Infliximab (IFX) is administered intravenously using weight-based dosing (5 mg/kg) in inflammatory bowel disease (IBD) patients. Our hypothesis is that especially young children need a more intensive treatment regimen than the current weight-based dose administration. We aimed to assess IFX pharmacokinetics (PK), based on existing therapeutic drug monitoring (TDM) data in IBD patients < 10 years. TDM data were collected retrospectively in 14 centres. Children treated with IFX were included if IFX was started as IBD treatment at age < 10 years (young patients, YP) and PK data were available. Older IBD patients aged 10-18 years were used as controls (older patients, OP). Two hundred and fifteen paediatric inflammatory bowel disease (PIBD) patients were eligible for the study (110 < 10 year; 105 ≥ 10 years). Median age was 8.3 years (IQR 6.9-8.9) in YP compared with 14.3 years (IQR 12.8-15.6) in OP at the start of IFX. At the start of maintenance treatment, 72% of YP had trough levels below therapeutic range (< 5.4 μg/mL). After 1 year of scheduled IFX maintenance treatment, YP required a significantly higher dose per 8 weeks compared with OP (YP; 9.0 mg/kg (IQR 5.0-12.9) vs. OP; 5.5 mg/kg (IQR 5.0-9.3); p < 0.001). The chance to develop antibodies to infliximab was relatively lower in OP than YP (0.329 (95% CI - 1.2 to - 1.01); p < 0.001), while the overall duration of response to IFX was not significantly different (after 2 years 53% (n = 29) in YP vs. 58% (n = 45) in OP; p = 0.56).Conclusion: Intensification of the induction scheme is suggested for PIBD patients aged < 10 years. What is Known? •Infliximab trough levels of paediatric IBD patients are influenced by several factors as dosing scheme, antibodies and inflammatory markers. •In 4.5-30% of the paediatric IBD patients, infliximab treatment was stopped within the first year. What is New? •The majority of young PIBD (< 10 years) have inadequate IFX trough levels at the start of maintenance treatment. •Young PIBD patients (< 10 years) were in need of a more intensive treatment regimen compared with older paediatric patients during 1 year of IFX treatment. •The chance to develop antibodies to infliximab was relatively higher in young PIBD patients (< 10 years).

• Klíčová slova
• Anti-TNF, Biologics, Clinical pharmacology, Crohn’s disease, Gastroenterology, Paediatric, Ulcerative colitis,
• MeSH
• dítě MeSH
• gastrointestinální látky * terapeutické užití   MeSH
• idiopatické střevní záněty * farmakoterapie   MeSH
• infliximab * terapeutické užití   MeSH
• lidé MeSH
• předškolní dítě MeSH
• retrospektivní studie MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• gastrointestinální látky * MeSH
• infliximab * MeSH

The presence of TEL/AML1 fusion gene in childhood acute lymphoblastic leukaemia (ALL) defines a subgroup of patients with better than average outcome. However, the prognostic significance of this aberration has recently been disputed by the Berlin-Frankfurt-Münster (BFM) study group due to its relatively high incidence found in relapsed patients (19.6% and 21.9%, in two cohorts). In contrast, only four out of 45 (8.9%) unselected relapsed patients (all of whom had been treated according to BFM protocols) in the Czech Republic carry this fusion. From March 1995 to June 1998, 41 out of 190 (21.6%) newly diagnosed children with ALL were TEL/AML1-positive. There is a statistically significant difference between the incidence of TEL/AML1 fusion at diagnosis and at relapse within our group (P = 0.035). Interim analysis of the minimal residual disease (MRD) detection shows heterogeneity within the group of newly diagnosed TEL/AML1-positive leukaemias--10 out of 24 patients tested at the end of induction therapy had detectable levels of MRD. However, only one of these patients reached relapse-predictive level (10(-3)) of MRD. In conclusion, we corroborate low frequency of TEL/AML1 positivity among relapsed patients with ALL among Czech children who are treated by the BFM protocols. Moreover, we demonstrate different patterns of bone marrow clean-up in TEL/AML1-positive patients.

• MeSH
• akutní lymfatická leukemie krev   diagnóza   genetika   patologie   MeSH
• dítě MeSH
• exony MeSH
• fúzní onkogenní proteiny * MeSH
• genová přestavba MeSH
• kostní dřeň patologie   MeSH
• lidé MeSH
• mladiství MeSH
• nádorové proteiny analýza   genetika   MeSH
• počet leukocytů MeSH
• prognóza MeSH
• protein PEBP2A2 MeSH
• recidiva MeSH
• translokace genetická MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• fúzní onkogenní proteiny * MeSH
• nádorové proteiny MeSH
• protein PEBP2A2 MeSH
• TEL-AML1 fusion protein MeSH Prohlížeč

Cornelia de Lange syndrome (CdLS) is a rare autosomal-dominant genetic disorder characterised by prenatal and postnatal growth and mental retardation, facial dysmorphism and upper limb abnormalities. Germline mutations of cohesin complex genes SMC1A, SMC3, RAD21 or their regulators NIPBL and HDAC8 have been identified in CdLS as well as somatic mutations in myeloid disorders. We describe the first case of a paediatric patient with CdLS with B-cell precursor Acute Lymphoblastic Leukaemia (ALL). The patient did not show any unusual cytogenetic abnormality, and he was enrolled into the high risk arm of AIEOP-BFM ALL2009 protocol because of slow early response, but 3 years after discontinuation, he experienced an ALL relapse. We identified a heterozygous mutation in exon 46 of NIPBL, causing frameshift and a premature stop codon (RNA-Targeted Next generation Sequencing Analysis). The analysis of the family indicated a de novo origin of this previously not reported deleterious variant. As for somatic cohesin mutations in acute myeloid leukaemia, also this ALL case was not affected by aneuploidy, thus suggesting a major impact of the non-canonical role of NIPBL in gene regulation. A potential biological role of NIPBL in leukaemia has still to be dissected.

• Klíčová slova
• haemato-oncology, molecular genetics, molecular oncology, paediatric haematology, paediatric pathology,
• MeSH
• de Langeové syndrom diagnóza   genetika   MeSH
• dědičnost MeSH
• fenotyp MeSH
• genetická predispozice k nemoci MeSH
• lidé MeSH
• mutace * MeSH
• mutační analýza DNA MeSH
• pre-B-buněčná leukemie diagnóza   genetika   terapie   MeSH
• předškolní dítě MeSH
• proteiny buněčného cyklu MeSH
• proteiny genetika   MeSH
• recidiva MeSH
• rodokmen MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• NIPBL protein, human MeSH Prohlížeč
• proteiny buněčného cyklu MeSH
• proteiny MeSH

BACKGROUND: Vedolizumab, an anti-integrin antibody, has proven to be effective in adults with inflammatory bowel disease [IBD], but the data in paediatrics are limited. We describe the short-term effectiveness and safety of vedolizumab in a European multi-centre paediatric IBD cohort. METHOD: Retrospective review of children [aged 2-18 years] treated with vedolizumab from 19 centres affiliated with the Paediatric IBD Porto group of ESPGHAN. Primary outcome was Week 14 corticosteroid-free remission [CFR]. RESULTS: In all, 64 children were included (32 [50%] male, mean age 14.5 ± 2.8 years, with a median follow-up 24 weeks [interquartile range 14-38; range 6-116]); 41 [64%] cases of ulcerative colitis/inflammatory bowel disease unclassified [UC/IBD-U] and 23 [36%] Crohn's disease [CD]. All were previously treated with anti-tumour necrosis factor [TNF] [28% primary failure, 53% secondary failure]. Week 14 CFR was 37% in UC, and 14% in CD [P = 0.06]. CFR by last follow-up was 39% in UC and 24% in CD [p = 0.24]. Ten [17%] children required surgery, six of whom had colectomy for UC. Concomitant immunomodulatory drugs did not affect remission rate [42% vs 35%; p = 0.35 at Week 22]. There were three minor drug-related adverse events. Only 3 of 16 children who underwent endoscopic evaluation had mucosal healing after treatment (19%). CONCLUSIONS: Vedolizumab was safe and effective in this cohort of paediatric refractory IBD. These data support previous findings of slow induction rate of vedolizumab in CD and a trend to be less effective compared with patients with UC.

• Klíčová slova
• Vedolizumab, inflammatory bowel disease, paediatric,
• MeSH
• Crohnova nemoc farmakoterapie   MeSH
• dítě MeSH
• humanizované monoklonální protilátky škodlivé účinky   terapeutické užití   MeSH
• idiopatické střevní záněty farmakoterapie   MeSH
• lidé MeSH
• mladiství MeSH
• předškolní dítě MeSH
• retrospektivní studie MeSH
• ulcerózní kolitida farmakoterapie   MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Názvy látek
• humanizované monoklonální protilátky MeSH
• vedolizumab MeSH Prohlížeč

Because the patents for biopharmaceutical monoclonal antibodies have or soon will expire, biosimilars are coming to the market. This will most likely lead to decreased drug costs and so easier access to these expensive agents. Extrapolation, however, of the limited available clinical data from adults with rheumatologic diseases to children with inflammatory bowel disease (IBD) should be done with caution and needs some considerations.Postmarketing surveillance programs for efficacy, safety, and immunogenicity should become mandatory in children with IBD using biosimilars, as for all biological drugs.

• MeSH
• antiflogistika nesteroidní škodlivé účinky   terapeutické užití   MeSH
• biomedicínský výzkum MeSH
• biosimilární léčivé přípravky škodlivé účinky   terapeutické užití   MeSH
• dítě MeSH
• gastrointestinální látky škodlivé účinky   terapeutické užití   MeSH
• idiopatické střevní záněty farmakoterapie   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• mladiství MeSH
• monoklonální protilátky škodlivé účinky   terapeutické užití   MeSH
• odhad potřeb MeSH
• pediatrie metody   MeSH
• postmarketingový dozor MeSH
• předškolní dítě MeSH
• společnosti lékařské MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• směrnice pro lékařskou praxi MeSH
• Geografické názvy
• Evropa MeSH
• Názvy látek
• antiflogistika nesteroidní MeSH
• biosimilární léčivé přípravky MeSH
• gastrointestinální látky MeSH
• monoklonální protilátky MeSH

The surgical treatment of paediatric thalamic gliomas has been burdened with high morbidity, and these lesions were often considered inoperable. With new approaches and intraoperative technologies, we can remove tumours once deemed inoperable. In our single centre, we have operated on 11 paediatric patients over the course of 8 years. We have performed eight GTR resections and three intended subtotal resections. The postoperative neurological deficit ranged from mild to very severe for motor weakness and none to severe for aphasia after surgery, with all of the patients improving at 3-month follow-up. Radicality in the surgical approach to thalamic gliomas in children has shown significant benefits when compared to more conservative approaches. For children with LGGs, extensive surgical resection is associated with improved prognosis and longer progression-free survival. However, it does not yield the same proportional benefit for HGGs due to its aggressive nature and worse outlook.

• Klíčová slova
• bithalamic gliomas, paediatric thalamic gliomas, radical surgery of gliomas in children,
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Risk benefit strategies in managing inflammatory bowel diseases (IBD) are dependent upon understanding the risks of uncontrolled inflammation vs those of treatments. Malignancy and mortality in IBD have been associated with disease-related inflammation and immune suppression, but data are limited due to their rare occurrence. AIM: To identify and describe the most common causes of mortality, types of cancer and previous or current therapy among children and young adults with paediatric-onset IBD. METHODS: Information on paediatric-onset IBD patients diagnosed with malignancy or mortality was prospectively collected via a survey in 25 countries over a 42-month period. Patients were included if death or malignancy occurred after IBD diagnosis but before the age of 26 years. RESULTS: In total, 60 patients were identified including 43 malignancies and 26 fatal cases (9 due to cancer). Main causes of fatality were malignancies (n = 9), IBD or IBD-therapy related nonmalignant causes (n = 10; including 5 infections), and suicides (n = 3). Three cases, all fatal, of hepatosplenic T-cell lymphoma were identified, all were biologic-naïve but thiopurine-exposed. No other haematological malignancies were fatal. The 6 other fatal cancer cases included 3 colorectal adenocarcinomas and 3 cholangiocarcinomas (CCAs). Primary sclerosing cholangitis (PSC) was present in 5 (56%) fatal cancers (1 colorectal carcinoma, 3 CCAs and 1 hepatosplenic T-cell lymphoma). CONCLUSIONS: We report the largest number of paediatric-onset IBD patients with cancer and/or fatal outcomes to date. Malignancies followed by infections were the major causes of mortality. We identified PSC as a significant risk factor for cancer-associated mortality. Disease-related adenocarcinomas were a commoner cause of death than lymphomas.

• MeSH
• dítě MeSH
• dospělí MeSH
• hodnocení rizik MeSH
• idiopatické střevní záněty komplikace   epidemiologie   mortalita   MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádory komplikace   epidemiologie   mortalita   MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• prospektivní studie MeSH
• rizikové faktory MeSH
• věk při počátku nemoci MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa epidemiologie   MeSH

Non-Hodgkin lymphoma (NHL) is the third most common malignancy diagnosed in children. The vast majority of paediatric NHL are either Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), anaplastic large cell lymphoma (ALCL), or lymphoblastic lymphoma (LL). Multi-agent chemotherapy is used to treat all of these types of NHL, and survival is over 90% but the chemotherapy regimens are intensive, and outcomes are generally poor if relapse occurs. Therefore, targeted therapies are of interest as potential solutions to these problems. However, the major problem with all targeted agents is the development of resistance. Mechanisms of resistance are not well understood, but increased knowledge will facilitate optimal management strategies through improving our understanding of when to select each targeted agent, and when a combinatorial approach may be helpful. This review summarises currently available knowledge regarding resistance to targeted therapies used in paediatric anaplastic lymphoma kinase (ALK)-positive ALCL. Specifically, we outline where gaps in knowledge exist, and further investigation is required in order to find a solution to the clinical problem of drug resistance in ALCL.

• Klíčová slova
• anaplastic large cell lymphoma, chemotherapy, nucleophosmin1-anaplastic lymphoma kinase, paediatric cancer, resistance,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

AIMS: We aimed to evaluate long-term utilization and results of paediatric radiofrequency catheter ablation (RFCA) in a population-based study. METHODS AND RESULTS: Data from all three centres performing paediatric RFCA for the whole population of the Czech Republic between 1993 and 2010 were retrospectively reviewed. A total of 708 ablation procedures in 633 consecutive patients <18 years for 716 different substrates were tracked, with accessory pathways = 439 (61.3%) and atrioventricular nodal reentry tachycardia (AVNRT) = 205 (28.6%) being most frequent. Incidence of RFCA reached 0.049 per 1000 children <18 years of age in the recent era (2006-10). Indications included patient preference (68.0%), drug refractoriness (15.5%), asymptomatic Wolff-Parkinson-White pre-excitation (8.4%), and malignant arrhythmia (6.1%). Median follow-up was 13.7 (interquartile range 5.7-21.5) months. Overall acute/long-term success of the primary procedure was 89.1/77.2% (accessory pathways 87.2/77.7%, AVNRT 98.5/84.4%). Re-ablation was performed in 73 of 163 substrates after a primary unsuccessful ablation resulting in a long-term cumulative efficacy of 96.3%. Between 1993-2005 and 2006-10, procedure/fluoroscopy time decreased from median 154/24 to 105/14 min. (P < 0.001 for both). Serious complications occurred in nine patients (1.4%). CONCLUSION: This population-based study could replicate data from previous single- or multi-centre reports confirming RFCA as a safe method of arrhythmia treatment in children with long-term cumulative efficacy exceeding 90% and significant decrease in the procedure and fluoroscopy time during the study period. The need for RFCA can be estimated at ∼0.05/1000 children <18 years using current indication criteria.

• Klíčová slova
• Children, Congenital heart disease, Paediatric, Radiofrequency ablation, Tachycardia,
• MeSH
• dítě MeSH
• katetrizační ablace statistika a číselné údaje   MeSH
• kojenec MeSH
• lidé MeSH
• longitudinální studie MeSH
• mladiství MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• prevalence MeSH
• přídatný svazek epidemiologie   chirurgie   MeSH
• recidiva MeSH
• retrospektivní studie MeSH
• rizikové faktory MeSH
• srdeční arytmie epidemiologie   chirurgie   MeSH
• vrozené srdeční vady epidemiologie   chirurgie   MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH

BACKGROUND: ABL-class fusion genes other than BCR-ABL1 have been identified in approximately 3% of children with newly diagnosed acute lymphocytic leukaemia, and studies suggest that leukaemic cells carrying ABL-class fusions can be targeted successfully by tyrosine-kinase inhibitors. We aimed to establish the baseline characteristics and outcomes of paediatric patients with ABL-class fusion B-cell acute lymphocytic leukaemia in the pre-tyrosine-kinase inhibitor era. METHODS: This multicentre, retrospective, cohort study included paediatric patients (aged 1-18 years) with newly diagnosed ABL-class fusion (ABL1 fusion-positive, ABL2 fusion-positive, CSF1R fusion-positive, and PDGFRB fusion-positive) B-cell acute lymphocytic leukaemia enrolled in clinical trials of multidrug chemotherapy done between Oct 3, 2000, and Aug 28, 2018, in which tyrosine-kinase inhibitors had not been given as a first-line treatment. Patients from 14 European, North American, and Asia-Pacific study groups of the Ponte di Legno group were included. No patients were excluded, and patients were followed up by individual study groups. Through the Ponte di Legno group, we collected data on the baseline characteristics of patients, including IKZF1, PAX5, and CDKN2A/B deletion status, and whether haematopoietic stem cell transplantation (HSCT) had been done, as well as treatment outcomes, including complete remission, no response, relapse, early death, and treatment-related mortality, response to prednisone, and minimal residual disease (MRD) at end of induction therapy. 5-year event-free survival and 5-year overall survival were estimated by use of Kaplan-Meier methods, and the 5-year cumulative incidence of relapse was calculated by use of a competing risk model. FINDINGS: We identified 122 paediatric patients with newly diagnosed ABL-class fusion B-cell acute lymphocytic leukaemia (77 from European study groups, 25 from North American study groups, and 20 from Asia-Pacific study groups). 64 (52%) of 122 patients were PDGFRB fusion-positive, 40 (33%) were ABL1 fusion-positive, ten (8%) were CSF1R fusion-positive, and eight (7%) were ABL2 fusion-positive. In all 122 patients, 5-year event-free survival was 59·1% (95% CI 50·5-69·1), 5-year overall survival was 76·1% (68·6-84·5), and the 5-year cumulative incidence of relapse was 31·0% (95% CI 22·4-40·1). MRD at the end of induction therapy was high (≥10-2 cells) in 61 (66%) of 93 patients, and most prevalent in patients with ABL2 fusions (six [86%] of 7 patients) and PDGFRB fusion-positive B-cell acute lymphocytic leukaemia (43 [88%] of 49 patients). MRD at the end of induction therapy of 10-2 cells or more was predictive of an unfavourable outcome (hazard ratio of event-free survival in patients with a MRD of ≥10-2vs those with a MRD of <10-2 3·33 [95% CI 1·46-7·56], p=0·0039). Of the 36 (30%) of 119 patients who relapsed, 25 (69%) relapsed within 3 years of diagnosis. The 5-year cumulative incidence of relapse in 41 patients who underwent HSCT (17·8% [95% CI 7·7-31·3]) was lower than in the 43 patients who did not undergo HSCT (45·1% [28·4-60·5], p=0·013), but event-free survival and overall survival did not differ between these two groups. INTERPRETATION: Children with ABL-class fusion B-cell acute lymphocytic leukaemia have poor outcomes when treated with regimens that do not contain a tyrosine-kinase inhibitor, despite the use of high-risk chemotherapy regimens and frequent HSCT upon first remission. Our findings provide a reference for evaluating the potential benefit of first-line tyrosine-kinase inhibitor treatment in patients with ABL-class fusion B-cell acute lymphocytic leukaemia. FUNDING: The Oncode Institute, Pediatric Cancer Foundation Rotterdam, Dutch Cancer Society, Kika Foundation, Deutsche Krebshilfe, Blood Cancer UK, Associazione Italiana per la Ricerca sul Cancro, Cancer Australia, National Cancer Institute, National Institute of Health, and St Baldrick's Foundation.

• MeSH
• alografty MeSH
• dítě MeSH
• doba přežití bez progrese choroby MeSH
• fúzní onkogenní proteiny genetika   MeSH
• inhibitory proteinkinas MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• následné studie MeSH
• pre-B-buněčná leukemie * genetika   mortalita   terapie   MeSH
• předškolní dítě MeSH
• přežití po terapii bez příznaků nemoci MeSH
• protoonkogenní proteiny c-abl genetika   MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• tyrosinkinasy genetika   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• multicentrická studie MeSH
• Názvy látek
• ABL1 protein, human MeSH Prohlížeč
• ARG tyrosine kinase MeSH Prohlížeč
• fúzní onkogenní proteiny MeSH
• inhibitory proteinkinas MeSH
• protoonkogenní proteiny c-abl MeSH
• tyrosinkinasy MeSH