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1.	Wright, NJ, et al. (author) Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study 2021 In: Lancet (London, England). - 1474-547X. ; 398:10297, s. 325-339 Journal article (peer-reviewed)
2.	Juul-Dam, K. L., et al. (author) Measurable residual disease assessment by qPCR in peripheral blood is an informative tool for disease surveillance in childhood acute myeloid leukaemia 2020 In: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 190:2, s. 198-208 Journal article (peer-reviewed)abstract Serial assessments of measurable (or minimal) residual disease (MRD) by qPCR may identify nascent relapse in children with acute myeloid leukaemia (AML) and enable pre-emptive therapy. We investigated the kinetics and prognostic impact of recurrent fusion transcripts (RUNX1-RUNX1T1, CBFB-MYH11, KMT2A-MLLT3 or KMT2A-ELL) in 774 post-induction samples from bone marrow (BM, 347) and peripheral blood (PB, 427) from 75 children with AML. BM MRD persistence during consolidation did not increase the risk of relapse, and MRD at therapy completion did not correlate to outcome (HR=0·64/MRD log reduction (CI: 0·32–1·26), P=0·19). In contrast, 8/8 patients with detectable MRD in PB after first consolidation relapsed. Persistence (n=4) and shifting from negative to positive (n=10) in PB during follow-up predicted relapse in 14/14 patients. All 253PB samples collected during follow-up from 36 patients in continuous complete remission were MRD negative. In core-binding factor AML, persistent low-level MRD positivity in BM during follow-up was frequent but an increment to above 5×10−4 heralded subsequent haematological relapse in 12/12 patients. We demonstrate that MRD monitoring in PB after induction therapy is highly informative and propose an MRD increment above 5×10−4 in PB and BM as a definition of molecular relapse since it always leads to haematological relapse. © 2020 British Society for Haematology and John Wiley & Sons Ltd
3.	Karlsson, Lene, et al. (author) Characteristics and outcome of primary resistant disease in paediatric acute myeloid leukaemia 2023 In: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 201:4, s. 757-765 Journal article (peer-reviewed)abstract A significant proportion of events in paediatric acute myeloid leukaemia (AML) are caused by resistant disease (RD). We investigated clinical and biological characteristics in 66 patients with RD from 1013 children with AML registered and treated according to the NOPHO-AML 93, NOPHO-AML 2004, DB AML-01 and NOPHO-DBH AML 2012 protocols. Risk factors for RD were age10 years or older and a white-blood-cell count (WBC) of 100 x 10(9)/L or more at diagnosis. The five-year overall survival (OS) was 38% (95% confidence interval [CI]: 28%-52%). Of the 63 children that received salvage therapy with chemotherapy, 59% (N = 37) achieved complete remission (CR) with OS 57% (95% CI: 42%-75%) compared to 12% (95% CI: 4%-35%) for children that did not achieve CR. Giving more than two salvage chemotherapy courses did not increase CR rates. OS for all 43 patients receiving allogeneic haematopoietic stem cell transplantation (HSCT) was 49% (95% CI: 36%-66%). Those achieving CR and proceeding to HSCT had an OS of 56% (95% CI: 41%-77%, N = 30). This study showed that almost 40% of children with primary resistant AML can be cured with salvage therapy followed by HSCT. Children that did not achieve CR after two salvage courses with chemotherapy did not benefit from additional chemotherapy.
4.	Benavent, N., et al. (author) Substantial contribution of iodine to Arctic ozone destruction 2022 In: Nature Geoscience. - : Springer Science and Business Media LLC. - 1752-0894 .- 1752-0908. ; 15, s. 770-773 Journal article (peer-reviewed)abstract Unlike bromine, the effect of iodine chemistry on the Arctic surface ozone budget is poorly constrained. We present ship-based measurements of halogen oxides in the high Arctic boundary layer from the sunlit period of March to October 2020 and show that iodine enhances springtime tropospheric ozone depletion. We find that chemical reactions between iodine and ozone are the second highest contributor to ozone loss over the study period, after ozone photolysis-initiated loss and ahead of bromine.
5.	Dellenmark-Blom, Michaela, 1983, et al. (author) Establishment of a condition-specific quality-of-life questionnaire for children born with esophageal atresia aged 2-7 across 14 countries 2023 In: Frontiers in Pediatrics. - 2296-2360. ; 11 Journal article (peer-reviewed)abstract BackgroundEsophageal atresia (EA) is a rare congenital anomaly characterized by a discontinuity of the esophagus. Following surgical repair, survival rates have improved dramatically the past decenniums and today exceed 90%, but the children commonly present with esophageal and respiratory morbidity. In 2018, a condition-specific quality-of-life questionnaire for children with esophageal atresia (EA) aged 2-7 in Sweden-Germany was finalized (The EA-QOL questionnaire). The study aim was to describe the evaluation of the new translations across 12 new countries in Europe, Asia, Africa, Central-and North America.MethodsFollowing forward-backward translation into the new languages, the 17-item EA-QOL questionnaire was tested in cognitive debriefing interviews with parents of children with EA aged 2-7. Parents rated if each item was easy to understand (clarity) and sensitive to answer (interference with personal integrity). They could skip responding to a non-applicable/problematic item and give open comments. Predefined psychometric criteria were used; item clarity >= 80%/item sensitive to answer <= 20%/item feasibility <= 5% missing item responses. The decision to modify the translation was based on native expert, patient stakeholder, and instrument developer review, and the need for harmonization between translations.ResultsSimilar to findings in the Swedish-German cognitive debriefing, the cross-cultural analysis of input from 116 parents from 12 new countries (4-14 parents, median 9 parents/country) showed that all items in the EA-QOL questionnaire fulfilled the criteria for item clarity >= 80% and sensitive to answer (ranging from 1%-4.5%), although results varied between countries. Four items had missing responses between 5.2% and 13.4%, three within the same domain and were in line with parents' explanations. Poor translations and feasibility were improved.ConclusionsBased on parent input, the collaboration between native experts, patient stakeholders, and instrument developers, a linguistic version of the EA-QOL questionnaire for children aged 2-7 for use in and across 14 countries has been established. These efforts have set the conditions for a cross-cultural field test of the EA-QOL questionnaire and will open the doors for a new chapter in outcome research, registries, and clinical practice concerning children with EA. In the long-term, this will help increase knowledge of the disease's burden, promote patient-centeredness, exchange of information between nations, and strengthen evidence-based treatments for children born with EA.
6.	Krali, Olga, et al. (author) Dna methylation signatures predict cytogenetic subtype and outcome in pediatric acute myeloid leukemia (Aml) 2021 In: Genes. - : MDPI AG. - 2073-4425. ; 12:6 Journal article (peer-reviewed)abstract Pediatric acute myeloid leukemia (AML) is a heterogeneous disease composed of clinically relevant subtypes defined by recurrent cytogenetic aberrations. The majority of the aberrations used in risk grouping for treatment decisions are extensively studied, but still a large proportion of pediatric AML patients remain cytogenetically undefined and would therefore benefit from additional molecular investigation. As aberrant epigenetic regulation has been widely observed during leukemogenesis, we hypothesized that DNA methylation signatures could be used to predict molecular subtypes and identify signatures with prognostic impact in AML. To study genome-wide DNA methylation, we analyzed 123 diagnostic and 19 relapse AML samples on Illumina 450k DNA methylation arrays. We designed and validated DNA methylation-based classifiers for AML cytogenetic subtype, resulting in an overall test accuracy of 91%. Furthermore, we identified methylation signatures associated with outcome in t(8;21)/RUNX1-RUNX1T1, normal karyotype, and MLL/KMT2A-rearranged subgroups (p < 0.01). Overall, these results further underscore the clinical value of DNA methylation analysis in AML. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
7.	Ringlander, Johan, et al. (author) Enrichment Reveals Extensive Integration of Hepatitis B Virus DNA in Hepatitis Delta Virus-Infected Patients 2024 In: JOURNAL OF INFECTIOUS DISEASES. - 0022-1899 .- 1537-6613. Journal article (peer-reviewed)abstract Background. Hepatitis B virus (HBV) DNA may become integrated into the human genome of infected human hepatocytes. Expression of integrations can produce the surface antigen (HBsAg) that is required for synthesis of hepatitis D virus (HDV) particles and the abundant subviral particles in the blood of HBV- and HDV-infected subjects. Knowledge about the extent and variation of HBV integrations and impact on chronic HDV is still limited. Methods. We investigated 50 pieces of liver explant tissue from 5 patients with hepatitis D-induced cirrhosis, using a deep-sequencing strategy targeting HBV RNA. Results. We found that integrations were abundant and highly expressed, with large variation in the number of integration-derived (HBV/human chimeric) reads, both between and within patients. The median number of unique integrations for each patient correlated with serum levels of HBsAg. However, most of the HBV reads represented a few predominant integrations. Conclusions. The results suggest that HBV DNA integrates in a large proportion of hepatocytes, and that the HBsAg output from these integrations vary >100-fold depending on clone size and expression rate. A small proportion of the integrations seems to determine the serum levels of HBsAg and HDV RNA in HBV/HDV coinfected patients with liver cirrhosis.
8.	Tulstrup, M., et al. (author) Effects of germ line DHFR and FPGS variants on methotrexate metabolism and relapse of leukemia 2020 In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 136:10, s. 1161-1168 Journal article (peer-reviewed)abstract Methotrexate (MTX) during maintenance therapy is essential for curing acute lymphoblastic leukemia (ALL), but dosing strategies aiming at adequate treatment intensity are challenged by interindividual differences in drug disposition. To evaluate genetic factors associated with MTX metabolism, we performed a genome-wide association study in 447 ALL cases from the Nordic Society for Pediatric Haematology and Oncology ALL2008 study, validating results in an independent set of 196 patients. The intergenic single-nucleotide polymorphism rs1382539, located in a regulatory element of DHFR, was associated with increased levels of short-chain MTX polyglutamates (P = 1.1 x 10(-8)) related to suppression of enhancer activity, whereas rs35789560 in FPGS (p.R466C, P = 5.6 x 10(-9)) was associated with decreased levels of long-chain MTX polyglutamates through reduced catalytic activity. Furthermore, the FPGS variant was linked with increased relapse risk (P = .044). These findings show a genetic basis for interpatient variability in MTX response and could be used to improve future dosing algorithms.
9.	White, T., et al. (author) Clinical outcomes of second relapsed and refractory first relapsed paediatric AML: A retrospective study within the NOPHO-DB SHIP consortium 2022 In: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 197:6, s. 755-765 Journal article (peer-reviewed)abstract As treatments for second relapsed and refractory first relapsed paediatric AML transition from purely palliative to more commonly curative in nature, comparative data is necessary for evaluating the effectiveness of emerging treatment options. Furthermore, little is known about predictors of prognosis following third-line therapy. From 2004 until 2019, 277 of the 869 patients enrolled in NOPHO-DB SHIP consortium trials experienced a first relapse and, of these patients, 98 experienced refractory first relapse and 59 a second relapse. Data on patient and disease characteristics within this cohort of 157 patients was analysed to determine probability of overall survival (pOS) and to identify factors influencing survival. Data on early treatment response and complete remission were not available. One and 5-year pOS were 22±3% and 14±3%, respectively. There was no statistically significant difference in survival between refractory first relapsed and second relapsed AML. Factors influencing prognosis included: late relapse, type of third-line treatment, FLT3 mutational status, and original treatment protocol. These data provide a baseline for evaluating the effectiveness of emerging therapies for the treatment of children with refractory first relapsed and second relapsed paediatric AML and evidence that select patients receiving third-line therapy can be cured. © 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.
10.	Abrahamsson, B., et al. (author) Six years of progress in the oral biopharmaceutics area - A summary from the IMI OrBiTo project 2020 In: European journal of pharmaceutics and biopharmaceutics. - : ELSEVIER. - 0939-6411 .- 1873-3441. ; 152, s. 236-247 Journal article (peer-reviewed)abstract OrBiTo was a precompetitive collaboration focused on the development of the next generation of Oral Biopharmaceutics Tools. The consortium included world leading scientists from nine universities, one regulatory agency, one non-profit research organisation, three small/medium sized specialist technology companies together with thirteen pharmaceutical companies. The goal of the OrBiTo project was to deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This goal was achieved through novel prospective investigations to define new methodologies or refinement of existing tools. Extensive validation has been performed of novel and existing biopharmaceutics tools using historical datasets supplied by industry partners as well as laboratory ring studies. A combination of high quality in vitro and in vivo characterizations of active drugs and formulations have been integrated into physiologically based in silico biopharmaceutics models capturing the full complexity of gastrointestinal drug absorption and some of the best practices has been highlighted. This approach has given an unparalleled opportunity to deliver transformational change in European industrial research and development towards model based pharmaceutical product development in accordance with the vision of model-informed drug development.
11.	Ahmad, Amais, et al. (author) IMI – Oral biopharmaceutics tools project – Evaluation of bottom-up PBPK prediction success part 4 : Prediction accuracy and software comparisons with improved data and modelling strategies 2020 In: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 156, s. 50-63 Journal article (peer-reviewed)abstract Oral drug absorption is a complex process depending on many factors, including the physicochemical properties of the drug, formulation characteristics and their interplay with gastrointestinal physiology and biology. Physiological-based pharmacokinetic (PBPK) models integrate all available information on gastro-intestinal system with drug and formulation data to predict oral drug absorption. The latter together with in vitro-in vivo extrapolation and other preclinical data on drug disposition can be used to predict plasma concentration-time profiles in silico. Despite recent successes of PBPK in many areas of drug development, an improvement in their utility for evaluating oral absorption is much needed. Current status of predictive performance, within the confinement of commonly available in vitro data on drugs and formulations alongside systems information, were tested using 3 PBPK software packages (GI-Sim (ver.4.1), Simcyp® Simulator (ver.15.0.86.0), and GastroPlusTM (ver.9.0.00xx)). This was part of the Innovative Medicines Initiative (IMI) Oral Biopharmaceutics Tools (OrBiTo) project.Fifty eight active pharmaceutical ingredients (APIs) were qualified from the OrBiTo database to be part of the investigation based on a priori set criteria on availability of minimum necessary information to allow modelling exercise. The set entailed over 200 human clinical studies with over 700 study arms. These were simulated using input parameters which had been harmonised by a panel of experts across different software packages prior to conduct of any simulation. Overall prediction performance and software packages comparison were evaluated based on performance indicators (Fold error (FE), Average fold error (AFE) and absolute average fold error (AAFE)) of pharmacokinetic (PK) parameters.On average, PK parameters (Area Under the Concentration-time curve (AUC0-tlast), Maximal concentration (Cmax), half-life (t1/2)) were predicted with AFE values between 1.11 and 1.97. Variability in FEs of these PK parameters was relatively high with AAFE values ranging from 2.08 to 2.74. Around half of the simulations were within the 2-fold error for AUC0-tlast and around 90% of the simulations were within 10-fold error for AUC0-tlast. Oral bioavailability (Foral) predictions, which were limited to 19 APIs having intravenous (i.v.) human data, showed AFE and AAFE of values 1.37 and 1.75 respectively. Across different APIs, AFE of AUC0-tlast predictions were between 0.22 and 22.76 with 70% of the APIs showing an AFE > 1. When compared across different formulations and routes of administration, AUC0-tlast for oral controlled release and i.v. administration were better predicted than that for oral immediate release formulations. Average predictive performance did not clearly differ between software packages but some APIs showed a high level of variability in predictive performance across different software packages. This variability could be related to several factors such as compound specific properties, the quality and availability of information, and errors in scaling from in vitro and preclinical in vivo data to human in vivo behaviour which will be explored further. Results were compared with previous similar exercise when the input data selection was carried by the modeller rather than a panel of experts on each in vitro test. Overall, average predictive performance was increased as reflected in smaller AAFE value of 2.8 as compared to AAFE value of 3.8 in case of previous exercise.
12.	Andresen Bergström, Moa, 1978, et al. (author) Rethinking Drug Analysis in Health Care: High-Throughput Analysis of 71 Drugs of Abuse in Oral Fluid Using Ion Mobility-High-Resolution Mass Spectrometry 2022 In: Journal of Analytical Toxicology. - : Oxford University Press (OUP). - 0146-4760 .- 1945-2403. ; 46:7, s. 765-775 Journal article (peer-reviewed)abstract We have identified a clinical need for a sensitive, specific, flexible, comprehensive and affordable analytical technology to efficiently detect polydrug use. In addition, the current standard practice of surveilled urine sampling is uncomfortable for the patient; hence, more patient-friendly sample collection methods are requested. To fill these needs, we have developed and validated a high-throughput liquid chromatography-high-resolution mass spectrometry (LC-HRMS) method for the analysis of drugs of abuse (DoA) in oral fluid (OF). The method covers a panel of 71 substances including traditional DoA, prescription narcotics and new psychoactive substances (NPS), with a guaranteed limit of identification of <3 mu g/L for 87% of the analytes. Method validation showed high accuracy (>99.7%), sensitivity (>99.7%) and specificity (100%). Most analytes had a high process efficiency during the salting-out liquid-liquid extraction sample preparation and no or only a minor matrix effect during the analysis. We have implemented this method in clinical routine and present data from 18,579 OF samples collected during routine patient treatment in mainly psychiatric and addiction clinics in West Sweden between September 2020 and June 2021. Seventy-one percent of the samples were positive and a total of 41,472 DoA findings were detected. Amphetamine (27%), buprenorphine (25%), nordiazepam (18%) and alprazolam (16%) were most prevalent. New psychoactive substances were detected in 189 samples (1.0%). The occurrence of polydrug use was common; 34% of the positive samples contained three analytes or more and 12% six or more. To the best of our knowledge, this is the first method for comprehensive analysis of DoA in OF using LC-HRMS and the largest dataset published on the detection of DoA in OF. With the current complex and variable drug use pattern, this broad, cost-effective and reliable method has largely replaced immunoassay screening in urine in our laboratory.
13.	Berg, Staffan, et al. (author) In Vitro and In Vivo Evaluation of 3D Printed Capsules with Pressure Triggered Release Mechanism for Oral Peptide Delivery 2021 In: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 110:1, s. 228-238 Journal article (peer-reviewed)abstract In this study a 3D printed capsule designed to break from the physiological pressures in the antropyloric region was evaluated for its ability to deliver the synthetic octapeptide octreotide in beagle dogs when co-formulated with the permeation enhancer sodium caprate. The pressure sensitive capsules were compared to traditional enteric coated hard gelatin capsules and enteric coated tablets. Paracetamol, which is completely absorbed in dogs, was included in the formulations and used as an absorption marker to give information about the in vivo performance of the dosage forms. The pressure sensitive capsules released drug in 50% of the dogs. In the cases where drug was released, there was no difference in octreotide bioavailability or C-max compared to the enteric coated dosage forms. When comparing all dosage forms, a correlation was seen between paracetamol C-max and octreotide bioavailability, suggesting that a high drug release rate may be beneficial for peptide absorption when delivered together with sodium caprate. (C) 2020 Published by Elsevier Inc.
14.	Dellenmark-Blom, Maria, 1983, et al. (author) Factors of family impact in a Swedish-German cohort of children born with esophageal atresia 2022 In: Orphanet Journal of Rare Diseases. - : Springer Science and Business Media LLC. - 1750-1172. ; 17:1 Journal article (peer-reviewed)abstract Background After repair of esophageal atresia (EA), childhood survivors commonly present with digestive and respiratory morbidity, and around 55% have associated anomalies. Although it is known that these problems can reduce health-related quality of life in children with EA, less is understood about the impact on the family. We aimed to identify factors related to family impact in children with EA. Methods One parent each of a child with EA (2-18 years) in 180 families from Sweden and Germany answered the PedsQL (TM) Family Impact Module as the dependent variable. The independent variables were the child's parent-reported health-related quality of life as measured by PedsQL (TM) 4.0, current symptoms, school situation, and parent/family characteristics together with child clinical data from the medical records. Results Stepwise multivariable regression analysis showed a multifactorial model of the total family impact scores (R-2 = 0.60), with independent factors being the child's overall generic health-related quality of life, school-absence >= 1/month, severe tracheomalacia, a family receiving carer's allowance, and a parent with no university/college education, p < 0.05. Logistic regression analysis showed that an increased number of symptoms in the child the preceding 4 weeks lowered the family impact scores; however, the child's feeding (R-2 = 0.35) and digestive symptoms (R-2 = 0.25) explained more in the variation of scores than the child's respiratory symptoms (R-2 = 0.09), p < 0.0001. Conclusions Family functioning may be a contributing factor to the maintenance of child health. The study findings suggest multifactorial explanations to family impact in children with EA, which are essential when optimizing the support to these families in clinical and psychosocial practice. Future research should explore experiences of family impact from all family members' perspectives and multicenter studies are warranted to understand better the effectiveness of psychosocial-educational interventions to families of children with EA.
15.	Guo, Jinan, et al. (author) A non-invasive 25-Gene PLNM-Score urine test for detection of prostate cancer pelvic lymph node metastasis 2024 In: Prostate Cancer and Prostatic Diseases. - : Nature Publishing Group. - 1365-7852 .- 1476-5608. Journal article (peer-reviewed)abstract Background: Prostate cancer patients with pelvic lymph node metastasis (PLNM) have poor prognosis. Based on EAU guidelines, patients with >5% risk of PLNM by nomograms often receive pelvic lymph node dissection (PLND) during prostatectomy. However, nomograms have limited accuracy, so large numbers of false positive patients receive unnecessary surgery with potentially serious side effects. It is important to accurately identify PLNM, yet current tests, including imaging tools are inaccurate. Therefore, we intended to develop a gene expression-based algorithm for detecting PLNM. Methods: An advanced random forest machine learning algorithm screening was conducted to develop a classifier for identifying PLNM using urine samples collected from a multi-center retrospective cohort (n = 413) as training set and validated in an independent multi-center prospective cohort (n = 243). Univariate and multivariate discriminant analyses were performed to measure the ability of the algorithm classifier to detect PLNM and compare it with the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram score. Results: An algorithm named 25 G PLNM-Score was developed and found to accurately distinguish PLNM and non-PLNM with AUC of 0.93 (95% CI: 0.85-1.01) and 0.93 (95% CI: 0.87-0.99) in the retrospective and prospective urine cohorts respectively. Kaplan-Meier plots showed large and significant difference in biochemical recurrence-free survival and distant metastasis-free survival in the patients stratified by the 25 G PLNM-Score (log rank P < 0.001 and P < 0.0001, respectively). It spared 96% and 80% of unnecessary PLND with only 0.51% and 1% of PLNM missing in the retrospective and prospective cohorts respectively. In contrast, the MSKCC score only spared 15% of PLND with 0% of PLNM missing. Conclusions: The novel 25 G PLNM-Score is the first highly accurate and non-invasive machine learning algorithm-based urine test to identify PLNM before PLND, with potential clinical benefits of avoiding unnecessary PLND and improving treatment decision-making.
16.	Guo, Jinan, et al. (author) Non-invasive Urine Test for Molecular Classification of Clinical Significance in Newly Diagnosed Prostate Cancer Patients 2021 In: Frontiers in Medicine. - : Frontiers Media S.A.. - 2296-858X. ; 8 Journal article (peer-reviewed)abstract Objective: To avoid over-treatment of low-risk prostate cancer patients, it is important to identify clinically significant and insignificant cancer for treatment decision-making. However, no accurate test is currently available.Methods: To address this unmet medical need, we developed a novel gene classifier to distinguish clinically significant and insignificant cancer, which were classified based on the National Comprehensive Cancer Network risk stratification guidelines. A non-invasive urine test was developed using quantitative mRNA expression data of 24 genes in the classifier with an algorithm to stratify the clinical significance of the cancer. Two independent, multicenter, retrospective and prospective studies were conducted to assess the diagnostic performance of the 24-Gene Classifier and the current clinicopathological measures by univariate and multivariate logistic regression and discriminant analysis. In addition, assessments were performed in various Gleason grades/ISUP Grade Groups.Results: The results showed high diagnostic accuracy of the 24-Gene Classifier with an AUC of 0.917 (95% CI 0.892-0.942) in the retrospective cohort (n = 520), AUC of 0.959 (95% CI 0.935-0.983) in the prospective cohort (n = 207), and AUC of 0.930 (95% 0.912-CI 0.947) in the combination cohort (n = 727). Univariate and multivariate analysis showed that the 24-Gene Classifier was more accurate than cancer stage, Gleason score, and PSA, especially in the low/intermediate-grade/ISUP Grade Group 1-3 cancer subgroups.Conclusions: The 24-Gene Classifier urine test is an accurate and non-invasive liquid biopsy method for identifying clinically significant prostate cancer in newly diagnosed cancer patients. It has the potential to improve prostate cancer treatment decisions and active surveillance.
17.	Johnson, Heather, et al. (author) Development and validation of a 25-Gene Panel urine test for prostate cancer diagnosis and potential treatment follow-up 2020 In: BMC Medicine. - : BioMed Central. - 1741-7015. ; 18 Journal article (peer-reviewed)abstract Background: Heterogeneity of prostate cancer (PCa) contributes to inaccurate cancer screening and diagnosis, unnecessary biopsies, and overtreatment. We intended to develop non-invasive urine tests for accurate PCa diagnosis to avoid unnecessary biopsies. Methods: Using a machine learning program, we identified a 25-Gene Panel classifier for distinguishing PCa and benign prostate. A non-invasive test using pre-biopsy urine samples collected without digital rectal examination (DRE) was used to measure gene expression of the panel using cDNA preamplification followed by real-time qRTPCR. The 25-Gene Panel urine test was validated in independent multi-center retrospective and prospective studies. The diagnostic performance of the test was assessed against the pathological diagnosis from biopsy by discriminant analysis. Uni- and multivariate logistic regression analysis was performed to assess its diagnostic improvement over PSA and risk factors. In addition, the 25-Gene Panel urine test was used to identify clinically significant PCa. Furthermore, the 25-Gene Panel urine test was assessed in a subset of patients to examine if cancer was detected after prostatectomy. Results: The 25-Gene Panel urine test accurately detected cancer and benign prostate with AUC of 0.946 (95% CI 0.963–0.929) in the retrospective cohort (n = 614), AUC of 0.901 (0.929–0.873) in the prospective cohort (n = 396), and AUC of 0.936 (0.956–0.916) in the large combination cohort (n = 1010). It greatly improved diagnostic accuracy over PSA and risk factors (p < 0.0001). When it was combined with PSA, the AUC increased to 0.961 (0.980–0.942). Importantly, the 25-Gene Panel urine test was able to accurately identify clinically significant and insignificant PCa with AUC of 0.928 (95% CI 0.947–0.909) in the combination cohort (n = 727). In addition, it was able to show the absence of cancer after prostatectomy with high accuracy. Conclusions: The 25-Gene Panel urine test is the first highly accurate and non-invasive liquid biopsy method without DRE for PCa diagnosis. In clinical practice, it may be used for identifying patients in need of biopsy for cancer diagnosis and patients with clinically significant cancer for immediate treatment, and potentially assisting cancer treatment follow-up.
18.	Karlsson, Lene, et al. (author) Fusion transcript analysis reveals slower response kinetics than multiparameter flow cytometry in childhood acute myeloid leukaemia 2022 In: International Journal of Laboratory Hematology. - : Wiley. - 1751-5521 .- 1751-553X. ; 44:6, s. 1094-1101 Journal article (peer-reviewed)abstract Introduction Analysis of measurable residual disease (MRD) is increasingly being implemented in the clinical care of children and adults with acute myeloid leukaemia (AML). However, MRD methodologies differ and discordances in results lead to difficulties in interpretation and clinical decision-making. The aim of this study was to compare results from reverse transcription quantitative polymerase chain reaction (RT-qPCR) and multiparameter flow cytometry (MFC) in childhood AML and describe the kinetics of residual leukaemic burden during induction treatment. Methods In 15 children who were treated in the NOPHO-AML 2004 trial and had fusion transcripts quantified by RT-qPCR, we compared MFC with RT-qPCR for analysis of MRD during (day 15) and after induction therapy. Eight children had RUNX1::RUNX1T1, one CBFB::MYH11 and six KMT2A::MLLT3. Results When >= 0.1% was used as cut-off for positivity, 10 of 22 samples were discordant. The majority (9/10) were MRD positive with RT-qPCR but MRD negative with MFC, and several such cases showed the presence of mature myeloid cells. Fusion transcript expression was verified in mature cells as well as in CD34 expressing cells sorted from diagnostic samples. Conclusions Measurement with RT-qPCR suggests slower response kinetics than indicated from MFC, presumably due to the presence of mature cells expressing fusion transcript. The prognostic impact of early measurements with RT-qPCR remains to be determined.
19.	Modvig, S, et al. (author) Value of flow cytometry for MRD-based relapse prediction in B-cell precursor ALL in a multicenter setting. 2021 In: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 35, s. 1894-1906 Journal article (peer-reviewed)abstract PCR of TCR/Ig gene rearrangements is considered the method of choice for minimal residual disease (MRD) quantification in BCP-ALL, but flow cytometry analysis of leukemia-associated immunophenotypes (FCM-MRD) is faster and biologically more informative. FCM-MRD performed in 18 laboratories across seven countries was used for risk stratification of 1487 patients with BCP-ALL enrolled in the NOPHO ALL2008 protocol. When no informative FCM-marker was available, risk stratification was based on real-time quantitative PCR. An informative FCM-marker was found in 96.2% and only two patients (0.14%) had non-informative FCM and non-informative PCR-markers. The overall 5-year event-free survival was 86.1% with a cumulative incidence of relapse (CIR5y) of 9.5%. FCM-MRD levels on days 15 (HzR 4.0, p<0.0001), 29 (HzR 2.7, p<0.0001), and 79 (HzR 3.5, p<0.0001) associated with hazard of relapse adjusted for age, cytogenetics, and WBC. The early (day 15) response associated with CIR5y adjusted for day 29 FCM-MRD, with higher levels in adults (median 2.4×10-2 versus 5.2×10-3, p<0.0001). Undetectable FCM- and/or PCR-MRD on day 29 identified patients with a very good outcome (CIR5y=3.2%). For patients who did not undergo transplantation, day 79 FCM-MRD>10-4 associated with a CIR5y=22.1%. In conclusion, FCM-MRD performed in a multicenter setting is a clinically useful method for MRD-based treatment stratification in BCP-ALL.
20.	Nielsen, S. N., et al. (author) No association between relapse hazard and thiopurine methyltransferase geno- or phenotypes in non-high risk acute lymphoblastic leukemia: a NOPHO ALL2008 sub-study 2021 In: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 88, s. 271-279 Journal article (peer-reviewed)abstract Purpose 6-mercaptopurine(6MP)/methotrexate maintenance therapy is essential to reduce relapse of childhood acute lymphoblastic leukemia (ALL). Common germline variants in TPMT cause low activity of thiopurine methyltransferase (TPMT) and higher 6MP metabolite (TGN) levels. Higher levels of TGNs incorporated into DNA (DNA-TG) and low TPMT activity have previously been associated with a lower relapse risk. We explored if TPMT geno- or phenotype was associated with DNA-TG levels and relapse rate in NOPHO ALL2008. Methods TPMT genotype, repeated phenotyping, and DNA-TG measurements were collected in 918 children with non-high risk ALL (NOPHO ALL2008 maintenance therapy study). Maintenance therapy started with 6MP at 50 and 75 mg/m(2) for TPMT heterozygous and wildtype patients and was adjusted to a target WBC of 1.5 - 3.0 x 10(9)/L. Results Of 918 patients, 78 (8.5%) were TPMT heterozygous and 903 had at least one TPMT measurement (total 3063). Mean TPMT activities were higher with wildtype than heterozygous TPMT (N = 752, 16.6 versus 9.6 U/mL ery., p < 0.001). The 5-year cumulative incidence of relapse was 6.4% and 6.0% for TPMT heterozygous and wildtype patients, and there was no association between genotype and relapse rate (N = 918, hazard ratio = 1.01, 95% confidence interval [CI] 0.40 - 2.54, p = 0.98). Although TPMT heterozygous patients had higher DNA-TG (N = 548, median 760.9 [interquartile range (IQR) 568.7 - 890.3] versus 492.7 [IQR 382.1 - 634.6] fmol/mu g, p < 0.001), TPMT activity was not associated with relapse rate (N = 813; hazard ratio = 0.98 per one U/mL ery. increase in TPMT activity, 95% CI 0.91 - 1.06, p = 0.67). Conclusion TPMT geno- and phenotype were not associated with relapse in non-high risk NOPHO ALL2008.
21.	Rank, Cecilie U., et al. (author) Asparaginase-Associated Pancreatitis in Acute Lymphoblastic Leukemia : Results From the NOPHO ALL2008 Treatment of Patients 1-45 Years of Age 2020 In: Journal of Clinical Oncology. - Alexandria : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 38:2, s. 145-154 Journal article (peer-reviewed)abstract PURPOSE: Asparaginase-associated pancreatitis (AAP) is common in patients with acute lymphoblastic leukemia (ALL), but risk differences across age groups both in relation to first-time AAP and after asparaginase re-exposure have not been explored.PATIENTS AND METHODS: We prospectively registered AAP (n = 168) during treatment of 2,448 consecutive ALL patients aged 1.0-45.9 years diagnosed from July 2008 to October 2018 and treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol.RESULTS: Compared with patients aged 1.0-9.9 years, adjusted AAP hazard ratios (HRa) were associated with higher age with almost identical HRa (1.6; 95% CI, 1.1 to 2.3; P = .02) for adolescents (10.0-17.9 years) and adults (18.0-45.9 years). The day 280 cumulative incidences of AAP were 7.0% for children (1.0-9.9 years: 95% CI, 5.4 to 8.6), 10.1% for adolescents (10.0 to 17.9 years: 95% CI, 7.0 to 13.3), and 11.0% for adults (18.0-45.9 years: 95% CI, 7.1 to 14.9; P = .03). Adolescents had increased odds of both acute (odds ratio [OR], 5.2; 95% CI, 2.1 to 13.2; P = .0005) and persisting complications (OR, 6.7; 95% CI, 2.4 to 18.4; P = .0002) compared with children (1.0-9.9 years), whereas adults had increased odds of only persisting complications (OR, 4.1; 95% CI, 1.4 to 11.8; P = .01). Fifteen of 34 asparaginase-rechallenged patients developed a second AAP. Asparaginase was truncated in 17/21 patients with AAP who subsequently developed leukemic relapse, but neither AAP nor the asparaginase truncation was associated with increased risk of relapse.CONCLUSION: Older children and adults had similar AAP risk, whereas morbidity was most pronounced among adolescents. Asparaginase re-exposure should be considered only for patients with an anticipated high risk of leukemic relapse, because multiple studies strongly indicate that reduction of asparaginase treatment intensity increases the risk of relapse.
22.	Ringlander, Johan, et al. (author) Deep sequencing of liver explant transcriptomes reveals extensive expression from integrated hepatitis B virus DNA 2020 In: Journal of Viral Hepatitis. - : Wiley. - 1352-0504 .- 1365-2893. ; 27:11, s. 1162-1170 Journal article (peer-reviewed)abstract Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC). Integration of HBV DNA into the human genome may contribute to oncogenesis and to the production of the hepatitis B surface antigen (HBsAg). Whether integrations contribute to HBsAg levels in the blood is poorly known. Here, we characterize the HBV RNA profile of HBV integrations in liver tissue in patients with chronic HBV infection, with or without concurrent hepatitis D infection, by transcriptome deep sequencing. Transcriptomes were determined in liver tissue by deep sequencing providing 200 million reads per sample. Integration points were identified using a bioinformatic pipeline. Explanted liver tissue from five patients with end-stage liver disease caused by HBV or HBV/HDV was studied along with publicly available transcriptomes from 21 patients. Almost all HBV RNA profiles were devoid of reads in the core and the 3 ' redundancy (nt 1830-1927) regions, and contained a large number of chimeric viral/human reads. Hence, HBV transcripts from integrated HBV DNA rather than from covalently closed circular HBV DNA (cccDNA) predominated in late-stage HBV infection, in particular in cases with hepatitis D virus co-infection. The findings support the suggestion that integrated HBV DNA can be a significant source of HBsAg in humans.
23.	Salunkhe, Vishal A., et al. (author) Digital lifestyle treatment improves long-term metabolic control in type 2 diabetes with different effects in pathophysiological and genetic subgroups 2023 In: Npj Digital Medicine. - 2398-6352. ; 6:1 Journal article (peer-reviewed)abstract To address the unmet need for scalable solutions for lifestyle treatment, we developed a new digital method to promote behavioral change. Here we report that patients with type-2 diabetes in Sweden (n = 331) exposed to the intervention have significantly improved HbA1c during a median follow-up of 1038 days (4 mmol/mol compared with matched controls; P = 0.009). This is paralleled by reduced body weight, ameliorated insulin secretion, increased physical activity, and cognitive eating restraints. Participants with high BMI and insulin resistance have an even larger response, as have non-risk allele carriers for the FTO gene. The findings open a new avenue for scalable lifestyle management with sustained efficacy and highlight a previously unrecognized opportunity for digital precision treatment based on genetics and individual pathophysiology. ClinicalTrials.gov NCT04624321.
24.	Scherer, D., et al. (author) RNA Sequencing of Hepatobiliary Cancer Cell Lines: Data and Applications to Mutational and Transcriptomic Profiling. 2020 In: Cancers. - : MDPI AG. - 2072-6694. ; 12:9 Journal article (peer-reviewed)abstract Cancer cell lines allow the identification of clinically relevant alterations and the prediction of drug response. However, sequencing data for hepatobiliary cancer cell lines in general, and particularly gallbladder cancer (GBC), are sparse. Here, we apply RNA sequencing to characterize 10 GBC, eight hepatocellular carcinoma, and five cholangiocarcinoma (CCA) cell lines. RNA extraction, quality control, library preparation, sequencing, and pre-processing of sequencing data were implemented using state-of-the-art techniques. Public data from the MSK-IMPACT database and a large cohort of Japanese biliary tract cancer patients were used to illustrate the usage of the released data. The total number of exonic mutations varied from 7207 for the cell line NOZ to 9760 for HuCCT1. Researchers planning experiments that require TP53 mutations could use the cell lines NOZ, OCUG-1, SNU308, or YoMi. Mz-Cha-1 showed mutations in ATM, SNU308 presented SMAD4 mutations, and the only investigated cell line that showed ARID1A mutations was GB-d1. SNU478 was the cell line with the global gene expression pattern most similar to GBC, intrahepatic CCA, and extrahepatic CCA. EGFR, KMT2D, and KMT2C generally presented a higher expression in the investigated cell lines than in Japanese primary GBC tumors. We provide the scientific community with detailed mutation and gene expression data, together with three showcase applications, with the aim of facilitating the design of future in vitro cell culture assays for research on hepatobiliary cancer.
25.	Stratmann, Svea, 1989-, et al. (author) Genomic characterization of relapsed acute myeloid leukemia reveals novel putative therapeutic targets 2021 In: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 5:3, s. 900-912 Journal article (peer-reviewed)abstract Relapse is the leading cause of death of adult and pediatric patients with acute myeloid leukemia (AML). Numerous studies have helped to elucidate the complex mutational landscape at diagnosis of AML, leading to improved risk stratification and new therapeutic options. However, multi-whole-genome studies of adult and pediatric AML at relapse are necessary for further advances. To this end, we performed whole-genome and whole-exome sequencing analyses of longitudinal diagnosis, relapse, and/or primary resistant specimens from 48 adult and 25 pediatric patients with AML. We identified mutations recurrently gained at relapse in ARID1A and CSF1R, both of which represent potentially actionable therapeutic alternatives. Further, we report specific differences in the mutational spectrum between adult vs pediatric relapsed AML, with MGA and H3F3A p.Lys28Met mutations recurrently found at relapse in adults, whereas internal tandem duplications in UBTF were identified solely in children. Finally, our study revealed recurrent mutations in IKZF1, KANSL1, and NIPBL at relapse. All of the mentioned genes have either never been reported at diagnosis in de novo AML or have been reported at low frequency, suggesting important roles for these alterations predominantly in disease progression and/or resistance to therapy. Our findings shed further light on the complexity of relapsed AML and identified previously unappreciated alterations that may lead to improved outcomes through personalized medicine.
26.	Stratmann, Svea, 1989-, et al. (author) Proteogenomic analysis of acute myeloid leukemia associates relapsed disease with reprogrammed energy metabolism both in adults and children 2023 In: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 37:3, s. 550-559 Journal article (peer-reviewed)abstract Despite improvement of current treatment strategies and novel targeted drugs, relapse and treatment resistance largely determine the outcome for acute myeloid leukemia (AML) patients. To identify the underlying molecular characteristics, numerous studies have been aimed to decipher the genomic- and transcriptomic landscape of AML. Nevertheless, further molecular changes allowing malignant cells to escape treatment remain to be elucidated. Mass spectrometry is a powerful tool enabling detailed insights into proteomic changes that could explain AML relapse and resistance. Here, we investigated AML samples from 47 adult and 22 pediatric patients at serial time-points during disease progression using mass spectrometry-based in-depth proteomics. We show that the proteomic profile at relapse is enriched for mitochondrial ribosomal proteins and subunits of the respiratory chain complex, indicative of reprogrammed energy metabolism from diagnosis to relapse. Further, higher levels of granzymes and lower levels of the anti-inflammatory protein CR1/CD35 suggest an inflammatory signature promoting disease progression. Finally, through a proteogenomic approach, we detected novel peptides, which present a promising repertoire in the search for biomarkers and tumor-specific druggable targets. Altogether, this study highlights the importance of proteomic studies in holistic approaches to improve treatment and survival of AML patients.
27.	Stratmann, Svea, 1989-, et al. (author) Transcriptomic analysis reveals proinflammatory signatures associated with acute myeloid leukemia progression 2022 In: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 6:1, s. 152-164 Journal article (peer-reviewed)abstract Numerous studies have been performed over the last decade to exploit the complexity of genomic and transcriptomic lesions driving the initiation of acute myeloid leukemia (AML). These studies have helped improve risk classification and treatment options. Detailed molecular characterization of longitudinal AML samples is sparse, however; meanwhile, relapse and therapy resistance represent the main challenges in AML care. To this end, we performed transcriptome-wide RNA sequencing of longitudinal diagnosis, relapse, and/or primary resistant samples from 47 adult and 23 pediatric AML patients with known mutational background. Gene expression analysis revealed the association of short event-free survival with overexpression of GLI2 and IL1R1, as well as downregulation of ST18. Moreover, CR1 downregulation and DPEP1 upregulation were associated with AML relapse both in adults and children. Finally, machine learning–based and network-based analysis identified overexpressed CD6 and downregulated INSR as highly copredictive genes depicting important relapse-associated characteristics among adult patients with AML. Our findings highlight the importance of a tumor-promoting inflammatory environment in leukemia progression, as indicated by several of the herein identified differentially expressed genes. Together, this knowledge provides the foundation for novel personalized drug targets and has the potential to maximize the benefit of current treatments to improve cure rates in AML. ß 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
28.	van Weelderen, Romy E., et al. (author) Measurable residual disease and fusion partner independently predict survival and relapse risk in childhood KMT2A-rearranged acute myeloid leukemia : a study by the international Berlin-Frankfurt-Münster study group 2023 In: Journal of Clinical Oncology. - : American Society of Clinical Oncology (ASCO). - 0732-183X .- 1527-7755. ; 41:16, s. 2963-2974 Journal article (peer-reviewed)abstract Purpose: A previous study by the International Berlin-Frankfurt-Münster Study Group (I-BFM-SG) on childhood KMT2A-rearranged (KMT2A-r) AML demonstrated the prognostic value of the fusion partner. This I-BFM-SG study investigated the value of flow cytometry-based measurable residual disease (flow-MRD) and evaluated the benefit of allogeneic stem-cell transplantation (allo-SCT) in first complete remission (CR1) in this disease.Methods: A total of 1,130 children with KMT2A-r AML, diagnosed between January 2005 and December 2016, were assigned to high-risk (n = 402; 35.6%) or non-high-risk (n = 728; 64.4%) fusion partner-based groups. Flow-MRD levels at both end of induction 1 (EOI1) and 2 (EOI2) were available for 456 patients and were considered negative (<0.1%) or positive (≥0.1%). End points were 5-year event-free survival (EFS), cumulative incidence of relapse (CIR), and overall survival (OS).Results: The high-risk group had inferior EFS (30.3% high risk v 54.0% non-high risk; P < .0001), CIR (59.7% v 35.2%; P < .0001), and OS (49.2% v 70.5%; P < .0001). EOI2 MRD negativity was associated with superior EFS (n = 413; 47.6% MRD negativity v n = 43; 16.3% MRD positivity; P < .0001) and OS (n = 413; 66.0% v n = 43; 27.9%; P < .0001), and showed a trend toward lower CIR (n = 392; 46.1% v n = 26; 65.4%; P = .016). Similar results were obtained for patients with EOI2 MRD negativity within both risk groups, except that within the non-high-risk group, CIR was comparable with that of patients with EOI2 MRD positivity. Allo-SCT in CR1 only reduced CIR (hazard ratio, 0.5 [95% CI, 0.4 to 0.8]; P = .00096) within the high-risk group but did not improve OS. In multivariable analyses, EOI2 MRD positivity and high-risk group were independently associated with inferior EFS, CIR, and OS.Conclusion: EOI2 flow-MRD is an independent prognostic factor and should be included as risk stratification factor in childhood KMT2A-r AML. Treatment approaches other than allo-SCT in CR1 are needed to improve prognosis.
29.	van Weelderen, Romy E., et al. (author) Optimized cytogenetic risk-group stratification of KMT2A-rearranged pediatric acute myeloid leukemia 2024 In: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 8:12, s. 3200-3213 Journal article (peer-reviewed)abstract A comprehensive international consensus on the cytogenetic risk-group stratification of KMT2A-rearranged (KMT2A-r) pediatric acute myeloid leukemia (AML) is lacking. This retrospective (2005-2016) International Berlin-Frankfurt-Münster Study Group study on 1256 children with KMT2A-r AML aims to validate the prognostic value of established recurring KMT2A fusions and additional cytogenetic aberrations (ACAs) and to define additional, recurring KMT2A fusions and ACAs, evaluating their prognostic relevance. Compared with our previous study, 3 additional, recurring KMT2A-r groups were defined: Xq24/KMT2A::SEPT6, 1p32/KMT2A::EPS15, and 17q12/t(11;17)(q23;q12). Across 13 KMT2A-r groups, 5-year event-free survival probabilities varied significantly (21.8%-76.2%; P < .01). ACAs occurred in 46.8% of 1200 patients with complete karyotypes, correlating with inferior overall survival (56.8% vs 67.9%; P < .01). Multivariable analyses confirmed independent associations of 4q21/KMT2A::AFF1, 6q27/KMT2A::AFDN, 10p12/KMT2A::MLLT10, 10p11.2/KMT2A::ABI1, and 19p13.3/KMT2A::MLLT1 with adverse outcomes, but not those of 1q21/KMT2A::MLLT11 and trisomy 19 with favorable and adverse outcomes, respectively. Newly identified ACAs with independent adverse prognoses were monosomy 10, trisomies 1, 6, 16, and X, add(12p), and del(9q). Among patients with 9p22/KMT2A::MLLT3, the independent association of French-American-British-type M5 with favorable outcomes was confirmed, and those of trisomy 6 and measurable residual disease at end of induction with adverse outcomes were identified. We provide evidence to incorporate 5 adverse-risk KMT2A fusions into the cytogenetic risk-group stratification of KMT2A-r pediatric AML, to revise the favorable-risk classification of 1q21/KMT2A::MLLT11 to intermediate risk, and to refine the risk-stratification of 9p22/KMT2A::MLLT3 AML. Future studies should validate the associations between the newly identified ACAs and outcomes and unravel the underlying biological pathogenesis of KMT2A fusions and ACAs.
30.	Versluys, A. B., et al. (author) Hematopoietic cell transplant in pediatric acute myeloid leukemia after similar upfront therapy; a comparison of conditioning regimens 2021 In: Bone Marrow Transplantation. - : Springer Science and Business Media LLC. - 0268-3369 .- 1476-5365. ; 56:6, s. 1426-1432 Journal article (peer-reviewed)abstract The impact of conditioning regimen prior to hematopoietic cell transplant (HCT) in pediatric AML-patients is not well studied. We retrospectively analyzed the impact of Busulfan-Cyclophosphamide (BuCy), Busulfan-Cyclophosphamide-Melphalan (BuCyMel) and Clofarabine-Fludarabine-Busulfan (CloFluBu) in pediatric AML-patients, with similar upfront leukemia treatment (NOPHO-DBHconsortium), receiving an HCT between 2010 and 2015. Outcomes of interest were LFS, relapse, TRM and GvHD. 103 patients were included; 30 received BuCy, 37 BuCyMel, and 36 CloFluBu. The 5-years LFS was 43.3% (SE +/- 9.0) in the BuCy group, 59.2 % (SE +/- 8.1) after BuCyMel, and 66.7 % (SE +/- 7.9) after CloFluBu. Multivariable Cox regression analysis showed a trend to lower LFS after BuCy compared to CloFluBu (p = 0.07). BuCy was associated with a higher relapse incidence compared to the other regimens (p = 0.06). Younger age was a predictor for relapse (p = 0.02). A strong correlation between Busulfan Therapeutic Drug Monitoring (TDM) and lower incidence of aGvHD (p < 0.001) was found. In conclusion, LFS after BuCyMel and CloFluBu was comparable, lower LFS was found after BuCy, due to higher relapse incidence. CloFluBu was associated with lower incidence of aGvHD, suggesting lower toxicity with this type of conditioning. This finding is also explained by the impact of Busulfan monitoring.

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