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Breakthroughs in medical research in the last century have led to a significant extension of the human lifespan, resulting in a shift towards an elderly population worldwide. Due to the ongoing progress of global development towards elevated standards of living, this study specifically examines Switzerland as a representative nation to explore the socioeconomic and healthcare ramifications associated with an ageing population, thereby highlighting the tangible impact experienced in this context. Beyond the exhaustion of pension funds and medical budgets, by reviewing the literature and analysing publicly available data, we observe a “Swiss Japanification”. Old age is associated with late-life comorbidities and an increasing proportion of time spent in poor health. To address these problems, a paradigm shift in medical practice is needed to improve health rather than respond to existing diseases. Basic ageing research is gaining momentum to be translated into therapeutic interventions and provides machine learning tools driving longevity medicine. We propose that research focus on closing the translational gap between the molecular mechanisms of ageing and a more prevention-based medicine, which would help people age better and prevent late-life chronic diseases.

Abstract Background The introduction of new therapy modalities has significantly improved the outcome of aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) patients. However, relatively little is known about the exact disease burden of AA/PNH since standardized assessments of symptoms including health-related quality of life (HRQoL) are frequently missing or inadequately designed for this rare patient group. We aimed to develop AA/PNH-specific questionnaires for self-reporting of symptoms, which could be included in electronic platforms for data collection and patient care. Methods By scoping review, we extracted any reported symptoms in AA/PNH and their prevalence from the literature (Phase I). Consensus rounds with patients and medical experts were conducted to identify core symptoms reported in the literature and to add missing items (Phase II). Ultimately, AA/PNH-specific patient-reported outcome (PRO) questionnaires including the selected measures were designed (Phase III). Results AA symptoms from 62 and PNH symptoms from 45 observational studies were extracted from the literature. Twenty-four patients and seven medical experts identified 11 core symptoms including HRQoL issues after three consensus rounds. Significant differences in the symptom ranking of patients versus medical experts could be observed. Therefore, patient- as well as expert-centered PRO questionnaires in AA and PNH were created following the concepts of validated instruments. Conclusion The development of symptom self-reporting questionnaires for AA and PNH was feasible and the disease-specific PRO questionnaires can now be validated within a web-based workflow in a subsequent feasibility study.

In Europe, there are currently some 30 different jurisdictions and no overarching legislation regarding CME-CPD accreditation, since legislative competency related to national health-care systems lies with national authorities. Thus, public demonstration of professional agreement regarding the principles, rules and practice of CME-CPD as well as its accreditation is a highly desirable professional and political objective in Europe, where free movement and freedom to offer professional (medical) services is a key feature of the EU vision of the single market. The newly formed association of independent European accreditors, Continuing Medical Education - European Accreditors (CME-EA) is committed to offering a platform for dialogue between individuals and organisations involved in definition of professional codes in general, and accreditation of CME-CPD in particular on the national level. The aim is to reach a European consensus on principles and rules applied in planning and delivery of CME-CPD. This includes consensus on constituent characteristics of accreditors as well as principles and practice of accreditation.

This position paper is the result of a collaborative approach of several European Specialty Accreditation Boards (ESABs) and, has been stimulated by their current experience in accreditation regarding roles and responsibilities assumed by sponsors of accredited continuing medical education (CME). The suggestions made in this paper aim to preserve the fundamental principle in CME accreditation that the physician in charge of the programme has sole responsibility for the selection of topics, speakers, content and format, as well as mode of presentation, and that sponsors will under no circumstances interfere with this principle. This is considered as a responsibility of an individual physician (or physicians), which cannot be delegated, even in part, to third parties. This responsibility has been extended to include all communication before and after the event. The paper also identifies undecided issues, about which ESABs are committed to elaborate proposals in the future.

Advances in hematopoietic cell transplantation (HCT) technology and supportive care techniques have led to improvements in long-term survival after HCT. Emerging indications for transplantation, introduction of newer graft sources (e.g. umbilical cord blood) and transplantation of older patients using less intense conditioning regimens have also contributed to an increase in the number of HCT survivors. These survivors are at risk for developing late complications secondary to pre-, periand post-transplant exposures and risk-factors. Guidelines for screening and preventive practices for HCT survivors were published in 2006. An international group of transplant experts was convened in 2011 to review contemporary literature and update the recommendations while considering the changing practice of transplantation and international applicability of these guidelines. This review provides the updated recommendations for screening and preventive practices for pediatric and adult survivors of autologous and allogeneic HCT.Os avanços na tecnologia do transplante de células hematopoéticas (TCH) e do tratamento de suporte levaram a melhoria na sobrevida a longo prazo após os TCH. Indicações emergentes de transplante, introdução de novas fontes de células (p.ex. sangue de cordão umbilical) e transplante de pacientes mais velhos utilizando regimes de condicionamento menos intensos também contribuíram para o aumento no número de sobreviventes após TCH. Estes sobreviventes estão sob risco de desenvolver complicações tardias devido a exposições e fatores de risco pré, peri e pós-transplante. Práticas recomendadas para a triagem e a prevenção de complicações em sobreviventes de TCH foram publicadas em 2006. Um grupo internacional de especialistas foi formado em 2011 para rever a literatura contemporânea e atualizar as recomendações, considerando as mudanças nas práticas de transplante e a aplicabilidade internacional destas recomendações. Esta revisão fornece as recomendações atualizadas para o diagnóstico precoce e práticas para prevenção de complicações aos sobreviventes de TCH autólogo e alogênico, adultos e crianças.

Background In the era of eculizumab, identifying patients with paroxysmal nocturnal hemoglobinuria who may benefit from allogeneic stem cell transplantation is challenging.Design and Methods We describe the characteristics and overall survival of 211 patients transplanted for paroxysmal nocturnal hemoglobinuria in 83 EBMT centers from 1978 to 2007. Next, we conducted a comparison with a cohort of 402 non-transplanted patients with paroxysmal nocturnal hemoglobinuria diagnosed between 1950 and 2005 in 92 French centers. We compared the occurrence of complications (i.e. thromboembolism and aplastic anemia) using either an individual or a stratum-matching procedure.Results After a median follow-up of 5 years, the 5-year overall survival rate ± standard error (%) was 68±3 in the transplanted group (54±7 in the case of thromboembolism, 69±5 in the case of aplastic anemia without thromboembolism and 86±6 in the case of recurrent hemolytic anemia without thromboembolism or aplastic anemia). Only thromboembolism as the indication for transplantation was associated with worse outcome (P=0.03). We identified 24 pairs of transplanted and non-transplanted patients with thromboembolism for the matched comparison, with worse overall survival for the transplanted patients (hazard ratio=10.0; 95% confidence interval, 1.3-78.1; P=0.007). This was confirmed by the global matching procedure (P=0.03). As regards aplastic anemia without thromboembolism, 30 pairs were identified for the matched comparison. It was not observed that transplanted patients had a significantly worse overall survival (hazard ratio=4.0; 95% confidence interval, 0.9-18.9; P=0.06). A global matching procedure was not feasible.Conclusions Allogeneic stem cell transplantation is probably not a suitable treatment option for life-threatening thromboembolism in paroxysmal nocturnal hemoglobinuria.

Background Bone marrow has been shown to be superior to peripheral blood, as a stem cell source, in young patients (

This follow-up study of a randomized, prospective trial included 192 patients with newly diagnosed severe aplastic anemia receiving antithymoglobulin and cyclosporine, with or without granulocyte colony-stimulating factor (G-CSF). We aimed to evaluate the long-term effect of G-CSF on overall survival, event-free survival, probability of secondary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), clinical paroxysmal nocturnal hemoglobinuria, relapse, avascular osteonecrosis and chronic kidney disease. The median follow-up was 11.7 years (95% CI, 10.9-12.5). The overall survival rate at 15 years was 57±12% in the group given G-CSF and 63±12% in the group not given G-CSF (P=0.92); the corresponding event-free survival rates were 24±10% and 23±10%, respectively (P=0.36). In total, 9 patients developed MDS or AML, 10 only a clonal cytogenetic abnormality, 7 a solid cancer, 18 clinical paroxysmal nocturnal hemoglobinuria, 8 osteonecrosis, and 12 chronic kidney disease, without any difference between patients treated with or without G-CSF. The cumulative incidence of MDS, AML or isolated cytogenetic abnormality at 15 years was 8.5±3% for the G-CSF group and 8.2±3% for the non-G-CSF group (P=0.90). The cumulative incidence of any late event including myelodysplastic syndrome or acute myeloid leukemia, isolated cytogenetic abnormalities, solid cancer, clinical paroxysmal nocturnal hemoglobinuria, aseptic osteonecrosis, chronic kidney disease and relapse was 50±12% for the G-CSF group and 49±12% for the non-G-CSF group (P=0.65). Our results demonstrate that it is unlikely that G-CSF has an impact on the outcome of severe aplastic anemia; nevertheless, very late events are common and eventually affect the prognosis of these patients, irrespectively of their age at the time of immunosuppressive therapy (NCT01163942).

We analyzed the outcome of 537 adolescents (age 12–18 years) with idiopathic aplastic anemia included in the database of the Severe Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplantation comparing: i) matched family donor hematopoietic stem cell transplantation performed as first-line treatment with ii) front-line immunosuppressive therapy not followed by subsequent transplant given for failure and with iii) hematopoietic stem cell transplantation performed after failed front-line immunosuppressive therapy. Overall survival was 86% in the matched family donor hematopoietic stem cell transplantation group, 90% in patients given front-line immunosuppressive alone (those who did not fail this treatment and who did not receive subsequent rescue with hematopoietic stem cell transplantation) and 78% in subjects who underwent hematopoietic stem cell transplantation post failed front-line immunosuppressive therapy (P=0.14). Event-free survival in the same groups was respectively 83%, 64% and 71% (P=0.04). Cumulative incidence of rejection was 8% in matched family donor hematopoietic stem cell transplantation and 9% in transplants post failed front-line immunosuppression (P=0.62). Cumulative incidence of acute graft-versus-host disease was 12% in matched family donor transplants and 18% in transplants post failed immunosuppression (P=0.18). Chronic graft-versus-host disease was higher in matched family donor hematopoietic stem cell transplantation (8%) than in transplants post failed immunosuppressive therapy (20%) (P=0.0009). Cumulative incidence of post-therapy malignancies was 0.7% in matched family donor transplantations, 7% in transplantations post failed immunosuppression and 21% after front-line immunosuppression (P=0.0017). In the whole cohort, under multivariate analysis, the diagnosis to treatment interval of two months or under positively affected overall survival whereas up-front immunosuppression alone (with no subsequent rescue transplants) negatively affected event-free survival. In transplanted patients an interval from diagnosis to treatment of 2 months or under, bone marrow as source of cells and first-line matched family donor transplants provided a significant advantage in overall and event-free survival. Aplastic anemia in adolescents has a very good outcome. If a matched family donor is available, hematopoietic stem cell transplantation using bone marrow cells is the first choice treatment. If such a donor is not available, immunosuppressive treatment may still be an acceptable second choice, also because, in case of failure, hematopoietic stem cell transplantation is a very good rescue option.

The purpose of this study was to examine changes in haematopoietic stem cell transplant (HSCT) characteristics and outcome in our combined paediatric and adult programme over the past four decades, since its implementation in 1973. The total number of transplant procedures rose from 109 in the first decade (1973–82) to 939 in the last decade (2003–12). Transplant characteristics changed significantly over time: patient age increased, peripheral blood largely replaced bone marrow as stem cell source, unrelated donors became an alternative to matched siblings, and patients are increasingly transplanted in more advanced disease stages. Advances such as improved supportive care and histocompatibility typing resulted in a steady decrease of transplant-related mortality after allogeneic HSCT (43% in the first decade, 22% in the last decade). Despite this, unadjusted survival rates were stable in the last three decades for allogeneic HSCT (approximately 50% 5–year survival) and in the last two decades for autologous HSCT (approximately 60% 5–year survival). After adjustment for covariates such as donor type, age and stage, the relative risk of treatment failure continuously dropped (for allogeneic HSCT: first decade 1.0, second decade 0.58, third decade 0.51, last decade 0.41). Collectively, these data suggest that improvements in peri- and post-transplant care have allowed considerable extension of transplant indications without having a negative impact on outcome.

BACKGROUND: Iron deficiency anaemia is a common disease with a prevalence of up to 19.2% in populations at risk. However, the prevalence of iron deficiency (ID) in hospitalised patients is not well known. The aims of this retrospective, observational cohort study were to evaluate the current diagnostic procedures for, and treatment of, ID as well as to estimate the prevalence of undiagnosed ID in hospitalised patients at the division of internal medicine in a Swiss tertiary university referral centre. METHODS: Within a study period of 6 months, data from all patients hospitalised at the division of internal medicine were analysed for the presence of anaemia (defined as haemoglobin levels for males

The aim of this study was to assess the degree of spermatogenesis defects in sperm analysis in long-term male survivors after allogeneic hematopoietic stem cell transplantation in order to identify the risk factors related to potential infertility after hematopoietic stem cell transplantation and to provide data on longitudinal sperm recovery after hematopoietic stem cell transplantation. Here, the Late Effects Working Party of the European Group for Blood and Marrow Transplantation reports data of sperm analysis from 224 males who underwent hematopoietic stem cell transplantation. Median time between transplantation and sperm analysis was 63 months (8–275 months). At last sperm analysis, presence of any degree of spermatozoa was reported in 70 (31%) and complete azoospermia in 154 (69%) patients. In multivariate analysis, being conditioned with total body irradiation (RR 7.1; 95% CI: 3.4–14.8) and age over 25 years at transplantation (RR 2.4; 95% CI: 1.09–5.2) were significantly associated with higher risk for azoospermia. In patients not conditioned with total body irradiation, ongoing chronic graft-versus-host disease is the main adverse factor for sperm recovery (RR of 3.11; 95% CI: 1.02–9.47; P=0.045). Already established risk factors, such as total body irradiation and age older than 25 years at hematopoietic stem cell transplantation, were seen to be the most relevant adverse risk factor for sperm production after hematopoietic stem cell transplantation. Furthermore, for the first time, ongoing graft-versus-host disease has been shown to be the most relevant adverse factor for sperm recovery, particularly in patients conditioned without total body irradiation. We also introduce a useful scoring system to predict the probability of male long-term survivors’ azoospermia.

The first hematopoietic stem cell transplantation (HSCT), the replacement of the hematopoietic system, by hematopoietic stem cells from the patient (autologous HSCT) or from another person (allogeneic HSCT), was performed almost 45 years ago. Today autologous HSCT is used to bridge hematopoietic failure after high dose chemotherapy for the treatment of selected hematopoietic and non-hematopoietic tumours. Allogeneic HSCT is used to treat congenital or acquired marrow failure, and, more commonly, to exploit the graft versus tumour effect of allogeneic cells against high risk hematologic malignancies. In 2010, 30,000 patients were treated with HSCT (12,000 allogeneic and 18,000 autologous HSCT) in Europe. Substantial progress has been made in the field of allogeneic HSCT in the last decade. First the article describes advances in patient and donor selection, the current concepts of choosing the optimal stem cell source and the most appropriate preparative regimen. Furthermore, recent advances in supportive care are described. We describe how these innovations have allowed indications for allogeneic HSCT to be expanded. Finally, prospects for future developments will be outlined.

We present a case of a 40-year-old female from Turkey, who was referred to our outpatient clinic for an undetermined thalassemia and sickle cell trait. At first consultation hemoglobin was decreased (71 g/L) with microcytosis (MCV 55.1 fL), and hypochromia (MCHC 239 g/L). The patient had severe iron deficiency. Brilliant cresyl blue staining showed >50% of the erythrocytes with typical Hemoglobin H (HbH) inclusions. High-performance liquid chromatography (HPLC) revealed normal levels of HbA2 and Hemoglobin F (HbF), and additionally a hemoglobin S (19%). Molecular diagnostics revealed the mutations α2 IVS-I donor site -5nt and a -- MED II deletion in the alpha gene complex and confirmed the heterozygote mutation of the beta-gene at codon 6 (HBB:c.20A>T; HbS). In conclusion, we present an extremely rare combination of HbH disease and sickle cell trait. This combination may explain the mild form of the HbH disease, with moderate anemia, splenomegaly but iron deficiency, rather than iron overload, as usually observed in HbH disease.

Background Hematopoietic stem cell transplantation has become an established procedure worldwide. Severe early and late complications are well described. Little is known about more subtle changes in general health status of very long-term survivors. The study objective was to assess health status of very long-term survivors in comparison with their respective human leukocyte antigen-identical sibling donors.Design and Methods Case matched comparison in a cross-sectional cohort was performed in a tertiary university hospital and referral center for hematopoietic stem cell transplantation. Forty-four pairs of recipients and their respective donors with a very long-term (17.5 years median; 11–26 years range) follow up after allogeneic hematopoietic stem cell transplantation were included. A comparative clinical evaluation and examination of routine clinical chemistry tests was carried out.Results Recipients more frequently had a lower Karnofsky score (P=0.05), hypertension (P=0.015) and dyslipidemia (P=0.002) but were less likely to be smokers (P=0.016). Recipients showed systematically lower glomerular filtration rates (P

Background Life-threatening infections are a major cause of death after allogeneic stem cell transplantation. Complement Mannose-binding lectin is a key component of innate immunity. Functional deficiency of mannose-binding lectin due to genetic polymorphism is frequent. Previous reports showed conflicting results with respect to the influence of functional mannose-binding lectin deficiency on infectious risk after allogeneic stem cell transplantation. The aim of this study was to clarify the impact of low mannose-binding lectin levels on infectious risk in a unique cohort of very long-term survivors after stem cell transplantation.Design and Methods Incidence of major infections was evaluable in 43 out of 44 very long-term survivors (over ten years) and studied retrospectively in relation to mannose-binding lectin serum concentrations.Results Recipients with mannose-binding lectin levels below 1,000 ng/mL were at increased risk to suffer from one or more major infections (P=0.002) during entire follow up. Infectious susceptibility was increased after neutrophil recovery, particularly until 24 months (Hazard Ratio 3.4) with sustained effects afterwards (Hazard Ratio 2.9). Mannose-binding lectin serum concentrations below 1,000 ng/mL were independently associated with major infections after neutrophil recovery (P=0.009). In subgroup analyses occurrence of severe herpes virus infections in particular was associated with significantly lower mannose-binding lectin levels (P=0.02).Conclusions Our findings indicate that low mannose-binding lectin levels may predict markedly increased susceptibility to severe infections with sustained effects even late after allogeneic stem cell transplantation. Determinations of mannose-binding lectin status should therefore be included into pre-transplantation risk assessment.

In a retrospective single center study we determined the time course of the JAK2-V617F or JAK2 exon 12 allele burden in DNA from purified granulocytes from 48 patients with myeloproliferative disorders. The percentage of change between the first and last sample in JAK2-V617F positive patients without cytoreductive therapy (n=16) was only +9% during a follow-up of 36±13 months, reflecting a remarkably stable mutant allele burden. When treatment with hydroxyurea was initiated during the course of the study, we observed a significant decrease of the JAK2-V617F allele burden (n=6). However, in JAK2-V617F positive patients who were already on hydroxyurea treatment before the first blood sampling (n=14), we observed stable allelic ratios with a variance of only +3% during a follow-up of 34±16 months. Our data suggest that in untreated myeloproliferative disorders patients, from whom samples at diagnosis are not available, the JAK2 allele burden determined at later stages could be equally informative.

Background Long-term outcome after hematopoietic stem cell transplantation including late transplant-related events is of increasing interest. The aim of this study was to evaluate the incidence of cardiovascular events after allogeneic HSCT and to search for their risk factors.Design and Methods This is a retrospective mutlicenter European Group of Blood and Marrow Transplantation (EBMT) analysis, including 548 long-term survivors treated in ten EBMT transplant centers, who underwent hematopoietic stem cell transplantation between 1990 and 1995 and survived ≥1 year after the transplant. All arterial events occurring after hematopoietic stem cell transplantation (cerebral, coronary, peripheral) were reported.Results Twenty (3.6%) out of 548 patients had a cardiovascular event in at least one arterial territory. The median age at occurence of cardiovascular events was 54 years (range, 41–70). The cumulative incidence of a first arterial event 15 years after hematopoietic stem cell transplantation was 6% (95% CI, 3%–10%). The cumulative incidence for patients with a high global cardiovascular risk score, defined as having ≥50% of the risk factors (arterial hypertension, diabetes, dys-lipidemia, increased body-mass index, physical inactivity, smoking) was 17%, as compared to 4% in those with a low risk score. In multivariate analysis age older than 30 years at last follow-up, and a high global cardiovascular risk score were associated with, respectively, 6.4-fold and 9.8-fold increases in the risk of an arterial event.Conclusions Long-term survivors after allogeneic hematopoietic stem cell transplantation are likely to have an increased risk of premature cardiovascular accidents.