bluuebunny/crossref_metadata_2025 huggingface dataset:
New Perspectives in the Management of Duchenne Muscular Dystrophy
Authors: Goemans Nathalie , Kirschner Janbernd , Mercuri Eugenio ,   Paediatric Neurologist, University Hospital of Leuven, Belgium,   Consultant Paediatric Neurologist, Department of Neuropaediatrics and Muscle Disorders, University Medical Centre Freiburg, Germany,   Professor, Paediatric Neurology Unit, Catholic University, Rome, Italy
Published: October 2015

Duchenne muscular dystrophy (DMD) is an X-linked, rare, progressive, life-threatening disease with no currently approved therapy targeting the underlying cause. DMD is characterised by a lack of dystrophin, which leads to severe myofibre degeneration. Laboratory techniques have evolved to enable identification of DMD patients from blood samples. The importance of a multi-disciplinary clinical management approach in achieving optimal outcomes in DMD is well recognised, and there is an emphasis on utilising care guidelines to treat effectively the multiple clinical manifestations of DMD. The aim of managing DMD is to prolong ambulation and delay other disease milestones, therefore maintaining quality of life for as long as possible. In the absence of any other approved treatments, corticosteroids have been adopted as a standard of treatment for DMD, with evidence supporting their clinical utility in delaying some disease milestones, while recognising their side effects. A major challenge with DMD has been the identification of meaningful clinical outcome measures for clinical studies. The 6-minute walk test (6MWT) has emerged as a strong predictor of physical functioning and disease progression, with strong evidence of validity and reliability. As a result, it is currently the most accepted primary clinical endpoint in ambulatory DMD clinical trials. The 6MWT has been utilised in a variety of DMD studies of potential drug treatments, including large multinational trials of the nonsense mutation readthrough agent, ataluren, which is under development for nonsense mutation-mediated DMD, in trials of exon skipping agents in development for specific exon linked DMD mutations and in trials investigating optimal steroid dose regimens.
The Diagnostic Path to Pompe Disease
Authors: Bodamer Olaf A , Hung Christina Y ,   Professor of Human Genetics, Biochemistry and Molecular Biology and Director,   Clinical Molecular Genetics Fellow (ABMG), Division of Clinical and Translational Genetics, Dr John T Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, US
Published: October 2015

Pompe disease (PD) is a lysosomal disease that primarily affects skeletal and smooth muscles due to a deficiency of acid alpha glucosidase. The resulting clinical phenotype reflects a continuum ranging from severe infantile to later onset forms of PD. Early diagnosis is essential o prevent long-term complications and/or disease progression through initiation of enzyme-replacement therapy. The diagnostic path o PD starts with the ascertainment of medical and family history as well as an in-depth clinical and neurological evaluation. The involvement of proximal muscle groups including hip and thigh muscles as well as the diaphragm is characteristic for later onset PD. Once PD is considered creatine kinase (CK) should be measured, realising that levels may be within normal limits in end stage disease. Ultimately, diagnostic confirmation is readily achieved by enzyme analysis in dried blood spots and/or leukocytes followed by molecular analysis. Muscle biopsy is not sensitive enough for diagnostic testing of PD but may be an important diagnostic test for the differential diagnosis of myopathies. Future diagnostic approaches include whole exome and genome sequencing, which may contribute to our understanding of genotype–phenotype correlation and phenotype prediction.
Autoimmune Encephalitis—Antibody Targets and Their Potential Pathogenicity in Immunotherapy-responsive Syndromes
Authors: Bera Katarzyna D , Vincent Angela , Irani Sarosh R ,   Medical Student,   Professor,   Clinical Fellow, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
Published: October 2015

Autoimmune encephalitis (AIE) associated with neural autoantibodies is increasingly recognised as a cause of subacute onset amnesia, confusion and seizures. In the past decade, several key antibody targets have been identified in AIE. These include the N-methyl D-aspartate (NMDA) receptors, voltage-gated potassium channel complexes – in particular leucine-rich glioma inactivated 1 (LGI1) and glutamic acid decarboxylase (GAD). There is accumulating clinical and laboratory evidence that antibodies targeting the extracellular domains of cell surface molecules are directly pathogenic. Each antibody target associates with a spectrum of clinical features and relative response to immunotherapies. These immunotherapies have been shown to improve short- and long-term clinical outcomes in affected patients. AIE is an important differential diagnosis to consider in patients presenting with symptoms of encephalitis as early diagnosis can lead to successful treatment.
New Perspectives in Non-oral Drug Delivery in Parkinson’s Disease
Authors: Poewe Werner , Lees Andrew , Chaudhuri K Ray , Isaacson Stuart ,   Professor of Neurology, Department of Neurology, Innsbruck Medical University, Innsbruck, Austria,   Professor of Neurology, The National Hospital for Neurology and Neurosurgery, Queen Square and Emeritus Director, Reta Lila Weston Institute of Neurological Studies, University College London, Institute of Neurology, London, UK,   Professor of Movement Disorders, Director National Parkinson Foundation Centre of Excellence, Kings College, Denmark Hill Campus, London, UK,   Associate Professor, Florida International University, Herbert Wertheim College School of Medicine, Miami; Director, Parkinson’s Disease and Movement Disorders Center of Boca Raton; Research Director, Marcus Neuroscience Institute, Boca Raton Regional Hospital, Boca Raton, Florida, US
Published: October 2015

Oral therapies, including levodopa, dopamine agonists and monoamine oxidase type B (MAO-B) inhibitors, form the mainstay of medical treatment for Parkinson’s disease (PD). However, over time, chronic treatment with multiple daily doses of oral agents is often associated with the development of motor fluctuations and dyskinesias. Alternative methods of dopaminergic drug delivery, particularly if they bypass the gastrointestinal system, may be of value for PD patients who have developed motor complications despite optimised oral therapy, in particular those with gastrointestinal absorption issues, including gastroparesis. This satellite symposium, held at the XX World Congress on Parkinson’s Disease and Related Disorders, Geneva, Switzerland, from 8–11 December 2013, was chaired by Professor Werner Poewe (Austria) and Professor Andrew Lees (UK) and discussed recent evidence regarding the benefits of using non-oral drug-delivery strategies with therapies such as subcutaneous apomorphine. Beginning with the history of apomorphine and its well-established use in PD both as an intermittent injection and a continuous infusion, the presenters set out the evidence for its efficacy in managing both motor and non-motor symptoms in PD. The significance of gastrointestinal involvement in PD and how this may influence responses to oral medications was also reviewed. Interim results from the ongoing Apokyn for Motor IMProvement of Morning AKinesia Trial (AM IMPAKT) study of the use of subcutaneous apomorphine in PD patients with morning akinesia were also presented and the continuing main role of apomorphine in the treatment of PD was discussed, including the selection of the most appropriate patients for this effective yet underused therapy.
Policy with a Brain – Challenges and Opportunities for the New European Institutions
Authors: Baker Mary ,   President, Year of the Brain, European Brain Council, Brussels, Belgium
Published: October 2015

The combination of ageing populations and lower economic growth is leading policy-makers to question the sustainability of European healthcare expenditure. At the same time as seeking to increase ‘cost-effectiveness’, however, we must also strengthen our focus on the outcomes our health systems deliver – for the patient, the economy and society. Disorders of the brain cost Europe €798 in 2010 – more than any other comparable disease area – and will become more prevalent as our populations grow older. The European Brain Council is launching The Year of the Brain to educate society about how to nurture and protect the brain, to improve care and treatment access for those affected by brain disease, and to increase investment in brain-related research and development. Working with the European institutions and Member States, we aim to make an important contribution to improving outcomes across Europe.
Do Seizures Promote Epileptogenesis and Cause Cognitive Decline?
Authors: Avanzini Giuliano ,   Professor, Istituto Neurologico Carlo Besta, Milan, Italy
Published: October 2015

The assumption that repeated seizures may induce a progression of epilepsies towards an intractable condition and a cognitive decline does not hold true for idiopathic epilepsies but can only be considered for mesial temporal lobe epilepsy and epileptic encephalopathies. The available evidence leads to the conclusion that in most cases the epilepsy worsening and cognitive decline are due to the progression of the underlying pathology or to its interference with the developmental programme, the notable exception being the epileptic encephalopathies with continuous epileptic activity during sleep.
Classification of Intracerebral Haemorrhages
Authors: Domingues Renan , Rossi Costanza , Cordonnier Charlotte ,   Neurologist and Professor; Neurologist and Professor, CAPES Foundation, Ministry of Education, Brasilia-DF, Brazil,   Neurologist,   Neurologist and Professor, Department of Neurology, University of Lille Nord de France, UDSL, CHU Lille, EA 1046, Lille, France
Published: October 2015

Spontaneous intracerebral haemorrhage (ICH) is defined as a collection of blood in the cerebral parenchyma that is not caused by trauma. ICH is the second most frequent cause of stroke, accounting for 10–15 % of all cases in high-income countries and about 20 % in low- to middle-income countries. Despite an apparent stability of incidence over the past decades, the profile of ICH has changed: there are fewer deep ICHs associated with pre-stroke hypertension, whereas the increasing age of the population associated with a more extensive use of antithrombotic drugs leads to an increase of lobar ICH. Deep perforating vasculopathy remains the most important cause of ICH, followed by cerebral amyloid angiopathy, these two aetiologies account for nearly 70 % of all ICH cases. Recent scientific evidence has highlighted new aspects of the pathophysiology of such disorders; nevertheless, the morbidity and mortality of ICH remain extremely high. In the present article, the different causes of ICH will be reviewed.
Time for Change – Evolution of Real-world Evidence Outcome Measures in Multiple Sclerosis Exemplified by Fingolimod
Authors: Eraksoy Mefkure , Butzkueven Helmut , Ziemssen Tjalf , Zivadinov Robert ,   Istanbul Faculty of Medicine, Istanbul University, Department of Neurology, Istanbul, Turkey,   Director, MS Service, Royal Melbourne and Box Hill Hospitals, Melbourne, Australia; Chair, MSBase Foundation, Department of Neurology, Royal Melbourne Hospital, Victoria, Australia,   Multiple Sclerosis Centre, Centre of Clinical Neuroscience, University Hospital Carl Gustav Carus, Dresden, Germany,   Department of Neurology, Buffalo Neuroimaging Analysis Center, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, NY, US; Professor of Neurology; Director, Buffalo Neuroimaging Analysis Center; Director, MRI Clinical Translational Research Center, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, NY, US
Published: October 2015

Real-world evidence provides important information concerning the long-term effectiveness and safety of disease-modifying treatments (DMTs) for multiple sclerosis (MS) in clinical practice in a large number of patients. These data enhance and extend the results from randomised clinical trials and include information that cannot easily be obtained in trials such as treatment efficacy in non-trial populations (e.g. those with co-morbidities, older patients and children) and long-term safety analyses. Such data are compatible with specialist clinical practice and, when accumulated in multicentre databases using an agreed minimum dataset, these data can provide invaluable information on long-term disease progression and treatment. Real-world evidence in terms of fingolimod is reviewed and clearly demonstrates its long-term effectiveness and safety. Currently, imaging data are not systematically collected but the development of improved standard magnetic resonance imaging (MRI) protocols and automated procedures now makes this a realistic option in the near future. Automated (or largely automated) MRI analytics are likely to greatly enhance and further strengthen real-world evidence for outcomes of different treatment algorithms incorporating more sophisticated MRI measures.
Botulinum Neurotoxin Revisited – An Individualised, Patient-centric Approach for the Treatment of Dystonia and Spasticity
Authors: Relja Maja , Jacinto Jorge , Jankovic Joseph , Albanese Alberto ,   University Hospital Center Zagreb, Croatia,   Centro de Medicina de Reabilitação de Alcoitão, Alcabideche, Portugal,   Baylor College of Medicine, Houston, Texas, US,   Istituto Nazionale Neurologico Carlo Besta, Milan, Italy
Published: October 2015

Botulinum toxin A (BoNT-A) has become the first-line therapy in cervical dystonia (CD), blepharospasm and spasticity. However, the current guidelines for the clinical use of BoNT-A are based on data published more than 20 years ago and patient satisfaction with current treatment regimens is low. There is a striking difference between the injection intervals given in everyday clinical practice and the injection intervals preferred by patients. Recent data have indicated that shorter injection intervals may improve overall patient satisfaction since re-emergence of symptoms could be prevented. Three double-blind studies have demonstrated that incobotulinumtoxin A (incoBoNT-A) is suitable for use in a flexible, patient-centric approach in blepharospasm and CD, with injection intervals starting from 6 weeks. The efficacy, tolerability and safety of this regime were excellent. There is a need to optimise and individualise the treatment using the three available formulations of BoNT- A, as well as to define parameters for switching between the formulations.
Neurochemistry of Idiopathic Restless Legs Syndrome
Authors: Jiménez-Jiménez Félix Javier , Alonso-Navarro Hortensia , García-Martín Elena , Agúndez José AG ,   hairman of the Section of Neurology; Professor of Neurology, Hospital Universitario del Sureste, Arganda del Rey, Madrid,Spain,   Consultant Neurologist, Section of Neurology, Hospital Universitario del Sureste, Arganda del Rey, Madrid, Spain,   Professor of Pharmacology, Universidad de Extremadura, Cáceres, Spain,   Full Professor of Pharmacology, Universidad de Extremadura, Cáceres, Spain.
Published: October 2015

The pathogenesis of idiopathic restless legs syndrome (iRLS) is not well established, but the most important hypothesis suggests dopaminergic dysfunction and iron deficiency. However, recent reports suggest a possible role for several neurotransmitters or neuromodulators, such as aspartate, glutamate, gamma-hydroxybutyric acid (GABA) and opiates, as well as relation with vitamin D deficiency. In this review, we summarise the studies related to neurochemical findings in iRLS.
Treatment Options for Idiopathic Restless Legs Syndrome
Authors: Jiménez-Jiménez Félix Javier , Alonso-Navarro Hortensia , García-Martín Elena , Agúndez José AG ,   Chairman of the Section of Neurology; Professor of Neurology, Hospital Universitario del Sureste, Arganda del Rey, Madrid, Spain,   Consultant Neurologist, Section of Neurology, Hospital Universitario del Sureste, Arganda del Rey, Madrid, Spain,   Professor of Pharmacology, Universidad de Extremadura, Cáceres, Spain,   Full Professor of Pharmacology, Universidad de Extremadura, Cáceres, Spain
Published: October 2015

The emergence of new effective therapies for idiopathic restless legs syndrome (iRLS) or WillisEkbom disease (WED) during the last 15 years resulted in an exponential increase of reports regarding this syndrome and, especially, treatment options. In this review, we summarise the main findings related to neuropharmacological aspects and non-pharmacological therapies of idiopathic RLS (iRLS). As was previously reported in several guidelines, dopamine agonists (fundamentally nonergotic derivatives), gabapentin and pregabalin should be considered as first-line therapies, as well as opiates as an alternative drug group. Preliminary results suggest that several non-pharmacological therapies should be promising as alternatives or adjuvants to drug treatments.
New Directions in Research and Therapies in Traumatic Brain Injury
Authors: Thome Johannes , Muresanu Dafin F ,   Director and Chair, Clinic and Policlinic for Psychiatry and Psychotherapy, University of Rostock, Germany,   Chairman, Department of Clinical Neurosciences, Iuliu Hatieganu University of Medicine and Pharmacy, Faculty for Medicine Cluj-Napoca, Romania
Published: October 2015

Traumatic brain injury (TBI) is a significant cause of disability and death and its incidence is rising in some specific populations. TBI can result in various disabilities, cognitive problems and psychiatric disorders, depending on the location of the injury and premorbid patient conditions. Effective pharmacological and surgical treatments, however, are currently limited. Most randomised clinical trials for TBI treatments carried out to date have failed to show significant benefits. Initiatives such as the TRACK-TBI have highlighted the large variability in TBI treatment quality at different hospitals and widely differing death rates. This stimulated the establishment of the International Initiative for TBI Research (InTIBR), which aims to improve disease characterisation and patient management. The development of effective treatments for TBI and their evaluation requires an understanding of the complex neuroregenerative processes that follow an injury. In the case of haematoma in TBI, decompressive craniectomy can be a life-saving intervention but must be performed rapidly. The neurotrophic agent, Cerebrolysin®, acts by mimicking neurotrophic factors (NTFs) and by stimulating the endogenous production of NTF in brain tissue. Experimental models show that this drug increases neurogenesis following TBI but these findings need to be converted into clinical practice. The potential of Cerebrolysin in TBI was demonstrated in a large retrospective cohort trial in Romania (n=7,769 adults). Cerebrolysin significantly improved Glasgow Outcome Scores (GOS) and respiratory distress (RDS) in patients with moderate or severe TBI at 10 and 30 days compared with controls. This and other experimental treatments have potential in TBI but, in developing such therapies, the design of clinical trials should closely reflect the reality of biological processes underlying natural recovery from brain injury.
Experimental and Clinical Approaches to Recovery after Stroke
Authors: Brainin Michael , Bornstein Natan ,   Department of Clinical Neurosciences and Preventive Medicine, Danube University Krems, Krems, Austria,   Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Israel
Published: October 2015

The development of effective treatments that aid recovery after stroke has been hampered in recent decades by a lack of knowledge regarding stroke complexity and the processes involved in neurological repair. Many stroke treatments tested so far have been monomodal, targeting only one neurobiological process whereas multimodal treatments are more likely to address the complex processes of stroke recovery. Understanding of stroke recovery, however, is increasing using imaging techniques, especially positron emission tomography (PET). This reveals features such as the tissue at risk in the peri-infarct area, which can be functionally restored if treatment is initiated rapidly. Understanding of stroke risk is also improving with the use of biomarkers. A promising approach to stroke therapy is non-invasive brain stimulation (NIBS), which can precisely target specific functional areas of the cortex. Clinical studies indicate that NIBS provides improvements in motor functions and aphasia but more supporting evidence is needed. When treating stroke it is critically important to take account of co-morbidities, such as diabetes and hypertension, since these have profound effects on outcomes. The provision of adequate rehabilitation soon after stroke is critical for optimal recovery and should include drug therapy. Such interventions at local treatment centres, however, are often under-resourced. Current developments are leading to a better understanding of pathophysiology and improved awareness of risks and treatments should, in future, also improve rehabilitation and hence benefit outcomes following a stroke.
New Perspectives on the Diagnosis and Management of Duchenne Muscular Dystrophy
Authors: Muntoni Francesco , Aartsma-Rus Annemieke , Mercuri Eugenio , Lochmüller Hanns ,   The Dubowitz Neuromuscular Centre, University College London, London, UK,   Leiden University Medical Center, Leiden, The Netherlands,   John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle, UK,   Catholic University of the Sacred Heart, Rome, Italy,   John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle, UK
Published: October 2015

Duchenne muscular dystrophy (DMD) is a rare X-linked recessive disorder that occurs in around one in 5,000 male births. The prevalence of DMD is expected to rise due to improved standards of care and implementation of guidelines, leading to longer survival. Specialist genetic confirmation of a DMD diagnosis is typically followed by access to specialist care and treatment: the exact DMD-causing mutation should be identified because it can influence prognosis and identify patients eligible for treatment. Since the majority of patients has a deletion or duplication of one or more exons (~70 %), generally multiplex ligation-dependent probe amplification suffices to identify the mutation. Exon sequencing is performed to pick up small mutations (~30 %). Greater awareness of DMD is needed among healthcare professionals to enable earlier diagnosis, which would facilitate family planning, as well as patient care and treatment. In DMD patients who are still able to walk, the 6-minute walk test (6MWT) has been shown to be a valid measure of physical functioning and a predictor of disease progression, with high inter-test reliability. In a study of the natural history of DMD, change in 6MWT of around 30 metres has been indicated to be clinically relevant and clinically meaningful. DMD patients responded to treatment as shown by the improvement in the 6MWT score in the large multinational trial of the nonsense mutation readthrough agent, ataluren (Translarna) 40 mg/kg/day, where treatment was associated with a 31.3 metres improvement on the 6MWT distance, after 48 weeks, compared with placebo. The Translational Research in EuropeAssessment & Treatment of Neuromuscular Diseases (TREAT-NMD) network was launched to provide an infrastructure to accelerate research and therapy development, increasing collaboration, improving patient care and helping to support clinical trial readiness. As such, the TREAT-NMD registry network is well placed to support further understanding of DMD and the impact of therapies that may be used over the long term, permitting a host of research questions to be explored.
The Management of Paroxysmal Nocturnal Haemoglobinuria – Recent Advances in Diagnosis and Treatment, and New Hope for Patients
Authors: Schrezenmeier Hubert , Höchsmann Britta ,   Institute of Transfusion Medicine, University of Ulm, and Institute of Clinical Transfusion Medicine and Immunogenetics, Ulm, Red Cross Blood Service, Baden-Württemberg-Hessen,   Institute of Transfusion Medicine, University of Ulm, and Institute of Clinical Transfusion Medicine and Immunogenetics, Ulm, Red Cross Blood Service, Baden-Württemberg-Hessen
Published: October 2015

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare life-threatening and debilitating disorder of haematopoiesis. It is characterised by the clinical triad of Coombs-negative acquired extracorpuscular haemolytic anaemia, thrombophilia and bone marrow failure. The sequelae of intravascular haemolysis drastically affect the quality of life of patients. Cytopenia and in particular thrombophilia can cause life-threatening complications. Thromboembolic events are the major cause of death. The only curative treatment for PNH is allogeneic stem cell transplantation from a related or unrelated stem cell donor. Recent reports demonstrated favourable outcomes. Other treatments were generally supportive in nature. Recently, eculizumab, a humanised monoclonal antibody that inhibits complement factor C5, was approved. It is a targeted, disease-modifying treatment of PNH. This article will summarise major advances in the management of PNH during the last year and, in particular, will discuss new results of eculizumab, treatment of thrombosis and stem cell transplantation. Given the new advances there is hope for improved survival of these patients.
Laboratory Diagnostics in Septic Disseminated Intravascular Coagulation
Authors: Lippi Giuseppe , Guidi Gian Cesare ,   Associate Professor,   Professor, Clinical Biochemistry and Clinical Molecular Biology, University of Verona
Published: October 2015

The diagnosis of septic disseminated intravascular coagulation (DIC) relies on clinical signs and symptoms, identification of the underlying disease and results of laboratory testing. Since no single test result alone can definitely establish or rule out the diagnosis, the laboratory diagnostics of septic DIC encompass a combination of tests for which simple diagnostic algorithms are now available. Global tests of haemostasis provide evidence of activation of blood coagulation and, ultimately, consumption of coagulation factors, but their diagnostic efficiency is as yet questionable. Fibrinolytic markers, namely D-dimer, reflect the extent of activation of both coagulation and fibrinolysis, so a normal value can be used in a ruling-out strategy. Decreased levels of the natural inhibitors are frequently observed in patients with septic DIC, but antithrombin and protein C measurements are not incorporated in any of the widely used diagnostic algorithms. Among the inflammatory biomarkers, procalcitonin is currently regarded as the gold standard to differentiate the type of infection and guide antibiotic therapy, but its clinical usefulness in identifying and predicting the outcome of patients with septic DIC is still circumstantial.
Indirect Effects of Cytomegalovirus Infection
Authors: Grigoleit Götz Ulrich , Kapp Markus , Einsele Hermann ,   Senior Physician,   Resident Physician,   Full Professor, Internal Medicine, and Director, Medical Clinic II, Julius Maxmilians University Würzburg
Published: October 2015

Primary cytomegalovirus (CMV) infection often presents as an asymptomatic self-limiting disease in immunocompetent individuals and is followed by latent persistence in different host tissues. However, solid organ transplant (SOT) recipients and patients undergoing allogeneic haematopoietic stem cell transplantation (alloHSCT) are at risk of life-threatening complications caused by CMV infection. Direct effects (or CMV disease) are marked by viral proliferation in a variety of tissues and organs. Clinical manifestations that are observed after SOT and alloHSCT are gastroenteritis, pneumonitis, hepatitis, uveitis, retinitis, encephalitis and graft rejection. In contrast to the direct effects, indirect effects are a consequence of the maintenance of persistent low-level viral replication and have been associated with an increased risk of rejection and graft dysfunction, graft-versus-host disease, accelerated atherosclerosis, opportunistic infections, malignancies, posttransplant diabetes and Guillain-Barré syndrome. This article aims to summarise these indirect effects of CMV, their possible causes and possible treatment strategies.
Unrelated Transplants for High-risk Adult Acute Lymphoblastic Leukaemia
Authors: Ferrà Christelle , Ribera Josep-Maria ,   Attending Physician,   Chief, Haematology Department, Catalan Institute of Oncology, University Hospital Germans Trias i Pujol
Published: October 2015

Standard chemotherapy has a poor outcome in adult patients with high-risk acute lymphoblastic leukaemia (ALL). Allogeneic haematopoietic stem cell transplant (alloSCT) is the treatment of choice, and SCT with alternative progenitors should be considered in the absence of a matched sibling donor. There is great heterogeneity in the data on unrelated SCT for adult patients with high-risk ALL. Many studies include both paediatric and adult patients, or provide combined data from ALL and acute myeloid leukaemia (AML) patients. Moreover, the follow-up of the reported series is highly variable, and the definition of high-risk criteria varies from one study to another. The reported disease-free survival (DFS) for adult ALL patients ranges from 30 to 70%, and leukaemia relapse (14–47%) is an important cause of treatment failure. Despite great improvements in recent years, transplant-related mortality (TRM) from unrelated SCT (USCT) remains unacceptably high (29–36%). The human leukocyte antigen (HLA) disparity in the unrelated donor setting with a high incidence of graft-versus-host disease (GvHD) and delayed immunological reconstitution with a high incidence of infectious events in the unrelated cord blood SCT are the most important causes of morbidity and mortality in unrelated transplants. Disease status at transplant and the presence of acute and/or chronic GvHD are the most important factors determining relapse in high-risk ALL adult patients undergoing USCT.
Oncogenic Anaplastic Lymphoma Kinase Rearrangements in Lymphoma
Authors: Roosbroeck Katrien Van , Wlodarska Iwona ,   PhD Student,   Staff Member, Centre for Human Genetics, University Hospital of Gasthuisberg, Catholic University of Leuven
Published: October 2015

Lymphomas expressing anaplastic lymphoma kinase (ALK) represent two distinct lymphoma entities: ALK-positive T-/null-cell anaplastic large cell lymphoma (ALK+ ALCL) and ALK-positive large B-cell lymphoma (ALK+ LBCL). In both subtypes, the inappropriate expression of ALK is driven by 2p23/ALK-involving chromosomal translocations found to target several partner genes. These translocations lead to constitutively activated and oncogenic ALK fusions, of which nucleophosmin (NPM1)-ALK associated with t(2;5)(p23;q35) is the most common. Recently, various ALK fusions, including those previously described in lymphomas, have been identified in several types of nonhaematological malignancy. Identification of further types of ALK+ tumours is clinically important because in future these patients may benefit from targeted therapy, already applied in neoplasms driven by, for example, the mutated ABL1, KIT and PDGFRA/B tyrosine kinases. In this article, we will focus mainly on oncogenic ALK rearrangements in lymphomas and their molecular consequences.
Myeloproliferative Neoplasms – Classification, Diagnostic and Therapeutic Options in the Light of Molecular Findings
Authors: Hellmann Andrzej , Bieniaszewska Maria ,   Professor of Medicine, and Head,   Haematologist, Department of Haematology and Transplantology, Medical University of Gdansk
Published: October 2015

The discovery of specific molecular aberrations (gene fusions or mutations) has had a profound effect on the understanding and management of myeloproliferative disorders (MPDs). First, it has provided clear evidence that all of these disorders are of neoplastic origin. This fact resulted in the change of the nomenclature proposed in the World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues 2008, where the term MPDs was replaced by myeloproliferative neoplasms (MPNs). Second, useful tools for diagnostic procedures were developed, i.e. polymerase chain reaction (PCR) or other molecular assays. Thanks to this, previous complicated diagnostic algorithms could be simplified and the numerical value requirements could be lowered, making the diagnosis simpler and quicker. The other implication of the molecular findings in myeloproliferative neoplasms is derived from the fact that all discovered mutations result in translation of proteins with tyrosine kinase activity. So, nowadays the majority of myeloproliferative neoplasms can be treated with target therapy using tyrosine kinase inhibitors.
Holotranscobalamin – An Early Marker for Laboratory Diagnosis of Vitamin B12 Deficiency
Authors: Herrmann Wolfgang , Obeid Rima ,   Senior Scientist,   Junior Professor, Department of Clinical Chemistry and Laboratory Medicine, University Hospital Homburg, Saarland University
Published: October 2015

Vitamin B12deficiency is widespread. Among the population groups at risk are older people, vegetarians, pregnant women and patients with renal or intestinal diseases. The neurological symptoms of vitamin B12deficiency are unspecific and can be irreversible. Early detection is therefore important. This article reviews the diagnostic performance of the different laboratory markers for vitamin B12status. Total serum vitamin B12is a relatively insensitive and unspecific biomarker of deficiency that does not reflect recent variations in cobalamin status. Holotranscobalamin (holoTC), the metabolically active portion of vitamin B12, is the earliest laboratory parameter that becomes decreased in case of a vitamin B12negative balance. Concentration of methylmalonic acid (MMA) is a functional vitamin B12marker that will increase when the vitamin B12stores are depleted. Isolated lowering of holoTC shows vitamin B12depletion (negative balance), while lowered holoTC plus elevated MMA (and homocysteine) indicates a metabolically manifested vitamin B12deficiency, although there still may be no clinical symptoms. The diagnostic use of holoTC allows the initiation of therapeutic measures before irreversible neurological damage develops. Because the clinical manifestations of vitamin B12deficiency are unspecific, people at risk should be identified and should regularly test their holoTC with or without MMA.
Availability and Accessibility of Opioids in Developing Countries, with Special Reference to Eastern Europe
Authors: Bond Sir Michael ,   Emeritus Professor of Psychological Medicine, University of Glasgow
Published: October 2015

Severe pain is present in about three-quarters of the millions who suffer from cancer or HIV/AIDS in developing countries. Opioids, especially morphine, are vital for pain relief, yet western European countries – in contrast to those in eastern Europe – account for 88% of the total European consumption of opioids. Eighty per cent of the world’s population live in developing countries but receive only 6% of the available morphine. Pain control is possible using World Health Organization (WHO) guidelines in 85–90% of cancer patients, but far fewer gain relief as a result of several barriers to treatment, including inadequate training of healthcare professionals in pain management, obstructions due to governmental health regulations, fear of opioid addiction in health professionals, government advisors and the general public and, in some cases, the costs of medication. The position is similar for HIV/AIDS sufferers.
Gliosarcoma – Clinico-pathology, Genetics and a Review of Rare Congenital Cases
Authors: Dunham Christopher ,   Neuropathologist, Department of Pathology and Laboratory Medicine, Division of Anatomic Pathology, Children’s and Women’s Health Centre of British Columbia
Published: October 2015

Congenital brain tumours are rare. In general, they are preferentially located in the supratentorial compartment, and despite the occurrence of low-grade entities, these tumours are associated with a very poor prognosis. When strictly defined, the most common forms of congenital neoplasia are teratomas and astrocytomas. Among the astrocytomas, all grades (World Health Organization [WHO] I–IV) and many of the different subtypes are represented. This includes the most prognostically worrisome ‘diffusely infiltrating’ astrocytomas. Gliosarcomas are a variant of glioblastoma (i.e. WHO grade IV astrocytoma) that exhibits both malignant astrocytic (i.e. glioblastoma) and mesenchymal (i.e. sarcoma) components. Despite their bi-phasic histology, genetic analyses of adult gliosarcoma cases suggest not only a molecular profile similar to glioblastoma, but also a monoclonal histogenesis for the glial and sarcomatous elements. Congenital gliosarcomas are extremely rare, with only a handful of cases being described in the literature. Not surprisingly, therefore, detailed clinical, pathological and genetic data are limited. However, based on a recent analysis of congenital glioblastomas, congenital gliosarcomas may constitute an entity that is genetically and prognostically distinct from adult cases.
Palliative Orthopaedic Surgery for Skeletal Metastases
Authors: Ashford Robert U ,   Consultant Orthopaedic and Musculoskeletal Tumour Surgeon, University Hospitals of Leicester NHS Trust
Published: October 2015

Advances in oncological therapies have resulted in improved survival in patients with skeletal metastases. The resultant effect is that the skeletal metastases result in an increased incidence of pathological fracture and bone pain. This article focuses on the options available to the orthopaedic surgeon in the treatment of patients with skeletal metastases. It covers the controversial area of prophylactic fixation and the roles of conventional internal fixation, cement, arthroplasty and endoprosthetic replacement. The role of radiotherapy in the management of patients with surgically treated skeletal metastases is highlighted. Treatment for these patients is always individualised and should always be subject to a multidisciplinary approach. Despite the prognosis, satisfying results can be obtained that achieve the aims of palliative surgery, namely pain relief and maintenance of or improvement in function.
Second- and Third-line Treatment in Advanced Non-small-cell Lung Cancer
Authors: Favaretto Adolfo , Pasello Giulia ,   Professor, Thoracic Surgery Speciality School, Padua University,   Researcher, Medical Oncology Department, Istituto Oncologico Veneto
Published: October 2015

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. About 50% of patients present with locally advanced or metastatic disease. First-line therapy usually consists of a combination of cisplatin or carboplatin with a third-generation agent (paclitaxel, docetaxel, gemcitabine or vinorelbine) that results in less than 5% five-year survival. In recent years advances in second- and third-line treatment have led to a prognostic improvement. Two cytotoxic agents, docetaxel and pemetrexed, are approved in NSCLC second-line treatment, and a new class of drugs against specific molecular targets – tyrosine kinase inhibitors – has emerged as an alternative to conventional treatment. Many trials are ongoing to assess the activity of new drugs, alone or in association, or new combinations of third-generation chemotherapeutic agents.
European Audit on Colorectal Cancer Treatment Outcome – The Next Step in Quality Assurance Initiated by the European Society of Surgical Oncology
Authors: Gijn Willem van , Dulk Marcel den , Velde Cornelius Jan Hadde van de ,   Department of Surgery, Leiden University Medical Centre,   Department of Surgery, Haga Hospital, The Hague,   Department of Surgery, Leiden University Medical Centre
Published: October 2015

In recent years there have been significant improvements in rectal cancer outcome. New surgical techniques and effective neoadjuvant treatment regimens have contributed to these improvements. It is important to spread these advances to every rectal cancer patient and to make sure that it is not only patients treated within the framework of clinical trials who may benefit from these advances. Throughout Europe there have been interesting quality programmes that have been proved to facilitate the spread of up-to-date knowledge and skills among medical professionals, resulting in improved treatment outcomes. Despite these laudable efforts, there is still wide variation in treatment outcomes between countries, regions and institutions, which calls for a European audit on cancer treatment outcomes.
Improving the Outcome of Patients with Castration-resistant Prostate Cancer Through Rational Targeting of the Androgen Receptor
Authors: Attard Gerhardt , Bono Johann S De , Parker Chris ,   Clinical Lecturer,   Senior Lecturer and Honorary Consultant, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust,   Senior Lecturer and Honorary Consultant, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust
Published: October 2015

Castration-resistant prostate cancer (CRPC) is now the second most common cause of male cancer-related mortality. Recent evidence confirms that androgen receptor signalling continues to drive a significant proportion of progressing prostate cancers despite castrate serum levels of testosterone and multiple hormonal interventions. An increased understanding of the molecular biology underlying CRPC is informing on therapeutic targets for this disease, and we hypothesise that this will lead to the development of more efficacious drugs.
Maternal Epithelial Ovarian Cancer
Authors: Palmer Julia , Vatish Manu , Tidy John ,   Consultant Gynaecological Oncologist, Royal Hallamshire Hospital,   Senior Lecturer, Clinical Sciences Research Institute, Warwick Medical School and Department of Obstetrics, University Hospitals Coventry & Warwickshire, and Visiting Professor/Fulbright Scholar, Department of Endocrinology, Albert Einstein College of Medicine,   Consultant Gynaecological Oncologist, Royal Hallamshire Hospital
Published: October 2015

Maternal epithelial ovarian cancer is rare; its rarity is reflected by the paucity of reported cases in the literature. Its incidence appears to be increased in the older pregnant patient, and since childbearing among older patients has markedly risen in more recent years it is likely that this disease will become more common. Currently, there are no definitive guidelines regarding patient management in maternal epithelial ovarian cancer. Management should therefore be case-dependent, individualised and multidisciplinary in nature. Data centralisation for individual cases including detailed information on clinico-pathological variables, treatment regimens, maternal and neonatal outcomes may be beneficial in identifying optimal management strategies in these rare tumours.
Chemotherapy for Early-stage High-risk Endometrial Cancer
Authors: Hogberg Thomas ,   Head, Department of Cancer Epidemiology, Lund University Hospital
Published: October 2015

Endometrial cancer generally has a good prognosis because most cases are diagnosed in stage I. It is possible to identify subgroups of patients with early-stage endometrial cancer with a poor prognosis. Despite a traditional generous use of adjuvant radiotherapy, these patients have five-year overall survival of approximately 80%. In this group there is a need for an effective systemic adjuvant therapy. Mainly based on superior response rates, doxorubicin + cisplatin was for many years the standard chemotherapy in endometrial cancer. Gynecologic Oncology Group (GOG)-177 was the first phase III study on chemotherapy in endometrial cancer that showed a survival advantage. Paclitaxel + doxorubicine + cisplatin was better than doxorubicine + cisplatin, but the toxicity of the three-drug regimen has precluded general acceptance. Paclitaxel + carboplatin has produced high response rates and is widely used, despite the lack of evidence based on randomised studies. GOG-122 compared doxorubicine + cisplatin with whole abdominal radiotherapy in advanced optimally operated endometrial cancer and showed that chemotherapy with doxorubicine + cisplatin resulted in superior survival. Two recent studies have compared adjuvant chemotherapy (cyclophosphamide + doxorubicine + cisplatin) with adjuvant radiotherapy in early-stage endometrial cancer. Both studies failed to show a difference between the treatments. Another study (NSGO-EC-9501/EORTC-55991) compared adjuvant radiotherapy plus chemotherapy with adjuvant radiotherapy, and showed better survival with the sequential combination.
Hypocholesterolaemia in Thalassaemia – Pathogenesis, Implications and Clinical Effects
Authors: Ricchi Paolo , Ammirabile Massimiliano , Maggio Aurelio ,   Assistant, Department of Oncohaematology, Microcythaemia Centre ‘A Mastrobuoni’, Antonio Cardarelli Hospital,   Fellow, Department of Oncohaematology, Microcythaemia Centre ‘A Mastrobuoni’, Antonio Cardarelli Hospital,   Director, Division of Haematology II, Villa Sofia-Cervello Hospital
Published: October 2015

In this review, the role of hypocholesterolaemia as a potential source of several clinical features of patients affected by thalassaemia is assessed. The primary focus is on the extent of the phenomenon among different forms of thalassaemia in order to highlight the particularly reduced level in patients with thalassaemia intermedia. In addition, we explore how the reduced levels of cholesterol could influence the atherogenic process and many typical clinical features of patients affected by thalassaemia.
The Use of Plerixafor for Peripheral Blood Stem Cell Mobilisation Reduces the Frequency of Mobilisation Failure in Patients Planned to Undergo Autologous Transplantation
Authors: Josefsen Dag , Rechnitzer Catherine , Parto Katriina , Kvalheim Gunnar ,   Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital,   Department of Paediatrics, Rigshospitalet, Copenhagen University Hospital,   Paediatric Haematology, Tampere University Hospital,   Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital
Published: October 2015

High-dose chemotherapy with or without radiation followed by autologous haematopoietic stem cell transplantation (auto-HSCT) is now the standard of care for patients with chemosensitive relapsed aggressive non-Hodgkin’s lymphoma (NHL), chemosensitive relapsed Hodgkin’s disease (HD) and multiple myeloma (MM). Autologous haematopoietic stem cells also provide haematopoietic support after the administration of high-dose chemotherapy in relapsed NHL and MM. However, certain patients fail to mobilise a sufficient number of haematopoietic stem cells using standard cytokine-assisted mobilisation strategies. Recently, plerixafor, a novel bicyclam capable of specifically and reversibly binding to the CXCR4 receptor on haematopoietic stem cells, has been granted European approval, in combination with granulocyte colony-stimulating factor, for the enhancement of haematopoietic stem cell mobilisation to the peripheral blood for collection and subsequent autotransplantation in poorly mobilising lymphoma and MM patients. In this article the authors present their initial experience with plerixafor in a case series at their own institutions in Scandinavia.