Publications by authors named "Kim Vettenranta"

85 Publications

Maternal autoimmune disease is not associated with cancer in the offspring.

Authors:

Laura K Seppälä Laura-Maria Madanat-Harjuoja Rebecca Troisi Joshua N Sampson Maarit K Leinonen Kim Vettenranta

Acta Paediatr 2021 Feb 27. Epub 2021 Feb 27.

University of Helsinki, Helsinki University hospital, Pediatrics.

Aim: Autoimmune disease and its medication are associated with increased cancer risk in adults, but it is unknown whether maternal autoimmune disease and/or medication use in pregnancy are associated with increased cancer risk in offspring.

Methods: In this case-control study we identified all patients under 20 years of age with their first cancer diagnosis in 1996-2014 from the Finnish Cancer Registry (n=2,029) and 1:5 population- based controls (n=10,103) from the Medical Birth Register. We obtained information on maternal autoimmune disease and its medication from the relevant Finnish registries and used conditional logistic regression to analyse the risk of offspring cancer after maternal autoimmune disease exposure.

Results: The odds ratio (OR) for cancer in offspring following maternal autoimmune exposure was 0.76 (95% confidence interval (CI) 0.47-1.23). Individual ORs for inflammatory bowel, connective tissue diseases were 1.08 (95% CI 0.56-2.01), 0.50 (95% CI 0.23-1.08), respectively. The OR for maternal autoimmune medication was 0.95 (95% CI 0.80-1.14) overall, and similar by drug subtype. There was an increased risk with medication in late pregnancy but the ORs were unstable owing to small numbers.

Conclusion: Our study does not support an increased cancer risk among offspring of women with autoimmune disease or its medication during pregnancy.

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http://dx.doi.org/10.1111/apa.15821	DOI Listing

February 2021

RhoG deficiency abrogates cytotoxicity of human lymphocytes and causes hemophagocytic lymphohistiocytosis.

Blood 2021 Jan 29. Epub 2021 Jan 29.

St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.

Exocytosis of cytotoxic granules (CG) by lymphocytes is required for the elimination of infected and malignant cells. Impairments in this process underly a group of diseases with dramatic hyperferritinemic inflammation termed hemophagocytic lymphohistiocytosis (HLH). Although genetic and functional studies of HLH have identified proteins controlling distinct steps of CG exocytosis, the molecular mechanisms that spatiotemporally coordinate CG release remain unclear. We studied a patient exhibiting characteristic clinical features of HLH associated with markedly impaired cytotoxic T lymphocyte (CTL) and natural killer (NK) cell exocytosis functions, who was bearing biallelic deleterious mutations in the gene encoding the small GTPase RhoG. Experimental ablation of RHOG in a model cell line and primary CTLs from healthy individuals uncovered a hitherto unappreciated role of RhoG in retaining CGs in the vicinity of the plasma membrane (PM), a fundamental prerequisite for CG exocytotic release. We discovered that RhoG engages in a protein-protein interaction with Munc13-4, an exocytosis protein essential for CG fusion with the PM. We show that this interaction is critical for docking of Munc13-4-positive CGs to the PM and subsequent membrane fusion and release of CG content. Thus, our study illuminates RhoG as a novel essential regulator of human lymphocyte cytotoxicity, and provides the molecular pathomechanism behind the identified here and previously unreported genetically-determined form of HLH.

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http://dx.doi.org/10.1182/blood.2020008738	DOI Listing

January 2021

Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multinational, Randomized, Noninferiority Phase III Study.

J Clin Oncol 2021 Feb 17;39(4):295-307. Epub 2020 Dec 17.

Goethe University, University Hospital Frankfurt, Department for Children and Adolescents, Division for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Frankfurt am Main, Germany.

Purpose: Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is efficacious, but long-term side effects are concerning. We investigated whether preparative combination chemotherapy could replace TBI in such patients.

Patients And Methods: FORUM is a randomized, controlled, open-label, international, multicenter, phase III, noninferiority study. Patients ≤ 18 years at diagnosis, 4-21 years at HSCT, in complete remission pre-HSCT, and with an HLA-compatible related or unrelated donor were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine, thiotepa, and either busulfan or treosulfan. The noninferiority margin was 8%. With 1,000 patients randomly assigned in 5 years, 2-year minimum follow-up, and one-sided alpha of 5%, 80% power was calculated. A futility stopping rule would halt random assignment if chemoconditioning was significantly inferior to TBI (EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129).

Results: Between April 2013 and December 2018, 543 patients were screened, 417 were randomly assigned, 212 received TBI, and 201 received chemoconditioning. The stopping rule was applied on March 31, 2019. The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91; 95% CI, 0.86 to 0.95; < .0001) versus chemoconditioning (0.75; 95% CI, 0.67 to 0.81). Two-year cumulative incidence of relapse and treatment-related mortality were 0.12 (95% CI, 0.08 to 0.17; < .0001) and 0.02 (95% CI, < 0.01 to 0.05; = .0269) following TBI and 0.33 (95% CI, 0.25 to 0.40) and 0.09 (95% CI, 0.05 to 0.14) following chemoconditioning, respectively.

Conclusion: Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. We therefore recommend TBI plus etoposide for patients > 4 years old with high-risk ALL undergoing allogeneic HSCT.

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http://dx.doi.org/10.1200/JCO.20.02529	DOI Listing

February 2021

Relapse risk following truncation of PEG-asparaginase in childhood acute lymphoblastic leukemia.

Authors:

Sofie Gottschalk Højfeldt Kathrine Grell Jonas Abrahamsson Bendik Lund Kim Vettenranta Olafur G Jonsson Thomas Leth Frandsen Benjamin Ole Wolthers Hanne Vibeke Hansen Marquart Goda Vaitkeviciene Kristi Lepik Mats Heyman Kjeld Schmiegelow Birgitte Klug Albertsen

Blood 2020 Nov 4. Epub 2020 Nov 4.

Aarhus University Hospital, Aarhus N, Denmark.

Truncation of asparaginase treatment due to asparaginase related toxicities or silent inactivation (SI) is common and may increase relapse risk in acute lymphoblastic leukemia (ALL). We investigated relapse risk following suboptimal asparaginase exposure among 1401 children aged 1-17 years, diagnosed with ALL between July 2008 and February 2016, and treated according to the NOPHO ALL2008 protocol including extended asparaginase exposure (1,000 IU/m2 intramuscularly weeks 5 to 33). Patients were included with delayed entry at their last administered asparaginase treatment or detection of SI and followed until relapse, death, secondary malignancy, or end of follow-up (median: 5.71 years, interquartile range: 4.02-7.64). In a multiple Cox model comparing patients with (n=358) and without (n=1043) truncated asparaginase treatment due to clinical toxicity, the adjusted relapse-specific hazard ratio (aHR) was 1.33 (95% confidence interval [CI]: 0.86-2.06, P=0.20). In a substudy including only patients with information on enzyme activity (n=1115), the 7-year cumulative incidence of relapse for the 301 patients with truncation of asparaginase treatment or SI (157 hypersensitivity, 53 pancreatitis, 14 thrombosis, 31 other, 46 SI) was 11.1% (95% CI: 6.9-15.4) versus 6.7% (95% CI: 4.7-8.6) for the 814 remaining patients. The relapse-specific aHR was 1.69 (95% CI: 1.05-2.74, P=0.03). The unadjusted bone-marrow relapse-specific HR was 1.83 (95% CI: 1.07-3.14, P=0.03) and 1.86 (95% CI: 0.90- 3.87, P=0.095) for any CNS relapse. These results emphasize the importance of therapeutic drug monitoring and appropriate adjustment of asparaginase therapy when feasible.

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http://dx.doi.org/10.1182/blood.2020006583	DOI Listing

November 2020

Preterm birth, neonatal therapies and the risk of childhood cancer.

Authors:

Laura K Seppälä Kim Vettenranta Maarit K Leinonen Viena Tommiska Laura-Maria Madanat-Harjuoja

Int J Cancer 2020 Oct 31. Epub 2020 Oct 31.

Finnish Cancer Registry, Helsinki, Finland.

Our aim was to study the impact of preterm birth and neonatal therapies on the risk of childhood cancer using a nationwide, registry-based, case-control design. Combining population-based data from Finnish Medical Birth Registry (MBR) and Finnish Cancer Registry, we identified a total of 2029 patients diagnosed with cancer under the age of 20 years and 10 103 age- and sex-matched controls over the years 1996 to 2014. Information on the prenatal and perinatal conditions was obtained from the MBR. Gestational age was categorized into early (<32) and late preterm (32-36) and term (≥37 weeks). Cancer risk among the preterm compared to term neonates was evaluated using conditional logistic regression. We identified 141 cancers among the preterm (20.8% of 678) vs 1888 cancers in the term children (16.5% of 11 454). The risk of any cancer was increased for the preterm (odds ratio [OR] 1.28, 95% confidence interval [CI] 1.06-1.57), especially for the early preterm (OR 1.84, 95% CI 1.16-2.92). The risk of acute myeloid leukemia (AML; OR 2.33, 95% CI 1.25-4.37), retinoblastoma (OR 3.21, 95% CI 1.22-8.41) and germ cell tumors (OR 5.89, 95% CI 2.29-15.18) was increased among the preterm compared to term. Germ cell tumors were diagnosed at a significantly younger age among the preterm. Neonatal therapies, for example, mechanical ventilation, were associated with an increased risk of childhood cancer independent of gestational age. Preterm, especially early preterm birth, is associated with an increased risk of childhood cancer, especially germ cell tumors and AML. Respiratory distress requiring neonatal intervention also appears to be associated with an increased risk.

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http://dx.doi.org/10.1002/ijc.33376	DOI Listing

October 2020

Correction: ABO incompatibile graft management in pediatric transplantation.

Bone Marrow Transplant 2021 Jan;56(1):297

Hospital for Children and Adolescents, Stammzelltransplantation und Immunologie, Klinik für Kinder- und Jugendmedizin, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.

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http://dx.doi.org/10.1038/s41409-020-01012-z	DOI Listing

January 2021

ABO incompatibile graft management in pediatric transplantation.

Bone Marrow Transplant 2021 Jan 27;56(1):84-90. Epub 2020 Jun 27.

Hospital for Children and Adolescents, Stammzelltransplantation und Immunologie, Klinik für Kinder- und Jugendmedizin, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.

Up to 40% of donor-recipient pairs in SCT have some degree of ABO incompatibility, which may cause severe complications. The aim of this study was to describe available options and survey current practices by means of a questionnaire circulated within the EBMT Pediatric Diseases Working Party investigators. Major ABO incompatibility (donor's RBCs have antigens missing on the recipient's cell surface, towards which the recipient has circulating isohemagglutinins) requires most frequently an intervention in case of bone marrow grafts, as immediate or delayed hemolysis, delayed erythropoiesis and pure red cell aplasia may occur. RBC depletion from the graft (82%), recipient plasma-exchange (14%) were the most common practices, according to the survey. Graft manipulation is rarely needed in mobilized peripheral blood grafts. In case of minor incompatible grafts (donor has isohemagglutinins directed against recipient RBC antigens), isohemagglutinin depletion from the graft by plasma reduction/centrifugation may be considered, but acute tolerability of minor incompatible grafts is rarely an issue. According to the survey, minor ABO incompatibility was either managed by means of plasma removal from the graft, especially when isohemagglutinin titer was above a certain threshold, or led to no intervention at all (41%). Advantages and disadvantages of each method are discussed.

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http://dx.doi.org/10.1038/s41409-020-0981-7	DOI Listing

January 2021

Myeloablative conditioning for allo-HSCT in pediatric ALL: FTBI or chemotherapy?-A multicenter EBMT-PDWP study.

Authors:

Andre Manfred Willasch Christina Peters Petr Sedláček Jean-Hugues Dalle Vassiliki Kitra-Roussou Akif Yesilipek Jacek Wachowiak Arjan Lankester Arcangelo Prete Amir Ali Hamidieh Marianne Ifversen Jochen Buechner Gergely Kriván Rose-Marie Hamladji Cristina Diaz-de-Heredia Elena Skorobogatova Gérard Michel Franco Locatelli Alice Bertaina Paul Veys Sophie Dupont Reuven Or Tayfun Güngör Olga Aleinikova Sabina Sufliarska Mikael Sundin Jelena Rascon Ain Kaare Damir Nemet Franca Fagioli Thomas Erich Klingebiel Jan Styczynski Marc Bierings Kálmán Nagy Manuel Abecasis Boris Afanasyev Marc Ansari Kim Vettenranta Amal Alseraihy Alicja Chybicka Stephen Robinson Yves Bertrand Alphan Kupesiz Ardeshir Ghavamzadeh Antonio Campos Herbert Pichler Arnaud Dalissier Myriam Labopin Selim Corbacioglu Adriana Balduzzi Jacques-Emmanuel Galimard Peter Bader

Bone Marrow Transplant 2020 08 17;55(8):1540-1551. Epub 2020 Mar 17.

Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents, University Hospital, Goethe University Frankfurt, Frankfurt, Germany.

Although most children with acute lymphoblastic leukemia (ALL) receive fractionated total body irradiation (FTBI) as myeloablative conditioning (MAC) for allogeneic hematopoietic stem cell transplantation (allo-HSCT), it is an important matter of debate if chemotherapy can effectively replace FTBI. To compare outcomes after FTBI versus chemotherapy-based conditioning (CC), we performed a retrospective EBMT registry study. Children aged 2-18 years after MAC for first allo-HSCT of bone marrow (BM) or peripheral blood stem cells (PBSC) from matched-related (MRD) or unrelated donors (UD) in first (CR1) or second remission (CR2) between 2000 and 2012 were included. Propensity score weighting was used to control pretreatment imbalances of the observed variables. 3.054 patients were analyzed. CR1 (1.498): median follow-up (FU) after FTBI (1.285) and CC (213) was 6.8 and 6.1 years. Survivals were not significantly different. CR2 (1.556): median FU after FTBI (1.345) and CC (211) was 6.2 years. Outcomes after FTBI were superior as compared with CC with regard to overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), and nonrelapse mortality (NRM). However, we must emphasize the preliminary character of the results of this retrospective "real-world-practice" study. These findings will be prospectively assessed in the ALL SCTped 2012 FORUM trial.

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http://dx.doi.org/10.1038/s41409-020-0854-0	DOI Listing

August 2020

Acute toxicity and outcome among pediatric allogeneic hematopoietic transplant patients conditioned with treosulfan-based regimens.

Authors:

Pasi Huttunen Mervi Taskinen Kim Vettenranta

Pediatr Hematol Oncol 2020 Aug 13;37(5):355-364. Epub 2020 Mar 13.

Division of Hematology-Oncology and Stem Cell Transplantation, New Children´s Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

Treosulfan-based regimens constitute a feasible and increasingly used, but still myeloablative, conditioning in pediatric allogeneic hematopoietic stem cell transplantation (HSCT). We retrospectively analyzed the acute toxicity and outcome of all consecutive (2004-2015) pediatric HSCT patients prepared for HSCT with treosulfan in a single-center setting. We included HSCTs performed for both nonmalignant ( = 23) and malignant diseases ( = 11). The controls were patients with nonmalignant diseases or hematological malignancies conditioned with cyclophosphamide (Cy)-total body irradiation (TBI)-based (39 patients) or busulfan-based regimens (11 patients). The major toxicities of the treosulfan-based regimens were limited to oral mucosa and skin. 50% of the patients needed IV morphine for severe mucositis compared to 31% in patients conditioned with Cy-TBI ( = 0.02). Other toxicities were rare. The disease-free survival (DFS) of patients transplanted for nonmalignant disorders was 88.9 ± 7.5% at 2 years. The event-free survival (EFS) at 2 years in this small cohort for those with a malignant disease and a treosulfan-based conditioning was 54.5 ± 1.5%. We conclude that a treosulfan-based conditioning regimen gives excellent DFS in pediatric HSCT performed for a nonmalignant disorder but with substantial mucosal toxicity. In a malignant disorder a treosulfan-based regimen looks promising but larger, preferably randomized, studies are needed to prove efficacy.

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http://dx.doi.org/10.1080/08880018.2020.1738604	DOI Listing

August 2020

Pediatric acute graft-versus-host disease prophylaxis and treatment: surveyed real-life approach reveals dissimilarities compared to published recommendations.

Authors:

Anita Lawitschka Giovanna Lucchini Brigitte Strahm Jean-Hugues Dalle Adriana Balduzzi Brenda Gibson Cristina Diaz De Heredia Jacek Wachowiak Arnaud Dalissier Kim Vettenranta Isaac Yaniv Victoria Bordon Dorothea Bauer Peter Bader Roland Meisel Christina Peters Selim Corbacioglu

Transpl Int 2020 Jul 2;33(7):762-772. Epub 2020 Apr 2.

Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, University of Hospital Regensburg, Regensburg, Germany.

Pediatric allogeneic hematopoietic cell transplantation (HCT) practices differ from those of adults, particularly the heterogeneity of transplantable nonmalignant diseases and the lower incidence of graft-versus-host disease (GVHD). Several guidelines regarding the management of acute (a) GVHD in adult HCT have been published. We aimed to capture the real-life approaches for pediatric aGVHD prophylaxis/treatment, and data from 75/193 (response rate 39%) EBMT centers (26 countries) were included, representing half (48%) of the pediatric EBMT-HCT activity. Results with ≥75% approval from respondents (74/75) for GVHD prophylaxis after myeloablative HCT for malignancies partially contradict published guidelines: Single-agent cyclosporine A (CsA) was used for matched sibling donor HCT in 47%; blood CsA levels were reported lower; the relapse risk in malignant diseases influenced GVHD prophylaxis with early withdrawal of CsA; distinct longer duration of CsA was employed in nonmalignant diseases. Most centers used additional anti-thymocyte globulin for matched unrelated and mismatched donor HCT, but not for matched siblings. Regarding prophylaxis in nonmyeloablative conditioning (mainly for nonmalignant diseases), responses showed broad heterogeneity. High conformity was found for first-line treatment; however, results regarding steroid-refractory aGVHD indicate an earlier diagnosis in children. Our findings highlight the need for standardized pediatric approaches toward aGVHD prophylaxis/treatment differentiated for malignant and nonmalignant underlying diseases.

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http://dx.doi.org/10.1111/tri.13601	DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384018	PMC

July 2020

Correction: Supportive care during pediatric hematopoietic stem cell transplantation: beyond infectious diseases. A report from workshops on supportive care of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT).

Bone Marrow Transplant 2020 Jun;55(6):1214

Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents, University Hospital, Goethe University, Frankfurt am Main, Germany.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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http://dx.doi.org/10.1038/s41409-020-0838-0	DOI Listing

June 2020

Supportive care during pediatric hematopoietic stem cell transplantation: beyond infectious diseases. A report from workshops on supportive care of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT).

Bone Marrow Transplant 2020 06 6;55(6):1126-1136. Epub 2020 Feb 6.

Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents, University Hospital, Goethe University, Frankfurt am Main, Germany.

Hematopoietic stem cell transplantation (HSCT) is currently the standard of care for many malignant and nonmalignant blood diseases. As several treatment-emerging acute toxicities are expected, optimal supportive measurements critically affect HSCT outcomes. The paucity of good clinical studies in supportive practices gives rise to the establishment of heterogeneous guidelines across the different centers, which hampers direct clinical comparison in multicentric studies. Aiming to harmonize the supportive care provided during the pediatric HSCT in Europe, the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) promoted dedicated workshops during the years 2017 and 2018. The present paper describes the resulting consensus on the management of sinusoidal obstructive syndrome, mucositis, enteral and parenteral nutrition, iron overload, and emesis during HSCT.

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http://dx.doi.org/10.1038/s41409-020-0818-4	DOI Listing

June 2020

Maternal diabetes and risk of childhood cancer in the offspring.

Authors:

Laura K Seppälä Kim Vettenranta Janne Pitkäniemi Elli Hirvonen Maarit K Leinonen Laura-Maria Madanat-Harjuoja

Int J Cancer 2020 08 27;147(3):662-668. Epub 2019 Nov 27.

Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland.

An association between maternal diabetes, its medication and childhood cancer has not been previously explored in a registry-based setting. With a case-control design, we aimed to explore whether maternal diabetes is associated with an increased risk of childhood cancer in the offspring. Combining data from population-based registries, we analyzed a total of 2,029 cases, that is, persons with childhood cancer diagnosed under the age of 20 years between years 1996-2014 and a total of 10,103 matched population controls. The mothers of the cases/controls and their diagnoses of diabetes (DM) before/during pregnancy as well as their insulin/metformin prescriptions during pregnancy were identified. Conditional logistic regression modeling was used to analyze the risk of childhood cancer. The OR for childhood cancer among those exposed to any maternal diabetes was 1.32 (95% CI 1.14-1.54) compared to the offspring of the nondiabetic mothers. The effect of maternal diabetes on the risk of childhood cancer remained elevated even after adjusting for maternal age, parity and smoking. Our data suggest that maternal diabetes medication may reduce the risk for childhood cancer (adjusted OR 0.83, 95% CI 0.36-1.94), especially in gestational diabetes (adjusted OR 0.26, 95% CI 0.05-1.25), compared to the diabetic mothers without medication. The risk of childhood leukemia was significantly higher among children exposed to any maternal diabetes (OR 1.36, CI 1.04-1.77) compared to the unexposed. Maternal diabetes appears to be associated with an increased risk of childhood cancer in the offspring. The possible risk-reducing effect of an exposure to diabetes medication on offspring cancer risk warrants further investigation.

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http://dx.doi.org/10.1002/ijc.32757	DOI Listing

August 2020

Neurologic disorders in long-term survivors of neuroblastoma - a population-based cohort study within the Adult Life after Childhood Cancer in Scandinavia (ALiCCS) research program.

Authors:

Filippa Nyboe Norsker Catherine Rechnitzer Elisabeth Wreford Andersen Karen Markussen Linnet Line Kenborg Anna Sällfors Holmqvist Laufey Tryggvadottir Laura-Maria Madanat-Harjuoja Ingrid Øra Halldora K Thorarinsdottir Kim Vettenranta Andrea Bautz Henrik Schrøder Henrik Hasle Jeanette Falck Winther

Acta Oncol 2020 Feb 8;59(2):134-140. Epub 2019 Oct 8.

Danish Cancer Society Research Center, Childhood Cancer Research Group, Copenhagen, Denmark.

Neuroblastoma is the commonest extracranial solid tumor of childhood, yet rare, and with poor survival before 1990, especially for high-risk disease; thus, information on late effects is sparse. With great advances in cancer treatment, survival has reached 80% in the Nordic countries. The aim of the study was to investigate the risk of developing neurologic disorders after neuroblastoma. Through population-based cancer registries of four Nordic countries we identified 654 5-year survivors of neuroblastoma (diagnosed 1959-2008) and 133,668 matched population comparisons. We grouped neurologic diagnoses from national hospital registries into 11 main diagnostic categories and 56 disease-specific sub-categories and calculated relative risks (RRs), absolute excess risks (AERs), cumulative incidence and mean cumulative count (MCC). Information on cancer treatment was available for 49% of survivors. A hospital contact for a neurologic disorder was observed in 181 survivors 5 years or more from cancer diagnosis with 59 expected, yielding a RR of 3.1 (95% CI 2.7-3.6) and an AER of 16 per 1,000 person-years (95% CI 12-19). The most frequent disorders included epilepsy, paralytic syndromes, diseases of the eyes and ears and hearing loss. The cumulative incidence of any neurologic disorder was 31% in survivors 20 years after cancer diagnosis with a MCC of 0.5 unique diagnoses. All risks were highest in survivors of high-risk neuroblastoma. Neuroblastoma survivors represent a population with a high risk of developing neurologic disorders. Our results should contribute to improving health care planning and underscores the need for systematic follow-up care of this vulnerable group of survivors.

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http://dx.doi.org/10.1080/0284186X.2019.1672892	DOI Listing

February 2020

Intermittent Versus Continuous PEG-Asparaginase to Reduce Asparaginase-Associated Toxicities: A NOPHO ALL2008 Randomized Study.

Authors:

Birgitte Klug Albertsen Kathrine Grell Jonas Abrahamsson Bendik Lund Kim Vettenranta Ólafur G Jónsson Thomas L Frandsen Benjamin O Wolthers Mats Heyman Kjeld Schmiegelow

J Clin Oncol 2019 07 12;37(19):1638-1646. Epub 2019 Apr 12.

2 University of Copenhagen, Copenhagen, Denmark.

Purpose: Asparaginase is an essential drug in childhood acute lymphoblastic leukemia (ALL) therapy and is frequently given for months to obtain continuous asparagine depletion. We randomly assigned patients to continuous versus intermittent pegylated-asparaginase (PEG-asp) treatment, hypothesizing there would be decreased toxicity with unchanged efficacy.

Methods: Children (median age, 4.2 years) treated for non-high-risk ALL according to the Nordic Society for Pediatric Hematology and Oncology ALL2008 protocol received five intramuscular PEG-asp injections (1,000 IU/m) every two weeks and were then randomly assigned to additional three doses (6-week intervals [experimental arm], n = 309) versus 10 doses (2-week intervals [standard arm], n = 316). The primary end point was noninferior (6% margin) disease-free survival. Toxicity reduction was a secondary end point. Occurrence of asparaginase-associated hypersensitivity, pancreatitis, osteonecrosis, and thromboembolism were prospectively registered.

Results: After a median follow-up of 4.1 years, the 5-year disease-free survival was 92.2% (95% CI, 88.6 to 95.8) and 90.8% (95% CI, 87.0 to 94.6) in the experimental and standard arms, respectively. The 3-year cumulative incidence of any first asparaginase-associated toxicity (hypersensitivity [n = 13]; osteonecrosis [n = 29]; pancreatitis [n = 24]; thromboembolism [n = 17]) was 9.3% in the experimental arm and 18.1% in the standard arm ( = .001). Asparaginase-associated toxicity reduction was confirmed in sex- and risk-group-adjusted Cox regression analysis stratified by age (≥ 10 and < 10 years; hazard ratio, 0.48; = .001). The experimental arm had the lowest incidences of all four toxicities, reaching significance for pancreatitis (6-month risk, 5.8% 1.3%; = .002).

Conclusion: The excellent cure rates and reduced toxicity risk support the use of intermittent PEG-asp therapy after the first 10 weeks in future childhood ALL trials that apply prolonged PEG-asp therapy.

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http://dx.doi.org/10.1200/JCO.18.01877	DOI Listing

July 2019

Low burden of minimal residual disease prior to transplantation in children with very high risk acute lymphoblastic leukaemia: The NOPHO ALL2008 experience.

Authors:

Marianne Ifversen Dominik Turkiewicz Hanne V Marquart Jacek Winiarski Jochen Buechner Karin Mellgren Johan Arvidson Jelena Rascon Lenne-Triin Körgvee Hans O Madsen Jonas Abrahamsson Bendik Lund Olafur G Jonsson Carsten Heilmann Mats Heyman Kjeld Schmiegelow Kim Vettenranta

Br J Haematol 2019 03 24;184(6):982-993. Epub 2019 Jan 24.

Department of Paediatrics, University of Helsinki, Helsinki, Finland.

The population-based Nordic/Baltic acute lymphoblastic leukaemia (ALL) Nordic Society for Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol combined minimal residual disease (MRD)-driven treatment stratification with very intense first line chemotherapy for patients with high risk ALL. Patients with MRD ≥5% at end of induction or ≥10 at end of consolidation or following two high risk blocks were eligible for haematopoietic cell transplantation (HCT) in first remission. After at least three high risk blocks a total of 71 children received HCT, of which 46 had MRD ≥5% at end of induction. Ten patients stratified to HCT were not transplanted; 12 received HCT without protocol indication. Among 69 patients with evaluable pre-HCT MRD results, 22 were MRD-positive, one with MRD ≥10 . After a median follow-up of 5·5 years, the cumulative incidence of relapse was 23·5% (95% confidence interval [CI]: 10·5-47·7) for MRD-positive versus 5·1% (95% CI: 1·3-19·2), P = 0·02) for MRD-negative patients. MRD was the only variable significantly associated with relapse (hazard ratio 9·1, 95% CI: 1·6-51·0, P = 0·012). Non-relapse mortality did not differ between the two groups, resulting in disease-free survival of 85·6% (95% CI: 75·4-97·2) and 67·4% (95% CI: 50·2-90·5), respectively. In conclusion, NOPHO block treatment efficiently reduced residual leukaemia which, combined with modern transplant procedures, provided high survival rates, also among pre-HCT MRD-positive patients.

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http://dx.doi.org/10.1111/bjh.15761	DOI Listing

March 2019

Stem cell transplantation for congenital dyserythropoietic anemia: an analysis from the European Society for Blood and Marrow Transplantation.

Haematologica 2019 08 24;104(8):e335-e339. Epub 2019 Jan 24.

Hematology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

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http://dx.doi.org/10.3324/haematol.2018.206623	DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669146	PMC

August 2019

Somatic late effects in 5-year survivors of neuroblastoma: a population-based cohort study within the Adult Life after Childhood Cancer in Scandinavia study.

Authors:

Filippa Nyboe Norsker Catherine Rechnitzer Luise Cederkvist Anna Sällfors Holmqvist Laufey Tryggvadottir Laura-Maria Madanat-Harjuoja Ingrid Øra Halldora K Thorarinsdottir Kim Vettenranta Andrea Bautz Henrik Schrøder Henrik Hasle Jeanette Falck Winther

Int J Cancer 2018 12 16;143(12):3083-3096. Epub 2018 Oct 16.

Danish Cancer Society, Danish Cancer Society Research Center, Copenhagen, Denmark.

Because of the rarity of neuroblastoma and poor survival until the 1990s, information on late effects in neuroblastoma survivors is sparse. We comprehensively reviewed the long-term risk for somatic disease in neuroblastoma survivors. We identified 721 5-year survivors of neuroblastoma in Nordic population-based cancer registries and identified late effects in national hospital registries covering the period 1977-2012. Detailed treatment information was available for 46% of the survivors. The disease-specific rates of hospitalization of survivors and of 152,231 randomly selected population comparisons were used to calculate standardized hospitalization rate ratios (SHRRs) and absolute excess risks (AERs). During 5,500 person-years of follow-up, 501 5-year survivors had a first hospital contact yielding a SHRR of 2.3 (95% CI 2.1-2.6) and a corresponding AER of 52 (95% CI 44-60) per 1,000 person-years. The highest relative risks were for diseases of blood and blood-forming organs (SHRR 3.8; 95% CI 2.7-5.4), endocrine diseases (3.6 [3.1-4.2]), circulatory system diseases (3.1 [2.5-3.8]), and diseases of the nervous system (3.0 [2.6-3.3]). Approximately 60% of the excess new hospitalizations of survivors were for diseases of the nervous system, urinary system, endocrine system, and bone and soft tissue. The relative risks and AERs were highest for the survivors most intensively treated. Survivors of neuroblastoma have a highly increased long-term risk for somatic late effects in all the main disease groups as compared to background levels. Our results are useful for counseling survivors and should contribute to improving health care planning in post-therapy clinics.

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http://dx.doi.org/10.1002/ijc.31631	DOI Listing

December 2018

Graft-versus-host disease in stem cell transplantation.

Authors:

Mervi Taskinen Samppa Ryhänen Kim Vettenranta

Duodecim 2017;133(3):251-8

Graft-versus-host disease (GvHD) remains a major treatment-related risk in patients undergoing stem cell transplantation. Although advances in HLA-typing and graft types have reduced the risk of GvHD, a breakthrough in the treatment of severe GvHD is still lacking. Allogenic stem cell transplant has potentially beneficial immunological effects on the malignant disease necessitating transplantation, and the importance of these effects must be considered when treating GvHD.

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January 2018

Individualized 6-mercaptopurine increments in consolidation treatment of childhood acute lymphoblastic leukemia: A NOPHO randomized controlled trial.

Authors:

Morten Tulstrup Thomas L Frandsen Jonas Abrahamsson Bendik Lund Kim Vettenranta Olafur Gisli Jonsson Hanne Vibeke Hansen Marquart Birgitte Klug Albertsen Mats Heyman Kjeld Schmiegelow

Eur J Haematol 2018 Jan 9;100(1):53-60. Epub 2017 Nov 9.

Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.

Objectives: This randomized controlled trial tested the hypothesis that children with non-high-risk acute lymphoblastic leukemia could benefit from individualized 6-mercaptopurine increments during consolidation therapy (NCT00816049). Primary and secondary end points were end of consolidation minimal residual disease (MRD) positivity and event-free survival.

Methods: 392 patients were randomized to experimental and 396 to standard therapy. Patients allocated to standard therapy received oral 6-mercaptopurine (25 mg/m /day) from days 30 to 85, while the experimental arm received stepwise increments of additional 25 mg/m /day beginning on days 50 and/or 71 unless dose-limiting myelosuppression had occurred.

Results: In the experimental arm, 166 patients (42%) received one dose increment, and 62 (16%) received two. Fifty-seven of 387 (15%) patients in the experimental arm were MRD positive at end of consolidation vs 77 of 389 (20%) in the control arm (P = .08). Five-year probability of event-free survival was 0.89 (95% CI: 0.85-0.93) in the experimental arm vs 0.93 (0.90-0.96) in the control arm (P = .13). The median accumulated length of 6-mercaptopurine treatment interruptions was 7 (IQR 2-12) in the experimental arm vs 4 (IQR 0-10) in the control arm (P = .002).

Conclusion: This study found no benefit from individualized 6-mercaptopurine increments compared to standard therapy.

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http://dx.doi.org/10.1111/ejh.12979	DOI Listing

January 2018

Long-Term Outcomes of Cord Blood Transplantation from an HLA-Identical Sibling for Patients with Bone Marrow Failure Syndromes: A Report From Eurocord, Cord Blood Committee and Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation.

Biol Blood Marrow Transplant 2017 Nov 7;23(11):1939-1948. Epub 2017 Aug 7.

Eurocord, Hôpital Saint Louis, Paris, France; Monacord, Monacord, Centre Scientifique de Monaco, Monaco; Service d'Hématologie et Thérapie Cellulaire, Hôpital Saint-Antoine, Paris, France. Electronic address:

Cord blood transplantation (CBT) from HLA-identical siblings is an attractive option for patients with bone marrow failure (BMF) syndrome because of the low risk of graft-versus-host disease (GVHD) and the absence of risk to the donor. We analyzed outcomes of 117 patients with inherited or acquired BMF syndrome who received CBT from a related HLA-identical donor in European Society for Blood and Marrow Transplantation centers between 1988 and 2014. Ninety-seven patients had inherited and 20 patients acquired BMF syndrome. Eighty-two patients received a single cord blood (CB) unit, whereas 35 patients received a combination of CB and bone marrow cells from the same donor. Median age at CBT was 6.7 years, and median follow-up was 86.7 months. The cumulative incidence function (CIF) of neutrophil recovery was 88.8% (95% CI, 83.1% to 94.9%), 100-day CIF of grades II to IV acute GVHD was 15.2%, and 7-year CIF of chronic GVHD was 14.5%. Overall survival at 7 years was 87.9% (95% CI, 80.8% to 92.6%), 89% for inherited and 81% for acquired BMF syndromes (P = .66). Results of this study are consistent with outcomes of bone marrow transplantation shown by previous series in the same setting and indicate that in pediatric patients with BMF syndrome, CBT from an HLA-identical sibling donor is associated with excellent long-term outcomes and that collection of CB unit at birth of a new sibling is strongly recommended.

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http://dx.doi.org/10.1016/j.bbmt.2017.08.004	DOI Listing

November 2017

Digital Multiplex Ligation-Dependent Probe Amplification for Detection of Key Copy Number Alterations in T- and B-Cell Lymphoblastic Leukemia.

Authors:

Anne Benard-Slagter Ilse Zondervan Karel de Groot Farzaneh Ghazavi Virinder Sarhadi Pieter Van Vlierberghe Barbara De Moerloose Claire Schwab Kim Vettenranta Christine J Harrison Sakari Knuutila Jan Schouten Tim Lammens Suvi Savola

J Mol Diagn 2017 09 19;19(5):659-672. Epub 2017 Jul 19.

Department of Tumour Diagnostics, MRC-Holland, Amsterdam, the Netherlands. Electronic address:

Recurrent and clonal genetic alterations are characteristic of different subtypes of T- and B-cell lymphoblastic leukemia (ALL), and several subtypes are strong independent predictors of clinical outcome. A next-generation sequencing-based multiplex ligation-dependent probe amplification variant (digitalMLPA) has been developed enabling simultaneous detection of copy number alterations (CNAs) of up to 1000 target sequences. This novel digitalMLPA assay was designed and optimized to detect CNAs of 56 key target genes and regions in ALL. A set of digital karyotyping probes has been included for the detection of gross ploidy changes, to determine the extent of CNAs, while also serving as reference probes for data normalization. Sixty-seven ALL patient samples (including B- and T-cell ALL), previously characterized for genetic aberrations by standard MLPA, array comparative genomic hybridization, and/or single-nucleotide polymorphism array, were analyzed single blinded using digitalMLPA. The digitalMLPA assay reliably identified whole chromosome losses and gains (including high hyperdiploidy), whole gene deletions or gains, intrachromosomal amplification of chromosome 21, fusion genes, and intragenic deletions, which were confirmed by other methods. Furthermore, subclonal alterations were reliably detected if present in at least 20% to 30% of neoplastic cells. The diagnostic sensitivity of the digitalMLPA assay was 98.9%, and the specificity was 97.8%. These results merit further consideration of digitalMLPA as a valuable alternative for genetic work-up of newly diagnosed ALL patients.

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http://dx.doi.org/10.1016/j.jmoldx.2017.05.004	DOI Listing

September 2017

Children with low-risk acute lymphoblastic leukemia are at highest risk of second cancers.

Authors:

Stine N Nielsen Frank Eriksson Susanne Rosthoej Mette K Andersen Erik Forestier Henrik Hasle Lisa L Hjalgrim Ann Aasberg Jonas Abrahamsson Mats Heyman Ólafur G Jónsson Kaie Pruunsild Goda E Vaitkeviciené Kim Vettenranta Kjeld Schmiegelow

Pediatr Blood Cancer 2017 Oct 13;64(10). Epub 2017 May 13.

Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Background: The improved survival rates for childhood acute lymphoblastic leukemia (ALL) may be jeopardized by the development of a second cancer, which has been associated with thiopurine therapy.

Procedure: We retrospectively analyzed three sequential Nordic Society of Paediatric Haematology and Oncology's protocols characterized by increasing intensity of thiopurine-based maintenance therapy. We explored the risk of second cancer in relation to protocols, risk group, thiopurine methyltransferase (TPMT) activity, ALL high hyperdiploidy (HeH), and t(12;21)[ETV6/RUNX1].

Results: After median 9.5 years (interquartile range, 5.4-15.3 yrs) of follow-up, 40 of 3,591 patients had developed a second cancer, of whom 38 had non-high-risk B-cell precursor ALL. Patients with standard-risk ALL, who received the longest maintenance therapy, had the highest adjusted hazard of second cancer (hazard ratio [HR], intermediate vs. standard risk: 0.16, 95% CI: 0.06-0.43, P < 0.001; HR, high vs. standard risk: 0.09, 95% CI: 0.02-0.49, P = 0.006); no significant effects of protocol, age, or white blood cell count at diagnosis, ALL HeH, or t(12;21)[ETV6/RUNX1] were observed. A subset analysis on the patients with standard-risk ALL did not show an increased hazard of second cancer from either HeH or t(12;21) (adjusted HR 2.02, 95% CI: 0.69-5.96, P = 0.20). The effect of low TPMT low activity was explored in patients reaching maintenance therapy in clinical remission (n = 3,368); no association with second cancer was observed (adjusted HR 1.43, 95% CI: 0.54-3.76, P = 0.47).

Conclusions: The rate of second cancer was generally highest in patients with low-risk ALL, but we could not identify a subset at higher risk than others.

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http://dx.doi.org/10.1002/pbc.26518	DOI Listing

October 2017

Hepatotoxicity During Maintenance Therapy and Prognosis in Children With Acute Lymphoblastic Leukemia.

Authors:

Maria S Ebbesen Ulrikka Nygaard Susanne Rosthøj Ditte Sørensen Jacob Nersting Kim Vettenranta Finn Wesenberg Jon Kristinsson Arja Harila-Saari Kjeld Schmiegelow

J Pediatr Hematol Oncol 2017 04;39(3):161-166

*Department of Pediatrics and Adolescent Medicine, Rigshospitalet †Section of Biostatistics, Department of Public Health #The Institute Clinical Medicine, University of Copenhagen, Copenhagen Denmark ‡Department of Pediatrics, University Hospital, Tampere, Finland §Department of Pediatrics, The University Hospital, Oslo, Norway ∥Department of Pediatrics, University Hospital, Reykjavik, Iceland ¶Department of Women's and Children's Health, Karolinska University Hospital and Karolinska Institutet, Solna, Stockholm, Sweden.

Hepatotoxicity is a known toxicity to treatment of childhood acute lymphoblastic leukemia. Hepatotoxicity occurs during maintenance therapy and is caused by metabolites of 6-Mercaptopurine (6 MP) and Methotrexate (MTX). Our objective was to investigate the association between alanine aminotransferases (ALAT) levels and relapse rate. We included 385 patients enrolled in the NOPHO ALL-92 protocol. Data on ALAT levels, 6 MP and MTX doses, cytotoxic MTX/6 MP metabolites, and thiopurine methyltransferase (TPMT) activity were prospectively registered. In total, 91% of the patients had a mean ALAT (mALAT) level above upper normal limit (40 IU/L) and ALAT levels were positively correlated to 6 MP doses (rs=0.31; P<0.001). In total, 47 patients suffered a relapse, no difference in mALAT levels were found in these compared with nonrelapse patients (median, 107 vs. 98 IU/L; P=0.39). mALAT levels in patients classified as TPMT high activity (TPMT) were higher than in TPMT low-activity patients (median, 103 vs. 82 IU/L; P=0.03). In a Cox regression model risk of relapse was not associated with ALAT levels (P=0.56). ALAT levels increased 2.7%/month during the last year of maintenance therapy (P<0.001). In conclusion, elevated ALAT levels are associated with TPMT and may indicate treatment adherence in these patients. If liver function is normal, elevated ALAT levels should not indicate treatment adaptation.

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http://dx.doi.org/10.1097/MPH.0000000000000733	DOI Listing

April 2017

Efficacy and Toxicity of Intrathecal Liposomal Cytarabine in First-line Therapy of Childhood Acute Lymphoblastic Leukemia.

Authors:

Mette Levinsen Arja Harila-Saari Kathrine Grell Olafur Gisli Jonsson Mervi Taskinen Jonas Abrahamsson Kim Vettenranta Ann Åsberg Juha Risteli Jesper Heldrup Kjeld Schmiegelow

J Pediatr Hematol Oncol 2016 11;38(8):602-609

*Department of Paediatrics and Adolescent Medicine, The University Hospital Rigshospitalet ‡Section of Biostatistics, Department of Public Health ‡‡The Institute of Clinical medicine, The Faculty of Medicine, University of Copenhagen, Copenhagen, Denmark †Department of Pediatrics, Astrid Lindgrens Hospital, Stockholm ¶Department of Pediatrics, Institution of Clinical Sciences, Sahlgrenska University Hospital, Gothenburg ††Department of Pediatrics, Skåne University Hospital, Lund, Sweden §Department of Pediatrics, Landspitali University Hospital, Reykjavík, Iceland ∥Division of Hematology-Oncology and Stem Cell Transplantation, Children and Adolescents, Helsinki **Department of Clinical Chemistry, Institute of Diagnostics, University of Oulu, Oulu, Finland #Department of Pediatrics, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway, NY.

We investigated efficacy and toxicity of replacing conventional triple (cytarabine, methotrexate, and hydrocortisone) intrathecal therapy (TIT) with liposomal cytarabine during maintenance therapy among 40 acute lymphoblastic leukemia patients. Twenty-eight of 29 patients in the TIT arm received TIT and 9/11 in the liposomal cytarabine arm received liposomal cytarabine. Arachnoiditis occurred in all initial 5 patients given liposomal cytarabine and intrathecal prednisolone succinate. Subsequently liposomal cytarabine was given with systemic dexamethasone. Neurotoxicity occurred at 6/27 liposomal cytarabine administrations with concomitant dexamethasone (22%). More liposomal cytarabine-treated patients experienced neurotoxicity in relation to intrathecal therapy during at least 1 cycle compared with TIT-treated patients (6/9 [67%] vs. 3/28 [11%], P=0.002). Apart from intermittent lower extremity sensory pain in 1 liposomal cytarabine-treated patient, no permanent adverse neurological sequelae were observed. In intention-to-treat analysis, projected 5-year event-free survival (pEFS-5y) was borderline higher for patients in the liposomal cytarabine arm compared with the TIT arm (1.0 vs. 0.69, P=0.046). However, pEFS-5y and projected 5-year relapse-free survival did not differ signficantly between patients treated with liposomal cytarabine or TIT (1.0 vs. 0.73, P=0.10; 1.0 vs. 0.76, P=0.12). Larger prospective trials are needed to explore whether liposomal cytarabine should be used as first-line prevention of relapse.

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http://dx.doi.org/10.1097/MPH.0000000000000642	DOI Listing

November 2016

Maintenance therapy of childhood acute lymphoblastic leukemia revisited-Should drug doses be adjusted by white blood cell, neutrophil, or lymphocyte counts?

Authors:

Kjeld Schmiegelow Jacob Nersting Stine Nygaard Nielsen Mats Heyman Finn Wesenberg Jon Kristinsson Kim Vettenranta Henrik Schrøeder Richard Weinshilboum Katrine Lykke Jensen Kathrine Grell Susanne Rosthoej

Pediatr Blood Cancer 2016 12 22;63(12):2104-2111. Epub 2016 Jul 22.

Section of Biostatistics, Department of Public Health, The University of Copenhagen, Copenhagen, Denmark.

Background: 6-Mercaptopurine (6MP) and methotrexate (MTX) based maintenance therapy is a critical phase of childhood acute lymphoblastic leukemia treatment. Wide interindividual variations in drug disposition warrant frequent doses adjustments, but there is a lack of international consensus on dose adjustment guidelines.

Procedure: To identify relapse predictors, we collected 28,255 data sets on drug doses and blood counts (median: 47/patient) and analyzed erythrocyte (Ery) levels of cytotoxic 6MP/MTX metabolites in 9,182 blood samples (median: 14 samples/patient) from 532 children on MTX/6MP maintenance therapy targeted to a white blood cell count (WBC) of 1.5-3.5 × 10 /l.

Results: After a median follow-up of 13.8 years for patients in remission, stepwise Cox regression analysis did not find age, average doses of 6MP and MTX, hemoglobin, absolute lymphocyte counts, thrombocyte counts, or Ery levels of 6-thioguanine nucleotides or MTX (including its polyglutamates) to be significant relapse predictors. The parameters significantly associated with risk of relapse (N = 83) were male sex (hazard ratio [HR] 2.0 [1.3-3.1], P = 0.003), WBC at diagnosis (HR = 1.04 per 10 × 10 /l rise [1.00-1.09], P = 0.048), the absolute neutrophil count (ANC; HR = 1.7 per 10 /l rise [1.3-2.4], P = 0.0007), and Ery thiopurine methyltransferase activity (HR = 2.7 per IU/ml rise [1.1-6.7], P = 0.03). WBC was significantly related to ANC (Spearman correlation coefficient, r = 0.77; P < 0.001), and only a borderline significant risk factor for relapse (HR = 1.28 [95% CI: 1.00-1.64], P = 0.046) when ANC was excluded from the Cox model.

Conclusions: This study indicates that a low neutrophil count is likely to be the best hematological target for dose adjustments of maintenance therapy.

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http://dx.doi.org/10.1002/pbc.26139	DOI Listing

December 2016

Speckle tracking echocardiography detects decreased cardiac longitudinal function in anthracycline-exposed survivors of childhood cancer.

Authors:

Kaisa Ylänen Anneli Eerola Kim Vettenranta Tuija Poutanen

Eur J Pediatr 2016 Oct 13;175(10):1379-86. Epub 2016 Sep 13.

Department of Pediatrics, Tampere University Hospital, PO BOX 2000, FIN-33521, Tampere, Finland.

Unlabelled: Longitudinal motion significantly contributes to the contraction of the ventricles. We studied the left (LV) and right ventricular (RV) longitudinal functions in 75 anthracycline-exposed, long-term childhood cancer survivors and 75 healthy controls with conventional echocardiography, tissue Doppler imaging (TDI), speckle tracking echocardiography (STE) of the mitral and tricuspid annular motion, and real-time three-dimensional echocardiography (RT-3DE). Cardiac magnetic resonance (CMR) imaging was performed on 61 of the survivors. The survivors had lower systolic myocardial velocities in the LV and lower diastolic velocities in both ventricles by TDI than did their healthy peers. The STE-based tissue motion annular displacement (TMAD) values describing the LV and RV systolic longitudinal function (MAD and TAD mid%, respectively) were also lower among the survivors (15.4 ± 2.4 vs. 16.1 ± 2.2 %, p = 0.049 and 22.5 ± 3.0 vs. 23.5 ± 3.0 %, p = 0.035). MAD and TAD mid in millimeters correlated with the respective ventricular volumes measured with RT-3DE or CMR.

Conclusion: Childhood cancer survivors exposed to low to moderate anthracycline doses had decreased longitudinal systolic and diastolic functions (TDI or STE) compared with healthy controls. The STE-based TMAD is a fast and reproducible method to assess cardiac longitudinal function. What is Known? • High anthracycline doses cause LV dysfunction as evidenced by a decreased ejection fraction. What is new? • Low to moderate anthracycline doses also have a negative impact on the LV and RV longitudinal systolic and diastolic function. • TMAD is a new and fast method to assess the cardiac longitudinal function after anthracycline exposure.

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http://dx.doi.org/10.1007/s00431-016-2776-9	DOI Listing

October 2016

Viremic co-infections in children with allogeneic haematopoietic stem cell transplantation are predominated by human polyomaviruses.

Authors:

Minna Koskenvuo Jaana Rahiala Mohammadreza Sadeghi Matti Waris Tytti Vuorinen Maija Lappalainen Päivi Norja Mari Toppinen Ulla Saarinen-Pihkala Tobias Allander Maria Söderlund-Venermo Klaus Hedman Olli Ruuskanen Kim Vettenranta

Infect Dis (Lond) 2017 Jan 28;49(1):35-41. Epub 2016 Jul 28.

a Division of Hematology-Oncology and Stem Cell Transplantation , Children's Hospital, Helsinki University Central Hospital, University of Helsinki , Finland.

Background: Viral infections remain the cause of key complications following haematopoietic stem cell transplantation (HSCT). The impact of multiple, concurrent viral reactivations/infections remains to be delineated.

Methods: The clinical correlates of single or multiple viremic infections following HSCT and especially the occurrence of respiratory viruses in the bloodstream were investigated. We retrospectively searched for 23 viruses in a total of 184 sera from 53 paediatric patients. The time-points of interest were pre-HSCT, one, two and three months post-HSCT, and at discharge or death. The viruses were analyzed by quantitative or qualitative PCR.

Results: Of the 53 patients, 13 (25%) had viraemias by multiple viruses and 27 (51%) by a single virus. Thirteen patients (25%) had no viruses detected by PCR during the study period. In the children with viremic co-infections, polyomaviruses predominated over herpes viruses. Nearly half the patients, 24/53 (45%) had a polyomavirus in their serum at one or more time-points. At 12/15 time-points and in 11/13 patients with co-infections polyomaviruses were involved, compared with 6/15 time-points and 6/13 patients for cytomegalovirus. Acute graft-versus-host disease (GvHD) and steroid use were significant risk factors for the viraemias caused by more than one virus.

Conclusions: Viral co-detection is a common finding in children undergoing HSCT. With large-scale viral screening also viruses other than CMV could be found as potential pathogens. In this study, BKPyV predominated over CMV as a contributor in viraemias caused by multiple viruses in children receiving HSCT.

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http://dx.doi.org/10.1080/23744235.2016.1210821	DOI Listing

January 2017

Single-centre study reports a 84% five-year overall survival rate for paediatric solid tumours.

Authors:

Eero Teppo Jarkko Penttinen Outi Myöhänen Kim Vettenranta Olli Lohi

Acta Paediatr 2016 Aug 24;105(8):952-8. Epub 2016 Apr 24.

Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland.

Aim: We investigated the characteristics and outcome of paediatric patients with solid tumours diagnosed and treated at the Tampere University Hospital, one of the five tertiary referral centres in Finland, for children and adolescents with malignancies.

Methods: This retrospective cohort study collected data from hospital medical records on survival, diagnosis, age, sex, tumour size and stage at diagnosis. We also observed the disease recurrence and use of autologous haematopoietic stem cell transplantation. Data analyses were carried out with the Kaplan-Meier method, various nonparametric and parametric tests, and Cox regression modelling.

Results: Between 1987 and May 2015, 424 children (59% boys), with a median age of 6.4 (IQR 2.5-11.8) years at diagnosis, were diagnosed and followed up for a median of 7.5 (range 0-27.9) years. Central nervous system (CNS) tumours were the most common (38%), followed by lymphomas (19%), soft tissue sarcomas (10%), renal tumours (9%) and neuroblastomas (9%). The five-year overall survival rate of all solid tumour patients was 84% (95% CI, 81-88%), 82% (95% CI, 76-89%) for CNS and 85% (95% CI, 80-90%) for non-CNS tumours. Advanced tumour stage at diagnosis predicted a poor prognosis.

Conclusion: The treatment results in our study are comparable with those previously published. A comprehensive local database allows for a timely follow-up of the characteristics and quality of treatment of childhood malignancies.

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http://dx.doi.org/10.1111/apa.13425	DOI Listing

August 2016

Polyomaviruses BK, JC, KI, WU, MC, and TS in children with allogeneic hematopoietic stem cell transplantation.

Authors:

Jaana Rahiala Minna Koskenvuo Mohammadreza Sadeghi Matti Waris Tytti Vuorinen Maija Lappalainen Ulla Saarinen-Pihkala Tobias Allander Maria Söderlund-Venermo Klaus Hedman Olli Ruuskanen Kim Vettenranta

Pediatr Transplant 2016 May 6;20(3):424-31. Epub 2016 Jan 6.

Division of Hematology-Oncology and Stem Cell Transplantation, Children's Hospital, University of Helsinki, Helsinki, Finland.

Timely and reliable detection of viruses is of key importance in early diagnosis of infection(s) following allogeneic HSCT. Among the immunocompetent, infections with BKPyV and JCPyV are mostly subclinical, while post-HSCT, the former may cause HC and the latter PML. The epidemiology and clinical impact of the newly identified KIPyV, WUPyV, MCPyV, and TSPyV in this context remain to be defined. To assess the incidence and clinical impact of BKPyV, JCPyV, KIPyV, WUPyV, MCPyV, and TSPyV infections, we performed longitudinal molecular surveillance for DNAemias of these HPyVs among 53 pediatric HSCT recipients. Surveillance pre-HSCT and for three months post-HSCT revealed BKPyV DNAemia in 20 (38%) patients. Our data demonstrate frequent BKPyV DNAemia among pediatric patients with HSCT and the confinement of clinical symptoms to high copy numbers alone. MCPyV and JCPyV viremias occurred at low and TSPyV viremia at very low prevalences. KIPyV or WUPyV viremias were not demonstrable in this group of immunocompromised patients.

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http://dx.doi.org/10.1111/petr.12659	DOI Listing

May 2016