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Background: Chest wall abnormalities are a poorly studied complication after treatment for childhood cancer. Chest wall abnormalities are not well-described in the literature, and little is known on the impact on daily life of survivors.Methods: We investigated prevalence and risk factors of chest wall abnormalities in childhood cancer survivors in a nationwide, population-based cohort study (Swiss Childhood Cancer Survivor Study) with a questionnaire survey. We then interviewed a nested sample of survivors to validate types of chest wall abnormalities and understand their impact on the daily life of survivors.Results: Forty-eight of 2382 (95%CI 2-3%) survivors reported a chest wall abnormality. Risk factors were older age at cancer diagnosis (16-20 years; OR 2.5, 95%CI 1.0-6.1), lymphoma (OR 3.8, 95%CI 1.2-11.4), and central nervous system tumors (OR 9.5, 95%CI 3.0-30.1) as underlying disease, and treatment with thoracic radiotherapy (OR 2.0, 95%CI 1.0-4.2), surgery to the chest (OR 4.5, 95%CI 1.8-11.5), or chemotherapy (OR 2.9, 95%CI 1.0-8.1). The nature of the chest wall abnormalities varied and included thoracic wall deformities (30%), deformations of the spine (5%) or both (55%), and scars (10%). Chest wall abnormalities affected daily life in two thirds (13/20) of those who reported these problems and necessitated medical attention for 15 (75%) survivors.Conclusion: It is important that, during follow-up care, physicians pay attention to chest wall abnormalities, which are rare late effects of cancer treatment, but can considerably affect the well-being of cancer survivors. [ABSTRACT FROM AUTHOR]

Background: The aetiology of most childhood cancers is largely unknown. Spatially varying environmental factors such as traffic-related air pollution, background radiation and agricultural pesticides might contribute to the development of childhood cancer. This study is the first investigation of the spatial disease mapping of childhood cancers using exact geocodes of place of residence. Methods: We included 5947 children diagnosed with cancer in Switzerland during 1985–2015 at 0–15 years of age from the Swiss Childhood Cancer Registry. We modelled cancer risk using log-Gaussian Cox processes and indirect standardisation to adjust for age and year of diagnosis. We examined whether the spatial variation of risk can be explained by modelled ambient air concentration of NO2, modelled exposure to background ionising radiation, area-based socio-economic position (SEP), linguistic region, duration in years of general cancer registration in the canton or degree of urbanisation. Results: For all childhood cancers combined, the posterior median relative risk (RR), compared to the national level, varied by location from 0.83 to 1.13 (min to max). Corresponding ranges were 0.96 to 1.09 for leukaemia, 0.90 to 1.13 for lymphoma, and 0.82 to 1.23 for central nervous system (CNS) tumours. The covariates considered explained 72% of the observed spatial variation for all cancers, 81% for leukaemia, 82% for lymphoma and 64% for CNS tumours. There was weak evidence of an association of CNS tumour incidence with modelled exposure to background ionising radiation (RR per SD difference 1.17; 0.98–1.40) and with SEP (1.6; 1.00–1.13). Conclusion: Of the investigated diagnostic groups, childhood CNS tumours showed the largest spatial variation. The selected covariates only partially explained the observed variation of CNS tumours suggesting that other environmental factors also play a role. [ABSTRACT FROM AUTHOR]

Follow-up care is important for childhood cancer survivors to facilitate early detection and treatment of late effects. We aimed to describe preferences for different organisational aspects and models of follow-up care among Swiss childhood cancer survivors, and characteristics associated with preferences for different models. We contacted 720 survivors aged 18+ years, diagnosed with cancer after 1990 (age 0-16 years), registered in the Swiss Childhood Cancer Registry ( SCCR), and Swiss resident, who previously participated in a baseline survey. They received questionnaires to assess attendance and preferences for follow-up (rated on 4-point scales, 0-3). Clinical information was available from the SCCR. Survivors ( n = 314: response rate 43.6%; 47.8% still attended follow-up) rated clinical reasons for follow-up higher than supportive reasons ( p < .001). They rated checking for cancer recurrence (mean = 2.78, SD = 0.53) and knowing about risks for my children most important (mean = 2.22, SD = 0.83). They preferred to attend a children's hospital (mean = 1.94, SD = 1.11), adult hospital (mean = 1.86, SD = 0.98) or general practitioner (mean = 1.86, SD = 1.01) rather than a central specialised late effects clinic (mean = 1.25, SD = 1.06, p < .001), and be seen by paediatric (mean = 2.24, SD = 0.72) or medical oncologist (mean = 2.17, SD = 0.69). Survivors preferred decentralised clinic-based follow-up, rather than one central specialised late effects clinic. Survivors' preferences should be considered to ensure future attendance. [ABSTRACT FROM AUTHOR]

Cluster of differentiation (CD)8+ T cells are like a double edged sword during chronic viral infections because they not only promote virus elimination but also induce virus-mediated immunopathology. Elevated levels of reactive oxygen species (ROS) have been reported during virus infections. However, the role of ROS in T-cell-mediated immunopathology remains unclear. Here we used the murine lymphocytic choriomeningitis virus to explore the role of ROS during the processes of virus elimination and induction of immunopathology. We found that virus infection led to elevated levels of ROS producing granulocytes and macrophages in virus-infected liver and spleen tissues that were triggered by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Lack of the regulatory subunit p47phox of the NADPH oxidase diminished ROS production in these cells. While CD8+ T cells exhibited ROS production that was independent of NADPH oxidase expression, survival and T-cell function was elevated in p47phox-deficient (Ncf1−/−) mice. In the absence of p47phox, enhanced T-cell immunity promoted virus elimination and blunted corresponding immunopathology. In conclusion, we find that NADPH-mediated production of ROS critically impairs the immune response, impacting elimination of virus and outcome of liver cell damage. [ABSTRACT FROM AUTHOR]

Presents a corrected reprint of an article concerning toll-like receptor engagement in T cell autoreactivity, published in the periodical "Nature Medicine."

Diamond-Blackfan anaemia (DBA), first described over 80 years ago, is a congenital disorder of erythropoiesis with a predilection for birth defects and cancer. Despite scientific advances, this chronic, debilitating, and life-limiting disorder continues to cause a substantial physical, psychological, and financial toll on patients and their families. The highly complex medical needs of affected patients require specialised expertise and multidisciplinary care. However, gaps remain in effectively bridging scientific discoveries to clinical practice and disseminating the latest knowledge and best practices to providers. Following the publication of the first international consensus in 2008, advances in our understanding of the genetics, natural history, and clinical management of DBA have strongly supported the need for new consensus recommendations. In 2014 in Freiburg, Germany, a panel of 53 experts including clinicians, diagnosticians, and researchers from 27 countries convened. With support from patient advocates, the panel met repeatedly over subsequent years, engaging in ongoing discussions. These meetings led to the development of new consensus recommendations in 2024, replacing the previous guidelines. To account for the diverse phenotypes including presentation without anaemia, the panel agreed to adopt the term DBA syndrome. We propose new simplified diagnostic criteria, describe the genetics of DBA syndrome and its phenocopies, and introduce major changes in therapeutic standards. These changes include lowering the prednisone maintenance dose to maximum 0·3 mg/kg per day, raising the pre-transfusion haemoglobin to 9-10 g/dL independent of age, recommending early aggressive chelation, broadening indications for haematopoietic stem-cell transplantation, and recommending systematic clinical surveillance including early colorectal cancer screening. In summary, the current practice guidelines standardise the diagnostics, treatment, and long-term surveillance of patients with DBA syndrome of all ages worldwide., Competing Interests: Declaration of interests AK declares honoraria from chiesi and Novartis and a research grant from Novaris. AK is on the advisory board of Chiesi and Novartis. FML declares honoraria from Chiesi and is on the advisory board of Chiesi. LK is on the advisory board of Agios, Amgen, Bayer, and Novartis. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Diencephalic syndrome is usually associated with tumors in the hypothalamic region, rarely occurring in patients with neurofibromatosis type 1 (NF1)-associated gliomas. We describe the clinical presentation and response to treatment in 3 patients with NF1 presenting with diencephalic syndrome as first symptom of optic pathway/hypothalamic glioma (OPHG). Because of the rarity of this constellation, knowledge about the clinical course and best treatment options for patients with NF1-associated OPHG and diencephalic syndrome is still limited. All 3 patients showed good response to treatment with normalization of body mass index and decrease in tumor volume within 6 months., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: In face of disparities in access to cancer care, it has been proposed to measure accessibility and to explore policy strategies for mitigating inequality of access. We aimed to determine the accessibility of Swiss paediatric oncology centres., Methods: We employed spatial accessibility analysis, calculating driving time to nearest facility. Four data types were used: disaggregated population data, administrative data, street network data and addresses of centres. Besides analysing general accessibility, we compared access of urban versus rural areas and of Swiss citizens versus foreign residents and evaluated designating a new centre to improve accessibility., Results: Overall, 97.4% could reach the nearest centre within 120 min (95.0% < 90 min, 86.5% < 60 min, 48.5% < 30 min). Accessibility could most effectively be improved by a new centre in Sion (city in the southwest of Switzerland). Access in urban areas was better than in rural areas. In urban areas, access of European Union/European Free Trade Association (EU/EFTA) and non-European residents was better than access of Swiss citizens and residents from non-EU European countries., Conclusion: Access is satisfactory. However, our study presents high-resolution insights which could serve as points of leverage for policymakers to mitigate inequalities by designating a new centre and to evaluate potential benefits of centralisation., (© 2022 The Authors. European Journal of Cancer Care published by John Wiley & Sons Ltd.)

Background and Purpose: Culturally diverse countries such as Switzerland face the challenge of providing cross-cultural competent care. Cross-cultural competent care needs an understanding of a patient's cultural context in order to provide safe and effective care. Therefore, we sought to examine cross-cultural competence of Swiss paediatric oncology care providers, and to explore their perceptions of barriers to and facilitators of cross-culturally competent care., Design and Sample: We conducted a cross-sectional study. The data collection period was three weeks. Providers were recruited through collaborators at the participating paediatric oncology centres. All occupational groups who are in direct contact with patients and involved in their care were eligible (e.g., physicians, nurses, social workers, occupational therapists and physiotherapists). Surveying providers online, we captured five subscales of their cross-cultural competence and their perceptions as to how to facilitate cross-culturally competent paediatric oncology care. We employed the Cross-Cultural Competence of Healthcare Professionals (CCCHP) questionnaire. Besides descriptive and inferential statistics, we performed content analysis., Findings: The response rate was 73.2% (n = 183/250). Analyses revealed differences in cross-cultural competence between occupational groups of paediatric oncology providers. Overall, social workers' cross-cultural competence was higher than nurses' or occupational therapists' and physiotherapists' cross-cultural competence. Physicians' cross-cultural competence was higher than nurses (with no statistically significant difference identified between physicians, occupational therapists and physiotherapists). Furthermore, our results suggest noteworthy differences among the four main occupational groups on the five CCCHP subscales. Physicians and social workers declared more positive attitudes than nurses; occupational therapists and physiotherapists reported lower skills than the other three groups; social workers scored higher on the emotions and empathy subscale than the other three groups; physicians were more knowledgeable and aware than nurses. Most frequently mentioned barriers were: language barriers (68.5%), different culture and values (19.2%), different illness understanding (9.2%). Most frequently mentioned facilitators were: professional translators (47.2%), continuous training (20.8%), professional cultural mediators (8.8%)., Conclusions/implications: Trainings and interventions are widely considered a principal strategy to advance providers' cross-cultural competence. Our findings of differences in cross-cultural competence among occupational groups further underpin the need to adapt training programmes and interventions to the respective occupational group and the respective dimension(s) of cross-cultural competence. In addition, professional translators and cultural mediators should be used. Lastly, reciprocal supervision and the promotion of multidisciplinary teams is crucial to enable oncology care providers to learn from each other and this exchange could also help to reduce some of the differences between the various occupational groups.

Motor vehicle exhaust is a major contributor to air pollution, and exposure to benzene or other carcinogenic components may increase cancer risks. We aimed to investigate the association between traffic-related air pollution and risk of childhood cancer in a nationwide cohort study in Switzerland. We identified incident cases from the Swiss Childhood Cancer Registry diagnosed < 16 years of age between 1990 and 2015 and linked them probabilistically with the census-based Swiss National Cohort study. We developed land use regression models to estimate annual mean ambient levels of nitrogen dioxide (NO 2 ) and benzene outside 1.4 million children's homes. We used risk-set sampling to facilitate the analysis of time-varying exposure and fitted conditional logistic regression models adjusting for neighborhood socio-economic position, level of urbanization, and background ionizing radiation. We included 2,960 cancer cases in the analyses. The adjusted hazard ratios (HR) and 95% confidence intervals for exposure to NO 2 per 10 μg/m 3 were 1.00 (95%-CI 0.88-1.13) for acute lymphoblastic leukemia (ALL) and 1.31 (95%-CI 1.00-1.71) for acute myeloid leukemia (AML). Using exposure lagged by 1 to 5 years instead of current exposure attenuated the effect for AML. The adjusted HR for exposure to benzene per 1 μg/m 3 was 1.03 (95%-CI 0.86-1.23) for ALL and 1.29 (95%-CI 0.86-1.95) for AML. We also observed increased HRs for other diagnostic groups, notably non-Hodgkin lymphoma. Our study adds to the existing evidence that exposure to traffic-related air pollution is associated with an increased risk of childhood leukemia, particularly AML., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Diamond-Blackfan anemia (DBA) is caused mainly by genetic mutations in large (RPL) or small ribosomal subunit genes (RPS) and presents with macrocytic anemia and congenital malformations. Clinical differences between genotypes are insufficiently understood. The aim of this study was to assess clinical features, treatment strategies, and genotypes in the Swiss pediatric DBA population. We retrospectively reviewed medical charts of pediatric patients with DBA in Switzerland and stratified patients by RPL versus RPS mutations. We report 17 DBA patients in Switzerland who were all genetically investigated. In our cohort, patients showed a wide spectrum of clinical presentations and treatment needs. We found a high proportion of physical malformations (77%) including lower limb (17%) and anorectal (12%) malformations. The two patients with anorectal malformations presented both with antepositioning of the anus needing surgery within the first 15 months of life. One of these patients had sphincteric dysfunction, the other coccygeal agenesis. We found that included patients with an RPL mutation more frequently tended to have physical malformations and a milder anemia compared to patients with an RPS mutation (median hemoglobin at diagnosis 76 g/l versus 22 g/l).Conclusion: We illustrate the wide clinical and genetic spectrum of DBA in Switzerland. Our findings highlight the need to take this diagnosis into consideration in patients with severe anemia but also in patients with mild anemia where malformations are present. Lower limb and anorectal malformation extend the spectrum of DBA-associated malformations. What is Known? • There is a large variation in the phenotype of Diamond-Blackfan Anemia (DBA) and diversity of genetic mutations. • Malformation of the upper limbs, head and face, heart, and genitourinary system is frequently identified. What is New? • Patients with lower limb and anorectal malformations were repetitively found in our cohort enlarging the clinical spectrum of malformations. • We show two patients of the same family with a DBA-like condition where the same RPL17 variant was identified., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The Hereditary TTP Registry is an international cohort study for patients with a confirmed or suspected diagnosis of hereditary thrombotic thrombocytopenic purpura (hTTP) and their family members. Hereditary TTP is an ultra-rare blood disorder (prevalence of ∼1-2 cases per million), the result of autosomal-recessively inherited congenital ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency (ADAMTS13 activity <10% of the normal), and associated with yet many unanswered questions. Until December 2017, the Hereditary TTP Registry had enrolled 123 confirmed hTTP patients. Their median age at disease onset was 4.5 years (range: 0-70) and at clinical diagnosis 16.7 years (range: 0-69), a difference that highlights the existing awareness gap in recognizing hTTP. The systematic collection of clinical data of individual patients revealed their substantial baseline comorbidities, as a consequence of recurring TTP episodes in the past. Most notable was the high proportion of patients having suffered from premature arterial thrombotic events, mainly transient ischemic attacks, ischemic strokes, and to a lesser extent myocardial infarctions. At 40 to 50 years of age and above, more than 50% of patients had suffered from at least one such event, and many had experienced arterial thrombotic events despite regular plasma infusions every 2 to 3 weeks that supplements the missing plasma ADAMTS13. The article by van Dorland et al. (Haematologica 2019;104(10):2107-2115) and the ongoing Hereditary TTP Registry cohort study were recognized with the Günter Landbeck Excellence Award at the 50th Hemophilia Symposium in Hamburg in November 2019, the reason to present the Hereditary TTP Registry in more detail here., Competing Interests: J.A.K.H. is a member of advisory board of Shire, member of the Takeda group of companies and of Ablynx, now part of Sanofi. All honoraria are paid to her employer, Insel Gruppe AG, Bern, Switzerland. The other authors have nothing to declare., (Thieme. All rights reserved.)

Background: Controversy exists as to what may be defined as standard of care (including markers for stratification) for patients with atypical teratoid/rhabdoid tumors (ATRTs). The European Rhabdoid Registry (EU-RHAB) recruits uniformly treated patients and offers standardized genetic and DNA methylation analyses., Methods: Clinical, genetic, and treatment data of 143 patients from 13 European countries were analyzed (2009-2017). Therapy consisted of surgery, anthracycline-based induction, and either radiotherapy or high dose chemotherapy following a consensus among European experts. Fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, and sequencing were employed for assessment of somatic and germline mutations in SWItch/sucrose nonfermentable related, matrix associated, actin dependent regulator of chromatin, subfamily B (SMARCB1). Molecular subgroups (ATRT-SHH, ATRT-TYR, and ATRT-MYC) were determined using DNA methylation arrays, resulting in profiles of 84 tumors., Results: Median age at diagnosis of 67 girls and 76 boys was 29.5 months. Five-year overall survival (OS) and event-free survival (EFS) were 34.7 ± 4.5% and 30.5 ± 4.2%, respectively. Tumors displayed allelic partial/whole gene deletions (66%; 122/186 alleles) or single nucleotide variants (34%; 64/186 alleles) of SMARCB1. Germline mutations were detected in 26% of ATRTs (30/117). The patient cohort consisted of 47% ATRT-SHH (39/84), 33% ATRT-TYR (28/84), and 20% ATRT-MYC (17/84). Age <1 year, non-TYR signature (ATRT-SHH or -MYC), metastatic or synchronous tumors, germline mutation, incomplete remission, and omission of radiotherapy were negative prognostic factors in univariate analyses (P < 0.05). An adjusted multivariate model identified age <1 year and a non-TYR signature as independent negative predictors of OS: high risk (<1 y + non-TYR; 5-y OS = 0%), intermediate risk (<1 y + ATRT-TYR or ≥1 y + non-TYR; 5-y OS = 32.5 ± 8.7%), and standard risk (≥1 y + ATRT-TYR, 5-y OS = 71.5 ± 12.2%)., Conclusions: Age and molecular subgroup status are independent risk factors for survival in children with ATRT. Our model warrants validation within future clinical trials., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Iron deficiency is the most prevalent nutritional deficiency affecting children and adolescents worldwide. A consistent body of epidemiological data demonstrates an increased incidence of iron deficiency at three timepoints: in the neonatal period, in preschool children, and in adolescents, where it particularly affects females.Conclusion: This narrative review focuses on the most suggestive symptoms of iron deficiency in childhood, describes the diagnostic procedures in situations with or without anemia, and provides Swiss expert-based management recommendations for the pediatric context.What is Known:• Iron deficiency (ID) is one of the most common challenges faced by pediatricians.• Significant progress in the diagnosis and therapy of ID has been made over the last decade.What is New:• Our expert panel provides ID management recommendations based on the best available evidence.• They include strategies for ID diagnosis and therapy, both oral and intravenous.

Background: Incidence of childhood cancer increased in most countries worldwide, but reasons are unclear. This study investigates trends of childhood cancer incidence in Switzerland from 1985 to 2014., Methods: We extracted data on all childhood cancer cases diagnosed at ages 0-14 years in Switzerland from the Swiss Childhood Cancer Registry. We included ICCC-3 main groups I-XII and calculated age-standardised, cumulative, and age-specific incidence for different diagnostic groups. We analysed trends of annual age-standardised incidence using JoinPoint regression models., Results: Over the study period from 1985 to 2014, 5104 of 5486 cancer diagnoses (93%) were microscopically verified. The proportion of children treated in paediatric cancer centres increased from 84% during 1985-1994 to 93% in 1995-2004 and 98% in 2005-2014 (p < 0.001). Using the World standard population, age-standardised incidence was 143 in 1985-1994, 154 in 1995-2004, and 162 per million in 2005-2014. Incidence increased by 0.7% (95% confidence interval (CI) 0.5; 1.0) per year for all cancers from 1985 to 2014, 0.8% (95% CI 0.2%-1.4%) for leukaemias over the same period, 3.0% (95% CI 0.2%-1.4%) for CNS tumours during 1985-2002, and 3.8% (95% CI 1.7%-6.0%) for epithelial neoplasms and melanomas over the period 1985-2014., Conclusion: Trends in incidence were driven mostly by increases among leukaemias and CNS tumours. For CNS tumours, observed trends may be explained at least partially by diagnostic changes and improved registration. For leukaemias, rising incidence may be real and due to risk factors that experience similar increases in trends., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Lived experiences of childhood cancer patients and their families have been described as interrupted and as a loss of normal life. Apart from symptoms due to the cancer disease, families continuously experience burden of treatment. Since coping capacities are unique to each individual, we captured variables that offer objective measures of treatment burden, with a particular focus on the disruptive effects of treatment on families' lives. Our sample was comprised by 193 children that died of cancer. Medical records were extracted retrospectively. Quantitative data were statistically analysed with respect to variables related to treatment burden. Deceased children with cancer and their families faced a significant burden of treatment. Results revealed that deceased leukaemia patients had a higher number of inpatient stays, spent more time in the hospital both during their illness and during the last month of their life, and were more likely to die in the hospital when compared to deceased patients with CNS neoplasms and with other diagnoses. Our findings highlight the disruptive effects of treatment that are likely to have a great impact on families' daily life, that go beyond exclusively focusing on side effects, and that needs to be taken into account by the treating staff., (© 2018 John Wiley & Sons Ltd.)

The goal is to present how shared decision-making in paediatric oncology occurs from the viewpoints of parents and physicians. Eight Swiss Pediatric Oncology Group centres participated in this prospective study. The sample comprised a parent and physician of the minor patient (<18 years). Surveys were statistically analysed by comparing physicians' and parents' perspectives and by evaluating factors associated with children's actual involvement. Perspectives of ninety-one parents and twenty physicians were obtained for 151 children. Results indicate that for six aspects of information provision examined, parents' and physicians' perceptions differed. Moreover, parents felt that the children were more competent to understand diagnosis and prognosis, assessed the disease of the children as worse, and reported higher satisfaction with decision-making on the part of the children. A patient's age and gender predicted involvement. Older children and girls were more likely to be involved. In the decision-making process, parents held a less active role than they actually wanted. Physicians should take measures to ensure that provided information is understood correctly. Furthermore, they should work towards creating awareness for systematic differences between parents and physicians with respect to the perception of the child, the disease, and shared decision-making.

Bernard-Soulier syndrome is a rare (1:1million), hereditary bleeding disorder caused by defects of the platelet GPIb-IX-V complex. Patients suffer from mucocutaneous bleedings. Typical are thrombocytopenia, giant platelets and impaired agglutination after stimulation with ristocetin. In populations in which consanguineous marriages are common the frequency of the disorder is increased because Bernard-Soulier syndrome is mostly inherited autosomal recessively. Genetic analyses of the disease-related genes may help to gain more insights regarding the phenotype/genotype correlation. Here, we investigated several patients with Bernard-Soulier syndrome from different families. We analyzed two patients with severe bleeding symptoms from one family of middle east origin and confirmed the diagnosis by identifying a pathogenic variant in GP1BB. We compared phenotype/genotype correlation of this GP1BB mutation with the GP9 (p.Asn61Ser) European founder mutation present in 9 patients out of 4 families for whom we also performed molecular genetic analysis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: The aim of the present study is to explore patient's perspectives in pediatric oncology on participation in discussions and decision-making surrounding their cancer diagnosis., Methods: Seventeen patients between 9 and 17 years of age receiving treatment at centers of the Swiss Pediatric Oncology Group were interviewed for this study. Their interview data was analyzed qualitatively to identify themes with regard to participation in medical communication and/or decision-making., Results: Participants highlighted how their roles in health care discussions varied from direct participation to indirect involvement. Overall, there were fewer accounts of involvement in decision-making than in overall health care discussions. Challenges with regard to completely understanding the information provided and making decisions were identified. Participants also discussed situations when they were not involved in medical communication or decision-making. While they generally valued their participation, the preferred level of involvement oscillated between participants as well as within one and the same child across time., Conclusions: The complex pattern of participation found in this study calls for a flexible model of involving children and adolescents in health care that accounts for the varying roles and preferences that they manifest. A patient may appreciate active involvement in some decisions while choosing to remain in the background for others. Copyright © 2015 John Wiley & Sons, Ltd., (Copyright © 2015 John Wiley & Sons, Ltd.)

The aetiology of childhood cancers remains largely unknown. It has been hypothesized that infections may be involved and that mini-epidemics thereof could result in space-time clustering of incident cases. Most previous studies support spatio-temporal clustering for leukaemia, while results for other diagnostic groups remain mixed. Few studies have corrected for uneven regional population shifts which can lead to spurious detection of clustering. We examined whether there is space-time clustering of childhood cancers in Switzerland identifying cases diagnosed at age <16 years between 1985 and 2010 from the Swiss Childhood Cancer Registry. Knox tests were performed on geocoded residence at birth and diagnosis separately for leukaemia, acute lymphoid leukaemia (ALL), lymphomas, tumours of the central nervous system, neuroblastomas and soft tissue sarcomas. We used Baker's Max statistic to correct for multiple testing and randomly sampled time-, sex- and age-matched controls from the resident population to correct for uneven regional population shifts. We observed space-time clustering of childhood leukaemia at birth (Baker's Max p = 0.045) but not at diagnosis (p = 0.98). Clustering was strongest for a spatial lag of <1 km and a temporal lag of <2 years (Observed/expected close pairs: 124/98; p Knox test = 0.003). A similar clustering pattern was observed for ALL though overall evidence was weaker (Baker's Max p = 0.13). Little evidence of clustering was found for other diagnostic groups (p > 0.2). Our study suggests that childhood leukaemia tends to cluster in space-time due to an etiologic factor present in early life., (© 2015 UICC.)

Background: This study compared frequency of alcohol consumption and binge drinking between young adult childhood cancer survivors and the general population in Switzerland, and assessed its socio-demographic and clinical determinants., Procedure: Childhood cancer survivors aged <16 years when diagnosed 1976-2003, who had survived >5 years and were currently aged 20-40 years received a postal questionnaire. Reported frequency of alcohol use and of binge drinking were compared to the Swiss Health Survey, a representative general population survey. Determinants of frequent alcohol consumption and binge drinking were assessed in a multivariable logistic regression., Results: Of 1,697 eligible survivors, 1,447 could be contacted and 1,049 (73%) responded. Survivors reported more often than controls to consume alcohol frequently (OR = 1.7; 95%CI = 1.3-2.1) and to engage in binge drinking (OR = 2.9; 95%CI = 2.3-3.8). Peak frequency of binge drinking in males occurred at age 24-26 years in survivors, compared to age 18-20 in the general population. Socio-demographic factors (male gender, high educational attainment, French and Italian speaking, and migration background from Northern European countries) were most strongly associated with alcohol consumption patterns among both survivors and controls., Conclusions: The high frequency of alcohol consumption found in this study is a matter of concern. Our data suggest that survivors should be better informed on the health effects of alcohol consumption during routine follow-up, and that such counseling should be included in clinical guidelines. Future research should study motives of alcohol consumption among survivors to allow development of targeted health interventions for this vulnerable group., (Copyright © 2011 Wiley Periodicals, Inc.)

Arenaviruses are important agents of zoonotic disease worldwide. The virions expose a tripartite envelope glycoprotein complex at their surface, formed by the glycoprotein subunits GP1, GP2 and the stable signal peptide. This complex is responsible for binding to target cells and for the subsequent fusion of viral and host-cell membranes for entry. During this process, the acidic environment of the endosome triggers a fusogenic conformational change in the transmembrane GP2 subunit of the complex. We report here the crystal structure of the recombinant GP2 ectodomain of the lymphocytic choriomeningitis virus, the arenavirus type species, at 1.8-Å resolution. The structure shows the characteristic trimeric coiled coil present in class I viral fusion proteins, with a central stutter that allows a close structural alignment with most of the available structures of class I and III viral fusion proteins. The structure further shows a number of intrachain salt bridges stabilizing the postfusion hairpin conformation, one of which involves an aspartic acid that appears released from a critical interaction with the stable signal peptide upon low pH activation.

The acquisition of pathogen-derived antigen by dendritic cells (DCs) is a key event in the generation of cytotoxic CD8(+) T cell responses. In mice, the intracellular bacterium Listeria monocytogenes is directed from the blood to splenic CD8α(+) DCs. We report that L. monocytogenes rapidly associated with platelets in the bloodstream in a manner dependent on GPIb and complement C3. Platelet association targeted a small but immunologically important portion of L. monocytogenes to splenic CD8α(+) DCs, diverting bacteria from swift clearance by other, less immunogenic phagocytes. Thus, an effective balance is established between maintaining sterility of the circulation and induction of antibacterial immunity by DCs. Other gram-positive bacteria also were rapidly tagged by platelets, revealing a broadly active shuttling mechanism for systemic bacteria.

Background: Previous studies on childhood cancer and nuclear power plants (NPPs) produced conflicting results. We used a cohort approach to examine whether residence near NPPs was associated with leukaemia or any childhood cancer in Switzerland., Methods: We computed person-years at risk for children aged 0-15 years born in Switzerland from 1985 to 2009, based on the Swiss censuses 1990 and 2000 and identified cancer cases from the Swiss Childhood Cancer Registry. We geo-coded place of residence at birth and calculated incidence rate ratios (IRRs) with 95% confidence intervals (CIs) comparing the risk of cancer in children born <5 km, 5-10 km and 10-15 km from the nearest NPP with children born >15 km away, using Poisson regression models., Results: We included 2925 children diagnosed with cancer during 21 117 524 person-years of follow-up; 953 (32.6%) had leukaemia. Eight and 12 children diagnosed with leukaemia at ages 0-4 and 0-15 years, and 18 and 31 children diagnosed with any cancer were born <5 km from a NPP. Compared with children born >15 km away, the IRRs (95% CI) for leukaemia in 0-4 and 0-15 year olds were 1.20 (0.60-2.41) and 1.05 (0.60-1.86), respectively. For any cancer, corresponding IRRs were 0.97 (0.61-1.54) and 0.89 (0.63-1.27). There was no evidence of a dose-response relationship with distance (P > 0.30). Results were similar for residence at diagnosis and at birth, and when adjusted for potential confounders. Results from sensitivity analyses were consistent with main results., Conclusions: This nationwide cohort study found little evidence of an association between residence near NPPs and the risk of leukaemia or any childhood cancer.

Unlabelled: The innate immune response plays an essential role in the prevention of early viral dissemination. We used the lymphocytic choriomeningitis virus model system to analyze the role of tissue macrophages/Kupffer cells in this process. Our findings demonstrated that Kupffer cells are essential for the efficient capture of infectious virus and for preventing viral replication. The latter process involved activation of Kupffer cells by interferon (IFN)-I and prevented viral spread to neighboring hepatocytes. In the absence of Kupffer cells, hepatocytes were not able to suppress virus replication, even in the presence of IFN-I, leading to prolonged viral replication and severe T cell-dependent immunopathology., Conclusion: Tissue-resident macrophages play a crucial role in early viral capture and represent the major liver cell type exhibiting responsiveness to IFN-I and providing control of viral replication.

Newborn higher vertebrates are largely immuno-incompetent and generally survive infections--including poxviruses--by maternal antibody protection. Here, we show that mice survived epidemics as adults only if exposed to lethal orthopoxvirus infections during infancy under the umbrella of maternal protective antibodies. This implies that both the absence of exposure to infection during early infancy or of effective vaccination renders the population highly susceptible to new or old re-emerging pathogens.

Neutrophils are the most abundant leukocytes in circulation and provide a primary innate immune defense function against bacterial pathogens before development of a specific immune response. These specialized phagocytes are short lived (12-24 hours) and continuously replenished from bone marrow. We found that if the host is overwhelmed by a high inoculum of Listeria monocytogenes, neutrophils are depleted despite high granulocyte-colony stimulating factor induction. In contrast to a low-dose innocuous L. monocytogenes infection, high-dose Listeria challenge blocks neutrophil recruitment to infectious abscesses and bacterial proliferation is not controlled, resulting in lethal outcomes. Administering synthetic TLR2-ligand or heat-killed bacteria during the innocuous L. monocytogenes infection reproduced these effects, once again leading to overwhelming bacterial propagation. The same stimuli also severely aggravated Salmonella typhimurium, Staphylococcus aureus, and Streptococcus pyogenes systemic infection. These data implicate systemic innate immune stimulation as a mechanism of bone marrow neutrophil exhaustion which negatively influences the outcome of bacterial infections.

Karyotype analysis of acute lymphoblastic leukemia (ALL) at diagnosis has provided valuable prognostic markers for treatment stratification. However, reports of cytogenetic studies of relapsed ALL samples are limited. We compared the karyotypes from 436 nonselected B-cell precursor ALL patients at initial diagnosis and of 76 patients at first relapse. We noticed a relative increase of karyotypes that did not fall into the classic ALL cytogenetic subgroups (high hyperdiploidy, t(12;21), t(9;22), 11q23, t(1;19), <45 chromosomes) in a group of 29 patients at relapse (38%) compared to 130 patients at presentation (30%). Non-classical cytogenetic aberrations in these 29 patients were mostly found on chromosomes 1, 2, 7, 9, 13, 14, and 17. We also describe six rare reciprocal translocations, three of which involved 14q32. The most frequent abnormalities were found in 9p (12/29 cases) and were associated with a marked decrease in the duration of the second remission, but not of the probability of 10-year event-free survival after relapse treatment. From 29 patients with non-classical cytogenetic aberrations, only 8 (28%) had been stratified to a high risk-arm on the first treatment protocol, suggesting that this subgroup might benefit from the identification of new prognostic markers in future studies.

Retroviruses have the potential to acquire host cell-derived genetic material during reverse transcription and can integrate into the genomes of larger, more complex DNA viruses. In contrast, RNA viruses were believed not to integrate into the host's genome under any circumstances. We found that illegitimate recombination between an exogenous nonretroviral RNA virus, lymphocytic choriomeningitis virus, and the endogenous intracisternal A-type particle (IAP) retrotransposon occurred and led to reverse transcription of exogenous viral RNA. The resulting complementary DNA was integrated into the host's genome with an IAP element. Thus, RNA viruses should be closely scrutinized for any capacity to interact with endogenous retroviral elements before their approval for therapeutic use in humans.

Anti-helminth immunity involves CD4+ T cells, yet the precise effector mechanisms responsible for parasite killing or expulsion remain elusive. We now report an essential role for antibodies in mediating immunity against the enteric helminth Heligmosomoides polygyrus (Hp), a natural murine parasite that establishes chronic infection. Polyclonal IgG antibodies, present in naive mice and produced following Hp infection, functioned to limit egg production by adult parasites. Comparatively, affinity-matured parasite-specific IgG and IgA antibodies that developed only after multiple infections were required to prevent adult worm development. These data reveal complementary roles for polyclonal and affinity-matured parasite-specific antibodies in preventing enteric helminth infection by limiting parasite fecundity and providing immune protection against reinfection, respectively. We propose that parasite-induced polyclonal antibodies play a dual role, whereby the parasite is allowed to establish chronicity, while parasite load and spread are limited, likely reflecting the long coevolution of helminth parasites with their hosts.

More than 500 million people worldwide are persistently infected with hepatitis B virus or hepatitis C virus. Although both viruses are poorly cytopathic, persistence of either virus carries a risk of chronic liver inflammation, potentially resulting in liver steatosis, liver cirrhosis, end-stage liver failure or hepatocellular carcinoma. Virus-specific T cells are a major determinant of the outcome of hepatitis, as they contribute to the early control of chronic hepatitis viruses, but they also mediate immunopathology during persistent virus infection. We have analyzed the role of platelet-derived vasoactive serotonin during virus-induced CD8(+) T cell-dependent immunopathological hepatitis in mice infected with the noncytopathic lymphocytic choriomeningitis virus. After virus infection, platelets were recruited to the liver, and their activation correlated with severely reduced sinusoidal microcirculation, delayed virus elimination and increased immunopathological liver cell damage. Lack of platelet-derived serotonin in serotonin-deficient mice normalized hepatic microcirculatory dysfunction, accelerated virus clearance in the liver and reduced CD8(+) T cell-dependent liver cell damage. In keeping with these observations, serotonin treatment of infected mice delayed entry of activated CD8(+) T cells into the liver, delayed virus control and aggravated immunopathological hepatitis. Thus, vasoactive serotonin supports virus persistence in the liver and aggravates virus-induced immunopathology.

Many vaccination strategies and immune cell therapies aim at increasing the numbers of memory T cells reactive to protective antigens. However, the differentiation lineage and therefore the optimal generation conditions of CD4 memory cells remain controversial. Linear and divergent differentiation models have been proposed, suggesting CD4 memory T cell development from naive precursors either with or without an effector-stage intermediate, respectively. Here, we address this question by using newly available techniques for the identification and isolation of effector T cells secreting effector cytokines. In adoptive cell transfers into normal, nonlymphopenic mice, we show that long-lived virus-specific memory T cells can efficiently be generated from purified interferon gamma-secreting T helper (Th) type 1 and interleukin (IL)-4- or IL-10-secreting Th2 effectors primed in vitro or in vivo. Importantly, such effector-derived memory T cells were functional in viral challenge infections. They proliferated vigorously, rapidly modulated IL-7 receptor expression, exhibited partial stability and flexibility of their cytokine patterns, and exerted differential effects on virus-induced immunopathology. Thus, cytokine-secreting effectors can evade activation-induced cell death and develop into long-lived functional memory cells. These findings demonstrate the efficiency of linear memory T cell differentiation and encourage the design of vaccines and immune cell therapies based on differentiated effector T cells.

We describe a Hb S/beta-thalassemia (beta-thal) mutation involving an AT transition at codon 132 of the beta-globin gene. The mutation, in the heterozygous state, unlike several other mutations in exon 3, shows no signs of dominant thalassemia but those of a typical beta(0) carrier. Compound heterozygosity with Hb S [beta6(A3)GluVal, GAGGTG] showed a severe clinical picture.