Neuroblastoma is a rare disease. Rare are also the possibilities to test new therapeutic options for neuroblastoma in clinical trials. Despite the constant need to improve therapy and outcomes for patients with advanced neuroblastoma, clinical trials currently only allow for testing few substances in even fewer patients. This increases the need to improve and advance preclinical models for neuroblastoma to preselect favorable candidates for novel therapeutics. Here we propose the use of a new patient-derived 3D slice-culture perfusion-based 3D model in combination with rapid treatment evaluation using isothermal microcalorimetry exemplified with treatment with the novel carbonic anhydrase IX and XII (CAIX/CAXII) inhibitor SLC-0111. Patient samples showed a CAIX expression of 18% and a CAXII expression of 30%. Corresponding with their respective CAIX expression patterns, the viability of SH-EP cells was significantly reduced upon treatment with SLC-0111, while LAN1 cells were not affected. The inhibitory effect on SH-SY5Y cells was dependent on the induction of CAIX expression under hypoxia. These findings corresponded to thermogenesis of the cells. Patient-derived organotypic slice cultures were treated with SLC-0111, which was highly effective despite heterogeneity of CAIX/CAXII expression. Thermogenesis, in congruence with the findings of the histological observations, was significantly reduced in SLC-0111-treated samples. In order to extend the evaluation time, we established a perfusion-based approach for neuroblastoma tissue in a 3D perfusion-based bioreactor system. Using this system, excellent tissue quality with intact tumor cells and stromal structure in neuroblastoma tumors can be maintained for 7 days. The system was successfully used for consecutive drug response monitoring with isothermal microcalorimetry. The described approach for drug testing, relying on an advanced 3D culture system combined with a rapid and highly sensitive metabolic assessment, can facilitate development of personalized treatment strategies for neuroblastoma.
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).
Childhood cancer survivors (CCS) are at risk of reduced bone health and premature osteoporosis. As physical activity with high impact loading (IL-PA) is known to promote bone health, we compared bone densitometry and microstructure between groups of CCS who performed different amounts of physical activities in their daily life. We used baseline data of a single-center PA trial including 161 CCS from the Swiss Childhood Cancer Registry, aged <16 at diagnosis, ≥16 at study and ≥5 years since diagnosis. Lower body bone health was assessed with peripheral quantitative computed tomography (pQCT) and dual-energy X-ray absorptiometry (DXA). Daily IL-PA (duration in activities >2 g acceleration and numbers of vertical impacts/hr >2 g) was captured using hip-worn accelerometers (1-3 weeks). For both IL-PA approaches, we formed low, middle and high activity groups based on tertiles. Bone health of the high and middle active groups was compared to the low active group. 63% of CCS had indication of at least one bone mineral density z-score ≤ -1 measured by pQCT or DXA. The high IL-PA group performing 2.8 min/day or 19.1 impact peaks/hr > 2 g (median) showed about 3-13% better microstructural and densitometric bone health as compared to the low IL-PA group with 0.38 min/day or 0.85 peaks/hr > 2 g. Just a few minutes and repetitions of high IL-PA as easily modifiable lifestyle factor may be sufficient to improve bone health in adult CCS. Future longitudinal research is needed to better understand pattern and dosage of minimal impact loading needed to strengthen bone in growing and adult CCS.
Abstract STUDY QUESTION In children affected by rhabdoid tumors (RT), are there clinical, therapeutic, and/or (epi-)genetic differences between those conceived following ART compared to those conceived without ART? SUMMARY ANSWER We detected a significantly elevated female predominance, and a lower median age at diagnosis, of children with RT conceived following ART (RT_ART) as compared to other children with RT. WHAT IS KNOWN ALREADY Anecdotal evidence suggests an association of ART with RT. STUDY DESIGN, SIZE, DURATION This was a multi-institutional retrospective survey. Children with RT conceived by ART were identified in our EU-RHAB database (n = 11/311 children diagnosed between January 2010 and January 2018) and outside the EU-RHAB database (n = 3) from nine different countries. A population-representative German EU-RHAB control cohort of children with RTs conceived without ART (n = 211) (EU-RHAB control cohort) during the same time period was used as a control cohort for clinical, therapeutic, and survival analyses. The median follow-up time was 11.5 months (range 0–120 months) for children with RT_ART and 18.5 months (range 0–153 months) for the EU-RHAB control cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS We analyzed 14 children with RT_ART diagnosed from January 2010 to January 2018. We examined tumors and matching blood samples for SMARCB1 mutations and copy number alterations using FISH, multiplex ligation-dependent probe amplification, and DNA sequencing. DNA methylation profiling of tumor and/or blood samples was performed using DNA methylation arrays and compared to respective control cohorts of similar age (n = 53 tumors of children with RT conceived without ART, and n = 38 blood samples of children with no tumor born small for gestational age). MAIN RESULTS AND THE ROLE OF CHANCE The median age at diagnosis of 14 individuals with RT_ART was 9 months (range 0–66 months), significantly lower than the median age of patients with RT (n = 211) in the EU-RHAB control cohort (16 months (range 0–253), P = 0.03). A significant female predominance was observed in the RT_ART cohort (M:F ratio: 2:12 versus 116:95 in EU-RHAB control cohort, P = 0.004). Eight of 14 RT_ART patients were diagnosed with atypical teratoid rhabdoid tumor, three with extracranial, extrarenal malignant rhabdoid tumor, one with rhabdoid tumor of the kidney and two with synchronous tumors. The location of primary tumors did not differ significantly in the EU-RHAB control cohort (P = 0.27). Six of 14 RT_ART patients presented with metastases at diagnosis. Metastatic stage was not significantly different from that within the EU-RHAB control cohort (6/14 vs 88/211, P = 1). The incidence of pathogenic germline variants was five of the 12 tested RT_ART patients and, thus, not significantly different from the EU-RHAB control cohort (5/12 versus 36/183 tested, P = 0.35). The 5-year overall survival (OS) and event free survival (EFS) rates of RT_ART patients were 42.9 ± 13.2% and 21.4 ± 11%, respectively, and thus comparable to the EU-RHAB control cohort (OS 41.1 ± 3.5% and EFS 32.1 ± 3.3). We did not find other clinical, therapeutic, outcome factors distinguishing patients with RT_ART from children with RTs conceived without ART (EU-RHAB control cohort). DNA methylation analyses of 10 tumors (atypical teratoid RT = 6, extracranial, extrarenal malignant RT = 4) and six blood samples from RT_ART patients showed neither evidence of a general DNA methylation difference nor underlying imprinting defects, respectively, when compared to a control group (n = 53 RT samples of patients without ART, P = 0.51, n = 38 blood samples of patients born small for gestational age, P = 0.1205). LIMITATIONS, REASONS FOR CAUTION RTs are very rare malignancies and our results are based on a small number of children with RT_ART. WIDER IMPLICATIONS OF THE FINDINGS This cohort of patients with RT_ART demonstrated a marked female predominance, and a rather low median age at diagnosis even for RTs. Other clinical, treatment, outcome, and molecular factors did not differ from those conceived without ART (EU-RHAB control cohort) or reported in other series, and there was no evidence for imprinting defects. Long-term survival is achievable even in cases with pathogenic germline variants, metastatic disease at diagnosis, or relapse. The female preponderance among RT_ART patients is not yet understood and needs to be evaluated, ideally in larger international series. STUDY FUNDING/COMPETING INTEREST(S) M.C.F. is supported by the ‘Deutsche Kinderkrebsstiftung’ DKS 2020.10, by the ‘Deutsche Forschungsgemeinschaft’ DFG FR 1516/4-1 and by the Deutsche Krebshilfe 70113981. R.S. received grant support by Deutsche Krebshilfe 70114040 and for infrastructure by the KinderKrebsInitiative Buchholz/Holm-Seppensen. P.D.J. is supported by the Else-Kroener-Fresenius Stiftung and receives a Max-Eder scholarship from the Deutsche Krebshilfe. M.H. is supported by DFG (HA 3060/8-1) and IZKF Münster (Ha3/017/20). BB is supported by the ‘Deutsche Kinderkrebsstiftung’ DKS 2020.05. We declare no competing interests. TRIAL REGISTRATION NUMBER N/A.
Abstract Background Epidemiological studies often rely on self-reported health problems and validation greatly improves study quality. In a study of late effects after childhood cancer, we validated self-reported cardiovascular problems by contacting general practitioners (GPs). This paper describes: (a) the feasibility of this approach; and (b) the agreement between survivor-reports and reports from their GP. Methods The Swiss Childhood Cancer Survivor Study (SCCSS) contacts all childhood cancer survivors registered in the Swiss Childhood Cancer Registry since 1976 who survived at least 5 years from cancer diagnosis. We validated answers of all survivors who reported a cardiovascular problem in the questionnaire. Reported cardiovascular problems were hypertension, arrhythmia, congestive heart failure, myocardial infarction, angina pectoris, stroke, thrombosis, and valvular problems. In the questionnaire, we further asked survivors to provide a valid address of their GP and a consent for contact. We sent case-report forms to survivors’ GPs and requested information on cardiovascular diagnoses of their patients. To determine agreement between information reported by survivors and GPs, we calculated Cohen’s kappa (κ) coefficients for each category of cardiovascular problems. Results We used questionnaires from 2172 respondents of the SCCSS. Of 290 survivors (13% of 2172) who reported cardiovascular problems, 166 gave consent to contact their GP and provided a valid address. Of those, 135 GPs (81%) replied, and 128 returned the completed case-report form. Survivor-reports were confirmed by 54/128 GPs (42%). Of the 54 GPs, 36 (28% of 128) confirmed the problems as reported by the survivors; 11 (9% of 128) confirmed the reported problem(s) and gave additional information on more cardiovascular outcomes; and seven GPs (5% of 128) confirmed some, but not all cardiovascular problems. Agreement between GPs and survivors was good for stroke (κ = 0.79), moderate for hypertension (κ = 0.51), arrhythmias (κ = 0.41), valvular problems (κ = 0.41) and thrombosis (κ = 0.56), and poor for coronary heart disease (κ = 0.15) and heart failure (κ = 0.32). Conclusions Despite excellent GP compliance, it was found unfeasible to validate self-reported cardiovascular problems via GPs because they do not serve as gatekeepers in the Swiss health care system. It is thus necessary to develop other validation methods to improve the quality of patient-reported outcomes.
BackgroundThe role of vincristine as a contributing risk factor for hearing loss among childhood cancer survivors (CCS) treated with platinum-based chemotherapy has not been fully elucidated. We examined the association of vincristine with hearing loss in a national cohort of CCS.MethodsWe included CCS registered in the Swiss Childhood Cancer Registry diagnosed at age ≤ 18 years and treated with platinum-based chemotherapy between 1990 and 2014. Audiogram and treatment data were extracted from medical records for all participants in our retrospective cohort study. We identified CCS exposed to vincristine and calculated the total cumulative dose. We defined clinically relevant hearing loss as grade ≥ 2 using the International Society of Pediatric Oncology (SIOP) Boston Ototoxicity Scale at latest follow-up.ResultsOur study population included 270 CCS (43% female; median age at cancer diagnosis 6.8 years; interquartile range [IQR]: 2.1–11.7 years) with median age at audiogram 13.5 years (IQR: 9.3–17.0 years). Vincristine exposure was associated with an increased risk of hearing loss in the multivariable logistic regression analysis (odds ratio [OR] 4.8; 95% confidence interval [CI]: 1.8–12.9). We found no evidence of dose-response relationship (OR 1.0; 95% CI: 0.97–1.04) or effect modification from vincristine from other ototoxic treatments, such as type of platinum agent, cranial radiotherapy, and hematopoietic stem cell transplantation.ConclusionVincristine is associated with a higher risk of hearing loss in CCS treated with platinum-based chemotherapy. We suggest future studies investigate the underlying mechanism and causality among CCS without exposure to other ototoxic cancer treatments.
Background Cardiovascular 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. Objective In 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. Methods For 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. Results We 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. Conclusions This 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 Registration ClinicalTrials.gov NCT03790943; https://clinicaltrials.gov/ct2/show/NCT03790943 International Registered Report Identifier (IRRID) DERR1-10.2196/17724
