Abstract Background and aims The modulation of serum lipids, in particular of the low-density lipoprotein cholesterol (LDL-C), by statins varies between individuals. The mechanisms regulating this interindividual variation are only poorly understood. Here, we investigated the relation between the gut microbiome and the regulatory properties of atorvastatin on the serum lipidome using mice with depleted gut microbiome. Methods Over a period of 6 weeks, mice (C57BL/6) with either an intact (conventional mice, CONV, n=24) or antibiotic-based depleted gut microbiome (antibiotic treated mice, ABS, n=16) were put on standard chow diet (SCD) or high fat diet (HFD), respectively. During the last 4 weeks of treatment atorvastatin (Ator, 10mg/kg body weight/day) or control vehicle was administered via daily oral gavage. Blood lipids (total cholesterol, VLDL, LDL-C, HDL-C) and serum sphingolipids were compared among the groups. The expressions of hepatic and intestinal genes involved in cholesterol metabolism were analyzed by qRT-PCR. Alterations in the gut microbiota profile of mice with intact gut microbiome were examined using 16S RNA qRT-PCR. Results In CONV mice, HFD led to significantly increased blood LDL-C levels as compared with SCD (HFD: 36.8±1.4 mg/dl vs. SCD: 22.0±1.8 mg/dl; P<0.01). In CONV mice atorvastatin treatment significantly reduced blood LDL-C levels after HFD, whereas in ABS mice the LDL-C lowering effect of atorvastatin was markedly attenuated (CONV+HFD+Ator: 31.0±1.8 mg/dl vs. ABS+HFD+Ator: 46.4±3 mg/dl; P<0.01). A significant reduction in the abundance of several plasma lipids, in particular sphingolipids and glycerophospholipids upon atorvastatin treatment was observed in CONV mice, but not in ABS mice. The expressions of distinct hepatic and intestinal cholesterol-regulating genes (ldlr, srebp2, pcsk9 and npc1l1) upon atorvastatin treatment were significantly altered in gut microbiota depleted mice. In response to HFD a decrease in the relative abundance of the bacterial phyla Bacteroides and an increase in the relative abundance of Firmicutes was observed. The altered ratio between Bacteroides and Firmicutes in HFD fed mice was partly reversed upon atorvastatin treatment. Conclusions Our findings indicate a crucial role of the gut microbiome for the regulatory properties of atorvastatin on the serum lipidome and, in turn, support a critical impact of atorvastatin on the gut microbial composition. The results provide novel insights into potential microbiota related mechanisms underlying interindividual variation in modulation of the serum lipidome by statins, given interindividual differences in microbiome composition and function. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): German Heart Research Foundation

OBJECTIVES:Infantile hemangiomas (IHs) are common; some cases require timely referral and treatment to prevent complications. We developed and validated a reliable instrument for timely and adequate referral of patients with IH to experts by nonexpert primary physicians. METHODS:In this multicenter, cross-sectional, observational study, we used a 3-stage process: (1) development of the Infantile Hemangioma Referral Score (IHReS) tool by IH experts who selected a representative set of 42 IH cases comprising images and a short clinical history, (2) definition of the gold standard for the 42 cases by a second independent committee of IH experts, and (3) IHReS validation by nonexpert primary physicians using the 42 gold standard cases. RESULTS:A total of 60 primary physicians from 7 different countries evaluated the 42 gold standard cases (without reference to the IHReS tool); 45 primary physicians evaluated these cases using the IHReS questionnaire, and 44 completed retesting using the instrument. IHReS had a sensitivity of 96.9% (95% confidence interval 96.1%-97.8%) and a specificity of 55.0% (95% confidence interval 51.0%-59.0%). The positive predictive value and negative predictive value were 40.5% and 98.3%, respectively. Validation by experts and primary physicians revealed substantial agreement for interrater reliability and intrarater repeatability. CONCLUSIONS:IHReS, a 2-part algorithm with a total of 12 questions, is an easy-to-use tool for primary physicians for the purpose of facilitating correct and timely referral of patients with IH. IHReS may help practitioners in their decision to refer patients to expert centers.

Pediatric patients with cancer are at high risk for severe infections and delayed treatment increases mortality. Infections can trigger changes of vital signs long before clinical symptoms arise. Continuous recording may detect such changes earlier than discrete measurements. This is the protocol for an investigator-initiated, single-center observational pilot study on the feasibility of continuous monitoring of health data with a wearable device (WD) in pediatric patients undergoing chemotherapy of cancer. A total of 20 patients will be included, including at least 4 patients <6 years. Each patient will wear the WD for 14 days and we expect study duration of three to four months. The protocol had been registered at www.clinicaltrials.com (NCT04134429) and was approved by the local Ethics Committees (Ethikkommission der Universitätskinderkliniken Bern, “Gesuch 1912”, Kantonale Ethikkommission Bern, BASEC-No.: 2019-01919).

BACKGROUND AND AIMSCardiovascular diseases (CVD) increase late morbidity and mortality in survivors of acute lymphoblastic leukaemia (ALL). We compared the risk of CVD in ALL survivors to siblings, examined time trends, quantified treatment-related risks, and investigated whether risk extends beyond patients treated with anthracyclines and chest radiotherapy.METHODSThe Swiss Childhood Cancer Survivor Study assessed CVD by patient questionnaire in 5-year ALL survivors diagnosed between 1976 and 2005 and their siblings. Participants were asked whether a physician had ever told them that they had hypertension, arrhythmia, heart failure, myocardial infarction, angina pectoris, stroke, thrombosis or valvular problems. We investigated treatment-related risk factors for CVD using multivariable logistic regression, adjusting for demographic and socioeconomic factors, BMI, smoking, diabetes mellitus, alcohol consumption and physical activity.RESULTSWe contacted 707 survivors and 1299 siblings, 511 (72%) and 709 (55%) of whom responded, respectively. Survivors had a higher risk of developing CVD than siblings (odds ratio [OR] 1.9, 95% confidence interval 1.3–2.8), in particular heart failure (OR 13.9, 1.8–107.4). Compared to patients treated 1976–85, the risk of CVD was 1.4 (0.7–2.8) for those treated 1985–1994 and 1.5 (0.6–3.7) for those treated 1995–2005. The overall CVD risks after anthracycline treatment (OR 3.1, 2.0–4.7), haematopoietic stem cell transplantation (OR 8.0, 2.4–26.9) or relapse (OR 4.1, 1.9–8.8) were increased compared to those of siblings, while the CVD risks of survivors treated without anthracycline or chest radiotherapy were similar (OR 1.0; 0.5–2.0).CONCLUSIONSDespite attempts to reduce cardiotoxicity in childhood cancer treatment, CVD risks in ALL survivors treated more recently do not seem to have declined.

STRUCTURED ABSTRACTBackgroundIncidence of childhood cancer increased in most countries worldwide, but the reasons are unclear. This study investigates trends in childhood cancer incidence in Switzerland from 1985 to 2014.MethodsWe 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 in annual age-standardised incidence using JoinPoint regression models.ResultsOver the study period from 1985-2014, 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 2010 European standard population, age-standardised incidence was 143 in 1985-1994, 154 in 1995-2004, and 162 per million in 2005-2014. Over the period 1985-2014, incidence for all cancers increased by 0.7% (95% confidence interval [CI] 0.5-1.0) per year, 0.8% (95% CI 0.2%-1.4%) for leukaemias, 3.8% (95% CI 1.7%-6.0%) for epithelial neoplasms and melanomas, and 3.0% (95% CI 1.3%-4.6%) for CNS tumours for the period 1985-2002.ConclusionTrends 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 at least partly due to changes in risk factors.HighlightsIn Switzerland, incidence of childhood cancer increased by 18% from 1985-2014.Increase in incidence was mainly caused by brain tumours and leukaemias.Improved registration and diagnostics may have increased brain tumour incidence.Increasing trend for leukaemias may be real, but reasons remain elusive.

Abstract Background and aims Statins show interindividual differences in the extent of low-density lipoprotein cholesterol (LDL-C) reduction. The mechanisms of this interindividual variation are not fully understood. Here, we examined the potential role of the gut microbiome for the LDL-C lowering property of atorvastatin. Methods Mice (C57BL/6) with either intact (conventional mice, CONV, n=24) or with antiobiotic depleted gut microbiome (gnotobiotic, n=16), were put on standard chow diet (SCD) (n=11) or high fat diet (HFD) (n=29) for 6 weeks. During the last 4 weeks atorvastatin (Ator, 10mg/kg body weight/day) or control vehicle was orally applied via gavage. Blood levels of LDL-C and glucose and body weight after 6 weeks of treatment were compared between the groups. Expression of genes involved in hepatic and intestinal cholesterol-metabolism were examined. Faeces of CONV mice were analyzed for alteration of the gut microbiota profile upon atorvastatin treatment using 16S rRNA qPCR. Results HFD fed mice with intact gut microbiome showed significantly increased blood LDL-C levels as compared to SCD (HFD: 36.8±1.4 mg/dl vs. SCD: 22.0±1.8 mg/dl; P<0.01). Bodyweight gain or blood glucose levels after HFD were not significantly different between CONV and gnotobiotic mice. While in CONV mice atorvastatin significantly reduced LDL-C levels after HFD, in gnotobiotic mice the LDL-C lowering effect of atorvastatin was attenuated (CONV+HFD+Ator: 31.0±1.8 mg/dl vs. gnotobiotic mice+HFD+Ator: 46.4±3 mg/dl; P<0.01). The expression of genes involved in hepatic cholesterol synthesis was not significantly altered in gnotobiotic mice as compared to CONV mice. In CONV mice HFD decreased the relative abundance of the bacterial phyla Bacteroidetes and increased the abundance of Firmicutes as compared to SCD. The ratio between Firmicutes to Bacteroidetes was shifted towards control conditions upon atorvastatin treatment. Conclusions The results of this study suggest a regulatory impact of atorvastatin on the gut-microbial profile and, in turn, a crucial role of the gut-microbiome for the LDL-C lowering effect of atorvastatin independent of its regulation of hepatic cholesterol synthesis. Our findings provide novel insight into potential microbiota-related mechanisms causing interindividual variation in LDL-C lowering effects of statins. Acknowledgement/Funding German Heart Research Foundation

IH, the most common tumor of infancy, has the unique ability to involute spontaneously after proliferation. Unfortunately, a subset rapidly develops complications, resulting in pain, functional impairment, life threatening or permanent disfigurement. A scoring tool (12 Yes/No items) supporting primary clinicians (PCs) to identify patients requiring referral to expert centers, has been developed by IH experts from 8 European countries. The aim of the present study is to validate the IH Referral Score (IHReS). A first board of experts has selected 42 relevant IH photos, corresponding to the most common cases seen by PCs, with a brief clinical description (gender, age, date of apparition of the IH, complications if any). An independent experts board has defined the suitable referral decision (Gold Standard) before having access to the IHReS. The tool has further been used by non-expert PCs (34 at this stage) from 3 countries (Italy, Spain, France) to classify the 42 clinical cases, with a re-test step 7 days later. IHReS enabled cases classification with 88.5% sensibility and 71.9% specificity (optimal cut-off score was determined using ROC curve and the Youden index). Cronbach's alpha correlation between items of 0.61 assessed the internal consistency. Fleiss' kappa, used to assess the inter-rater agreement, was 0.50 (Moderate agreement) and increased to 0.62 (Substantial agreement) in the re-test step for PCs (respectively 0.66 and 0.73 for experts). Kappa of Cohen, used to assess the intra-rater agreement between test and re-test steps, was 0.67 for PCs (0.77 for experts). IHReS has proven to be a simple and validated algorithm, with good intrinsic properties, reliability (inter-rater) and repeatability (intra-rater). Learning curve to use the tool is fast and IHReS can easily be used by primary care physicians to help them to refer, when necessary, the right infantile hemangiomas to expert centers.

To determine the incidence, effect (defined according to treatment rate), and health care costs of infantile hemangiomas (IHs) in Germany from 2007 to 2012 by analyzing patient data of German statutory health insurances.

Les traitements médicaux ont progressivement trouvé leur place dans la prise en charge des hémangiomes et des malformations vasculaires afin, soit d’en accélérer la régression (hémangiome), soit de réduire la fréquence des complications (malformations vasculaires). Les bêta-bloquants ne sont plus discutés dans certaines localisations d’hémangiomes infantiles, mais leur plus large prescription en reste discutée. La cible des antithrombotiques dans les malformations veineuses est dominée par les épisodes thrombotiques. Les anti-XA y ont pris une place importante dans cette indication. La Rapamycine (sirolimus) a été proposée dans le traitement des lésions complexes symptomatiques, lymphatiques et veineuses. La cible pharmacologique de ce produit serait le contrôle de mutation dans les cellules endothéliales. Les expériences cliniques sont limitées, l’intérêt porte surtout sur la douleur, l’impact tissulaire est plus limité. Les bêta-bloquants seraient intéressants sur les malformations artério-veineuses à haut débit. En l’absence de réduction du débit, l’objectif est de réduire la pression dans les ectasies veineuses en aval du nidus. Le but en est ainsi de limiter la souffrance cutanée en regard et les complications hémorragiques. C’est la première proposition thérapeutique avant toute décision d’embolisation.

Journal of the European Academy of Dermatology and VenereologyVolume 30, Issue 7 p. 1209-1211 Letter to the Editor Surgical management of extranasal nasal glioma A.C. Harttrampf, Corresponding Author A.C. Harttrampf Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center, Freiburg, GermanyCorrespondence: A.C. Harttrampf. E-mail: [email protected]Search for more papers by this authorW. Schupp, W. Schupp Department of Oral and Maxillofacial Surgery, University Medical Center, Freiburg, GermanySearch for more papers by this authorS. Timme, S. Timme Department of Pathology, University Medical Center, Freiburg, GermanySearch for more papers by this authorC.M. Niemeyer, C.M. Niemeyer Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center, Freiburg, GermanySearch for more papers by this authorJ.E. Otten, J.E. Otten Department of Oral and Maxillofacial Surgery, University Medical Center, Freiburg, GermanySearch for more papers by this authorJ. Rössler, J. Rössler Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center, Freiburg, GermanySearch for more papers by this author A.C. Harttrampf, Corresponding Author A.C. Harttrampf Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center, Freiburg, GermanyCorrespondence: A.C. Harttrampf. E-mail: [email protected]Search for more papers by this authorW. Schupp, W. Schupp Department of Oral and Maxillofacial Surgery, University Medical Center, Freiburg, GermanySearch for more papers by this authorS. Timme, S. Timme Department of Pathology, University Medical Center, Freiburg, GermanySearch for more papers by this authorC.M. Niemeyer, C.M. Niemeyer Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center, Freiburg, GermanySearch for more papers by this authorJ.E. Otten, J.E. Otten Department of Oral and Maxillofacial Surgery, University Medical Center, Freiburg, GermanySearch for more papers by this authorJ. Rössler, J. Rössler Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center, Freiburg, GermanySearch for more papers by this author First published: 28 March 2015 https://doi.org/10.1111/jdv.13129Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1Valencia MP, Castillo M. Congenital and acquired lesions of the nasal septum: a practical guide for differential diagnosis. Radiographics 2008; 28: 205–224. 2Hedlund G. Congenital frontonasal masses: developmental anatomy, malformations, and MR imaging. Pediatr Radiol 2006; 36: 647–662. 3Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taïeb A. Propranolol for severe hemangiomas of infancy. N Engl J Med 2008; 358: 2649–2651. 4Lamesch P, Froment N, Lamesch AJ. Nasal glioma. Pediatr Surg Int 1988; 3: 176–180. 5Thomson HG, al-Qattan MM, Becker LE. Nasal glioma: is dermis involvement significant? Ann Plast Surg 1995; 34: 168–172. Volume30, Issue7July 2016Pages 1209-1211 ReferencesRelatedInformation

A 15-year-old boy was diagnosed with desmoplastic melanoma of the left thigh (tumor thickness 2.1 mm, Clark level IV). According to European guidelines [1], the patient received resection of the primary tumor with risk adapted safety margins of 2 cm. Sentinel lymph node dissection was performed demonstrating two micrometastatic lymph nodes followed by complete inguinal lymph node dissection (pT3aN2aM0, stage IIIA according to AJCC classification 2009). He further received adjuvant immunotherapy with interferon α-2b (IFN-α) according to the high-dose (Kirkwood) regime for 52 weeks [2]. During high-dose IFN-α therapy our patient developed several side effects (severity evaluated by Common Terminology Criteria for Adverse Events “CTCAE” score v4.0). Suffering from grade 1 hyperuricemia and grade 2 hypertriglyceridemia (Uric acid max. 8.2 mg/dL, triglycerides max. 543 mg/dL) he was treated with allopurinol and gemfibrozil. Levels normalized within 5 months. Moreover, a mild and transient grade 2 hepatotoxicity and grade 2–3 hematotoxicity occurred (min. leukocytes 1.6 G/L, min. platelets 60 G/L) and resolved after end of therapy. Management of toxicities was performed according to Kirkwood et al. [3]. About three months after having started IFN-α therapy, the patient first suffered from fatigue-like symptoms (grade 2 toxicity), but soon showed typical features of a depressive mood disorder (grade 4 toxicity). Six months after the end of IFN-α therapy, he mentioned suicidal thoughts and therefore had to be admitted to pediatric psychiatry inpatient care. After mirtazapin therapy was introduced, he recovered from depression within the next 10 months. Recently, we were able to stop antidepressant medication, but the patient still needs outpatient psychiatric care. Regular follow-up care has been performed by both pediatric oncology and dermatology departments. More than 24 months after the end of IFN-α therapy, the patient still is in full remission.

Radio-iodinated metaiodobenzylguanidine ((123)I-MIBG) is used for the detection and staging of neuroblastoma, pheochromcytoma and other neuroendocrine tumours in diagnostic nuclear medicine. A specific uptake and storage mechanism provides the basis for imaging with (123)I-MIBG. Nevertheless, cases of false-positive (123)I-MIBG scintigraphy with accumulation in non-chromaffin tumours have been described. Here, we present a case of a false-positive (123)I-MIBG scan in a case of a mast-cell infiltrated infantile haemangioma and discuss the possible uptake mechanism.