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Autor(en)	Titel	Quelle
Nachman J	Allotransplantation in pediatric HL.	Blood 2009 Sep 3; 114: 2008
Nägele V, Kratzer A, Zugmaier G, Holland C, Hijazi Y, Topp MS, Gökbuget N, Baeuerle PA, Kufer P, Wolf A, Klinger M	Changes in clinical laboratory parameters and pharmacodynamic markers in response to blinatumomab treatment of patients with relapsed/refractory ALL.	Experimental hematology & oncology 2017, 6: 14
Blinatumomab has shown a remission rate of 69% in an exploratory single-arm, phase II dose-escalation study in adult patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). We evaluated changes in laboratory parameters and immunopharmacodynamic markers in patients who received blinatumomab in the exploratory phase II study.
Nägele V, Zugmaier G, Goebeler ME, Viardot A, Bargou R, Kufer P, Klinger M	Relationship of T- and B-cell kinetics to clinical response in patients with relapsed/refractory non-Hodgkin lymphoma treated with blinatumomab.	Experimental hematology 2021,S0301-472X00245
Blinatumomab is a first-in-class immunotherapy based on the bispecific T-cell engager (BiTE®) immune-oncology platform, which redirects CD3 T cells to kill CD19 target cells. The objective of this analysis was to describe the correlation between B- and T-cell kinetics and response to blinatumomab in patients with relapsed or refractory (r/r) non-Hodgkin lymphoma (NHL). The clinical efficacy of treatment with blinatumomab in patients with r/r NHL was recently investigated in a phase 1 dose-escalation and expansion trial (NCT00274742) wherein 76 patients received blinatumomab by continuous intravenous infusion at various doses (0.5-90 μg/m/day). B-Cell depletion and expansion of CD3, CD4, and CD8 T cells was analyzed in patients stratified per clinical response (complete response [CR], n = 16; partial response [PR], stable disease [SD], or progressive disease [PD], n = 54) for at least 4 weeks (additional 4 weeks after clinical benefit) from the date of administration of blinatumomab until dose-limiting toxicity or PD. B-cell depletion kinetics were faster in patients who had a CR than in patients who did not have a complete response (PR, SD, or PD). T-cell expansion (T-cell counts exceeding the baseline level on day 22) was more pronounced in patients with CR than in patients without CR. T-cell expansion in patients with CR correlated with increased T-cell counts of both CD4 and CD8 T cells compared with patients without CR. Patients with r/r NHL who achieved a CR had faster B-cell depletion and increased expansion of CD3, CD4, and CD8 T cells than patients who did not achieve a CR.
Naik RP, Streiff MB, Haywood C Jr, Nelson JA, Lanzkron S	Venous thromboembolism in adults with sickle cell disease: a serious and under-recognized complication.	The American journal of medicine 2013, 126: 443
Sickle cell disease is recognized as a hypercoagulable state; however, the frequency and characteristics of venous thromboembolism in sickle cell patients have not been well defined. The purpose of this study was to establish the prevalence and risk factors for venous thromboembolism in a large cohort of patients with sickle cell disease and determine the relationship between venous thromboembolism and mortality.
Namouni F, Doz F, Tanguy ML, Quintana E, Michon J, Pacquement H, Bouffet E, Gentet JC, Plantaz D, Lutz P, Vannier JP, Validire P, Neuenschwander S, Desjardins L, Zucker JM	High-dose chemotherapy with carboplatin, etoposide and cyclophosphamide followed by a haematopoietic stem cell rescue in patients with high-risk retinoblastoma: a SFOP and SFGM study.	European journal of cancer (Oxford, England : 1990) 1997, 33: 2368
This study investigates the role of high-dose chemotherapy with haematopoietic stem cell rescue as consolidation treatment in high-risk retinoblastoma (extraocular disease at diagnosis or relapse or invasion of cut end of optic nerve). 25 patients received high-dose chemotherapy including carboplatin (250 mg/m2/day from day 1 to day 5 for the 6 first patients and 350 mg/m2/day from day 1 to day 5 for the other patients), etoposide (350 mg/m2/day from day 1 to day 5) and cyclophosphamide (1.6 g/m2/day from day 2 to day 5) (CARBOPEC) followed by autologous haematopoietic stem cell rescue. 19 patients received this drug combination for chemosensitive extraocular relapse. The other 6 patients with histological high-risk factors were given this treatment as consolidation after enucleation and conventional chemotherapy. The three year disease-free survival was 67.1%. In 7 of the 9 relapsing patients, the first site of relapse was the central nervous system. All patients with central nervous system disease died except one. The main toxicity was haematological and digestive (mucositis and diarrhoea). 2 of the 13 evaluable patients had grade III and IV ototoxicity. One patient experienced an acute grade I reversible cardiotoxicity. The CARBOPEC regimen seems to be a promising therapeutic strategy in patients with high-risk retinoblastoma, especially those with bone and/or bone marrow involvement. This treatment did not improve the outcome of patients with central nervous system disease.
Naouri M, Schill T, Maruani A, Bross F, Lorette G, Rossler J	Successful treatment of ulcerated haemangioma with propranolol.	Journal of the European Academy of Dermatology and Venereology : JEADV 2010, 24: 1109
Ulceration is a frequent complication of proliferating haemangioma.
Netzwerk ActiveOncoKids	S2k-Leitlinie: Bewegungsförderung und Bewegungstherapie in der pädiatrischen Onkologie - S2k-Leitlinie der Gesellschaft für Pädiatrische Onkologie und Hämatologie - Arbeitsgemeinschaft Netzwerk ActiveOncoKids.	AWMF online 10/2021
The National Academies - National Research Council	Report in Brief. Beir VII: Health Risks from Exposure to Low Levels of Ionizing Radiation.	National Academy Press 2006
Narla A, Vlachos A, Nathan DG	Diamond Blackfan anemia treatment: past, present, and future.	Seminars in hematology 2011, 48: 117
Despite significant improvements in our understanding of the pathophysiology of Diamond Blackfan anemia (DBA), there have been few advances in therapy. The cornerstones of treatment remain corticosteroids, chronic red blood cell transfusions, and hematopoietic stem cell transplantation, each of which is fraught with complications. In this article, we will review the history of therapies that have been offered to patients with DBA, summarize the current standard of care, including management of side effects, and discuss novel therapeutics that are being developed in the context of the research into the roles of ribosomal haplo-insufficiency and p53 activation in Diamond Blackfan anemia.
National Toxicology Program	NTP-CERHR monograph on the potential human reproductive and developmental effects of hydroxyurea.	NTP CERHR MON 2008,:vii-viii, v, ix-III1
The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) conducted an evaluation of the potential for hydroxyurea to cause adverse effects on reproduction and development in humans. Hydroxyurea is a drug used to treat cancer, sickle cell disease, and thalassemia. It is the only treatment for sickle cell disease in children, aside from blood transfusion and, in severe cases, hematopoietic stem cell transplantation. Hydroxyurea is FDA-approved for use in adults with sickle cell anemia to reduce the frequency of painful crises and the need for blood transfusions. Hydroxyurea may be given to children and adults with sickle cell disease for an extended period of time or for repeated cycles of therapy. Treatment with hydroxyurea is associated with known side effects such as cytotoxicity and myelosuppression, and hydroxyurea is genotoxic (can damage DNA). CERHR selected hydroxyurea for evaluation because of: its increasing use for treatment of sickle cell disease in children and adults, knowledge that it inhibits DNA synthesis and is cytotoxic, and published evidence of reproductive and developmental toxicity in rodents. The results of this evaluation are published in the NTP-CERHR Monograph on Hydroxyurea, which includes the NTP Brief and Expert Panel Report on the Reproductive and Developmental Toxicity of Hydroxyurea. Additional information related to the evaluation process, including public comments received on the draft NTP Brief and the final expert panel report, are available on the CERHR website (http:// cerhr.niehs.nih.gov/). See hydroxyurea under
Nazar GB, Hoffman HJ, Becker LE, Jenkin D, Humphreys RP, Hendrick EB	Infratentorial ependymomas in childhood: prognostic factors and treatment.	J Neurosurg 1990, 72: 408
Needle MN, Goldwein JW, Grass J, Cnaan A, Bergman I, Molloy P, Sutton L, Zhao H, Garvin JH Jr, Phillips PC	Adjuvant chemotherapy for the treatment of intracranial ependymoma of childhood.	Cancer 1997, 80: 341
BACKGROUND: Current treatment for childhood intracranial ependymomas with surgery and radiation therapy (RT) yields 5-year survival rates ranging from 50-70% after complete resection to 0-30% after incomplete surgical resection. The role of chemotherapy in the treatment of ependymoma has not been established. In this pilot study, children with newly diagnosed intracranial ependymoma were treated with RT and chemotherapy using agents comparable to those found to be active in the treatment of intracranial ependymoma in infants. METHODS: Nineteen children age 3-14 years (median, 7.5 years) were treated with postoperative RT and chemotherapy. Chemotherapy was comprised of carboplatin, 560 mg/m2, with vincristine, 1.5 mg/m2, weekly for 3 weeks, alternating at 4-week intervals with ifosfamide, 1.8 g/m2, and etoposide, 100 mg/m2, for 5 consecutive days for a total of 4 cycles. RESULTS: The 5-year progression free survival (PFS) estimate was 74%. The extent of surgical resection was not a significant prognostic factor in this study. By contrast, ependymomas located in the posterior fossa were associated with a higher rate of progression (P = 0.036). Toxicity, limited predominantly to myelosuppression, was manageable. CONCLUSIONS: The PFS for children with postoperative residual ependymoma treated with RT and chemotherapy in this study was higher than published survival results for RT alone. These results suggest a role for multialkylator chemotherapy in incompletely resected intracranial ependymoma and provide the rationale for a randomized trial comparing this strategy with conventional postoperative RT.
Neglia JP, Robison LL, Stovall M, Liu Y, Packer RJ, Hammond S, Yasui Y, Kasper CE, Mertens AC, Donaldson SS, Meadows AT, Inskip PD	New primary neoplasms of the central nervous system in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.	Journal of the National Cancer Institute 2006 Nov 1; 98: 1528
Subsequent primary neoplasms of the central nervous system (CNS) have frequently been described as late events following childhood leukemia and brain tumors. However, the details of the dose-response relationships, the expression of excess risk over time, and the modifying effects of other host and treatment factors have not been well defined.
Negre O, Eggimann AV, Beuzard Y, Ribeil JA, Bourget P, Borwornpinyo S, Hongeng S, Hacein-Bey S, Cavazzana M, Leboulch P, Payen E	Gene Therapy of the ß-Hemoglobinopathies by Lentiviral Transfer of the ß(A(T87Q))-Globin Gene.	Human gene therapy 2016, 27: 148
ß-globin gene disorders are the most prevalent inherited diseases worldwide and result from abnormal ß-globin synthesis or structure. Novel therapeutic approaches are being developed in an effort to move beyond palliative management. Gene therapy, by ex vivo lentiviral transfer of a therapeutic ß-globin gene derivative (ß(AT87Q)-globin) to hematopoietic stem cells, driven by cis-regulatory elements that confer high, erythroid-specific expression, has been evaluated in human clinical trials over the past 8 years. ß(AT87Q)-globin is used both as a strong inhibitor of HbS polymerization and as a biomarker. While long-term studies are underway in multiple centers in Europe and in the United States, proof-of-principle of efficacy and safety has already been obtained in multiple patients with ß-thalassemia and sickle cell disease.
Nemes K, Bens S, Bourdeaut F, Hasselblatt M, Kool M, Johann P, Kordes U, Schneppenheim R, Siebert R, Frühwald MC, In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A (eds)	Rhabdoid Tumor Predisposition Syndrome.	GeneReviews 2017
Nemes K, Frühwald MC	Emerging therapeutic targets for the treatment of malignant rhabdoid tumors.	Expert opinion on therapeutic targets 2018, 22: 365
Malignant Rhabdoid Tumor (MRT) is a rare and highly aggressive malignancy primarily affecting infants and young children. The most common anatomic locations are the central nervous system (AT/RT), the kidneys (RTK) and other soft tissues (eMRT). The genetic origin of this disease is linked to mutations in SMARCB1, a gene encoding a core subunit of the SWI/SNF chromatin-remodeling complex. Areas covered: Conventional multimodal treatment may offer a significant survival benefit to certain patients. It remains to be determined, however, which patients will prove resistant to chemotherapy and need novel therapeutic approaches. Herein we discuss key signal transduction pathways involved in the pathogenesis of rhabdoid tumors for potential targeted therapy (EZH2, DNMT, HDAC, CDK4/6/Cyclin D1/Rb, AURKA, SHH/GLI1, Wnt/ß-Catenin, immunotherapy). Additional agents currently evaluated in preclinical settings and experimental clinical trials are discussed. Expert opinion: MRTs are genetically homogeneous, but epigenetically distinct malignancies. While there is an abundance of experimental in vitro studies evaluating potential therapeutic avenues, a dearth of clinical trials specifically for this entity persists. In order to improve outcome patients need to be carefully stratified and treated by targeted therapies combined with conventional chemotherapy or with new, less selective experimental agents in phase I/II clinical trials.
Nemes K, Clément N, Kachanov D, Bens S, Hasselblatt M, Timmermann B, Schneppenheim R, Gerss J, Siebert R, Furtwängler R, Bourdeaut F, Frühwald MC, EU-RHAB consortium	The extraordinary challenge of treating patients with congenital rhabdoid tumors-a collaborative European effort.	Pediatric blood & cancer 2018, 65:e26999
Congenital rhabdoid tumors are rare and highly aggressive malignancies. In general, patients are considered to be incurable and are often treated using an exclusive, primarily palliative approach.
Nemes K, Bens S, Kachanov D, Teleshova M, Hauser P, Simon T, Tippelt S, Woessmann W, Beck O, Flotho C, Grigull L, Driever PH, Schlegel PG, Khurana C, Hering K, Kolb R, Leipold A, Abbink F, Gil-Da-Costa MJ, Benesch M, Kerl K, Lowis S, Marques CH, Graf N, Nysom K, Vokuhl C, Melchior P, Kröncke T, Schneppenheim R, Kordes U, Gerss J, Siebert R, Furtwängler R, Frühwald MC	Clinical and genetic risk factors define two risk groups of extracranial malignant rhabdoid tumours (eMRT/RTK).	European journal of cancer 2021, 142: 112
Extracranial rhabdoid tumours are rare, highly aggressive malignancies primarily affecting young children. The EU-RHAB registry was initiated in 2009 to prospectively collect data of rhabdoid tumour patients treated according to the EU-RHAB therapeutic framework.
Nenning UC, Eckert C, Wellmann S, Barth A, Henze G, Seeger K	Re: Prognostic significance of a short sequence insertion in the MCL-1 promoter in chronic lymphocytic leukemia.	Journal of the National Cancer Institute 2005, 97: 1091-2; author reply 1093
Ness KK, Krull KR, Jones KE, Mulrooney DA, Armstrong GT, Green DM, Chemaitilly W, Smith WA, Wilson CL, Sklar CA, Shelton K, Srivastava DK, Ali S, Robison LL, Hudson MM	Physiologic frailty as a sign of accelerated aging among adult survivors of childhood cancer: a report from the St Jude Lifetime cohort study.	J Clin Oncol 2013, 31: 4496
Frailty, a phenotype reported among 9.9% of individuals 65 years old and older (9.6% of women; 5.2% of men), has not been assessed among adult childhood cancer survivors (CCS). We estimated the prevalence of frailty and examined associations with morbidity and mortality.
Neth O, Seidemann K, Jansen P, Mann G, Tiemann M, Ludwig W, Riehm H, Reiter A	Precursor B-cell lymphoblastic lymphoma in childhood and adolescence.	Med Pediatr Oncol 2000, 35: 20
Nettersheim D, Oing C, Schönberger S, Skowron M, Vermeulen M, Müller M, Watolla M, Bremmer F, Pfister D, Calaminus G, Looijenga L, Lorch A, Albers P	[Current research on pediatric and adult germ cell tumors : A report from the first "Düsseldorfer Testis Cancer Day"].	Der Urologe 2019, 58: 804
Neuendank A, Hartmann R, Fengler R, Erttmann R, Zintl F, Koscielniak E, Henze G	Interim results of a phase II study with idarubicin in relapsed childhood acute lymphoblastic leukemia.	Haematol Blood Transfus 1995, 254
von Neuhoff C, Reinhardt D, Sander A, Zimmermann M, Bradtke J, Betts DR, Zemanova Z, Stary J, Bourquin JP, Haas OA, Dworzak MN, Creutzig U	Prognostic Impact of Specific Chromosomal Aberrations in a Large Group of Pediatric Patients With Acute Myeloid Leukemia Treated Uniformly According to Trial AML-BFM 98.	Journal of clinical oncology 2010, 28: 2682
PURPOSE Because cytogenetic data are essential for risk stratification of childhood acute myeloid leukemia (AML), the impact of chromosomal aberrations is crucial. PATIENTS AND METHODS Data of a large group of patients younger than 18 years treated according to study AML-Berlin-Frankfurt-Münster (BFM) 98 (n = 454), including their cytogenetics, were analyzed. Results The favorable outcome in the subgroups of patients with t(8;21), inv(16), and t(15;17), with an overall survival of 91% (SE, 4%), 92% (SE, 6%), and 87% (SE, 5%), respectively, was confirmed. Within this group, the 5-year probability of event-free survival (pEFS) of all 17 children with t(8;21) and additional aberrations apart from del(9q) or -X/-Y was 100%. As expected, the cytogenetic finding of a complex karyotype (n = 35; pEFS, 33%; SE, 8%) or a monosomy 7 (n = 12; pEFS, 17%; SE, 11%) was associated with a poor outcome. Compared with remaining patients with cytogenetic data (pEFS, 48%; SE, 2%), prognosis in patients with an MLL rearrangement (n = 91) was inferior (pEFS, 34%; SE, 5%; P = .0005). Particularly, children with t(9;11) and additional aberrations (n = 13; pEFS, 31%; SE, 14%) and MLL rearrangements other than t(9;11) and t(11;19) (n = 41; pEFS, 24%; SE, 7%) had an unfavorable outcome. Nine patients with aberrations in 12p showed an adverse prognosis (pEFS, 11%; SE, 10%). The outcome of patients with aberrations of chromosome 5 (n = 13) was better than expected (pEFS, 50%; SE, 13%). CONCLUSION Because the prognostic value of rare recurrent chromosomal aberrations still has to be elucidated, these data will contribute to future risk stratification for the treatment of pediatric AML.
Neunert C, Lim W, Crowther M, Cohen A, Solberg L Jr, Crowther MA, American Society of Hematology	The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia.	Blood 2011; 117: 4190
Immune thrombocytopenia (ITP) is commonly encountered in clinical practice. In 1996 the American Society of Hematology published a landmark guidance paper designed to assist clinicians in the management of this disorder. Since 1996 there have been numerous advances in the management of both adult and pediatric ITP. These changes mandated an update in the guidelines. This guideline uses a rigorous, evidence-based approach to the location, interpretation, and presentation of the available evidence. We have endeavored to identify, abstract, and present all available methodologically rigorous data informing the treatment of ITP. We provide evidence-based treatment recommendations using the GRADE system in those areas in which such evidence exists. We do not provide evidence in those areas in which evidence is lacking, or is of lower quality--interested readers are referred to a number of recent, consensus-based recommendations for expert opinion in these clinical areas. Our review identified the need for additional studies in many key areas of the therapy of ITP such as comparative studies of
Neunert CE	Individualized treatment for immune thrombocytopenia: predicting bleeding risk.	Seminars in hematology 2013, 50 Suppl 1:S55
Treatment of patients with immune thrombocytopenia (ITP) is often directed at increasing the platelet count and preventing significant hemorrhage even when there is minimal bleeding present. This approach, however, requires that a large number of patients receive prophylactic treatment to prevent major bleeding events. Identification of initial risk factors for development of severe bleeding would allow for more directed and personalized therapy. This review provides a summary of the current literature with the intent to explore various clinical and laboratory risk factors for severe bleeding including mucosal bleeding, platelet count, and aspects of platelet function.
Neumann JE, Spohn M, Obrecht D, Mynarek M, Thomas C, Hasselblatt M, Dorostkar MM, Wefers AK, Frank S, Monoranu CM, Koch A, Witt H, Kool M, Pajtler KW, Rutkowski S, Glatzel M, Schüller U	Molecular characterization of histopathological ependymoma variants.	Acta neuropathologica 2020, 139: 305
According to the WHO classification, ependymal tumors are classified as subependymomas, myxopapillary ependymomas, classic ependymomas, anaplastic ependymomas, and RELA-fusion-positive ependymomas (RELA-EPN). Among classic ependymomas, the WHO defines rare histological variants, i.e., the clear cell, papillary, and tanycytic ependymoma. In parallel, global DNA methylation patterns distinguish nine molecular groups, some of which tightly overlap with histopathological subgroups. However, the match of the aforementioned histological variants to DNA methylation classes remains unclear. We analyzed histomorphology, clinical parameters, and global DNA methylation of tumors with the initial histological diagnoses of tanycytic (n = 12), clear cell (n = 14), or papillary ependymoma (n = 19). Forty percent of these tumors did not match to the epigenetic profile of ependymomas, using a previously published DNA methylation-based classifier for brain tumors. Instead, they were classified as low-grade glioma (n = 3), plexus tumor (n = 2), CNS high-grade neuroepithelial tumor with MN1 alteration (n = 2), papillary tumor of the pineal region (n = 2), neurocytoma (n = 1), or did not match to any known brain tumor methylation class (n = 8). Overall, integrated diagnosis had to be changed in 35.6% of cases as compared to the initial diagnosis. Among the tumors molecularly classified as ependymoma (27/45 cases), tanycytic ependymomas were mostly located in the spine (5/7 cases) and matched to spinal or myxopapillary ependymoma. 6/8 clear cell ependymomas were found supratentorially and fell into the methylation class of RELA-EPN. Papillary ependymomas with a positive ependymoma match (12/19 cases) showed either a "papillary" (n = 5), a "trabecular" (n = 1), or a "pseudo-papillary" (n = 6) growth pattern. The papillary growth pattern was strongly associated with the methylation class B of posterior fossa ependymoma (PFB, 5/5 cases) and tumors displayed DNA methylation sites that were significantly different when compared to PFB ependymomas without papillary growth. Tumors with pseudo-papillary histology matched to the methylation class of myxopapillary ependymoma (4/6 cases), whereas the trabecular case was anatomically and molecularly a spinal ependymoma. Our results show that the diagnosis of histological ependymoma variants is challenging and epigenetic profiles may improve diagnostic accuracy of these cases. Whereas clear cell and papillary ependymomas display correlations between localization, histology, and methylation, tanycytic ependymoma does not represent a molecularly distinct subgroup.
Newton HB, Henson J, Walker RW	Extraneural metastases in ependymoma.	J Neurooncol 1992, 14: 135
Nicholson JC, Punt J, Hale J, Saran F, Calaminus G, Germ Cell Tumour Working Groups of the United Kingdom Children's Cancer Study Group (UKCCSG) and International Society of Paediatric Oncology (SIOP)	Neurosurgical management of paediatric germ cell tumours of the central nervous system--a multi-disciplinary team approach for the new millennium.	British journal of neurosurgery 2002, 16: 93
Nickel RS, Hendrickson JE, Haight AE	The ethics of a proposed study of hematopoietic stem cell transplant for children with .	Blood 2014, 124: 861
Hematopoietic stem cell transplant (HSCT) is the only cure for sickle cell disease (SCD). HSCT using an HLA-identical sibling donor is currently an acceptable treatment option for children with severe SCD, with expected HSCT survival >95% and event-free survival >85%. HSCT for children with less severe SCD (children who have not yet suffered overt disease complications or only had mild problems) is controversial. It is important to consider the ethical issues of a proposed study comparing HLA-identical sibling HSCT to best supportive care for children with less severe SCD. In evaluating the principles of nonmaleficence, respect for individual autonomy, and justice, we conclude that a study of HLA-identical sibling HSCT for all children with SCD, particularly hemoglobin SS and Sβ(0)-thalassemia disease, is ethically sound. Future work should explore the implementation of a large trial to help determine whether HSCT is a beneficial treatment of children with less severe SCD.
Nickel RS, Hendrickson JE, Haight AE	The ethics of a proposed study of hematopoietic stem cell transplant for children with .	Blood 2014, 124: 861
Hematopoietic stem cell transplant (HSCT) is the only cure for sickle cell disease (SCD). HSCT using an HLA-identical sibling donor is currently an acceptable treatment option for children with severe SCD, with expected HSCT survival >95% and event-free survival >85%. HSCT for children with less severe SCD (children who have not yet suffered overt disease complications or only had mild problems) is controversial. It is important to consider the ethical issues of a proposed study comparing HLA-identical sibling HSCT to best supportive care for children with less severe SCD. In evaluating the principles of nonmaleficence, respect for individual autonomy, and justice, we conclude that a study of HLA-identical sibling HSCT for all children with SCD, particularly hemoglobin SS and Sβ(0)-thalassemia disease, is ethically sound. Future work should explore the implementation of a large trial to help determine whether HSCT is a beneficial treatment of children with less severe SCD.
Niemeyer C, Stollmann-Gibbels B, Ebell W, Gaedicke G, Creutzig U	Myelodysplastic diseases in childhood.	Klin Pädiatr 1992, 204: 190
Niemeyer C, Stollmann-Gibbels B, Ebell W, Gaedicke G, Creutzig U	Myelodysplastic diseases in childhood.	Klin Pädiatr 1992, 204: 190
Niethammer D, Dopfer R, Henze G, Bender-Götze C, Burdach S, Ebell W, Ehninger G, Friedrich W, Gadner H, Klingebiel T, Peters C, Riehm H, Suttorp M	Allogeneic bone marrow transplantation for childhood acute lymphoblastic leukemia in second remission as part of the treatment strategies within the German BFM-and CoALL-protocols.	Haematol Blood Transfus 1992, 34
Niemeyer C, Arico M, Basso G, Biondi A, Cantu Rajnoldi, Creutzig U, Haas O, Harbott J, Hasle H, Kerndrup G, Locatelli F, Mann G, Stollmann-Gibbels B, Veer-Korthof E, van Wering E, Zimmermann M	Chronic myelomonocytic leukemia in childhood.	Blood 1997, 89: 3534
Niemeyer C, Fenu S, Hasle H, Mann G, Stary J, van Wering E	Differentiating juvenile myelomonocytic leukemia from infectious disease.	Blood 1998, 91: 365
Niehues T, Kapaun P, Harms D, Burdach S, Kramm C, Körholz D, Janka-Schaub G, Göbel U	A classification based on T cell selection-related phenotypes identifies a subgroup of childhood T-ALL with favorable outcome in the COALL studies.	Leukemia 1999, 13: 614
Niemeyer C	Myelodysplastic syndrome and aplastic anemia in children.	Europ School of Oncology 2000, 31
Niehuis T, Schellong G, Dörffel W, Bucsky P, Gadner H, Körholz D, Göbel U	Immunodeficiency and Hodgkin's disease.	Klin Pädiatr 2003,im Druck
Niemeyer C, Kratz C	Juvenile myelomonocytic leukemia.	Curr Treat Options Oncol 2003, 4: 203
Niehues T, Weiß M	Klassifikation angeborener Immundefekte.	Allergologie 2003, 11: 497–503
Niemeyer C, Kontny U	Tumoren der Ewing-Sarkom-Familie, in: Gutjahr P (Hrsg.): Krebs bei Kindern und Jugendlichen.	Deutscher Ärzte-Verlag Köln 5. Aufl. 2004, 491
Nielsen P, Gaedicke, G	Physiologie und Pathophysiologie des Eisenstoffwechsels.	In: Helmut Gadner, Gerhard Gaedicke, Charlotte Niemeyer (Hrsg.): Pädiatrische Hämatologie und Onkologie 2006
Niemeyer C, Meepol J, Hrsg: Gadner H, Gaedicke G, Niemeyer C, Ritter, J	Aplastische Anämien.	Pädiatrische Hämatologie und Onkologie, Springer Verlag 2006
Niemeyer C, Ammann R	Zweitneoplasien, in: Gadner H, Gaedicke G, Niemeyer CH, Ritter J (Hrsg): Pädiatrische Hämatologie und Onkologie.	Springer Medizin Verlag Heidelberg 2006 2006, 1094
Niewerth D, Creutzig U, Bierings MB, Kaspers GJ	A review on allogeneic stem cell transplantation for newly diagnosed pediatric acute myeloid leukemia.	Blood 2010,
Survival of pediatric acute myeloid leukemia (AML) has improved considerably over the past decades. Since 1985, allo-SCT is widely recommended for patients that have a matched sibling donor. However, it remains controversial whether allo-SCT is superior to chemotherapy for newly diagnosed children with AML. This review summarizes phase III clinical trials which compared allo-SCT with chemotherapy (including auto-SCT) in pediatric AML, excluding studies that did not use the intention-to-treat analysis or correct for time-to-transplant. While allo-SCT might prevent more relapses than chemotherapy, the number needed to transplant (with allo-SCT) in order to prevent one relapse is in the order of 10 patients. Moreover, overall survival is similar with both modalities in most recent studies, apparently because of increased salvagability of a relapse when initial therapy concerned chemotherapy only, and because of a higher treatment-related mortality (TRM) with allo-SCT. Because allo-SCT also gives more severe side-effects and results more often in secondary malignancies than chemotherapy, we do not recommend allo-SCT in first remission for pediatric AML in general. Further research should focus on the possibility that subgroups might benefit from allo-SCT, aiming at further improvements in the prognosis of pediatric AML.
Niemeyer CM, Kang MW, Shin DH, Furlan I, Erlacher M, Bunin NJ, Bunda S, Finklestein JZ, Sakamoto KM, Gorr TA, Mehta P, Schmid I, Kropshofer G, Corbacioglu S, Lang PJ, Klein C, Schlegel PG, Heinzmann A, Schneider M, Starý J, van den Heuvel-Eibrink MM, Hasle H, Locatelli F, Sakai D, Archambeault S, Chen L, Russell RC, Sybingco SS, Ohh M, Braun BS, Flotho C, Loh ML	Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia.	Nat Genet 2010, 42: 794
CBL encodes a member of the Cbl family of proteins, which functions as an E3 ubiquitin ligase. We describe a dominant developmental disorder resulting from germline missense CBL mutations, which is characterized by impaired growth, developmental delay, cryptorchidism and a predisposition to juvenile myelomonocytic leukemia (JMML). Some individuals experienced spontaneous regression of their JMML but developed vasculitis later in life. Importantly, JMML specimens from affected children show loss of the normal CBL allele through acquired isodisomy. Consistent with these genetic data, the common p.371Y>H altered Cbl protein induces cytokine-independent growth and constitutive phosphorylation of ERK, AKT and S6 only in hematopoietic cells in which normal Cbl expression is reduced by RNA interference. We conclude that germline CBL mutations have developmental, tumorigenic and functional consequences that resemble disorders that are caused by hyperactive Ras/Raf/MEK/ERK signaling and include neurofibromatosis type 1, Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome and Legius syndrome.
Niemeyer CM, Baumann I	Classification of childhood aplastic anemia and myelodysplastic syndrome.	Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program 2011, 2011, 84
Hypoplastic BM disorders in children and adolescents comprise a broad spectrum of disorders. Acquired severe aplastic anemia (SAA), refractory cytopenia of childhood (RCC), a subtype of myelodysplastic syndrome (MDS), and inherited BM failure (IBMF) disorders are the main and most difficult hematological differential diagnoses. Whereas IBMF disorders can often be diagnosed by their clinical features and/or underlying genetic aberrations, the morphological distinction between SAA and hypocellular RCC has been controversial. The histopathological pattern of RCC consists of islands of immature erythroid precursors accompanied by sparsely distributed granulocytic cells. Megakaryocytes are significantly decreased or absent and, rarely, micromegakaryocytes are detected on immunohistochemistry. Because fatty tissue between areas of hematopoiesis can mimic SAA, 2 biopsies are recommended to facilitate the detection of representative BM spaces. Recent data indicate that the response to immunosuppressive therapy is inferior in RCC compared with SAA. Furthermore, approaches to allogeneic hematopoietic transplantation differ. Controlled prospective clinical studies in patients with hypoplastic BM failure disorders will require comprehensive guidelines for diagnosing SAA, RCC, and the different IBMF disorders.
Niemeyer CM, Loh ML, Cseh A, Cooper T, Dvorak CC, Chan R, Xicoy B, Germing U, Kojima S, Manabe A, Dworzak M, De Moerloose B, Starý J, Smith OP, Masetti R, Catala A, Bergstraesser E, Ussowicz M, Fabri O, Baruchel A, Cavé H, Zwaan M, Locatelli F, Hasle H, van den Heuvel-Eibrink MM, Flotho C, Yoshimi A	Criteria for evaluating response and outcome in clinical trials for children with juvenile myelomonocytic leukemia.	Haematologica 2015, 100: 17
Juvenile myelomonocytic leukemia is a rare myeloproliferative disease in young children. While hematopoietic stem cell transplantation remains the only curative therapeutic option for most patients, children with juvenile myelomonocytic leukemia increasingly receive novel agents in phase I-II clinical trials as pre-transplant therapy or therapy for relapse after transplantation. However, response criteria or definitions of outcome for standardized evaluation of treatment effect in patients with juvenile myelomonocytic leukemia are currently lacking. Here we propose criteria to evaluate the response to the non-transplant therapy and definitions of remission status after hematopoietic stem cell transplantation. For the evaluation of non-transplant therapy, we defined 6 clinical variables (white blood cell count, platelet count, hematopoietic precursors and blasts in peripheral blood, bone marrow blast percentage, spleen size and extramedullary disease) and 3 genetic variables (cytogenetic, molecular and chimerism response) which serve to describe the heterogeneous picture of response to therapy in each individual case. It is hoped that these criteria will facilitate the comparison of results between clinical trials in juvenile myelomonocytic leukemia.
Niemeyer C, Kratz C	Myelodysplastische Syndrome.	in Niemeyer C, Eggert A (Hrsg): Pädiatrische Onkologie und Hämatologie 2017, Springer Verlag; 715
Niehues T, Bogdan C, Hecht J, Mertens T, Wiese-Posselt M, Zepp F	Impfen bei Immundefizienz : Anwendungshinweise zu den von der StÃ¤ndigen Impfkommission empfohlenen Impfungen(I) Grundlagenpapier.	Bundesgesundheitsblatt 2017, 60: 674
Niehues T, Bogdan C, Hecht J, Mertens T, Wiese-Posselt M, Zepp F	Impfen bei Immundefizienz : Anwendungshinweise zu den von der Ständigen Impfkommission empfohlenen Impfungen(I) Grundlagenpapier.	Bundesgesundheitsblatt 2017, 60: 674
Niemeyer C, Eggert A (Hrsg)	Pädiatrische Hämatologie und Onkologie.	Springer-Verlag GmbH Deutschland 2. vollständig überarbeitete Auflage 2018
Niktoreh N, Lerius B, Zimmermann M, Gruhn B, Escherich G, Bourquin JP, Dworzak M, Sramkova L, Rossig C, Creutzig U, Reinhardt D, Rasche M	Gemtuzumab ozogamicin in children with relapsed or refractory acute myeloid leukemia: a report by Berlin-Frankfurt-Münster study group.	Haematologica 2019, 104: 120
Despite intensified salvage treatments, children with relapsed/refractory acute myeloid leukemia (AML) have poor survival. We evaluated gemtuzumab ozogamicin (CD33-targeted drug) used on a compassionate basis in patients diagnosed from 1995 until 2014 within Acute Myeloid Leukemia Berlin-Frankfurt-Münster studies, and identified 76 patients (<18 years) with highly-advanced and pre-treated AML [refractory acute myeloid leukemia (n=10), AML refractory to relapse (1 early: n=41; 1 late: n=10; 2 or more: n=10), and secondary AML (n=5)]. At doses of 2.5-10 mg/m, gemtuzumab ozogamicin was administered in 1-4 cycles as single agent (47%), combined with cytarabine (47%), or others (6%). Most common grade 3/4 adverse events were infections or febrile neutropenia (78% of severe adverse events), infusion-related immunological reactions (6%), and gastrointestinal symptoms (5%). Three patients experienced veno-occlusive disease (one fatal due to exacerbation of a pre-existing cardiomyopathy). Sixty-four percent received subsequent hematopoietic stem cell transplantation. Probability of 4-year overall survival was 18±5% in all, 27±7% in patients with and 0% in patients without hematopoietic stem cell transplantation (<0.0001). Administration of gemtuzumab ozogamicin on a patient-specific, compassionate use basis was frequently considered in our study group and proved to be effective for bridging children with very advanced AML to hematopoietic stem cell transplantation. Uniform prospective studies for these patients are urgently needed.
Nitz A, Kontopantelis E, Bielack S, Koscielniak E, Klingebiel T, Langer T, Paulides M	Prospective evaluation of cisplatin- and carboplatin-mediated ototoxicity in paediatric and adult soft tissue and osteosarcoma patients.	Oncology letters 2013, 5: 311
Platinum-compound chemotherapy is known to have ototoxic side-effects. However, there is a paucity of literature examining hearing function prospectively and longitudinally in cohorts containing paediatric and adult patients treated within the same cisplatin- or carboplatin-containing treatment trial protocols. In Germany, Austria and Switzerland, late effects of treatment for osteosarcoma and soft tissue sarcoma have been prospectively and longitudinally registered by the Late Effects Surveillance System since 1998. The aim of this study was to analyse cisplatin- and carboplatin-induced ototoxity in a group of 129 osteosarcoma and soft tissue sarcoma patients treated within the COSS-96, CWS-96 and CWS-2002P treatment trials. The cohort consisted of 112 children and 17 adults. The median age at diagnosis was 13.56 (IQR, 10.26-16.27) years. Follow-up was 6.97 (IQR, 0.87-15.63) months. Hearing function was examined by audiometry before and after platinum treatment. A total of 108 patients were treated with cisplatin with a median cumulative dose of 360 mg/m(2). Thirteen patients received carboplatin with a median cumulative dose of 1500 mg/m(2) and 8 patients were treated with both platinum compounds (median cisplatin dose, 240 mg/m(2); IQR, 240-360 mg/m(2) and median carboplatin dose: 1200 mg/m(2); IQR, 600-3000 mg/m(2)). Following cessation of therapy, 47.3% of the patients demonstrated a hearing impairment, namely 55 children (49.1%) and 6 adults (42.1%). Out of thirteen children treated with carboplatin with a cumulative dose of 1500 mg/m(2), six revealed a significant hearing impairment. Although ototoxicity caused by platinum compounds is considered irreversible, we identified hearing improvements over time in 11 children (9.8%) and 3 adults (17.6%). None of these patients received irradiation to the head. We conclude that hearing loss is frequent in children treated with protocols containing platinum compounds and recommend prospective testing via audiometry.
Noeker M	[Survivors of pediatric cancer. Developmental paths and outcomes between trauma and resilience].	Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz 2012, 55: 481
In Europe and North America, about 80% of all patients with cancer in childhood and adolescence survive their leukemia, lymphomas or tumors. Therefore, neuropsychological impairments, psychopathological comorbidity and health-related quality of life become relevant parameters for treatment evaluation and conceptualization of future therapy protocols. During the last decade, a number of patient registries, multicenter studies and meta-analyses have analyzed the interaction of disease- and treatment-associated risk factors with pre-existing socio-demographic and psychosocial vulnerability factors. Brain tumors and treatment strategies including CNS surgery, cranial radiotherapy and intrathecal chemotherapy carry an increased risk for neurological and neuropsychological long-term outcomes, which in turn also threatens the patients' psychosocial and vocational participation. In the area of psychosocial adaptation, a wide range of developmental paths results, ranging from increased psychological comorbidity, to subclinical impairments in quality of life, to normal courses to resilient outcomes, even with a developmental benefit. A hypothetical model is presented to explain this enormous variance in outcomes. Protective cognitive-emotional schemata already established at the premorbid stage predispose patients to be able to cope successfully with cancer-related challenges and thus further enhance the patients' future adaptability. In contrast, dysfunctional schemata at the premorbid level increase risks of coping failure and thus intensify the long-term risk for psychopathological comorbidity in terms of post-traumatic stress disorder, anxiety disorder or depression.
Nogami K, Shima M	New therapies using nonfactor products for patients with hemophilia and inhibitors.	Blood 2019 Jan 31; 133: 399
National Organization for Rare Disorders	Neonatal Hemochromatosis.	aufgerufen am 14.12.2020
Northcott PA, Robinson GW, Kratz CP, Mabbott DJ, Pomeroy SL, Clifford SC, Rutkowski S, Ellison DW, Malkin D, Taylor MD, Gajjar A, Pfister SM	Medulloblastoma.	Nature reviews. Disease primers 2019, 5: 11
Medulloblastoma (MB) comprises a biologically heterogeneous group of embryonal tumours of the cerebellum. Four subgroups of MB have been described (WNT, sonic hedgehog (SHH), Group 3 and Group 4), each of which is associated with different genetic alterations, age at onset and prognosis. These subgroups have broadly been incorporated into the WHO classification of central nervous system tumours but still need to be accounted for to appropriately tailor disease risk to therapy intensity and to target therapy to disease biology. In this Primer, the epidemiology (including MB predisposition), molecular pathogenesis and integrative diagnosis taking histomorphology, molecular genetics and imaging into account are reviewed. In addition, management strategies, which encompass surgical resection of the tumour, cranio-spinal irradiation and chemotherapy, are discussed, together with the possibility of focusing more on disease biology and robust molecularly driven patient stratification in future clinical trials.
Nowak-Göttl U, Schaudin E, Hoffmann C, Eckhoff-Donovan S, Mertes N, Winkelmann W, Jürgens H	Intraoperative clotting factor dilution and activated hemostasis in children with Ewing's sarcoma or osteosarcoma.	haematologica 1995, 80: 311
Nowak-Göttl U, Münchow N, Klippel U, Paulussen M, Bielack S, Ullrich K, Ehrenforth S	The course of fibrinolytic proteins in children with malignant bone tumours.	Eur J Pediatr 1999, 158 Suppl 3:S151-S153
Nowak-Goettl U, Heller C, Knoefler R et al.	S1-Leitlinie Thrombosen im Kindesalter.	Leitlinien Kinderheilkunde und Jugendmedizin 2004, K3
Nowacki S, Skowron M, Oberthuer A, Fagin A, Voth H, Brors B, Westermann F, Eggert A, Hero B, Berthold F, Fischer M	Expression of the tumour suppressor gene CADM1 is associated with favourable outcome and inhibits cell survival in neuroblastoma.	Oncogene 2008, 27: 3329
Cell adhesion molecule 1 (CADM1) is a putative tumour suppressor gene, which is downregulated in many solid tumours. In neuroblastoma, loss of CADM1 expression has recently been found in disseminated tumours with adverse outcome, prompting us to investigate its role in neuroblastoma tumour progression. Oligonucleotide-microarray analysis of 251 neuroblastoma specimens demonstrated that CADM1 downregulation is associated with unfavourable prognostic markers like disseminated stage 4, age >18 months, MYCN amplification and chromosome 11q alterations (P<0.001 each). Furthermore, low CADM1 expression was significantly correlated with unfavourable gene expression-based classification (P<0.001) and adverse patient outcome (P<0.001). Bisulphite sequencing and genetic analysis of 18 primary neuroblastomas suggested that neither haploinsufficiency nor hypermethylation is regularly involved in CADM1 gene silencing in neuroblastoma, which is in contrast to results obtained in other malignancies. In addition, no mutations disrupting the CADM1 reading frame were found in 25 primary neuroblastomas. Over-expression of CADM1 in neuroblastoma cells resulted in significant reduction of proliferation, viability and colony formation in soft agar. Collectively, our results suggest that downregulation of CADM1 tumour suppressor gene expression is a critical event in neuroblastoma pathogenesis resulting in tumour progression and unfavourable patient outcome.
Nowak-Goettl U, Janssen V, Manner D, Kenet G	Venous thromboembolism in neonates and children--update 2013.	Thrombosis research 2013, 131 Suppl 1:S39
Nowak J, Seidel C, Pietsch T, Friedrich C, von Hoff K, Rutkowski S, Warmuth-Metz M	Ependymoblastoma of the brainstem: MRI findings and differential diagnosis.	Pediatric blood & cancer 2014, 61: 1132
Ependymoblastoma (EBL) is a rare malignant CNS tumor of early childhood, listed as a subgroup of primitive neuroectodermal tumors (PNET) in the 2007 WHO Classification of Tumours of the Central Nervous System. Histologically, EBL can be defined by multilayered, mitotically active
Nowak J, Alkonyi B, Rutkowski S, Homola GA, Warmuth-Metz M	Hypertrophic olivary degeneration with gadolinium enhancement after posterior fossa surgery in a child with medulloblastoma.	ChNS 2014, 30: 959
Hypertrophic olivary degeneration (HOD) is a rare transsynaptic form of degeneration occurring secondary to the disruption of the dentato-rubro-olivary pathway ("Guillain-Mollaret triangle"). HOD can be caused by ischemic, hemorrhagic, traumatic, or neoplastic lesions, and it can also occur following posterior fossa surgery. MRI characteristics of HOD include T2 signal increase and hypertrophy. To date, blood–brain barrier disruption has not been reported in HOD. Here, we present the first case of HOD with temporary gadolinium enhancement in a 10-year-old child 7 months after resection of a posterior fossa medulloblastoma. The recognition of gadolinium enhancement as a radiological feature of HOD may help to distinguish between this benign secondary condition and tumor recurrence.
Nowak J, Nemes K, Hohm A, Vandergrift LA, Hasselblatt M, Johann PD, Kool M, Frühwald MC, Warmuth-Metz M	Magnetic resonance imaging surrogates of molecular subgroups in atypical teratoid/rhabdoid tumor.	Neuro-oncology 2018 Nov 12; 20: 1672
Recently, 3 molecular subgroups of atypical teratoid/rhabdoid tumor (ATRT) were identified, but little is known of their clinical and magnetic resonance imaging (MRI) characteristics.
Nowak J, Jünger ST, Huflage H, Seidel C, Hohm A, Vandergrift LA, von Hoff K, Rutkowski S, Pietsch T, Warmuth-Metz M	MRI Phenotype of RELA-fused Pediatric Supratentorial Ependymoma.	Clinical neuroradiology 2019, 29: 595
Epigenetic profiling has recently identified clinically and molecularly distinct subgroups of ependymoma. The 2016 World Health Organization (WHO) classification recognized supratentorial ependymomas (ST-EPN) with REL-associated protein/p65 (RELA) fusion as a clinicopathological entity. These tumors represent 70% of pediatric ST-EPN characterized by recurrent C11orf95-RELA fusion transcripts, which lead to pathological activation of the nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NF-κB) signaling pathway. Cyclin-dependent kinase inhibitor 2A (CDKN2A) inactivation has also been reported to correlate with poor prognosis. Here, we systematically describe magnetic resonance imaging (MRI) characteristics of RELA-fused ST-EPN, with respect to CDKN2A deletion status.
Nurden AT, Freson K, Seligsohn U	Inherited platelet disorders.	Haemophilia 2012, 18 Suppl 4: 154
Inherited diseases of the megakaryocyte lineage give rise to bleeding when platelets fail to fulfill their hemostatic function upon vessel injury. Platelet defects extend from the absence or malfunctioning of adhesion (GPIb-IX-V, Bernard-Soulier syndrome) or aggregation receptors (integrin αIIbβ3, Glanzmann thrombasthenia) to defects of primary receptors for soluble agonists, secretion from storage organelles, activation pathways and the generation of procoagulant activity. In disorders such as the Chediak-Higashi, Hermansky-Pudlak, Wiskott-Aldrich and Scott syndromes the molecular lesion extends to other cells. In familial thrombocytopenia (FT), platelets are produced in insufficient numbers to assure hemostasis. Some FT affect platelet morphology and give rise to the 'giant platelet' syndromes (e.g. MYH9-related diseases) with changes in megakaryocyte maturation within the bone marrow and premature release of platelets. Diseases of platelet production may also affect other cells and in some cases interfere with development and/or functioning of major organs. Diagnosis of platelet disorders requires platelet function testing, studies often aided by the quantitative analysis of receptors by flow cytometry and fluorescence and electron microscopy. New generation DNA-based procedures including whole exome sequencing offer an exciting new perspective. Transfusion of platelets remains the most common treatment of severe bleeding, management with desmopressin is often used for mild disorders. Substitute therapies are available including rFVIIa and the potential use of thrombopoietin analogues for FT. Stem cell or bone marrow transplantation has been successful for several diseases while gene therapy shows promise in the Wiskott-Aldrich syndrome.
Nustede R, Klimiankou M, Klimenkova O, Kuznetsova I, Zeidler C, Welte K, Skokowa J	ELANE mutant-specific activation of different UPR pathways in congenital neutropenia.	British journal of haematology 2016, 172: 219
A number of studies have demonstrated induction of the unfolded protein response (UPR) in patients with severe congenital neutropenia (CN) harbouring mutations of ELANE, encoding neutrophil elastase. Why UPR is not activated in patients with cyclic neutropenia (CyN) carrying the same ELANE mutations is unclear. We evaluated the effects of ELANE mutants on UPR induction in myeloid cells from CN and CyN patients, and analysed whether additional CN-specific defects contribute to the differences in UPR induction between CN and CyN patients harbouring identical ELANE mutations. We investigated CN-specific p.C71R and p.V174_C181del (NP_001963.1) and CN/CyN-shared p.S126L (NP_001963.1) ELANE mutants. We found that transduction of haematopoietic cells with p.C71R, but not with p.V174_C181del or p.S126L ELANE mutants induced expression of ATF6, and the ATF6 target genes PPP1R15A, DDIT3 and HSPA5. Recently, we found that levels of secretory leucocyte protease inhibitor (SLPI), a natural ELANE inhibitor, are diminished in myeloid cells from CN patients, but not CyN patients. Combined knockdown of SLPI by shRNA and transduction of ELANE p.S126L in myeloid cells led to elevated levels of ATF6, PPP1R15A and HSPA5 RNA, suggesting that normal levels of SLPI in CyN patients might protect them from the UPR induced by mutant ELANE. In summary, different ELANE mutants have different effects on UPR activation, and SLPI regulates the extent of ELANE-triggered UPR.
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