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Pipette calibration and the ISO 8655 standard

2nd July 2006

Sami Koivisto
MSc(Tech) EUR ING
Technical subcommittee
CEN/TC 332
European Committee for Standardization

As a concept, calibration can be understood in several ways  and the interpretation can vary between different devices.  When associated with pH meters, calibration means adjusting  the device to give a specific value with a defined standard  solution. With balances the same word means only the  determination of the difference between the reference weight  mass and the reading obtained from the device display. The  understanding of these concepts can vary even within the  same organisation. It is important that the concepts used in  discussion are understood. In this article the following  definitions apply:

  • Calibration is the determination of the difference between  the mean volume of the measurement series and the selected  volume on the pipette display.
  • Adjustment is the alteration of pipette settings for the  actual volume to correspond to the selected volume.

This means that during calibration no physical changes are  made to the device itself and the process gives only the  measurement result. During the adjustment phase the device  is physically altered to deliver a different volume. To  confirm the effect of adjustment the device needs to be  recalibrated.

Calibration in practice
In practice, calibration means the functional verification  of the pipette. This begins at the factory, where the  pipettes are adjusted and calibrated for quality assurance.  It is recommended that the clients perform an inspection of  the devices before they are released for operator use. This  is due to the different operating conditions, which can have  an effect on the calibration results. However, very often  the pipettes are not calibrated until the first maintenance  session.

The calibration procedures are usually performed according  to a standard method and only the functionality of the  pipette is verified. The standard check is always performed  using water. Since pure water is seldom used in laboratory  applications, the actual amount of liquid can differ from  the standard calibration value. The result obtained in  calibration is bound to time, place, ambient conditions, the  liquid used and the operator. Therefore, in addition to the  reference calibration it is suggested that a calibration is  performed using the liquid to be transferred. This should be  done in laboratory conditions by each operator using the  pipette to verify that a desired volume amount is obtained.  The pipetting method and the equipment setting (pipette + tip) demanded by the application should also be included in  the test.

However, adjustment is not recommended for liquids other  than water due to the insufficient or approximate  correlation data (mass to volume conversion). The operator  should also bear in mind that pipettes will be used to  transfer different liquid types with deviating properties.  Adjustments would have to be done each time a liquid is  changed. Water is officially accepted as a standard  calibration liquid due to thorough research and statistical  results. This gives reliable reference values for the  devices. The follow-up of the mechanical functioning of the  pipette is therefore easier for the user and better accepted  by official parties.

The calibration values obtained using liquids other than  water can be referred to the obtained reference values and  necessary corrective actions can be taken accordingly. For  example the statistical deviation of these results can be  added to the uncertain calculations used by accredited  laboratories.

International standard ISO 8655 for POVA devices
In January 2003 the new EN ISO 8655 standard for  piston-operated volumetric apparatus (POVA) was published as  a result of the work of joint technical subcommittees ISO TC  48/SC1 and CEN/TC 332/WG1. This standard replaced the  well-known DIN 12650 standard, used since 1997. The previous  DIN standard was mainly directed at manufacturer use, but  the present ISO standard is also directed at service houses  and end-users. ISO 8655 contains seven parts covering  different kinds of piston-operated liquid transfer devices. The sections that relate  to piston pipettes are:

  • Part 1: Terminology, general requirements and user  recommendations.
  • Part 2: Piston pipettes.
  • Part 6: Gravimetric methods for the determination of  measurement error.
  • Part 7: Nongravimetric methods for the assessment of  equipment performance.

Part 1 contains valuable general information for all parties  including vocabulary. Part 2 describes the structure and  operation principle of a piston pipette and also contains  the acceptance tolerances for calibration – according to  nominal volumes. The actual gravimetric testing procedure is  described in Part 6. The demanded calibration conditions are  also stated. Part 7 describes alternative calibration  methods and the terms when these methods can be used to  fulfil the standard requirements. Present methods include  the photometric method (horizontal direction) and the  titrimetric method.

Coverage of ISO 8655
The standard states the acceptance specifications, test  methods and testing conditions for pipettes. It also gives  some information about the basic pipetting errors affecting  the procedure. The standard is directed to manufacturers as  a basis for product type testing and quality control,  including, when appropriate, the issuance of manufacturer’s  declarations of conformity. The standard also addresses the  needs of test houses and other bodies as a basis for  independent certification of conformity, and the needs of  equipment users to enable routine performance checking.

The test method described in ISO 8655-6 can be applied in  every calibration procedure regardless of the ambient  conditions. However, when the functionality of the equipment  or the conformance to official acceptance limits are  concerned, only the conditions mentioned in the standard are  acceptable. The acceptance limits in the standard do not  apply to liquids other than water or pipetting methods  different from the forward pipetting technique.

Manufacturer’s acceptance specifications versus ISO 8655  acceptance specifications
One of the puzzling questions about ISO 8655 is the  difference between the manufacturer’s acceptance limits and  acceptance specifications. The specifications in the  standard are designed to serve all parties from  manufacturers to end-users. Since the acceptance limits are  the same for everyone, the manufacturers continue to use  their internal quality control limits to demonstrate the  performance capabilities of the pipettes. The manufacturer’s  acceptance limits are usually much stricter than the  specifications mentioned in the standard, especially where  adjustable pipettes and small volumes are concerned.

The standard specifications are wider than the corresponding manufacturer’s specifications since there is no actual need for more accurate or precise dosing in applications where POVA devices, such as pipettes, are used. Although the sensitivity of laboratory applications has increased, in many cases the required level of measurement accuracy can still be more than 10-fold compared with device acceptance limits. Naturally, it is good to minimise known error sources, but most are not caused by the device itself. Knowing and understanding the most critical error factors demands both theoretical and practical knowledge from the operator.

The main difference between the manufacturer’s acceptance limits and standard specifications concerns the variable volume pipettes. Manufacturers give volume-bound specifications for certain test volumes. These volumes are usually the nominal volume of the pipette (maximum volume) and the minimum volume or 10% of the nominal volume. Sometimes additional specifications, such as the middle volume (50% of the nominal value), are also published. The standard, however, gives specific values that are bound to the nominal volume values of the pipettes. All other  selectable volumes have the same absolute acceptance limit values as the model specific nominal volume. For example, a pipette model of 100–1000µl has an acceptance value of 8µl at the maximum volume for systematic error (inaccuracy). This is 0.8% of the nominal volume. At the setting of 100µl, the acceptance limit is the same (8µl). However, the relative value is 8%. The limits are always defined according to the absolute error values.

Special requirements of ISO 8655
ISO 8655 standard describes many requirements that end-users and independent test-house operators should follow to fulfil the standard. These requirements can be classified under different categories.

Use of pipettes
To ensure safe and efficient use of the device the standard  requires the user to follow instructions provided by the  manufacturer. Special care should be taken to prevent the  entry of liquid into the pipette interior. The user is also  responsible for ensuring that used pipettes and pipette tips  are resistant to the transferred liquids.

Calibration performed by the user
To achieve the needed reliability of volume measurement, users should establish their own acceptance maximum error limits for both systematic (inaccuracy) and random  (imprecision) error. These requirements are determined by the applications where pipettes are used. Conformity to the defined acceptance limits should be tested by the user at  regular intervals as part of their own quality protocol. The required time interval should be based on the frequency of use, number of operators using the device, nature of the  liquids and finally the demands of the applications. The  time interval can be, for example, three months but no more than one year, and the defined protocols should be recorded into the user’s quality system. In case pipette tips different from those of the manufacturer are used, the operator should confirm the suitability and functionality of the tips with the pipette.

Maintenance of the pipette
Many laboratories send their pipettes to other test houses  or the manufacturer for maintenance and calibration  procedures. In these cases it is the responsibility of the  user to perform pipette decontamination. Nondecontaminated devices should not be sent for servicing.

Other uses of the standard method
When the standard method is used by the manufacturer for  purposes other than type testing, such as quality control or  functional verification as part of the after-sales service,  the standard allows the manufacturer to define:

  • The number of needed test volumes.
  • The number of measurements used per volume.
  • For multichannel pipettes, the number of channels tested.

According to these definitions, many manufacturers use their own testing protocols in quality assurance. Both one- and two-test volumes are used. The results are determined using four or more measurement values per volume. Results from multichannel pipette calibration can be reported for two or more individual channels. These choices are mainly based on the reference measurements and extensive statistical experience of the manufacturer. The present quality systems require increasing attention to the equipment performance and to traceable reference calibration records. This can be  achieved by using a standardised calibration method such as the procedure described in the ISO 8655 standard. It is  recommended that pipettes are also adjusted according to a standard procedure.

[[HHE06_fig1_L36]]

Although the best way to assure the functional performance  of the pipette is to follow a standard procedure, the real  situation within the laboratory can be different. To ensure reliable results, it is recommended that pipettes are calibrated in a “real” laboratory environment in addition to undertaking traceable standard quality control. This, however, demands both good theoretical and practical  knowledge from the operators.

Further reading
International standard EN ISO 8655. Piston-operated volumetric apparatus. Geneva: ISO; 2002.
Technical report. ISO/TR 20461. Determination of uncertainty for volume measurements made using the gravimetric method, Geneva: ISO; 2000. 

Promoting research in cardiovascular pharmacology and drug therapy

1st July 2006

Kurt Stoschitzky
MD FESC
Universitätsklinik für Innere Medizin
Abteilung für Kardiologie
Graz, Austria
T: +43 316 385 80261
E: kurt.stoschitzky@meduni-graz.at
W: www.escardio.org/bodies/WG/wg03

Cardiovascular pharmacology and drug therapy is one of the most essential parts of cardiology. It is important to remember that not only cardiologists but also specialists in internal medicine, general practitioners and doctors in all kinds of different specialised hospital departments have to deal with questions of cardiovascular pharmacology and drug therapy. Principally, this is because cardiovascular diseases remain extremely prevalent throughout the world and they still belong to the most frequent causes of death, particularly in the developed countries. Therefore, questions, problems, newer developments and solutions concerning cardiovascular pharmacology and drug therapy are present in daily medical practice all over the world, which is why it one of the main field of interests and activities of the European Society of Cardiology’s (ESC) Working Group on Cardiovascular Pharmacology and Drug Therapy.

The aims of the Working Group are: to promote and organise research in the field of cardiovascular pharmacology and drug therapy; to gather and exchange information regarding research and related activities within the Working Group; to organise teaching workshops on topics related to cardiovascular pharmacology and drug therapy; to hold regular meetings of the Working Group on specific topics; to be involved in task forces of the ESC related to cardiovascular pharmacology; to contribute to the organisation and preparation of the Annual Congress of the ESC; to participate and support other scientific meetings and symposia. In addition to these aims, a further goal of the Working Group is to provide a forum of expertise and debate regarding all aspects of cardiovascular pharmacology and drug therapy, encompassing the entire spectrum from molecular pharmacology, including pharmacogenomics, to cardiovascular clinical trials. We are able to be a truly multidisciplinary task anticipated to gain significantly in importance in cardiovascular medicine.

Current areas of interest
This year the Working Group co-organised the following symposia with the World Congress of Cardiology, which also reflect the main interests of the Working Group, at this year’s ESC Annual Congress in Barcelona, Spain. Noncompliance to medication in cardiovascular patients: cause for concern? Chaired by TM Norekvaal (Norway) and E Ambrosioni (Italy), this symposium contained the following lectures: How to measure noncompliance in research and in clinical practice (L Burke, US); How to deal with non-compliance in heart failure trials (F Zannad, France); Is aspirin resistance explained by noncompliance? (E Kaluski, Israel); Consequences of nonadherence to immunosuppressive therapy in heart transplant recipients (F Dobbels, Belgium); Interventions to improve compliance to medication in cardiovascular patients (SM de Geest, Switzerland). An economic view of cardiovascular care. Chaired by L Ryden (Sweden) and SC Hammill (US), this symposium contained the following lectures: Health economics: what is important for clinicians worldwide? (B Jonsson, Sweden); Economic issues in cardiovascular prevention with drugs (DB Mark, US); Economic issues in the clinical use of electrical devices (G Boriani, Italy); Economic issues in the clinical use of percutaneous coronary interventions (KA Fox, UK). Interpretation and misinterpretation of cardiovascular trial results. Chaired by R Collins (UK), F Zannad (France), this symposium contained the following lectures: Use and misuse of composite endpoints in cardiovascular clinical trials (J Lubsen, Switzerland); Subgroup analyses that influenced drug approval and/or clinical practice (AP Maggioni, Italy); Positive control trials (ie,antihypertensive A versus antihypertensive B) and what are they for? (SE Kjeldsen, Norway); Tricks and pitfalls of reporting results of cardiovascular trials (SJ Pocock, UK). In addition to the above topics, there are ongoing discussions in other fields of cardiovascular pharmacology and drug therapy that the Working Group is currently involved with. These include:

  • How to treat hyperlipidaemia: Statins and/or cholesterol absorption inhibitors, nicotinic acid/niacin, rimonabant.
  • The position of thrombolysis in acute ST elevation myocardial infarction in the upcoming era of acute coronary intervention.
  • Heparin, low-molecular-weight heparins, bivalirudin, fondaparinux, aspirin, clopidogrel and GP IIb IIIa inhibitors in the treatment of ST-elevation myocardial infarction, Non-ST-elevation myocardial infarction and acute coronary syndromes.
  • ACE inhibitors versus angiotensin receptor blockers in the treatment of arterial hypertension and heart failure.

Working Group structure
The Working Group is directed by the chairman and the vice-chairman or past-chairman. The vice-chairman is proposed by the Nucleus and elected by the ordinary members. He/she serves for one year and then becomes chairman. The chairman serves for two years and represents the Working Group at official functions of the ESC, then he serves for one further year as a past-chairman. There is also a serving treasurer and a secretary. Nucleus meetings are performed three times a year: at every Global CVCT Forum in spring (where the Working Group is an official participant); at every ESC Congress; and at every Educational Autumn Meeting. The annual business meeting of the Working Group is held during each annual Congress of the ESC where all members are invited to attend and to participate actively in order to bring in their ideas, criticisms, and proposals. In addition, all decisions about who will be the members of the Nucleus, the next chairman and vice-chairman, the treasurer and the secretary will be made at these meetings.

[[HHE06_box1_P6]]

People working in any field of cardiovascular pharmacology who are interested to become members of the Working Group can apply either directly or through a proposal to the chairman of the Working Group submitting a brief curriculum vitae including relevant references. The chairman presents the applications from suitable new members to the Nucleus for ratification. Unsuitable applicants (as far as formal requirements are concerned) may be rejected by a majority vote of the Nucleus. If an application is rejected by the Nucleus, there is no obligation to give reasons to the applicant. Membership shall be granted for life unless the member is expelled from his National Society belonging to the ESC, in which case his/her membership of the Working Group will automatically cease to exist. Currently no membership fee is required.

Barriers to the development of modern pharmaceutical care

Jiri Vlcek
President
European Society of Clinical Pharmacy

Healthcare is a service made up of interdisciplinary teams dedicated to patient care. Patients have to profit from the knowledge, skills and empathy of healthcare workers to get better. However, pharmacists are not formally considered as healthcare workers by law in many countries. Similar postgraduate education for pharmacists and physicians has been developed in a restricted number of European countries, even though in many others no postgraduate education system controls the quality of work or increases knowledge and skills. Consequently, pharmacists are evaluated according to the volume of drugs they sell and not according to the quality of care they provide.

The pharmacy profession is closely linked to industry and many pharmacists sell drugs as their main activity, which does not require much clinical pharmacy knowledge. As a result, pharmacists fluctuate between being a salesperson and a genuine healthcare worker, which confuses their relationship with patients.

Pharmacy in flux
The European Society of Clinical Pharmacy (ESCP) aims to support the healthcare side of pharmaceutical practice, in view of the fact that there is not a satisfactory level of pharmaceutical care in old EU countries, while the situation is even worse in new EU countries. Sadly, new EU countries did not protect the good level of pharmaceutical care developed during the socialist era (when pharmaceutical care was managed centrally together with medical care). Today, the pharmacy network is not regulated in new EU countries and pharmacists have started to compete on price alone. Some industry figures see this as an advantage as they can concentrate their marketing activities on the physicians who make the clinical decisions, without having to deal with pharmacists.

What’s more, politicians and patients don’t see any added value in the pharmaceutical service and believe that reducing cost in this area can help to solve more general financial problems in healthcare. Drug prices are not fixed, so patients travel between pharmacies to find the cheapest drug. However, they are confused as to why reimbursements vary. Industry can cause fluctuations in drug prices to occur by selecting a few pharmacies to reduce reimbursements. In addition, physicians can increase their income if they dispense drugs and they, together with politicians, don’t think enough about the risks related to patient safety.

The modern face of pharmacy?
Hospital pharmacists may think they are in a better position because of their closer links with other healthcare workers, but the reality is different. Many hospital managers do not expect hospital pharmacies to provide tasks other than patient safety support, controlling medication errors, carrying out pharmacoeconomical analyses and cooperating in pharmacotherapy.
 
Some hospital pharmacies have outpatient drug dispensing units, which increase hospital income. There are clever hospital managers who allow part of this money to be used for developing hospital pharmacy services, but if the margin goes down then it is immediately seen as the “wrong” policy.
 
Hospitals, insurance companies and governments are often not used to accepting the pharmacy as a valid element of healthcare. When they do discuss this topic, reducing margins and implementing more market economics are often the focus. Of course, this is not the picture everywhere in the EU, but in general Europeans are not as successful at transforming pharmaceutical activities as they are in the US, Australia or some Asian countries. What are the reasons for this? Many think that it is a communication problem between pharmacists and pharmaceutical associations with the public and physicians, between pharmacists themselves, and between experienced pharmacies and graduates. Many older colleagues and pharmacy owners have got different expectations and do not support clinical pharmacy activities as a general concept, which does not allow hospitals to develop the modern face of pharmacy.

Cooperation and communication
European studies that could help to provide evidence about today’s activities and differentiate the pharmacy practice with a focus on patients are, unfortunately, not available. Such examples do exist in the US, but we think the advantage of the European healthcare system is the number of well-educated general practitioners and community pharmacists. These two main key professions cooperate well in the Netherlands and reason is simple: the Dutch government supported communication between the two professions and put them on the same collegiate level.

We have to base improved cooperation and communication on the development of clinical pharmacy. The ESCP is trying to stimulate debate to find out how best to achieve this; we are looking for strategic partners, such as the European Association of Hospital Pharmacists (EAHP), the Pharmaceutical Group of the European Union (PGEU), the World Health Organization and some physician associations, with the aim of providing better care for patients. The EAHP agrees that clinical pharmacy should become a specialisation in hospital pharmacy. All professionals involved in pharmacy should be focused on clinical pharmacy, improving praxis on the ward and participating in training the rest of the pharmacy team and pharmaceutical students. In the future hospital pharmacies should become training centres for community pharmacy.
 
We are also in discussion with PGEU representatives. We need to accept that only when pharmacists are united can they show that they are a valuable part of the healthcare team and a good partner for all patients, physicians, managers and payers. The ESCP has ambitions as a society of individuals who wish to develop clinical pharmacy in both settings, joining hospital and community pharmacies under one umbrella. We hope that effective care for patients is the basis for this.

Effective care
But, what does effective care mean? Pharmacists can support pharmacotherapy by encouraging optimal self-medication and by the rational use and choice of prescription drugs. Pharmacists are able to maximise benefit, minimise risk, control compliance and control cost. These are main areas for protecting rational pharmacotherapy and we need to know how and what are our barriers are, and what we as pharmacists can improve on in terms of reducing medical errors that occur during prescribing, transcribing and dispensing. We have to be proud of it and use complementary knowledge about pharmacotherapy, which is missing from the curricula of medical faculties.The ESCP offers its services to all pharmacists. It is our hope that the hospital and community pharmacists on the ESCP board cooperate and develop clinical pharmacy together. Clinical pharmacy is one of the keys to improve the image of pharmacy around to Europe. Physicians and patients need this service.

The dawn of a golden age of medical oncology

Hakan Mellstedt
President
European Society for Medical Oncology
W: www.esmo.org

The coming decades will be the golden age of medical treatment in oncology. Today about 60% of all cancer patients can be cured. It is expected that within 10–15 years this rate will rise to 75%. These impressive achievements are primarily attributed to novel medical therapeutic approaches, particularly targeted therapies, and also, in part, to early detection. As for more conventional treatments, such as chemotherapy and hormonal therapy, their level of use is expected to remain more or less unchanged.

Targeted therapies
Targeted therapies offer the possibility of multiple treatment options. Many new drugs will target the angiogenesis process (the formation of new blood vessels in the tumour), which are crucial for tumour cell survival. Therefore, a focus on destroying these tumour vessels, and thereby killing the tumour cells, is of primary importance. Drugs inhibiting pathological signalling systems within the tumour cells are under development. Drugs that can specifically turn off such signals eliminate the prerequisite that is necessary for tumour cells to survive. Monoclonal antibodies, which activate the immune system and interface with abnormal signals, also provide important weapons for treatment.
 
In addition, new vaccines are expected to be part of the therapeutic arsenal against cancer. They can be divided into prophylactic and therapeutic vaccines. Prophylactic vaccines will be used for prevention – a possibility in viral-associated cancers. There are great hopes are being placed on prophylactic vaccines for use against hepatocellular carcinoma and cervical cancer, with the hope that cervical cancer may be eradicated. Other vaccines are therapeutic and will be used earlier on in the course of the disease or as secondary prevention to avoid relapse.

Novel targeted therapies will also be used in combination to better target multiple defects within the tumour cells. However, targeted therapies will not be without induced side-effects, although these can be quite different from those experienced with chemotherapy (ie, hypertension bleedings, intestinal necrosis with bevacizumab or rash from erlotinib). Some side-effects may even be severe, as witnessed by the recently reported case of CD28 targeting antibodies and resulting in life-threatening consequences to healthy volunteers from the UK.

Another breakthrough in new drugs for cancer treatment is that many of them can be administered orally, adding significant practical advantages for both oncologists and patients.
 
In summary, the role of medical oncology in treating cancer remains central. New developments add not only to improvements in antitumour efficacy of treatment approaches, but also heighten the supportive care offered to patients in order to provide them with the best possible treatment options and quality of life.

The voice of medical oncology in Europe
Because medicine is involved in almost every aspect of cancer treatment, the European Society for Medical Oncology (ESMO) believes that cancer patients should be treated by qualified medical oncologists. In Europe, ESMO is a highly respected institution in the field of oncology and the leading professional society of medical oncologists. The major focus of all ESMO activities is to improve the prevention, early diagnosis and treatment of cancer, as well as the follow up care of cancer patients. Through its Cancer Patient Working Group, and in addition to working with patient advocacy groups, ESMO organises patient and family seminars in accordance with its mission to embrace patients’ needs. The initial theme of patient–physician communication has led to the forging of a patient–physician partnership – to which patients bring their needs and direct experiences, while physicians contribute with evidence-based science – in a united effort to improve healthcare services throughout Europe.

Current developments in oncology indicate the need for treatment by multidisciplinary teams. To this end, ESMO offers multidisciplinary programmes that foster collaboration between different disciplines within the Society such as medical oncology, radiation oncology, surgical oncology, paediatric oncology, oncology nursing, oncology pharmacy and basic research.

ESMO addresses global inequalities in cancer care through the statistical analysis of data concerning discrepancies in the prerequisites for the practice of oncology in Europe and developing countries. The summary reports from this data analysis help to identify necessary improvements in the infrastructure of those countries that have less than optimal healthcare systems. They also help to face the challenge of reducing disparities in the quality of care available to patients residing in different European countries. Furthermore, they will provide further evidence of the need to recognise medical oncology as an independent specialty throughout Europe and worldwide.

Together with the Organization of European Cancer Institutes, ESMO is seeking to identify the necessary criteria for medical oncology units in comprehensive cancer centres. In addition, the new ESMO Oncology Accreditation Committee will examine accreditation criteria for the quality control of patient care and physician education in European cancer institutes, oncology centres and major university oncology departments.

Standardised training in medical oncology, based on a solid background in internal medicine, has been defined in the Recommendations for a Global Core Curriculum in Medical Oncology, produced by ESMO in joint collaboration with the American Society of Clinical Oncology (the training curriculum was published in the November 2004 issues of both Annals of Oncology and the Journal of Clinical Oncology). The ESMO Examination in medical oncology certifies medical oncologists and is required to practice medical oncology or be a full member of medical oncology societies in several European countries.
 
Information, knowledge and experience combine to form the backbone of excellence in clinical practice. Following the publication of the ESMO Policy on Palliative and Supportive Care, for example, the Society has moved ahead to identify “designated centres of integrated oncology and palliative care” that meet a comprehensive list of criteria and are capable of providing specific training in this important aspect of patient care.
 
ESMO continues to serve its members by supporting them in their daily practice and careers. The ESMO Minimum Clinical Recommendations assess diagnosis and treatment of various cancers. They are intended as guidelines for clinical practice and prerequisites for basic healthcare services. For ESMO members who seek a specialist’s opinion on difficult and complicated cases, a web-based clinical discussion forum that allows them to consult directly with ESMO Faculty members is available on the ESMO website. For young oncologists, ESMO offers a career development programme of fellowships, translational research unit visits, masterclasses, special educational activities, oncology handbooks – and much more.
 
The great strides and improvements that are on the horizon bring with them the need to transform a wholly scientifically oriented organisation into a society focusing on a multidisciplinary approach to oncology and one that is willing and able to face the multifaceted aspects of cancer care and research. As the voice and driving force of medical oncology in Europe, ESMO is eager to continue to expand its role in multidisciplinary oncology in order to meet the challenges that lie ahead.

The new face of organ transplantation

Bernard Charpentier
PhD
President
European Society of Organ Transplantation
W: www.esot.org

Transplantation is one of the best examples of basic and clinical investigations developing at the same time. Since the pioneering works of the early 1950s, transplantation now touches many different fields of research. It seems, however, that much of this research has been going round in circles for some time. Developing new areas of research, such as emerging technologies, stem cells, in- vitro embryogenesis and the interface between physics and biology, would be beneficial to the whole transplantation community.

Major advances
This fact was illustrated during the past 12 months through articles in the journal Transplant International and conference papers, such as those at the 12th Congress of the European Society for Organ Transplantation (ESOT) in Geneva. Major advances have been made in the basic aspect of tolerance and clinical trials of tolerance induction, T-cell regulation and immune deviation. A major role has been defined for FOX P3 gene polymorphism,cytokine polymorphism, the CD25+ FOX P3+ regulatory cells in transplantation tolerance and ex-vivo gene therapy.
 
Stem cells are a particular area of interest currently, with progress being made in the transplantation of embryonic organs, stem cell transplantation for cardiac regeneration, liver regeneration with mesenchymal stem cells and stem cells for pancreatic islet generation. However, major advances have been made in the clinical aspects of transplantation, such as HIV and organ transplantation, high-risk donors, split liver and surgical techniques of liver transplantation, rituximab and acute vascular rejection, limb transplantation, microsurgical bench arterial reconstruction and laparoscopic live donor nephrectomy.

Finally, emerging technologies will ensure new approaches to, for example, the treatment of diabetes and alternatives to whole pancreas transplantation. Major advances have also been seen in the xenotransplantation of pig islets, the bioartificial endocrine pancreas and porcine islet cells microencapsulation.

ESOT
ESOT was founded in 1982 and today has more than 1,000 transplant professionals dedicated to patient care, clinical and basic research, and clinical and basic education in the field of transplantation. ESOT is designed as a forum for knowledge exchange in the field of transplantation between European transplant physicians, surgeons, biologists and scientists. As a major society that encourages “science”, the ESOT biannual congress and Transplant International will be open to new areas of research mentioned above and a forum for all the basic science and clinical investigations around the world.

ESOT also wishes to strengthen the partnership with pharmaceutical industries and academic institutions; both have now developed a fantastic “panoplia-armamentarium” of new drugs, instruments and devices, and their progress will be clearly focused on subtle parameters such as graft quality and quality of life of the recipient. Partnership therefore remains mandatory for the future progress of transplantation.

Promotion of transplantation research is an important part of ESOT’s mission. With the support of Astellas, Roche, Novartis, Fresenius, Genzyme and Kohler Chemie, different grants are made available for younger physicians aiming at a career in the field of transplantation.

Best foot forward: advancing rheumatology in Europe

Tore K Kvien
President
European League Against Rheumatism
W: www.eular.org

Rheumatic disease is an umbrella term that covers inflammatory rheumatic diseases, degenerative joint diseases (eg, osteoarthritis), chronic pain conditions in the musculoskeletal system (eg, fibromyalgia) and other musculoskeletal diseases such as osteoporosis. This group of diseases is the single most costly group of disorders in Europe, if measured in terms of hospital costs, medication costs, rehabilitation costs and costs of lost days at work. Every family has at least one member who is affected by a rheumatic disease. Despite these facts, there is a need to improve the awareness of rheumatic disease and to raise their priority when decision-makers are allocating resources both for research and care. Fortunately, several advances in treatment have been made over the last few years, such as improved understanding of pathophysiological processes, access to new technologies, including new imaging tools (MRI and ultrasonography), new drugs and better treatment strategies. The most common inflammatory rheumatic disease is rheumatoid arthritis. Patients with this disease have pain, stiffness and joint swelling, and the inflammation may destroy the joint structure with subsequent joint deformities, limited motion and disability. Newly developed and improved treatment strategies include early diagnosis, early and aggressive use of disease modifying antirheumatic drugs, regular monitoring of the disease and adjustment of therapy according to changes in disease status. Additionally, new important biological drugs, the anti-TNF therapies, have become available and three other biological agents will probably be available within a couple of years.
 
Treatment opportunities for patients with ankylosing spondylitis and psoriatic arthritis have also improved with access to new biological therapies. For patients with osteoporosis, new treatments are under development and better management strategies are available, including public health strategies with a focus on early detection of patients at risk and prevention of bone loss. More treatment alternatives will shortly become available both for patients with gout and those suffering from severe connective tissue diseases such as systemic lupus erythematosus. However, the situation for patients with osteoarthritis is less promising. The increased awareness and focus on side-effects from coxibs and traditional nonsteroidal anti-inflammatory drugs have influenced patients’ perceptions about the risk-benefit ratios of these agents. The consequence has been that an overuse of these medications have been eliminated, but many clinicians feel that many patients now avoid them, despite regular risk benefit considerations showing their value. Glucosamine and chondroitine sulphate have been considered as promising treatment opportunities, but results from recent trials have been rather conflicting about their efficacy. However, osteoarthritis is an area of increased research focus and one major objective is to develop therapies that may modify key disease processes such as cartilage destruction.

EULAR
Patients and health professionals working with rheumatic diseases need strong organisations, both to raise the awareness and priority on a political level, and to work for early implementation of new therapies and findings into the daily healthcare. EULAR (European League Against Rheumatism) is the umbrella organisation of scientific rheumatology societies from 42 European countries and 30 national patient organisations. The key objective is to foster research and to support and organise educational activities that can be translated into improved prevention, treatment and rehabilitation of patients with rheumatic and musculoskeletal diseases. To achieve its goals, EULAR is organised with seven standing committees: international clinical studies, including therapeutic trials; investigative rheumatology; paediatric rheumatology; epidemiology and healthcare services; education and training; social leagues, and a committee for allied health professionals in rheumatology. The committee for education and training coordinates educational activities, including EULAR courses, and EULAR also gives patronage to meeting and courses that are of high quality and are of major relevance to European rheumatology.
 
EULAR publishes The Annals of Rheumatic Diseases, the monthly EULAR journal, which is distributed to around 9,000 subscribers.(1) The journal is obviously an important tool for dissemination of new knowledge to both researchers and clinicians. EULAR is also establishing high-standard networks of centres of excellence in rheumatologiscal research, offers research grants to collaborative projects in Europe, gives bursaries to research fellows, and sponsors a visiting professor programmes. One particularly successful EULAR activity has been to develop recommendations for management of rheumatic diseases. Recommendations have been elaborated for the management of knee and hip osteoarthritis, of ankylosing spondylitis, early arthritis and gout. EULAR also wants to influence political processes to improve the awareness and priority of rheumatic diseases in Europe. The current research framework programme in the European Community gives special priority to the major diseases (cardiovascular diseases, cancer, infectious diseases, brain disorders and diabetes). The “Alliance Against Arthritis” was established in 2004 as a campaigning arm of EULAR to influence the political priorities. One of the goals is to have rheumatic diseases included as a prioritised area in the upcoming Research Framework Programme 7 – on the same level as the other major diseases. A major step in the right direction was that a written declaration, presented for the European Parliament in July 2005, was signed by 406 members of the European Parliament.(1) This result was reached after a strong collaboration in the lobbying activities between the patient representatives in EULAR and the rheumatologists, health professionals and scientists. This declaration from September last year calls on the Commission and Council to:

  • Ensure that the EU’s 7th Research Framework Programme makes rheumatic diseases one of its explicit priorities.
  • Ensure that the EU’s new health strategy makes arthritis (musculoskeletal disorders) one of its priorities.
  • Strengthen legislation to outlaw disability discrimination through a specific Disability Directive.
  • Encourage Member States to take measures to ensure better access to the full range of treatments in all EU countries.

EULAR is also working with the European regional office of WHO to ensure that rheumatic diseases will be part of the European Strategy on Noncommunicable Diseases and the future programme on counteracting obesity, which is of particular relevance in osteoarthritis. Since 2000 EULAR has organised annual congresses in rheumatology. The meetings in 2004 in Berlin and 2005 in Vienna had nearly 10,000 participants, while the 2006 congress in Amsterdam had more than 11,000 participants from 107 countries. The number of submitted scientific abstracts reached 3,000 (an increase by 20% on the previous year), and recommendations for the management of hand osteoarthritis, fibromyalgia and systemic lupus erythematosus were presented. Importantly, EULAR and the American College of Rheumatology are in the process of developing task forces with experts from both organisations that will result in joint criteria in certain areas of rheumatology. The congresses have also separate programmes for patient organisations and health professionals, as well as joint sessions. They are, therefore, a meeting point for scientists, clinicians, health professionals and patients for exchange of knowledge, ideas and experiences, and gives opportunities for a unique interaction between patients and professionals within a scientific and educational setting. This worldwide growth in rheumatology is a reflection of the advances that have been achieved over the last few years in a variety of areas. These achievements also call for a global strategy as we know that far from all patients have access to new therapeutic opportunities. Strategies for improved management of rheumatic diseases should have a broad focus and include research, education, prevention, treatment as well as rehabilitation, and educational activities should also be directed to primary care physicians. One particular strength of EULAR is the partnership between patients, rheumatologists and health professionals. This partnership makes EULAR more powerful and we will continue to support research and educational activities that may improve the situation for patients with all different types of rheumatic diseases.

Reference

  1. Available from: www.europarl.eu.int/activities/expert/writtenDecl.do?YEAR_VAL=2005

Immunotherapy and vaccines for HIV-1 treatment

Nesrina Imami
MD PhD
Reader in Immunology

Frances Gotch
PhD FRCPath
Professor of Immunology/Head of Department
Department of Immunology
Imperial College London
Chelsea and Westminster Hospital
London, UK
E: f.gotch@imperial.ac.uk

Our understanding of the pathogenic effects of HIV-1 and the potentially protective immune responses that may be specifically elicited by the virus have increased almost exponentially in the past 20 years.(1,2) However, tens of millions of people in the world have become infected with HIV-1, and treatments to alleviate the effects of the infection are still limited.(3) Highly active antiretroviral therapy (HAART), a great success since its introduction in 1996, has revolutionised the way that the developed world thinks about HIV-1. However, there are many drawbacks as HAART does not eradicate latent HIV-1 in the host, and emergence of virus resistant to the effects of drugs is common. This is slowly leading to fewer treatment options in the infected population.(4) The drugs have unacceptable toxicities and induce unpleasant side-effects in some individuals and, until very recently, have been unaffordable or unobtainable for the majority of HIV-1(+) patients in the developing world. It should nevertheless be noted that, in the majority of individuals receiving HAART, plasma viral loads drop, CD4 T-cell counts rise and potentially life-threatening opportunistic infections do not occur. However, low levels of viraemia always persist, and high levels of virus immediately reappear if HAART is suspended.(5) Treatments to induce long-term nonprogressor (LTNP) status in the absence of drugs (or even to rid the host of virus and cure the infection) seem to be a distant dream. However, it appears that HAART, with all its imperfections, may allow a window of opportunity to manipulate the immune system to the patient’s advantage.

The long-term nonprogressor (LTNP)
The clinical hallmarks of LTNPs are that, in the absence of HAART, there is no sign of immuno-suppression, CD4 T-cell counts remain high, ­viraemia is low/undetectable with no escape from CD8 cytotoxic T lymphocyte (CTL) responses, and no opportunistic infections emerge. From an immunological point of view, LTNPs possess large numbers of broadly reactive, HIV-1-specific CTL, fully functional CD4 T-cells that proliferate and produce cytokines in response to HIV-1 and other stimuli, low levels of neutralising antibodies, good thymic output with no thymic or lymph node destruction, and no observable defects in antigen- presenting cell function.(6)

Immune-based therapy
When considering the potential of therapeutic vaccination and other forms of immune-based therapy (IBT) for HIV-1(+) patients, it is important to consider why long-term use of HAART during chronic HIV-1 infection may allow partial restoration of immune responses to some opportunistic pathogens, but does not apparently allow regeneration of HIV-1-specific immune responses that have the potential to keep the virus under control. In the vast majority of cases (the exception perhaps being when HAART is administered extremely early after initial infection),(7) HAART alone does not allow establishment of LTNP status – that is, allow reconstitution or regeneration of potentially protective HIV-1-specific immune responses that keep viraemia under control and protect CD4 T-helper (Th) cells from infection and destruction – thus eventually allowing discontinuation of HAART. It has been felt that much of the early damage is irreparable; however, we now believe that, rather than being deleted, some HIV-1-specific CD4 T-cell clones are anergised and thus fail to provide help to critical CD8(+) CTL. This implies a potentially reversible process.(8)

The aim of IBT must therefore be to induce LTNP status and to augment, establish or re-establish the kind of cellular and humoral immune responses seen in LTNPs, which have the potential to control viraemia and opportunistic infections in the absence of HAART. Qualitative and quantitative defects in immune responses must be reversed, and the emergence of drug-resistant virus must be delayed. Ideally, viral reservoirs should be depleted. The burden of disease must be reduced and the patient’s quality of life improved.

Therapeutic immunisation, cytokine-and hormone-based therapies
Therapeutic vaccines used in the context of HAART-induced aviraemia may have the potential to activate selectively the immune system against specific viral proteins. By presenting viral proteins in different, novel ways with or without specific adjuvants, or by presenting proteins that are somewhat different to those already present in vivo, specific beneficial memory responses may be augmented and anergy may be reversed. Cytokines such as interleukin-2(IL-2), interferon and granulocyte macrophage colony- stimulating factor (GM-CSF), as well as hormones such as recombinant human growth hormone (rhGH) and thymosine-alpha1, have the potential to expand useful subsets of immunoregulatory cells in vivo. Over the past few years, several small phase I therapeutic trials of vaccines, passive infusions of neutralising antibodies and/or immunotherapy with cytokines or other immunomodulators have been conducted.(9,10) All appear to work better if administered when viral load is low (in the context of HAART). Transient HIV-1-specific responses have been induced in many cases, but these do not persist. Parallel transient reductions of viral load have been observed, together with increases in viral load-doubling times following treatment interruptions and lower viral set-points. Some clinical benefits such as delayed virological failure and decreased mortality have been reported.(11)

There seems little doubt that immunotherapy has optimal chance of success if HAART is started very early after infection, and the conundrum that we now face is the possibility that such therapy may work well only at this early disease stage, before inevitable damage has been inflicted on the immune system. Current BHIVA (British HIV Association) guidelines suggest that HAART should be ­initiated in asymptomatic individuals when their CD4 T-cell counts drop to between 200 and 350 cells/µl blood.(12) In asymptomatic patients with CD4 T-cell counts >350, therapy should be considered if viral load is above 100,000 copies/ml. Therefore, trials of IBT in chronically infected patients (the ­majority of whom start HAART relatively late in the disease) and attempts to reverse the damage that will have already occurred in chronic and late-stage disease are warranted, and some such investigations have recently been conducted by our group. These include:

  • Induction of virus-specific T-cell responses by administration of IL-2 and/or a therapeutic vaccine (Remune) in individuals successfully treated with HAART during chronic HIV-1 infection.(13)
  • Induction of virus-specific T-cell responses by concomitant administration of IL-2 and GM-CSF in individuals successfully treated with HAART during late-stage HIV-1 infection.(14,15)
  • Induction of virus-specific responses by administration of rhGH in HIV-1(+) ­chronically infected individuals receiving successful HAART.(16)
  • Induction of virus-specific T-cell responses by autoimmunisation, which occurs during treatment interruption in individuals successfully treated with HAART during chronic HIV-1 infection.(17)

In the trials outlined above, some potentially beneficial immunological effects, which may translate into clinical benefit, have been observed. Others have seen similar benefit in similar trials performed elsewhere.(5,18–20)

Conclusion
In many cases, potentially beneficial transient HIV-1-specific responses that may translate into clinical benefit have been induced by IBT in chronic HIV infection in the context of HAART, but these do not persist. Future studies, where novel immunogens and other immunotherapeutic agents are further defined and optimised, where therapeutic regimens are carefully and rationally designed and where patients are followed for protracted periods of time to observe clinical benefit, are warranted.

References

  1. Microbiol Rev 1993;57:183-289.
  2. Curr HIV Res 2005;3:113-32.
  3. UNAIDS. AIDS Epidemic Update December 2005. Geneva,Switzerland: UNAIDS; 2005. Available from: http://www.unaids.org
  4. AIDS Rev 2003;5:140-55.
  5. PLoS Med 2004;1:e64.
  6. AIDS 1994;8:S95-108.
  7. N Engl J Med 1995;7:450-1.
  8. J Infect Dis 2000;182:792-8.
  9. Expert Opin Biol Ther 2001;1:803-16.
  10. HIV Clin Trials 2004;5:91-8.
  11. HIV Med 2004;5:317-25.
  12. HIV Med 2005;6 Suppl 2:1-61.
  13. AIDS Res Hum Retroviruses 2003;19:103-9.
  14. Clin Exp Immunol 1999;118:78-86.
  15. J Immune Based Ther Vaccines 2005;3:7.
  16. Antivir Ther 2004;9:67-75.
  17. Clin Exp Immunol 2005;142:354-61.
  18. J HIV Ther 2004;9:57-9.
  19. Curr Opin HIV AIDS 2006;1:69-73.
  20. Curr Opin HIV AIDS 2006;1:74-81.

Osteoporosis: an emerging epidemic

Pierre D Delmas
MD PhD
President
International Osteoporosis Foundation
W: www.osteofound.org

Osteoporosis was first officially recognised as a disease by the World Health Organization (WHO) in 1994, and has since attracted increasing public and professional concern. Aside from its personal and human cost, osteoporosis is a major public health problem with enormous social and economic impact. Worldwide it is estimated that one in three women and one in five men over the age of 50 years will sustain an osteoporotic fracture. In the EU, someone has a fracture as a result of osteoporosis every 30 seconds, and with an ageing population, the yearly incidence of hip fracture alone in the EU is expected to more than double from approximately 500,000 to 1,000,000 over the next 50 years.(1) Of the estimated nine million osteoporotic fractures that occurred worldwide in the year 2000, 1.6 million were hip fractures, 1.7 million were forearm fractures, and 1.4 million were clinical vertebral fractures; the greatest number of osteoporotic fractures occurred in Europe (34.8% of the total).(2)
 
Although osteoporosis can be easily diagnosed and treated, studies have shown that it remains seriously underdiagnosed and undertreated. It is estimated that only one out of three vertebral fractures comes to clinical attention.(3) Despite this, it is known that having one spine fracture increases the risk for sustaining additional spine fractures fivefold within the next year, a phenomenon commonly known as the fracture cascade.(4) In Europe, osteoporotic fractures are responsible for a higher disease burden, in terms of disability and excess mortality, than common cancers with the exception of lung cancer.(2)

Advances in diagnosis
The most common diagnostic method is a bone mineral density (BMD) test of the hip or spine using dual energy X-ray absorptiometry (DXA). DXA employs a very low radiation X-ray, which is capable of detecting quite low percentages of bone loss with high precision, and is a fast, painless and non-invasive scan. According to WHO guidelines, a BMD score in a postmenopausal Caucasian woman that is more than 2.5 standard deviations below the average for the young healthy female population implies a diagnosis of osteoporosis. For every standard deviation below the reference BMD, fracture risk increases by 50% to 100%.
 
Despite DXA being the gold standard for osteoporosis diagnosis, DXA provision within many European countries is patchy. In addition, in the absence of population-screening programmes, DXA-based diagnosis relies on case-finding strategies which results in many high-risk individuals remaining undetected. A new diagnostic paradigm for osteoporosis is currently in development under the auspices of the WHO, supported by the International Osteoporosis Foundation (IOF) and the US’s National Osteoporosis Foundation (NOF), and publication of the associated Technical Report is anticipated in late 2006 or 2007. The new approach employs an algorithm based on clinical risk factors, can be used either alone or in conjunction with DXA, and represents a more accurate way of identifying those at risk of osteoporotic fractures.(5)
 
The clinical risk factors included in the WHO model have been validated in an analysis of 12 international cohorts (approximately 60,000 men and women) and include age, gender, femoral neck BMD, prior fragility fracture after age 50 years, body mass index, use of glucocorticoids, secondary osteoporosis (eg, associated with rheumatoid arthritis), parental history of hip fracture, current cigarette smoking and alcohol intake of more than two units per day. The algorithm will yield a score that will be an estimate of 10-year absolute fracture risk for an individual.

Current and potential treatments
The management of osteoporosis necessitates appropriate drug treatment, particularly since this chronic disease may affect up to a third of a patient’s life. Several new treatments for osteoporosis have been introduced in the past decade and many more are in the pipeline. The majority of currently available treatments are antiresorptive agents (those that inhibit bone resorption and attenuate bone loss), namely bisphosphonates, selective oestrogen receptor modulators (SERMs), and calcitonin. Bisphosphonates are the most commonly prescribed, and have been demonstrated to reduce fracture risk by up to 50%. Daily and weekly (alendronate and risedronate) and monthly (ibandronate) oral formulations are currently used, and intravenous formulations with reduced dosing frequency are available (ibandronate) or are in late-phase development (zoledronate). Currently the only marketed SERM is raloxifene, which is indicated for the prevention of vertebral fractures in postmenopausal women, although other SERMs are currently in late-stage clinical development (lasofoxifene, bazedoxifene and arzoxifene).

The only available anabolic (bone forming) treatment for osteoporosis is recombinant human parathyroid hormone (PTH). PTH reduces the risk of both vertebral and nonvertebral fractures, and is indicated for the treatment of severe osteoporosis (low bone density plus prevalent fractures). Another newly available treatment in some European countries is strontium ranelate, whose mechanism of action is not fully understood, but appears to involve a dual effect of reduced bone resorption and a maintenance or modest increase of bone formation. One drug in the pipeline, denosumab, has a potentially novel mechanism of action and is a human monoclonal antibody to the receptor activator of nuclear factor kß ligand (RANKL), the primary mediator of osteoclastic differentiation, activation and survival. Given as a subcutaneous injection every three or six months, denosumab decreased bone resorption and increased bone density, and is currently in phase III trials to evaluate fracture efficacy.

The IOF
Founded in 1998, the IOF is a global, nonprofit, nongovernmental organisation dedicated to the worldwide fight against osteoporosis. The structure of the IOF is somewhat unique, comprising three committees:

  • A committee of scientific advisors (currently 76 members).
  • A committee of national societies (currently 172 members in 85 countries, patient, medical and research societies).
  • A committee of corporate advisors (currently 35 members from different sectors including pharmaceuticals, diagnostics, banking, advertising, food and packaging).

The mission of the IOF is threefold: to support national osteoporosis societies in order to maximise their effectiveness; to increase the awareness and understanding of osteoporosis; and to motivate people to take action to prevent, diagnose and treat osteoporosis.

The IOF supports an ambitious science programme including publication of two scientific journals, Osteoporosis International and Progress in Osteoporosis, organisation of scientific meetings around the world including the biannual IOF World Congress on Osteoporosis, and running training courses for physicians and other healthcare professionals. The IOF also provides direct support to its global members, through a wide range of activities including events such as World Osteoporosis Day (held every 20 October) and a biannual World Wide Conference of Osteoporosis Patient Societies, plus the provision of numerous grants and targeted support. Within its policy and advocacy programme, IOF supports national, European and international policy initiatives to increase access to diagnosis and treatment, publishes the newsletter Osteoporosis Action, and carries out workshops and media events. The IOF membership grows at approximately 20% annually, and it is anticipated that this will continue as the organisation provides a focal point for a disease that has increasingly important public health implications.

References

  1. Blanchard F. EC Report CE-09-97-915-EN-C. Building strong bones and preventing fractures – action for prevention. Brussels: European Communities; 1998.
  2. Johnell O, Kanis J. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int 2006; in press.
  3. Cooper C, Atkinson EJ, O’Fallon WM, et al. Incidence of clinically diagnosed vertebral fractures: a population-based study in Rochester, Minnesota, 1985-1989. J Bone Miner Res 1992;7:221-7.
  4. Lindsay R, Silverman SL, Cooper C, et al. Risk of new vertebral fracture in the year following a fracture. JAMA 2001;285:320-3.
  5. Kanis JA, Borgstrom F, De Laet C, et al. Assessment of fracture risk. Osteoporos Int 2005;16:581-9.

Challenges in digital mammography

Chantal Van Ongeval MD
E: chantal.vanongeval@uz.kuleuven.ac.be

André Van Steen
MD

Hilde Bosmans
PhD
Department of Radiology
University Hospitals Leuven Belgium

Full-field digital mammography (FFDM) has definitive  (practical) advantages over screen-film mammography (SFM).  For some systems, the workflow can be markedly increased.  Images are digital; thus, they can be archived  electronically and sent to a remote site for second  ­reading. Computer-aided detection (CAD) can be applied on  the full depth of the data, and dedicated image processing  can improve the perception of the lesions. The performance  of a digital system, however, should ultimately be evaluated  by clinical patient ­studies. The role of the new modality  for screening should be tested in a screening environment.  The first such studies were run on a Senographe 2000D (GE,  Milwaukee, WI, USA). These studies concluded that there was  no difference in detection rate between FFDM and SFM.(1–3)  In the ACRIN (American College of Radiology Imaging Network)  trial, multiple systems of ­different vendors were included.  This trial also concluded that the overall diagnostic  accuracy of digital and film mammography in a screening  environment is similar for the entire population, but that  FFDM is more accurate in women under the age of 50 years.(4)

Technical acceptance tests aim to guarantee an acceptable  level in terms of clinical performance. A first protocol was  recently published by the European Commission.(5) The main  system test discussed in this protocol is the  contrast-detail analysis. This test relies on a test object  with inserts of different size and depth and limiting values  on the minimal thickness (or contrasts) that should be  visible for specified diameters. This test is the subject of  a lot of debate in the literature. There is an important  degree of ­subjectivity ­related to this test, as images  have to be scored manually.
 
The main parameters that characterise the performance of the  detector are: the spatial resolution (or modulation transfer  function: MTF), noise and detective quantum efficiency  (DQE).(6) Currently, the digital detector is still  considered to have a dominant impact on image quality, while  processing protocols and viewing conditions are often not  evaluated.(7) The link between these parameters and clinical  performance remains a challenge today. We are in need of  more information regarding their impact on clinical  performance. One next challenge is concerned with the use of  these modalities in ­screening. How should all digital  advantages be used efficiently?

Clinically and physically, the overall ­conclusion is that  FFDM should become the method of choice in the detection of  breast cancer. But before the method can be considered a  mature ­technology, the challenges, as formulated above,  should be addressed.

The first group of challenges is related to the specific  technical characteristics of FFDM
The requirements on spatial resolution, contrast resolution  and noise of a detector system depend on the radiological  task. Breast cancer can be present as microcalcifications or  masses. Detection of calcifications requires a very  high-resolution imaging technique.(8) Masses induce only  small changes in contrast, and their detection necessitates  high-contrast images. Compared with general radiology,  mammography is a very demanding technique. The spatial  resolution of digital mammography is limited by the pixel  size. FFDM has intrinsically a lower spatial resolution than  SFM. This could cause problems in detecting subtle  microcalcifications. However, a better performance at lower  spatial frequencies seems to compensate for the relatively  large pixel sizes. The apparent contrast resolution is  largely dependent upon the energy of the X-rays and the  image processing that takes place in the ­computer system  after signal acquisition. Differences in X-ray densities can  be more accentuated by post- processing (see Figure 1).  Image processing may react in very different ways on these  anatomical backgrounds. Processing is often driven by the  X-ray distribution in the detector and the texture of the breast. The influence of the X-ray distribution on the result of the applied processing is only rarely investigated. Small studies on the evaluation of image quality showed that processing was not optimal in all patients and for all exposure settings. With inappropriate postprocessing tools, differentiation between noise, calcifications and small densities can be difficult.

[[HHE06_fig1_R16]]

In practice, aspects of spatial resolution, contrast  resolution, noise and processing are interrelated. It is  difficult to predict the outcome of combinations of  characteristics on image quality. Image quality criteria are  necessary for the quantification of the global image  quality. The experience with such criteria remains limited  today and, as far as we know, even criteria for conventional  mammography have not been applied on a large scale, and  limiting values or acceptance levels have not been  proposed.(9)

In digital mammography, there is a shift from hardcopy to  softcopy display and ­reading. Many different display  stations are on the market, but until now there has been no investigation of the effect of a monitor on the reading  results of the ­radiologist. Practical tools are being  developed to control the stability of the monitors.(10)

The second group of challenges is related to screening  mammography
In the screening population, FFDM offers specific  advantages. Integrating FFDM into an existing screening  programme, however, creates a lot of practical problems, in  terms of both informatics and image quality. Different types  of imaging systems are on the market. All of them have other physical charateristics. In addition, most manufacturers have developed image-processing algorithms along with their acquisition system. This results in an always different look to images in the different systems. Images of subsequent runs in a screening programme can therefore appear very variable because of upgrading of the system, changes in the applied processing, etc. Image processing will be vendor-specific, and image quality differences, induced by different quality of processing, will be obvious.
 
Radiologists involved in second reading (ie, reading images  from other mammographic sites) have to deal with all these  different kinds of images (see Figure 2). Can they compare  conventional and digital images of subsequent rounds of the same patient?

[[HHE06_fig2_R17]]
 
For all these reasons, radiologists face an important  learning stage. Dose reduction while maintaining sufficient  image quality is of high importance in a ­screening  population, especially when screening starts at the age of  40 years.(4,11) For a lot of systems, it remains to be  explored at which dose level images should be acquired. The  cost-benefit of a screening programme should not be worse  than with conventional systems. This figure of merit of the  screening programme should be reassessed. As CAD might be  used as a second reader and as this tool has already been  shown to improve cancer detection, application of CAD to all  the images of a screening population is of great interest.  The improvement, however, is dependent on the experience of  the radiologist in mammographic reading and on the type of  lesion (better for calcifications than for masses).(11)

Conclusion
FFDM is already a solution to many of the ­inherent  limitations of screen-film mammography. A series of items  are not fully understood today. The influence of the type of  detectors, processing and display possibilities on the image  and on cancer detection is not sufficiently investigated.  More studies are also needed to explore the optimal dose  levels. Finally, there is only limited experience with  turning an existing screening unit into a fully digital  environment that takes full advantage of the digital nature  of these systems.

References

  1. Skaane P, Young K, Skjennald A. Population-based  mammography screening: comparison of screen-film and  full-field digital mammography with soft-copy reading – the  Oslo I study. Radiology 2003;229:877-84.
  2. Skaane P, Skjennald A. Screen-film mammography versus  full-field digital mammography with soft-copy reading:randomized trial in a population-based screening program –  The Oslo II Study. Radiology 2004;232:197-204.
  3. Lewin FM, Hendrick RE, D’Orsi CJ, Isaacs MF. Comparison  of full-field digital mammography with screen-film  mammography for cancer detection: results of 4.945 paired  examinations. Radiology 2001;218:873-80.
  4. Pisano ED, Gatsonis C, Hendrick E. Diagnostic performance  of digital versus film mammography for breast-cancer  screening.N Engl Med 2005;353.
  5. European Commission. European Guidelines for Quality  Assurance in Mammography Screening Part B: Digital  mammography. In the Fourth Edition of the European  Guidelines for Breast Cancer Screening. In print by the  European Commission. Downloadable from:www.euref.org
  6. Noel A, Thibault F. Digital detectors for mammography:  the technical challenges.Eur Radiol 2004;14:1990-8.
  7. Bosman s H, Carton AK, Rogge F, Zanca F, Jacobs J, Van  Ongeval C et al. Image quality measurements and metrics in  full-field digital mammography: an overview. Rad Prot  Dosimetry 2005;117(1-3):120-30.
  8. Fischer U, Baum F, Obenauer S, et al.Comparative Study in  patients with microcalcifications: full-field digital  mammography vs screen-film mammography.Eur Radiol  2002;12:2679-83.
  9. Van Ongeval C, Bosmans H, Van Steen A. Current challenges  of full field digital mammography.Rad Prot Dosimetry  2005;117(1-3):148-53.
  10. Jacobs J, Deprez T, Rogge F, Marchal G, Bosmans H.  Validation of a new dynamic pattern for daily quality  control of medical screen devices. 91st Scientific Assembly  and Annual Meeting of the RSNA, McCormick Place, Chicago,  November 2005.
  11. Fischer U, Hermann KP, Baum F. Digital mammography:  current state and future aspects. Eur Radiol 2006;16:38-44.

Treating displaced or unstable long bone fractures

Ian Moorcroft
Technical Director
Intelligent Orthopaedics Ltd.
Stoke on Trent
UK
T: +44 (0) 1782 847 840
W: www.intelligentorthopaedics.co.uk

During the 1990s teams from the universities of Keele and Staffordshire, and the University Hospital of North Staffordshire, UK, were conducting research into the healing of long bone fractures, particularly fractured tibia. As part of one particular comparative clinical study it was necessary to precisely reduce tibial fractures in order to minimise the variable factors that could impact on healing times and eventual outcomes. The device that was originally made for this purpose was intended for the study only. However, all the surgeons that used the device found it to be so beneficial that they wanted to continue to use it after the study had concluded. It became apparent that the device, Staffordshire Orthopaedic Reduction Machine (STORM), would be a valuable surgical device in its own right.

Treating displaced or unstable fractures
STORM is used in the treatment of displaced or unstable fractures (Figure 1) where the patient will need a general anaesthetic and an operation. During the operation the surgeon will realign the fracture fragments, which is known as reduction. Obtaining an acceptable fracture reduction by other methods can be extremely difficult and time consuming as it requires considerable force to manipulate the fragments back into their correct alignment. In some circumstances the surgeon may need to open the fracture in order to achieve an acceptable reduction. The complexity of this process often results in the surgeon making a compromise between the quality of reduction and the time taken to achieve it. Once the fracture has been reduced the surgeon will then need to apply some kind of fixation to provide support to the fracture limb while it heals.

[[HHE06_fig1_T48]]
 
The type of fixation is dependent on a number of things including the type and location of the fracture, the facilities available at the point of treatment and the preferences of the surgeon and/or patient. In most methods the process of reducing the fracture is built into the operative technique and/or the design of the device, whether that be an intramedullary nail, screws and plate or external fixation system. In this way the fixation device must perform two distinctly different functions. First, it must allow the surgeon to manipulate the fragments to achieve a reduction. Second, it must support the fracture until it has united. The first function occurs in the sterile environment of the operating theatre and is for a short period only, while the second may last many weeks or months as the patient mobilises on the injured limb. These two opposing functions mean that the process of reducing the fracture is not optimised and current devices can be over complicated. Therefore, there is a need to make the process of fracture reduction easier to manage.

To perform the operative technique tensioned wires are inserted through the calcaneum and proximal tibia, and are held by a robust frame with independently controlled movements. Crucial to STORM’s function is the ability to apply uniform and sustained traction while allowing easy correction of rotation about the long axis of the bone. With traction applied and rotation corrected, unicortical bone screws are inserted into the proximal and distal fragments near to the fracture site and held in special attachments to the device. The bone screws can then be independently and accurately moved in both the sagittal and coronal planes. This enables precise alignment of the fracture ends. Once reduction is achieved, STORM firmly holds the bone fragments in place while the chosen method of fixation (internal or external) is applied. Figure 2 illustrates the STORM configuration.

[[HHE06_fig2_T49]]

Benefits
STORM, which has been used in over 300 operations on many types of lower limb fractures, aids the surgeon during fracture reduction by providing a controlled procedure, which lessens the unpredictability associated with lower leg fractures and, in most cases, results in perfect anatomical reductions. STORM also allows a progressive controlled technique to achieve the necessary distraction and then to correct rotation, angulation and translation.
 
The ability to accurately reduce the fracture before applying the fixation allows the surgeon to simply change the preferred fixation method during the operation to better suit the individual patient. Another proven benefit is that STORM helps in the planning of trauma cases where every case is different and can often present unexpected problems.

Patient and healthcare providers also benefit. Patients benefit from a shorter time under general anaesthetic and improved functional and aesthetic outcome. Healthcare providers benefit from shorter and more predictable operation times, which have direct cost savings, and allows for improved scheduling of operating lists.

STORM is used in conjunction with all main methods of fixation including; external fixators, minimally invasive plating systems, intramedullary nails, ring/frame and hybrid systems. In trials carried out in the University Hospital of North Staffordshire, the use of STORM with an external fixator was shown to shorten operating times by an average of 23% (p<0.02) and shorten the time to reduce the fracture by 53% (p<0.001). The accuracy of reduction using the STORM is significantly improved compared with conventional methods (p<0.01).

In the case of external fixation, the STORM method eliminates the need for complicated joint mechanisms in the fixator itself. Following the success of STORM the research team formed a spinout company, Intelligent Orthopaedics Ltd, which has since developed other product ideas. One of these, a simple external fixator, is designed for use in conjunction with the STORM. Figure 3 shows how this fixator can be easily applied with all pins in alignment while the STORM holds the bone fragments securely.

[[HHE06_fig3_T49]]

Finally, the emergence of Minimally Invasive Plating systems has presented new challenges including how to reduce the fracture without an open reduction technique. STORM helps in these cases by providing control of the bone fragments with minimal soft tissue damage (Figure 4).

[[HHE06_fig4_T50]]

Conclusion
The STORM technique provides benefits to the patient, surgeon and healthcare provider. Patients benefit from a shorter time under general anaesthetic and improved fracture fragment proximity, which reduces the likelihood of complications during fracture healing. Evidence also suggests that shorter healing times and fewer long-term problems are associated with improved reduction.
 
Feedback from surgeons indicates that it gives greater control with more predictability when used with all common forms of fixation of unstable fractures from the tibial plafond to distal femur. Finally, healthcare providers can on average expect shorter and more predictable operating times enabling better scheduling of operating lists with improved direct and indirect costs.

[[HHE06_box1_T49]]

Reference

  1. Moorcroft CI,Ogrodnik PJ, Thomas PB, Verborg SA. A device for improved reduction of tibial fractures treated with external fixation. Proc Inst Mech Eng Part H 2000;214:449-57.