative biopsy or a large prostate volume reduced the likelihood of future PCa. The risk of having PCa 4 yr after an initially negative screen was 3.6% (interquartile range: 1.0–4.7%). Additional 8-yr follow-up data confirmed these predictions. Although data were based on sextant biopsies and a strict protocol-based biopsy indication, we suggest that men with a low predicted 4-yr risk (eg, ≤1.0%) could be rescreened at longer intervals or not at all, depending on competing risks, while men with an elevated 4-yr risk (eg, ≥5%) might benefit from immediate retesting. These findings need to be validated externally.

Conclusions

This 4-yr future risk calculator, based on age, PSA, DRE, family history, prostate volume, and previous biopsy status, may be a promising tool for reducing uncertainty, unnecessary testing, and overdiagnosis of PCa.     

CXCL5 is required for angiogenesis,but not structural adaptation after small bowel resection

Purpose

Intestinal adaptation is the compensatory response to massive small bowel resection (SBR) and characterized by lengthening of villi and deepening of crypts, resulting in increased mucosal surface area. Previous studies have demonstrated increased villus capillary blood vessel density after SBR, suggesting a role for angiogenesis in the development of resection-induced adaptation. Since we have previously shown enhanced expression of the proangiogenic chemokine CXCL5 after SBR, the purpose of this study was to determine the effect of disrupted CXCL5 expression on intestinal adaptation.

Methods

CXCL5 knockout (KO) and C57BL/6 wild type (WT) mice were subjected to either a 50% proximal SBR or sham operation. Ileal tissue was harvested on postoperative day 7. To assess for adaptation, villus height and crypt depth were measured. Submucosal capillary density was measured by CD31 immunohistochemistry.

Results

Both CXCL5-KO and WT mice demonstrated normal structural features of adaptation. Submucosal capillary density increased in the WT but not in the KO mice following SBR.

Conclusion

CXCL5 is required for increased intestinal angiogenesis during resection-induced adaptation. Since adaptive villus growth occurs despite impaired CXCL5 expression and enhanced angiogenesis, this suggests that the growth of new blood vessels is not needed for resection-induced mucosal surface area expansion following massive SBR.     

Eleven-Year Outcome of Patients with Prostate Cancers Diagnosed During Screening After Initial Negative Sextant Biopsies

Background

The appropriate way of biopsying a prostate remains controversial. Is sextant biopsy still adequate with repeat screening?

Objective

Within the European Randomized Study of Screening for Prostate Cancer (ERSPC), lateralized sextant biopsies were applied. In this analysis we use distant end points to study the fate of prostate cancers (PCa) potentially missed by initial biopsies.

Design, setting, and participants

This retrospective study included 19 970 men ages 55–74 identified from the Rotterdam population registry and screened repeatedly for PCa between 1993 and 2005. PCa detected later in men with initially negative biopsies were considered as missed. Rescreening every 4 yr and a complete follow-up of 11 yr allowed an inventory of progressive and deadly disease in these men.

Intervention

Sextant biopsies initially, later lateralized, in screen-positive men.

Measurements

The fate of PCa potentially missed by initial sextant biopsies in terms of progression-free and PCa-specific survival were the main outcome measures. Kaplan-Meier analysis was used to evaluate differences between subgroups.

Results and limitations

In 3056 men with negative biopsies at the first screen, 287 PCa were subsequently detected. Of these 287 cases, 26 developed progressive disease and 7 died of PCa. Poor outcomes were encountered mainly in 20 interval cases. The seven PCa deaths in men with initially negative biopsies amounted to only 0.03% compared to the 0.35% PCa death rate in the whole population of 19 970 men. Limitations include the retrospective character of this analysis.

Conclusions

The number of potentially missed cancers with a poor outcome in terms of progression-free survival and deaths from PCa is very low. Despite some limitations, our data show that lateralized sextant biopsy is not obsolete if repeated screening is applied.     

Age-Specific Risk of Incident Prostate Cancer and Risk of Death from Prostate Cancer Defined by the Number of Affected Family Members

Background

The thorough assessment of familial prostate cancer (PCa) risk is as important as ever to provide a basis for clinical counselling and screening recommendations.

Objective

Our aim was to determine the age-specific risks of PCa and the risk of death from PCa according to the number and the age of affected first-degree relatives.

Design, setting, and participants

The nationwide Swedish Family-Cancer Database includes a record of >11.8 million individuals and their cancers from 1958 to 2006. All men from the database with identified parents (>3.9 million individuals) were followed between 1961 and 2006. The study included 26 651 PCa patients, of whom 5623 were familial.

Measurements

The age-specific hazard ratios (HRs) of PCa and the HRs of death from PCa were calculated according to the number and age of affected fathers and brothers.

Results and limitations

The HRs of PCa diagnosis increased with the number of affected relatives and decreased with increasing age. The highest HRs were observed for men <65 yr of age with three affected brothers (HR: approximately 23) and the lowest for men between 65 and 74 yr of age with an affected father (HR: approximately 1.8). The HRs increased with decreasing paternal or fraternal diagnostic age. The pattern of the risk of death from familial PCa was similar to the incidence data.

Conclusions

The present results should guide clinical counselling and demonstrate the vast increases in risk when multiple first-degree relatives are affected.     

Obesity and Prostate Cancer: Weighing the Evidence

Context

Obesity and prostate cancer (PCa) affect substantial proportions of Western society. Mounting evidence, both epidemiologic and mechanistic, for an association between the two is of public health interest. An improved understanding of the role of this modifiable risk factor in PCa etiology is imperative to optimize screening, treatment, and prevention.

Objective

To consolidate and evaluate the evidence for an epidemiologic link between obesity and PCa, in addition to examining the proposed underlying molecular mechanisms.

Evidence acquisition

A PubMed search for relevant articles published between 1991 and July 2012 was performed by combining the following terms: obesity, BMI, body mass index and prostate cancer risk, prostate cancer incidence, prostate cancer mortality, radical prostatectomy, androgen-deprivation therapy, external-beam radiation, brachytherapy, prostate cancer and quality of life, prostate cancer and active surveillance, in addition to obesity, BMI, body mass index and prostate cancer and insulin, insulin-like growth factor, androgen, estradiol, leptin, adiponectin, and IL-6. Articles were selected based on content, date of publication, and relevancy, and their references were also searched for relevant articles.

Evidence synthesis

Increasing evidence suggests obesity is associated with elevated incidence of aggressive PCa, increased risk of biochemical failure following radical prostatectomy and external-beam radiotherapy, higher frequency of complications following androgen-deprivation therapy, and increased PCa-specific mortality, although perhaps a lower overall PCa incidence. These results may in part relate to difficulties in detecting and treating obese men. However, multiple molecular mechanisms could explain these associations as well. Weight loss slows PCa in animal models but has yet to be fully tested in human trials.

Conclusions

Obesity appears to be linked with aggressive PCa. We suggest clinical tips to better diagnose and treat obese men with PCa. Whether reversing obesity slows PCa growth is currently unknown, although it is an active area of research.