Autoimmunity and immunodeficiency associated with monoallelic LIG4 mutations via haploinsufficiency.

BACKGROUND: Biallelic mutations in LIG4 encoding DNA-ligase 4 cause a rare immunodeficiency syndrome manifesting as infant-onset life-threatening and/or opportunistic infections, skeletal malformations, radiosensitivity and neoplasia. LIG4 is pivotal during DNA repair and during V(D)J recombination as it performs the final DNA-break sealing step. OBJECTIVES: This study explored whether monoallelic LIG4 missense mutations may underlie immunodeficiency and autoimmunity with autosomal dominant inheritance. METHODS: Extensive flow-cytometric immune-phenotyping was performed. Rare variants of immune system genes were analyzed by whole exome sequencing. DNA repair functionality and T-cell-intrinsic DNA damage tolerance was tested with an ensemble of in vitro and in silico tools. Antigen-receptor diversity and autoimmune features were characterized by high-throughput sequencing and autoantibody arrays. Reconstitution of wild-type versus mutant LIG4 were performed in LIG4 knockout Jurkat T cells, and DNA damage tolerance was subsequently assessed. RESULTS: A novel heterozygous LIG4 loss-of-function mutation (p.R580Q), associated with a dominantly inherited familial immune-dysregulation consisting of autoimmune cytopenias, and in the index patient with lymphoproliferation, agammaglobulinemia, and adaptive immune cell infiltration into nonlymphoid organs. Immunophenotyping revealed reduced naive CD4+ T cells and low TCR-Vα7.2+ T cells, while T-/B-cell receptor repertoires showed only mild alterations. Cohort screening identified 2 other nonrelated patients with the monoallelic LIG4 mutation p.A842D recapitulating clinical and immune-phenotypic dysregulations observed in the index family and displaying T-cell-intrinsic DNA damage intolerance. Reconstitution experiments and molecular dynamics simulations categorize both missense mutations as loss-of-function and haploinsufficient. CONCLUSIONS: This study provides evidence that certain monoallelic LIG4 mutations may cause human immune dysregulation via haploinsufficiency.

Supportive Care During Pediatric Hematopoietic Stem Cell Transplantation: Prevention of Infections. A Report From Workshops on Supportive Care of the Paediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT).

Specific protocols define eligibility, conditioning, donor selection, graft composition and prophylaxis of graft vs. host disease for children and young adults undergoing hematopoietic stem cell transplant (HSCT). However, international protocols rarely, if ever, detail supportive care, including pharmaceutical infection prophylaxis, physical protection with face masks and cohort isolation or food restrictions. Supportive care suffers from a lack of scientific evidence and implementation of practices in the transplant centers brings extensive restrictions to the child's and family's daily life after HSCT. Therefore, the Board of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) held a series of dedicated workshops since 2017 with the aim of initiating the production of a set of minimal recommendations. The present paper describes the consensus reached within the field of infection prophylaxis.

X-Linked Lymphoproliferative Disease Mimicking Multisystem Inflammatory Syndrome in Children-A Case Report.

Most children with a SARS-CoV-2 infection are asymptomatic or exhibit mild symptoms. However, a small number of children develop features of substantial inflammation temporarily related to the COVID-19 also called multisystem inflammatory syndrome in children (MIS-C) or pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS), clinically similar to Kawasaki disease, toxic shock syndrome and hemophagocytic lymphohistiocytosis (HLH). It is well-known that genetic pre-disposition plays an important role in virally-triggered diseases such as Epstein-Barr virus (EBV)-associated HLH, while this has not yet been established for patients with MIS-C. Here we describe a male patient fulfilling the diagnostic criteria of MIS-C, who was initially treated according to current consensus guidelines. Presence of hypofibrinogenemia, normal lymphocyte counts and C-reactive protein, but substantial hyperferritinemia distinguish this patient from others with MIS-C. The clinical course following initial presentation with acute respiratory distress syndrome was marked by fatal liver failure in the context of EBV-associated HLH despite treatment with steroids, intravenous immunoglobulins, interleukin (IL)-1 receptor blockade and eventually HLH-directed treatment. X-linked lymphoproliferative disease type 1 (XLP1), a subtype of primary HLH was diagnosed in this patient post-mortem. This case report highlights the importance of including HLH in the differential diagnosis in MIS-C with severe disease course to allow specific, risk-adapted treatment and genetic counseling.

Transfusions in Aplastic Anemia Patients Cause HLA Alloimmunization: Comparisons of Current and Past Cohorts Demonstrate Progress.

Transfusions are the mainstay of supportive therapy in patients with aplastic anemia (AA) and may lead to anti- HLA alloimmunization, thereby also increasing the risk for donor-specific antibodies in the setting of HLA-mismatched transplantation. Historically, AA patients were thought to be at particularly high risk for HLA alloimmunization. In past decades, blood product manufacturing (leukoreduction) and HLA antibody testing have improved significantly by single antigen bead (SAB) technology. It is currently unknown how those developments have impacted HLA alloimmunization and treatment outcome in patients with AA. We retrospectively investigated 54 AA patients treated by immunosuppressive therapy or allogeneic hematopoietic cell transplantation after the introduction of the SAB assay at our center. We compared the HLA antibody results to a historical AA cohort (n = 26), treated before introduction of leukoreduced blood products from 1975 to 1995. HLA alloimmunization was detected in 43 of 54 (80%) recently treated patients. Past pregnancy, female gender, disease severity, age, and a history of other transfusions were significantly associated with a larger number or higher intensity (mean fluorescence intensity) of HLA antibodies. Treatment outcome including bleeding episodes, response to treatment, engraftment, graft-versus-host disease, and overall survival was not associated with HLA alloimmunization. In the historical cohort a significantly higher number of HLA antibodies (P < .01) with a higher mean fluorescent intensity (P < .01) was observed. HLA alloimmunization remains frequent in AA tested by current techniques, but it has significantly decreased since prior decades and does not affect treatment outcome. © 2021 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Cytokines in saliva as biomarkers of oral and systemic oncological or infectious diseases: A systematic review.

Recent evidence suggests that salivary cytokines provide information about both oral conditions and systemic diseases. This review summarizes evidence for the use of salivary cytokines as biomarkers for oral and systemic diseases. We included studies in adults and children with a focus on the latter, due to the importance of non-invasive diagnostic methods in the paediatric age group. A systematic review was performed using Medline and Web of Science covering the period of January 1996 to December 2019 according to the preferred reporting items for systematic reviews. Thirty-four studies were included in the final analysis, for a total of 2407 patients and healthy controls. Pro-inflammatory cytokines including interleukin (IL)-1ß, IL-2, IL-6 and tumor necrosis factor (TNF)-α were associated with the severity of oral mucosal tissue damage in patients with cancer, and IL-1ß may be an early marker of graft-versus-host disease. Salivary interferon-γ levels were correlated with oral complications and the presence of the underlying disease in HIV-infected individuals, and salivary cytokine patterns may be useful for diagnosing tuberculosis. In summary, current data illustrate that salivary cytokines are associated with oral inflammation, making them potential biomarkers for disease diagnosis and treatment efficacy. Because of the simplicity of saliva collection, this method may be useful in pediatric studies and in resource-limited settings.

Communication and ethical considerations for fertility preservation for patients with childhood, adolescent, and young adult cancer: recommendations from the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Patients with childhood, adolescent, and young adult cancer who will be treated with gonadotoxic therapies are at increased risk for infertility. Many patients and their families desire biological children but effective communication about treatment-related infertility risk and procedures for fertility preservation does not always happen. The PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group reviewed the literature and developed a clinical practice guideline that provides recommendations for ongoing communication methods for fertility preservation for patients who were diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger and their families. Moreover, the guideline panel formulated considerations of the ethical implications that are associated with these procedures. Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the evidence and recommendations. In this clinical practice guideline, existing evidence and international expertise are combined to develop transparent recommendations that are easy to use to facilitate ongoing communication between health-care providers and patients with childhood, adolescent, and young adult cancer who might be at high risk for fertility impairment and their families.

Very long-term follow-up of aplastic anemia treated with immunosuppressive therapy or allogeneic hematopoietic cell transplantation.

INTRODUCTION: Since the 1970s outcome of aplastic anemia (AA) patients has improved significantly due to the introduction of immunosuppressive therapy (IST) and allogeneic hematopoietic transplantation (HCT). However, patients may suffer from persistent disease, relapse, clonal evolution, graft-versus-host disease and other late effects. Here, we analyse very long-term outcome of all AA patients at our institution comparing not only survival, but also response status and complications. METHODS: Patient charts of all 302 AA patients treated between 1973 and 2017 at the University Hospital Basel, Switzerland, were retrospectively analysed. RESULTS: First line treatment was IST in 226 (75%) and HCT in 76 (25%) patients. Overall survival at 30 years was similar in patients treated initially by HCT and IST (44% (±14%), and 40% (± 9%) respectively, with better results in more recent years. Partial and no response occurred more frequently after IST, relapse incidence after IST was 24 %, whereas non-engraftment and graft failure was documented in 15 patients (19 %) after HCT. Clonal evolution to myelodysplastic syndrome / acute myeloid leukemia was 16 % at 25 years in IST patients, 1.3 % in HCT patients, iron overload (18 versus 4 %, p = 0.002) and cardiovascular events (11 versus 1 %, p=0.011) occured significantly more often in IST than HCT treated patients. The majority of long-term survivors, 96% of those alive at 25 years, were in complete remission at last follow up, irrespective of the initial treatment modality. CONCLUSION: Very long term survivors after AA are those with stable hematopoietic recovery.

Moving Beyond the Friend-Foe Myth: A Scoping Review of the Use of Social Media in Adolescent and Young Adult Oncology.

Purpose: Adolescents and young adults (AYA) with cancer present a unique challenge to health care institutions. Their cancer diagnosis and treatment have a profound impact upon their health and well-being. Despite the various support services aimed at improving their quality of life, their needs and preferences are often underestimated or misjudged. Recent studies show that patients are empowered by the knowledge and support they receive online. Given the extensive use of social media among AYA, we aim to identify promises, challenges, and recommendations for integrating these platforms in AYA cancer care. Methodology: We systematically searched seven databases systematically: Scopus, PubMed, PsycInfo, Web of Science, CINAHL, SocINDEX, and Media. We placed no restriction on the type of methodology used in the studies. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses was used to frame the research. Results: Many studies argued that health care professionals need to integrate social media in their clinical practice to engage with patients' lifeworld. Social media were considered important allies in optimizing cancer care at all levels of support, ranging from information provision, treatment adherence, diet and exercise interventions, to professional, peer, and psychosocial self-care. Lack of research on the efficacy of social media in the context of psychosocial support was a commonly cited problem. A small number of publications paid attention to the inherent risks of promoting self-care online. Conclusion: Future studies should continue to pursue empirical research on the efficacy of online psychosocial care, while not neglecting the ethical challenges of social media research.

Bayesian spatial modelling of childhood cancer incidence in Switzerland using exact point data: a nationwide study during 1985-2015.

BACKGROUND: The aetiology of most childhood cancers is largely unknown. Spatially varying environmental factors such as traffic-related air pollution, background radiation and agricultural pesticides might contribute to the development of childhood cancer. This study is the first investigation of the spatial disease mapping of childhood cancers using exact geocodes of place of residence. METHODS: We included 5947 children diagnosed with cancer in Switzerland during 1985-2015 at 0-15 years of age from the Swiss Childhood Cancer Registry. We modelled cancer risk using log-Gaussian Cox processes and indirect standardisation to adjust for age and year of diagnosis. We examined whether the spatial variation of risk can be explained by modelled ambient air concentration of NO2, modelled exposure to background ionising radiation, area-based socio-economic position (SEP), linguistic region, duration in years of general cancer registration in the canton or degree of urbanisation. RESULTS: For all childhood cancers combined, the posterior median relative risk (RR), compared to the national level, varied by location from 0.83 to 1.13 (min to max). Corresponding ranges were 0.96 to 1.09 for leukaemia, 0.90 to 1.13 for lymphoma, and 0.82 to 1.23 for central nervous system (CNS) tumours. The covariates considered explained 72% of the observed spatial variation for all cancers, 81% for leukaemia, 82% for lymphoma and 64% for CNS tumours. There was weak evidence of an association of CNS tumour incidence with modelled exposure to background ionising radiation (RR per SD difference 1.17; 0.98-1.40) and with SEP (1.6; 1.00-1.13). CONCLUSION: Of the investigated diagnostic groups, childhood CNS tumours showed the largest spatial variation. The selected covariates only partially explained the observed variation of CNS tumours suggesting that other environmental factors also play a role.

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).

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

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).

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.

Physical activity and screen time in children who survived cancer: A report from the Swiss Childhood Cancer Survivor Study.

BACKGROUND: Physical activity (PA) can reduce the risk of chronic adverse health conditions in childhood cancer survivors. We examined PA and sedentary screen time behavior in a nationwide study in Switzerland. PROCEDURES: The Swiss Childhood Cancer Survivor Study sent questionnaires to parents of all Swiss resident ≥5-year survivors diagnosed between 1995 and 2010. We assessed PA including compulsory school sport, recreational sport, commuting to school, and time spent with screen media in those aged 5-15 years, and compared results with international recommendations. RESULTS: We included 766 survivors with a median age at diagnosis of 2.8 (interquartile range 1.4-5.0) years and a median age at study of 12.5 (10.0-14.3) years. Median PA time was 7.3 (4.8-10.0) h/week and median screen time was 82 (45-120) min/day. Compulsory school sport hours and walking or cycling to school contributed significantly to total PA. Note that 55% of survivors met PA and 68% screen time recommendations. PA was lower for children living in regions of Switzerland speaking French or Italian compared to German, and for those who had a relapse or musculoskeletal/neurological conditions. Screen time was higher in males, children with lower parental education, and a migration background. CONCLUSIONS: PA and sedentary screen watching were associated with social factors, and PA also with clinical risk factors. Structural preventions that afford active commuting to school and sufficient school sport are essential, as is counseling vulnerable survivor groups such as those with musculoskeletal and neurological problems, and those who have had a relapse.

Gonadal Function after Busulfan Compared with Treosulfan in Children and Adolescents Undergoing Allogeneic Hematopoietic Stem Cell Transplant.

Gonadal impairment is an important late effect with a significant impact on quality of life of transplanted patients. The aim of this study was to compare gonadal function after busulfan (Bu) or treosulfan (Treo) conditioning regimens in pre- and postpubertal children. This retrospective, multicenter study included children transplanted in pediatric European Society for Blood and Marrow Transplantation (EBMT) centers between 1992 and 2012 who did not receive gonadotoxic chemoradiotherapy before the transplant. We evaluated 137 patients transplanted in 25 pediatric EBMT centers. Median age at transplant was 11.04 years (range, 5 to 18); 89 patients were boys and 48 girls. Eighty-nine patients were prepubertal at transplant and 48 postpubertal. One hundred eighteen children received Bu and 19 Treo. A higher proportion of girls treated with Treo in the prepubertal stage reached spontaneous puberty compared with those treated with Bu (P = .02). Spontaneous menarche was more frequent after Treo than after Bu (P < .001). Postpubertal boys and girls treated with Treo had significantly lower luteinizing hormone levels (P = .03 and P = .04, respectively) compared with the Bu group. Frequency of gonadal damage associated with Treo was significantly lower than that observed after Bu. These results need to be confirmed in a larger population.

Heart-sparing volumetric modulated arc therapy for whole lung irradiation.

PURPOSE: Whole lung irradiation (WLI) is indicated for subgroups of patients with lung metastases from Wilms' tumor (nephroblastoma). WLI has traditionally been performed with an anterior/posterior field arrangement with poor potential for heart sparing; thus, new techniques are desirable to achieve a lower dose to the heart. MATERIALS AND METHODS: We utilized volumetric modulated arc therapy (VMAT) for WLI with 18 Gy in a patient with metastatic nephroblastoma. The planning results were compared against a three-dimensional (3D) conformal plan. RESULTS: VMAT resulted in adequate target volume coverage with the prescribed dose. Mean heart dose was 10.2 Gy. The dose to organs at risk (OAR) was generally more favorable with VMAT when compared with a 3D-conformal radiotherapy plan. DISCUSSION: WLI with VMAT provides superior sparing of OARs and especially a considerably lower dose to the heart.

Fertility preservation in pediatric and adolescent cancer patients in Switzerland: A qualitative cross-sectional survey.

Fertility preservation (FP) is an important topic of discussion in the field of oncology, particularly in pediatric oncology. Despite the awareness of severe impact of infertility on quality of life and different guidelines available in this area, the options in FP are not routinely discussed with the pediatric cancer patients and their parents. To the best of our knowledge, this is the first survey report concerned to FP counseling and procedures in pediatric and adolescent cancer patients in Switzerland. This survey was conducted from June 2014 to October 2014 on the counseling and procedures performed between 2009 and 2013; the questionnaire was completed by one of the professional from hematology/oncology centers in Switzerland. Currently, only four out of nine centers have a program for FP. In 2013, 45/301 (15%) patients received FP counseling and 36/301 (12%) underwent an FP procedure. The most commonly performed procedures from 2009 to 2013 were administration of gonadotropin releasing hormone agonist (3%) and cryopreservation of ovarian tissue in females (3%) and cryopreservation of sperms in males (6%); the most frequently cited reason for the absence of FP counseling was lack of time (55%). Therefore, this survey should help to develop and harmonize practices with respect to FP counseling and procedures in Switzerland, and to establish FP as a standard of care during cancer treatment.

Intracranial Hemorrhage as the First Manifestation of Severe Congenital Factor X Deficiency in a 20-Month-Old Male: Case Report and Review of the Literature.

Factor X deficiency (FXD) is a rare bleeding disorder, which can result in severe bleeding symptoms such as intracranial hemorrhage (ICH). The most common bleeding symptoms are epistaxis and gum bleeding. ICH is reported in 9-26% of all patients with FXD, mostly during the first month of life. Here, we present a rare case of a male presenting with ICH at the age of 20 months as the first manifestation of FXD. Secondary prophylaxis with factor X substitution once weekly prevented further bleeding.

Transient myeloproliferative disorder in neonates without Down syndrome: case report and review.

Transient myeloproliferative disorder (TMD) is a clonal proliferation of megakaryoblasts, typically occurring in newborns with Down syndrome. It is believed that TMD occurs in the presence of GATA1 mutation together with trisomy 21. However, a limited number of patients with TMD but without Down syndrome have been reported, all with a blast population with numeric or rarely structural chromosome 21 abnormalities. We present the first case of a newborn boy with a TMD without trisomy 21 and without any of the mentioned molecular or cytogenetic abnormalities. This case report suggests that unknown disease mechanisms may provoke or mimic TMD. This case report is followed by a concise review of the literature discussing the different entities and pathomechanisms of TMD and acute megakaryocytic leukaemia in patients with or without Down syndrome.

The importance of 'awareness' for understanding fetal pain.

Our understanding of when the fetus can experience pain has been largely shaped by neuroanatomy. However, completion of the cortical nociceptive connections just after mid-gestation is only one part of the story. In addition to critically reviewing evidence for whether the fetus is ever awake or aware, and thus able to truly experience pain, we examine the role of endogenous neuro-inhibitors, such as adenosine and pregnanolone, produced within the feto-placental unit that contribute to fetal sleep states, and thus mediate suppression of fetal awareness. The uncritical view that the nature of presumed fetal pain perception can be assessed by reference to the prematurely born infant is challenged. Rigorously controlled studies of invasive procedures and analgesia in the fetus are required to clarify the impact of fetal nociception on postnatal pain sensitivity and neural development, and the potential benefits or harm of using analgesia in this unique setting.