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Background We previously demonstrated that APR-246 could be an efficient treatment option against neuroblastoma (NB), the most common pediatric extracranial solid tumor. APR-246’s mechanism of action is not completely understood and can differ between cell types. Here we investigate the involvement of well-known oncogenic pathways in NB’s response to APR-246. Methods A proteome profiler kinase assays and western blot analysis were used to identify the molecular pathways involved in the responses to APR-246. Bulk ATP levels were used to determine the viability of cells and the IC50 for APR-246. Cystine-FITC was used to measure the cellular uptake of cysteine. PmRNA5 was used to affect ERK1/2 and pshRNA1 was used to silence HSP27. An IMR-32 xenograft zebrafish embryo model was used to assess APR-246 and sulfasalazine efficacy in vivo. Results After APR-246 treatment, the most deregulated signaling protein identified was ERK1/2, an end-point kinase of the RAS-MAPK pathway. Induction of phospho-ERK1/2 resulted in increased glutathione (GSH) levels, increased cystine uptake and increased resistance of NB cells to APR-246. Using ERK1/2 inhibitors in combination with APR-246, we were able to categorize cells into synergistic and antagonistic groups. After co-treatment, these two groups differ by their levels of SLC7A11 and Hsp27 phosphorylation, cystine uptake and BIM expression. Using erastin and sulfasalazine, both inhibitors of SLC7A11 and activators of ferroptosis, we were able to reverse the antagonistic effects of ERK1/2 inhibitors and demonstrate a strong synergistic action in vitro and in vivo in zebrafish models. Conclusions These results demonstrated a pivotal role of the RAS-MAPK pathway in the NB cellular response to APR-246 via the modulation of intracellular concentrations of GSH and the transport of cystine, phosphorylation of Hsp27, and programed cell death. Combining APR-246 with RAS-MAPK pathway inhibitors can, in some cases, lead to antagonistic action, which can be reversed by combining APR-246 with the clinically approved drug sulfasalazine.

HLA antigen presentation and T-cell immunity are critical to control viral infection such as SARS-CoV-2. This study performed on samples collected in the pre-COVID-19 era demonstrates that individuals are fully equiped at the genetic level in terms of TCR repertoire and HLA variants to recognize and kill SARS-CoV-2 infected cells. HLA diversity, heterologous immunity and random somatic TCR recombination could explain these observations.

Neuroblastoma is the most common extra-cranial solid tumor in children, representing approximately 8% of all malignant childhood tumors and 15% of pediatric cancer-related deaths. Recent sequencing and transcriptomics studies have demonstrated the RAS-MAPK pathway’s contribution to the development and progression of neuroblastoma. This review compiles up-to-date evidence of this pathway’s involvement in neuroblastoma. We discuss the RAS-MAPK pathway’s general functioning, the clinical implications of its deregulation in neuroblastoma, and current promising therapeutics targeting proteins involved in signaling. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-01967-x.

Background: Glutathione S-transferases (GSTs) are phase II metabolic enzymes crucial for the metabolism of electrophilic drugs. Additionally, several GST isoforms are involved in protein- protein interaction with mitogen-activated protein kinases (MAPKs), modulating apoptosis pathways. Methods: To assess the potential change of enzymatic activity, we performed a GST enzyme assay with human recombinant GSTM1 in the presence and absence of MAPK8. Recently, GSTM1 has been demonstrated to interact with MAPK8 both in silico and in vitro. The binding interface predicted in silico comprised amino acid residues present on the surface of the protein and a few were deep in the active site of the protein. Results: The experiment demonstrated that the GSTM1 activity was conserved even in the presence of MAPK8 in the assay. Conclusion: The possible alteration in the activity of MAPK8 in this interaction needs to be evaluated in further experiments.

BACKGROUND Hearing loss is a potential side effect from childhood cancer treatment. We described the severity of hearing loss assessed by audiometry in a representative national cohort of childhood cancer survivors (CCS) and identified clinical risk factors. PROCEDURE We included all CCS from the Swiss Childhood Cancer Registry who were diagnosed ≤18 age and treated with platinum-based chemotherapy between 1990 and 2014. We extracted audiograms, treatment-related information, and demographic data from medical records. Two reviewers independently assessed the severity of hearing loss at latest follow-up using the Münster Ototoxicity Scale. We used ordered logistic regression to identify clinical risk factors for severity of hearing loss. RESULTS We analyzed data from 270 CCS. Median time from cancer diagnosis to last audiogram was 5 years (interquartile range 2.5-8.1 years). We found 53 (20%) CCS with mild, 78 (29%) with moderate, and 75 (28%) with severe hearing loss. Higher severity grades were associated with (a) younger age at cancer diagnosis (odds ratio [OR] 5.4, 95% confidence interval [CI]: 2.5-12.0 for 450 mg/m2 ); (d) concomitant cranial radiation therapy (CRT) (OR 4.4, 95% CI: 2.5-7.8); and (e) hematopoietic stem cell transplantation (HSCT) (OR 2.7, 95% CI: 1.0-7.2). CONCLUSION Three of four CCS treated with platinum-based chemotherapy experienced some degree of hearing loss. We recommend closely monitoring patient's hearing function if treated at a young age with high cumulative cisplatin doses, and concomitant CRT as part of long-term care.

In busulfan-based conditioning regimen for hematopoietic stem cell transplantation in children, accurate a priori determination of the first dose is important because of its narrow therapeutic window. Sickle cell disease (SCD) influences pharmacokinetics of the commonly used drugs by affecting organs responsible for drug metabolism and elimination. This pharmacokinetics study assesses the influence of SCD on the metabolic pathway of busulfan that is mainly metabolized in the liver. In this retrospective cross-sectional case-control study, 16 patients with SCD were matched to 50 patients without SCD on known busulfan clearance's covariates (glutathione-S-transferase alpha1 polymorphisms, age, weight). Clearance of the first dose of busulfan was not significantly different independently of genetic or anthropometric factors in patients with or without SCD.

The pharmacokinetics of low-dose busulfan (BU) were investigated as a nonmyeloablative conditioning regimen for autologous gene therapy (GT) in pediatric subjects with adenosine deaminase-deficient severe combined immunodeficiency disease (ADA SCID). In 3 successive clinical trials, which included either γ-retroviral (γ-RV) or lentiviral (LV) vectors, subjects were conditioned with BU using different dosing nomograms. The first cohort received BU doses based on body surface area (BSA), the second cohort received doses based on actual body weight (ABW), and in the third cohort, therapeutic drug monitoring (TDM) was used to target a specific area under the concentration-time curve (AUC). Neither BSA-based nor ABW-based dosing achieved a consistent cumulative BU AUC; in contrast, TDM-based dosing led to more consistent AUC. BU clearance increased as subject age increased from birth to 18 months. However, weight and age alone were insufficient to accurately predict the dose that would consistently achieve a target AUC. Furthermore, various clinical, laboratory, and genetic factors (eg, genotypes for glutathione-S-transferase isozymes known to participate in BU metabolism) were analyzed, but no single finding predicted subjects with rapid versus slow clearance. Analysis of BU AUC and the postengraftment vector copy number (VCN) in granulocytes, a surrogate marker of the level of engrafted gene-modified hematopoietic stem and progenitor cells (HSPCs), demonstrated gene marking at levels sufficient for therapeutic benefit in the subjects who had achieved the target BU AUC. Although many factors determine the ultimate engraftment following GT, this work demonstrates that the BU AUC correlated with the eventual level of engrafted gene-modified HSPCs within a vector group (γ-RV versus LV), with significantly higher levels of granulocyte VCN in the recipients of LV-modified grafts compared to recipients of γ-RV-transduced grafts. Taken together, these findings provide insight into low-dose BU pharmacokinetics in the unique setting of autologous GT for ADA SCID, and these dosing principles may be applied to future GT trials using low-dose BU to open the bone marrow niche.

Busulfan and cyclophosphamide (BuCy) is a frequently used myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT). Theoretical considerations and pharmacological data indicate that application of busulfan prior to subsequent cyclophosphamide (BuCy) may trigger liver toxicity. Reversing the order of application to cyclophosphamide-busulfan (CyBu) might be preferable, a hypothesis supported by animal data and retrospective studies. We performed a prospective randomized trial to determine impact of order of application of Bu and Cy before allo-HCT in 70 patients with hematological malignancy, 33 patients received BuCy and 37 CyBu for conditioning. In the short term, there were minimal differences in liver toxicity favoring CyBu over BuCy, significant only for alanine amino transferase at day 30 (p = 0.03). With longer follow-up at 4 years, non-relapse mortality (6% versus 27%, p = 0.05) was lower and survival (63% versus 43%, p = 0.06) was higher with CyBu compared to BuCy. Other outcomes, such as engraftment (p = 0.21), acute and chronic graft-versus-host disease (p = 0.40; 0.36), and relapse (p = 0.79), were similar in both groups. We prospectively show evidence that the order of application of Cy and Bu in myeloablative conditioning in allo-HCT patients has impact on outcome.

RationaleChildhood cancer survivors (CCSs) are at increased risk for pulmonary morbidity due to exposure to lung-toxic treatments, including specific chemotherapies, radiotherapy, and surgery. Longitudinal data on lung function, with information on how outcomes change over time, in CCSs are scarce.ObjectivesTo investigate lung function trajectories in childhood cancer survivors over time and investigate the association with lung-toxic treatment.MethodsThis retrospective, multi-center cohort study included CCSs, who were diagnosed between 1990 and 2013 in Switzerland and had been exposed to lung-toxic chemotherapeutics or thoracic radiotherapy. Pulmonary function tests (PFTs) were obtained from hospital charts. We assessed quality of PFTs systematically and calculated z-scores and percentage predicted of forced expiratory volume in first second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, total lung capacity (TLC) and diffusion capacity for carbon-monoxide (DLCO) based on recommended reference equations. We described lung function over time and determined risk factors for change in FEV1 and FVC using multivariable linear regression.ResultsWe included 790 PFTs from 183 CCSs, with a median age of 12 years (IQR 7 – 14) at diagnosis. Common diagnoses were lymphoma (55%), leukemia (11%) and CNS tumors (12%). Median follow-up time was 5.5 years. Half (49%) of CCSs had at least one abnormal pulmonary function parameter, with restrictive impairment being common (22%). Trajectories of FEV1 and FVC started at z-scores of -1.5 at diagnosis and remained low throughout follow-up. CCSs treated with thoracic surgery started particularly low, with an FEV1 of -1.08 z-scores (−2.02 to -0.15) and an FVC of -1.42 z-scores (−2.27 to -0.57) compared to those without surgery. In CCS exposed to lung-toxic chemotherapeutics FEV1 z-scores increased slightly over time (0.12 per year; 95%CI 0.02 - 0.21).ConclusionThe large proportion of CCSs with reduced lung function identified in this study underlines the need for more research and long-term surveillance of this vulnerable population.

IntroductionChildhood cancer and its treatment may lead to various health complications. Related impairment in quality of life, excess in deaths and accumulated healthcare costs are relevant. Genetic variations are suggested to contribute to the wide inter-individual variability of complications but have been used only rarely to risk-stratify treatment and follow-up care. This study aims to identify germline genetic variants associated with acute and late complications of childhood cancer.Methods and analysisThe Genetic Risks for Childhood Cancer Complications Switzerland (GECCOS) study is a nationwide cohort study. Eligible are patients and survivors who were diagnosed with childhood cancers or Langerhans cell histiocytosis before age 21 years, were registered in the Swiss Childhood Cancer Registry (SCCR) since 1976 and have consented to the Paediatric Biobank for Research in Haematology and Oncology, Geneva, host of the national Germline DNA Biobank Switzerland for Childhood Cancer and Blood Disorders (BISKIDS).GECCOS uses demographic and clinical data from the SCCR and the associated Swiss Childhood Cancer Survivor Study. Clinical outcome data consists of organ function testing, health conditions diagnosed by physicians, second primary neoplasms and self-reported information from participants. Germline genetic samples and sequencing data are collected in BISKIDS. We will perform association analyses using primarily whole-exome or whole-genome sequencing to identify genetic variants associated with specified health conditions. We will use clustering and machine-learning techniques and assess multiple health conditions in different models.DiscussionGECCOS will improve knowledge of germline genetic variants associated with childhood cancer-associated health conditions and help to further individualise cancer treatment and follow-up care, potentially resulting in improved efficacy and reduced side effects.Ethics and disseminationThe Geneva Cantonal Commission for Research Ethics has approved the GECCOS study.Research findings will be disseminated through national and international conferences, publications in peer-reviewed journals and in lay language online.Trial registration numberNCT04702321.

Background Given that social media is quickly penetrating clinical practice, it is essential to explore how these technologies can be used to improve patient-centered care. This is particularly important for healthcare professionals caring for adolescents and young adults (AYA), amid whom the use of social media is nearly universal and whose medical and psychosocial needs are often underestimated by the pediatric or adult oncology settings in which they are treated. Objectives To examine the perspectives of various medical professionals on the emerging role of social media in AYA oncology. Methods Three focus groups were performed with Swiss healthcare professionals involved in the care of AYA patients with cancer. The focus groups were analyzed using thematic coding. Results Healthcare professionals caring for AYA cancer patients in Switzerland are reluctant to step into the social media sphere because they find it difficult to navigate professional boundaries in an unfamiliar space where different contexts collapse. Nurses and younger healthcare professionals who tend to have a more intimate relationship with AYA, often lack virtual mentorship to know how to maintain online professionalism. Adolescents and young adults cancer-related social media presence was unknown to our participants which resulted in missed occasions to inform, educate and care for this often underserved population of cancer patients. Conclusions More practical guidance is needed to help healthcare professionals with how to integrate social media into clinical practice. Setting up fruitful collaborations between medical institutions and existing AYA support groups online might be the best way forward.

Sinusoidal obstruction syndrome (SOS) is a well-recognized and potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). SOS arises from endothelial cell damage and hepatocellular injury mostly due to the transplantation conditioning regimens but also to other patient, disease, and treatment-related factors. Understanding risk factors associated with the development of SOS is critical for early initiation of treatment or prophylaxis. The knowledge about genetic contribution is limited; few studies investigated so far selected a set of genes. To get more comprehensive insight in the genetic component, we performed an exome-wide association study using genetic variants derived from whole-exome sequencing. The analyses were performed in a discovery cohort composed of 87 pediatric patients undergoing HSCT following a busulfan-containing conditioning regimen. Eight lead single-nucleotide polymorphisms (SNPs) were identified after correction for multiple testing and subsequently analyzed in a validation cohort (n = 182). Three SNPs were successfully replicated, including rs17146905 ( P = .001), rs16931326 ( P = .04), and rs2289971 ( P = .03), located respectively in the UGT2B10, BHLHE22, and KIAA1715 genes. UGT2B10 and KIAA1715 were retained in a multivariable model while controlling for nongenetic covariates and previously identified risk variants in the GSTA1 promoter. The modulation of associations by conditioning regimens was noted; KIAA1715 was dependent on the intensity of the conditioning regimen, whereas the effect of UGT2B10 was equally applicable to all of them. Combined effect of associated loci was also observed ( P = .00006) with a genotype-related SOS risk of 9.8. To our knowledge, this is the first study addressing the genetic component of SOS at an exome-wide level and identifying novel genetic variations conferring a higher risk of SOS, which might be useful for personalized prevention and treatment strategies. (C) 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

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.

BACKGROUND Busulfan (Bu) is one of the conditioning regimen components for pediatric hematopoietic stem cell transplantation. Bu therapeutic drug monitoring (TDM) is essential for a successful treatment outcome and toxicity evasion. Dried blood spot (DBS) sampling is a rapid and simple method for Bu TDM, compared with conventional plasma sampling. This study evaluated the feasibility of using the DBS method for Bu TDM. The hematocrit (Hct) and conditioning day were also examined for their impact on the DBS method's performance. METHODS Venous blood collected from 6 healthy volunteers was diluted, using their plasma into 4 samples of varying Hct values. Each sample was spiked with Bu calibrators (300, 600, and 1400 ng/mL), prepared using DBS and dried plasma spot (DPS) sampling and analyzed using a validated liquid-chromatography tandem-mass spectrometry method. Clinical blood samples (n = 153) from pediatric patients (n = 15) treated with Bu (mainly from doses 1, 2, 5, and 9) were used to prepare paired volumetric DBS and DPS samples. A Bland-Altman plot and Deming regression were used to define the agreement between the paired DBS and DPS measurements. Passing-Bablok regression analyses investigated the effects of Hct and conditioning day on the linearity between both methods. RESULTS In vitro analyses showed good agreement between DBS and DPS measurements, with a mean difference of -5.4% and a 95% confidence interval on the limits of agreement of -15.3% to 4.6%. Clinical samples showed good correlation (Pearson correlation coefficient = 0.96; slope = 1.00) between the DBS and DPS methods. The DBS method met the clinical acceptance limits for clinical samples, with a bias

The most frequent complication of allogeneic hematopoietic stem cell transplantation is acute Graft versus Host Disease (aGVHD). Proliferation and differentiation of donor T cells initiate inflammatory response affecting the skin, liver, and gastrointestinal tract. Besides recipient–donor HLA disparities, disease type, and the conditioning regimen, variability in the non-HLA genotype have an impact on aGVHD onset, and genetic variability of key cytokines and chemokines was associated with increased risk of aGVHD. To get further insight into the recipient genetic component of aGVHD grades 2–4 in pediatric patients, we performed an exome-wide association study in a discovery cohort (n = 87). Nine loci sustained correction for multiple testing and were analyzed in a validation group (n = 168). Significant associations were replicated for ERC1 rs1046473, PLEK rs3816281, NOP9 rs2332320 and SPRED1 rs11634702 variants through the interaction with non-genetic factors. The ERC1 variant was significant among patients that received the transplant from HLA-matched related individuals (p = 0.03), bone marrow stem cells recipients (p = 0.007), and serotherapy-negative patients (p = 0.004). NOP9, PLEK, and SPRED1 effects were modulated by stem cell source, and serotherapy (p < 0.05). Furthermore, ERC1 and PLEK SNPs correlated with aGVHD 3-4 independently of non-genetic covariates (p = 0.02 and p = 0.003). This study provides additional insight into the genetic component of moderate to severe aGVHD.

Background: Diffuse intrinsic pontine glioma (DIPG) is one of the most devastating diseases among children with cancer, thus novel strategies are urgently needed. Aims: We retrospectively evaluated DIPG patients exposed to the carbohydrate restricted ketogenic diet (KD) with regard of feasibility, safety, and overall survival (OS). Methods and results: Searches of MEDLINE and Embase identified five hits meeting the search criteria (diagnosis of DIPG and exposure to KD). One additional case was identified by contact with experts. Individual patient data were extracted from publications or obtained from investigators. The inclusion criteria for analysis of the data were defined as DIPG patients who were exposed to the KD for ≥3 months. Feasibility, as described in the literature, was the number of patients able to follow the KD for 3 months out of all DIPG patients identified. OS was estimated by the Kaplan-Meier method. Five DIPG patients (males, n = 3; median age 4.4 years; range, 2.5-15 years) meeting the inclusion criteria were identified. Analysis of the available data suggested that the KD is generally relatively well tolerated. Only mild gastro-intestinal complaints, one borderline hypoglycemia (2.4 mmol/L) and one hyperketosis (max 7.2 mmol/L) were observed. Five out of six DIPG patients identified adhered for ≥3 months (median KD duration, 6.5 months; range, 0.25-2 years) to the diet. The median OS was 18.7 months. Conclusion: Our study provides evidence that it may be feasible for pediatric DIPG patients to adhere for at least 3 months to KD. In particular cases, diet modifications were done. The clinical outcome and OS appear not to be impacted in a negative way. KD might be proposed as adjuvant therapy when large prospective studies have shown feasibility and safety. Future studies might ideally assess the impact of KD on clinical outcome, quality of life, and efficacy.

International audience; We previously reported results of a French randomized clinical trial (RCT) comparing the risk of transplantation failure (including transplant-related mortality [TRM], engraftment failure, and autologous recovery) in single and double unrelated cord blood (UCB) transplantation in children and young adults with hematologic malignancies. We concluded that single-UCB transplantation with an adequate cell dose is the standard of care, leading to a 70% two-year overall survival (OS). It remains unclear, however, whether RCT participants have better outcomes than comparable patients not treated in the setting of a clinical trial. We compared the characteristics and outcomes of RCT participants (n = 137) to a Francophone population-based registry of patients (real-world [RW] group) fulfilling the eligibility criteria used in our RCT and transplanted with 1 or 2 UCB units after a myeloablative conditioning (MAC) regimen between March 2015 (end of inclusion in the RCT) and February 2019 (n = 141). The primary endpoint was the 2-year cumulative incidence (CI) of transplantation strategy failure as defined in our RCT. The 2 groups were comparable in terms of age, disease distribution, hematologic status at transplantation, follow-up, and HLA compatibility. Patients in the RW group were more likely to be transplanted with a single-unit UCB (87.9% versus 49.6%, P< .001) and to receive a radiation-free regimen (39.0% versus 60.6%, P< .001). The 2-year CI of transplantation strategy failure, TRM, and the 2-year probability of OS were similar between the 2 groups, although the relapse risk was higher in the RW group (31.2% ± 7.7% versus 20.4% ± 6.8%, P= .01), resulting in a significantly lower disease-free survival (DFS) (59.2% ± 8.4% versus 69.3% ± 8.0%, P= .047). This difference remained statistically significant only in the group of patients with acute lymphoid leukemia (ALL) who did not receive the conditioning regimen recommended by the RCT (fludarabine 75 mg/m2, total body irradiation 12 Gy, cyclophosphamide 120 mg/kg). The results of our RCT appear to be reproducible in real-world conditions, provided that the same cord blood selection criteria and conditioning regimen are used.

Sinusoidal obstruction syndrome (SOS), also known as hepatic veno-occlusive disease (VOD), is a well-known complication of allogeneic hematopoietic stem cell transplantation (HSCT) associated with a mortality rate of up to 85%. Defibrotide has shown efficacy in treatment of SOS/VOD. Moreover, evidence exists supporting the efficacy of defibrotide as SOS/VOD prophylaxis. We have previously reported our single center experience on 52 HSCT recipients receiving defibrotide as SOS/VOD prophylaxis, which has shown that the patients did not develop any SOS/VOD under this prophylaxis. The aim of the present study was to see if we can confirm the previous results, mainly on the decrease incidence of SOS/VOD, as well as improve event-free survival (EFS) on a larger study population. We extended our previous study in a single-center retrospective analysis to include 237 consecutive patients (248 transplantations) who underwent transplantation between 1999 and 2009 for hematological diseases and receiving intravenous defibrotide as prophylaxis. This cohort was compared to 241 patients (248 transplantations) treated before 1999 or after 2009 when defibrotide prophylaxis was not routinely used in our center. Median follow-up for the study group was 10 (range 2-16) years and for the control group 2.7 (range 1-18) years. None of the 237 patients in the defibrotide group developed SOS/VOD. The cumulative incidence (CI) of SOS/VOD was 0% in the defibrotide group as compared to 4.8% (95% confidence interval [CI], 2.6-8%; P= .00046) in the control group. There was also a better 1-year EFS with 38% (95% CI, 32%-44%) in the defibrotide group versus 28% (95% CI, 22%-34%) (P= .00969) and decreased cumulative incidence of acute graft-versus-host disease (GvHD) in the defibrotide group 31% (95% CI, 25%-37%) versus 42% (95% CI, 36%-48%) (P= .026). The 1-year overall survival, relapse incidence, and non-relapse mortality were not statistically different. Multivariable analysis, performed taking into account clinical factors known to influence the risk of SOS/VOD, confirmed the favorable impact of defibrotide on SOS/VOD (HR 1.38e-08 [95% CI, 3.28e-09-5.80e-08]; P.00001). Conversely, multivariable analysis failed to confirm the impact of defibrotide on 1-year EFS or acute GvHD. This large retrospective study on SOS/VOD-prophylaxis with defibrotide suggests that this approach may be of benefit. These results need to be confirmed in a prospective randomized trial.

Purpose This study aimed to retrospectively evaluate the genetic association of null variants of glutathione S-transferases GSTM1 and GSTT1 with relapse incidence in children with hematological malignancies (HMs) undergoing busulfan (BU)- containing allogeneic hematopoietic stem cell transplantation (HSCT) and to assess the impact of these variants on BU-induced cytotoxicity on the immortalized lymphoblastoid cell lines (LCLs) and tumor THP1 GST gene-edited cell models. Methods GSTM1- and GSTT1-null alleles were genotyped using germline DNA from whole blood prior to a conditioning BU-based regimen. Association of GSTM1- and GSTT1-null variants with relapse incidence was analyzed using multivariable competing risk analysis. BU-induced cell death studies were conducted in GSTs- null and non-null LCLs and CRISPR–Cas9 gene-edited THP1 leukemia cell lines. Results Carrying GSTM1/GSTT1 double null genotype was found to be an independent risk factor for post-HSCT relapse in 86 children (adjusted HR: 6.52 [95% Cl, 2.76–15.42; p = 1.9 × 10–5]). BU-induced cell death preferentially in THP1GSTM1(non−null) and LCLsGSTM1(non−null) as shown by decreased viability, increased necrosis and levels of the oxidized form of glutathione compared to null cells, while GSTT1 non-null cells showed increased baseline proliferation. Conclusion The clinical association suggests that GSTM1/GSTT1 double null genotype could serve as genetic stratification biomarker for the high risk of post-HSCT relapse. Functional studies have indicated that GSTM1 status modulates BU-induced cell death. On the other hand, GSTT1 is proposed to be involved in baseline cell proliferation.

Glutathione S-transferases (GSTs) are phase II metabolic enzymes crucial for the metabolism of electrophilic drugs. Additionally, several GST isoforms are involved in protein- protein interaction with mitogen-activated protein kinases (MAPKs), modulating apoptosis pathways.To assess the potential change of enzymatic activity, we performed a GST enzyme assay with human recombinant GSTM1 in the presence and absence of MAPK8. Recently, GSTM1 has been demonstrated to interact with MAPK8 both in silico and in vitro. The binding interface predicted in silico comprised amino acid residues present on the surface of the protein and a few were deep in the active site of the protein.The experiment demonstrated that the GSTM1 activity was conserved even in the presence of MAPK8 in the assay.The possible alteration in the activity of MAPK8 in this interaction needs to be evaluated in further experiments.

Background. Fever in neutropenia (FN) remains an unavoidable, potentially lethal complication of chemotherapy. Timely administration of empirical broad-spectrum intravenous antibiotics has become standard of care. But the impact of time to antibiotics (TTA), the lag period between recognition of fever or arrival at the hospital to start of antibiotics, remains unclear. Here we aimed to analyze the association between TTA and safety relevant events (SRE) in data from a prospective multicenter study. Procedure. We analyzed the association between time from recognition of fever to start of antibiotics (F-TTA) and SRE (death, admission to intensive care unit (ICU), severe sepsis and bacteremia) with three-level mixed logistic regression. We adjusted for possible triage bias using a propensity score and stratified the analysis by severity of disease at presentation. Results. We analyzed 266 FN episodes, including 53 (20%) with SRE, reported in 140 of 269 patients recruited from April 2016 to August 2018. F-TTA (median, 120min; interquartile range, 49 to 180min) was not associated with SRE, with a trend for less SREs in episodes with longer F-TTA. Analyses applying the propensity score suggested a relevant triage bias. Only in patients with severe disease at presentation there was a trend for an association of longer TTA with more SRE. Conclusion. We found little evidence that longer TTA leads to a higher risk of poor clinical outcome in pediatric patients with FN, except for those with severe disease at presentation. We saw strong evidence for triage bias which could only be partially adjusted.

The study aimed to explore the attitudes of Swiss healthcare professionals toward the use of social media in adolescent and young adult oncology, and to examine whether the ongoing social restrictions due to COVID-19 might have altered these attitudes.This research was a survey study. The subjects were healthcare providers working in pediatric or adult oncology settings in Switzerland. 62 providers completed the survey. We performed descriptive and inferential statistical analyses.While considered useful for various professional aspects (professional life 62.1%, educational purposes 72.7%, networking 83.3%, patient engagement 57.6%, clinical trial recruitment 51.5%), only a small proportion of participants actually used social media for professional reasons weekly (32.8%). Just over half considered themselves skillful in using these platforms (56.1%). Regression analysis revealed that self-assessed skillfulness with social media, the Covid-19 impact on attitudes, and the oncology setting, significantly predicted assessment of the usefulness of social media. Although, in answers to open items, institutional guidelines were deemed crucial to improve social media use, many respondents seemed unaware of their existence (50.8%). Only a minority reported an impact of Covid-19 on their attitudes towards the professional implementation of social media (25.0%).The global health crisis creates important challenges for young patients with cancer and their healthcare providers. In times of social restrictions, social media may be a promising tools to facilitate health information provision, connectivity, and patient care. Virtual mentorship and targeted social media training interventions might be a good way to improve familiarity with using social media and to increase awareness about existing ethical guidelines for their use.

Background Fever in neutropenia (FN) remains a frequent complication in pediatric patients undergoing chemotherapy for cancer. There are only conflicting and weak recommendations for and against antibiotic prophylaxis during chemotherapy. Procedure Pediatric patients were observed in a prospective multicenter study (NCT02324231). A score predicting the risk to develop FN with safety relevant events (SRE; bacteremia, severe sepsis, intensive care unit admission, death) was developed using multivariate mixed Poisson regression. Its predictive performance was assessed by internal cross-validation and compared with the performance of published rules. Results In 238 patients, 318 FN episodes were recorded, including 53 (17%) with bacteremia and 68 (21%) with SRE. The risk prediction score used three variables: chemotherapy intensity, time since diagnosis and type of malignancy. Its cross-validated performance, assessed by the time needed to cover (TNC) one event, exceeded the performance of published rules. Two clinically useful score thresholds were found: a threshold of ≥11 resulted in 2.3% time at risk and 4.1 months TNC; a threshold of ≥8 in 24.9% time at risk and 12.1 months TNC. Using external information on efficacy and timing of intermittent antibiotic prophylaxis, 4.3 months of prophylaxis were needed to prevent one FN with bacteremia, and 5.2 months to prevent one FN with SRE, using a threshold of ≥11. Conclusions This score, based on three routinely accessible characteristics, accurately identifies pediatric patients at risk to develop FN with SRE during chemothearpy. The score can help to design clinical decision rules on targeted primary antibiotic prophylaxis and corresponding efficacy studies.

Background: Relapse is the major cause of treatment failure in children with hematological malignancies (HMs) undergoing busulfan (BU)- based allogeneic hematopoietic stem cell transplantation (HSCT). Glutathione S-transferases (GSTs) isoforms that participate in BU detoxification and protect cells against stress and cell death may be linked to post-HSCT outcomes. This study aimed to retrospectively evaluate the genetic association of null variants of Glutathione S-transferases GSTM1 and GSTT1 with relapse incidence in children with HMs undergoing BU- containing allogeneic HSCT and to assess the impact of these variants on BU-induced cytotoxicity on the immortalized and tumor lymphoblastoid cell lines (LCLs).Methods: GSTM1- and GSTT1- null alleles were genotyped using germline DNA from whole blood prior to a conditioning BU-based regimen. Association of GSTM1- and GSTT1- null variants with relapse incidence was analyzed using multivariable competing risk analysis. BU-induced cell-death studies were conducted in GSTs- null and non-null LCLs and CRISPR-Cas9 gene-edited THP1 leukemia cell lines. Results: Carrying GSTM1/GSTT1 double null genotype was found to be an independent risk factor for post-HSCT relapse in 86 children (adjusted HR: 6.52 [95% Cl, 2.76 - 15.42; p= 1.9 x 10-5]). BU induced cell death preferentially in THP1GSTM1(non-null) and LCLsGSTM1(non-null) as shown by decreased viability, increased necrosis and levels of the oxidized form of glutathione compared to null cells, while GSTT1 non-null cells showed increased baseline proliferation. Conclusion: The clinical association suggests that GSTM1/GSTT1 double null genotype could serve as genetic stratification biomarker for the high risk of post-HSCT relapse. Functional studies have indicated that GSTM1 status modulates BU-induced cell death. On the other hand, GSTT1 is proposed to be involved in baseline cell proliferation. Trial registration: ClinicalTrials.gov identifier: NCT01257854, Registered February 2008 – retrospectively registered.

BackgroundRelapse is the major cause of treatment failure in children with hematological malignancies (HMs) undergoing busulfan (BU)- based allogeneic hematopoietic stem cell transplantation (HSCT). Glutathione S-transferases (GSTs) isoforms that participate in BU detoxification and protect cells against stress and cell death may be linked to post-HSCT outcomes. This study aimed to retrospectively evaluate the genetic association of null variants of Glutathione S-transferases GSTM1 and GSTT1 with relapse incidence in children with HMs undergoing BU- containing allogeneic HSCT and to assess the impact of these variants on BU-induced cytotoxicity on the immortalized lymphoblastoid cell lines (LCLs) and tumor THP1 GST-gene edited cell models.MethodsGSTM1- and GSTT1- null alleles were genotyped using germline DNA from whole blood prior to a conditioning BU-based regimen. Association of GSTM1- and GSTT1- null variants with relapse incidence was analyzed using multivariable competing risk analysis. BU-induced cell-death studies were conducted in GSTs- null and non-null LCLs and CRISPR-Cas9 gene-edited THP1 leukemia cell lines. ResultsCarrying GSTM1/GSTT1 double null genotype was found to be an independent risk factor for post-HSCT relapse in 86 children (adjusted HR: 6.52 [95% Cl, 2.76 - 15.42; p= 1.9 x 10-5]). BU induced cell death preferentially in THP1GSTM1(non-null) and LCLsGSTM1(non-null) as shown by decreased viability, increased necrosis and levels of the oxidized form of glutathione compared to null cells, while GSTT1 non-null cells showed increased baseline proliferation. ConclusionThe clinical association suggests that GSTM1/GSTT1 double null genotype could serve as genetic stratification biomarker for the high risk of post-HSCT relapse. Functional studies have indicated that GSTM1 status modulates BU-induced cell death. On the other hand, GSTT1 is proposed to be involved in baseline cell proliferation. Trial registrationClinicalTrials.gov identifier: NCT01257854, Registered February 2008 – retrospectively registered.

Aim: The need for pharmacogenomic education is becoming more and more urgent. Our aim was to evaluate the progress in pharmacogenomics education since then, and to put forward further recommendations. Methods: A survey was sent to 248 schools of medicine, pharmacy, nursing and health professions around the world. Results: The majority of the study programs (87%) include pharmacogenomics education, which is generally taught as part of the pharmacology curriculum. On average, educators and teachers have selected appropriate and highly relevant pharmacogenomics biomarkers to include in their teaching programs. Conclusions: Based on the results, we can conclude that the state of pharmacogenomics education at the surveyed universities has improved substantially since 2005. ispartof: PHARMACOGENOMICS vol:20 issue:9 pages:643-657 ispartof: location:England status: published

Purpose The development of advanced nursing practices (ANP) can meet challenges presented by evolving needs of health care. We aimed at describing the approach taken to implement ANP in a pediatric oncology-hematology unit. Method The Participatory, Evidence-informed, Patient-centered Process for Advanced practice was considered as a conceptual framework for the development, implementation and evaluation of the nursing role. Successive steps were taken for identifying patients and family needs, defining the health care priorities, and establishing a new health care model. Results The seven steps of the PEPPA framework were carried out over a year and contributed to the identification of the tasks and the role of the advanced nurse practitioner in the patient care pathway. The implementation of ANP was gradually achieved with the development of new evidenced-based health care procedures. The subsequent approval of a contract specification for advanced nurse practitioners facilitated the onset of a specific consultation, which facilitated a holistic approach. Conclusion The impact of the implementation can be appreciated at different levels: i) the patient and his or her family, with improvement of communication and continuity of care; ii) the interdisciplinary team, with development of a dynamic and greater motivation of the health care providers; and iii) the profession, with a greater recognition of the competencies and conceptualization of the new role. An assessment of the process, the structure and the results should be carried out to validate the role of the advanced nurse practitioner throughout the long journey of a child with leukemia.

Data on stem cell transplantation (SCT) for Diamond-Blackfan Anemia (DBA) is limited. We studied patients transplanted for DBA and registered in the EBMT database. Between 1985 and 2016, 106 DBA patients (median age, 6.8 years) underwent hematopoietic stem cell transplantation from matched-sibling donors (57%), unrelated donors (36%), or other related donors (7%), using marrow (68%), peripheral blood stem cells (20%), both marrow and peripheral blood stem cells (1%), or cord blood (11%). The cumulative incidence of engraftment was 86% (80% to 93%), and neutrophil recovery and platelet recovery were achieved on day +18 (range, 16 to 20) and +36 (range, 32 to 43), respectively. Three-year overall survival and event-free survival were 84% (77% to 91%) and 81% (74% to 89%), respectively. Older patients were significantly more likely to die (hazard ratio, 1.4; 95% confidence interval, 1.06 to 1.23; P < .001). Outcomes were similar between sibling compared to unrelated-donor transplants. The incidence of acute grades II to IV of graft-versus-host disease (GVHD) was 30% (21% to 39%), and the incidence of extensive chronic GVHD was 15% (7% to 22%). This study shows that SCT may represent an alternative therapeutic option for transfusion-dependent younger patients. (C) 2021 Published by Elsevier Inc. on behalf of The American Society for Transplantation and Cellular Therapy.

Background: 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). Patients and methods: 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. Results: 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). Conclusion: 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.

BackgroundChildhood cancer and its treatment may lead to many acute and chronic health complications. Related impairment in quality of life, excess in deaths, and accumulated health care costs are relevant. There is a wide inter-individual variability in the type and severity of health complications. Genetic variations are suggested to contribute to individual susceptibility. So far, only few genetic variants have been used to risk-stratify treatment and follow-up care. This study platform aims to identify germline genetic variants associated with acute and late complications of childhood cancer.MethodsThe Genetic Risks for Childhood Cancer Complications Switzerland (GECCOS) study is a nationwide cohort study. It includes patients and survivors who were diagnosed with childhood cancers or Langerhans cell histiocytosis before age 21 years, were registered in the Swiss Childhood Cancer Registry (SCCR) since 1976 and have consented to the Pediatric Biobank for Research in Hematology and Oncology (BaHOP), Geneva, host of the Germline DNA Biobank Switzerland for Childhood Cancer and Blood Disorders (BISKIDS). BISKIDS is a national biobank for the collection of germline DNA in childhood cancer patients and survivors.GECCOS uses demographic and clinical data from the SCCR and the associated Swiss Childhood Cancer Survivor Study (SCCSS), which contains health-related data of survivors. Phenotypic data consist of objective measurements, health conditions diagnosed by physicians, second primary neoplasms, self-reported and health-related information from participants. Germline genetic samples and sequencing data have been collected in BISKIDS. We will perform gene panel sequencing, whole-exome sequencing, or whole-genome sequencing depending on the research questions. We will perform association analyses to identify genetic variants associated with specified health conditions. We will use clustering and machine-learning techniques and assess multiple health conditions in different models.DiscussionGECCOS will serve as an overarching platform to enable genotype-phenotype association analyses on complications associated with childhood cancer and its treatments. Knowledge of germline genetic variants associated with childhood cancer-associated health conditions will help to further individualize cancer treatment and follow-up care, potentially resulting in improved efficacy and reduced side effects, for personalized cancer care.Trial registrationClinicaltrials.gov: NCT04702321

BackgroundChest wall abnormalities are a poorly studied complication after treatment for childhood cancer. Chest wall abnormalities are not well described in the literature, and little is known on the impact on daily life of survivors.MethodsWe investigated chest wall abnormalities in the nationwide, population-based cohort study (Swiss Childhood Cancer Survivor Study) with a questionnaire survey to describe prevalence and risk factors. We then interviewed a nested sample of survivors to understand types of chest wall abnormalities and their impact on daily life of survivors.Results48 of 2,382 (95%CI 2%–3%) survivors reported a chest wall abnormality. Risk factors were older age at cancer diagnosis (16–20 years; OR 2.5, 95%CI 1.0– 6.1), lymphoma (OR 3.8, 95%CI 1.2–11.4), and central nervous system tumors (OR 9.5, 95%CI 3.0–30.1) as underlying disease, and treatment with thoracic radiotherapy (OR 2.0, 95%CI 1.0–4.2), surgery to the chest (OR 4.5, 95%CI 1.8–11.5), or chemotherapy (OR 2.9, 95%CI 1.0–8.1) .The nature of the chest wall abnormalities varied and included thoracic wall deformities (30%), deformations of the spine (5%) or both (55%), and scars (10%). Chest wall abnormalities affected the daily life in two thirds (13/20) of those who reported these problems, and 15 (75%) had required chest wall abnormalities-related medical attention.ConclusionIt is important that during follow-up care physicians pay attention to chest wall abnormalities, which are rare late-effect of cancer treatment, but can considerably affect well-being of cancer survivors.

Coronavirus disease-2019 in children has been linked to various clinical presentation, from paucisymptomatic cutaneous eruptions, to multisystemic inflammatory syndrome. We report the case of an 8-year-old boy who presented with persistent fever and pancytopenia, associated to a skin rash. An extensive etiological workup showed a positive serology for severe acute respiratory syndrome coronavirus 2 and Epstein-Barr virus. A few weeks later, type B acute lymphocytic leukemia was diagnosed. This case underlines the polymorphic appearance of coronavirus disease-2019 and the need for critical appraisal.

Acute Graft versus Host Disease (aGvHD) grades 2–4 occurs in 15–60% of pediatric patients undergoing allogeneic haematopoietic stem-cell transplantation (allo-HSCT). The collateral damage to normal tissue by conditioning regimens administered prior to allo-HSCT serve as an initial trigger for aGvHD. DNA-repair mechanisms may play an important role in mitigating this initial damage, and so the variants in corresponding DNA-repair protein-coding genes via affecting their quantity and/or function. We explored 51 variants within 17 DNA-repair genes for their association with aGvHD grades 2–4 in 60 pediatric patients. The cumulative incidence of aGvHD 2–4 was 12% (n = 7) in the exploratory cohort. MGMT rs10764881 (G>A) and EXO rs9350 (c.2270C>T) variants were associated with aGvHD 2–4 [Odds ratios = 14.8 (0 events out of 40 in rs10764881 GG group) and 11.5 (95% CI: 2.3–191.8), respectively, multiple testing corrected p ≤ 0.001]. Upon evaluation in an extended cohort (n = 182) with an incidence of aGvHD 2–4 of 22% (n = 40), only MGMT rs10764881 (G>A) remained significant (adjusted HR = 2.05 [95% CI: 1.06–3.94]; p = 0.03) in the presence of other clinical risk factors. Higher MGMT expression was seen in GG carriers for rs10764881 and was associated with higher IC50 of Busulfan in lymphoblastoid cells. MGMT rs10764881 carrier status could predict aGvHD occurrence in pediatric patients undergoing allo-HSCT.

Purpose Initial genetic alterations in the development of childhood leukemia occur in utero or before conception; both genetic and environmental factors are suspected to play a role. We aimed to investigate the associations between childhood leukemia and perinatal characteristics including birth order, birth interval to older siblings, parental age, birth weight, and multiple birth. Methods We identified cases diagnosed between 1981 and 2015 and born in Switzerland between 1969 and 2015 from the Swiss Childhood Cancer Registry and randomly sampled five controls per case from national birth records matched on date of birth, sex, and municipality of residence at birth. We used conditional logistic regression to investigate associations between perinatal characteristics and leukemia at ages 0–15 and 0–4 years, and the subtypes acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Results The study included 1,403 cases of leukemia. We observed increased risks associated with high birth weight (adjusted OR 1.37, 95% CI 1.12–1.69) and multiple birth (1.89, 1.24–2.86). These associations were similar for ALL and stronger for leukemia at ages 0–4 years. For AML, we observed an increased risk for higher birth order (3.08, 0.43–22.03 for fourth or later born children). We found no associations with other perinatal characteristics. Conclusion This register-based case–control study adds to the existing evidence of a positive association between high birth weight and risk of childhood leukemia. Furthermore, it suggests children from multiple births are at an increased risk of leukemia.

Background: Fever in neutropenia (FN) remains a frequent complication in pediatric patients undergoing chemotherapy for cancer. Preventive strategies, like primary antibiotic prophylaxis, need to be evidence-based. Procedure: Data on pediatric patients with any malignancy from the prospective multicenter SPOG 2015 FN Definition Study (NCT02324231) were analyzed. A score predicting the risk to develop FN with safety-relevant events (SRE; bacteremia, severe sepsis, intensive care unit admission, death) was developed using multivariate mixed Poisson regression. Its predictive performance was assessed by internal cross-validation and compared with the performance of published rules. Results: In 238 patients, 318 FN episodes were recorded, including 53 (17%) with bacteremia and 68 (21%) with SRE. The risk-prediction score used three variables: chemotherapy intensity, defined according to the expected duration of severe neutropenia, time since diagnosis, and type of malignancy. Its cross-validated performance, assessed by the time needed to cover (TNC) one event, exceeded the performance of published rules. A clinically useful score threshold of ≥11 resulted in 2.3% time at risk and 4.1 months TNC. Using external information on efficacy and timing of intermittent antibiotic prophylaxis, 4.3 months of prophylaxis were needed to prevent one FN with bacteremia, and 5.2 months to prevent one FN with SRE, using a threshold of ≥11. Conclusions: This score, based on three routinely accessible characteristics, accurately identifies pediatric patients at risk to develop FN with SRE during chemotherapy. The score can help to design clinical decision rules on targeted primary antibiotic prophylaxis and corresponding efficacy studies.

Childhood cancer survivors (CCSs) are at increased risk of developing chronic health conditions. This may potentially be reduced by a balanced diet. We aimed to compare dietary intake and diet quality using the Alternative Healthy Eating Index (AHEI) of adult CCSs and the general Swiss population. A food frequency questionnaire (FFQ) was completed by CCSs with a median age of 34 (IQR: 29–40) years. We compared dietary intake of 775 CCSs to two population-based cohorts who completed the same FFQ: 1276 CoLaus and 2529 Bus Santé study participants. CCSs consumed particular inadequate amounts of fiber and excessive amounts of sodium and saturated fat. Dietary intake was similar in CCSs and the general population. The mean AHEI was low with 49.8 in CCSs (men: 47.7, women: 51.9), 52.3 in CoLaus (men: 50.2, women: 54.0), and 53.7 in Bus Santé (men: 51.8, women: 54.4) out of a maximum score of 110. The AHEI scores for fish, fruit, vegetables, and alcohol were worse in CCSs than in the general population, whereas the score for sugar-sweetened beverages was better (all p &lt, 0.001). Diet quality at follow-up did not differ between clinical characteristics of CCSs. Long-term CCSs and the general population have poor dietary intake and quality in Switzerland, which suggests similar population-based interventions for everyone.

Background Research on germline genetic variants relies on enough eligible participants which is difficult to achieve for rare diseases such as childhood cancer. With self-collection kits, participants can contribute genetic samples conveniently from their home. Demographic and clinical factors were identified previously that influenced participation in mailed self-collection. People with pre-existing heritable diagnoses might participate differently in germline DNA collection which might render sampling biased in this group. In this nationwide cross-sectional study, we analysed predictive factors of participation in DNA self-collection including heritable diagnoses. Methods We identified childhood cancer survivors from the Swiss Childhood Cancer Registry for invitation to germline DNA self-sampling in September 2019. Participants received saliva sampling kits by postal mail at their home, were asked to fill them, sign an informed consent, and send them back by mail. Two reminders were sent to non-participants by mail. We compared demographic, clinical, and treatment information of participants with non-participants using univariable and multivariable logistic regression models. Results We invited 928 childhood cancer survivors in Switzerland with a median age of 26.5 years (interquartile range 19-37), of which 463 (50%) participated. After the initial send out of the sampling kit, 291 (63%) had participated, while reminder letters led to 172 additional participants (37%). Foreign nationality (odds ratio [OR] 0.5; 95%-confidence interval [CI] 0.4-0.7), survivors aged 30-39 years at study versus other age groups (OR 0.5; CI 0.4-0.8), and survivors with a known cancer predisposition syndrome (OR 0.5; CI 0.3-1.0) were less likely to participate in germline DNA collection. Survivors with a second primary neoplasm (OR 1.9; CI 1.0-3.8) or those living in a French or Italian speaking region (OR 1.3; CI 1.0-1.8) tended to participate more. Conclusions We showed that half of childhood cancer survivors participated in germline DNA self-sampling relying completely on mailing of sample kits. Written reminders increased the response by about one third. More targeted recruitment strategies may be advocated for people of foreign nationality, aged 30-39 years, and those with cancer predisposition syndromes. Perceptions of genetic research and potential barriers to participation of survivors need to be better understood. Trial registration Biobank: https://directory.bbmri-eric.eu/#/collection/bbmri-eric:ID:CH_HopitauxUniversitairesGeneve:collection:CH_BaHOP Research project: Clinicaltrials.gov: NCT04702321.

Childhood cancer survivors treated with hematopoietic stem cell transplantation are at high risk for pulmonary morbidity and mortality. In this retrospective study we described transplant characteristics of pediatric patients who underwent hematopoietic stem cell transplantation in Switzerland and how these characteristics changed over time, compared self-reported pulmonary outcomes between transplanted and non-transplanted survivors, and investigated risk factors for the reported pulmonary outcomes. As part of the population-based Swiss Childhood Cancer Survivor Study, we sent questionnaires to all ≥5-year childhood cancer survivors diagnosed 1976–2010 at age ≤20 years. We included 132 transplanted survivors and 368 matched non-transplanted survivors. During the study period transplant characteristics changed, with decreasing use of total body irradiation and increased use of peripheral blood stem cells and mismatched and unrelated donors as transplant source. One-fifth of transplanted survivors (20%, 95%CI 13–27%) and 18% of non-transplanted survivors (95%CI 13–21%) reported at least one pulmonary outcome. None of the analyzed factors was significantly associated with an increased risk of pulmonary outcomes in multivariable analysis. We found that pulmonary outcomes were frequently reported in transplanted and non-transplanted childhood cancer survivors, indicating a strong need for long-term pulmonary follow-up care.

Ovarian failure is a major long-term adverse event following gonadotoxic treatment of malignant diseases. Ovarian tissue cryopreservation can be offered in some conditions to preserve fertility. We report the case of a 13-year-old female with a diagnosis of acute myeloid leukemia, who presented with hypergonadotropic hypogonadism after unilateral ovariectomy for fertility preservation and before highly gonadotoxic treatment. Even though damage seemed only partial, this case suggests that the remaining contralateral ovarian function may be compromised after ovarian tissue cryopreservation, leading per se to a hypergonadotropic hypogonadism. Although indication of ovarian cryopreservation is not called into question in situations of highly gonadotoxic therapy, this procedure should only be performed after evaluation by a specialized multidisciplinary team and provided a solid indication.

Glutathione S-transferases (GSTs) are metabolic enzymes responsible for the elimination of endogenous or exogenous electrophilic compounds by glutathione (GSH) conjugation. In addition, GSTs are regulators of mitogen-activated protein kinases (MAPKs) involved in apoptotic pathways. Overexpression of GSTs is correlated with decreased therapeutic efficacy among patients undergoing chemotherapy with electrophilic alkylating agents. Using GST inhibitors may be a potential solution to reverse this tendency and augment treatment potency. Achieving this goal requires the discovery of such compounds, with an accurate, quick, and easy enzyme assay. A spectrophotometric protocol using 1-chloro-2,4-dinitrobenzene (CDNB) as the substrate is the most employed method in the literature. However, already described GST inhibition experiments do not provide a protocol detailing each stage of an optimal inhibition assay, such as the measurement of the Michaelis-Menten constant (Km) for CDNB or indication of the employed enzyme concentration, crucial parameters to assess the inhibition potency of a tested compound. Hence, with this protocol, we describe each step of an optimized spectrophotometric GST enzyme assay, to screen libraries of potential inhibitors. We explain the calculation of both the half-maximal inhibitory concentration (IC50) and the constant of inhibition (Ki)-two characteristics used to measure the potency of an enzyme inhibitor. The method described can be implemented using a pool of GSTs extracted from cells or pure recombinant human GSTs, namely GST alpha 1 (GSTA1), GST mu 1 (GSTM1) or GST pi 1 (GSTP1). However, this protocol cannot be applied to GST theta 1 (GSTT1), as CDNB is not a substrate for this isoform. This method was used to test the inhibition potency of curcumin using GSTs from equine liver. Curcumin is a molecule exhibiting anti-cancer properties and showed affinity towards GST isoforms after in silico docking predictions. We demonstrated that curcumin is a potent competitive GST inhibitor, with an IC50 of 31.6 ± 3.6 µM and a Ki of 23.2 ± 3.2 µM. Curcumin has potential to be combined with electrophilic chemotherapy medication to improve its efficacy.

GSTA1 encodes a member of a family of enzymes that function to add glutathione to target electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins, and products of oxidative stress. GSTA1 has several functional SNPs within its promoter region that are responsible for a change in its expression by altering promoter function. This study aims to investigate distributions of GSTA1 promoter haplotypes across different human populations and to assess their impact on the expression of GSTA1. PHASE 2.1.1 was used to infer haplotypes and diplotypes of six GSTA1 promoter SNPs on 2501 individuals from 26 populations classified by the 1000 Genomes Project into five super-populations that included Africa (N = 660), America (N = 347), East Asia (N = 504), Europe (N = 502), and South Asia (N = 488). We used pairwise FST analysis to compare sub-populations and luciferase reporter assay (LRA) to evaluate the impact of each SNP on activation of transcription and interaction with other SNPs. The distributions of GSTA1 promoter haplotypes and diplotypes were significantly different among the different human populations. Three new promoter haplotypes were found in the African super-population. LRA demonstrated that SNPs at -52 and -69 has the most impact on GSTA1 expression, however other SNPs have a significant impact on transcriptional activity. Based on LRA, a new model of cis-elements interaction is presented. Due to the significant differences in GSTA1 diplotype population frequencies, future pharmacogenomics or disease-related studies would benefit from the inclusion of the complete GSTA1 promoter haplotype based on the newly proposed metabolic grouping derived from the LRA results.

Background Irreversible sensorineural hearing loss is a common side effect of platinum treatment with the potential to significantly impair the neurocognitive, social and educational development of childhood cancer survivors. Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in the FDA drug label and a pharmacogenetic guideline. The aim of this cross-sectional cohort study was to confirm the genetic associations in a large pan-European population and to evaluate the diagnostic accuracy of the genetic markers. Methods: Eligibility criteria required patients to be aged less than 19 years at the start of chemotherapy, which had to include cisplatin and/or carboplatin. Patients were assigned to three phenotype categories: no, minor, and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1, andACYP2) were investigated. Multinomial logistic regression was performed to model the relationship between genetic predictors and platinum ototoxicity, adjusting for clinical risk factors. Additionally, measures of the diagnostic accuracy of the genetic markers were determined. Findings: 900 patients were included in this study. In the multinomial logistic regression, significant unique contributions were found from SLC22A2 rs316019, the age at start of platinum treatment, cranial radiation, and the interaction term [platinum compound]*[cumulative dose of cisplatin]. Meta-analysis confirmed an allelic association of SLC22A2 rs316019 with cisplatin ototoxicity (odds ratio 1.46, 95% CI 1.10–1.95, p=0.009). Predictive performance of the genetic markers was poor, compared with the clinical risk factors. Interpretation: PanCareLIFE is the largest study of cisplatin-induced ototoxicity to date and confirmed a role for the polyspecific organic cation transporter SLC22A2. However, our study cannot recommend the use of any of the investigated genetic markers to guide the management and prevention of cisplatin-induced hearing loss. The study results will require a revision of the pharmacogenetic guideline and the FDA drug label. Funding Statement: This work was supported by the PanCareLIFE project that has received funding from the European Union’s Seventh Framework Programme for research, technological development, and demonstration under grant agreement no. 602030. CEK was funded by the Swiss Cancer Research Foundation (grant no. 4157-02-2017), the Swiss Cancer League (grant no. 3412-02-2014), the Bernese Cancer League, and the Lung League Bern. JFW received supplementary funding from the Danish Childhood Cancer Foundation and Soroptimist International Helsingor, Denmark. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The PanCareLIFE study has been approved by the local ethics committees: Kantonale Ethikkommission Bern, 362/2015; Comitate Etico Regionale, 507REG2014; Ethical Committee University Hospital Brno, June 11, 2016; Ethics Committee Fakultni Nemocnice v Motole, Prague; De Videnskabsetiske Komiteer Region Hovedstaden, H-1- 2014-125; Ethikkommission Medizinische Universitat Graz, 27-015 ex 14/15; Ethikkommission der Universitat Ulm, 160/17; Ethikkommission der Universitat zu Lubeck, 14/181; Ethik-Kommission der Arztekammer Westfalen-Lippe und der Westfalischen Wilhelms-Universitat Munster, 2014-619; Medische Ethische Toetsings Commissie Erasmus MC; Medisch Ethische Toetsingscommissie, 2015_202. The informed consent of the patient (if adult) or his/her legal representative has been obtained.

Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The PanCareLIFE cross-sectional cohort study evaluated the genetic associations in a large pan-European population and assessed the diagnostic accuracy of the genetic markers. 1,112 pediatric cancer survivors who had provided biomaterial for genotyping were screened for participation in the pharmacogenetic association study. 900 participants qualified for inclusion. Based on the assessment of original audiograms, patients were assigned to three phenotype categories: no, minor, and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFSI, and ACYP2) were genotyped. The genotype and phenotype data represent a resource for conducting metaanalyses to derive a more precise pooled estimate of the effects of genes on the risk of hearing loss due to platinum treatment. (C) 2020 The Authors. Published by Elsevier Inc.

BackgroundChildhood 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).Patients and methodsThis cohort study used data from the Swiss Childhood Cancer Registry. We included patients with first primary neoplasms (FPN) until age 21 years from 1986 to 2015 and identified SPNs occurring before age 21. We calculated standardized incidence ratios (SIR) and absolute excess risks (AER) using Swiss population cancer incidence data and cumulative incidence of SPNs. We calculated hazard ratios (HR) of risk factors for SPNs using Fine and Gray competing risk regression.ResultsAmong 8,074 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 increased in childhood cancer patients compared to 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 and 3% in those without. 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), hematopoietic 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).ConclusionCPSs are associated with a high risk of SPNs before age 21 years. Identification of CPSs is important for appropriate cancer surveillance and targeted screening.

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