Ulf-Håkan Stenman

National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers

BACKGROUND Updated National Academy of Clinical Biochemistry (NACB) Laboratory Medicine Practice Guidelines for the use of tumor markers in the clinic have been developed. METHODS Published reports relevant to use of tumor markers for 5 cancer sites--testicular, prostate, colorectal, breast, and ovarian--were critically reviewed. RESULTS For testicular cancer, alpha-fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase are recommended for diagnosis/case finding, staging, prognosis determination, recurrence detection, and therapy monitoring. alpha-Fetoprotein is also recommended for differential diagnosis of nonseminomatous and seminomatous germ cell tumors. Prostate-specific antigen (PSA) is not recommended for prostate cancer screening, but may be used for detecting disease recurrence and monitoring therapy. Free PSA measurement data are useful for distinguishing malignant from benign prostatic disease when total PSA is <10 microg/L. In colorectal cancer, carcinoembryonic antigen is recommended (with some caveats) for prognosis determination, postoperative surveillance, and therapy monitoring in advanced disease. Fecal occult blood testing may be used for screening asymptomatic adults 50 years or older. For breast cancer, estrogen and progesterone receptors are mandatory for predicting response to hormone therapy, human epidermal growth factor receptor-2 measurement is mandatory for predicting response to trastuzumab, and urokinase plasminogen activator/plasminogen activator inhibitor 1 may be used for determining prognosis in lymph node-negative patients. CA15-3/BR27-29 or carcinoembryonic antigen may be used for therapy monitoring in advanced disease. CA125 is recommended (with transvaginal ultrasound) for early detection of ovarian cancer in women at high risk for this disease. CA125 is also recommended for differential diagnosis of suspicious pelvic masses in postmenopausal women, as well as for detection of recurrence, monitoring of therapy, and determination of prognosis in women with ovarian cancer. CONCLUSIONS Implementation of these recommendations should encourage optimal use of tumor markers.

Prostate Cancer Mortality Reduction by Prostate-Specific Antigen-Based Screening Adjusted for Nonattendance and Contamination in the European Randomised Study of Screening for Prostate Cancer (ERSPC)

BACKGROUND Prostate-specific antigen (PSA) based screening for prostate cancer (PCa) has been shown to reduce prostate specific mortality by 20% in an intention to screen (ITS) analysis in a randomised trial (European Randomised Study of Screening for Prostate Cancer [ERSPC]). This effect may be diluted by nonattendance in men randomised to the screening arm and contamination in men randomised to the control arm. OBJECTIVE To assess the magnitude of the PCa-specific mortality reduction after adjustment for nonattendance and contamination. DESIGN, SETTING, AND PARTICIPANTS We analysed the occurrence of PCa deaths during an average follow-up of 9 yr in 162,243 men 55-69 yr of age randomised in seven participating centres of the ERSPC. Centres were also grouped according to the type of randomisation (ie, before or after informed written consent). INTERVENTION Nonattendance was defined as nonattending the initial screening round in ERSPC. The estimate of contamination was based on PSA use in controls in ERSPC Rotterdam. MEASUREMENTS Relative risks (RRs) with 95% confidence intervals (CIs) were compared between an ITS analysis and analyses adjusting for nonattendance and contamination using a statistical method developed for this purpose. RESULTS AND LIMITATIONS In the ITS analysis, the RR of PCa death in men allocated to the intervention arm relative to the control arm was 0.80 (95% CI, 0.68-0.96). Adjustment for nonattendance resulted in a RR of 0.73 (95% CI, 0.58-0.93), and additional adjustment for contamination using two different estimates led to estimated reductions of 0.69 (95% CI, 0.51-0.92) to 0.71 (95% CI, 0.55-0.93), respectively. Contamination data were obtained through extrapolation of single-centre data. No heterogeneity was found between the groups of centres. CONCLUSIONS PSA screening reduces the risk of dying of PCa by up to 31% in men actually screened. This benefit should be weighed against a degree of overdiagnosis and overtreatment inherent in PCa screening.

A comprehensive nomenclature for serine proteases with homology to tissue kallikreins

Abstract The human kallikrein locus on chromosome 19q13.3–13.4 contains kallikrein 1 – the tissue kallikrein – and 14 related serine proteases. Recent investigations into their function and evolution have indicated that the present nomenclature for these proteins is inadequate or insufficient. Here we present a new nomenclature in which proteins without proven kininogenase activity are denoted kallikrein-related peptidase. Names are also given to the unique rodent proteins that are closely related to kallikrein 1.

High Levels of Circulating Insulin-Like Growth Factor-I Increase Prostate Cancer Risk: A Prospective Study in a Population-Based Nonscreened Cohort

PURPOSE Insulin-like growth factor-I (IGF-I) stimulates proliferation and inhibits apoptosis in prostate cancer cells, and IGF-I has been associated with increased prostate cancer risk in some, but not all, epidemiologic studies. SUBJECTS AND METHODS We extended our previous case-control study nested in the Northern Sweden Health and Disease Cohort, a population-based cohort from a region where little prostate specific antigen (PSA) screening is done. Levels of IGF-I and IGF binding protein-3 (IGFBP-3) were measured in prediagnostic blood samples from a total of 281 men who were subsequently diagnosed with prostate cancer after recruitment (median, 5 years after blood collection) and from 560 matched controls. RESULTS Logistic regression analyses showed increases in prostate cancer risk with increasing plasma peptide levels, up to an odds ratio (OR) for top versus bottom quartile of IGF-I of 1.67 (95% CI, 1.02 to 2.71; Ptrend = .05), which was attenuated after adjustment for IGFBP-3 to an OR of 1.47 (95% CI, 0.81 to 2.64; P (trend) =.32). For men younger than 59 years at recruitment, OR for top versus bottom quartile of IGF-I was 4.12 (95% CI, 1.01 to 16.70; Ptrend = .002), which was significantly stronger than for men older than 59 years (P (interaction) = .006). For men with advanced cancer, OR for top versus bottom quartile of IGF-I was 2.87 (95% CI, 1.01 to 8.12; Ptrend = .10). CONCLUSION Our data add further support for IGF-I as an etiologic factor in prostate cancer and indicate that circulating IGF-I levels measured at a comparatively young age may be most strongly associated with prostate cancer risk.

Hypothermia-treated cardiac arrest patients with good neurological outcome differ early in quantitative variables of EEG suppression and epileptiform activity.

Objective:To evaluate electroencephalogram-derived quantitative variables after out-of-hospital cardiac arrest. Design:Prospective study. Setting:University hospital intensive care unit. Patients:Thirty comatose adult patients resuscitated from a witnessed out-of-hospital ventricular fibrillation cardiac arrest and treated with induced hypothermia (33°C) for 24 hrs. Interventions:None. Measurements and Main Results:Electroencephalography was registered from the arrival at the intensive care unit until the patient was extubated or transferred to the ward, or 5 days had elapsed from cardiac arrest. Burst-suppression ratio, response entropy, state entropy, and wavelet subband entropy were derived. Serum neuron-specific enolase and protein 100B were measured. The Pulsatility Index of Transcranial Doppler Ultrasonography was used to estimate cerebral blood flow velocity. The Glasgow-Pittsburgh Cerebral Performance Categories was used to assess the neurologic outcome during 6 mos after cardiac arrest. Twenty patients had Cerebral Performance Categories of 1 to 2, one patient had a Cerebral Performance Categories of 3, and nine patients had died (Cerebral Performance Categories of 5). Burst-suppression ratio, response entropy, and state entropy already differed between good (Cerebral Performance Categories 1–2) and poor (Cerebral Performance Categories 3–5) outcome groups (p = .011, p = .011, p = .008) during the first 24 hrs after cardiac arrest. Wavelet subband entropy was higher in the good outcome group between 24 and 48 hrs after cardiac arrest (p = .050). All patients with status epilepticus died, and their wavelet subband entropy values were lower (p = .022). Protein 100B was lower in the good outcome group on arrival at ICU (p = .010). After hypothermia treatment, neuron-specific enolase and protein 100B values were lower (p = .002 for both) in the good outcome group. The Pulsatility Index was also lower in the good outcome group (p = .004). Conclusions:Quantitative electroencephalographic variables may be used to differentiate patients with good neurologic outcomes from those with poor outcomes after out-of-hospital cardiac arrest. The predictive values need to be determined in a larger, separate group of patients.

Prostate cancer and PSA among statin users in the Finnish prostate cancer screening trial

Decreased risk of advanced prostate cancer has been reported among men using statins. However, the evidence on overall prostate cancer risk is conflicting. We compared the relative risk between current users and non‐users of statins or other cholesterol‐lowering medications in a population undergoing systematical prostate cancer screening. The study cohort comprised of 23,320 men participating in the screening arm of the Finnish prostate cancer screening trial during 1996–2004. Information on medication use was obtained from a comprehensive national prescription database. Cox proportional hazards regression was used to calculate multivariable adjusted hazard ratios (HRs) for prostate cancer. Serum prostate‐specific antigen (PSA) level was compared between current users and non‐users of cholesterol‐lowering drugs. Compared with medication non‐users, the overall prostate cancer incidence was decreased among statin users [HR 0.75, 95% confidence interval (CI) 0.63–0.89]. The inverse association was dose‐dependent with cumulative amount of statin use, and strongest for low‐grade and early stage tumors. The incidence was nonsignificantly lower also among users of other types of cholesterol‐lowering drugs (HR 0.62, 95% CI 0.28–1.38), but without dose‐dependence. Age‐adjusted median serum PSA tended to be lower among users of cholesterol‐lowering drugs, but the relative risk decrease among statin users was not related to decreased PSA. Overall incidence of prostate cancer was lowered among statin users when bias due to differential PSA testing between medication users and non‐users was eliminated by systematical prostate cancer screening. Cholesterol‐lowering with statins seems beneficial for prostate cancer prevention.

Matrix metalloproteinase (MMP)-9 type IV collagenase/gelatinase implicated in the pathogenesis of Sjogren's syndrome

Type IV collagenases/gelatinases (matrix metalloproteinases MMP-2 and MMP-9) in labial salivary glands (LSG) and saliva in Sjögrens syndrome (SS) and healthy controls were studied. Zymograms and Western blots disclosed that SS saliva contained 92/82 kD MMP-9/type IV collagenase duplex. Specific activity measurement disclosed 53.1+/-9.8 U/mg protein MMP-9 in SS compared to 16.5+/-2.6 U/mg in healthy controls (p=0.01). MMP-2 did not differ between SS and controls. In SS salivary glands, MMP-2 and MMP-9 were also expressed, in addition to stromal fibroblasts and occasional infiltrating neutrophils, respectively, in acinar end piece cells. In addition, an effective proMMP-9 activator, human trypsin-2 (also known as tumor-associated trypsin-2 or TAT-2), was found in acinar end piece cells and in saliva. Interestingly, proteolytically processed MMP-9 was found in saliva (vide supra), and in vivo activated MMP-9 was significantly higher in SS than in controls (p=0.002). LSGs, particularly in SS, were characterized ultrastructurally by areas containing small cytoplasmic vesicles in the basal parts of the epithelial cells associated with areas of disordered and thickened basal lamina. Based on our results, we conclude here that SS saliva contains increased concentrations of MMP-9, which is of glandular origin in part. Pro MMP-9 is to a large extent proteolytically activated. This is probably mediated by the most potent pro MMP-9 activator found in vivo thus far, namely trypsin-2. Therefore, the MMP 9/trypsin-2 cascade may be responsible for the increased remodelling and/or structural destruction of the basement membrane scaffolding in salivary glands in SS. Due to the role of basal lamina as an important molecular sieve and extracellular matrix-cell signal, these pathological changes may contribute to the pathogenesis of the syndrome.

Loss of PTEN is associated with aggressive behavior in ERG positive prostate cancer

Background: The associations of ERG overexpression with clinical behavior and molecular pathways of prostate cancer are incompletely known. We assessed the association of ERG expression with AR, PTEN, SPINK1, Ki-67, and EZH2 expression levels, deletion, and mutations of chromosomal region 3p14 and TP53, and clinicopathologic variables. Methods: The material consisted of 326 prostatectomies, 166 needle biopsies from men treated primarily with endocrine therapy, 177 transurethral resections of castration-resistant prostate cancers (CRPC), and 114 CRPC metastases obtained from 32 men. Immunohistochemistry, FISH, and sequencing was used for the measurements. Results: ERG expression was found in about 45% of all patient cohorts. In a multivariate analysis, ERG expression showed independent value of favorable prognosis (P = 0.019). ERG positivity was significantly associated with loss of PTEN expression in prostatectomy (P = 0.0348), and locally recurrent CRPCs (P = 0.0042). Loss of PTEN expression was associated (P = 0.0085) with shorter progression-free survival in ERG-positive, but not in negative cases. When metastases in each subject were compared, consistent ERG, PTEN, and AR expression as well as TP53 mutations were found in a majority of subjects. Conclusions: A similar frequency of ERG positivity from early to late stage of the disease suggests lack of selection of ERG expression during disease progression. The prognostic significance of PTEN loss solely in ERG-positive cases indicates interaction of these pathways. The finding of consistent genetic alterations in different metastases suggests that the major genetic alterations take place in the primary tumor. Impact: Interaction of PTEN and ERG pathways warrants further studies. Cancer Epidemiol Biomarkers Prev; 22(12); 2333–44. ©2013 AACR.

Lead-time in prostate cancer screening (Finland).

Objective: Lead-time in prostate cancer screening was estimated using data from the Finnish randomized, population-based trial. Methods: Lead-time was defined as the duration of follow-up needed to accrue the same expected number of incident prostate cancer cases in the absence of screening as detected in the initial screening round. Expected numbers were calculated using an age-cohort model. Results: Based on findings among 10,000 men screened in 1996–1997 with 292 screen-detected cancers, lead-time was estimated as approximately 5–7 years, depending on the reference rates used. This corresponds to a mean duration of the detectable preclinical phase (DPCP) of 10–14 years, given that the cancers were detected on average at the midpoint of the DPCP. Conclusions: The findings suggest that a screening interval substantially longer than the 2 years generally used for mammography screening is unlikely to cause a substantial loss of sensitivity. A long screening interval is further justified in order to diminish the extent of overdiagnosis, until mortality effects can be evaluated.

VALIDITY OF THE PROSTATE SPECIFIC ANTIGEN TEST FOR PROSTATE CANCER SCREENING: FOLLOWUP STUDY WITH A BANK OF 21,000 SERA IN FINLAND

PURPOSE We investigate the validity of prostate specific antigen (PSA) as a screening test for prostate cancer. MATERIALS AND METHODS A registry of serum samples drawn from 1968 to 1976 from 21,387 men was linked to the Finnish Cancer Registry. During followup from 1968 to 1991, 104 prostate cancers were identified. A matched case control design with incidence density sampling and nested in the serum sample bank was applied, and PSA was assessed. RESULTS The estimated sensitivity of the test was 44% and specificity 94% at a cutoff of 4.0 microg./l. in the total material. The sensitivity had improved to 86% in patients diagnosed in 5 years after the sample drawing. The test had a better sensitivity (93%) and specificity (96%) in men younger than 65 years at the time of the sample drawing compared to those older. The sensitivity further improved to 100% with a cutoff of 2.5 microg./l. CONCLUSIONS PSA is a valid screening test for prostate cancer, which compares favorably with mammography for breast cancer. However, until an effect on mortality has been shown, routine screening cannot be recommended.