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BackgroundBronchial artery dilatation (BAD) is associated with haemoptysis in advanced cystic fibrosis (CF) lung disease. Our aim was to evaluate BAD onset and its association with disease severity by magnetic resonance imaging (MRI).Methods188 CF patients (mean±sdage 13.8±10.6 years, range 1.1–55.2 years) underwent annual chest MRI (median three exams, range one to six exams), contributing a total of 485 MRI exams including perfusion MRI. Presence of BAD was evaluated by two radiologists in consensus. Disease severity was assessed using the validated MRI scoring system and spirometry (forced expiratory volume in 1 s (FEV1) % pred).ResultsMRI demonstrated BAD in 71 (37.8%) CF patients consistently from the first available exam and a further 10 (5.3%) patients first developed BAD during surveillance. Mean MRI global score in patients with BAD was 24.5±8.3 compared with 11.8±7.0 in patients without BAD (p<0.001) and FEV1% pred was lower in patients with BAD compared with patients without BAD (60.8%versus82.0%; pPseudomonas aeruginosainfectionversusin patients without infection (63.6%versus28.0%; p<0.05). Youden indices for the presence of BAD were 0.57 for age (cut-off 11.2 years), 0.65 for FEV1% pred (cut-off 74.2%) and 0.62 for MRI global score (cut-off 15.5) (p<0.001).ConclusionsMRI detects BAD in patients with CF without radiation exposure. Onset of BAD is associated with increased MRI scores, worse lung function and chronicP. aeruginosainfection, and may serve as a marker of disease severity.

Society of International Pediatric Oncology - Renal Tumor Study Group (SIOP-RTSG) treatment recommendations for relapsed Wilms tumour (WT) are stratified by the intensity of first-line treatment. To explore the evidence for the treatment of patients relapsing after vincristine and actinomycin-D (VA) treatment for primary WT, we retrospectively evaluated rescue treatment and survival of this patient group. We included 109 patients with relapse after VA therapy (no radiotherapy) for stage I-II primary low- or intermediate-risk WT from the SIOP 93-01 and SIOP 2001 studies. Univariate Cox regression analysis was performed to study the effect of relapse treatment intensity on event-free survival (EFS) and overall survival (OS). Relapse treatment intensity was classified into vincristine, actinomycin-D, and either doxorubicin or epirubicin (VAD), and more intensive therapies (ifosfamide/carboplatin/etoposide [ICE]/≥ 4 drugs/high-dose chemotherapy with haematopoietic stem cell transplantation [HD HSCT]). Relapse treatment regimens included either VAD, or cyclophosphamide/carboplatin/etoposide/doxorubicin (CyCED), or ICE backbones. Radiotherapy was administered in 62 patients and HD HSCT in 15 patients. Overall, 5-year EFS and OS after relapse were 72.3% (95% confidence interval [CI]: 64.0-81.6%) and 79.3% (95% CI: 71.5-88.0%), respectively. Patients treated with VAD did not fare worse when compared with patients treated with more intensive therapies (hazard ratio EFS: 0.611 [95% CI: 0.228-1.638] [p-value = 0.327] and hazard ratio OS: 0.438 [95% CI: 0.126-1.700] [p-value = 0.193]). Patients with relapsed WT after initial VA-only treatment showed no inferior EFS and OS when treated with VAD regimens compared with more intensive rescue regimens. A subset of patients relapsing after VA may benefit from less intensive rescue treatment than ICE/CyCED-based regimens and deserve to be pinpointed by identifying additional (molecular) prognostic factors in future studies.

Chronic rhinosinusitis (CRS) contributes to morbidity in patients with cystic fibrosis (CF). However, longitudinal data on CRS onset and progression is lacking.To longitudinally evaluate CRS in CF from infancy to school age with paranasal sinus magnetic resonance imaging (MRI).64 children with CF (mean age at baseline 1.1±1.6y, range 0-5y) underwent a mean of 5.8±2.2 (range 3-11) subsequent annual MRI examinations. Additional 24 children (9.2±4.4y, range 3-17y) homozygous for the F508del mutation underwent MRI before and at least two months after starting lumacaftor/ivacaftor. MRI was assessed using the previously evaluated CRS-MRI score.In infancy, 65-87% of paranasal sinuses were opacified, and mucosal swelling was the dominant abnormality (58-97%). At preschool age (1-5y), 79-94% of sinuses were opacified (P0.05 vs. infancy), and mucosal swelling was the most dominant abnormality (79-94%, P0.05). At school age (≥6y), almost all sinuses were opacified (71-99%, P0.001-0.357 vs. preschool age), and mucopyoceles were the dominant abnormality in maxillary and frontal sinuses (53-56%, P0.05-0.808). The CRS-MRI sum score increased from 22.4±9.6 in infancy to 34.2±9.6 in preschool age (P0.001) and was 34.0±5.7 in school age (P=0.052). In children under lumacaftor/ivacaftor therapy the CRS-MRI sum score (-0.5±3.3, P0.05) and maxillary sinus subscore (-0.5±1.5, P0.05) improved.Longitudinal paranasal sinus MRI detects an early onset and progression of severity of CRS from infancy to school age, and response to lumacaftor/ivacaftor therapy in children with CF. Our data support its role for comprehensive non-invasive monitoring of CRS in children with CF. Clinical trial registered with ClinicalTrials.gov (NCT02270476).

Malignant renal tumors account for approximately 6% of pediatric malignancies, with Wilms tumor (WT) representing approximately 90% of pediatric renal tumors. This paper provides consensus-based imaging guidelines for the initial evaluation of a child with suspected WT and follow-up during and after therapy co-developed by the Children's Oncology Group (COG) Diagnostic Imaging and Society for Pediatric Radiology (SPR) oncology committees. The guidelines for Wilms Tumor Imaging in the Society of International Pediatric Oncology (SIOP) are briefly discussed to highlight some of the differences in imaging approach.

Malignant renal tumors are rare in children, and Wilms tumors (WTs) are the most common subtype. Imaging plays an essential role in the diagnosis, staging, and follow-up of these patients. Initial workup for staging is mainly performed by cross-sectional imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI). Imaging approach within the two core international groups, the Children's Oncology Group (COG, North America) and the International Society of Pediatric Oncology - Renal Tumor Study Group (SIOP-RTSG, Europe), differs. Whereas abdominal ultrasound (US) is used for the initial diagnosis of a suspected pediatric renal tumor globally, COG protocols support the use of CT or MRI for locoregional staging, contrary to the preference for MRI over CT for abdominopelvic evaluation within the SIOP-RTSG. The purpose of this manuscript is to summarize current imaging approaches, highlighting differences and similarities within these core international groups, while focusing on future innovative efforts and collaboration within the HARMONICA initiative.

This study aims to identify factors associated with the occurrence of local relapse (LR) after treatment for unilateral nephroblastoma.Despite the fact that LR is rare (~5%) its adverse impact on the need for relapse treatment and outcome (40-80% OS) cannot be neglected. Identifying the causative factors may improve initial treatment to achieve better local control.Altogether 2386 patients with unilateral nephroblastoma prospectively enrolled over a period of 32 years (1989 - 2020) by the German Society for Pediatric Oncology and Hematology (SIOP-9/GPOH, SIOP-93-01/GPOH and SIOP-2001/GPOH) were retrospectively analyzed. Hazard ratios (HR) of LR were calculated for sex, age, size, local staging, histology, type of removal, rupture, lymph node removal using univariate and multivariate Cox models.Age48 months, tumor volume500 mL, histology and lymph node (LN) extent of removal were identified as significant risk factors for LR (HR 1.68, P=0.018, CI 1.09 - 2.58; HR 1.84, P=0.015, CI 1.13 - 3.00; HR 3.19, P0.001, CI 2.03 - 5.00; HR 2.26, P=0.002, CI 1.36 - 3.576). LR occur significantly more often in Stage I and II, even if no LN are removed. The risk of metastases is significantly increased after local recurrence (HR 11.5, P0.001, CI 7.11 - 18.60). LR is associated with a subsequent 18.79-fold increased risk of death (HR 18.79, P0.001, CI 2.07 - 5.28).Several factors are responsible for the occurrence of LR. Surgical ones, like LN sampling allow further reduction of LR and consequently a better outcome of patients with unilateral nephroblastoma.

In children, renal cell carcinoma (RCC) is rare. This study is the first report of pediatric patients with RCC registered by the International Society of Pediatric Oncology-Renal Tumor Study Group (SIOP-RTSG). Pediatric patients with histologically confirmed RCC, registered in SIOP 93-01, 2001 and UK-IMPORT databases, were included. Event-free survival (EFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. Between 1993 and 2019, 122 pediatric patients with RCC were registered. Available detailed data (n = 111) revealed 56 localized, 30 regionally advanced, 25 metastatic and no bilateral cases. Histological classification according to World Health Organization 2004, including immunohistochemical and molecular testing for transcription factor E3 (TFE3) and/or EB (TFEB) translocation, was available for 65/122 patients. In this group, the most common histological subtypes were translocation type RCC (MiT-RCC) (36/64, 56.3%), papillary type (19/64, 29.7%) and clear cell type (4/64, 6.3%). One histological subtype was not reported. In the remaining 57 patients, translocation testing could not be performed, or TFE-cytogenetics and/or immunohistochemistry results were missing. In this group, the most common RCC histological subtypes were papillary type (21/47, 44.7%) and clear cell type (11/47, 23.4%). Ten histological subtypes were not reported. Estimated 5-year (5y) EFS and 5y OS of the total group was 70.5% (95% CI = 61.7%-80.6%) and 84.5% (95% CI = 77.5%-92.2%), respectively. Estimated 5y OS for localized, regionally advanced, and metastatic disease was 96.8%, 92.3%, and 45.6%, respectively. In conclusion, the registered pediatric patients with RCC showed a reasonable outcome. Survival was substantially lower for patients with metastatic disease. This descriptive study stresses the importance of full, prospective registration including TFE-testing.

ZusammenfassungDie Langzeit-Sauerstofftherapie hat einen hohen Stellenwert sowohl zur Verminderung der Letalität als auch zur Verbesserung der Leistungsfähigkeit bei Patienten mit chronischen Lungenerkrankungen.Die Grundvoraussetzung für die Langzeit-Sauerstofftherapie ist die adäquate Diagnostik und Indikationsstellung. Sinnvoll ist eine kausale Unterscheidung in eine chronische hypoxämische oder hyperkapnische respiratorische Insuffizienz, aus der sich die Differentialindikation zur nichtinvasiven Beatmung ergibt.Die revidierte Leitlinie behandelt u. a. die Diagnostik und die Indikation bei chronischen Lungen- und Herzerkrankungen sowie den Einsatz in der Palliativmedizin und gibt eine detaillierte Beschreibung der verfügbaren Sauerstoffsysteme. Die Leitlinie soll dazu beitragen, die teilweise bestehende Unter-, Fehl- und Überversorgung zu vermeiden. Zudem wird im Kapitel „Postakute Sauerstofftherapie“ die im Alltag relevante, bisher nicht definierte Vorgehensweise für die Verschreibung einer Sauerstofftherapie am Ende eines stationären Aufenthaltes für den häuslichen Bereich diskutiert. Ein weiterer wichtiger Punkt, die korrekte Verordnung mobiler Sauerstoffsysteme, wird auch in der Leitlinie dargestellt. Die vorliegende aktualisierte Leitlinie zur Langzeit-Sauerstofftherapie löst die alte im Jahr 2008 publizierte Version ab.

Background: Histologically nephroblastomatosis consists of ≥2 microscopic foci of nephrogenic rests. In contrast, clinically apparent nephroblastomatosis consists of single, multiple or diffuse hyperplastic nephrogenic rests (HNR) that can be mistaken for nephroblastoma on imaging. Their treatment and outcome are as variable as published results.Methods: Analysis of 78 patients having clinically apparent uni- or bilateral nephroblastomatosis out of 2347 patients registered for a renal tumor in the consecutive International Society of Pediatric Oncology (SIOP)93-01/GPOH and SIOP2001/GPOH studies between 1993 and 2014. Results: Median age at diagnosis and follow-up was 13 months (0–12.7 years) and 9.2 years, respectively. 59% of patients were female, 57% had bilateral and 53% multifocal or diffuse nephroblastomatosis. Radiologic diagnosis was conclusive in 67% when reviewed centrally versus 30% without review (p=0.015). 27% of patients developed nephroblastoma(s). On histology 45% were high-risk, 30% intermediate-risk and 25% upfront-surgery-blastemal subtype. 5-year-event-free (EFS), nephroblastoma-free-(NFS) and overall-survival (OS) were 60.7%, 79.8% and 95.5%, respectively. Univariate risk factors for EFS/NFS were female gender (p), bilateral (p=0.002/p=0.03) and diffuse HNR at diagnosis (p), and non-complete remission (non-CR) at the end of first-line-treatment (both p). Gender and non-CR remained significant in multivariate COX regression analysis for EFS (p=0.005 and ), non-CR also for NFS (p=0.002). 34 of 74 evaluable patients achieved CR within 12 weeks after diagnosis, 25 of them had no further treatment and were followed, 9 received chemotherapy. Their EFS was 78% and 100%, respectively.Conclusion: Nephroblastomatosis confronts clinicians with a variety of pitfalls, but overall survival is excellent. However, patients need an extended follow-up for more than a decade. In patients who have achieved CR within 12 weeks, a relatively short treatment is sufficient. Contrary, the risk of progression for patients having bilateral and diffuse HNR is significantly increased, despite prolonged treatment. A clear common terminology is needed for future trials to facilitate true comparability of results.

PURPOSE Rhabdoid tumor of the kidney (RTK) is one of the most aggressive childhood renal tumors. Overall survival ranges from 22% to 47%. The indication for radiation therapy (RT) in usually very young patients is an ongoing discussion. Recent protocols recommend RT independent of local stage, the latter being a good discriminator in other childhood kidney tumors. In this study, we analyze the evidence for RT in regard to risk factors, including tumor stage. METHODS AND MATERIALS This study analyzed 58 patients with RTK from Austria, Switzerland, and Germany treated in the framework of 4 consecutive, prospective renal/rhabdoid tumor studies from 1991 to 2014. All treatment protocols included multimodality treatment, including high-intensity chemotherapy, surgery, and RT. RESULTS Local stage distribution was not applicable, I, II, and III in 1, 6, 11, and 40, respectively. Twenty-nine (50%) patients had stage IV disease at diagnosis. Thirty-seven patients (64%) achieved complete remission, and 49% (18/37) relapsed. Thirty-four patients (60%) patients had progressive disease and died, 17 had local disease, 10 had combined disease, and 7 had distant disease; 2 treatment-related deaths were reported (3%). Twenty-one patients received RT during first-line treatment, 18 of them to all involved sites. Eight of the 34 cases of progressive disease occurred in irradiated patients. The local failure rate of treated patients with local stage II or III disease was 29% (6/18) in patients irradiated to all sites compared with 68% (15/22) in nonirradiated patients. One of 6 stage I patients received RT, and 1 patient experienced distant relapse (2-year progression-free and overall survival both 83% ± 15%). Progression-free survival for local stage II and III disease treated with RT, adjusted for early relapse or treatment abandonment, was 67% ± 11%, compared with 15% ± 7% without RT (P < .0001). CONCLUSION The 68% local failure rate in nonirradiated patients underlines the importance of local treatment. Our experience supports the use of RT for local control in higher stage disease. In contrast, no local relapse in 6 local stage I patients, including 5 nonirradiated patients, suggests omission of RT in this favorable subset of usually infant patients with RTK.

BACKGROUND Noninvasive monitoring of early abnormalities and therapeutic intervention in cystic fibrosis (CF) lung disease using MRI is important. Lung T1 mapping has shown potential for local functional imaging without contrast material. Recently, it was discovered that observed lung T1 depends on the measurement echo time (TE). PURPOSE To examine TE-dependence of observed T1 in patients with CF and its correlation with clinical metrics. STUDY TYPE Prospective. POPULATION In all, 75 pediatric patients with CF (8.6 ± 6.1 years, range 0.1-23 years), with 32 reexamined after 1 year. FIELD STRENGTH/SEQUENCE Patients were examined at 1.5T using an established MRI protocol and a multiecho inversion recovery 2D ultrashort echo time (UTE) sequence for T1 (TE) mapping at five TEs including TE1 = 70 μs. ASSESSMENT Morphological and perfusion MRI were assessed by a radiologist (M.W.) with 11 years of experience using an established CF-MRI scoring system. T1 (TE) was quantified automatically. Clinical data including spirometry (FEV1pred%) and lung clearance index (LCI) were collected. STATISTICAL TESTS T1 (TE) was correlated with the CF-MRI score, clinical data, and LCI. RESULTS T1 (TE) showed a different curvature in CF than in healthy adults: T1 at TE1 was shorter in CF (1157 ms ± 73 ms vs. 1047 ms ± 70 ms, P

Wilms tumor; Pediatric; Renal tumor Tumor de Wilms; Pediatría; Tumor renal Tumor de Wilms; Pediatria; Tumor renal Background: The SIOP-Renal Tumor Study Group (RTSG) does not advocate invasive procedures to determine histology before the start of therapy. This may induce misdiagnosis-based treatment initiation, but only for a relatively small percentage of approximately 10% of non-Wilms tumors (non-WTs). MRI could be useful for reducing misdiagnosis, but there is no global consensus on differentiating characteristics. Purpose: To identify MRI characteristics that may be used for discrimination of newly diagnosed pediatric renal tumors. Study type: Consensus process using a Delphi method. Population: Not applicable. Field strength/sequence: Abdominal MRI including T1- and T2-weighted imaging, contrast-enhanced MRI, and diffusion-weighted imaging at 1.5 or 3 T. Assessment: Twenty-three radiologists from the SIOP-RTSG radiology panel with ≥5 years of experience in MRI of pediatric renal tumors and/or who had assessed ≥50 MRI scans of pediatric renal tumors in the past 5 years identified potentially discriminatory characteristics in the first questionnaire. These characteristics were scored in the subsequent second round, consisting of 5-point Likert scales, ranking- and multiple choice questions. Statistical tests: The cut-off value for consensus and agreement among the majority was ≥75% and ≥60%, respectively, with a median of ≥4 on the Likert scale. Results: Consensus on specific characteristics mainly concerned the discrimination between WTs and non-WTs, and WTs and nephrogenic rest(s) (NR)/nephroblastomatosis. The presence of bilateral lesions (75.0%) and NR/nephroblastomatosis (65.0%) were MRI characteristics indicated as specific for the diagnosis of a WT, and 91.3% of the participants agreed that MRI is useful to distinguish NR/nephroblastomatosis from WT. Furthermore, all participants agreed that age influenced their prediction in the discrimination of pediatric renal tumors. Data conclusion: Although the discrimination of pediatric renal tumors based on MRI remains challenging, this study identified some specific characteristics for tumor subtypes, based on the shared opinion of experts. These results may guide future validation studies and innovative efforts. This work was supported by a grant (Grant Number 341) from the Stichting Kinderen Kankervrij (KiKa).

SummaryThe Austrian Society of Pneumology (ASP) launched a first statement on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in May 2020, at a time when in Austria 285 people had died from this disease and vaccinations were not available. Lockdown and social distancing were the only available measures to prevent more infections and the breakdown of the health system. Meanwhile, in Austria over 13,000 patients have died in association with a SARS-CoV‑2 infection and coronavirus disease 2019 (COVID-19) was among the most common causes of death; however, SARS-CoV‑2 has been mutating all the time and currently, most patients have been affected by the delta variant where the vaccination is very effective but the omicron variant is rapidly rising and becoming predominant. Particularly in children and young adults, where the vaccination rate is low, the omicron variant is expected to spread very fast. This poses a particular threat to unvaccinated people who are at elevated risk of severe COVID-19 disease but also to people with an active vaccination. There are few publications that comprehensively addressed the special issues with SARS-CoV‑2 infection in patients with chronic lung diseases. These were the reasons for this updated statement. Pulmonologists care for many patients with an elevated risk of death in case of COVID-19 but also for patients that might be at an elevated risk of vaccination reactions or vaccination failure. In addition, lung function tests, bronchoscopy, respiratory physiotherapy and training therapy may put both patients and health professionals at an increased risk of infection. The working circles of the ASP have provided statements concerning these risks and how to avoid risks for the patients.

(1) Background: Wilms tumor (WT) treated preoperatively is cured in over 90% of cases. However, how long preoperative chemotherapy can be given is unknown. (2) Methods: 2561/3030 patients with WT (age < 18 years) treated between 1989 and 2022 according to SIOP-9/GPOH, SIOP-93-01/GPOH, and SIOP-2001/GPOH are retrospectively analyzed to assess the risk of time to surgery (TTS) for relapse-free survival (RFS) and overall survival (OS). (3) Results: TTS was calculated for all surgeries, with the mean being 39 days (38.5 ± 12.5) for unilateral tumors (UWT) and 70 days (69.9 ± 32.7) for bilateral disease (BWT). Relapse occurred in 347 patients, of which 63 (2.5%) were local, 199 (7.8%) were metastatic, and 85 (3.3%) were combined. Moreover, 184 patients (7.2%) died, 152 (5.9%) due to tumor progression. In UWT, recurrences and mortality are independent of TTS. For BWT without metastases at diagnosis, the incidence of recurrence is less than 18% up to 120 days and increases to 29% after 120 days, and to 60% after 150 days. The risk of relapse (Hazard Ratio) adjusted for age, local stage, and histological risk group increases to 2.87 after 120 days (CI 1.19–7.95, p = 0.022) and to 4.62 after 150 days (CI 1.17–18.26, p = 0.029). In metastatic BWT, no influence of TTS is detected. (4) Conclusions: The length of preoperative chemotherapy has no negative impact on RFS or OS in UWT. In BWT without metastatic disease, surgery should be performed before day 120, as the risk of recurrence increases significantly thereafter.

(1) Background: about 10% of Wilms Tumor (WT) patients have a malformation or cancer predisposition syndrome (CPS) with causative germline genetic or epigenetic variants. Knowledge on CPS is essential for genetic counselling. (2) Methods: this retrospective analysis focused on 2927 consecutive patients with WTs registered between 1989 and 2017 in the SIOP/GPOH studies. (3) Results: Genitourinary malformations (GU, N = 66, 2.3%), Beckwith-Wiedemann spectrum (BWS, N = 32, 1.1%), isolated hemihypertrophy (IHH, N = 29, 1.0%), Denys-Drash syndrome (DDS, N = 24, 0.8%) and WAGR syndrome (N = 20, 0.7%) were reported most frequently. Compared to others, these patients were younger at WT diagnosis (median age 24.5 months vs. 39.0 months), had smaller tumors (349.4 mL vs. 487.5 mL), less often metastasis (8.2% vs. 18%), but more often nephroblastomatosis (12.9% vs. 1.9%). WT with IHH was associated with blastemal WT and DDS with stromal subtype. Bilateral WTs were common in WAGR (30%), DDS (29%) and BWS (31%). Chemotherapy induced reduction in tumor volume was poor in DDS (0.4% increase) and favorable in BWS (86.9% reduction). The event-free survival (EFS) of patients with BWS was significantly (p = 0.002) worse than in others. (4) Conclusions: CPS should be considered in WTs with specific clinical features resulting in referral to a geneticist. Their outcome was not always favorable.

Nierentumoren im Kindesalter werden nach Vorgaben der Renal Tumor Study Group der Internationalen Gesellschaft fur padiatrische Onkologie (RTSG-SIOP) behandelt. Der haufigste renale Tumor im Kindesalter ist das Nephroblastom. Die Magnetresonanztomographie (MRT) ist nach der Sonographie die bevorzugte bildgebende Methode. Die Aufgabe der Bildgebung umfasst die Differenzialdiagnose renaler Tumoren im Kindesalter anhand epidemiologischer und morphologischer Kriterien. Neu ist die Einfuhrung der Thorax-Computertomographie (CT) in der initialen Diagnostik. Neue Studien zu Nephroblastomsubtypen mit Diffusionsbildgebung (DWI) zeigen, dass durch Auswertungen des ADC(„apparent diffusion coefficient“)-Histogramms blastemreiche und anaplastische High-risk-Tumoren zu differenzieren sind. Bildgebende Kriterien zur nierenerhaltenden chirurgischen Therapie sind aktuell festgelegt und erlauben eine individuelle Therapie bei unilateralen, aber insbesondere bei bilateralen Tumoren. Differenzialdiagnosen sind neben dem kongenitalen mesoblastischen Nephrom, der Rhabdoidtumor, das Klarzellsarkom und das Nierenzellkarzinom. Herausfordernd ist die Diagnose nephrogener Reste und der Nephroblastomatose. Durch standardisierte Bildgebung verbessert sich Diagnostik und Therapie renaler Tumoren im Kindesalter, und neue prognostische Marker konnen zukunftig in der Bildgebung etabliert werden.

Objectives To validate adult height predictions (BX) using automated and Greulich–Pyle bone age determinations in children with chronic endocrine diseases. Methods Heights and near-adult heights were measured in 82 patients (48 females) with chronic endocrinopathies at the age of 10.45 ± 2.12 y and at time of transition to adult care (17.98 ± 3.02 y). Further, bone age (BA) was assessed using the conventional Greulich–Pyle (GP) method by three experts, and by BoneXpert™. PAH were calculated using conventional BP tables and BoneXpert™. Results The conventional and the automated BA determinations revealed a mean difference of 0.25 ± 0.72 y (p = 0.0027). The automated PAH by BoneXpert™ were 156.26 ± 0.86 cm (SDS − 2.01 ± 1.07) in females and 171.75 ± 1.6 cm (SDS − 1.29 ± 1.06) in males, compared to 153.95 ± 1.12 cm (SDS − 2.56 ± 1.5) in females and 169.31 ± 1.6 cm (SDS − 1.66 ± 1.56) in males by conventional BP, respectively and in comparison to near-adult heights 156.38 ± 5.84 cm (SDS − 1.91 ± 1.15) in females and 168.94 ± 8.18 cm (SDS − 1.72 ± 1.22) in males, respectively. Conclusion BA ratings and adult height predictions by BoneXpert™ in children with chronic endocrinopathies abolish rater-dependent variability and enhance reproducibility of estimates thereby refining care in growth disorders. Conventional methods may outperform automated analyses in specific cases.

Introduction Seizures count to critical situations emergency medical systems (EMS) are confronted with. Objectives Evaluation of a modified treatment algorithm (MTAS-EMS) using diazepam and midazolam due to a supply bottleneck of iv lorazepam in 2012. Methods Retrospective study where data from patients treated for seizures by the EMS of the city of Zurich were analyzed. Effectiveness of the MTAS-EMS and i.v. diazepam in children and adults was compared with respect of cessation of seizure without recurrence over the period until arrival at the hospital. The chi-square and Fisher's exact test were used to compare categorical data. The Student’s t-test and Mann Whitney test were used to compare numerical data. p-values Results Of 584 documented missions, 165 treated patients (126 adults and 39 children) were included. 115 patients (80 adults and 35 children) were treated according the MTAS-EMS. Cessation of seizure was achieved in 85% of the adults and in 97% of the children, if all options of the MTAS-EMS were used. The first dose of nasal midazolam was more successful in children compared to adults (p = 0.012). In adults, the single dose of i.v. diazepam terminated the seizure in 98% (p = 0.001) compared to 57% for the single dose of iv and 64% for nasal midazolam. Conclusions The treatment success of the MTAS-EMS is high. However, in adults the single dose of i.v. diazepam is as successful as the completely used MTAS-EMS and seems to be superior to the single dose iv and nasal midazolam.

While Wilms tumors (WT) typically present solely with an abdominally palpable mass, rare cases exhibiting vascular tumor growth can also present with circulatory problems. Here, we report the case of a 2.5-year-old girl presenting with upper venous congestion and arterial hypertension as the primary symptoms of intraventricular tumor growth exhibiting remarkable tubular and perfused morphology. Clinical situation stabilized after initiation of neoadjuvant chemotherapy (NAC) with actinomycin D and vincristine, followed by surgical resection via laparotomy and sternotomy supported by cardiopulmonary bypass and deep hypothermia. Our results highlight the previously reported feasibility of this approach, even in primarily unstable patients.

Highlights • Wilkie’s syndrome (WS) is a rare but impairing condition. • WS is defined by an aorto-mesenteric artery angle, Introduction Wilkie’s syndrome (WS), also known as superior mesenteric artery syndrome, is a rare clinical entity caused by compression of the horizontal (third) part of the duodenum between the superior mesenteric artery and the abdominal aorta leading to duodenal obstruction. Presentation of case We report a case of a 16 years girl with long-term history of spontaneous vomiting and self-induced vomiting, also suffering from recurrent retrosternal pain, weight loss and thus reduced quality of life. Contrast intestinal series showed a large axial hernia which was laparoscopically reduced and treated by hiatoplasty and anterior hemifundoplication. After initial relief, recurrent postprandial nausea and vomiting reoccurred 4 weeks postoperatively. Abdominal MRI study revealed findings compatible with WS. After endoscopic exclusion of an anatomical duodenal lumen stenosis, she was successfully treated by duodeno-jejunostomy with a favorable outcome. Discussion WS might be hidden behind presumably more evident diagnoses such as bulimia, significant axial hernia and gastro-esophageal reflux disease in patients with recurred vomiting, abdominal pain and weight loss. Conclusion The rare clinical entity of a WS necessitates a targeted diagnostic evaluation and therapy. Clinical details, diagnostic studies and treatment are discussed here.

(1) Background: Vena cava thrombus (VCT) is rare in Wilms tumor (WT) (4–10%). The aim of this study is to identify factors for an outcome to improve treatment for better survival. (2) Methods: 148/3015 patients with WT (aged < 18 years) and VCT, prospectively enrolled over a period of 32 years (1989–2020) by the German Society for Pediatric Oncology and Hematology (SIOP-9/GPOH, SIOP-93-01/GPOH and SIOP-2001/GPOH), are retrospectively analyzed to describe clinical features, response to preoperative chemotherapy (PC) (142 patients) and surgical interventions and to evaluate risk factors for overall survival (OS). (3) Results: 14 VCT regressed completely with PC and another 12 in parts. The thrombus was completely removed in 111 (85.4%), incompletely in 16 (12.3%), and not removed in 3 (2.3%). The type of removal is unknown in four patients. Patients without VCT have a significantly (p < 0.001) better OS (97.8%) than those with VCT (90.1%). OS after complete resection is (89.9%), after incomplete (93.8%) and with no resection (100%). Patients with anaplasia or stage IV without complete remission (CR) after PC had a significantly worse OS compared to the remaining patients with VCT (77.1% vs. 94.4%; p = 0.002). (4) Conclusions: As a result of our study, two risk factors for poor outcomes in WT patients with VCT emerge: diffuse anaplasia and metastatic disease, especially those with non-CR after PC.

In children, renal cell carcinoma (RCC) is rare. This study is the first report of pediatric patients with RCC registered by the International Society of Pediatric Oncology‐Renal Tumor Study Group (SIOP‐RTSG). Pediatric patients with histologically confirmed RCC, registered in SIOP 93‐01, 2001 and UK‐IMPORT databases, were included. Event‐free survival (EFS) and overall survival (OS) were analyzed using the Kaplan‐Meier method. Between 1993 and 2019, 122 pediatric patients with RCC were registered. Available detailed data (n = 111) revealed 56 localized, 30 regionally advanced, 25 metastatic and no bilateral cases. Histological classification according to World Health Organization 2004, including immunohistochemical and molecular testing for transcription factor E3 (TFE3) and/or EB (TFEB) translocation, was available for 65/122 patients. In this group, the most common histological subtypes were translocation type RCC (MiT‐RCC) (36/64, 56.3%), papillary type (19/64, 29.7%) and clear cell type (4/64, 6.3%). One histological subtype was not reported. In the remaining 57 patients, translocation testing could not be performed, or TFE‐cytogenetics and/or immunohistochemistry results were missing. In this group, the most common RCC histological subtypes were papillary type (21/47, 44.7%) and clear cell type (11/47, 23.4%). Ten histological subtypes were not reported. Estimated 5‐year (5y) EFS and 5y OS of the total group was 70.5% (95% CI = 61.7%‐80.6%) and 84.5% (95% CI = 77.5%‐92.2%), respectively. Estimated 5y OS for localized, regionally advanced, and metastatic disease was 96.8%, 92.3%, and 45.6%, respectively. In conclusion, the registered pediatric patients with RCC showed a reasonable outcome. Survival was substantially lower for patients with metastatic disease. This descriptive study stresses the importance of full, prospective registration including TFE‐testing., What's new? Pediatric renal cell carcinoma (RCC) is a rare malignancy, knowledge of which is based largely on adult RCC. Here, pediatric RCC was retrospectively studied using data from the International Society of Pediatric Oncology – Renal Tumor Study Group (SIOP‐RTSG). Pediatric RCC patients had a 5‐year overall survival rate of 84.5 percent, with notably lower survival for patients with metastatic disease. In pediatric RCC patients tested for transcription factor E3 and EB, 56.3 percent presented with translocation type. The findings highlight the importance of full registration of pediatric RCCs, with information on germline genetics and transcription factor testing.

Purpose To assess the value of diffusion-weighted MRI (DW-MRI) in the non-invasive prediction of blastemal remnant after neoadjuvant chemotherapy in nephroblastoma. Methods This IRB-approved study included 32 pediatric patients with 35 tumors who underwent DW-MRI prior and after completion of neoadjuvant chemotherapy and subsequent surgical resection. Two blinded radiologists volumetrically assessed each tumor on pre- and post-neoadjuvant images and the parameters mean ADC, median ADC, 12.5th/25th/75th ADC percentile, skewness, and kurtosis were calculated. Blastemal remnant was determined per the pathology report. Associations between imaging features and blastemal remnant quartiles were examined using the Kruskal–Wallis test and adjusted for false discovery rate. Results Inter-reader agreement was high for mean ADC, skewness, kurtosis, and volume (ICC: 0.76–0.998). Pre-therapeutic histogram parameters skewness and kurtosis were found to be higher in patients with a higher amount of blastemal remnant for reader 1 (overall p = 0.035) and for kurtosis in reader 2 (overall p = 0.032) with skewness not reaching the level of statistical significance (overall p = 0.055). Higher tumor volume on pre-treatment imaging was associated with a higher amount of blastemal remnant after therapy (overall p = 0.032 for both readers). Conclusions Pre-treatment skewness and kurtosis of ADC histogram analysis were significantly associated with a larger fraction of a blastemal remnant after neoadjuvant chemotherapy. These findings could be incorporated into a more personalized chemotherapeutic regime in these patients and offer prognostic information at the time of initial diagnosis.

PURPOSE: To assess the value of diffusion-weighted MRI in the pre-therapeutic evaluation of pediatric renal cortical tumors. METHODS: This IRB-approved, retrospective multi-center study included 122 pediatric patients with 130 renal tumors, who underwent MRI including DWI before neoadjuvant chemotherapy and nephrectomy. Two radiologists independently assessed each tumor volumetrically, and apparent diffusion coefficient (ADC) values were calculated on a voxel-wise basis, including parameters derived from histogram and texture analysis. RESULTS: Inter-reader agreement was excellent (ICC: 0.717–0.975). For both readers, patients with locally aggressive tumor growth (SIOP 3 stage) or with metastases (M1) had significantly lower 12.5(th)-percentile ADC values (p≤0.028) compared to those with lower-stage tumors, and the parameter Energy differed significantly between patients with M1 and those with M0 status (p≤0.028). Contrast and Homogeneity differed significantly between benign nephroblastomatosis and malignant nephroblastoma (p≤0.045, both readers). As compared to all other subtypes, the blastemal subtype demonstrated significantly higher Skewness (p≤0.022, both readers) and the diffuse anaplastic subtype demonstrated significantly higher 75(th)-percentile ADC values (p≤0.042, both readers). CONCLUSIONS: Diffusion-weighted MRI may be of value in identifying benign nephroblastomatosis and assessing nephroblastoma subtypes. Therefore, further research is warranted to assess its value in risk stratification for pediatric patients with renal tumors in the future.

Currently, liver histology is the gold standard for the detection of liver fibrosis. In recent years, new methods such as transient elastography (TE) have been introduced into clinical practice, which allow a non-invasive assessment of liver fibrosis. The aim of the present study was to investigate the predictive value of TE for higher grade fibrosis and whether there is any relevance which histologic score is used for matching. For this purpose, we compared TE with 4 different histologic scores in pediatric patients with hepatopathies. Furthermore, we also determined the aspartate aminotransferase-to-platelet ratio (APRI) score, another non-invasive method, to investigate whether it is equally informative. Therefore, liver fibrosis in 75 children was evaluated by liver biopsy, TE and laboratory values. Liver biopsies were evaluated using four common histological scoring systems (Desmet, Metavir, Ishak and Chevalier’s semi-quantitative scoring system). The median age of the patients was 12.3 years. TE showed a good correlation to the degree of fibrosis severity independent of the histological scoring system used. The accuracy of the TE to distinguish between no/minimal fibrosis and severe fibrosis/cirrhosis was good (p = 0.001, AUC-ROCs > 0.81). The optimal cut-off value for the prediction of severe fibrosis was 10.6 kPa. In contrast, the APRI score in our collective showed no correlation to fibrosis.Conclusion: TE shows a good correlation to the histological findings in children with hepatopathy, independent of the used histological scoring system. What is Known:• The current gold standard for detecting liver fibrosis is liver biopsy. Novel non-invasive ultrasound-based methods are introduced to clinical diagnostics.• Most histological scores have been developed and evaluated in adult populations and for only one specific liver disease.What is New:• Transient elastography (TE) in children showed a good correlation to fibrosis severity irrespective of the utilized histological scoring system.• The aspartate aminotransferase-to-platelet ratio (APRI) showed no correlation with different stages of liver fibrosis in children.

Cystic fibrosis (CF) is the most common fatal autosomal recessive disease in the Caucasian population. A mutation in the cystic fibrosis transmembrane regulator protein (CFTR) gene leads to the production of abnormally viscous mucus and secretions in the lungs of these patients. A similar pathology also occurs in other organs. In the abdomen, among others the gastrointestinal tract, the pancreas, and the hepatobiliary system are affected. The involvement of the pancreas leads to its exocrine and endocrine insufficiency. Hepatic manifestations include hepatic steatosis, focal biliary and multilobular cirrhosis, and portal hypertension. Biliary complications include cholelithiasis, microgallbladder, and sclerosing cholangitis. In the gastrointestinal tract, complications such as the distal intestinal obstruction syndrome, invaginations, chronic constipation, wall thickening, and fibrosis in the colon may occur. An important renal manifestation is nephrolithiasis. With currently rapidly increasing life expectancy of patients with cystic fibrosis, complications of extrapulmonary cystic fibrosis manifestations including hepatic and gastrointestinal malignancy could be an increasing cause of morbidity and mortality of these patients. It is therefore important for radiologists to know and recognize these clinical patterns and to monitor these manifestations in follow-up exams. Previous therapy of extrapulmonary manifestations has been largely symptomatic. Fortunately, the new CFTR modulators seem to represent an effective causal therapeutic approach here.

Noninvasive monitoring of early abnormalities and therapeutic intervention in cystic fibrosis (CF) lung disease using MRI is important. Lung TTo examine TE-dependence of observed TProspective.In all, 75 pediatric patients with CF (8.6 ± 6.1 years, range 0.1-23 years), with 32 reexamined after 1 year.Patients were examined at 1.5T using an established MRI protocol and a multiecho inversion recovery 2D ultrashort echo time (UTE) sequence for TMorphological and perfusion MRI were assessed by a radiologist (M.W.) with 11 years of experience using an established CF-MRI scoring system. TTTTE should be considered when measuring lung T2 TECHNICAL EFFICACY STAGE: 1 J. MAGN. RESON. IMAGING 2020;52:1645-1654.

Introduction In children with pneumonia, chest x-ray (CXR) is typically the first imaging modality used for diagnostic work-up. Repeated CXR or computed tomography (CT) are often necessary if complications such as abscesses or empyema arise, thus increasing radiation exposure. The aim of this retrospective study was to evaluate the potential of radiation-free chest magnetic resonance imaging (MRI) to detect complications at baseline and follow-up, compared to CXR with and without additional lung ultrasound (LUS). Methods Paired MRI and CXR scans were retrospectively reviewed by two blinded readers for presence and severity of pulmonary abscess, consolidation, bronchial wall thickening, mucus plugging and pleural effusion/empyema using a chest MRI scoring system. The scores for MRI and CXR were compared at baseline and follow-up. Furthermore, the MRI scores at baseline with and without contrast media were evaluated. Results 33 pediatric patients (6.3±4.6 years), who had 33 paired MRI and CXR scans at baseline and 12 at follow-up were included. MRI detected significantly more lung abscess formations with a prevalence of 72.7% compared to 27.3% by CXR at baseline (p = 0.001), whereas CXR+LUS was nearly as good as MRI. MRI also showed a higher sensitivity in detecting empyema (p = 0.003). At follow-up, MRI also showed a slightly better sensitivity regarding residual abscesses. The overall severity of disease was rated higher on MRI. Contrast material did not improve detection of abscesses or empyema by MRI. Conclusion CXR and LUS seem to be sufficient in most cases. In cases where LUS cannot be realized or the combination of CXR+LUS might be not sufficient, MRI, as a radiation free modality, should be preferred to CT. Furthermore, the admission of contrast media is not mandatory in this context.

Background: Congenital cardiovascular malformations (CCVM) may cause infrequently airway pathologies (AP) in children and are of prognostic and therapeutic relevance. While computed tomography (CT) is considered first-line imaging modality in many centres, we started using magnetic resonance imaging (MRI) more and more in the last years to detect CCVM and AP to avoid radiation in this patient group. Objective: The aim of this retrospective study was to determine and to compare the diagnostic accuracy of CT and MRI when used to detect CCVM and/or AP. Methods: All patients suspected to have CCVM and/or AP and examined either by CT or MRI between 2000 and 2013 in our hospital were included. Extension and type of CCVM, as well as their relationship to esophagus, trachea or bronchi were assessed and related to findings of tracheobronchoscopy, cardiac catheterization or surgery if available. Results: One hundred six patients (median [range] 4 years [2 days to 66 years]) were examined by CT (n = 27) or MRI (n = 79). In 78 patients (74%), CCVM and/or AP were found with either of the imaging methods. CCVM were found in 63 subjects. Forty-six of 63 subjects had both, CCVM and AP. The presence of CCVM was always detected correctly by CT or MRI, although both techniques had a weakness detecting atretic segments directly. AP (n = 61) were correctly diagnosed in all patients not intubated for artificial ventilation by CT (n = 17) and in all but 2 patients by MRI (39 out of 41). Conclusions: MRI is sensitive to detect CCVM associated with AP equally to CT without any radiation exposure.

Introduction Osimertinib is standard treatment for patients with advanced EGFR T790M-mutated non–small-cell lung cancer who have been pre-treated with EGFR–tyrosine kinase inhibitors (TKIs). We studied whether cell-free plasma DNA for T790M detection can be used to select patients for osimertinib treatment in the clinical routine. Methods From April 2015 to November 2016, we included 119 patients with advanced EGFR -mutated non–small-cell lung cancer who had progressed under treatment with an EGFR-TKI. The T790M mutation status was assessed in cell-free plasma DNA by droplet digital polymerase chain reaction in all patients and by tissue analyses in selected patients. Results T790M mutations were detected in 85 (93%) patients by analyses of cell-free plasma DNA and in 6 (7%) plasma-negative patients by tumor re-biopsy. Eighty-nine of 91 T790M-positive patients received osimertinib. Median progression-free survival (PFS) was 10.1 months (95% confidence interval [CI]: 8.1–12.1). Median survival was not reached and the 1-year survival was 64%. The response rate was 70% in T790M-positive patients (n = 91) in the intention-to-treat population. PFS trended to be shorter in patients with high T790M copy number (≥10 copies/mL) compared to those with low T790M copy number ( p = 0.09). A comparable trend was observed for overall survival (hazard ratio for overall survival = 2.16, 95% CI: 0.89–5.25, p = 0.09). No difference in response rate was observed based on T790M copy numbers. Conclusion Plasma genotyping using digital polymerase chain reaction is clinically useful for the selection of patients who had progressed during first-line EGFR-TKI therapy for treatment with osimertinib.

// Matthias Felix Haefner 1, 2, * , Frederik Lars Giesel 3, * , Matthias Mattke 1, 2 , Daniel Rath 3 , Moritz Wade 3, 4 , Jacob Kuypers 3, 4 , Alan Preuss 3, 4 , Hans-Ulrich Kauczor 5 , Jens-Peter Schenk 5 , Juergen Debus 1, 2 , Florian Sterzing 2, 6 and Roland Unterhinninghofen 4, 7 1 Department of Radiation Oncology, Heidelberg University Hospital, 69120 Heidelberg, Germany 2 National Center for Radiation Research in Oncology (NCRO), Heidelberg Institute for Radiation Oncology (HIRO), 69120 Heidelberg, Germany 3 Department of Nuclear Medicine, Heidelberg University Hospital, 69120 Heidelberg, Germany 4 Institute of Antropomatics and Robotics, Karlsruhe Institute of Technology (KIT), 76131 Karlsruhe, Germany 5 Department of Diagnostic and Interventional Radiology, Heidelberg University Hospital, 69120 Heidelberg, Germany 6 Department of Radiation Oncology Kempten, 87439 Kempten, Germany 7 Institute of Robotics and Mechatronics, German Aerospace Center, 82234 Oberpfaffenhofen-Wesling, Germany * These authors contributed equally to the manuscript and share the first authorship Correspondence to: Matthias Felix Haefner, email: matthias.haefner@med.uni-heidelberg.de Keywords: immobilization; radiotherapy; 3D-printing; setup accuracy; head mask Received: October 07, 2017 Accepted: January 02, 2018 Published: January 08, 2018 ABSTRACT We developed a new approach to produce individual immobilization devices for the head based on MRI data and 3D printing technologies. The purpose of this study was to determine positioning accuracy with healthy volunteers. 3D MRI data of the head were acquired for 8 volunteers. In-house developed software processed the image data to generate a surface mesh model of the immobilization mask. After adding an interface for the couch, the fixation setup was materialized using a 3D printer with acrylonitrile butadiene styrene (ABS). Repeated MRI datasets (n=10) were acquired for all volunteers wearing their masks thus simulating a setup for multiple fractions. Using automatic image-to-image registration, displacements of the head were calculated relative to the first dataset (6 degrees of freedom). The production process has been described in detail. The absolute lateral (x), vertical (y) and longitudinal (z) translations ranged between −0.7 and 0.5 mm, −1.8 and 1.4 mm, and −1.6 and 2.4 mm, respectively. The absolute rotations for pitch (x), yaw (y) and roll (z) ranged between −0.9 and 0.8°, −0.5 and 1.1°, and −0.6 and 0.8°, respectively. The mean 3D displacement was 0.9 mm with a standard deviation (SD) of the systematic and random error of 0.2 mm and 0.5 mm, respectively. In conclusion, an almost entirely automated production process of 3D printed immobilization masks for the head derived from MRI data was established. A high level of setup accuracy was demonstrated in a volunteer cohort. Future research will have to focus on workflow optimization and clinical evaluation.

In the original article [1] there was a mistake in Table 2 as published. Table 2 contains wrong percentages in lines Bilateral disease and Patients with CPS or GU. For this reason the table should be replaced with the correct one as shown below.

Urea cycle disorders (UCDs) still have a poor prognosis despite several therapeutic advancements. As liver transplantation can provide a cure, liver cell therapy (LCT) might be a new therapeutic option in these patients. Twelve patients with severe UCDs were included in this prospective clinical trial. Patients received up to six infusions of cryopreserved human heterologous liver cells via a surgically placed catheter in the portal vein. Portal vein pressure, portal vein flow, and vital signs were monitored continuously. Calcineurin inhibitors and steroids were used for immunosuppression. In four patients, ureagenesis was determined with stable isotopes. Number and severity of hyperammonemic events and side effects of immunosuppression were analyzed during an observation period of up to 2 years. No study-related mortality was observed. The application catheter dislocated in two children. No significant side effects of catheter application or cell infusion were noted in the other ten patients. The overall incidence of infections did not differ significantly from a historical control group, and no specific side effects of immunosuppression were found. Seven patients were treated per protocol and could be analyzed for efficacy. Severe metabolic crises could be prevented in all of these patients, moderate crises in four of seven. Ureagenesis increased after cell infusion in all patients investigated. We found a favorable safety profile with respect to catheter placement, intraportal liver cell infusion, and immunosuppression. More than half of the children treated per protocol experienced metabolic stabilization and could be safely bridged to liver transplantation.

Fragestellung Das hepatopulmonale Syndrom (HPS) ist eine Storung der arteriellen Oxygenierung, welche bei bis zu 30 % der Patienten mit Leberzirrhose auftritt und mit deutlich erhohter Sterblichkeit einhergeht. Ikterus und cholestatische Dysfunktion sind von zentraler pathogenetischer Rolle in akuter als auch chronischer Lebererkrankung. Ziel Deshalb war es Ziel dieser Studie den Stellenwert der Serum-Gallensauren bei Patienten mit HPS zu untersuchen. Methodik 74 Patienten mit Leberzirrhose wurden in diese Studie eingeschlossen. Cholestasemarker, Gesamt- als auch individuelle Gallensauren wurden bestimmt und alle Patienten auf das Vorhandensein von HPS gescreent. 26 Patienten (35 %) erfullten die Kriterien fur HPS. Ergebnisse Serum-Gallensauren waren signifikant hoher bei Patienten mit HPS im Vergleich zu denen ohne (mediane Gesamt-Gallensauren 83,5 μmol/l, IQR 43,1 – 148,9 vs. 26,9 μmol/l, 11 – 75,6; p Schlussfolgerung Serum-Gallensauren sind mit dem Vorhandensein von HPS assoziiert und korrelieren mit dem Schweregrad der Butgasaustauschstorung. Zukunftige Studien sollten den Stellenwert der Gallensauren bei HPS sowie den Einfluss einer direkten Regulation des Gallensaure-Metabolismus untersuchen. Background Hepatopulmonary syndrome (HPS) occurs in 20 – 30 % of patients with cirrhosis and is associated with increased mortality. Cholestasis and accumulation of bile acids (BAs) play a major role in chronic liver disease. Aim We aimed to evaluate the clinical role of serum BAs in patients with HPS. Methods Seventy-four patients with cirrhosis were included in this prospective study. Marker for cholestasis as total and individual serum BAs, bilirubin, alkaline phosphatase (AP), and gamma-glutamyl transpeptidase (GGT) were analyzed in patients screened for HPS. Criteria of HPS were fulfilled in 26 patients (35 %). Results In contrast to AP and GGT, bilirubin and serum BAs were significantly elevated in patients with HPS (median total BAs in HPS 83.5 μmol/L, IQR 43.1 – 148.9 vs. no HPS 26.9 μmol/L, 11 – 75.6; p Conclusion BA retention is associated with HPS and gas exchange abnormalities. Future studies should assess whether modulation of BAs signaling may impact the course of HPS.

Additional file 1: Figure S1. a Linear correlation Cmax (ng/mL) – Dose (mg/m2/d). b Concentration of vorinostat in plasma according to dose level.

Background Until today, adult and pediatric clinical trials investigating single-agent or combinatorial HDAC inhibitors including vorinostat in solid tumors have largely failed to demonstrate efficacy. These results may in part be explained by data from preclinical models showing significant activity only at higher concentrations compared to those achieved with current dosing regimens. In the current pediatric trial, we applied an intra-patient dose escalation design. The purpose of this trial was to determine a safe dose recommendation (SDR) of single-agent vorinostat for intra-patient dose escalation, pharmacokinetic analyses (PK), and activity evaluation in children (3–18 years) with relapsed or therapy-refractory malignancies. Results A phase I intra-patient dose (de)escalation was performed until individual maximum tolerated dose (MTD). The starting dose was 180 mg/m2/day with weekly dose escalations of 50 mg/m2 until DLT/maximum dose. After MTD determination, patients seamlessly continued in phase II with disease assessments every 3 months. PK and plasma cytokine profiles were determined. Fifty of 52 patients received treatment. n = 27/50 (54%) completed the intra-patient (de)escalation and entered phase II. An SDR of 130 mg/m2/day was determined (maximum, 580 mg/m2/day). n = 46/50 (92%) patients experienced treatment-related AEs which were mostly reversible and included thrombocytopenia, fatigue, nausea, diarrhea, anemia, and vomiting. n = 6/50 (12%) had treatment-related SAEs. No treatment-related deaths occurred. Higher dose levels resulted in higher Cmax. Five patients achieved prolonged disease control (> 12 months) and showed a higher Cmax (> 270 ng/mL) and MTDs. Best overall response (combining PR and SD, no CR observed) rate in phase II was 6/27 (22%) with a median PFS and OS of 5.3 and 22.4 months. Low levels of baseline cytokine expression were significantly correlated with favorable outcome. Conclusion An SDR of 130 mg/m2/day for individual dose escalation was determined. Higher drug exposure was associated with responses and long-term disease stabilization with manageable toxicity. Patients with low expression of plasma cytokine levels at baseline were able to tolerate higher doses of vorinostat and benefited from treatment. Baseline cytokine profile is a promising potential predictive biomarker. Trial registration ClinicalTrials.gov, NCT01422499. Registered 24 August 2011

BackgroundSeveral studies have shown that statins have beneficial effects in COPD regarding lung function decline, rates and severity of exacerbation, hospitalisation and need for mechanical ventilation.MethodsWe performed a randomised double-blind placebo-controlled single-centre trial of simvastatin at a daily dose of 40 mg versus placebo in patients with Global Initiative for Chronic Obstructive Lung Disease criteria grades 2–4 at a tertiary care pulmonology department in Austria. Scheduled treatment duration was 12 months and the main outcome parameter was time to first exacerbation.ResultsOverall, 209 patients were enrolled. In the 105 patients taking simvastatin, time to first exacerbation was significantly longer compared to the 104 patients taking placebo: median 341 versus 140 days (log-rank test pversus 147 (59%) (p=0.003). The annualised exacerbation rate was 1.45 events per patient-year in the simvastatin group and 1.9 events per patient-year in the placebo group (incidence rate ratio 0.77, 95% CI 0.60–0.99). We found no effect on quality of life, lung function, 6-min walk test and high-sensitivity C-reactive protein. More patients dropped out in the simvastatin group compared to the placebo group (39 versus 29).ConclusionIn our single-centre RCT, simvastatin at a dose of 40 mg daily significantly prolonged time to first COPD exacerbation and reduced exacerbation rate.