European Screening Programmes Research Articles

Home-use faecal immunochemical testing: primary care diagnostic technology update.

#### Clinical Question What is the evidence base for home faecal immunochemical testing for colorectal cancer? A variety of home-use faecal occult blood testing (FOBt) kits remain commercially available to UK patients despite caution regarding their safety and accuracy. FOBt is a relatively non-invasive and inexpensive test. The NHS Bowel Cancer Screening Programme (BCSP) and the majority of European screening programmes uses guaiac FOBt (gFOB). A Cochrane Review has shown that biennial population screening with card-based postal laboratory-analysed gFOB can reduce colorectal mortality by 15% (relative risk [RR] 0.85, confidence interval [CI] = 0.78 to 0.92) in people aged 45–74 years.1 Those who attend screening have a 25% reduction (RR 0.75, CI = 0.66 to 0.84) in their risk of death, but only 40% return all three BCSP gFOB kits, although involving GPs in screening increases uptake.1,2 Faecal immunochemical testing (FIT) measures the globin component of human haemoglobin. Unlike gFOB, FIT does not require dietary restriction, is specific to lower gastrointestinal (GI) cancers as upper GI enzymes degrade human globin, and is less affected by concomitant medication use. FIT has started to replace gFOB in some regions (for example, the Czech Republic and Italy) and guidelines (for example, the US) given these gains in diagnostic accuracy. Home FIT kits are designed to obtain samples from multiple parts of a single stool and use immunochromatography to provide an immediate (qualitative) positive or negative result, avoiding the delay and costs associated with laboratory (quantitative) FIT and gFOB. Patients may present to primary care having used home bowel-testing kits, and so this report outlines the existing evidence detailing the potential accuracy and utility of the home FIT available to the adult consumer. Based on a search conducted in December 2013, Box 1 shows the CE approved FIT kits retailing to the UK …

Lung cancer screening: 360 degree review

The most compelling evidence supporting the use of low dose computed tomography in the screening of high risk populations for lung cancer was generated by the National Lung Cancer Screening Trial carried out in the United States by the National Cancer Institute and the American College of Radiology Imaging Network.[1] This trial was a randomized prospective study which included over 53,000 participants. The two arms consisted of patients who were randomized to low dose CT and those who received standard radiography. Data from the NLST demonstrated that screening reduced mortality by 20% in the CT arm. Other smaller studies carried out in Europe have reported no mortality benefit. However, these studies included a younger screening population and had a smaller number of participants and probably did not have the power to show a mortality benefit.[2] Major medical societies and US government agencies such as US Preventative Services Task Force and now the Center for Medicare Services have now recommended LDCT. These decisions not only recommend screening but require US insurance companies and Medicare in the US to provide reimbursement.[3] Some of the caveats of screening result from the limits of generalization of the NLST results based on risk groups and demographics. There are also potential harms and complications from the LDCT screening which include radiation exposure, over diagnosis, the use of invasive procedures for diagnosis and the high false positive rate. [1,4] Lung cancer screening could have a strong impact on health care in Europe where there are over 268,000 lung cancer deaths per annum. Screening could save thousands of lives. However, lung cancer screening is currently not reimbursed and there are no screening programs accessible through health care systems or health plans. Important factors for lung cancer screening in Europe include refinement of inclusion criteria and stratification of risks, modeling of cost effectiveness data, and inclusion of evidence from European trials. Implementation of screening programs in Europe will require a collaborative effort among professional specialties, societies, organizations, and additional trial data. The American College of Radiology has developed a reporting system for lung cancer screening designated “Lung Rads.” [5] It is a reporting system which is very similar to Bi-Rads that includes numeric categories. It associates CT findings with guideline based management decisions. LDCT findings are categorized from 1-4 according to the likelihood of malignancy. 1 and 2 are considered benign findings and 3 and 4 have a higher probability of malignancy. There are descriptions for each of the 4 categories plus an enumeration of findings. The categories include characterization of nodules including size and density (solid, part-solid, or non- solid ground glass). In addition to the categories and findings there are guidelines for management in each category with estimates of the probability of malignancy and the estimated population prevalence. Constructing a lung cancer screening program in your institution presents many challenges. (6) Stake holders include the hospital leadership, referral providers, a multidisciplinary team, and support staff. Patient and physician outreach and education are essential. Standard protocols should be developed for image acquisition. Ideally image review should be performed by radiologists experienced in chest CT and nodule detection. Imaging software that combines CAD and volumetric measurements is desirable. Findings should be recorded according to the lung imaging reporting and data system such as Lung Rads. Communication of results to both the patient and physician is important and such communication should be stratified according to urgency.

Colorectal cancer: from prevention to personalized medicine.

Colorectal cancer (CRC) is a very heterogeneous disease that is caused by the interaction of genetic and environmental factors. CRC develops through a gradual accumulation of genetic and epigenetic changes, leading to the transformation of normal colonic mucosa into invasive cancer. CRC is one of the most prevalent and incident cancers worldwide, as well as one of the most deadly. Approximately 1235108 people are diagnosed annually with CRC, and 609051 die from CRC annually. The World Health Organization estimates an increase of 77% in the number of newly diagnosed cases of CRC and an increase of 80% in deaths from CRC by 2030. The incidence of CRC can benefit from different strategies depending on its stage: health promotion through health education campaigns (when the disease is not yet present), the implementation of screening programs (for detection of the disease in its early stages), and the development of nearly personalized treatments according to both patient characteristics (age, sex) and the cancer itself (gene expression). Although there are different strategies for screening and although the number of such strategies is increasing due to the potential of emerging technologies in molecular marker application, not all strategies meet the criteria required for screening tests in population programs; the three most accepted tests are the fecal occult blood test (FOBT), colonoscopy and sigmoidoscopy. FOBT is the most used method for CRC screening worldwide and is also the primary choice in most population-based screening programs in Europe. Due to its non-invasive nature and low cost, it is one of the most accepted techniques by population. CRC is a very heterogeneous disease, and with a few exceptions (APC, p53, KRAS), most of the genes involved in CRC are observed in a small percentage of cases. The design of genetic and epigenetic marker panels that are able to provide maximum coverage in the diagnosis of colorectal neoplasia seems a reasonable strategy. In recent years, the use of DNA, RNA and protein markers in different biological samples has been explored as strategies for CRC diagnosis. Although there is not yet sufficient evidence to recommend the analysis of biomarkers such as DNA, RNA or proteins in the blood or stool, it is likely that given the quick progression of technology tools in molecular biology, increasingly sensitive and less expensive, these tools will gradually be employed in clinical practice and will likely be developed in mass.

Mammography Screening - as of 2013.

Introduction: Since 2008 the German Mammography Screening Programme has been available throughout Germany to all women aged between 50 and 69. The programme strictly follows the European Guidelines. There are controversial discussions in the media as well as in the specialised press. Materials and Methods: Overview of the available data with regard to an evaluation of randomised studies and with regard to quality-assured screening programmes in accordance with EU Guidelines (including data from 18 screening countries). Results: Positive effects of screening: reduction in mortality, less invasive treatment. Negative effects: False-positive diagnoses and biopsy recommendations, so-called overdiagnoses, radiation dose. Limits of screening: Interval carcinomas, incomplete reduction in mortality. A mathematical synopsis of the latest publications from the European screening programmes with the diagnosis rates in Germany determined from > 4.6 million screening examinations produces the following: a total of 10 000 mammograms are created for 1000 women (P) taking part in the Mammography Screening Programme (each of whom undergoes 10 mammograms in 20 years). Overall, the risk of triggering breast cancer through a mammogram is very clearly below the annual natural risk of suffering from breast cancer. In the German screening, of these 1000 women, an average of 288 women are called back once in 20 years as a result of changes that are ultimately benign (< 3 % per cycle). Of these, 74 of the 288 women undergo a biopsy due to a benign change (false-positive biopsy recommendations, usually punch or vacuum biopsies). According to EUROSCREEN, 71 carcinomas develop among participants (56 are discovered in the screening, 15 in the interval), and 67 carcinomas among non-participants (N-P) (in some cases, several years later) during this period. The 4 additional diagnoses among the Ps are referred to as overdiagnoses, as they do not contribute to a reduction in mortality (these participants die beforehand from other causes of death). With regard to the carcinomas that concern the screening periods, 11 women out of 1000 die among the Ps; there are 19 deaths among the N-Ps (within the observation period plus follow-up period). Discussion: The false-positive rate is unavoidable, but is far lower with mammography screening than with other methods. Overdiagnoses are to be expected with any early detection. All calculations require assumptions and are therefore highly discrepant. They have very low evidence levels. The radiation dose should not be an argument against screening when applied correctly due to the very low risk and significant benefits. Interval carcinomas indicate the limits of a mammography screening programme. False-negatives only represent a subset of the interval carcinomas and are not to be equated with them. There is a very high evidence level for a significant reduction in mortality through mammography screening. For the first time, an independent expert commission has confirmed the results of the randomised studies and the statement of the WHO from 2002 and their further validity. Participants can expect a reduction in mortality of 30 %. Data from the current European screening programmes confirm a mortality reduction of 43 %, corresponding to 8/19 saved lives among 71 women with breast cancer or 1000 asymptomatic Ps. Many additional Ps benefit from less invasive treatment due to the early detection. Conclusions: As a result of the risk/benefit ratio, mammography screening should absolutely be recommended to asymptomatic women aged between 50-69. High importance is given to the provision of education for women by the treating gynaecologists as regards the opportunities for quality-assured early detection available to them in the healthcare system.

Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Influence of immunohistochemistry on the final diagnosis of breast biopsies

Because of the introduction of mammography screening programmes in Europe, the number of breast biopsies performed is increasing. We investigated the influence of immunohistochemistry (IHC) on the final diagnosis of breast biopsies by comparing the primary diagnoses (based on the results of haematoxylin and eosin staining only) with the final diagnoses (based on the additional information provided by IHC). We analysed the breast biopsies which were performed at the University of Halle-Wittenberg between 2006 and 2010 and for which the pathologist requested IHC for making the final diagnosis. According to the B-categorization scheme, the primary diagnosis changed in 37 of a total of 429 biopsies (8.6%). In 18 of these biopsies (48.6%) the category changed from B1-B2 to B3-B5 or vice versa, which would imply a different work-up. Only 77% of the primary diagnoses of breast cancer in situ were confirmed. IHC has a considerable influence on the final diagnosis of breast biopsies in several situations, including those in which the biopsied women are at risk of inadequate therapeutic intervention. The influence is particularly notable among those biopsies for which IHC is performed in order to assess the suspicion of breast cancer in situ.

OP143: Leonardo da Vinci Partnership – A lifelong learning programme to raise awareness of dental and medical professionals within Europe for the early detection of oral cancer – Phase 2

Objective To create cooperation among institutions at an European level in order to raise awareness on oral cancer among dental and medical professionals. To develop educational material for purposes of screening and for the early detection of oral cancer and potentially malignant disorders. Methods In order to understand gaps in knowledge and performance, during Phase I of this project we undertook: 1. A review of literature on dentist’s awareness, opinions and behaviors in published studies regarding early detection and prevention or oral cancer in Europe. 2. A Delphi survey among opinion leaders on issues pertaining to defining ways of improving early diagnosis of oral cancer. 3. A review of literature on oral cancer screening programs in Europe. 4. Catalogued and reviewed all available teaching resources (including e-learning) on screening for oral cancer. We set out to develop e-learning materials on the topic of early detection. Results Dentists encounter oral cancer patients infrequently during their life time performance. The diagnostic dilemma is complicated by oral mucosal disorders that may be mistaken for cancer. The reviews of literature confirm fundamental gaps in knowledge and understanding of early signs and symptoms. There are inequalities in screening performances within as well as between European countries largely based on available resources of training. During Phase 1 of the Leonardo Partnership, the group produced a comprehensive e learning package ( www.oralcancerldv.org ) in three languages for Europe wide use. Conclusions The Leonardo da Vinci Partnership will address the failures to implement screening for oral cancer by recommending strategies on involvement of medical and dental professionals. The partnership has a resolute drive to develop further e-learning material to improve skills in early detection and tobacco cessation that could be translated to other European languages. Relevance A three to five year agenda within Europe which will lead to key educational improvements to support dentists’ and doctors’ performance in the early detection of oral cancer and giving advice on tobacco cessation.

The Present and Future of Cervical Cancer Screening Programmes in Europe

The Present and Future of Cervical Cancer Screening Programmes in Europe

The Present and Future of Cervical Cancer Screening Programmes in Europe

The identification of HPV as the cause of cervical cancer has changed the information required for surveillance. HPV prevalence and screening uptake worldwide are now necessary to describe the epidemiology of this cancer. In low-income countries cervical cancer incidence varies from low to very high levels and is strongly influenced by virus prevalence. In high-income countries, instead, incidence is low and little influenced by the virus prevalence, thanks to screening. The European Guidelines currently recommend Pap test every 3-5 years starting at age 22-30 and stopping at age 60-65. HPV testing is now limited to triage of borderline lesions? and to post-CIN follow up. Pilot studies evaluating HPV testing as primary test are recommended. Future governmental agency Guidelines in Europe will probably include HPV testing as viable for primary screening, with cytology triage for HPV-positive women (those positive to cytology will be directly referred to colposcopy, those negative will repeat HPV at one year. Persistence of HPV positivity will refer to colposcopy directly, clearance to regular screening). The interval after an HPV-negative test should be at least 5 years and starting age should be age 30/35. Pap test is still recommended for women under 30.

False-Positive Results in Mammographic Screening for Breast Cancer in Europe: A Literature Review and Survey of Service Screening Programmes

To estimate the cumulative risk of a false-positive screening result in European mammographic screening programmes, and examine the rates and procedures of further assessment. A literature review was conducted to identify studies of the cumulative risk of a false-positive result in European screening programmes (390,000 women). We then examined aggregate data, cross-sectional information about further assessment procedures among women with positive results in 20 mammographic screening programmes from 17 countries (1.7 million initial screens, 5.9 million subsequent screens), collected by the European Network for Information on Cancer project (EUNICE). The estimated cumulative risk of a false-positive screening result in women aged 50-69 undergoing 10 biennial screening tests varied from 8% to 21% in the three studies examined (pooled estimate 19.7%). The cumulative risk of an invasive procedure with benign outcome ranged from 1.8% to 6.3% (pooled estimate 2.9%). The risk of undergoing surgical intervention with benign outcome was 0.9% (one study only). From the EUNICE project, the proportions of all screening examinations in the programmes resulting in needle biopsy were 2.2% and 1.1% for initial and subsequent screens, respectively, though the rates differed between countries; the corresponding rates of surgical interventions among women without breast cancer were 0.19% and 0.07%. The specific investigative procedures following a recall should be considered when examining the cumulative risk of a false-positive screening result. Most women with a positive screening test undergo a non-invasive assessment procedure. Only a small proportion of recalled women undergo needle biopsy, and even fewer undergo surgical intervention.

Mammographic Screening Programmes in Europe: Organization, Coverage and Participation

To summarize participation and coverage rates in population mammographic screening programmes for breast cancer in Europe. We used the European Network for Information on Cancer (EUNICE), a web-based data warehouse (EUNICE Breast Cancer Screening Monitoring, EBCSM) for breast cancer screening, to obtain information on programme characteristics, coverage and participation from its initial application in 10 national and 16 regional programmes in 18 European countries. The total population targeted by the screening programme services covered in the report comprised 26.9 million women predominantly aged 50-69. Most of the collected data relates to 2005, 2006 and/or 2007. The average participation rate across all programmes was 53.4% (range 19.4-88.9% of personally invited); or 66.4% excluding Poland, a large programme that initiated personal invitations in 2007. Thirteen of the 26 programmes achieved the European Union benchmark of acceptable participation (>70%), nine achieved the desirable level (>75%). Despite considerable invitation coverage across all programmes (79.3%, range 50.9-115.2%) only 48.2% (range 28.4-92.1%) of the target population were actually screened. The overall invitation and examination coverage excluding Poland was 70.9% and 50.3%, respectively. The results demonstrate the feasibility of European-wide screening monitoring using the EBCSM data warehouse, although further efforts to refine the system and to harmonize standards and data collection practices will be required, to fully integrate all European countries. The more than three-fold difference in the examination coverage should be taken into account in the evaluation of service screening programmes.

Decision-making in healthcare: a practical application of partial least square path modelling to coverage of newborn screening programmes

BackgroundDecision-making in healthcare is complex. Research on coverage decision-making has focused on comparative studies for several countries, statistical analyses for single decision-makers, the decision outcome and appraisal criteria. Accounting for decision processes extends the complexity, as they are multidimensional and process elements need to be regarded as latent constructs (composites) that are not observed directly. The objective of this study was to present a practical application of partial least square path modelling (PLS-PM) to evaluate how it offers a method for empirical analysis of decision-making in healthcare.MethodsEmpirical approaches that applied PLS-PM to decision-making in healthcare were identified through a systematic literature search. PLS-PM was used as an estimation technique for a structural equation model that specified hypotheses between the components of decision processes and the reasonableness of decision-making in terms of medical, economic and other ethical criteria. The model was estimated for a sample of 55 coverage decisions on the extension of newborn screening programmes in Europe. Results were evaluated by standard reliability and validity measures for PLS-PM.ResultsAfter modification by dropping two indicators that showed poor measures in the measurement models’ quality assessment and were not meaningful for newborn screening, the structural equation model estimation produced plausible results. The presence of three influences was supported: the links between both stakeholder participation or transparency and the reasonableness of decision-making; and the effect of transparency on the degree of scientific rigour of assessment. Reliable and valid measurement models were obtained to describe the composites of ‘transparency’, ‘participation’, ‘scientific rigour’ and ‘reasonableness’.ConclusionsThe structural equation model was among the first applications of PLS-PM to coverage decision-making. It allowed testing of hypotheses in situations where there are links between several non-observable constructs. PLS-PM was compatible in accounting for the complexity of coverage decisions to obtain a more realistic perspective for empirical analysis. The model specification can be used for hypothesis testing by using larger sample sizes and for data in the full domain of health technologies.

Newborn screening programmes in Europe; arguments and efforts regarding harmonization. Part 1 – From blood spot to screening result

In many European countries neonatal screening has been introduced over the last 50 years as an important public health programme. Depending on health care structure, available funds, local politics, input from professional groups, parent groups, and the general public this introduction has led to different approaches in the way the screening programmes have been set up, financed and governed. To get some insight about the current situation, in 2009 the European Union, via its EAHC agency, put out a call for a tender that was acquired by our project group. An online survey was compiled in which the whole screening programme was covered by a questionnaire. This survey covered the EU member states, (potential) candidate member states and EFTA countries, in total 40 countries. Results showed little consensus concerning 1. information of parents including informed consent; 2. which conditions are screened for, ranging from 1 to around 30 conditions; 3. sampling time post partum; 4. screening methodology including cut-offs values even between screening laboratories within countries.; 5. storage of residual specimens, varying from 3 months to 1000 years. In addition, confirmatory diagnostics and follow-up also show large discrepancies (Burgard et al. http://www.iss.it/cnmr/prog/cont.php?id=1621&lang=1&tipo=64 2011). In addition to the current practices report an expert opinion document has been produced with recommendations to the EU Commission for future improvements, e.g. in parallel to the way the USA has harmonized its practices based on recommendations by the American College of Medical Genetics (Watson et al., Pediatrics 117: S296-S307, 2006).

The Detection of Heterozygous Familial Hypercholesterolemia in Ireland

Heterozygous familial hypercholesterolemia (HeFH) is an autosomal dominant condition with a population prevalence of 1 in 500, and is associated with significant cardiovascular morbidity and mortality. It may be caused by mutations in the low-density lipoprotein (LDL) receptor, apolipoprotein B100 (Apo B100), or proprotein convertase subtilisin/kexin type 9 (PCSK9) genes, with over 1,000 causative mutations described. Statin therapy in HeFH is considered effective and safe. Audit data suggest that approximately 80% of the putative HeFH population remains unidentified and, therefore, there is a need to develop a strategy for the identification of affected individuals so that early lipid-lowering treatment may be offered. There is good evidence showing the effectiveness and acceptability of HeFH screening programs in Europe. The authors describe a protocol for an all island approach to HeFH detection in the Republic of Ireland/Northern Ireland. Index cases will be identified by opportunistic screening using the Simon Broome, or Make Early Diagnosis to Prevent Early Death (MedPed) and World Health Organization (WHO) criteria. Patients identified as "definite," "probable," or "possible" HeFH criteria will be offered genetic testing. The authors expect causative mutations to be identified in approximately 80% of patients with "definite" HeFH but in only approximately 20% of patients with "possible" HeFH. Cascade screening will be undertaken in first-degree relatives of the index case using genetic testing (where a causative mutation has been identified), or otherwise using LDL cholesterol concentration. The establishment of a HeFH screening program on an all-island basis will require: expansion of the existing molecular genetics diagnostic services, the establishment of a cohort of nurses/genetic counselors, a HeFH database to support cascade testing, the development of a network of lipid clinics (in a primary or secondary care setting), and an educational initiative to raise awareness of HeFH among healthcare professionals and the general population.

Newborn screening programmes in Europe; arguments and efforts regarding harmonization. Part 2 – From screening laboratory results to treatment, follow‐up and quality assurance

In a survey conducted in 2010/2011 data from the 28 EU member states, four EU candidate states (Croatia, FYROM, Iceland, Turkey), three potential EU candidate states (Bosnia Herzegovina, Montenegro, Serbia), and two EFTA states (Norway and Switzerland) were collected. The status and function of newborn screening (NBS) programmes were investigated from the information to prospective parents and the public via confirmation of a positive screening result up to decisions on treatment. This article summarises the results from screening laboratory findings to start of treatment. In addition we asked about the existence of feedback loops reporting the conclusions of confirmation of screening results to the screening laboratory and communication of long-term outcome to diagnostic units and possibly existing central registries. Parallel to the description of actual practices of where, how and by whom the different steps of the programmes are executed, we also asked for the existence of guidelines or directives regulating the screening programmes, material to support information of parents about diagnoses and treatment and training facilities for professionals involved in the programmes. This survey gives a first comprehensive overview of the steps following a positive screening result in European NBS programmes. The 37 data sets reveal substantial variation of national screening panels, but also a lot of similarities. Analysis across all countries revealed that actual practice is often organised but not regulated by guidelines. Material to inform patients is available more often for explaining treatment (69 %) than explaining the necessity of confirmatory diagnostics (41 %). Training of professionals is rarely regulated by a guideline (2 %), but is offered for paediatricians (40 %) and dieticians (29 %) and only rarely for other professions (e.g. geneticists, clinical nurse specialists, psychologists). Registry-based evaluation of long-term outcome is as yet almost nonexistent (3 %).

Image quality assessment in digital mammography: part II. NPWE as a validated alternative for contrast detail analysis

Assessment of image quality for digital x-ray mammography systems used in European screening programs relies mainly on contrast-detail CDMAM phantom scoring and requires the acquisition and analysis of many images in order to reduce variability in threshold detectability. Part II of this study proposes an alternative method based on the detectability index (d′) calculated for a non-prewhitened model observer with an eye filter (NPWE). The detectability index was calculated from the normalized noise power spectrum and image contrast, both measured from an image of a 5 cm poly(methyl methacrylate) phantom containing a 0.2 mm thick aluminium square, and the pre-sampling modulation transfer function. This was performed as a function of air kerma at the detector for 11 different digital mammography systems. These calculated d′ values were compared against threshold gold thickness (T) results measured with the CDMAM test object and against derived theoretical relationships. A simple relationship was found between T and d′, as a function of detector air kerma; a linear relationship was found between d′ and contrast-to-noise ratio. The values of threshold thickness used to specify acceptable performance in the European Guidelines for 0.10 and 0.25 mm diameter discs were equivalent to threshold calculated detectability indices of 1.05 and 6.30, respectively. The NPWE method is a validated alternative to CDMAM scoring for use in the image quality specification, quality control and optimization of digital x-ray systems for screening mammography.

Prenatal ultrasound screening of congenital heart disease in an unselected national population: a 21-year experience

ObjectiveTo determine the prevalence and spectrum of congenital heart disease (CHD) and the impact of a national prenatal ultrasound screening programme on outcome in a well-characterised population.Design and settingA comprehensive...

Diagnosis of glutathione synthetase deficiency in newborn screening

Glutathione synthetase (GSS) deficiency is a rare disorder of glutathione metabolism with varying clinical severity. Patients may present with haemolytic anaemia alone or together with acidosis and central nervous system impairment. Diagnosis is made by clinical presentation and detection of elevated concentrations of 5-oxoproline in urine and low GSS activity in erythrocytes or cultured skin fibroblasts. Diagnosis can be confirmed by mutational analysis. Treatment consists of the correction of acidosis, blood transfusion, and supplementation with antioxidants. The most important determinants for outcome and survival in patients with GSS deficiency are early diagnosis and early initiation of treatment. The case of a newborn with GSS deficiency diagnosed by tandem mass spectrometry (MS/MS)-based newborn screening is described. After onset of clinical symptoms on the 2nd day of life, expanded newborn screening revealed normal results for all disorders included in the German screening programme; however, selective MS/MS screening revealed a >10-fold elevation of 5-oxoproline in dried blood, leading to the presumptive diagnosis of GSS deficiency by the 5th day of life. Diagnosis was later confirmed by detection of markedly reduced glutathione concentration in erythrocytes and mutational analysis of the GSS gene. Presently, GSS deficiency is not included in newborn screening programmes in Europe. As outcome depends significantly on early start of treatment, routine inclusion of this disorder in newborn screening panels should be considered.

Process performance of cervical screening programmes in Europe

Standardised tables of aggregated data were collected from 15 European national or regional cervical screening programmes and key performance indicators computed as reported in European Union (EU) Guidelines, 2nd edition. Cytological results varied widely between countries both for the total proportion of abnormal tests (from 1.2% in Germany (Mecklenburg-Vorpommern) to 11.7% in Ireland-Midwest Region) and for their distribution by grade. Referral rates for repeat cytology (ranging from 2.9% of screened women in the Netherlands to 16.6% in Slovenia) or for colposcopy (ranging from 0.8% in Finland to 4.4% in Romania-Cluj) and the Positive Predictive Value (PPV) of colposcopic attendance (ranging from 8% in Romania-Cluj to 52% in Lithuania) were strongly influenced by management protocols, in particular for atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) cytology. However, cytology-specific PPV also showed remarkable variability. The detection rate of CIN2+ histology ranged from <0.1% of screened women in Poland to >1% in England and Denmark. Low attendance for colposcopy after referral was observed in some east-European countries. These comparisons may be useful for improving the performance of cervical screening in general and more so if new screening technologies and vaccination for Human Papillomavirus are introduced. Overall, quality was better in countries that have operated organised programmes for a longer time, plausibly as a result of long-lasting monitoring and quality assurance activities. Therefore, the availability of these data, the first comparing European countries, and the increased number of countries that can provide such data (only five in 2004) represent progress. Nevertheless, there is a clear need to standardise the cytological and histological classifications used in screening, as well as data registration systems across Europe.

Can we manage B3 lesions better?

Within mammographic breast screening programmes in Europe, a categorisation for nonoperative histology reporting is used from B1 normal and B2 benign through to B5 malignant. Definitive diagnosis is possible for the majority of lesions on core biopsies, but there remains a small proportion in the borderline category of B3, uncertain malignant potential. These are lesions that are either benign but known to be associated with malignancy, or which are known to be heterogeneous and where sampling may have missed a more worrisome area. B3 lesions include entities such as radial scars, papillary lesions and phyllodes tumours. Often more diagnostically difficult for the pathologist are the atypical epithelial proliferations such as atypical intraductal proliferations (akin to atypical ductal hyperplasia), lobular neoplasia and columnar cell atypia/flat epithelial atypia. Advances have been made regarding management of some of these processes; it is established that the atypical intraductal epithelial proliferations are more frequently definitively upgraded with the use of wider gauge devices (for example, 11 G, 8 G) to ductal carcinoma in situ. In such cases, diagnostic excision can be avoided and therapeutic surgery undertaken. Conversely, it has been shown that some papillary lesions may be excised by mammotomy. There are still few robust data, however, on outcome following a B3 diagnosis of lobular neoplasia or of flat epithelial atypia. The management of these lesions when identified in the core can cause controversy and debate. Collaborative data collection of the outcome of these uncommon entities is central to resolving the question of optimal clinical management.