ABSTRACT 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 (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. Results Among 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). 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.
Background: Obesity is sequelae after childhood acute lymphoblastic leukaemia (ALL) treatment, but evidence is conflicting. We aimed to compare the prevalence of overweight/obesity between ≥5-year survivors of ALL in the North American Childhood Cancer Survivor Study (CCSS) and the Swiss Childhood Cancer Survivor Study (SCCSS) and describe risk factors.Methods: We included adult childhood ALL survivors diagnosed 1976‒1999. CCSS participants were matched (3:1) to SCCSS participants on sex and attained age. Body mass index (BMI) was calculated from self-reported heights and weights for 1287 CCSS and 429 SCCSS participants and compared to 2034 North American and 678 Swiss siblings. We assessed risk factors for overweight (BMI 25‒29·9 kg/m2) and obesity (≥30 kg/m2) using multinomial regression.Findings: Overweight/obesity were significantly more common in North American than Swiss survivors (overweight: 30%, 95% CI 27‒32 vs. 24%, 21‒29; obesity: 29%, 27‒32 vs. 7%, 5‒10) and siblings (overweight: 30%, 27‒32 vs. 25%, 22‒29; obesity: 24%, 22‒26 vs. 6%, 4‒8). North American (odds ratio [OR]=1·24, 1·01–1·53) and Swiss survivors (1·27, 0·74–2·21) were slightly more often obese than siblings. Among survivors, risk factors for obesity were: residency in North America (5·8, 3·7–9·0), being male (1·7, 1·3–2·3), attained age (≥45 years: 5·1, 2·4–10·8), Non-Hispanic Black (3·4, 1·6–7·0), low household income (2·3, 1·4–3·5), and young age at diagnosis (1·6, 1·1–2·2). Cranial radiotherapy ≥18 Gray was only a risk factor for overweight (1·4, 1·0–1·8), steroids were not associated with overweight and obesity. Interaction tests found no evidence of difference in risk factors between cohorts.Interpretation: While treatment-related risk for overweight/obesity was similar between regions, higher prevalence among North American survivors identifies important socio-demographic drivers that should inform health policy and targeted intervention trials.Trial Registration: clinicaltrials.gov identifier: NCT01120353 (CCSS) and NCT03297034 (SCCSS).Funding: The CCSS is supported by the National Cancer Institute (CA55727, G.T. Armstrong, Principal Investigator). Support to St. Jude Children’s Research Hospital also provided by American Lebanese-Syrian the Cancer Center Support (CORE) grant (CA21765, C. Roberts, Principal Investigator) and the Associated Charities (ALSAC).The SCCSS is supported by the Swiss Cancer League (KLS-3886-02-2016; KLS-3644-02-2015), Cancer Research Switzerland (KFS-5027-02-2020; KFS-4722-02-2019), CS is supported by the “Stiftung für krebskranke Kinder, Regio Basiliensis” and the University of Basel Research Fund for Excellent Junior Researchers.Declaration of Interest: JR was head of Paediatric Haematology/Oncology at the University Hospital in Bern, Switzerland during the study conduct; currently he is an employee of Novartis Pharma AG. All other authors declare no competing financial interests.Ethical Approval: Ethical approval was granted by the Ethics Committee of the Canton of Bern, Switzerland (KEK-BE: 166/2014 and 2021-01462).
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.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.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 <±20%. Bland-Altman plots showed good agreement, with only 5.8% of paired measurements exceeding the limits of agreement (±1.96 SD), although within its 95% confidence interval. Hct observations ranged from 21.7% to 34.7% and did not affect Bu concentrations measured from DBS in either the in vitro or in vivo studies.These results show that DBS is a useful method for Bu TDM, provided samples are analyzed on the collection day. DBS sampling offers advantages over traditional plasma sampling in infants and younger children because only small volumes of blood are required.
Abstract 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.
Background Haematopoietic stem cell transplantation (HSCT) is the only current curative treatment for Sickle Cell Disease (SCD), with potential life-threatening consequences. Busulfan is an alkylating agent used in HSCT conditioning regimen. Because of its narrow therapeutic window, determining the optimal first dose a priori remains a challenge. Busulfan is metabolized in the liver by conjugation with glutathione, which is catalyzed by Glutathione-S-Transferases (GSTs). GSTA1 is a known determinant of Busulfan clearance 1 2 (just like age and weight) suggesting that those characteristics should be known a priori to adjust the first dose of Busulfan. Haemoglobinopathies (SCD and thalassemia) are not associated with changes in Busulfan clearance in a recent study. 3 However, SCD is known to alter pharmacokinetics of other drugs. 4 5 As it leads namely to liver dysfunction 6 it may affect busulfan pharmacokinetics independently from genetic or anthropometric factors. Our aim is to compare the clearance of the first dose of Bu between patients with and without SCD, considering other constitutional factors. Methods Patients with SCD were paired to patients without SCD on known Busulfan clearance’s covariates including GSTA1 group, age and frequency of administration. Data were collected retrospectively from the HSCT Unit database at Sainte-Justine Hospital and also used in previous studies. 1 2 Weight adjusted clearance was compared between the two paired groups using a mixed procedure on SAS software. Results Among the 129 patients included, 16 had SCD . Each patient was matched with up to 4 controls (total of 50 controls). Mean weight adjusted clearance was 3.04 ml/min/kg [SD:0,18] in patients with SCD versus 3.11 ml/min/kg [SD :0,14] in controls (difference 0.07 ml/min/kg F= 0,14 p >F =0.714 ) . Conclusions The diagnosis of SCD did not reveal to influence independently the clearance of the first dose of Bu. Consequently, no dose tailoring is needed in those patients only by the fact of being affected by SCD. References Ansari M, Curtis PH-D, Uppugunduri CRS, Rezgui MA, Nava T, Mlakar V, et al . GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study. Oncotarget 2017 Oct 31;8(53). Nava T, Kassir N, Rezgui MA, Uppugunduri CRS, Curtis PH-D, Duval M, et al. Incorporation of GSTA1 genetic variations into a population pharmacokinetic model for IV busulfan in paediatric hematopoietic stem cell transplantation. British Journal of Clinical Pharmacology . 84(7):1494–504. McCune JS, Baker KS, Blough DK, Gamis A, Bemer MJ, Kelton-Rehkopf MC, et al. Variation in prescribing patterns and therapeutic drug monitoring of intravenous busulfan in pediatric hematopoietic cell transplant recipients. Journal of Clinical Pharmacology . 2013 Mar;53(3):264–75. Maksoud E, Koehl B, Kaguelidou F, et al. Population Pharmacokinetics of Cefotaxime and Dosage Recommendations in Children with Sickle Cell Disease. Antimicrob Agents Chemother 2018 Apr;62(4). Dampier CD, Setty BN, Logan J, Ioli JG, Dean R. Intravenous morphine pharmacokinetics in pediatric patients with sickle cell disease. J Pediatr 1995 Mar;126(3):461–7. Gremse DA, Fillingim E, Hoff CJ, Wells DJ, Boerth RC. Hepatic function as assessed by lidocaine metabolism in sickle cell disease. J Pediatr 1998 Jun;132(6):989–93. Disclosure(s) Nothing to disclose
Isocitrate Dehydrogenase-1 (IDH1) is a driver gene in several cancers including brain tumors such as low-grade and high-grade gliomas. Mutations of SMARCB1 were described in atypical teratoid rhabdoid tumors and to date have not been associated with the pathogenesis of medulloblastoma. We report concurrent IDH1 and SMARCB1 mutations in a medulloblastoma patient. We searched the catalogue of somatic mutations in cancer (COSMIC) database and other mutation databases and -to our knowledge- this is the first reported case of medulloblastoma harboring both mutations together. Our patient is a thirteen-year-old male presenting with headache and vomiting at diagnosis. MRI revealed left cerebellar expansive lesion with no evidence of metastasis. A histopathological diagnosis of desmoplastic/nodular medulloblastoma was made after complete resection of the tumor. Immunophenotypic characterization and methylation profiling suggested a medulloblastoma with SHH activation. Next generation sequencing of a panel of 400 genes revealed heterozygous somatic IDH1(p.R132C), SMARCB1(p.R201Q), and CDH11(p.L625T) mutations. The patient was treated according to the HIT-SIOP PNET 4 protocol. He is in complete remission more than two years after diagnosis. In conclusion, increasing use of high throughput sequencing will certainly increase the frequency with which rare mutations or mutation combinations are identified. The exact frequency of this mutation combination and whether it has any particular therapeutic implications or prognostic relevance requires further investigation.
