Search

Background: In randomised controlled trials, men with advanced, non-metastatic prostate cancer (PCa) treated with anti-androgen monotherapy (AA) had similar all-cause mortality as men treated with gonadotropin-releasing hormone (GnRH) agonists. Using real-world evidence (i.e., observational data), we aimed to further assess the difference in mortality between these two drug categories. Material and Methods: We emulated a trial using data from Prostate Cancer data Base Sweden 3.0. We specifically focused on men diagnosed in 2006-2012 with high-risk PCa who had no distant metastasis. They either received primary hormonal therapy with AA (n¼2078) or GnRH agonists (n¼4878) who were followed for a median time of 5 years. Risk of death from PCa and other causes was assessed using competing risk analyses and Cox proportional hazards regression analyses, including propensity score matching. Results: The cumulative 5-year PCa mortality was lower for men treated with AA (16% [95% confidence interval, CI, 15-18%]) than men treated with GnRH agonists (22% [95% CI 21-24%]). The 5-year other cause mortality was also lower for men on AA (17% [95% CI 15-19%] compared to men on GnRH agonists (27% [95% CI 25-28%]). In regression analyses, the risk of PCa death was similar, GnRH agonists versus AA (reference), hazard ratio (HR) 1.08 (95% CI 0.95-1.23), but the risk of death from all causes was higher for men on GnRH agonists, HR 1.23 (95% CI 1.13-1.34). Consistent results were seen in the propensity score-matched cohort. Conclusion: Our results indicate that the use of AA as primary hormonal therapy in men with highrisk non-metastatic PCa does not increase PCa-specific mortality compared to GnRH. Using AA instead of GnRH agonists may result in shorter time on/exposure to GnRH-treatment, which may reduce the risk of adverse events associated with this treatment. [ABSTRACT FROM AUTHOR]

Background: Multi-step testing might enhance performance of the prostate cancer diagnostic pipeline. Using PSA >1 ng/ml for first-line risk stratification and the Stockholm 3 Model (S3M) blood-test >10% risk of Gleason Score > 7 prostate cancer to inform biopsy decisions has been suggested. We aimed to determine the effects of changing the PSA cutoff to perform reflex testing with S3M and the subsequent S3M cutoff to recommend prostate biopsy while maintaining the sensitivity to detect Gleason Score ≥ 7 prostate cancer.Methods: We used data from the prospective, population-based, paired, diagnostic Stockholm 3 (STHLM3) study with participants invited by date of birth from the Swedish Population Register during 2012-2014. All participants underwent testing with PSA and S3M (a combination of plasma protein biomarkers [PSA, free PSA, intact PSA, hK2, MSMB, MIC1], genetic polymorphisms, and clinical variables [age, family, history, previous prostate biopsy, prostate exam]). Of 47,688 men in the STHLM3 main study, we used data from 3133 men with S3M >10% and prostate biopsy data. Logistic regression models were used to calculate prostate cancer detection rates and proportion saved biopsies.Results: 44.2%, 62.5% and 67.9% of the participants had PSA <1, <1.5 and <1.7 ng/ml, respectively. Increasing the PSA cut-off for additional work-up from 1 ng/ml to 1.5 ng/ml would thus save 18.3% of the performed tests, 4.9% of the biopsies and 1.3% (10/765) of Gleason Grade ≥ 7 cancers would be un-detected. By lowering the S3M cutoff to recommend biopsy, sensitivity to high-grade prostate cancer can be restored, to the cost of increasing the number of performed biopsies modestly.Conclusion: The sensitivity to detect prostate cancer can be maintained when using different PSA cutoffs to perform additional testing. Biomarker cut-offs have implications on number of tests and prostate biopsies performed. A PSA cutoff of 1.5 ng/ml to perform additional testing such as the S3M test might be considered.Trial Registration: ISRCTN84445406 . [ABSTRACT FROM AUTHOR]

Purpose We compared clinical characteristics and cancer specific mortality in men diagnosed with prostate cancer before vs after age 50 years. Materials and Methods A total of 919 men 35 to 49 years old and 45,098 men 50 to 66 years old who were diagnosed with prostate cancer between 1998 and 2012 were identified in PCBaSe (Prostate Cancer data Base Sweden). Cancer specific mortality was compared among age groups (35 to 49, 50 to 59, 60 to 63 and 64 to 66 years) with and without adjusting for cancer characteristics, comorbidity and education in a multivariable Cox proportional hazards model. Results Clinical cancer characteristics indicated that most nonmetastatic cancer in men younger than 50 years was detected after prostate specific antigen testing. The proportion of nonmetastatic vs metastatic disease at diagnosis was similar in all age groups. A strong association between younger age and poor prognosis was apparent in men in whom metastatic disease was diagnosed before age 50 to 55 years. The crude and adjusted HRs of cancer specific mortality were 1.41 (95% CI 1.12–1.79) and 1.28 (95% CI 1.01–1.62) in men diagnosed before age 50 and at age 50 to 59 years, respectively. In men with nonmetastatic disease crude cancer specific mortality increased with older age but adjusted cancer specific mortality was similar in all age groups. Conclusions Our findings suggest that an aggressive form of metastatic prostate cancer is particularly common in men younger than 50 to 55 years. Genetic studies and trials of intensified systemic treatment are warranted in this patient group. [ABSTRACT FROM AUTHOR]

Objective.The aim of this study was to determine whether educational length affects prostate-specific antigen (PSA) testing and the time to prostate biopsy for men with raised PSA values. Materials and methods.Using register data on all men in Stockholm County in 2013 (n = 1,052,841), the limited-duration point prevalence of PSA testing and time between test and prostate biopsy or repeat testing were analysed. Patterns of follow-up were assessed using Kaplan–Meier product limit estimators and Cox proportional hazard models. Educational length was categorized as short (≤9 years), intermediate (10–12 years) or long (≥13 years). Results.PSA testing increased with educational length in all age groups. Among men aged 50–69 years, 61% with long and 54% with short education had had a PSA test within the preceding 10 years (p < 0.001). In men with PSA 4–10 ng/ml, 40% [95% confidence interval (CI) 38–41] with long and 27% (95% CI 26–29) with short education underwent a prostate biopsy within 12 months. After adjusting for PSA level and age, educational length was still associated with the chance of having a prostate biopsy in men with PSA 4–10 ng/ml (hazard ratio 1.22, 95% CI 1.12–1.31), but not in men with higher PSA values. Conclusion.PSA testing increased with educational length. Men with long education were more likely to have a prostate biopsy after an increased PSA value below 10 ng/ml than men with short education. These differences may contribute to the worse prostate cancer outcomes observed among men with lower socioeconomic status. [ABSTRACT FROM AUTHOR]

Background: The prostate-specific antigen (PSA) test is used to screen for prostate cancer but has a high false-positive rate that translates into unnecessary prostate biopsies and overdiagnosis of low-risk prostate cancers. We aimed to develop and validate a model to identify high-risk prostate cancer (with a Gleason score of at least 7) with better test characteristics than that provided by PSA screening alone.Methods: The Stockholm 3 (STHLM3) study is a prospective, population-based, paired, screen-positive, diagnostic study of men without prostate cancer aged 50-69 years randomly invited by date of birth from the Swedish Population Register kept by the Swedish Tax Agency. Men with prostate cancer at enrolment were excluded from the study. The predefined STHLM3 model (a combination of plasma protein biomarkers [PSA, free PSA, intact PSA, hK2, MSMB, MIC1], genetic polymorphisms [232 SNPs], and clinical variables [age, family, history, previous prostate biopsy, prostate exam]), and PSA concentration were both tested in all participants enrolled. The primary aim was to increase the specificity compared with PSA without decreasing the sensitivity to diagnose high-risk prostate cancer. The primary outcomes were number of detected high-risk cancers (sensitivity) and the number of performed prostate biopsies (specificity). The STHLM3 training cohort was used to train the STHLM3 model, which was prospectively tested in the STHLM3 validation cohort. Logistic regression was used to test for associations between biomarkers and clinical variables and prostate cancer with a Gleason score of at least 7. This study is registered with ISCRTN.com, number ISRCTN84445406.Findings: The STHLM3 model performed significantly better than PSA alone for detection of cancers with a Gleason score of at least 7 (p<0·0001), the area under the curve was 0·56 (95% CI 0·55-0·60) with PSA alone and 0·74 (95% CI 0·72-0·75) with the STHLM3 model. All variables used in the STHLM3 model were significantly associated with prostate cancers with a Gleason score of at least 7 (p<0·05) in a multiple logistic regression model. At the same level of sensitivity as the PSA test using a cutoff of ≥3 ng/mL to diagnose high risk prostate cancer, use of the STHLM3 model could reduce the number of biopsies by 32% (95% CI 24-39) and could avoid 44% (35-54) of benign biopsies.Interpretation: The STHLM3 model could reduce unnecessary biopsies without compromising the ability to diagnose prostate cancer with a Gleason score of at least 7, and could be a step towards personalised risk-based prostate cancer diagnostic programmes.Funding: Stockholm County Council (Stockholms Läns Landsting). [ABSTRACT FROM AUTHOR]

Despite limited scientific support, a repeat prostate-specific antigen (PSA) test before prostate biopsy decisions is common. We analyzed biopsy outcomes in 1686 men from the STHLM3 study with PSA 3-10 ng/mL and two PSA tests taken within eight weeks and before prostate biopsy using percentages and multinomial logistic regression. We found that omitting prostate biopsy for men with PSA values decreasing to PSAs of 3 ng/mL or less would save 16.8% of biopsy procedures, while missing 5.4% of the cancers with Gleason scores (GSs) of 7 or higher. The proportion of cancers with GSs of 6 or lower was independent of the first PSA value, as well as of PSA change. Also, the risk of tumors with GSs of 7 or higher decreased with both decreasing and increasing PSA levels: It was 18.6% (95% confidence interval [CI] = 16.3% to 20.9%) for men with PSA changes of less than 20%, 12.1% (95% CI = 8.0% to 16.2%) for men with PSA levels increasing at least 20%, and 6.6% (95% CI = 3.8% to 9.3%) for men with PSA levels decreasing at least 20%. [ABSTRACT FROM AUTHOR]

Purpose: We investigated hospital readmission frequency during the 90 days after radical prostatectomy and assessed the readmission risk associated with potentially related variables. Materials and Methods: Using the population based, nationwide PCBaSe (Prostate Cancer data Base Sweden) we identified men diagnosed with incident prostate cancer between 2000 and 2011 who underwent radical prostatectomy as primary treatment. We used logistic regression analysis to examine the association of the risk of 90-day postoperative readmission with surgical method, calendar period, tumor risk category, hospital case load and patient characteristics. Results: During 90 postoperative days 2,317 of the 24,122 men (10%) identified were nonelectively readmitted, specifically 10% after retropubic, 9% after robot-assisted and 11% after laparoscopic radical prostatectomy. The range in readmission frequency among hospitals was 0% to 35%. Higher readmission risk was associated with the early calendar period (2009 to 2011 vs 2000 to 2002 OR 0.71, 95% CI 0.61–0.83), greater age (70 or greater vs less than 60 years OR 1.17, 95% CI 1.00–1.36), higher risk category (high vs low OR 1.78, 95% CI 1.57–2.03), high comorbidity (Charlson comorbidity index 3 or greater vs 0 OR 1.77, 95% CI 1.29–2.44) and low hospital surgical volume (150 or greater vs fewer than 30 radical prostatectomies per year OR 0.70, 95% CI 0.60–0.81). Conclusions: Readmission rates after different radical prostatectomy methods were similar, ranging from 9% to 11%, with wide variation among hospitals. Readmission rates can be used as an indicator of perioperative care quality but potential confounders must be adjusted to avoid bias. [Copyright &y& Elsevier]

BACKGROUND: The occurrence of multiple cancers may indicate common etiology; and, although some studies have investigated the risk of second primary cancers after prostate cancer (PCa), there are no studies on cancers before PCa. METHODS: The PCBaSe Sweden database is based on the National Prostate Cancer Register (NPCR), which covers >96% of PCa cases. The authors estimated the prevalence and cumulative incidence of different cancers before and after PCa diagnosis in 72,613 men according to PCa treatment and disease stage in PCBaSe and their matched comparison cohort of men who were free of PCa. RESULTS: In total, 6829 men were diagnosed with another primary cancer before their PCa diagnosis, including 138 men at the time of PCa diagnosis and 5230 men were diagnosed after PCa diagnosis. Cancer of the bladder or colon and nonmelanoma of the skin were the 3 most frequently observed cancers before and after PCa diagnosis. At the time of PCa diagnosis, the prevalence of these 3 cancers was 1.94% for bladder cancer, 1.08% for colon cancer, and 1.08% for nonmelanoma skin cancer, compared with 1.30%, 0.96%, and 1.03%, respectively, for the matched comparison cohort. Five years after PCa diagnosis, the difference in incidence proportion between PCa men and their comparison cohort was 7‰ (95% CI, 5.6‰-8.5‰), 1.3‰ (0‰-2.6‰), and 1.6‰ (0.6‰-2.6‰) for these 3 cancers, respectively. From a uro-oncologic point of view, it is interesting to note that the prevalence of kidney cancer at the time of PCa diagnosis was 0.42% compared with 0.28% for the matched comparison cohort. CONCLUSIONS: Approximately 17% of all PCa occurred in combination with another primary cancer (before or after PCa diagnosis). Detection bias probably explains part of this observation, but further investigations are required to assess possible underlying mechanisms. Cancer 2012. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

Objective. To investigate the effects of prostate-specific antigen (PSA) testing of men without clinical signs of prostate cancer on the incidence of prostate cancer in Sweden. Material and methods. Information on the cause of diagnosis, tumour characteristics and primary treatment for patients diagnosed with prostate cancer between January 1999 and December 2007 was extracted from the National Prostate Cancer Register of Sweden. This register includes data for 95% of Swedish prostate cancer cases. Results. The total age-standardized annual incidence of prostate cancer per 100 000 men increased from 187 in 1999 to 233 in 2004, but decreased thereafter to 196 in 2007. The incidence of asymptomatic cases also peaked in 2004 (at 62 per 100 000 men), but varied six-fold between different counties in that year (16-98 per 100 000 men). Asymptomatic cases ( n = 17 143) constituted 15% of all new cases in 2000 and 30% in 2007. Almost as many cases were diagnosed in stage T1c in men with symptoms, usually from the lower urinary tract. Together these two groups constituted 29% of all new cases in 2000 and 52% in 2007. It was estimated that at least one-third of all Swedish men aged 50-75 years had a PSA test between 2000 and 2007. Conclusions. Even though screening for prostate cancer is not recommended in Sweden, PSA testing of men without clinical signs of prostate cancer is common. The effects on the Swedish incidence of prostate cancer were similar to those reported from the USA. [ABSTRACT FROM AUTHOR]

Autopsy studies suggest that most aging men will develop lesions that, if detected clinically, would be diagnosed as prostate cancer (PCa). Most of these cancers are indolent and remain localized; however, a subset of PCa is aggressive and accounts for more than 27,000 deaths in the United States annually. Identification of factors specifically associated with risk for more aggressive PCa is urgently needed to reduce overdiagnosis and overtreatment of this common disease. To search for such factors, we compared the frequencies of SNPs among PCa patients who were defined as having either more aggressive or less aggressive disease in four populations examined in the ,Genetic Markers of Susceptibility (CGEMS) study performed by the National Cancer Institute. SNP5 showing possible associations with disease severity were further evaluated in an additional three independent study populations from the United States and Sweden. In total, we studied 4,829 and 12,205 patients with more and less aggressive disease, respectively. We found that the frequency of the Yr genotype of SNP rs4054823 at 17p12 was consistently higher among patients with more aggressive compared with less aggressive disease in each of the seven populations studied, with an overall P value of 2.1 × 10-8 under a recessive model, exceeding the conservative genome-wide significance level. The difference in frequency was largest between patients with high-grade, non-organ-confined disease compared with those with low-grade, organ-confined disease. This study demonstrates that inherited variants predisposing to aggressive but not indolent PCa exist in the genome, and suggests that the clinical potential of such variants as potential early markers for risk of aggressive PCa should be evaluated. [ABSTRACT FROM AUTHOR]

Abstract: Objective: This observational cohort study describes the long-term outcome of patients with clinically localized prostate cancer managed with watchful waiting, the prognostic value of tumour ploidy, and the impact of comorbidity. Methods: A total of 119 patients with clinically localized (T1–2) prostate cancer consecutively diagnosed from 1978 to 1982 were prospectively managed by watchful waiting, with treatment given if progression occurred. Results: Median age was 68 yr. Median observation time was 24 yr±6.25 (SD). Of the 112 patients who died, 42 died of prostate cancer. Disease-specific survival rates were 85% (95% CI: 77–93%), 58% (46–70%), and 32% (19–46%) at 10, 15, and 20 yr, respectively. Treatment-free survival rate was 43% (95% CI: 33–54%) at 10 yr. Patients aged 70 yr and over had a statistically significant increased risk of dying from any cause. There was a statistically significant increased risk of dying from prostate cancer for patients with nondiploid tumours. Conclusion: In the present series from the pre-PSA era, watchful waiting yielded a relatively high long-term disease-specific survival rate in patients with well- or moderately differentiated clinically localized prostate cancer, and almost half were not treated 10 yr after diagnosis. Watchful waiting may be an option at least for such patients with a 10- to 15-yr life expectancy. Age of 70 yr or more predicted an increased overall mortality. High comorbidity increased the risk (although not statistically significant) for death from any cause and for death from prostate cancer. Patients with nondiploid tumours were at an increased risk to die from prostate cancer. [Copyright &y& Elsevier]

Substantial gaps exist in the data of the assessment of risk and prognosis that limit our understanding of the complex mechanisms that contribute to the greatest cancer epidemic, prostate cancer, of our time. This report was prepared by an international multidisciplinary committee of the World Health Organization to address contemporary issues of epidemiology and statistical methods in prostate cancer, including a summary of current risk assessment methods and prognostic factors. Emphasis was placed on the relative merits of each of the statistical methods available. We concluded that: An international committee should be created to guide the assessment and validation of molecular biomarkers. The goal is to achieve more precise identification of those who would benefit from treatment. Prostate cancer is a predictable disease despite its biologic heterogeneity. However, the accuracy of predicting it must be improved. We expect that more precise statistical methods will supplant the current staging system. The simplicity and intuitive ease of using the current staging system must be balanced against the serious compromise in accuracy for the individual patient. The most useful new statistical approaches will integrate molecular biomarkers with existing prognostic factors to predict conditional life expectancy (i.e. the expected remaining years of a patient's life) and take into account all-cause mortality. [ABSTRACT FROM AUTHOR]

Presents a guideline for the clinical management of prostatic intraepithelial neoplasia (PIN). Patients eligible for curative treatment of prostate cancer; Features of biopsies needing repeat biopsies; Use of core biopsies for adequate diagnosis of PIN.

An introduction to the journal is presented in which the editor discusses the issue of prostate cancer screening and the article by Hans-Olov Adami "The prostate cancer pseudo-epidemic" contained within the issue.

A response from the authors of the article "Role of Fear in Overdiagnosis and Overtreatment--An Essay" in the October 24, 2014 issue is presented.

Purpose: To investigate the risk of thromboembolic disease (TED) after radiation therapy (RT) with curative intent for prostate cancer (PCa).Patients and Methods: We identified all men who received RT as curative treatment (n=9410) and grouped according to external beam RT (EBRT) or brachytherapy (BT). By comparing with an age- and county-matched comparison cohort of PCa-free men (n=46,826), we investigated risk of TED after RT using Cox proportional hazard regression models. The model was adjusted for tumor characteristics, demographics, comorbidities, PCa treatments, and known risk factors of TED, such as recent surgery and disease progression.Results: Between 2006 and 2013, 6232 men with PCa received EBRT, and 3178 underwent BT. A statistically significant association was found between EBRT and BT and risk of pulmonary embolism in the crude analysis. However, upon adjusting for known TED risk factors these associations disappeared. No significant associations were found between BT or EBRT and deep venous thrombosis.Conclusion: Curative RT for prostate cancer using contemporary methodologies was not associated with an increased risk of TED. [ABSTRACT FROM AUTHOR]

Abstract: Background: Prostate-specific antigen (PSA) testing has increased in several countries. There is incomplete knowledge of PSA testing patterns. Objective: Determine the prevalence of PSA testing and explore patterns of PSA retesting in Stockholm County, Sweden. Design, setting, and participants: A population-based study was performed. Through registry linkages, we collected population information, data on PSA tests, pathology reports, and clinical information. The study population comprised males living in Stockholm County in 2011 (n =1034129), of which 229 872 had a PSA test during the period 2003–2011. Outcome measurements and statistical analysis: We determined limited-duration-point prevalence of PSA testing and performed survival analysis on PSA retesting for men aged 40–89 yr. Results and limitations: The number of PSA tests increased from 54239 in 2003 to 124613 in 2011. During the 9-yr study period, 46%, 68%, and 77% of men without a prior prostate cancer (PCa) diagnosis and aged 50–59 yr, 60–69 yr, and 70–79 yr, respectively, had a PSA test. During 2010 and 2011, 25%, 40%, and 46% of men aged 50–59 yr, 60–69 yr, and 70–79 yr, respectively, had a PSA test. The prevalence of PSA testing increased from 2003 to 2011. The probability of retesting was PSA and age dependent, with a 26-mo cumulative incidence of 0.337 (95% confidence interval, 0.333–0.341) if the first PSA value was <1 ng/ml. The main limitations were (1) that PSA data prior to 2003 were not available and (2) that the study cohort was restricted to men who were alive in 2011. Conclusions: Although screening for PCa is not recommended in Sweden, PSA testing in Stockholm County was high across ages ranging from 40 to 89 yr and increased during the period 2003–2011. The probability of PSA retesting was high, regardless of the original PSA level. These results contrast with current clinical recommendations and raise calls for a change, either through structured PCa testing or more detailed guidelines on PSA testing. [Copyright &y& Elsevier]

Abstract: Background: To date, adverse events of prostate cancer (PCa) treatment have only been studied as a single event, and little is known about the risk of subsequent adverse events. Objective: We assessed the frequency of multiple events (fractures, stroke, heart disease [HD], and thromboembolic disease [TED]) following PCa diagnosis. Design, setting, and participants: PCBaSe Sweden is based on the National Prostate Cancer Register (NPCR) that covers >96% of incident PCa cases in Sweden. Measurements: We evaluated the number of events (fractures, stroke, HD, and TED) leading to hospitalisation recorded in the National Hospital Discharge Registry after PCa diagnosis and conducted multivariate age-adjusted Cox proportional hazards regression to estimate the risk of developing multiple events. Results and limitations: Between 1997 and 2007, 30 642 men received primary endocrine treatment, 26 432 curative treatment, and 19 526 surveillance: 75% had no event during follow-up, 17% had one event, and 9% had more than one event. The incidence of any event was 102 in 1000 person-years. Men who already had experienced an event, particularly HD, before or after the date of PCa diagnosis were more likely to have multiple events afterwards. For example, the hazard ratio of developing a third event for those with two or more events of HD before PCa diagnosis was 1.40 (95% confidence interval, 1.28–1.52) compared with those with no events of HD before PCa diagnosis. Events treated without hospitalisation were not included, so the number of adverse events is possibly underestimated. Conclusions: A third of PCa patients with an adverse event after treatment subsequently experienced another adverse event, but apart from history of HD or stroke before PCa diagnosis, no specific characteristics were found for these men. Thus PCa management needs to take into account the risk of adverse events in all PCa patients, especially those with a history of adverse events before PCa diagnosis. [Copyright &y& Elsevier]

Abstract: Background: More than 1 million prostate biopsies are conducted yearly in the United States. The low specificity of prostate-specific antigen (PSA) results in diagnostic biopsies in men without prostate cancer (PCa). Additional information, such as genetic markers, could be used to avoid unnecessary biopsies. Objective: To determine whether single nucleotide polymorphisms (SNPs) associated with PCa can be used to determine whether biopsy of the prostate is necessary. Design, settings, and participants: The Stockholm-1 cohort (n =5241) consisted of men who underwent a prostate biopsy during 2005 to 2007. PSA levels were retrieved from databases and family histories were obtained using a questionnaire. Thirty-five validated SNPs were analysed and converted into a genetic risk score that was implemented in a risk-prediction model. Results and limitations: When comparing the nongenetic model (based on age, PSA, free-to-total PSA, and family history) with the genetic model and using a fixed number of detected PCa cases, it was found that the genetic model required significantly fewer biopsies than the nongenetic model, with 480 biopsies (22.7%) avoided, at a cost of missing a PCa diagnosis in 3% of patients characterised as having an aggressive disease. However, the overall genetic model does not discriminate between aggressive and nonaggressive cases. Conclusion: Although the genetic model reduced the number of biopsies more than the nongenetic model, the clinical significance of this finding requires further evaluation. [Copyright &y& Elsevier]