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Executive SummaryThe EC Directive 2013/59/Euratom states in article 56 that exposures of target volumes in nuclear medicine treatments shall be individually planned and their delivery appropriately verified. The Directive also mentions that medical physics experts should always be appropriately involved in those treatments. Although it is obvious that, in nuclear medicine practice, every nuclear medicine physician and physicist should follow national rules and legislation, the EANM considered it necessary to provide guidance on how to interpret the Directive statements for nuclear medicine treatments.For this purpose, the EANM proposes to distinguish three levels in compliance to the optimization principle in the directive, inspired by the indication of levels in prescribing, recording and reporting of absorbed doses after radiotherapy defined by the International Commission on Radiation Units and Measurements (ICRU): Most nuclear medicine treatments currently applied in Europe are standardized. The minimum requirement for those treatments is ICRU level 1 (“activity-based prescription and patient-averaged dosimetry”), which is defined by administering the activity within 10% of the intended activity, typically according to the package insert or to the respective EANM guidelines, followed by verification of the therapy delivery, if applicable. Non-standardized treatments are essentially those in developmental phase or approved radiopharmaceuticals being used off-label with significantly (> 25% more than in the label) higher activities. These treatments should comply with ICRU level 2 (“activity-based prescription and patient-specific dosimetry”), which implies recording and reporting of the absorbed dose to organs at risk and optionally the absorbed dose to treatment regions. The EANM strongly encourages to foster research that eventually leads to treatment planning according to ICRU level 3 (“dosimetry-guided patient-specific prescription and verification”), whenever possible and relevant. Evidence for superiority of therapy prescription on basis of patient-specific dosimetry has not been obtained. However, the authors believe that a better understanding of therapy dosimetry, i.e. how much and where the energy is delivered, and radiobiology, i.e. radiation-related processes in tissues, are keys to the long-term improvement of our treatments.

As part of an International Agency for Research on Cancer (IARC) international epidemiological study of workers in the pulp and paper industry, previously unpublished exposure measurements were assembled in a database. This article summarizes the results of 3,873 measurements carried out in the production departments of paper and paperboard mills and recycling plants in 12 countries. In the paper and paperboard mills, most of the agents were measured in the pulping and refining departments and in on-machine coating and winding of paper/paperboard. Exposures to asbestos, carbon monoxide, formaldehyde, fungal spores, bacteria, nitrogen dioxide, minerals dusts, paper dust, sulphuric acid and different solvents sometimes exceeded exposure limit values. In the re-pulping and de-inking departments of recycling plants high exposures to formaldehyde, fungal spores, bacteria and paper dust were observed. High exposures to asbestos, bioaerosols, carbon monoxide and paper dust were found in many departments; ammonia, formaldehyde, mineral and paper dust and solvents were found in coating machines; and diphenyl and polychlorobiphenyls (PCBs) were found in some special circumstances. Measurements in the newsprint and uncoated paper machine departments revealed only a few elevated exposures. In nearly all departments, measurements of epichlorohydrin, PCBs, sulphur dioxide, hydrogen sulphide and mercaptans tended to be low, often even below their detection limits. In spite of some uncertainties in the measurement data, the study provides new insights into the level and variation of occupational exposures of production workers in the paper and paperboard industry. © Springer-Verlag 2004.

The Papers Presented at the Annual Meetings of the Knee Society Symposium includes selected papers read at the 2007 Annual Interim Meeting of the Knee Society held in Sienna, Italy in September 2007, and the 2008 Open Scientific Meeting of the Knee Society, held in San Francisco in March 2008. The wide range and high quality of the scientific material presented here is a credit to the excellent work of the Knee Society education committee and particularly to its Program Chair, Gil Scuderi, MD. Each of these papers is focused, concise and highly readable, which is a credit to the outstanding work of the staff at CORR in providing clear and consistent guidelines for each of the authors whose work was accepted for publication. The 2008 Ranawat Award was authored by Dr. Patricia Franklin and colleagues for their work on patient-specific attributes that affect the functional outcome after total knee replacement. While considerable interest in patient outcomes research has been present for some time now, we are still uncovering the hidden power, and the hidden pitfalls, of such evaluation tools in orthopaedics. Dr. Franklin and colleagues effectively demonstrate the substantial influence of specific patient characteristics in determining the ultimate functional outcome after knee replacement. These data are useful for surgeons and patients alike as part of the preoperative discussion so that expectations can be managed more appropriately. Further, this paper provides some insight into additional strategies that might be employed prior to knee replacement to affect some patient attributes that adversely impact outcome. The 2008 Coventry Award paper was authored by D’Lima, Colwell, and colleagues from the Scripps Clinic for their innovative report that directly measured the in vivo forces that the knee experiences after total knee arthroplasty. In an outstanding collaboration between basic science researchers, engineers, and clinicians, Dr. Colwell’s group designed and implanted in three patients an instrumented tibial component that allowed the direct measurement of both knee forces and moments in vivo. These results begin to give us a true glimpse of the forces that are seen by total knee bearing surfaces and fixation interfaces thus providing us with a more scientific approach to what have otherwise been empiric recommendations regarding physical activities after total knee arthroplasty. The 2008 John Insall Award paper was authored by Dr. Steven MacDonald and colleagues from London, Ontario and addressed the specific impact of gender on the clinical outcome after total knee arthroplasty. The introduction into the marketplace of so-called gender-specific total knee components has been met with a competing mix of interest and skepticism among surgeons, while among patients curiosity might be the most appropriate descriptor. This scientific work again highlights the powerful relationship between preoperative variables and postoperative outcomes. These authors rightly highlight the importance of focusing on the change or improvement in preoperative to postoperative outcomes measures and balance that against the absolute scores. Female gender was associated with lower preoperative scores with these outcomes tools so perhaps it is not surprising some of the postoperative scores remain lower than those observed in males. The change or improvement from preoperative to postoperative, however, appears to be similar between males and females after total knee arthroplasty. The remaining papers in this symposium are grouped to include new information regarding total knee surgical technique, gender-related issues in technique and outcome, computer navigation, patellar resurfacing, total knee materials and design issues and revision total knee concerns. As surgeons we have specific interest in improving our intraoperative skills. In this symposium there is information on a method to determine rotational position of total knee components, data on the impact of a ligament balancing technique on the rate of lateral retinacular release, and the introduction of an extramedullary femoral referencing system to facilitate less invasive surgery. Gender-related issues are addressed in a series of papers that look at both documenting physical measurement differences in knee anatomy and then measuring outcomes differences. While little doubt exists that gender-associated differences can be measured, what remains to be determined is the clinical importance of such findings, and in that area we collectively still have work to do. While it appears that the initial wave of enthusiasm for computer navigation in total knee arthroplasty has crested, we are now at a point where more definitive scientific data are emerging regarding the benefits and drawbacks to this particular technology. Two of the implicit promises of computer navigation have been that it may make the occasional knee surgeon more like the expert surgeon, and that a navigation system can be the eye that facilitates accurate minimally invasive surgery. In this symposium there are scientific data that cast some doubt on promise number two, and all of us in the scientific community continue to look for evidence that navigation is reproducibly accurate when used by the occasional knee surgeon. The added costs of this technology is an issue yet to be addressed. Revision TKA is an area of ascending importance as the demographics of our population point to a growing need in this area. In this Symposium there are useful data on the outcomes differences between primary and revision TKA, comparative data on in-hospital complications between primary and revision TKA, isolated patellar revision, patellar bone loss problems and the use of stems in conjunction with constrained condylar knee designs. The Knee Society remains committed to advancing scientific knowledge and educating clinicians worldwide regarding surgery of the knee. We hope that our readers find this Symposium to be intellectually rigorous and clinically useful.

Five years ago our department migrated from a film-based imaging environment to a PACS-based environment. We discovered that our reliance on paper tracking forms for clinical history and dictation information was hindering our practice. Integrating dictation with PACS was one of three key components we needed to free ourselves from the tyranny of paper, the other two being an online worklist and an online patient history. We discuss our evolution to a (mostly) paperless reading room environment, our implementation, general performance, and future development plans, focusing on integrated dictation.

Custom-made mandibular advancement devices are an effective treatment option for snoring, upper airway resistance syndrome, and obstructive sleep apnea (OSA). Evidence-based data indicates their efficacy, and international sleep societies recommend oral appliance (OA) therapy for patients with sleep-related breathing disorders. The following position paper by the German Society of Dental Sleep Medicine (DGZS) is to guide the interdisciplinary team (sleep physician and sleep disorder dentist) in detail when to prescribe oral appliances. This position paper supports the responsible use of OA as an effective treatment option for patients with sleep-related breathing disorders. The paper advises of proper indication regarding OSA severity, body mass index (BMI), and dentition. It emphasizes the interdisciplinary approach of oral appliance therapy and suggests treatment under the guidance of dentists trained in dental sleep medicine.

The syndromic primary immunodeficiencies are disorders in which not only the immune system but also other organ systems are affected. Other features most commonly involve the ectodermal, skeletal, nervous, and gastrointestinal systems. Key in identifying syndromic immunodeficiencies is the awareness that increased susceptibility to infections or immune dysregulation in a patient known to have other symptoms or special features may hint at an underlying genetic syndrome. Because the extraimmune clinical features can be highly variable, it is more difficult establishing the correct diagnosis. Nevertheless, correct diagnosis at an early age is important because of the possible treatment options. Therefore, diagnostic work-up is best performed in a center with extensive expertise in this field, having immunologists and clinical geneticists, as well as adequate support from a specialized laboratory at hand. This paper provides the general pediatrician with the main clinical features that are crucial for the recognition of these syndromes.

Cilia are antenna-like organelles found on the surface of most cells. They transduce molecular signals and facilitate interactions between cells and their environment. Ciliary dysfunction has been shown to underlie a broad range of overlapping, clinically and genetically heterogeneous phenotypes, collectively termed ciliopathies. Literally, all organs can be affected. Frequent cilia-related manifestations are (poly)cystic kidney disease, retinal degeneration, situs inversus, cardiac defects, polydactyly, other skeletal abnormalities, and defects of the central and peripheral nervous system, occurring either isolated or as part of syndromes. Characterization of ciliopathies and the decisive role of primary cilia in signal transduction and cell division provides novel insights into tumorigenesis, mental retardation, and other common causes of morbidity and mortality, including diabetes mellitus and obesity. New technologies ("Next generation sequencing/NGS") have considerably improved genetic research and diagnostics by allowing simultaneous investigation of all disease genes at reduced costs and lower turn-around times. This is undoubtedly a result of the dynamic development in the field of human genetics and deserves increased attention in genetic counselling and the management of affected families.

Fractures are reported to be the second most common findings in child abuse, after skin lesions such as bruises and contusions. This makes careful interpretation of childhood fractures in relation to the provided clinical history important. In this literature review, we address imaging techniques and the prevailing protocols as well as fractures, frequently seen in child abuse, and the differential diagnosis of these fractures. The use of a standardised protocol in radiological imaging is stressed, as adherence to the international guidelines has been consistently poor. As fractures are a relatively common finding in childhood and interpretation is sometimes difficult, involvement of a paediatric radiologist is important if not essential. Adherence to international guidelines necessitates review by experts and is therefore mandatory. As in all clinical differential diagnoses, liaison between paediatricians and paediatric radiologists in order to obtain additional clinical information or even better having joint review of radiological studies will improve diagnostic accuracy. It is fundamental to keep in mind that the diagnosis of child abuse can never be solely based on radiological imaging but always on a combination of clinical, investigative and social findings. The quality and interpretation, preferably by a paediatric radiologist, of radiographs is essential in reaching a correct diagnosis in cases of suspected child abuse.

Primary antibody deficiencies (PADs) are the most common primary immunodeficiencies and are characterized by a defect in the production of normal amounts of antigen-specific antibodies. PADs represent a heterogeneous spectrum of conditions, ranging from often asymptomatic selective IgA and IgG subclass deficiencies to the severe congenital agammaglobulinemias, in which the antibody production of all immunoglobulin isotypes is severely decreased. Apart from recurrent respiratory tract infections, PADs are associated with a wide range of other clinical complications. This review will describe the pathophysiology, diagnosis, and treatment of the different PADs.

I have recently returned from the Society for Imaging Informatics in Medicine (SIIM) 2012 Annual Meeting and was reading Dr. Bruce Reiner and Matthew McKinley’s (“Reiner and McKinley’s”) excellent paper on the plane ride home, entitled “Application of Innovation Economics to Medical Imaging and Information System Technologies”, JDI, June 2012. The paper is courageous and shines the light on an incredibly important topic for SIIM, our industry and the healthcare system that we all collectively serve. I was struck by many statements in the paper, and would like to share my thoughts. First, these are the extracted areas that most resonated

The authors present a case of a spondylolisthesis with obvious foraminal stenosis on both sides as shown on the preoperative MRI. A proper operative technique in this case would include a restoration of disc height and the (partial) reduction of the slip. This technique would widen both foramina and no complication like opposite nerve root compression would occur. If reduction or disc height restoration cannot be achieved, decompression of both foramina should be performed. In mild cases a simple posterior distraction may be enough. In their paper the authors agree to this point as they write “decompression of the opposite side has not been judged necessary in the past as it has been commonly assumed that the TLIF spacer increases the disc space height and the foraminal height in the opposite foramen of the TLIF approach.” However, it seems that in the current case the authors failed to achieve restoration of disc height. Figure 7 shows differences between the preoperative and the postoperative CT scan of 1 mm (4 vs. 5 mm) and 1.5 mm (6.5 vs. 8 mm), respectively. The same is true for the “decrease” of foraminal height of 2 mm. I think that these measurements are not reliable since there is no calibration and no matching between the slices. Hence no obvious increase in disc height or decrease in foraminal height can be measured accurately. Anyway, the clinical significance of 1 or 2 mm of reduced foraminal height, if really present, seems to be questionable.

The work, "Ricardo M. The effect of ultrasound on the healing of muscle-pediculated bone graft in scaphoid non-union. Int Orthop. 2006 Apr;30(2):123–127", published by the prestigious journal International Orthopaedics, contains some misprints. In the paper it is reported that the ultrasound intensity emitted by the equipment employed in the study, a Theramed 101B, was 30 mW/cm2. Actually, the reported intensity should have been 50mW/cm2. The error could have come about since initially in the Department of Orthopedics and Traumatology of the Manuel Fajardo Teaching Hospital, a preliminary study was conducted for the stimulation of bone repair that indeed used 30mW/cm2. The first results of this preliminary study were published in the following reference, "O. Rodriguez, R. Monreal. Acceleration of Osseous Fracture Repair by Low-intensity Pulsed Ultrasound Therapy: A Preliminary Study", Proceedings of the II Latin-American Congress on Biomedical Engineering (ISBN 959-7132-57-5), Havana, Cuba, Cod. 265, (2001). Nevertheless after that preliminary study and since the beginning of 2000, the Theramed 101B equipment was modified for an emmision of 50 mW/cm2. Therefore, the year for the beginning of the study described by author should be 2000 and not 1999, and the reported intensity must be 50 mW/cm2, and not 30 mW/cm2. Sincerely yours, Orlando R. Rodriguez Rua (MD), Researcher of the “Instituto de Cibernetica, Matematica y Fisica”, La Habana Cuba. Chief of the project PRI/1/1 of the “Agencia Cubana de Energia Nuclear y Tecnologias de Avanzadas” under which the Theramed 101B was Developer with the collaboration of the “Departamento de Ingenieria Electrica y Electronica, Instituto Tecnologico y de Estudios Superiores de Monterrey, Campus Estado de Mexico, Mexico” and the “Seccion de Bioelectronica, Departamento de Ingenieria Electrica, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional, Mexico DF, Mexico”.

This is a case report of a child with double neural tube defect (NTD) comprising a parietal encephalocoele and an open thoracic myelomeningocoele. The authors use this case to endorse the multi-site neural tube closure theory as aetiology for all multiple NTDs. Proponents of this theory claim that neural tube defects occur at “collision sites” of neural tube closure with opposing closure directions, and because up to five or six of these waves are thought to be operational, there are, accordingly, multiple collision sites. The multi-site closure theory was used originally to explain the different favoured locations of encephalcoeles, and as such, the theory is seductive. At collision sites, the overlying myocutaneous tissues may be potentially weaker and, therefore, susceptible to being stretched but not disrupted by a focal herniation of the alar plates of the already closed cranial neural tube and surrounding meninges. The disorganised gyral development and cortical dysplasia of the herniated brain may be secondary to early tissue distortion. The overlying skin and meninges are intact. Spinal open neural tube defects (ONTD) are due to focal absence of neural plate closure, as shown in numerous, very credible animal experiments. The skin, muscles, neural arches and dura are wide open, and the exposed neural material is an unfused neural plate. This true “closure lesion” is thus fundamentally different from a “collision lesion” exemplified by the encephalocoele. Most spinal ONTDs are terminal lesions involving the end of the primary neural tube, but there are rare examples of segmental lesions in which the “suspended” open neural placode is flanked by normal spinal cord both rostrally and caudally. The incomplete neural plate closure occurs in a square-pulse fashion followed by resumption of normal closure. Three percent of ONTDs in our unit are segmental placodes. Most hemi-myelomeningocoeles associated with split cord malformation (SCM) are segmental lesions. Limited dorsal myeloschisis (LDM), though not technically “open”, is a segmental neural tube closure abnormality, as is dorsal lipoma, a lesion of segmental premature disjunction. If there can be one segmental closure failure, why not two or even three square pulse insults, separated in time, causing in tandem closure lesions resulting in either two segmental ONTDs or one segmental and one terminal ONTD? Other multiple neural tube closure abnormalities, though rare, have been reported, such as double LDMs, double dorsal lipomas and double dermal sinus tracts. Even double SCMs caused by multi-focal gastrulation defects with multiple endomeschymal tracts are well known in the literature. Thus, multiple spinal ONTDs can conceivably occur without invoking the multiple closure-wave theory, which, in the spinal cord will produce a very different lesion. It is not known why there should be abrupt recovery of normal neural tube closure after the square pulse insult. There could conceivably be transient presence of a teratogenic impulse that disturbs certain downstream transcription factors, without a fixed genomic mutation that would perpetuate the developmental error. It is thus the timing of the next transient insult that determines the location of the second neural tube defect, rather than the activities of the colliding zippers.

Objectives EQ-5D-Y-3L health states are valued by adults taking the perspective of a 10-year-old child. Compared to valuation of adult EQ-5D instruments, this entails two changes to the perspective: (i) child health states are valued instead of adult health states and: (ii) health states are valued for someone else instead of for oneself. Although earlier work has shown that these combined changes yield different values for child and adult health states that are otherwise equal, it currently remains unclear why. Hence, we aimed to disentangle the effects of both changes. Methods A sample of 205 students (mean age: 19.48) was surveyed. Each respondent completed visual analogue scale (VAS) and time trade-off (TTO) tasks for five EQ-5D-Y-3L states, using four randomly ordered perspectives: (i) self-adult (themselves), (ii) other-adult (someone their age), (iii) self-child (themselves as a 10-year-old), (iv) other-child (a child of 10 years old). We compared how each perspective impacted outcomes, precision and quality of EQ-5D-Y-3L valuation. Results Overall, differences between perspectives were consistent, with their direction being dependent on the health states and respondents. For VAS, the effect on outcomes of valuation depended on severity, but variance was higher in valuation with child perspectives. For TTO, we observed that EQ-5D-Y-3L states valued on behalf of others (i.e., children or adults) received higher valuations, but lower variances. Conclusion The use of a different perspective appears to yield systematic differences in EQ-5D-Y-3L valuation, with considerable heterogeneity between health states and respondents. This may explain mixed findings in earlier work.

Background Multiparametric MRI (mpMRI) became recognised in investigating those with suspected prostate cancer between 2010 and 2012; in the USA, the preventative task force moratorium on PSA screening was a strong catalyst. In a few short years, it has been adopted into daily urological and oncological practice. The pace of clinical uptake, born along by countless papers proclaiming high accuracy in detecting clinically significant prostate cancer, has sparked much debate about the timing of mpMRI within the traditional biopsy-driven clinical pathways. There are strongly held opposing views on using mpMRI as a triage test regarding the need for biopsy and/or guiding the biopsy pattern. Objective To review the evidence base and present a position paper on the role of mpMRI in the diagnosis and management of prostate cancer. Methods A subgroup of experts from the ESUR Prostate MRI Working Group conducted literature review and face to face and electronic exchanges to draw up a position statement. Results This paper considers diagnostic strategies for clinically significant prostate cancer; current national and international guidance; the impact of pre-biopsy mpMRI in detection of clinically significant and clinically insignificant neoplasms; the impact of pre-biopsy mpMRI on biopsy strategies and targeting; the notion of mpMRI within a wider risk evaluation on a patient by patient basis; the problems that beset mpMRI including inter-observer variability. Conclusions The paper concludes with a set of suggestions for using mpMRI to influence who to biopsy and who not to biopsy at diagnosis. Key Points • Adopt mpMRI as the first, and primary, investigation in the workup of men with suspected prostate cancer. • PI-RADS assessment categories 1 and 2 have a high negative predictive value in excluding significant disease, and systematic biopsy may be postponed, especially in men with low-risk of disease following additional risk stratification. • PI-RADS assessment category lesions 4 and 5 should be targeted; PI-RADS assessment category lesion 3 may be biopsied as a target, as part of systematic biopsies or may be observed depending on risk stratification. Electronic supplementary material The online version of this article (10.1007/s00330-019-06166-z) contains supplementary material, which is available to authorized users.

Oligodendrogliomas are defined at the molecular level by the presence of an IDH mutation and codeletion of chromosomal arms 1p and 19q. In the past, case reports and small studies described gliomas with sarcomatous features arising from oligodendrogliomas, so called oligosarcomas. Here, we report a series of 24 IDH-mutant oligosarcomas from 23 patients forming a distinct methylation class. The tumors were recurrences from prior oligodendrogliomas or developed de novo. Precursor tumors of 12 oligosarcomas were histologically and molecularly indistinguishable from conventional oligodendrogliomas. Oligosarcoma tumor cells were embedded in a dense network of reticulin fibers, frequently showing p53 accumulation, positivity for SMA and CALD1, loss of OLIG2 and gain of H3K27 trimethylation (H3K27me3) as compared to primary lesions. In 5 oligosarcomas no 1p/19q codeletion was detectable, although it was present in the primary lesions. Copy number neutral LOH was determined as underlying mechanism. Oligosarcomas harbored an increased chromosomal copy number variation load with frequent CDKN2A/B deletions. Proteomic profiling demonstrated oligosarcomas to be highly distinct from conventional CNS WHO grade 3 oligodendrogliomas with consistent evidence for a smooth muscle differentiation. Expression of several tumor suppressors was reduced with NF1 being lost frequently. In contrast, oncogenic YAP1 was aberrantly overexpressed in oligosarcomas. Panel sequencing revealed mutations in NF1 and TP53 along with IDH1/2 and TERT promoter mutations. Survival of patients was significantly poorer for oligosarcomas as first recurrence than for grade 3 oligodendrogliomas as first recurrence. These results establish oligosarcomas as a distinct group of IDH-mutant gliomas differing from conventional oligodendrogliomas on the histologic, epigenetic, proteomic, molecular and clinical level. The diagnosis can be based on the combined presence of (a) sarcomatous histology, (b) IDH-mutation and (c) TERT promoter mutation and/or 1p/19q codeletion, or, in unresolved cases, on its characteristic DNA methylation profile.

Objectives To compare the cost-effectiveness of first-line gefitinib, erlotinib, afatinib, and osimertinib in patients with non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations. Methods A systematic review and network meta-analysis (NMA) were conducted to compare the relative efficacy of gefitinib, erlotinib, afatinib, and osimertinib in EGFR-mutated NSCLC. To assess the cost-effectiveness of these treatments, a Markov model was developed from Dutch societal perspective. The model was based on the clinical studies included in the NMA. Incremental costs per life-year (LY) and per quality-adjusted life-year (QALY) gained were estimated. Deterministic and probabilistic sensitivity analyses (PSA) were conducted. Results Total discounted per patient costs for gefitinib, erlotinib, afatinib, and osimertinib were €65,889, €64,035, €69,418, and €131,997, and mean QALYs were 1.36, 1.39, 1.52, and 2.01 per patient, respectively. Erlotinib dominated gefitinib. Afatinib versus erlotinib yielded incremental costs of €27,058/LY and €41,504/QALY gained. Osimertinib resulted in €91,726/LY and €128,343/QALY gained compared to afatinib. PSA showed that gefitinib, erlotinib, afatinib, and osimertinib had 13%, 19%, 43%, and 26% probability to be cost-effective at a threshold of €80,000/QALY. A price reduction of osimertinib of 30% is required for osimertinib to be cost-effective at a threshold of €80,000/QALY. Conclusions Osimertinib has a better effectiveness compared to all other TKIs. However, at a Dutch threshold of €80,000/QALY, osimertinib appears not to be cost-effective.

Background Several multi-attribute utility instruments (MAUIs) are available from which utilities can be derived for use in cost-utility analysis (CUA). This study provides a review of recommendations from national health technology assessment (HTA) agencies regarding the choice of MAUIs. Methods A list was compiled of HTA agencies that provide or refer to published official pharmacoeconomic (PE) guidelines for pricing, reimbursement or market access. The guidelines were reviewed for recommendations on the indirect calculation of utilities and categorized as: a preference for a specific MAUI; providing no MAUI preference, but providing examples of suitable MAUIs and/or recommending the use of national value sets; and recommending CUA, but not providing examples of MAUIs. Results Thirty-four PE guidelines were included for review. MAUIs named for use in CUA: EQ-5D (n = 29 guidelines), the SF-6D (n = 11), HUI (n = 10), QWB (n = 3), AQoL (n = 2), CHU9D (n = 1). EQ-5D was a preferred MAUI in 15 guidelines. Alongside the EQ-5D, the HUI was a preferred MAUI in one guideline, with DALY disability weights mentioned in another. Fourteen guidelines expressed no preference for a specific MAUI, but provided examples: EQ-5D (n = 14), SF-6D (n = 11), HUI (n = 9), QWB (n = 3), AQoL (n = 2), CHU9D (n = 1). Of those that did not specify a particular MAUI, 12 preferred calculating utilities using national preference weights. Conclusions The EQ-5D, HUI, and SF-6D were the three MAUIs most frequently mentioned in guidelines. The most commonly cited MAUI (in 85% of PE guidelines) was EQ-5D, either as a preferred MAUI or as an example of a suitable MAUI for use in CUA in HTA.

Objectives Aortic valve disease is the most frequent indication for heart valve replacement with the highest prevalence in elderly. Tissue-engineered heart valves (TEHV) are foreseen to have important advantages over currently used bioprosthetic heart valve substitutes, most importantly reducing valve degeneration with subsequent reduction of re-intervention. We performed early Health Technology Assessment of hypothetical TEHV in elderly patients (≥ 70 years) requiring surgical (SAVR) or transcatheter aortic valve implantation (TAVI) to assess the potential of TEHV and to inform future development decisions. Methods Using a patient-level simulation model, the potential cost-effectiveness of TEHV compared with bioprostheses was predicted from a societal perspective. Anticipated, but currently hypothetical improvements in performance of TEHV, divided in durability, thrombogenicity, and infection resistance, were explored in scenario analyses to estimate quality-adjusted life-year (QALY) gain, cost reduction, headroom, and budget impact. Results Durability of TEHV had the highest impact on QALY gain and costs, followed by infection resistance. Improved TEHV performance (− 50% prosthetic valve-related events) resulted in lifetime QALY gains of 0.131 and 0.043, lifetime cost reductions of €639 and €368, translating to headrooms of €3255 and €2498 per hypothetical TEHV compared to SAVR and TAVI, respectively. National savings in the first decade after implementation varied between €2.8 and €11.2 million (SAVR) and €3.2–€12.8 million (TAVI) for TEHV substitution rates of 25–100%. Conclusions Despite the relatively short life expectancy of elderly patients undergoing SAVR/TAVI, hypothetical TEHV are predicted to be cost-effective compared to bioprostheses, commercially viable and result in national cost savings when biomedical engineers succeed in realising improved durability and/or infection resistance of TEHV.

This study analyzes the relation between attention-deficit hyperactivity disorder (ADHD) and later-life labor market outcomes in the United States and whether these relationships are mediated by educational attainment. To overcome endogeneity concerns in the estimation of these relationships, we exploit the polygenic risk score (PRS) for ADHD in a cohort where the diagnosis of and treatment for ADHD were generally not available. We find that an increase in the PRS for ADHD reduces the likelihood of employment, individual income, and household wealth. Moreover, it increases the likelihood of receiving social security disability benefits, unemployment or worker compensation, and other governmental transfers. We provide evidence that educational attainment mediates these relationships to a considerable extent (14-58%).

Background We aimed to investigate the burden of informal care in Hungary (HU), Poland (PL) and Slovenia (SI). Methods A cross-sectional online survey was performed involving representative samples of 1000 respondents per country. Caregiving situations were explored; health status of informal caregivers/care recipients and care-related quality of life were assessed using the EQ-5D-5L and CarerQol-7D. Results The proportion of caregivers was (HU/PL/SI) 14.9, 15.0 and 9.6%, respectively. Their mean age was 56.1, 45.6 and 48.0, and the average time spent on informal care was 27.6, 35.5 and 28.8 h/week. Chronic care was dominant (> 1 year: 78.5%, 72.0%, 74.0%) and care recipients were mainly (own/in-law) parents. Average EQ-5D-5L scores of care recipients were 0.53, 0.49 and 0.52. For Poland and Slovenia, EQ-5D-5L scores of informal care providers were signifcantly lower than of other respondents. Average CarerQol-7D scores were (HU/PL/SI) 76.0, 69.6 and 70.9, and CarerQol-VAS was 6.8, 6.4 and 6.6, respectively. Overall, 89, 87, and 84% of caregivers felt some or a lot fulflment related to caring. Problems with combining tasks with daily activities were most important in Hungary and Slovenia. Women had a higher probability of being a caregiver in Hungary. CarerQol-7D scores were signifcantly associated with caregivers’ EQ-5D-5L scores. In Hungary and Poland, living in a larger household was positively, while caring for patients with mental health problems was negatively associated with CarerQol-7D scores. Conclusions These frst results from the Central and Eastern European region using preference-based measures for the evaluation of informal care can serve as a valuable input for health economic analyses.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Swiss National Science Foundation OnBehalf Swiss-AF Investigators Background Atrial fibrillation (AF) is associated with loss of cognition and dementia. Cardiac autonomic dysfunction has been linked to cognitive decline. We aimed to investigate if reduced cardiac autonomic function (CAF) is associated with cognitive impairment in AF patients. Methods Patients with paroxysmal, persistent and permanent AF were enrolled from a multicenter cohort study if they presented in AF ("AF group") or in sinus rhythm ("SR group") on a baseline 5-minute ECG recording. Parameters quantifying CAF (heart rate variability triangular index (HRVI), mean heart rate (MHR), the root mean square of successive differences (RMSSD) and the standard deviation of the normal-to-normal intervals (SDNN)) were calculated. We used the Montreal Cognitive Assessment (MoCA) to assess global cognitive function. Results 1,685 AF patients with a mean age of 73 ± 8 years, 29% females, were included. The MoCA score was 24.5 ± 3.2 in the AF group (n = 710 patients) and 25.4 ± 3.2 in the SR group (n = 975 patients). After adjusting for multiple confounders, lower HRVI was associated with lower MoCA scores, both in the SR group (β=0.049; 95% confidence interval (CI): 0.016 to 0.081; p = 0.003) and in the AF group (β=0.068; 95% CI: 0.020 to 0.116; p = 0.006). In the AF group, higher MHR was associated with a poorer performance in the MoCA (β=-0.008; 95% CI: -0.014 to -0.002; p = 0.014 ). Other parameters of CAF were not associated with cognition. Conclusion Our data suggest that impaired CAF is associated with worse cognitive performance in patients with AF. Elderly AF patients with impaired HRVI might undergo cognitive testing in order to screen for cognitive impairment.

We study the extremely high and low residual spenders in individual health insurance markets in three countries. A high (low) residual spender is someone for whom the residual—spending less payment (from premiums and risk adjustment)—is high (low), indicating that the person is highly underpaid (overpaid). We begin with descriptive analysis of the top and bottom 1% and 0.1% of residuals building to address the question of the degree of persistence in membership at the extremes. Common findings emerge among the countries. First, the diseases found among those with the highest residual spending are also disproportionately found among those with the lowest residual spending. Second, those at the top of the residual spending distribution (where spending exceeds payments the most) account for a massively high share of the unexplained variance in the predictions from the risk adjustment model. Third, in terms of persistence, we find that membership in the extremes of the residual spending distribution is highly persistent, raising concerns about selection-related incentives targeting these individuals. As our results show, the one-in-a-thousand people (on both sides of the residual distribution) play an outsized role in creating adverse incentives associated with health plan payment systems. In response to the observed importance of the extremes of the residual spending distribution, we propose an innovative combination of risk-pooling and reinsurance targeting the predictively undercompensated group. In all three countries, this form of risk sharing substantially improves the overall fit of payments to spending. Perhaps surprisingly, by reducing the burden on diagnostic indicators to predict high payments, our proposed risk sharing policy reduces the gap between payments and spending not only for the most undercompensated individuals but also for the most overcompensated people.

The questionnaire format applied in a CV study represents the way in which the WTP estimates are obtained. Payment scales are often used in CV studies as the questionnaire format of choice. The study summarized here analyzes the impact of the design of two payment scales (PS) on the monetary value of QALY gains. The scales differed in terms of their end-points, mid points, and coarseness. We judged the performance of the two PS against several indicators: the average WTP per QALY estimates, post-estimation uncertainty levels, the existence of mid-point concentration, and the dependency on end-points. Our results show that PS design influences respondents’ WTP values. The results also suggest that a more detailed scale with a more realistic range may help respondents to elicit values closer to their “true” WTP values, hence produce higher-quality outcomes. Further research and pretesting strategies are suggested to explore and minimize the effects of PS design on WTP estimates, which may ultimately increase the quality of WTP estimates.

T cells are considered pivotal in the pathology of multiple sclerosis (MS), but their function and antigen specificity are unknown. To unravel the role of T cells in MS pathology, we performed a comprehensive analysis on T cells recovered from paired blood, cerebrospinal fluid (CSF), normal-appearing white matter (NAWM) and white matter lesions (WML) from 27 MS patients with advanced disease shortly after death. The differentiation status of T cells in these compartments was determined by ex vivo flow cytometry and immunohistochemistry. T-cell reactivity in short-term T-cell lines (TCL), generated by non-specific stimulation of T cells recovered from the same compartments, was determined by intracellular cytokine flow cytometry. Central memory T cells predominated in CSF and effector memory T cells were enriched in NAWM and WML. WML-derived CD8+ T cells represent chronically activated T cells expressing a cytotoxic effector phenotype (CD95L and granzyme B) indicative for local antigenic stimulation (CD137). The same lesions also contained higher CD8+ T-cell frequencies expressing co-inhibitory (TIM3 and PD1) and co-stimulatory (ICOS) T-cell receptors, yet no evidence for T-cell senescence (CD57) was observed. The oligoclonal T-cell receptor (TCR) repertoire, particularly among CD8+ T cells, correlated between TCL generated from anatomically separated WML of the same MS patient, but not between paired NAWM and WML. Whereas no substantial T-cell reactivity was detected towards seven candidate human MS-associated autoantigens (cMSAg), brisk CD8+ T-cell reactivity was detected in multiple WML-derived TCL towards autologous Epstein–Barr virus (EBV) infected B cells (autoBLCL). In one MS patient, the T-cell response towards autoBLCL in paired intra-lesional TCL was dominated by TCRVβ2+CD8+ T cells, which were localized in the parenchyma of the respective tissues expressing a polarized TCR and CD8 expression suggesting immunological synapse formation in situ. Collectively, the data suggest the involvement of effector memory cytotoxic T cells recognizing antigens expressed by autoBLCL, but not the assayed human cMSAg, in WML of MS patients. Electronic supplementary material The online version of this article (doi:10.1007/s00401-017-1744-4) contains supplementary material, which is available to authorized users.

The limited efficacy of glucocorticoids (GCs) during therapy of acute relapses in multiple sclerosis (MS) leads to long-term disability. We investigated the potential of vitamin D (VD) to enhance GC efficacy and the mechanisms underlying this VD/GC interaction. In vitro, GC receptor (GR) expression levels were quantified by ELISA and induction of T cell apoptosis served as a functional readout to assess synergistic 1,25(OH)2D3 (1,25D)/GC effects. Experimental autoimmune encephalomyelitis (MOG35–55 EAE) was induced in mice with T cell-specific GR or mTORc1 deficiency. 25(OH)D (25D) levels were determined in two independent cohorts of MS patients with stable disease or relapses either responsive or resistant to GC treatment (initial cohort: n = 110; validation cohort: n = 85). Gene expression of human CD8+ T cells was analyzed by microarray (n = 112) and correlated with 25D serum levels. In vitro, 1,25D upregulated GR protein levels, leading to increased GC-induced T cell apoptosis. 1,25D/GC combination therapy ameliorated clinical EAE course more efficiently than respective monotherapies, which was dependent on GR expression in T cells. In MS patients from two independent cohorts, 25D deficiency was associated with GC-resistant relapses. Mechanistic studies revealed that synergistic 1,25D/GC effects on apoptosis induction were mediated by the mTOR but not JNK pathway. In line, 1,25D inhibited mTORc1 activity in murine T cells, and low 25D levels in humans were associated with a reduced expression of mTORc1 inhibiting tuberous sclerosis complex 1 in CD8+ T cells. GR upregulation by 1,25D and 1,25D/GC synergism in vitro and therapeutic efficacy in vivo were abolished in animals with a T cell-specific mTORc1 deficiency. Specific inhibition of mTORc1 by everolimus increased the efficacy of GC in EAE. 1,25D augments GC-mediated effects in vitro and in vivo in a T cell-specific, GR-dependent manner via mTORc1 inhibition. These data may have implications for improvement of anti-inflammatory GC therapy. Electronic supplementary material The online version of this article (10.1007/s00401-019-02018-8) contains supplementary material, which is available to authorized users.

A case-mix project started in the Netherlands with the primary goal to define a complete set of health care products for hospitals. The definition of the product structure was completed 4 years later. The results are currently being used for billing purposes. This paper focuses on the methodology and techniques that were developed and applied in order to define the casemix product structure. The central research question was how to develop a manageable product structure, i.e., a limited set of hospital products, with acceptable cost homogeneity. For this purpose, a data warehouse with approximately 1.5 million patient records from 27 hospitals was build up over a period of 3 years. The data associated with each patient consist of a large number of a priori independent parameters describing the resource utilization in different stages of the treatment process, e.g., activities in the operating theatre, the lab and the radiology department. Because of the complexity of the database, it was necessary to apply advanced data analysis techniques. The full analyses process that starts from the database and ends up with a product definition consists of four basic analyses steps. Each of these steps has revealed interesting insights. This paper describes each step in some detail and presents the major results of each step. The result consists of 687 product groups for 24 medical specialties used for billing purposes.

We examine the impact of price, service quality and information search on people's propensity to switch health insurers in the competitive Dutch health insurance market. Using panel data from annual household surveys and data on health insurers' premiums and quality ratings over the period 2006-2012, we estimate a random effects logit model of people's switching decisions. We find that switching propensities depend on health plan price and quality, and on people's age, health, education and having supplementary or group insurance. Young people (18-35 years) are more sensitive to price, whereas older people are more sensitive to quality. Searching for health plan information has a much stronger impact on peoples' sensitivity to price than to service quality. In addition, searching for health plan information has a stronger impact on the switching propensity of higher than lower educated people, suggesting that higher educated people make better use of available health plan information. Finally, having supplementary insurance significantly reduces older people's switching propensity.

Objects Deliberate termination of life of newborns (involuntary euthanasia) with meningomyelocele (MMC) is practiced openly only in the Netherlands. ‘Unbearable and hopeless suffering’ is the single most cited criterion for this termination, together with the notion that ‘there are no other proper medical means to alleviate this suffering’. In this paper, both (and other) statements are questioned, also by putting them in a broader perspective. Methods First, a historical overview of the treatment of newborns with MMC is presented, concentrating on the question of selection for treatment. Second, a thorough analysis is made of the criteria used for life termination. Third, a case of a newborn with a very severe MMC is presented as a ‘reference case’. Conclusion ‘Unbearable and hopeless suffering’ cannot be applied to newborns with MMC. They are not ‘terminally ill’ and do have ‘prospects of a future’. In these end-of-life decisions, ‘quality of life judgments’ should not be applied. When such a newborn is not treated, modern palliative care always will suffice in eliminating possible discomfort. There is no reason whatsoever for active life-termination of these newborns.

Public concern about the presence of natural and anthropogenic compounds which affect human health by modulating normal endocrine functions is continuously growing. Fast and simple high-throughput screening methods for the detection of hormone activities are thus indispensable. During the last two decades, a panel of different in vitro assays has been developed, mainly for compounds with an estrogenic mode of action. Here we describe the development of an androgen transcription activation assay that is easy to use in routine screening. Recombinant yeast cells were constructed that express the human androgen receptor and yeast enhanced green fluorescent protein (yEGFP), the latter in response to androgens. Compared with other reporters, the yEGFP reporter protein is very convenient because it is directly measurable in intact living cells, i.e., cell wall disruption and the addition of a substrate are not needed. When yeast was exposed to 17beta-testosterone, the concentration where half-maximal activation is reached (EC(50)) was 50 nM. The relative androgenic potencies, defined as the ratio between the EC(50) of 17beta-testosterone and the EC(50) of the compound, of 5alpha-dihydrotestosterone, methyltrienolone, and 17beta-boldenone are 2.3, 1.4, and 0.15 respectively. The results presented in this paper demonstrate that this new yeast androgen bioassay is fast, sensitive, and very specific and also suited to detect compounds that have an antiandrogenic mode of action.

Gonadotroph adenomas comprise 15–40 % of all pituitary tumors, are usually non-functioning and are often large and invasive at presentation. Surgery is the first-choice treatment, but complete resection is not always achieved, leading to high recurrence rates. As gonadotroph adenomas poorly respond to conventional pharmacological therapies, novel treatment strategies are needed. Their identification has been hampered by our incomplete understanding of the molecular pathogenesis of these tumors. Recently, we demonstrated that MENX-affected rats develop gonadotroph adenomas closely resembling their human counterparts. To discover new genes/pathways involved in gonadotroph cells tumorigenesis, we performed transcriptome profiling of rat tumors versus normal pituitary. Adenomas showed overrepresentation of genes involved in cell cycle, development, cell differentiation/proliferation, and lipid metabolism. Bioinformatic analysis identified downstream targets of the transcription factor SF-1 as being up-regulated in rat (and human) adenomas. Meta-analyses demonstrated remarkable similarities between gonadotroph adenomas in rats and humans, and highlighted common dysregulated genes, several of which were not previously implicated in pituitary tumorigenesis. Two such genes, CYP11A1 and NUSAP1, were analyzed in 39 human gonadotroph adenomas by qRT-PCR and found to be up-regulated in 77 and 95 % of cases, respectively. Immunohistochemistry detected high P450scc (encoded by CYP11A1) and NuSAP expression in 18 human gonadotroph tumors. In vitro studies demonstrated for the first time that Cyp11a1 is a target of SF-1 in gonadotroph cells and promotes proliferation/survival of rat pituitary adenoma primary cells and cell lines. Our studies reveal clues about the molecular mechanisms driving rat and human gonadotroph adenomas development, and may help identify previously unexplored biomarkers for clinical use. Electronic supplementary material The online version of this article (doi:10.1007/s00401-013-1132-7) contains supplementary material, which is available to authorized users.

Mutations in the small heat shock protein HSPB1 (HSP27) are a cause of axonal Charcot–Marie–Tooth neuropathy (CMT2F) and distal hereditary motor neuropathy. To better understand the effect of mutations in HSPB1 on the neuronal cytoskeleton, we stably transduced neuronal cells with wild-type and mutant HSPB1 and investigated axonal transport of neurofilaments (NFs). We observed that mutant HSPB1 affected the binding of NFs to the anterograde motor protein kinesin, reducing anterograde transport of NFs. These deficits were associated with an increased phosphorylation of NFs and cyclin-dependent kinase Cdk5. As Cdk5 mediates NF phosphorylation, inhibition of Cdk5/p35 restored NF phosphorylation level, as well as NF binding to kinesin in mutant HSPB1 neuronal cells. Altogether, we demonstrate that HSPB1 mutations induce hyperphosphorylation of NFs through Cdk5 and reduce anterograde transport of NFs. Electronic supplementary material The online version of this article (doi:10.1007/s00401-013-1133-6) contains supplementary material, which is available to authorized users.

Purpose To compare the efficacy and safety of TDR to that of the fusion for the treatment of lumbar degenerative disc disease (LDDD). Methods Randomized controlled trials comparing TDR with any other intervention for LDDD were acquired by a comprehensive search in PubMedCentral, MEDLINE, EMBASE, BIOSIS, ClinicalTrials.gov, and the FDA trials register. Methodologic quality was assessed and relevant data were retrieved, and appropriate meta-analysis was performed. Two review authors independently selected studies, extracted data, and assessed risk of bias. Results and upper bounds of confidence intervals were compared with predefined clinically relevant differences. Results Six relevant randomized controlled trials (RCTs) involving 1,603 patients were identified and reported two year follow-up results. Patients in TDR group compared with lumbar fusion group demonstrated significant improvements in ODI, VAS scores and complication rates at the two year follow-up. Meanwhile, except for operating time in anterior group, intra-operative blood loss, operating time in posterior group, and reoperation rate were without clinical significance between the two groups. In addition, the range of motion (ROM) was maintained within normal ranges after TDR. Conclusions The results showed the TDR has significant safety and efficacy comparable to lumbar fusion at two year follow-up. Although superiority compared to fusion could not be proved, by comparing clinical symptoms relieved, motion preserved, and the low reoperation rate during long-term follow-up on TDR, TDR was considered safe and effective. Therefore, the authors suggest adopting TDR on a large scale; with failure of TDR, interbody fusion would be performed.

Purpose Trastuzumab and chemotherapy is the current standard of care in HER2+ early or locally advanced breast cancer, but there are scanty literature data of its real world effectiveness. Methods We retrospectively reviewed 205 patients with HER2+ breast cancer diagnosed in 10 Italian Medical Oncology Units between July 2003 and October 2011. All patients received neoadjuvant systemic therapy (NST) with trastuzumab in association with chemotherapy. Many different chemotherapy regimens were used, even if 90 % of patients received schemes including anthracyclines and 99 % received taxanes. NST was administered for more than 21 weeks (median: 24) in 130/205 (63.4 %) patients, while trastuzumab was given for more than 12 weeks (median: 12 weeks) in 101/205 (49.3 %) patients. pCR/0 was defined as ypT0+ypN0, and pCR/is as ypT0/is+ypN0. Results pCR/0 was obtained in 24.8 % and pCR/is in 46.8 % of the patients. At multivariate logistic regression, nonluminal/HER2+ tumors (P

The aim of this health economic analysis was to compare the cost-effectiveness of ticagrelor versus clopidogrel within the German health care system. A two-part decision model was adapted to compare treatment with ticagrelor or clopidogrel in a low-dose acetylsalicylic acid (ASA) cohort (≤150 mg) for all ACS patients and subtypes NSTEMI/IA and STEMI. A decision-tree approach was chosen for the first year after initial hospitalization based on trial observations from a subgroup of the PLATO study. Subsequent years were estimated by a Markov model. Following a macro-costing approach, costs were based on official tariffs and published literature. Extensive sensitivity analyses were performed to test the robustness of the model. One-year treatment with ticagrelor is associated with an estimated 0.1796 life-years gained (LYG) and gained 0.1570 quality-adjusted life-years (QALY), respectively, over the lifetime horizon. Overall average cost with ticagrelor is estimated to be EUR 11,815 vs. EUR 11,387 with generic clopidogrel over a lifetime horizon. The incremental cost-effectiveness ratio (ICER) was EUR 2,385 per LYG (EUR 2,728 per QALY). Comparing ticagrelor with Plavix® or the lowest priced generic clopidogrel, ICER ranges from dominant to EUR 3,118 per LYG (EUR 3,567 per QALY). These findings are robust under various additional sensitivity analyses. Hence, 12 months of ACS treatment using ticagrelor/ASA instead of clopidogrel/ASA may offer a cost-effective therapeutic option, even when the generic price for clopidogrel is employed. Electronic supplementary material The online version of this article (doi:10.1007/s00392-013-0552-7) contains supplementary material, which is available to authorized users.

Angiogenesis is regarded as a hallmark of cancer progression and it has been postulated that solid tumor growth depends on angiogenesis. At present, however, it is clear that tumor cell invasion can occur without angiogenesis, a phenomenon that is particularly evident by the infiltrative growth of malignant brain tumors, such as glioblastomas (GBMs). In these tumors, amplification or overexpression of wild-type (wt) or truncated and constitutively activated epidermal growth factor receptor (EGFR) are regarded as important events in GBM development, where the complex downstream signaling events have been implicated in tumor cell invasion, angiogenesis and proliferation. Here, we show that amplification and in particular activation of wild-type EGFR represents an underlying mechanism for non-angiogenic, invasive tumor growth. Using a clinically relevant human GBM xenograft model, we show that tumor cells with EGFR gene amplification and activation diffusely infiltrate normal brain tissue independent of angiogenesis and that transient inhibition of EGFR activity by cetuximab inhibits the invasive tumor growth. Moreover, stable, long-term expression of a dominant-negative EGFR leads to a mesenchymal to epithelial-like transition and induction of angiogenic tumor growth. Analysis of human GBM biopsies confirmed that EGFR activation correlated with invasive/non-angiogenic tumor growth. In conclusion, our results indicate that activation of wild-type EGFR promotes invasion and glioblastoma development independent of angiogenesis, whereas loss of its activity results in angiogenic tumor growth. Electronic supplementary material The online version of this article (doi:10.1007/s00401-013-1101-1) contains supplementary material, which is available to authorized users.

Purpose The aim of the study was to assess bone graft incorporation after revision hip arthroplasty in patients with rheumatoid arthritis (RA). Methods We report an acetabular reconstruction using impacted, morselized, frozen, radiation sterilized bone allografts in 71 patients suffering from RA. There were sixty-six women and five men at a mean age of 57.5 years. Reconstruction was performed in 78 revision total hip arthroplasties (THAs) for aseptic loosening of acetabular component. The mean follow-up was five years and four months. In 38 cases, a revision was done with use of reinforcement devices. Results In four revised hips (10 %) without reinforcement implants, resorption of the allografts was noticed. All Mueller rings and 50 % of unscrews cages (Link, Howmedica) were revised because of aseptic loosening and bone graft resorption. In all of 17 hips with the Burch-Schneider cage, no measurable migration or bone allografts resorption occurred. There were no major general complications. Conclusions Acetabular reconstruction with use of morselized, frozen, radiation sterilized bone allografts and the Burch-Schneider cage can be highly successful in managing massive deficiency of acetabular bone stock in revision hip arthroplasty in RA patients.

Purpose Recurrences and deaths are known to occur, even if less frequently, in small, node-negative breast cancer patients, and decision on adjuvant treatments remains controversial. In the present analysis, we evaluate recurrence risk in patients with pT1 a, b, c, node-negative, breast cancer, accordingly with some prognostic biological factors. Methods We retrospectively evaluated 900 node-negative patients (pT1a, b, c) surgery treated between 2000 and 2009 in four Italian oncologic centers. We defined 3 different cohorts: ER positive (ER+); Her-2 positive (Her-2+); and triple negative (TN). Results pT1a was seen in 7.6% of patients, 37.7 % pT1b, 54.8 % pT1c. Concerning the 3 different cohorts, 58.2 % were ER+; 10.8 % were Her-2+; 8.2 % were TN. Overall, chemotherapy was given to 3.0 %, 27.2 %, 69.8 % of pT1a, b, c, respectively, and to 22.7 %, 58.8 %, 68.9 % of ER+, Her-2+, TN subgroups. At a median follow-up of 67 months, 5-year DFS was 96.3 %, 89.2 %, 89.4 % in pT1a, b, c, respectively (100 %, 93.6 %, 89.8 % in ER+; 100 %, 78.7 %, 85.0 % in Her-2+; 100 %, 76.8 %, 85.2 % in TN) (p = ns). At multivariate analysis, histologic grade and Ki-67 resulted independent prognostic factors. Overall, 5-year OS was 98 %, without differences among pT1a, b, c, or among the 3 cohorts. Conclusions Overall, 5-year DFS was very favorable in this series of small, node-negative breast cancers, but Her-2+ and TN cohorts have a higher recurrence rate than ER+ cohort (p

The aim of this study was to evaluate the clinical effectiveness of covered Niti-S stent placement under multidetector CT and fluoroscopy guidance for the palliation of dysphagia in patients with cervical esophageal cancer. Under radiological imaging guidance using axial and sagittal CT scans, and fluoroscopy, Niti-S esophageal stents were placed in ten consecutive patients with complete obstruction caused by cervical esophageal cancer (9 men and 1 woman; age range = 54–79 years; mean age = 68.1 years) between February 2010 and December 2011. The procedure time and technical success rate were evaluated. Swallowing improvement was assessed by the following items: ability to eat and/or swallow (graded as follows: 3 = ability to eat normal diet, 2 = ability to eat semisolids, 1 = ability to swallow liquids, 0 = complete obstruction). Procedural and post-procedural complications were also evaluated. Survival (mean ± SD) was examined. The mean (±SD) procedure time was 40 ± 19 min (range = 21–69 min). Stent placement was technically successful in all patients; inadequate stent deployment did not occur in any case. Ability to eat and/or swallow was improved and scored 2.4 (score 3 in 5 cases, score 2 in 4 cases, score 1 in 1 case, and score 0 in no case) after stent placement. No major or post-procedural complications were encountered. The mean survival time was 131 ± 77 days (range = 31–259 days). Niti-S stents appeared to be a safe and effective device for the palliation of dysphagia caused by advanced cervical esophageal cancer. Multidetector CT and fluoroscopy image guidance helped the operators accurately place the stents in the cervical esophagus.

Background Drug-coated balloons (DCBs) have been developed for the percutaneous treatment of coronary artery disease. An initial focus has been the management of in-stent restenosis (ISR) but randomised controlled trials (RCTs) have been small and powered only for angiographic endpoints. Objective The aim of the work was to assess the clinical and angiographic outcomes of patients treated for ISR with DCB versus control (balloon angioplasty or drug-eluting stents) by a meta-analysis of RCTs. Methods A comprehensive search was performed of RCTs where patients with ISR were randomly assigned to either DCB or alternative coronary intervention. Outcome measurements were death, myocardial infarction (MI), target lesion revascularisation (TLR), binary definition of restenosis and in-lesion late luminal loss (LLL). Results Four studies were identified that fulfilled the inclusion criteria. Pooled odds ratios (ORs) were calculated for patients treated for ISR (n = 399). Mean follow-up duration was 14.5 months. DCBs were associated with lower rates of TLR [8.8 vs. 29.7 % OR (95 % confidence interval, CI) 0.20 (0.11–0.36), p

Purpose Surgical treatment of an acute Achilles tendon rupture can effectively reduce the risk of re-rupture, but it increases the probability of surgical complications. We postulated that a minimally invasive surgical treatment might reduce the number of complications related to open surgery and improve the functional results. Method We enrolled 47 patients with acute Achilles tendon ruptures in a prospective, randomised trial to compare clinical results and complications between a minimally invasive procedure with the Achillon® device and traditional open surgery with Krackow-type sutures. The average patient age was 46 years. The follow up time was 24 months. Results No Achilles tendon re-rupture or nerve injury occurred in treated patients. There were two cases of wound infections in the open surgery group, and one superficial wound infection occurred in the minimally invasive group. The groups were not significantly different in the amount of pain, range of ankle movements, the single heel-rise test, calf circumference, or time to return to work and sports. Conclusion After a two year follow-up period, we found no significant differences in clinical outcomes between groups treated with traditional open surgery or minimally invasive surgery.

Myxovirus resistance A (MxA) is a major interferon (IFN)-inducible antiviral protein. Promoter single-nucleotide polymorphisms (SNPs) of MxA near the IFN-stimulated response element (ISRE) have been frequently associated with various viral diseases, including emerging respiratory infections. We investigated the expression profile of MxA transcripts with distinct first exons in human bronchial epithelial cells. For primary culture, the bronchial epithelium was isolated from lung tissues with different genotypes, and total RNA was subjected to real-time reverse transcription polymerase chain reaction. The previously reported MxA transcript (T1) and a recently registered transcript with a distinct 5′ first exon (T0) were identified. IFN-β and polyinosinic–polycytidylic acid induced approximately 100-fold higher expression of the T1 transcript than that of the T0 transcript, which also had a potential ISRE motif near its transcription start site. Even without inducers, the T1 transcript accounted for approximately two thirds of the total expression of MxA, levels of which were significantly associated with its promoter and exon 1 SNPs (rs17000900, rs2071430, and rs464138). Our results suggest that MxA observed in respiratory viral infections is possibly dominated by the T1 transcript and partly influenced by relevant 5′ SNPs. Electronic supplementary material The online version of this article (doi:10.1007/s00251-012-0663-8) contains supplementary material, which is available to authorized users.

Objective We tested whether bedside testing for H-FABP is, alone or integrated in combination models, useful for rapid risk stratification of non-high-risk PE. Methods We prospectively studied 136 normotensive patients with confirmed PE. H-FABP was determined using a qualitative bedside-test showing a positive result for plasma concentration >7 ng/ml. Results Overall, 11 patients (8.1 %) had an adverse 30-day outcome. Of 58 patients (42.6 %) with a positive H-FABP bedside-test, 9 (15.5 %) had an unfavourable course compared to 2 of 78 patients (2.6 %) with a negative test result (p = 0.009). Logistic regression analysis indicated a sevenfold increased risk for an adverse outcome (95 % CI, 1.45–33.67; p = 0.016) for patients with a positive H-FABP bedside-test. Additive prognostic information were obtained by a novel score including the H-FABP bedside-test (1.5 points), tachycardia (2 points), and syncope (1.5 points) (OR 11.57 [2.38–56.24]; p = 0.002 for ≥3 points). Increasing points were associated with a continuous exponential increase in the rate of an adverse 30-day outcome (0 % for patients with 0 points and 44.4 % for ≥5 points). Notably, this simple score provided similar prognostic value as the combination of the H-FABP bedside-test with echocardiographic signs of right ventricular dysfunction (OR 12.73 [2.51–64.43]; p = 0.002). Conclusions Bedside testing for H-FABP appears a useful tool for immediate risk stratification of non-high-risk patients with acute PE, who may be at increased risk of an adverse outcome, in particular if integrated in a novel score without the need of echocardiographic examination.

Greig cephalopolysyndactyly syndrome (GCPS) and isolated preaxial polydactyly type IV (PPD-IV) are rare autosomal dominant disorders, both caused by mutations in the GLI3 gene. GCPS is mainly characterised by craniofacial abnormalities (macrocephaly/prominent forehead, hypertelorism) and limb malformations, such as PPD-IV, syndactyly and postaxial polydactyly type A or B (PAPA/B). Mutations in the GLI3 gene can also lead to Pallister–Hall syndrome (PHS) and isolated PAPA/B. In this study, we investigated 16 unrelated probands with the clinical diagnosis of GCPS/PPD-IV and found GLI3 mutations in 12 (75 %) of them (nine familial and three sporadic cases). We also performed a detailed clinical evaluation of all 12 GLI3-positive families, with a total of 27 patients. The hallmark triad of GCPS (preaxial polydactyly, macrocephaly/prominent forehead, hypertelorism) was present in 14 cases (52 %), whereas at least one typical dysmorphic feature was manifested in 17 patients (63 %). Upon sequencing of the GLI3 gene, we demonstrated eight novel and two previously reported heterozygous point mutations. We also performed multiplex ligation-dependent probe amplification (MLPA) to screen for intragenic copy number changes and identified heterozygous deletions in the two remaining cases (16.7 %). Our findings fully support previous genotype–phenotype correlations, showing that exonic deletions, missense mutations, as well as truncating variants localised out of the middle third of the GLI3 gene result in GCPS/PPD-IV and not PHS. Additionally, our study shows that intragenic GLI3 deletions may account for a significant proportion of GCPS/PPD-IV causative mutations. Therefore, we propose that MLPA or quantitative polymerase chain reaction (qPCR) should be implemented into routine molecular diagnostic of the GLI3 gene.

Oxylipins, including eicosanoids, affect a broad range of biological processes, such as the initiation and resolution of inflammation. These compounds, also referred to as lipid mediators, are (non-) enzymatically generated by oxidation of polyunsaturated fatty acids such as arachidonic acid (AA). A plethora of lipid mediators exist which makes the development of generic analytical methods challenging. Here we developed a robust and sensitive targeted analysis platform for oxylipins and applied it in a biological setting, using high performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) operated in dynamic multiple reaction monitoring (dMRM). Besides the well-described AA metabolites, oxylipins derived from linoleic acid, dihomo-γ-linolenic acid, α-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid were included. Our comprehensive platform allows the quantitative evaluation of approximately 100 oxylipins down to low nanomolar levels. Applicability of the analytical platform was demonstrated by analyzing plasma samples of patients undergoing cardiac surgery. Altered levels of some of the oxylipins, especially in certain monohydroxy fatty acids such as 12-HETE and 12-HEPE, were observed in samples collected before and 24 h after cardiac surgery. These findings indicate that this generic oxylipin profiling platform can be applied broadly to study these highly bioactive compounds in relation to human disease. Figure LC-MS/MS chromatogram of 104 oxylipins on a Triple Quadrupole MS system employing dynamic MRM in the Negative Ion Electrospray mode Electronic supplementary material The online version of this article (doi:10.1007/s00216-012-6226-x) contains supplementary material, which is available to authorized users.

Pediatric glioblastomas (GBM) including diffuse intrinsic pontine gliomas (DIPG) are devastating brain tumors with no effective therapy. Here, we investigated clinical and biological impacts of histone H3.3 mutations. Forty-two DIPGs were tested for H3.3 mutations. Wild-type versus mutated (K27M-H3.3) subgroups were compared for HIST1H3B, IDH, ATRX and TP53 mutations, copy number alterations and clinical outcome. K27M-H3.3 occurred in 71 %, TP53 mutations in 77 % and ATRX mutations in 9 % of DIPGs. ATRX mutations were more frequent in older children (p

There is a broad literature on the consequences of applying different welfare standards in merger control. Total welfare is usually defined as the sum of consumer and provider surplus, i.e., potential external effects are not considered. The general result is then that consumer welfare is a more restrictive standard than total welfare, which is advantageous in certain situations. This relationship between the two standards is not necessarily true when the merger has significant external effects. We model mergers on hospital markets and allow for not-profit-maximizing behavior of providers and mandatory health insurance. Mandatory health insurance detaches the financial and consumption side of health care markets, and the concept consumer in merger control becomes non-evident. Patients not visiting the merging hospitals still are affected by price changes through their insurance premiums. External financial effects emerge on not directly affected consumers. We show that applying a restricted interpretation of consumer (neglecting externality) in health care merger control can reverse the relation between the two standards; consumer welfare standard can be weaker than total welfare. Consequently, applying the wrong standard can lead to both clearing socially undesirable and to blocking socially desirable mergers. The possible negative consequences of applying a simple consumer welfare standard in merger control can be even stronger when hospitals maximize quality and put less weight on financial considerations. We also investigate the implications of these results for the practice of merger control.

Rare disruptions of FOXP2 have been strongly implicated in deficits in language development. Research over the past decade has suggested a role in the formation of underlying neural circuits required for speech. Until recently no evidence existed to suggest that the closely related FOXP1 gene played a role in neurodevelopmental processes. However, in the last few years, novel rare disruptions in FOXP1 have been reported in multiple cases of cognitive dysfunction, including intellectual disability and autism spectrum disorder, together with language impairment. As FOXP1 and FOXP2 form heterodimers for transcriptional regulation, one may assume that they co-operate in common neurodevelopmental pathways through the co-regulation of common targets. Here we compare the phenotypic consequences of FOXP1 and FOXP2 impairment, drawing on well-known studies from the past as well as recent exciting findings and consider what these tell us regarding the functions of these two genes in neural development. Electronic supplementary material The online version of this article (doi:10.1007/s00439-012-1193-z) contains supplementary material, which is available to authorized users.

Immune-mediated rejection of human cancer is a relatively rare but well-documented phenomenon. Its rate of occurrence progressively increases from the occasional observation of spontaneous regressions to the high rate of complete remissions observed in response to effective treatments. For two decades, our group has focused its interest in understanding this phenomenon by studying humans following an inductive approach. Sticking to a sequential logic, we dissected the phenomenon by studying to the best of our capability both peripheral and tumor samples and reached the conclusion that immune-mediated cancer rejection is a facet of autoimmunity where the target tissue is the cancer itself. As we are currently defining the strategy to effectively identify the mechanisms leading in individual patients to rejection of their own tumors, we considered useful to summarize the thought process that guided us to our own interpretation of the mechanisms of immune responsiveness.