bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of allergy and anaphylactic symptoms in 210 adult and pediatric patients with mastocytosis in Spain: a study of the Spanish network on mastocytosis (REMA)
Authors: González de Olano D. , De La Hoz Caballer B. , Núñez López R. , Sánchez Muñoz L. , Cuevas Agustín M. , Diéguez M. C. , Álvarez Twose I. , Castells M. C. , Escribano Mora L.
Published: September 2007

Background
Mast cells (MCs) play a key role in allergic diseases through the release of inflammatory mediators, which are responsible of allergic symptoms. Mastocytosis is characterized by an abnormal proliferation and accumulation of mast cells, in which mediators are released intermittingly or continuously. Despite these clinical similarities, few studies have addressed the presence of allergic symptoms in mastocytosis patients, including anaphylaxis.

Objective
A prospective evaluation was carried out to study the prevalence of allergic diseases in patients with mastocytosis and their impact on the natural history of mastocytosis.

Methods
A questionnaire was given to 210 patients with mastocytosis to evaluate the history of asthma, rhinitis, conjunctivitis, atopic dermatitis, urticaria and anaphylaxis. Patients underwent total IgE, Phadiatop® infant (aeroallergens and food allergens), specific IgE to latex and to Anisakis simplex determinations. Skin tests were done to 72 patients.

Results
The prevalence of allergy, as defined by clinical symptoms associated to specific IgE, was 23.9%. Total IgE level was significantly higher in patients with allergy as compared with patients without allergy (median 58 vs. 16.5 kU/L, P<0.0001). Anaphylactic symptoms were present in 36 patients (22%), in nine the allergen was identified. Males had more allergy and anaphylactic symptoms than females (61.5% vs. 38.5% and 72% vs. 28%, respectively).

Conclusions
Allergic diseases coexist in patients with mastocytosis with similar frequency as compared with the general population. Anaphylactic symptoms are more prevalent in males with mastocytosis and in patients with elevated IgE.

Capsule summary
The prevalence of allergy in mastocytosis is similar to the general population. Anaphylactic symptoms are more prevalent in males and in patients with elevated IgE. The coexistence of atopy does not influence mastocytosis‐associated symptoms.
Allergic skin disease: investigation of both immediate‐ and delayed‐type hypersensitivity is essential
Authors: Usmani N. , Wilkinson S. M.
Published: September 2007

Background
In our clinic we routinely patch test patients referred from occupational health for the investigation of latex contact urticaria. We also undertake both patch and prick testing (where indicated) in patients referred with persistent dermatitis/eczema. If investigation of allergic skin disease is undertaken by a non‐dermatologist, it is unlikely that patch testing will be performed.

Objective
To carry out a retrospective analysis of patients who had been prick tested to establish whether an incomplete diagnosis would have been reached if patch testing had been omitted.

Methods
Details of patients who had attended for patch testing between July 2004 and December 2005 were analysed. Patients who had had prick tests and patch testing were identified. The outcomes of prick tests and patch testing were documented together with the clinical relevance.

Results
Three hundred and thirty out of 1060 patients referred to the clinic were prick tested. 54.2% patients were referred from dermatologists. 26.6% were referred from occupational health, 68 patients had positive reactions on prick testing of whom 36 had positive patch tests (52.9%), which were of current relevance in 27 patients (39.7%). Nine out of 106 health workers referred to exclude latex contact urticaria had positive prick tests to latex. Fifty of these patients demonstrated delayed‐type hypersensitivity with nickel, cobalt, rubber and its additives being the most common allergens found. Of the 262 patients who had negative prick tests, 121 had positive patch tests (46.1%) of current relevance to patient history in 92 subjects (35.1%). While none of the six patients referred for investigation of reaction to local anaesthetics had a positive prick test, one was allergic to local anaesthetic on patch testing.

Conclusion
Omission of patch testing from the investigation of allergic skin disease, even when contact urticaria may be the sole suspected diagnosis, would result in the frequent missed diagnosis of contact allergy. We recommend that patients with suspected allergic skin disease are investigated in an environment where investigation of both immediate‐ and delayed‐type hypersensitivity can be undertaken. In particular, patients with atopic eczema, suspected latex rubber allergy, hand dermatitis (particularly occupational) and drug reactions should be targeted to receive both investigations.
Quality of life in allergic rhinitis: relationship with clinical, immunological, and functional aspects
Authors: Ciprandi G. , Klersy C. , Cirillo I. , Marseglia G. L.
Published: September 2007

Background
The relationship among nasal obstruction, T‐helper type 2‐dependent inflammation, nasal airflow limitation, and reversibility to the nasal decongestion test has been evidenced in allergic rhinitis (AR). Moreover, quality of life (QoL) has been widely evaluated in AR and its evaluation is considered in numerous trials.

Objective
The aim of this cross‐sectional study was to identify the QoL as measured by the Quality of Life Questionnaire in a population of patients with AR and to compare it with clinical, immunological, and functional parameters.

Methods
One hundred and twenty‐three patients with persistent AR were prospectively and consecutively evaluated. Clinical evaluation, skin prick test, nasal scraping for cytology, rhinomanometry, decongestion test, and QoL questionnaire were performed in all subjects.

Results
There was a significant relationship among QoL and functional and immunological parameters. Particularly, the multivariate analysis showed that having more than two sensitivities was a determinant of the QoL. The eosinophil count was significantly associated with QoL as well as the baseline nasal flow (mL/s) with the eye symptoms scale only.

Conclusions
This study provides the first evidence that QoL in AR is strictly associated with allergic inflammation and eye symptoms significantly contribute to impairment of QoL. QoL, moreover, represents an important aspect to consider in managing patients with AR as it has a relationship with clinical, immunological, and functional parameters.
The diagnosis of polycystic ovary syndrome: the criteria are insufficiently robust for clinical research
Authors: Barth Julian H. , Yasmin Ephia , Balen Adam H.
Published: September 2007

Polycystic ovary syndrome (PCOS) is a common disorder but has considerable phenotypic variability and this has led to controversy over its exact definition and diagnosis. The objective of this study was to review the recently proposed diagnostic criteria to determine whether they were sufficiently robust for clinical and research practise. We have reviewed the literature pertaining to clinical measurement and quality of laboratory analysis in relation to clinical and biochemical hyperandrogenism. The recently published statements regarding the diagnosis of PCOS assume that the clinical, laboratory and imaging studies are dichotomous variables, without considering the effect of observer subjectivity or measurement variability on the outcome. The data suggest that there is considerable uncertainty of all measurements and lack of clarity of the definition of the term ‘hyperandrogenaemia’ which can lead to misdiagnosis. The current diagnostic strategies for PCOS are defined too vaguely to ascertain that individuals fit the definition of the syndrome. A pragmatic approach may be taken in the management of an individual depending upon her particular symptoms and needs. However, research into the epidemiology, pathophysiology and treatment of PCOS will require the production of robust definitions of the diagnostic criteria. We propose specific criteria that would answer the criticisms that we have raised.
Unravelling the phenotypic map of polycystic ovary syndrome (PCOS): a prospective study of 634 women with PCOS
Authors: Diamanti‐Kandarakis Evanthia , Panidis Dimitrios
Published: September 2007

Background  The phenotypic spectrum of PCOS has been broadened but the prevalence and clinical significance of PCOS phenotypes continue to challenge the scientific community.

Objective  Analysis of the phenotypic spectrum of PCOS and determination of the association between metabolic, hormonal and new ultrasonographic criteria.

Design  Clinical prospective study.

Patients  Six hundred and thirty‐four women with PCOS (18–35 years) and comparable body mass index (BMI), diagnosed by ESHRE/ASRM criteria, were categorized into two major groups of phenotypes: classic (NIH) and nonclassic (ESHRE/ASRM), and then subdivided into phenotypes with all possible combinations of diagnostic characteristics. One hundred and eight healthy women of reproductive age, matched for BMI, were recruited as the control group.

Measurements  Ultrasonographic (ovarian follicle number and volume), hormonal and metabolic parameters.

Results  Classic PCOS phenotype was more frequent (85·96%) than the nonclassic phenotype (14·04%). The patients were also classified according to the presence of biochemical (80·60%) or clinical hyperandrogenaemia (12·62%), and, in the newly introduced group, to absence of evidence of hyperandrogenaemia (6·78%). Subjects with classic PCOS with biochemical hyperandrogenaemia (74·76%) were more insulin resistant than controls. In women with PCOS, follicle number was positively related to both insulin resistance and biochemical hyperandrogenaemia. Additionally, women with PCOS had a 6·58‐fold increased relative risk (RR) of > 12 follicles on intravaginal ultrasound and a 2·94‐fold increased RR of ovarian volume > 10 cm3 compared to controls.

Conclusion  The most frequent PCOS phenotype is the subgroup with biochemical hyperandrogenaemia only within the classic phenotype, which is more insulin resistant than the control group. The follicle number, a newly introduced ultrasonographic marker, is related to both metabolic and hormonal features of PCOS.
Concentrations of the acute phase reactants high‐sensitive C‐reactive protein and YKL‐40 and of interleukin‐6 before and after treatment in patients with acromegaly and growth hormone deficiency
Authors: Andreassen Mikkel , Vestergaard Henrik , Kristensen Lars Østergaard
Published: September 2007

Background  Acromegaly is accompanied by increased cardiovascular mortality and a cluster of proatherogenic risk factors. In the general population, ischaemic heart disease (IHD) is associated with elevated levels of inflammatory markers. The acute phase reactant (APR) C‐reactive protein (CRP) has been reported to be reduced in acromegaly and increase after treatment, suggesting that excess of GH/IGF‐I could have anti‐inflammatory effects. This is in accordance with results obtained in patients with growth hormone deficiency (GHD), where increased levels of CRP have been reported.

Objective To investigate the hypothesis that the GH/IGF‐I system is a suppressive regulator of inflammatory processes.

Subjects and methods  Twenty‐one acromegalic patients and 19 GH‐deficient patients were studied. The two APRs CRP and YKL‐40 and the proinflammatory cytokine interleukin‐6 (IL‐6) were measured before and after treatment and in healthy matched controls.

Results  In acromegalic patients, serum concentrations of high‐sensitive CRP (hsCRP) and YKL‐40 were reduced compared to controls (P < 0·001) and increased (P < 0·001) after treatment, together with IL‐6 (P = 0·021), to levels comparable with controls. Pretreatment serum YKL‐40 and IL‐6 showed a significant inverse correlation with IGF‐I and GH. In GH‐deficient patients, hsCRP and YKL‐40 were elevated compared to controls (P = 0·001 and P = 0·048). During treatment, levels of both APRs showed a trend towards a decrease (P = 0·087 and P = 0·060), and after treatment, levels of YKL‐40 no longer differed from that of controls. Serum IL‐6 was not different from controls and did not change during GH treatment.

Conclusion  The results point to the possibility of a relationship between GH disturbances and inflammatory processes.
Pregnancy outcomes following cabergoline treatment: extended results from a 12‐year observational study
Authors: Colao Annamaria , Abs Roger , Bárcena David González , Chanson Philippe , Paulus Wolfgang , Kleinberg David L.
Published: September 2007

Objective  Cabergoline is a dopamine agonist used to treat hyperprolactinaemia. Because hyperprolactinaemia is a significant cause of infertility in women, cabergoline and other dopamine agonists are frequently prescribed to reduce prolactin levels and restore normal menses. They are usually discontinued shortly after the patient becomes pregnant. Although cabergoline has been used to treat hyperprolactinaemia since the mid‐1990s, safety data related to maternal and foetal exposure to this agent are still limited.

Design  The current prospective, observational study reports on a total of 380 pregnancies. This extends by 154 pregnancies the results of a previously published interim report on the outcomes of 226 pregnancies in women treated with cabergoline up to 1994.

Main outcome measures  Outcomes examined include the incidence of abortions and premature delivery and the number and types of foetal malformations or abnormalities.

Results  Follow‐up data were available for 329 pregnancies, including 258 (78%) deliveries and 71 (22%) abortions. Of the 71 reported abortions, 31 (44%) were voluntary, 30 (42%) were spontaneous miscarriages, and nine (13%) were therapeutic. Of the 258 deliveries, 250 (97%) were live deliveries, four (2%) were stillbirths, and the status of delivery was unknown for the remaining four (2%). Of the 250 live deliveries, 193 (77%) were term deliveries (gestational period > 37 weeks), 45 (18%) were preterm deliveries (gestational period ≤ 37 weeks), and 62% of the infants had normal birthweights (i.e. 3–4 kg). Neonatal abnormalities were recorded for 23 (9%) of the infants with no apparent pattern in type or severity.

Conclusion  The results of this study suggest that foetal exposure to cabergoline through early pregnancy does not induce any increase in the risk of miscarriage or foetal malformation.
Effect of the combination of the variants –75G/A APOA1 and Trp64Arg ADRB3 on the risk of type 2 diabetes (DM2)
Authors: Morcillo Sonsoles , Cardona Fernando , Rojo‐Martínez Gemma , Almaraz M Cruz , Esteva Isabel , Ruiz‐De‐Adana María Soledad , Olveira Gabriel , García‐Fuentes Eduardo , Gómez‐Zumaquero Juan Miguel , Soriguer Federico
Published: September 2007

Objective  Numerous genes have been associated with the risk for type 2 diabetes mellitus (DM2). In an attempt to understand how specific variants of different genes interact and intervene in the molecular and physiological mechanisms of disorders such as diabetes or insulin resistance, the search for gene–gene interactions is constantly growing. We searched for a possible interaction between two polymorphisms (Trp64Arg of ADRB3 gene and –75G/A of APOA1gene) and the risk for DM2 in a population from southern Spain.

Design and methods  A cross‐sectional study in southern Spain of 1020 people, aged 18–65 years. All persons underwent a clinical, anthropometrical and biochemical evaluation, including an oral glucose tolerance test (OGTT). Insulin resistance was measured by homeostasis model of assessment (HOMA). The polymorphisms –75G/A of APOA1 and Trp64Arg of ADRB3 were detected by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) and real‐time PCR, respectively.

Results  The genotype frequencies of the –75G/A polymorphism of the APOA1 gene were 62·7% GG, 25·7% GA and 11·6% AA, whereas for the Trp64Arg polymorphism of the ADRB3 gene, they were 87·5% Trp/Trp, 11·7% Trp/Arg and 0·8% Arg/Arg. Subjects with both gene variants had a greater odds ratio (OR) of having DM2 [OR = 5·5; 95% confidence interval (CI) = 1·2–23·5] than persons with one or none of the variants, after adjusting for age, sex, body mass index (BMI) and homeostasis model assessment of insulin resistance (HOMA‐IR).

Conclusions  Joint association of allele –75A (APOA1) and allele Arg64 (ADRB3) increase the risk of DM2 in a population from southern Spain.
Respiratory Cytology
Authors: DeMay R.
Published: September 2007

The key diagnoses in respiratory cytology are infections, eg, virus and fungus, and cancer, which in essence is small cell carcinoma vs nonsmall cell carcinoma, or metastases. The basic specimens include exfoliative specimens, including sputum (increasingly uncommon), bronchial cytology (washings, brushings), and bronchoalveolar lavage, and FNA biopsy specimens, including percutaneous, bronchoscopic, and endoscopic ultrasound biopsies. All are cytologically similar. The lecture will review basic respiratory cytology as well as diagnosis and differential diagnosis of reactive and neoplastic pulmonary diseases.
Transbronchial needle aspiration in the diagnosis of malignant and benign pulmonary disease
Authors: Linnane S. J.
Published: September 2007

Transbronchial needle aspiration (TBNA) is a useful adjunct to bronchoscopic airway sampling. A 21 or 19 gauge needle is past down the bronchoscope and through the airway wall into the target regions. Material is aspirated into the needle core for cytological analysis.

Exophytic endobronchial tumours, submucosal disease or extra luminal peribronchial tissue such as mediastinal lymphnodes can be sampled. The technique is useful for the diagnosis in particular malignant but also benign pulmonary disease. It also has a useful role in the staging of malignant disease.

Health economic analysis have demonstrated the relative cheap cost of implementing this service with significant savings in bed days by patients who can avoid mediastinoscopy or other invasive tissue sampling.

Repeated surveys in Europe and North America have consistently demonstrated that this technique is under utilized. The exact reasons for this are unclear but probably include the fact that the procedure must be done blindly and that initial yields are often disappointing.

With adequate training and preparation a diagnostic yield of 40%–80% is reported in the literature. A number of factors affect performance; these include operative skill, pre‐text probability of malignancy, size of the target lesion and availability of rapid onsite cytological evaluation (ROSE).

The most significant recent development has been the introduction of real time endobronchial ultrasound. This allows the placement of a cytological analysis needle within the target lesion under direct vision. While this innovation is associated with increased cost it is significantly increased sensitivity and is likely to see the more widespread application of TBNA as a diagnostic tool.

The optimum integration of TBNA services with PET evaluation of malignant mediastinal lesions remains to be evaluated.
Diagnostic difficulties with lymphoid infiltrates
Authors: Kocjan G.
Published: September 2007

Diagnostic dilemmas associated with the presence of lymphoid cells in FNAC samples are usually considered to be associated with the diagnosis of lymphomas. However, whilst the majority of lymphomas can be diagnosed without difficulty, there are other aspects of lymphoid infiltrates in FNAC samples that may be either misleading or difficult. The lecture will give examples of the conditions where observing the details of lymphoid infiltrates may be important in making the diagnosis, in particular: granulomatous infiltrates, lymphoid infiltrates in extranodal sites and neoplasms containing lymphocytes. Granulomatous infiltrates: tuberculosis, sarcoidosis, Kikuchi‐Fujimoto disease, SLE, multicentric Castleman's disease, cat‐scratch disease, all can be diagnosed with FNAC as can leishmaniasis, Kimura's disease and sinus histiocytosis with massive lymphadenopathy. Malignant lymphomas and solid tumours may be also associated with epithelioid granulomata. The finding of lymphoid cells in FNAC samples of extranodal sites e.g. thyroid, salivary gland, breast is always noteworthy. In these cases lymphoid cells may define the underlying pathology and contribute to accurate diagnosis. The presence of non‐circulating lymphoid cells indicates presence of lymphoid follicles and may be significant for diagnosis. Neoplasms containing lymphoid cells may be either lymphomas or other non‐haemopoetic neoplasms which typically contain lymphocytes as part of their morphological appearances. According to the WHO, morphological diagnosis of NHL relies largely on cytological detail, although the development of new technologies has helped to define several clinical entities. Cytological assessment of the sample taken with FNAC is often the first line morphological investigation of lymphoma achieving the overall accuracy rate of 79∼90% for high grade NHL and Hodgkin–s disease (with the exception of the LP). The examples of solid neoplasms containing lymphocytes are: acinic cell carcinoma, paediatric follicular carcinomas, lymphoepithelioma‐like carcinoma, seminoma, sebaceous lymphadenoma, Warthin–s tumour, thymoma and others.
Chernobyl, the pathology of a nuclear accident
Authors: Williams E. D.
Published: September 2007

The accident at the Chernobyl nuclear power plant took place more than 20 years ago, on April 26th 1986, but its effects are still being felt, and its consequences influence the debate on nuclear power generation. The consequences for those working to contain the accident resembled those after the atomic bomb, 28 died from acute radiation sickness, and a further approximately 20 have died from the consequences of whole body radiation. The consequences for the millions exposed to high levels of fallout were quite different from those after the atomic bomb, and the talk will consider particularly the dramatic rise in thyroid carcinoma; currently estimated as about 4 000 cases. Fortunately only a small proportion has died from the disease. Initial studies concentrated on validating the diagnoses, later studies have shown a link between the molecular and morphologic pathology, the latent period and the aggressiveness of the tumours. These points will be reviewed, together with the link between radiation and thyroid carcinogenesis, and the possible future effects. The thyroid cancers are of particular significance because they represent the largest number of human tumours of one type due to one cause on one date that has ever occurred.
Urinary tract cytology
Authors: DeMay R.
Published: September 2007

Tumors of the urinary tract are relatively inaccessible to direct biopsy and are often multifocal. Since urine is easily ortained and washes over the entire mucosal surface, urine cytology is, in theory, the perfect specimen to examine to detect a tumor. Unfortunately, interpretation of urine cytology is difficult, and both false‐negative and false‐positive results are very well known. Diagnostic accuracy increases with the grade of the tumor. Low‐grade noninvasive papillary tumors are the sources of most false‐negatives. Reactive and degenerative changes due to conditions such as inflammation, stones, prostatic hyperplasia, and therapy are responsible for most false‐positives. This lecture will review basic urine cytology and give some pointers to help avoid diagnostic pitfalls.
CPA assessment – the regional assessors’ experience
Authors: Guthrie G.
Published: September 2007

With the introduction in January 2006 of the new posts of Regional Assessors, the process and focus of CPA assessment changed to reflect the inclusion in the current standards of Quality Management systems and processes.

Regional Assessors, trained in Quality Management Systems and their assessment against international standards, now form a vital part of the CPA assessment teams, looking specifically at this aspect of laboratory service provision. Their role in the new assessment process will be explained.

The presentation will cover differences and similarities in the nature and number of non‐compliances experienced since April 2006 when the new format of assessment was introduced. It will also look at a new format of timetable for assessment visits and explain the benefits of good two‐way communication between all parties involved in the process ‐ the laboratory, the assessors, particularly the Regional Assessor assigned to that site, and CPA Office staff.

Understanding what is required by the standards, particularly in terms of evidential material, their interpretation and their classification of status – Critical, Non‐Critical or Observation ‐ is an aspect of assessment which is often not well understood. The presentation will seek to clarify these issues.

The successful and timely clearance by laboratories of any non‐compliances raised during the visits is vital to the achievement of accredited status and the presentation will give guidance as to how this is best achieved.

The current standards, based on the international ISO 15189 standards, are considerably more challenging than the old ones. There is now a significant emphasis on Quality Management and its understanding, ethos and implementation within the laboratory, a key element which underpins all aspects of a laboratory's service. The achievement of accredited status assures our users of␣the type of client and patient focused service expected of a modern laboratory.
Pitfalls in Gynaecological Cytology
Authors: Turnbull L.
Published: September 2007

The implementation of liquid based technologies for cervical cytology has delivered many of the expected benefits but is also accompanied by a raft of new challenges for the cytomorphologist. Differences in the presentation of cellular material may on occasion make it more difficult to detect subtle or scanty abnormalities and novel cellular appearances expand the existing list of differential diagnoses. This presentation will focus on these changes and will examine strategies which may assist the practitioner in the reliable reporting of cervical samples.
What does airport baggage screening have to do with cervical cancer screening?
Authors: Wolfe J.
Published: September 2007

At the most obvious level, baggage screening and cervical cancer screening are both visual search tasks in which an observer searches for targets in visual displays containing distracting items. This talk will introduce you to some of the basic principles that have been uncovered in many laboratories over the last thirty years and more. More than this, however, baggage screening and cervical cancer screening share several other properties. They are both socially important, difficult tasks where ‘miss’ errors may be a matter of life and death. Of most relevance to this talk, they are both tasks involving search for rare items – what we will call low ‘target prevalence’. We have examined the effect of target prevalence on the likelihood that targets will be missed in a variety of visual search tasks including simulations of baggage screening. Miss error rates are much higher at low prevalence (targets present on 1%–2% of trials) than at high prevalence (targets present on 50% of trials). In several experiments, we have shown that this prevalence effect is very robust. It can be replicated with different types of stimuli from oriented lines to x‐ray images of luggage. I will describe a couple of ways to reduce or eliminate this effect. Finally, I will demonstrate that, even if a search task is easy, you can readily miss something that is happening right in front of your eyes.
Cervical screening policies 2008 and beyond
Authors: Winder R.
Published: September 2007

There are many developments in cytology and in the NHS that will impact on the NHS Cervical Screening Programme over the next few years. In the short term HPV is a major issue, whether triage, primary screening or vaccination with further evidence coming forward from NHS early implementers and from research trials. Cytology automation is also already being trialled for the UK.

So far as NHS developments go, we already have the two Carter reports, one on pathology modernisation and one on commissioning are both likely to impact on our service, as is the forthcoming Cancer Reform Strategy which should be out in a few months time. This will set out a blue print for cancer services in 2012, by which time the cervical screening programme could have a very different shape.
HPV trials update
Authors: Arbyn M.
Published: September 2007

Background: More than ever, clinicians need regularly updated reviews given the continuously increasing amount of new information regarding innovative cervical cancer prevention methods.

Methods: A summary is given from recently published meta‐analyses on three possible clinical applications of HPV DNA testing: triage of women with equivocal or low‐grade cytological abnormalities; prediction of the therapeutic outcome after treatment of CIN lesions, and last not but not least, primary screening for cervical cancer and pre‐cancer.

Results: Consistent evidence is available indicating thatHPV‐triage with the Hybrid Capture‐2 assay (HC2) is more accurate (significantly higher sensitivity, similar specificity) than repeat cytology to triage women with equivocal Pap smear results. When triaging women with LSIL, a reflex HC2 test shows a not significantly higher sensitivity, but a substantially and significantly lower specificity compared to a repeat Pap smear. After conservative treatment of cervical lesions, HPV testing picks up more quickly, with higher sensitivity and not lower specificity residual or recurrent CIN than follow‐up cytology. Primary screening with HC2 generally detects 23% (95% CI: 13%–23%) more CIN2+ compared to cytology at the lowest cutoff ASCUS or LSIL, but is 6% (95% CI: 4%–8%) less specific. By combined HPV and cytology screening a further 4% (95% CI: 3%–5%) more CIN3 lesions can be identified but at the expense of a 7% (95% CI: 5%–9%) loss in specificity, in comparison with isolated HC2 screening.

Conclusions: Sufficient evidence exists to recommend HPV testing in triage of women with atypical cytology and in surveillance after treatment of CIN lesions. In the United States, recently reviewed knowledge has resulted in the approval of combined cytology and HC2 primary screening in women older than 30 years. However, in Europe, cytology‐based screening still remains the standard screening method. The European screening policy will be reviewed based on the results of randomized population trials which are currently underway.
Erica Wachtel Lecture of Mice & Women
Authors: Williams D.
Published: September 2007

Diagnostic cytology of the female genital tract was introduced almost simultaneously by Aurel Babes in Bucharest, and George Papanicolaou in New York, in 1928. However, neither of these seminal observations made any immediate major clinical impact, and it was not until Papanicolaou and Traut's later published works on uterine cancer detection in the 1940’s, that any momentum was really gained.

George Papanicolaou was neither a pathologist nor a gynaecologist. He was an anatomist, and the original Pap smear was designed to assess the hormonal status of mice. However, womankind eventually somehow replaced the mice, and modern exfoliative cytology was born, and the face of cervical cancer management was changed forever.

My talk will be scroll through the history of cervical cancer prevention in Britain from 1960 until now, and will be based for the most part on my personal experiences and observations of 36 years before the mast in the Department of Gynaecology and Obstetrics at Birmingham University, and my brushes with some of the past and present Pioneers of the cytology screening programme in the UK, especially in those early years.
O‐1 Results from TOMBOLA (trial of management of borderline and other low‐grade abnormal smears)
Authors: Cotton S. , Smart L.
Published: September 2007

Annually in the UK around 250 000 cervical smears show low‐grade abnormalities. Alternative management policies following a low‐grade smear are cytological surveillance or referral for colposcopy. Their effectiveness and cost‐effectiveness, and the potential for human papillomavirus (HPV) testing to triage women to either management, has been debated. Trial of management of borderline and other low‐grade abnormal smears (TOMBOLA) (a large RCT) addresses these uncertainties, considering clinical, psychosocial and economic outcomes. 4439 women aged 20–59, resident in Grampian, Tayside or Nottingham with a low‐grade smear were randomised to cytological surveillance (six‐monthly smears in primary care) or hospital‐based colposcopy. At colposcopy, women with visible abnormality were randomised to immediate treatment or biopsy and recall for treatment if necessary. Recruitment HPV status was assessed using PCR techniques. Women were followed for three years to an exit colposcopy. Cumulative incidence of CIN2 or more severe disease (CIN2+) in the colposcopy arm was 7.9% per year, higher than in cytological surveillance (5.8%; OR = 1.43, 95% CI 1.23–1.67). This difference was less marked for CIN3+ (OR = 1.27, 1.04–1.55), suggesting spontaneous regression of some CIN2, and that initial colposcopy can lead to over‐treatment. There was little difference in psychosocial outcomes between arms. In comparison of biopsy and recall versus immediate treatment, there was no difference in cumulative incidence of CIN2+ or psychosocial outcomes. There was over‐treatment and increased frequency/duration of bleeding with immediate treatment. There was no compelling economic reason to favour any one management method. Testing for HPV does not appear to be effective in triage. Based on these findings, we make management recommendations for women with low‐grade smears.
O‐12 The use of control samples in the PAPANICOLAOU technical external quality assessment scheme
Authors: Boucher N. , Rose B.
Published: September 2007

Technical external quality assessment (TEQA) in Wales is based on NHSCSP publication 19, which sets out policy and procedures for the scheme. The purpose of EQA is to sustain and improve the quality of patient care by promoting a high standard of performance. Following the introduction of liquid base cytology (LBC) technical limitations, particularly in assessing counterstaining, have been noted. LBC provides the means to address these limitations ‐ As part of a development plan for TEQA in Wales, a control sample procedure was introduced to the scheme. A pooled control sample was composed, containing residual material from six ‘matched’ negative samples, re‐suspended in collection fluid. Aliquots of this sample were distributed for processing and staining, to the 13 laboratories registered with the scheme. The slides produced were assessed at a scheduled TEQA assessment in accordance with the standard criteria. Initial overall scoring for these control samples produced acceptable levels of staining for 12 of the laboratories ‐ one laboratory produced a marginal score. Repeat distributions have shown maintained or improved results. This method provides a prospective quality assessment tool, which counters the emphasis on slide selection and eliminates potential selection bias, whilst introducing consistency and improving comparability across participant laboratories. The method may also prove helpful in identifying technical inconsistencies such as equipment or handling errors that may occur during sample processing prior to or during staining. The control process, which is now used routinely in the Welsh TEQA scheme; is considered complimentary to, and not a replacement for, the selection process established in NHSCSP #19. However, we feel that this development could be considered as a new initiative in the National TEQA scheme. The control process is applicable to all LBC systems in current use.
O‐2 Preliminary results of the ARTISTIC study: a randomised trial in screening to improve cytology
Authors: Almonte M. , Kitchener H. , Desai M. , Sargent A. , Bailey A. , Turner A. , Thomson C. , Julian P.
Published: September 2007

Introduction:  The ARTISTIC trial was set up within the NHS Cervical Screening Programme in Greater Manchester to evaluate the effectiveness of human papillomavirus (HPV) testing in primary cervical screening. Here we present preliminary final results.

Methods:  24 510 women aged 25–64 were enrolled in the study after consenting to be tested for high‐risk human papillomavirus infection (HR–HPV) in addition to liquid‐based cytology. Participants were randomised to HPV revealed or HPV concealed results arms in a 3:1 ratio. HPV testing was carried out using the Hybrid Capture‐II test (HC‐II) and all HC‐II positive samples were genotyped using the Roche line blot assay (LBA). Those in the revealed arm who had negative cytology and were HPV positive at entry were recalled every other 12 months for repeated HPV tests.

Results:  1675 women showed no abnormality on cytology and tested positive for HPV at entry. At the time of analysis, 1200 (72%) of them had returned for a second HC‐II test. The overall HR‐HPV persistence rate by HC‐II was 43% in women who were retested less than 6 months after a positive entry sample, 40% between 16–24 months and 29% after more than 24 months. The prevalence of infections with HPV16 and HPV18 were 15%, and 7% at entry, and 38% and 32% of these infections were persistent at second screening. Among women with negative cytology and HPV positive test at entry, there were 1 and 12 cases of CIN3+ at the second visit and six and nine at exit in the concealed and revealed arm respectively.

Discussion:  These preliminary data suggests that the combination of liquid‐based cytology with additional HPV testing over two screening rounds is not more sensitive than cytology alone.
O‐3 Assessment of the tripath focal point™ slide profiler as a quality assurance tool within the cervical screening programme in wales
Authors: Rose B. , Nuttall D. , Beer H. , Seager V. , Savage A.
Published: September 2007

The use of computer assisted screening (CAS) in cervical screening is established in the USA and Europe and is currently undergoing trials in the UK (HTA). Following the introduction of SurePath™ LBC technology to Wales, Cervical Screening Wales (CSW) has implemented a study into applications of CAS within the CSP in Wales, agreed during LBC procurement negotiations. Technological support was provided by TriPath Europe and Medical Solutions UK Ltd. Evaluation centred on the use of CAS in Quality Assurance procedures, comparing it with rapid screening (review and preview), as HTA studies are already established to assess the primary screening role.

Assessment included

• Evaluation of CAS across a laboratory network – assessing sample identification, tracking processes and transportation

• Assessment of Quintile Ranking verses abnormality distribution

• Assessment of the NFR (no further review) category as a reliable indicator of sample negativity

• Monitoring screener performance using CAS: Focal Point/LGS has the capability to monitor operator/observer functions

Three laboratories in North Wales participated in the study. Slides were scanned centrally using Focal Point LGS and returned to laboratories for assessment.

Slide assessment followed a twin track protocol.

• The ‘manual’ arm assessed slides according to standard laboratory procedures

• The ‘CAS’ arm assessed slides using location guidance and screening

Data were collected and analysed by CSW. Approximately 12 000 samples were scanned; results were compared for both arms.

Results show that the technology has a number of benefits, in supporting and enhancing performance within the screening programme.

• CAS compares favourably with rapid screening

• Quintile ranking data reflects the distribution of abnormalities

• The technology is well suited to shared use through laboratory networks

• Variations in screener aptitude were noted.
O‐6 Preliminary results from the CPA funded virtual microscope pilot of the north west non gynaecological cytology EQA scheme
Authors: Hales S. A.
Published: September 2007

Circulation E of the North West non gynaecological cytology EQA scheme was split into two with one half receiving conventional glass slides and the other half receiving digital images supplied by the SlidePath company over the web. More of the participants eligible participated in the slide half (43/65) than the digital half (17/41).

Similar results were obtained for seven out of ten of the scoring cases and for both the educational cases. However for one case eight of the digital participants could not obtain the images over the web. In the remaining three scoring cases the digital participants were less good at obtaining the correct answer compared to the slide based participants. The use of this virtual microscopy has shortened the circulation length considerably. The digital participants complained about the speed the digital slides appeared on their computers and whilst most agreed that this is the way forward they are still uncomfortable with their performance being marked on their digital submissions. Delegates will have the opportunity of viewing still images taken for each case from this circulation.
O‐7 Pilot study for LBC preparation (Cytyc thinprep®) of bone marrow aspirates
Authors: Al‐Sam S. , Allerston A. , McGoogan E. , Al‐Refaie F.
Published: September 2007

Liquid based cytology (LBC) preparations are replacing many of the traditional methods used to examine non‐gynaecological cytology specimens. However, bone marrow aspirates which historically proceeded almost all non‐gynaecological cytology samples remain examined by direct air dried smears. This pilot study examined bone marrow aspirates using LBC. Material from 50 bone marrow aspirates from patients with lymphoma, multiple myeloma, leukaemia, metastatic carcinoma, myelodysplasia and other causes of anaemia were examined using ThinPrep® and the results were compared to direct smears. All cases had trephine biopsy performed during the same visit. We established a protocol for bone marrow ThinPrep® preparation as follows: 20 drops of bone marrow aspirate centrifuged in 30 ml CytoLyt® for 10 minutes at 2000 rpm; cell pellet re‐suspended, then washed with CytoLyt®/ GAA mix; following further centrifugation, cell pellet transferred to PreservCyt® solution. Slides were prepared on a ThinPrep® 2000 Processor and stained with various stains. The slides were superior preparations for examination and assessment of pathological abnormality. All haemopoetic cell lines were represented and elimination of RBCs allowed quicker and easier assessment of bone marrow cells. All cases were photomicrographed and images of bone marrow ThinPrep® preparations were compared to those of direct smears and bone marrow trephine biopsies. All 50 cases were presented at the local MDT meetings over an 8 months period. The ThinPrep® preparation made a significant contribution to diagnosis and management of patients with bone marrow abnormalities. We acknowledge the support from Cytyc UK Ltd for this research project.
O‐8 Detection of human telomerase gene (TERC) amplification in cervical neoplasia: a retrospective study of 50 patients with normal smears or mild or moderate dyskaryosis
Authors: Crookes R. E. , Dyson M. , Smith J. F. , Maltby E.
Published: September 2007

Recent comparative genomic hybridisation studies (Heselmeyer‐Haddad et al., 2003) indicated the involvement of extra copies of 3q in invasive cervical carcinoma. In 2005, the same group demonstrated the use of a FISH probe set, involving the human telomerase gene (TERC) located at 3q26, on conventional cervical smears. Their retrospective study of 59 patients showed that gains of TERC could predict progression from lower grade smear abnormality (mild or moderate dyskaryosis) to CIN3 and invasive carcinoma. It also demonstrated that 33% of normal conventional smears from women that subsequently developed CIN3 or invasive carcinoma showed extra copies of TERC. We present the results from a larger retrospective FISH study, using the same TERC probe kit (under development by Vysis/Abbott), on a selection of 50 patients with normal smears or mild or moderate dyskaryosis that later progressed to CIN3, Using the probe set along with an adapted de‐staining technique we achieved a 92% success rate compared to the previous study, achieving only 50%. The results showed that TERC gains increase with the grade of dyskaryosis (60% for mild dyskaryosis and 82.4% for moderate dyskaryosis). This concurs with previous studies which have proposed that the acquisition of TERC is an important genetic event in the progression of cervical dysplasia to cervical cancer. For the cohort of patients classified as cytologically normal that subsequently developed CIN3, 28.5% were positive for TERC gain, demonstrating the potential use of TERC detection by FISH as an early prognostic indicator of disease progression.
O‐9 Uncommon subtypes of borderline nuclear changes: cytological features and predictive value
Authors: Evered A.
Published: September 2007

In 2002 the British Society for Clinical Cytology proposed the introduction of borderline reporting category subtypes in the UK cervical screening programmes. Although yet to be implemented nationally the terms ‘borderline changes, high grade dyskaryosis cannot be excluded’ (BC‐H) and ‘borderline changes in endocervical cells’ (BC‐E) have been in use for some time at this centre. The aims of this study were to determine the frequency of use of BC‐H and BC‐E, to calculate their predictive value and to describe their morphological features. The reporting categories BC‐H and BC‐E are rarely used at this centre, each comprising just 0.05% of the routine cervical cytology workload and 1.4% of the borderline fraction. The predominant presentation of BC‐H in SurePathTM samples is that of hyperchromatic crowded cell groups. Approximately half these cases are associated with a significant cervical lesion (CIN2 or worse). BC‐E displays heterogeneous cytological features. Approximately 1 in 5 cases are associated with a significant histological lesion and only 1 in 10 cases harbour a significant glandular lesion (CGIN or worse).
Liposomal cytarabine for treatment of myeloid central nervous system relapse in chronic myeloid leukaemia occurring during imatinib therapy
Authors: Aichberger K. J. , Herndlhofer S. , Agis H. , Sperr W. R. , Esterbauer H. , Rabitsch W. , Knöbl P. , Haas O. A. , Thalhammer R. , Schwarzinger I. , Sillaber C. , Jäger U. , Valent P.
Published: September 2007

Background  Central nervous system (CNS) relapse in chronic myeloid leukaemia (CML) is rare and if recorded is usually found to occur in patients with lymphoblastic transformation. The BCR/ABL tyrosine kinase inhibitor imatinib is highly effective in patients with CML, but hardly crosses the blood–brain barrier.

Patients and methods  We report on two CML patients who developed a myeloid CNS relapse during treatment with imatinib. One patient was in major cytogenetic response at the time of CNS relapse. In both cases, the myeloid origin of neoplastic cells in the cerebrospinal fluid (CSF) was demonstrable by immunophenotyping, and their leukaemic origin by detection of the BCR/ABL oncoprotein. No BCR/ABL kinase domain mutations were found. Both patients received intrathecal liposomal cytarabine (50 mg each cycle; 6 cycles). In one patient, additional CNS radiation was performed, whereas in the other, consecutive treatment with dasatinib (70 mg per os twice daily) was started.

Results  In response to therapy, the clinical symptoms resolved, and the leukaemic cells in the CSF disappeared in both cases. After three months of observation, both patients are in complete cytogenetic and major molecular response, without evidence for a systemic or a CNS relapse.

Conclusions  ‘Anatomic’ resistance against imatinib in the CNS can lead to a myeloid CNS relapse. Liposomal cytarabine with or without radiation is effective as local therapy in these patients. For systemic treatment and prophylaxis, BCR/ABL kinase inhibitors crossing the blood–brain barrier such as dasatinib should be considered in patients with CNS relapse.