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BackgroundCardiovascular disease is the leading nonmalignant cause of late deaths in childhood cancer survivors. Cardiovascular disease and cardiac dysfunction can remain asymptomatic for many years, but eventually lead to progressive disease with high morbidity and mortality. Early detection and intervention are therefore crucial to improve outcomes. ObjectiveIn our study, we aim to assess the prevalence of preclinical cardiac dysfunction in adult childhood cancer survivors using conventional and speckle tracking echocardiography; determine the association between cardiac dysfunction and treatment-related risk factors (anthracyclines, alkylating agents, steroids, cardiac radiation) and modifiable cardiovascular risk factors (abdominal obesity, hypertension); investigate the development of cardiac dysfunction longitudinally in a defined cohort; study the association between cardiac dysfunction and other health outcomes like pulmonary disease, endocrine disease, renal disease, quality of life, fatigue, strength and endurance, and physical activity; and gain experience conducting a clinical study of childhood cancer survivors that will be extended to a national, multicenter study of cardiac complications. MethodsFor this retrospective cohort study, we will invite ≥5-year childhood cancer survivors who were treated at the University Children's Hospital Bern, Switzerland with any chemotherapy or cardiac radiation since 1976 and who are ≥18 years of age at the time of the study for a cardiac assessment at the University Hospital Bern. This includes 544 childhood cancer survivors, of whom about half were treated with anthracyclines and/or cardiac radiation and half with any other chemotherapy. The standardized cardiac assessment includes a medical history focusing on signs of cardiovascular disease and its risk factors, a physical examination, anthropometry, vital parameters, the 1-minute sit-to-stand test, and echocardiography including 2-dimensional speckle tracking. ResultsWe will invite 544 eligible childhood cancer survivors (median age at the time of the study, 32.5 years; median length of time since diagnosis, 25.0 years) for a cardiac assessment. Of these survivors, 300 (55%) are at high risk, and 244 (45%) are at standard risk of cardiac dysfunction. ConclusionsThis study will determine the prevalence of preclinical cardiac dysfunction in Swiss childhood cancer survivors, inform whether speckle tracking echocardiography is more sensitive to cardiac dysfunction than conventional echocardiography, and give a detailed picture of risk factors for cardiac dysfunction. The results will help improve primary treatment and follow-up care of children with cancer. Trial RegistrationClinicalTrials.gov NCT03790943; https://clinicaltrials.gov/ct2/show/NCT03790943 International Registered Report Identifier (IRRID)DERR1-10.2196/17724

Background: Genotype-phenotype analyses of rare diseases often suffer from a lack of power, due to small sample size, which makes identifying significant associations difficult. Sinusoidal obstruction syndrome (SOS) of the liver is a rare but life-threatening complication of hematopoietic stem cell transplantation (HSCT). The alkylating agent busulfan is commonly used in HSCT and known to trigger SOS. We developed a novel pipeline to identify genetic determinants in rare diseases by combining in vitro information with clinical whole-exome sequencing (WES) data and applied it in SOS patients and controls. Methods: First, we analysed differential gene expression in six lymphoblastoid cell lines (LCLs) before and after incubation with busulfan. Second, we used WES data from 87 HSCT patients and estimated the association with SOS at the SNP and the gene levels. We then combined the results of the expression and the association analyses into an association statistic at the gene level. We used an over-representation analysis to functionally characterize the genes that were associated with a significant combined test statistic. Results: After treatment of LCLs with busulfan, 1708 genes were significantly up-, and 1385 down-regulated. The combination of the expression experiment and the association analysis of WES data into a single test statistic revealed 35 genes associated with the outcome. These genes are involved in various biological functions and processes, such as "Cell growth and death", "Signalling molecules and interaction", "Cancer", and "Infectious disease". Conclusions: This novel data analysis pipeline integrates two independent omics datasets and increases statistical power for identifying genotype-phenotype associations. The analysis of the transcriptomics profile of cell lines treated with busulfan and WES data from HSCT patients allowed us to identify potential genetic contributors to SOS. Our pipeline could be useful for identifying genetic contributors to other rare diseases where limited power renders genome-wide analyses unpromising. Trial registration: For the clinical dataset: Clinicaltrials.gov: NCT01257854. https://clinicaltrials.gov/ct2/history/NCT01257854. [ABSTRACT FROM AUTHOR]

Diamond-Blackfan anemia (DBA) is caused mainly by genetic mutations in large (RPL) or small ribosomal subunit genes (RPS) and presents with macrocytic anemia and congenital malformations. Clinical differences between genotypes are insufficiently understood. The aim of this study was to assess clinical features, treatment strategies, and genotypes in the Swiss pediatric DBA population. We retrospectively reviewed medical charts of pediatric patients with DBA in Switzerland and stratified patients by RPL versus RPS mutations. We report 17 DBA patients in Switzerland who were all genetically investigated. In our cohort, patients showed a wide spectrum of clinical presentations and treatment needs. We found a high proportion of physical malformations (77%) including lower limb (17%) and anorectal (12%) malformations. The two patients with anorectal malformations presented both with antepositioning of the anus needing surgery within the first 15 months of life. One of these patients had sphincteric dysfunction, the other coccygeal agenesis. We found that included patients with an RPL mutation more frequently tended to have physical malformations and a milder anemia compared to patients with an RPS mutation (median hemoglobin at diagnosis 76 g/l versus 22 g/l). Conclusion: We illustrate the wide clinical and genetic spectrum of DBA in Switzerland. Our findings highlight the need to take this diagnosis into consideration in patients with severe anemia but also in patients with mild anemia where malformations are present. Lower limb and anorectal malformation extend the spectrum of DBA-associated malformations. What is Known? • There is a large variation in the phenotype of Diamond-Blackfan Anemia (DBA) and diversity of genetic mutations. • Malformation of the upper limbs, head and face, heart, and genitourinary system is frequently identified. What is New? • Patients with lower limb and anorectal malformations were repetitively found in our cohort enlarging the clinical spectrum of malformations. • We show two patients of the same family with a DBA-like condition where the same RPL17 variant was identified. [ABSTRACT FROM AUTHOR]

Childhood cancer patients are at increased risk of second primary neoplasms (SPNs). We assessed incidence and risk factors for early SPNs with a focus on cancer predisposition syndromes (CPSs). This cohort study used data from the Swiss Childhood Cancer Registry. We included patients with first primary neoplasms (FPNs) diagnosed before age 21 years from 1986 to 2015 and identified SPNs occurring before age 21. We calculated standardised incidence ratios (SIRs) and absolute excess risks (AERs) using Swiss population cancer incidence data, and cumulative incidence of SPNs. We calculated hazard ratios (HRs) of risk factors for SPNs using Fine and Gray competing risk regression. Among 8074 childhood cancer patients, 304 (4%) were diagnosed with a CPS and 94 (1%) developed early SPNs. The incidence of SPNs was more than 10-fold higher in childhood cancer patients than the incidence of neoplasms in the general population (SIR = 10.6, 95% confidence interval [CI]: 8.7–13.1) and the AER was 179/100,000 person-years (CI: 139–219). Cumulative incidence of SPNs 20 years after FPN diagnosis was 23% in patients with CPSs (CI: 12–41%) and 2.7% in those without (CI: 2.0–3.6%). Risk factors for SPNs were CPSs (HR = 7.8, CI: 4.8–12.7), chemotherapy (HR = 2.2, CI: 1.1–4.6), radiotherapy (HR = 1.9, CI = 1.2–2.9), haematopoietic stem cell transplantation (HR = 1.8, CI: 1–3.3), and older age (15–20 years) at FPN diagnosis (HR = 1.9, CI: 1.1–3.2). CPSs are associated with a high risk of SPNs before age 21 years. Identification of CPSs is important for appropriate cancer surveillance and targeted screening. Image 1 • The incidence of second primary neoplasms (SPNs) before age 21 years was 10-fold higher after childhood cancer compared to the general population. • Cancer predisposition syndromes (CPSs) were the strongest predictor of SPNs. • The cumulative incidence of SPNs was 23% (95%CI 12–41%) in CPSs after 20 years of follow-up. [ABSTRACT FROM AUTHOR]

Primary immunodeficiency disorders represent a heterogeneous spectrum of diseases, predisposing to recurrent infections, allergy, and autoimmunity. While an association between primary immunodeficiency disorders and increased risk of cancer has been suggested since the 1970s, renewed attention has been given to this topic in the last decade, largely in light of the availability of large registries as well as advances in next generation sequencing. In this narrative review, we will give an insight of the primary immunodeficiencies that are commonly responsible for the greater number of cancers in the primary immunodeficiency disorders population. We will describe clinical presentations, underlying genetic lesions (if known), molecular mechanisms for carcinogenesis, as well as some management considerations. We will also comment on the future directions and challenges related to this topic.Conclusion: The awareness of the association between several primary immunodeficiencies and cancer is crucial to provide the best care for these patients.What is Known: • Patients with primary immunodeficiency have an increased risk of malignancy. The type of malignancy is highly dependent on the specific primary immunodeficiency disorder.What is New: • Survival in patients with primary immunodeficiency disorders has been improving, and conversely also their lifetime risk of malignancy. • International collaboration and multinational registries are needed to improve our knowledge and therapeutic strategies. [ABSTRACT FROM AUTHOR]

Human adenovirus (HAdV) is recognized as a serious pathogen after allogeneic hematopoietic stem cell transplantation (HSCT), causing morbidity and mortality. Currently, there is no universal agreement regarding routine HAdV surveillance after HSCT. We assessed the impact of HAdV weekly monitoring by polymerase chain reaction (PCR) on HAdV viremia rates and the risk factors that influence survival. Three-hundred and fifty-six pediatric allogeneic HSCT were done between 2007 and 2015. Until July 2011, HAdV testing was performed based on clinical suspicion (cohort 1, n = 175) and from August 2011, weekly blood-HAdV monitoring was done (cohort 2, n = 181) until day +100. Twenty-three patients (4 [2.3%] from cohort 1 and 19 [10.5%] from cohort 2, p =.001) were found with HAdV viremia and seven of them died. Both cohorts had a similar incidence of HAdV-associated mortality (3/175; 1.7% in cohort 1 and 4/181; 2.2% in cohort 2). Respiratory failure was the cause of death in all patients. Clinical symptoms appeared prior to or within 5 days of HAdV detection in cohort 2. In summary, weekly monitoring was associated with higher detection of HAdV. The study could not assess survival benefit due to small numbers of HAdV-positive cases. In many instances, symptoms occurred with the development of positive HAdV blood PCR results and hence, symptomatology could have triggered the test. Future studies are needed to provide data that help establishing a uniform approach for regular monitoring of HAdV post-transplant. [ABSTRACT FROM AUTHOR]

Sinusoidal obstruction syndrome (SOS) is a potentially life-threatening complication after hematopoietic stem cell transplantation (HSCT) or antineoplastic treatment without HSCT. Genetic variants were investigated for their association with SOS, but the evidence is inconclusive. We performed a systematic literature review to identify genes, gene variants, and methods of association analyses of genetic markers with SOS. We identified 23 studies after HSCT and 4 studies after antineoplastic treatment without HSCT. One study (4%) performed whole-exome sequencing (WES) and replicated the analysis in an independent cohort, 26 used a candidate-gene approach. Three studies included >200 participants (11%), and six were of high quality (22%). Variants in 34 genes were tested in candidate gene studies after HSCT. Variants in GSTA1 were associated with SOS in three studies, MTHFR in two, and CPS1, CTH, CYP2B6, GSTM1, GSTP1, HFE, and HPSE in one study each. UGT2B10 and LNPK variants were identified in a WES analysis. After exposure to antineoplastic agents without HSCT, variants in six genes were tested and only GSTM1 was associated with SOS. There was a substantial heterogeneity of populations within and between studies. Future research should be based on sufficiently large homogenous samples, adjust for covariates, and replicate findings in independent cohorts. [ABSTRACT FROM AUTHOR]