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High-grade prostatic intraepithelial neoplasia in needle biopsy as risk factor for detection of adenocarcinoma: current level of risk in screening population.

OBJECTIVES: To assess the current incidence of prostate carcinoma detection in serial biopsies in a prostate-specific antigen-based screening population after a diagnosis of isolated high-grade prostatic intraepithelial neoplasia (HG-PIN) in needle biopsy tissue. METHODS: We retrospectively identified 190 men with a diagnosis of isolated HG-PIN in needle biopsy tissue. Most men (86%) were diagnosed from 1996 to 2000. Logistic regression analysis was used to predict the presence of carcinoma in these 190 men and in a control group of 1677 men with only benign prostatic tissue in needle biopsy tissue. RESULTS: The cumulative risk of detection of carcinoma on serial sextant follow-up biopsies was 30.5% for those with isolated HG-PIN compared with 26.2% for the control group (P = 0.2). Patient age (P = 0.03) and serum prostate-specific antigen level (P = 0.02) were significantly linked to the risk of cancer detection, but suspicious digital rectal examination findings (P = 0.1), the presence of HG-PIN (P = 0.2), and the histologic attributes of PIN were not (all with nonsignificant P values). HG-PIN found on the first repeat biopsy was associated with a 41% risk of subsequent detection of carcinoma compared with an 18% risk if benign prostatic tissue was found on the first repeat biopsy (P = 0.01). CONCLUSIONS: The results of our study have shown that the current level of risk for the detection of prostate carcinoma in a screened population is 30.5% after a diagnosis of isolated HG-PIN in a needle biopsy. This risk level is lower than the previously reported risk of 33% to 50%. HG-PIN is a risk factor for carcinoma detection only when found on consecutive sextant biopsies. The data presented here should prompt reconsideration of repeat biopsy strategies for HG-PIN, and re-evaluation of the absolute necessity of repeat biopsy for all patients with HG-PIN.

Adenocarcinoma↗

[Population screening for breast cancer: between euphoria and scepticism].

Forty years after the first mammograms were made, doubts are cast on the effectiveness of population screening for breast cancer. Disease-specific and overall mortality appear to have diminished, but any real effect is small. Proponents of breast cancer screening point at the possibility of saving lives and at the obligation to do so, whereas opponents emphasise that the screening may do more harm than good and that the large funds involved might be better spent in other health care areas. If the experts cannot decide on the effectiveness, simply leaving the choice of whether or not to take part up to citizens offers no solution. These complex health care matters require complex answers, which have to be found before any population screening for cancer of prostate, colon or lung can be implemented.

Breast Neoplasms↗

Population screening in the NHS: a systematic pathway from evidence to policy formulation.

In 1994 the Chief Medical Officer of England set out a framework for the evaluation and implementation of national screening programmes in the National Health Services (NHS). The framework highlighted the importance of the link between research evidence and the formulation of national policy. It also stressed the necessity for monitoring, evaluation and quality control as integral components for all new screening programmes. There is now an established link between the Health Technology Assessment programme of the NHS Research and Development Directorate and the NHS's new policy advisory group, the National Screening Committee. The objective of this systematic approach is to ensure that screening programmes are not introduced into the NHS unless there is robust evidence that benefit outweighs harm. The Population Screening Panel, an advisory panel of the NHS Health Technology Assessment programme, has the responsibility for determining priorities in research on proposed or existing population screening programmes. The National Screening Committee has a remit to consider this research evidence and to advise government ministers and the NHS on the appropriateness of the implementation, development and modification of national screening programmes. The example of prostatic cancer screening is presented as an illustration of how the NHS is developing a systematic approach to the implementation of screening policy based upon the strategic commissioning of research evidence.

Cost-Benefit Analysis↗

Population screening for abdominal aortic aneurysm: do the benefits outweigh the costs?

To prevent the high mortality rate associated with ruptured abdominal aortic aneurysm (AAA), population screening at or soon after retirement age has been advocated, with elective operations being performed on patients with the appropriate indications. There is considerable pressure on some health authorities to fund such programmes even though there is substantial uncertainty about the consequent benefits. The ultrasound screening test is acceptable and accurate. Also, other health problems may be detected in the same screen. However, screening would lead to a questionable increase in surgery, as most patients with AAA die from other causes and not from a ruptured aneurysm. In addition, there is an elective operative mortality of around 5 per cent. Furthermore, as many of those who have a positive result on screening would never have known that they harbour an aneurysm, there is the possibility of unnecessary anxiety arising from the test. An economic analysis has been conducted for two identical, hypothetical cohorts of men using the best available data. One cohort was assumed to undergo screening and a number of men were indicated for immediate elective aneurysm repair or for follow-up, and surgery if their aneurysms become large. The other cohort was assumed not to be screened and would thereby face the possibility of rupture with its adverse outcome. The survival prospects of the two cohorts were calculated as life expectancies and in terms of life-years: the incremental life-years gained were compared with the incremental costs of the programme. Although there are considerable uncertainties in the analysis parameters, the base-line result and sensitivity analysis indicate that, on the basis of current knowledge, population screening should not be introduced.

Age Factors↗

Epidemiology of breast cancer in a screened population.

Breast cancer risk factors were examined in a screened population expected to exhibit selection bias. Data were obtained for 1,383 breast cancer cases and 2,543 randomly selected controls screened at the Guttman Breast Diagnostic Institute between 1968 and 1979. Relative risk (RR) estimates were found to be elevated for the usual factors: greater age, greater weight, early menarche, late first live birth or nulliparity, late menopause, and family history of breast cancer. Adjustment for screening variables (number of screenings, breast symptomatology, and year of first screening) removed substantial bias in RR estimates. The unadjusted analysis tended to reduce the magnitude of RR for family history and weight among screenees in general and for age among women screened only once. Although the unadjusted analysis showed no effects for either previous breast biopsy or religion, adjustment for screening variables indicated that among rescreened women, previous biopsy, Jewish and Catholic religion were associated with increased risk; among women screened once only, these characteristics were associated with decreased risk of breast cancer.

Adult↗

Atypical squamous cells of undetermined significance on cervical smears: follow-up study of an Asian screening population.

BACKGROUND: The current study reports on the significance of cervical smears identified as atypical squamous cells of undetermined significance (ASCUS) in the largest Asian screening population to date. METHODS: From January 1998 to December 1999, 190,000 cervical smears were evaluated by the cervical cytology laboratory at the University of Hong Kong (Hong Kong, China). From these smears, 5579 ASCUS were identified. Follow-up cytology and histology findings were analyzed. RESULTS: Follow-up cytology or biopsy results were retrieved for 3601 women (64.5%). Of these, 544 (9.8%) and 96 women (1.7%) were found to have low-grade (LSIL) and high-grade (HSIL) squamous intraepithelial lesions, respectively. Biopsy results were obtained for 198 (36.4%) of the 544 women with LSIL. One hundred seventy-nine (32.9%) and 19 women (3.5%) were confirmed to have cervical intraepithelial neoplasia (CIN)-1 and CIN-2-CIN-3, respectively. Biopsy results were retrieved for 53 (55.2%) women with HSIL. Forty patients (41.7%) were confirmed to have CIN-2-CIN-3, whereas CIN-1 was found in the remaining patients. One woman with squamous cell carcinoma was diagnosed by colposcopic biopsy after immediate referral following a diagnosis of ASCUS. There was a significantly larger proportion of LSIL or HSIL (P < 0.0001) or higher-grade findings in women with ASCUS compared with the general screening population. Infective organisms were identified in 412 women (7.4%) with ASCUS. These women had a decreased risk of subsequent development of LSIL (P < 0.0001) or HSIL (P = 0.027). CONCLUSIONS: ASCUS smears indicated an increased risk of HSIL or carcinoma. The authors suggested careful patient follow-up in such cases.

Adolescent↗

[Population screening for colorectal cancer: a systematic review].

INTRODUCTION: Colorectal cancer (CRC) is a serious public health problem due to its high frequency and the mortality it provokes. This disease presents a series of characteristics that make it an ideal candidate for population screening. The aim of the present study was to analyze current knowledge on the efficacy/effectiveness of CRC screening through the fecal occult blood test (FOBT), rectosigmoidoscopy and colonoscopy in individuals without symptoms of this disease. METHOD: We performed a systematic review of the literature on each of the methods of early detection. The databases consulted were MEDLINE and PREMEDLINE (1966-2002), Embase (1980-2002), HTA and Cochrane, among others. Articles were selected using explicit criteria and were classified according to their level of scientific evidence. RESULTS: The best validated test is the FOBT, with the greatest number of randomized controlled trials. The results on the sensitivity and specificity of this test and reduction in mortality from CRC varied widely, depending on the technique used. The decrease in mortality from CRC in groups that underwent screening through FOBT was between 15% and 33%. The number and quality of the studies performed to evaluate flexible sigmoidoscopy and colonoscopy as methods of early detection were much lower. Although the rate of detection of polyps is greater than with the FOBT, the value of these tests as screening techniques has not been analyzed through randomized controlled trials. CONCLUSION: Population screening for CRC reduces mortality from this disease. However, consensus is lacking on the screening method of choice and on the frequency with which screening should be performed. The method best supported by the evidence as a primary detection test is the FOBT. To date, sigmoidoscopy and colonoscopy should be used as diagnostic tests only, mainly because of their invasiveness.

Clinical Trials as Topic↗

International consensus guidance for general population screening for islet autoantibodies to diagnose early-stage type 1 diabetes: a nominal group technique process.

Type 1 diabetes is an autoimmune disease that targets and destroys insulin-producing beta cells in the pancreatic islets. The incidence of type 1 diabetes is rising globally. At the clinical diagnosis of type 1 diabetes, between 20% and 67% of children and adolescents present with diabetic ketoacidosis (DKA) requiring hospitalisation, and one-third of these require intensive care. Type 1 diabetes can be detected in early stages, prior to the insulin-requiring clinical diagnosis, through screening for islet autoantibodies (IAbs). Identifying individuals with early-stage type 1 diabetes, combined with monitoring of and education on disease progression, prevents DKA and results in a milder clinical onset. This allows for timely insulin initiation in outpatient settings and improved long-term glucose management. Early diagnosis also enables access to novel disease-modifying therapies that can delay the clinical onset of diabetes. In this international consensus, we provide guidance on the principles and practice of implementing general population screening for IAbs to diagnose early-stage type 1 diabetes. We also outline the minimum requirements for establishing effective population screening programmes to diagnose early-stage type 1 diabetes through IAb detection. This consensus statement has been endorsed by the following professional associations: Advanced Technologies & Treatments for Diabetes (ATTD); Association of Diabetes Care and Education Specialists (ADCES); Association Belge Du Diab&#xe8;te; Associazione Medici Diabetologi (AMD); Australian Diabetes Society (ADS); Belgian Diabetes Liga; Breakthrough T1D; Czech Diabetes Society (&#x10c;DS); EASD; Finnish Diabetes Association (FDS); Fondazione Italiana Diabete (FID); International Diabetes Federation (IDF)-Europe; International Society of Paediatric and Adolescent Diabetes (ISPAD); Paediatric Endocrinology Nursing Society (PENS); Polish Diabetes Society; Portuguese Diabetes Association (APDP); Sociedade Portuguesa de Diabetologia (SPD); Societ&#xe0; Italiana di Diabetologia (SID); Soci&#xe9;t&#xe9; Francophone du Diab&#xe8;te (SFD) and Type 1 Diabetes Exchange (T1D Exchange).

Consensus report↗

Does population screening for Chlamydia trachomatis raise anxiety among those tested? Findings from a population based chlamydia screening study.

BACKGROUND: The advent of urine testing for Chlamydia trachomatis has raised the possibility of large-scale screening for this sexually transmitted infection, which is now the most common in the United Kingdom. The purpose of this study was to investigate the effect of an invitation to be screened for chlamydia and of receiving a negative result on levels of anxiety, depression and self-esteem. METHODS: 19,773 men and women aged 16 to 39 years, selected at random from 27 general practices in two large city areas (Bristol and Birmingham) were invited by post to send home-collected urine samples or vulvo-vaginal swabs for chlamydia testing. Questionnaires enquiring about anxiety, depression and self-esteem were sent to random samples of those offered screening: one month before the dispatch of invitations; when participants returned samples; and after receiving a negative result. RESULTS: Home screening was associated with an overall reduction in anxiety scores. An invitation to participate did not increase anxiety levels. Anxiety scores in men were lower after receiving the invitation than at baseline. Amongst women anxiety was reduced after receipt of negative test results. Neither depression nor self-esteem scores were affected by screening. CONCLUSION: Postal screening for chlamydia does not appear to have a negative impact on overall psychological well-being and can lead to a decrease in anxiety levels among respondents. There is, however, a clear difference between men and women in when this reduction occurs.

Adolescent↗

Mid trimester sonographic findings for the prediction of Down syndrome in a sonographically screened population.

OBJECTIVE: The purpose of this study was to report the adjusted effect sizes of mid trimester sonographic findings that are associated with Down syndrome in a sonographically screened population. STUDY DESIGN: A large prospective single-center cohort study was conducted between March 1993 and December 2002 in South-East Queensland with women who were first scanned between 15 to 22 weeks of gestation. Univariate and multivariable logistic regression modeling was used to relate karyotypically ascertained Down syndrome fetuses and their control counterparts against routinely collected demographic and sonographic findings. RESULTS: Data were available for 73 Down-affected and 16,891 unaffected pregnancies. Strong colinearity existed between short humerus and short femurs that necessitated the removal of FL in pursuant multivariable models. In the most parsimonious model, which was adjusted for maternal age and gestational age, pregnancies with thick nuchal skinfold (regression coefficient beta [+/- SE], 2.100 +/- 0.545), short humerus length (regression coefficient beta, 2.304 +/- 0.314), presence of echogenic bowel (regression coefficient beta, 1.602 +/- 0.412), presence of echogenic intracardiac focus (regression coefficient beta, 1.975 +/- 0.308), presence of renal pelvic dilation (regression coefficient beta, 1.281 +/- 0.420), presence of aneuploid associated anomalies (regression coefficient beta, 4.473 +/- 0.535), the interaction between gestational age and thick nuchal skinfold (regression coefficient beta, 0.465 +/- 0.210), and the interaction between short humerus length and the presence of aneuploid associated anomalies (regression coefficient beta, -1.693 +/- 0.811) all were associated significantly with Down syndrome risk (all P < .05). Adjusted relative risk estimates were substantially different from their crude estimates. CONCLUSION: Routinely collected mid trimester sonographic findings are associated significantly with Down syndrome risk in a sonographically screened population after accounting for maternal age and gestational age. Because of dependencies between ultrasonic findings, risk estimates should be derived from appropriate multivariable models.

Abnormalities, Multiple↗

Visual acuity, residual amblyopia and ocular pathology in a screened population of 12-13-year-old children in Sweden.

PURPOSE: To establish the distribution of visual acuity and the prevalence of residual amblyopia and other ocular disorders in a vision-screened population group of 12-13-year-old children. METHODS: In total 1046 children were examined in a field study in Sweden. The examination included visual acuity, stereopsis, cover testing, red reflex, refractive retinoscopy and examination of the posterior pole. In selected cases VEP was also performed. RESULTS: Visual acuity > or =1.0 in at least one eye was present in 98% of cases. Residual amblyopia (< or =0.5) was found in 1.1% of the population. Manifest strabismus was found in 2.7%. There were only a small number of ocular opacities and posterior pole abnormalities. Ocular albinism was found in 7 cases. In 15 children the cause of subnormal VA was unexplained. CONCLUSION: Results for visual acuity, residual amblyopia and other ocular disorders are very similar to previous Nordic, vision-screened populations.

Adolescent↗

Prognostic value of morphometry and DNA flow-cytometry features of invasive breast cancers detected by population screening: comparison with control group of hospital patients.

Using the prognostic value of morphometric and flow-cytometric features, a group of patients with invasive breast cancers detected with population screening (PS, n = 70) has been evaluated and compared with a random control group in 2 hospitals (H group, n = 225) diagnosed in the same period. The results show that the PS patients had smaller tumors, less positive lymph nodes, better differentiated tumors with a lower mitotic activity index (MAI) and lower values of the morphometric prognostic index (MPI). Furthermore, the women more frequently had diploid tumors and tumors with small nuclei. The second purpose was to evaluate whether quantitative microscopical features, in comparison with other prognostic features such as size of primary tumor, nodal status and histologic grade, are as strong prognosticators in PS tumors as in H-detected breast cancers. In comparison with H tumors, morphometric and flow-cytometric features, as well as tumor size, had the same prognostic value for the PS tumors. In contrast, nodal status was not significant within the PS group, and the same phenomenon was found in a subgroup of H patients with similar sized tumors. Of all quantitative microscopical features (MPI, MAI, mean nuclear area (MNA) and DNA Index (DI], the MAI had the strongest prognostic value. DI showed additional prognostic value to the MAI for patients with small tumors and with small tumor-cell nuclei, because a diploid pattern in these cases (this combination occurred in 21 patients of the total group = 30%) was correlated with a 95% 10-year survival rate. Histologic grade, although significant within the large H group, was of no prognostic value within the PS group, and also not as in the H sub-group with small tumors. It is concluded from morphometric and DNA flow-cytometric criteria that these prognostic features in invasive breast cancers detected by PS were all more favorable than in randomly detected hospital breast cancers. This may account for the reported better survival rate of PS patients. Furthermore, the prognosis of patients with small invasive breast cancers detected by population screening can be more accurately deduced by quantitative microscopical features than by axillary-lymph-node status.

Aged↗

Estimated analytic validity of HFE C282Y mutation testing in population screening: the potential value of confirmatory testing.

PURPOSE: The purpose of this study was to estimate analytic sensitivity and specificity of HFE testing for C282Y homozygosity in the hypothetical setting of population screening for hemochromatosis. METHODS: We analyzed published results of the Molecular Genetics Survey performed by the American College of Medical Genetics/College of American Pathologists between 1998 and 2002, taking into account its educational nature. RESULTS: Analytic sensitivity for C282Y homozygosity is 98.4% (95% CI 95.9%-99.5%). The analytic specificity is 99.8% (99.4%-99.9%). At a frequency of 40 per 10,000 for the homozygous genotype, the analytic positive predictive value is 66%. CONCLUSION: HFE testing for C282Y homozygosity is highly reliable. Homozygosity is uncommon in population screening, however, and confirmatory testing should be considered.

Genetic Testing↗

Detection of memory impairment in the general population: screening by questionnaire and telephone compared to subsequent face-to-face assessment.

BACKGROUND: Development of efficient methods for identifying subjects with Mild Cognitive Impairment (MCI) from the general population is warranted, because these subjects represent an important group for (epidemiological) research purposes. OBJECTIVES: (1) To describe a two-step population screening for identifying adults with MCI from the general population for research purposes, by questionnaire and telephone; (2) to compare screening by telephone (method 1) to a subsequent face-to-face assessment (method 2). METHODS: In method 1, subjects with memory complaints were identified from the general population (n = 5491) by a postal questionnaire. Subsequently, cognitive status and memory were assessed in a telephone interview using the Telephone Interview for Cognitive Status and the Ten Word Learning Test. Next, subjects with MCI according to method 1 were subjected to a face-to-face assessment for method 2, in which cognitive status and memory were assessed using the Mini Mental State Examination (MMSE) and the Auditory Verbal Learning Test (AVLT). RESULTS: Two hundred and twenty-seven subjects completed both the telephone interview and the face-to-face assessment. Ninety-three subjects (41%) had MCI according to both methods. Seven subjects (3%) failed to meet MCI criteria according to method two because of an MMSE score <24; 127 subjects (56%) failed because of normal AVLT scores. CONCLUSION: (1) The two-step population screening was able to detect a considerable number of MCI-subjects in the general population; (2) agreement between both methods was moderate. Therefore, the method of recruiting subjects for (epidemiological) studies has to be taken into consideration when interpreting results of these studies.

Aged↗

A novel method for detecting point mutations or polymorphisms and its application to population screening for carriers of phenylketonuria.

We describe a method termed PCR (polymerase chain reaction) amplification of specific alleles (PASA), a generally applicable technique for detection of point mutations or polymorphisms. The ease and technical simplicity of PASA will make genetic analyses more accessible to the general medical community. In addition, PASA shows promise for population screening because the technique is rapid, highly reproducible, inexpensive, nonisotopic, and amenable to automation. PASA is a modification of PCR that depends on the synthesis of a PCR oligonucleotide primer that precisely matches with one of the alleles but mismatches with the other. When the mismatch occurs near the 3' end of the PCR primer, amplification is inefficient. Therefore, preferential amplification of the perfectly matched allele is obtained. We demonstrate the applicability of PASA by performing carrier detection in the family of a patient with phenylketonuria (PKU) and by screening a population of unrelated subjects for the presence of the two mutations most commonly associated with PKU. Multiple persons were screened simultaneously for the mutant alleles because a mutation could be detected in the presence of at least a 40-fold excess of the normal allele. The two PKU mutations could be detected concurrently by using a mixture of only three PCR primers, an indication that simultaneous screening of multiple mutations can be done even if three or more mutations are closely clustered. In addition to the detection of mutations, PASA can be used to detect polymorphic alleles rapidly and to distinguish pseudogenes or repetitive sequences that differ by as little as one base.

Alleles↗

[Less pap-2 results ('minor abnormalities') in the population screening for cervical cancer since the introduction of new guidelines in 1996].

OBJECTIVE: To determine whether the 1996 implementation of new guidelines for the classification and management of cervical smears in the Dutch population screening programme for cervical cancer (i.e. inflammatory symptoms are no longer classified as moderate dysplasia and women with two smears with moderate dysplasia are referred directly to the gynaecologist) was followed by a reduction in both the number of women with repeat smears and the length of follow-up. METHODS: The results of all smears of women aged 35-54 years from 1990 onwards, were retrieved from the Dutch Network and National Database for Pathology (PALGA). The percentage of smears with moderate dysplasia was analysed with respect to time. The percentage of women with a histological examination during the follow-up phase of the population screening programme (1990 and 1991) was compared with that for the new screening programme (1996). RESULTS: Following the implementation of the new guidelines, the percentage of smears with moderate dysplasia was reduced from 10% to 2%. The percentage of women with a histological examination during the follow up of two smears with moderate dysplasia remained the same. The new recommendations for additional smears were not followed: for 28% no repeat smear was available after 2.25 years versus 10% in 1992. There were indications that the referral of women with two cases of moderate dysplasia to a gynaecologist was not strictly adhered to either. Since the introduction of the new guidelines, the estimated percentage of women that should be referred to the gynaecologist following smears with moderate dysplasia has not changed. CONCLUSION: The new recommendations have lead to fewer smears being classified as moderate dysplasia. The long-term effects, such as a reduction in the length of the follow-up period, can only be analysed in a few years time.

Adult↗

Liquid-based cytology and conventional cervical smears: a comparison study in an Asian screening population.

BACKGROUND: This study compared the findings of cervical cytology screening by ThinPrep Papanicolaou (Pap) tests (TP) with the findings of screening by conventional cervical smears (CS) in a screening population involving what to the authors' knowledge is the largest sample of ThinPrep Pap tests published to date. METHOD: Data from 191,581 CS that were screened in the period from March 1, 1998 to February 28, 2000 were compared with data from 190,667 TP performed from March 1, 2000 to February 28, 2002 and that were obtained from the same sources. RESULTS: With TP, the unsatisfactory rate was reduced from 0.48% to 0.32%. Fewer cases were considered to be suboptimal (19.12% vs. 12.97%). The detection rates of squamous cell carcinomas, adenocarcinomas, and high-grade squamous intraepithelial lesions (HSIL) were essentially unchanged in the TP group (0.005%, 0.003%, and 0.25%, respectively) compared with the rates for the CS group (0.01%, 0.006%, and 0.25%, respectively). There was an increase in the detection of atypical squamous cells of undetermined significance (ASCUS; 3.74% vs. 3.19%) and low-grade SIL (LSIL; 1.67% vs. 1.01%) with a decrease in the ASCUS-to-LSIL ratio from 3.15 for CS to 2.33 for TP. The detection of atypical glandular cells of undetermined significance (AGUS) increased slightly from 0.07% to 0.09%. The proportion of cells reported to have reactive atypia dropped from 2.71% to 1.48%. Limited biopsy correlation (range, 73.2-76.2%) confirmed the increased sensitivity of TP. More actinomyces (1.07% vs. 0.52%) were detected in TP samples despite of a similar portion of intrauterine-device users. The average primary screening and rapid rescreening time of each slide were reduced from 8 minutes to 4 minutes and from 2 minutes to less than 1 minute, respectively. CONCLUSIONS: The preliminary experience of the authors of the current study appears to support the use of the ThinPrep Pap test to enhance the efficiency of cervical cytology screening.

Adenocarcinoma↗