Radical prostatectomy or watchful waiting in early prostate cancer.

BACKGROUND: Radical prostatectomy reduces mortality among men with localized prostate cancer; however, important questions regarding long-term benefit remain. METHODS: Between 1989 and 1999, we randomly assigned 695 men with early prostate cancer to watchful waiting or radical prostatectomy and followed them through the end of 2012. The primary end points in the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) were death from any cause, death from prostate cancer, and the risk of metastases. Secondary end points included the initiation of androgen-deprivation therapy. RESULTS: During 23.2 years of follow-up, 200 of 347 men in the surgery group and 247 of the 348 men in the watchful-waiting group died. Of the deaths, 63 in the surgery group and 99 in the watchful-waiting group were due to prostate cancer; the relative risk was 0.56 (95% confidence interval [CI], 0.41 to 0.77; P=0.001), and the absolute difference was 11.0 percentage points (95% CI, 4.5 to 17.5). The number needed to treat to prevent one death was 8. One man died after surgery in the radical-prostatectomy group. Androgen-deprivation therapy was used in fewer patients who underwent prostatectomy (a difference of 25.0 percentage points; 95% CI, 17.7 to 32.3). The benefit of surgery with respect to death from prostate cancer was largest in men younger than 65 years of age (relative risk, 0.45) and in those with intermediate-risk prostate cancer (relative risk, 0.38). However, radical prostatectomy was associated with a reduced risk of metastases among older men (relative risk, 0.68; P=0.04). CONCLUSIONS: Extended follow-up confirmed a substantial reduction in mortality after radical prostatectomy; the number needed to treat to prevent one death continued to decrease when the treatment was modified according to age at diagnosis and tumor risk. A large proportion of long-term survivors in the watchful-waiting group have not required any palliative treatment. (Funded by the Swedish Cancer Society and others.).

Case-control estimation of the impact of oncolytic adenovirus on the survival of patients with refractory solid tumors.

Oncolytic immunotherapy with cytokine armed replication competent viruses is an emerging approach in cancer treatment. In a recent randomized trial, an increase in response rate was seen but the effect on overall survival is not known with any virus. To facilitate randomized trials, we performed a case-control study assessing the survival of 270 patients treated in an Advanced Therapy Access Program (ATAP), in comparison to matched concurrent controls from the same hospital. The overall survival of all virus treated patients was not increased over controls. However, when analysis was restricted to GMCSF-sensitive tumor types treated with GMSCF-coding viruses, a significant improvement in median survival was present (from 170 to 208 days, P = 0.0012, N = 148). An even larger difference was seen when analysis was restricted to good performance score patients (193 versus 292 days, P = 0.034, N = 90). The survival of ovarian cancer patients was especially promising as median survival nearly quadrupled (P = 0.0003, N = 37). These preliminary data lend support to initiation of randomized clinical trials with GMCSF-coding oncolytic adenoviruses.

Radical prostatectomy versus watchful waiting in early prostate cancer.

BACKGROUND: In 2008, we reported that radical prostatectomy, as compared with watchful waiting, reduces the rate of death from prostate cancer. After an additional 3 years of follow-up, we now report estimated 15-year results. METHODS: From October 1989 through February 1999, we randomly assigned 695 men with early prostate cancer to watchful waiting or radical prostatectomy. Follow-up was complete through December 2009, with histopathological review of biopsy and radical-prostatectomy specimens and blinded evaluation of causes of death. Relative risks, with 95% confidence intervals, were estimated with the use of a Cox proportional-hazards model. RESULTS: During a median of 12.8 years, 166 of the 347 men in the radical-prostatectomy group and 201 of the 348 in the watchful-waiting group died (P=0.007). In the case of 55 men assigned to surgery and 81 men assigned to watchful waiting, death was due to prostate cancer. This yielded a cumulative incidence of death from prostate cancer at 15 years of 14.6% and 20.7%, respectively (a difference of 6.1 percentage points; 95% confidence interval [CI], 0.2 to 12.0), and a relative risk with surgery of 0.62 (95% CI, 0.44 to 0.87; P=0.01). The survival benefit was similar before and after 9 years of follow-up, was observed also among men with low-risk prostate cancer, and was confined to men younger than 65 years of age. The number needed to treat to avert one death was 15 overall and 7 for men younger than 65 years of age. Among men who underwent radical prostatectomy, those with extracapsular tumor growth had a risk of death from prostate cancer that was 7 times that of men without extracapsular tumor growth (relative risk, 6.9; 95% CI, 2.6 to 18.4). CONCLUSIONS: Radical prostatectomy was associated with a reduction in the rate of death from prostate cancer. Men with extracapsular tumor growth may benefit from adjuvant local or systemic treatment. (Funded by the Swedish Cancer Society and the National Institutes of Health.).

Prostate cancer risk variants are not associated with disease progression.

BACKGROUND: Currently used prognostic markers are limited in their ability to accurately predict disease progression among patients with localized prostate cancer. We examined 23 reported prostate cancer susceptibility variants for association with disease progression. METHODS: Disease progression was explored among 4,673 Swedish patients treated for clinically localized prostate cancer between 1997 and 2002. Prostate cancer progression was defined according to primary treatment as a composed event reflecting termination of deferred treatment, biochemical recurrence, local progression, or presence of distant metastasis. Association between single variants, and all variants combined, were performed in Cox regression analysis assuming both log-additive and co-dominant genetic models. RESULTS: Three of the 23 genetic variants explored were nominally associated with prostate cancer progression; rs9364554 (P = 0.041) on chromosome 6q25 and rs10896449 (P = 0.029) on chromosome 11q13 among patients treated with curative intent; and rs4054823 (P = 0.008) on chromosome 17p12 among patients on surveillance. However, none of these associations remained statistically significant after correction for multiple testing. The combined effect of all susceptibility variants was not associated with prostate cancer progression neither among patients receiving treatment with curative intent (P = 0.14) nor among patients on surveillance (P = 0.92). CONCLUSIONS: We observed no evidence for an association between any of 23 established prostate cancer genetic risk variants and disease progression. Accumulating evidence suggests separate genetic components for initiation and progression of prostate cancer. Future studies systematically searching for genetic risk variants associated with prostate cancer progression and prognosis are warranted.

LifeGene--a large prospective population-based study of global relevance.

Studying gene-environment interactions requires that the amount and quality of the lifestyle data is comparable to what is available for the corresponding genomic data. Sweden has several crucial prerequisites for comprehensive longitudinal biomedical research, such as the personal identity number, the universally available national health care system, continuously updated population and health registries and a scientifically motivated population. LifeGene builds on these strengths to bridge the gap between basic research and clinical applications with particular attention to populations, through a unique design in a research-friendly setting. LifeGene is designed both as a prospective cohort study and an infrastructure with repeated contacts of study participants approximately every 5 years. Index persons aged 18-45 years old will be recruited and invited to include their household members (partner and any children). A comprehensive questionnaire addressing cutting-edge research questions will be administered through the web with short follow-ups annually. Biosamples and physical measurements will also be collected at baseline, and re-administered every 5 years thereafter. Event-based sampling will be a key feature of LifeGene. The household-based design will give the opportunity to involve young couples prior to and during pregnancy, allowing for the first study of children born into cohort with complete pre-and perinatal data from both the mother and father. Questions and sampling schemes will be tailored to the participants' age and life events. The target of LifeGene is to enroll 500,000 Swedes and follow them longitudinally for at least 20 years.

Prospective study of human papillomavirus and risk of cervical adenocarcinoma.

Human papillomaviruses (HPV) are established as a major cause of cervical carcinoma. However, causality inference is dependent on prospective evidence showing that exposure predicts risk for future disease. Such evidence is available for squamous cell carcinoma, but not for cervical adenocarcinoma. We followed a population-based cohort of 994,120 women who participated in cytological screening in Sweden for a median of 6.7 years. Baseline smears from women who developed adenocarcinoma during follow-up (118 women with in situ disease and 164 with invasive disease) and their individually matched controls (1,434 smears) were analyzed for HPV using PCR. Conditional logistic regression was used to estimate odds ratios (OR) of future adenocarcinoma with 95% confidence intervals (CI). Being positive for HPV 16 in the first cytologically normal smear was associated with increased risks for both future adenocarcinoma in situ (OR: 11.0, 95% CI: 2.6-46.8) and invasive adenocarcinoma (OR: 16.0, 95% CI: 3.8-66.7), compared to being negative for HPV 16. Similarly, an HPV 18 positive smear was associated with increased risks for adenocarcinoma in situ (OR: 26.0, 95% CI: 3.5-192) and invasive adenocarcinoma (OR: 28.0, 95% CI: 3.8-206), compared to an HPV 18 negative smear. Being positive for HPV 16/18 in 2 subsequent smears was associated with an infinite risk of both in situ and invasive adenocarcinoma. In conclusion, infections with HPV 16 and 18 are detectable up to at least 14 years before diagnosis of cervical adenocarcinoma. Our data provide prospective evidence that the association of HPV 16/18 with cervical adenocarcinoma is strong and causal.

Testing association in the presence of linkage using the GRE and multiple markers.

It has recently been shown that testing for association in the presence of linkage using a score test based on a gamma random effects (GRE) model is substantially more powerful than using the Family-Based Association Test. A reason for the increased power lies in better specification of the within family correlation structure, induced by linkage. The GRE, as presented in (Jonasdottir et al. 2007 Genet Epidemiol. 31:528-540), only considers one marker at a time and does not readily handle missing parental information. Here we extend the GRE to incorporate information from more than one marker. This extension leads to a haplotype GRE test and also to efficient handling of missing data on parental genotypes. We show that the haplotype GRE, the H-GRE, is substantially more powerful than the haplotype FBAT, the Haplotype-Based-Association Test. We demonstrate the usefulness of the extended GRE, by reanalyzing the collaborative study on the genetics of alcoholism data, allowing for missing parental information.

Sensitivity analysis for principal stratum direct effects, with an application to a study of physical activity and coronary heart disease.

SUMMARY: In many studies, the aim is to learn about the direct exposure effect, that is, the effect not mediated through an intermediate variable. For example, in circulation disease studies it may be of interest to assess whether a suitable level of physical activity can prevent disease, even if it fails to prevent obesity. It is well known that stratification on the intermediate may introduce a so-called posttreatment selection bias. To handle this problem, we use the framework of principal stratification (Frangakis and Rubin, 2002, Biometrics 58, 21-29) to define a causally relevant estimand--the principal stratum direct effect (PSDE). The PSDE is not identified in our setting. We propose a method of sensitivity analysis that yields a range of plausible values for the causal estimand. We compare our work to similar methods proposed in the literature for handling the related problem of "truncation by death."

Radical prostatectomy versus watchful waiting in early prostate cancer.

BACKGROUND: In 2002, we reported the initial results of a trial comparing radical prostatectomy with watchful waiting in the management of early prostate cancer. After three more years of follow-up, we report estimated 10-year results. METHODS: From October 1989 through February 1999, 695 men with early prostate cancer (mean age, 64.7 years) were randomly assigned to radical prostatectomy (347 men) or watchful waiting (348 men). The follow-up was complete through 2003, with blinded evaluation of the causes of death. The primary end point was death due to prostate cancer; the secondary end points were death from any cause, metastasis, and local progression. RESULTS: During a median of 8.2 years of follow-up, 83 men in the surgery group and 106 men in the watchful-waiting group died (P=0.04). In 30 of the 347 men assigned to surgery (8.6 percent) and 50 of the 348 men assigned to watchful waiting (14.4 percent), death was due to prostate cancer. The difference in the cumulative incidence of death due to prostate cancer increased from 2.0 percentage points after 5 years to 5.3 percentage points after 10 years, for a relative risk of 0.56 (95 percent confidence interval, 0.36 to 0.88; P=0.01 by Gray's test). For distant metastasis, the corresponding increase was from 1.7 to 10.2 percentage points, for a relative risk in the surgery group of 0.60 (95 percent confidence interval, 0.42 to 0.86; P=0.004 by Gray's test), and for local progression, the increase was from 19.1 to 25.1 percentage points, for a relative risk of 0.33 (95 percent confidence interval, 0.25 to 0.44; P<0.001 by Gray's test). CONCLUSIONS: Radical prostatectomy reduces disease-specific mortality, overall mortality, and the risks of metastasis and local progression. The absolute reduction in the risk of death after 10 years is small, but the reductions in the risks of metastasis and local tumor progression are substantial.

A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer.

BACKGROUND: Radical prostatectomy is widely used in the treatment of early prostate cancer. The possible survival benefit of this treatment, however, is unclear. We conducted a randomized trial to address this question. METHODS: From October 1989 through February 1999, 695 men with newly diagnosed prostate cancer in International Union against Cancer clinical stage T1b, T1c, or T2 were randomly assigned to watchful waiting or radical prostatectomy. We achieved complete follow-up through the year 2000 with blinded evaluation of causes of death. The primary end point was death due to prostate cancer, and the secondary end points were overall mortality, metastasis-free survival, and local progression. RESULTS: During a median of 6.2 years of follow-up, 62 men in the watchful-waiting group and 53 in the radical-prostatectomy group died (P=0.31). Death due to prostate cancer occurred in 31 of 348 of those assigned to watchful waiting (8.9 percent) and in 16 of 347 of those assigned to radical prostatectomy (4.6 percent) (relative hazard, 0.50; 95 percent confidence interval, 0.27 to 0.91; P=0.02). Death due to other causes occurred in 31 of 348 men in the watchful-waiting group (8.9 percent) and in 37 of 347 men in the radical-prostatectomy group (10.6 percent). The men assigned to surgery had a lower relative risk of distant metastases than the men assigned to watchful waiting (relative hazard, 0.63; 95 percent confidence interval, 0.41 to 0.96). CONCLUSIONS: In this randomized trial, radical prostatectomy significantly reduced disease-specific mortality, but there was no significant difference between surgery and watchful waiting in terms of overall survival.

E-Science technologies in a workflow for personalized medicine using cancer screening as a case study.

OBJECTIVE: We provide an e-Science perspective on the workflow from risk factor discovery and classification of disease to evaluation of personalized intervention programs. As case studies, we use personalized prostate and breast cancer screenings. MATERIALS AND METHODS: We describe an e-Science initiative in Sweden, e-Science for Cancer Prevention and Control (eCPC), which supports biomarker discovery and offers decision support for personalized intervention strategies. The generic eCPC contribution is a workflow with 4 nodes applied iteratively, and the concept of e-Science signifies systematic use of tools from the mathematical, statistical, data, and computer sciences. RESULTS: The eCPC workflow is illustrated through 2 case studies. For prostate cancer, an in-house personalized screening tool, the Stockholm-3 model (S3M), is presented as an alternative to prostate-specific antigen testing alone. S3M is evaluated in a trial setting and plans for rollout in the population are discussed. For breast cancer, new biomarkers based on breast density and molecular profiles are developed and the US multicenter Women Informed to Screen Depending on Measures (WISDOM) trial is referred to for evaluation. While current eCPC data management uses a traditional data warehouse model, we discuss eCPC-developed features of a coherent data integration platform. DISCUSSION AND CONCLUSION: E-Science tools are a key part of an evidence-based process for personalized medicine. This paper provides a structured workflow from data and models to evaluation of new personalized intervention strategies. The importance of multidisciplinary collaboration is emphasized. Importantly, the generic concepts of the suggested eCPC workflow are transferrable to other disease domains, although each disease will require tailored solutions.

Molecular Differences between Screen-Detected and Interval Breast Cancers Are Largely Explained by PAM50 Subtypes.

Purpose: Interval breast cancer is of clinical interest, as it exhibits an aggressive phenotype and evades detection by screening mammography. A comprehensive picture of somatic changes that drive tumors to become symptomatic in the screening interval can improve understanding of the biology underlying these aggressive tumors.Experimental Design: Initiated in April 2013, Clinical Sequencing of Cancer in Sweden (Clinseq) is a scientific and clinical platform for the genomic profiling of cancer. The breast cancer pilot study consisted of women diagnosed with breast cancer between 2001 and 2012 in the Stockholm/Gotland regions. A subset of 307 breast tumors was successfully sequenced, of which 113 were screen-detected and 60 were interval cancers. We applied targeted deep sequencing of cancer-related genes; low-pass, whole-genome sequencing; and RNA sequencing technology to characterize somatic differences in the genomic and transcriptomic architecture by interval cancer status. Mammographic density and PAM50 molecular subtypes were considered.Results: In the univariate analyses, TP53, PPP1R3A, and KMT2B were significantly more frequently mutated in interval cancers than in screen-detected cancers. Acquired somatic copy number aberrations with a frequency difference of at least 15% between the two groups included gains in 17q23-q25.3 and losses in 16q24.2. Gene expression analysis identified 447 significantly differentially expressed genes, of which 120 were replicated in an independent microarray dataset. After adjusting for PAM50, most differences were no longer significant.Conclusions: Molecular differences by interval cancer status were observed, but they were largely explained by PAM50 subtypes. This work offers new insights into the biological differences between the two tumor groups. Clin Cancer Res; 23(10); 2584-92. ©2016 AACR.

Comprehensive analysis of the ATM, CHEK2 and ERBB2 genes in relation to breast tumour characteristics and survival: a population-based case-control and follow-up study.

BACKGROUND: Mutations in the ataxia-telangiectasia mutated (ATM) and checkpoint kinase 2 (CHEK2) genes and amplification of the v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ERBB2) gene have been suggested to have an important role in breast cancer aetiology. However, whether common variation in these genes has a role in the development of breast cancer or breast cancer survival in humans is still not clear. METHODS: We performed a comprehensive haplotype analysis of the ATM, CHEK2 and ERBB2 genes in a Swedish population-based study, which included 1,579 breast cancer cases and 1,516 controls. We followed the cases for 8.5 years, on average, and retrieved information on the date and cause of death during that period from the nationwide Swedish causes of death registry. We selected seven haplotype-tagging SNPs (tagSNPs) in the ATM gene, six tagSNPs in the CHEK2 gene and seven tagSNPs in the ERBB2 gene that predicted both haplotypic and single locus variations in the respective genes with R2 values > or = 0.8. These tagSNPs were genotyped in the complete set of cases and controls. We computed expected haplotype dosages of the tagSNP haplotypes and included the dosages as explanatory variables in Cox proportional hazards or logistic regression models. RESULTS: We found no association between any genetic variation in the ATM, CHEK2 or ERBB2 genes and breast cancer survival or the risk of developing tumours with certain characteristics. CONCLUSION: Our results indicate that common variants in the ATM, CHEK2 or ERBB2 genes are not involved in modifying breast cancer survival or the risk of tumour-characteristic-defined breast cancer.

Linkage disequilibrium mapping of CHEK2: common variation and breast cancer risk.

BACKGROUND: Checkpoint kinase 2 (CHEK2) averts cancer development by promoting cell cycle arrest and activating DNA repair in genetically damaged cells. Previous investigation has established a role for the CHEK2 gene in breast cancer aetiology, but studies have largely been limited to the rare 1100delC mutation. Whether common polymorphisms in this gene influence breast cancer risk remains unknown. In this study, we aimed to assess the importance of common CHEK2 variants on population risk for breast cancer by capturing the majority of diversity in the gene using haplotype tagging single nucleotide polymorphisms (tagSNPs). METHODS AND FINDINGS: We analyzed 14 common SNPs spanning 52 kilobases (kb) of the CHEK2 gene in 92 Swedish women. Coverage evaluation indicated that these typed SNPs would efficiently convey association signal also from untyped SNPs in the same region. Six of the 14 SNPs predicted well both the haplotypic and single SNP variations within CHEK2. We genotyped these six tagSNPs in 1,577 postmenopausal breast cancer cases and 1,513 population controls, but found no convincing association between any common CHEK2 haplotype and breast cancer risk. The 1100delC mutation was rare in our Swedish population--0.7% in cases and 0.4% in controls--with a corresponding odds ratio for carriers versus noncarriers of 2.26 (95% confidence interval, 0.99-5.15). Estimates of the population frequency and the odds ratio of 1100delC indicate that our sample is representative of a Northern European population. CONCLUSIONS: Notwithstanding the involvement of the CHEK2 gene in breast cancer aetiology, we show that common polymorphisms do not influence postmenopausal breast cancer risk.

Synergy between cigarette smoking and human papillomavirus type 16 in cervical cancer in situ development.

BACKGROUND: A majority of studies have implicated the involvement of cigarette smoking in cervical cancer development, although its mechanism of action remains unclear. We conducted a large population-based case-control study to address the potential interaction between smoking and human papillomavirus type 16 (HPV-16) in development of cervical cancer in situ (CIS). METHODS: Information on risk factors for CIS was collected via interview, and archival cervical smears were tested for HPV-16 DNA presence in cases (n = 375) and controls (n = 363). Adjusted odds ratios (OR) for the effects of smoking, HPV-16 presence/absence, and load at first smear (taken, on average, 9 years before diagnosis) were calculated. RESULTS: The risk for CIS among current smokers who were HPV-16 positive at time of first smear was >14-fold [adjusted OR, 14.4; confidence interval (95% CI), 5.6-36.8] compared with HPV-16-negative current smokers. In contrast, the risk for CIS among HPV-16-positive nonsmokers was only 6-fold (adjusted OR, 5.6; 95% CI, 2.7-11.5), compared with HPV-16-negative nonsmokers. HPV-16-positive smokers with high viral load at time of first smear exhibited a high risk for CIS (adjusted OR, 27.0; 95% CI, 6.5-114.2) compared with HPV-16-negative smokers. Within nonsmokers, however, high HPV-16 load contributed only a 6-fold increased risk compared with HPV-16-negative nonsmokers (adjusted OR, 5.9; 95% CI, 2.4-14.6). Interaction was observed (P = 0.03) between duration of smoking and HPV-16 presence in CIS development. CONCLUSION: Results suggest a synergistic effect between smoking and both HPV-16 status and HPV-16 viral load, which may occur almost a decade before CIS detection.

Variation in DNA repair genes ERCC2, XRCC1, and XRCC3 and risk of follicular lymphoma.

The reasons for the positive association between skin cancer and non-Hodgkin's lymphoma are not known but may be due to common susceptibility involving suboptimal DNA repair. Therefore, we investigated selected polymorphisms and haplotypes in three DNA repair genes, previously associated with skin cancer and DNA repair capacity, in risk of follicular lymphoma, including possible gene interaction with cigarette smoking and sun exposure. We genotyped 19 single nucleotide polymorphisms (SNP) in the ERCC2, XRCC1, and XRCC3 genes in 430 follicular lymphoma patients and 605 controls within a population-based case-control study in Denmark and Sweden. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression and haplotype associations were assessed with a global score test. We observed no associations between variation in the ERCC2 and XRCC1 genes and follicular lymphoma risk. In XRCC3, increased risk of follicular lymphoma was suggested for rare homozygotes of three SNPs [Rs3212024: OR, 1.8 (95% CI, 1.1-2.8); Rs3212038: OR, 1.5 (95% CI, 1.0-2.4); Rs3212090: OR, 1.5 (95% CI, 1.0-2.5)]. These results were strengthened in current cigarette smokers. However, evidence of differences in XRCC3 haplotype distributions between follicular lymphoma cases and controls was weak, both overall and in current smokers. We conclude that polymorphic variation in the XRCC3 gene, but not in ERCC2 or XRCC1, may be of importance for susceptibility to follicular lymphoma, perhaps primarily in current smokers. The link between skin cancer and follicular lymphoma is unlikely to be mediated through common variation in the studied DNA repair gene polymorphisms.

Early biochemical outcomes following permanent interstitial brachytherapy as monotherapy in 1050 patients with clinical T1-T2 prostate cancer.

BACKGROUND AND PURPOSE: Five European centres (France, Finland, Italy, Spain and the UK) have pooled data to generate a large patient series involving 1175 patients treated with prostate brachytherapy. This paper reports preliminary data on PSA outcome up to 4 years. PATIENTS AND METHODS: Out of 1175 in the database, 1050 patients with localised prostate cancer who had received transperineal seed implantation as monotherapy between May 1998 and August 2003 were stage T1-T2. A total of 668 (63.6%) patients met the low-risk group definition, 297 (28.3%) as intermediate-risk definition and 66 (6.3%) the high-risk group definition. The majority of patients were Gleason score 6 or less (n=951) and disease stage was T1c in 557 patients. RESULTS: Of the 1050 patients, PSA data up to 4 years were available for 210 patients, while 364 patients with PSA values up to 36 months were evaluable by the Kaplan-Meier method for freedom from biochemical failure. The biochemical progression-free rate at 3 years was estimated to be 91%, with a 93% and 88% rate for low- and intermediate-risk groups, respectively, versus 80% for the high-risk group. PSA kinetics provide encouraging evidence of treatment efficacy. CONCLUSION: These data on 4-year PSA follow-up on patients treated with prostate brachytherapy reflect those previously reported in the literature. This patient series will be followed to provide long-term outcome in the future.

Prognostic markers under watchful waiting and radical prostatectomy.

A suitable setting to analyze factors that determine prognosis or treatment response in prostate cancer is an unbiased comparison of radical prostatectomy and watchful waiting as in the Scandinavian Prostate Cancer Group Trial number 4. In our previous presentation of 10-year results, we studied Gleason score, serum prostate-specific antigen (PSA) at diagnosis, and age at diagnosis as modifiers of the effect of radical prostatectomy on survival. Because overall prognostic information obtained by these parameters or by tumor stage was not provided in our publication, we now present these data in the two study arms separately.

Bias in variance components due to nonresponse in twin studies.

Incomplete data on trait values may bias estimates of genetic and environmental variance components obtained from twin analyses. If the nonresponse mechanism is 'ignorable' then methods such as full information maximum likelihood estimation will produce consistent variance component estimates. If, however, nonresponse is 'nonignorable', then the situation is more complicated. We demonstrate that a within-pair correlation of nonresponse, possibly different for monozygotic (MZ) and dizygotic (DZ) twins, may well be compatible with 'ignorability'. By means of Monte Carlo simulation, we assess the potential bias in variance component estimates for different types of nonresponse mechanisms. The simulation results guide the interpretation of analyses of data on perceptual speed from the Swedish Adoption/Twin Study of Aging. The results suggest that the dramatic decrease in genetic influences on perceptual speed observed after 13 years of follow-up is not attributable solely to dropout from the study, and thus support the hypothesis that genetic influences on some cognitive abilities decrease with age in late life.

The Swedish Twin Registry in the third millennium: an update.

The Swedish Twin Registry was first established in the late 1950s. Today it includes more than 170,000 twins--in principle, all twins born in Sweden since 1886. In this article we describe some ongoing and recently completed projects based on the registry. In particular, we describe recent efforts to screen all twins born between 1959 and 1985, and young twin pairs when they turn 9 and 12 years of age. For these studies, we present initial frequencies of common conditions and exposures.