B-cell acute lymphoblastic leukemia (B-ALL) is the commonest childhood cancer and the prognosis of children with relapsed or therapy refractory disease remains a challenge. Treatment with chimeric ...antigen receptor-modified T cells targeting the CD19 antigen (CART-19 therapy) has been presented as a promising approach toward improving the outcome of relapsed or refractory disease. However, 10%-20% of the patients suffer another relapse. Epitope-loss under therapy pressure has been suggested as a mechanism of tumor cells to escape the recognition from CART-19 therapy. In this work, we analyzed the expression of CD19 isoforms in a cohort of 14 children with CD19 B-ALL and 6 nonleukemia donors. We showed that an alternatively spliced CD19 mRNA isoform lacking exon 2, and therefore the CART-19 epitope, but not isoforms lacking the transmembrane and cytosolic domains are expressed in leukemic blasts at diagnosis in children and in the bone marrow of nonleukemia donors. Furthermore, we clarified the sequence of a further isoform lacking the epitope recognized by CART-19 therapy and disclosed the presence of new isoforms. In comparison with the children, we showed that alternatively spliced CD19 mRNA isoforms affecting exon 2 are also expressed in 6 adult patients with CD19 B-ALL. On top of that, one of the adults expressed an isoform lacking the CD19 transmembrane and cytosolic domains. In conclusion, we proved that some of the CD19 isoforms contributing to CART-19 escape already preexist at diagnosis and could evolve as a dominant clone during CART-19 therapy suggesting the application of combined treatment approaches.
The growing population of long‐term childhood cancer survivors is at increased risk for severe, therapy‐related late effects and premature mortality. The cardiac and vascular late sequelae in ...long‐term survivors of childhood cancer (CVSS) study is a cohort of patients from Germany diagnosed with a neoplasia prior to 15 years of age in the time period 1980 to 1990. Late mortality was evaluated in a total of 4505 individuals who survived 5 years or more after the initial diagnosis (5‐year survivors). Survivors with a second primary tumor were excluded. Standardized mortality ratios (SMRs) were calculated. By December 2014, 400 patients had died. Available cause of death information from 188 individuals was used to estimate cause‐specific mortality for all deceased persons. Compared to the population of (former) West Germany, we observed an excess overall mortality risk (SMR = 9.53, 95% confidence interval CI = 8.62‐10.51). After correcting for missing cause of death information, an increased cancer mortality (SMR = 43.50, 95% CI = 25.79‐73.50) in the 5‐year survivors was detected. Cardiac death was ascertained in 14 individuals, resulting in an SMR of 10.85 (95% CI = 2.80‐32.02) after correcting for missing values. In conclusion, childhood cancer survivors diagnosed in Germany in 1980 to 1990 have a higher mortality risk overall and an elevated risk of dying from cancer and cardiac causes in particular. The results are consistent with those of international cohort studies. However, the reported results are based on few cases and individuals with secondary cancers were excluded.
What's new?
Since the 1970s, significant improvements have been made in the survival of patients diagnosed with childhood malignancies. Long‐term survivors of childhood cancer, however, have elevated risks for late‐developing therapy‐related effects, including premature mortality. The present study examined long‐term survival specifically within a cohort of 5‐year survivors of childhood cancer in Germany. An excess long‐term overall mortality risk was observed among individuals who experienced childhood malignancies. Cancer and cardiac sequelae were the primary causes of death. Cardiac mortality was noticeably elevated in females. The findings emphasize the importance of monitoring and managing long‐term health in childhood cancer survivors.
Background
Considering the improved outcome, a better understanding of the late effects in Wilms tumor survivors (WT-S) is needed. This study was aimed at evaluating renal function and determining ...the prevalence of clinical and subclinical renal dysfunction in a cohort of WT-S using a multimodal diagnostic approach.
Methods
Thirty-seven WT-S were included in this prospective cross-sectional single center study. To evaluate renal function, glomerular filtration rate (GFR) and urinary protein excretion were assessed. Additionally, kidney sonomorphology and blood pressure were analyzed.
Results
All examined WT-S (mean age 28.7 years, mean follow-up 24.8 years) had been treated with a combination of surgery and chemotherapy; 59.5% had received adjuvant radiotherapy. Impaired glomerular renal function was detected in a considerable proportion of WT-S, with age-adjusted cystatin-based GFR estimation below age norm in 55.9%. A lower cystatin-based estimated GFR (eGFR) correlated with longer follow-up time and higher irradiation dose. In 5 patients (13.5%) albuminuria was identified. Analysis of sonomorphology detected compensatory contralateral renal hypertrophy in 83.3% of WT-S. Chronic kidney disease (CKD) ≥ stage II was present in 55.9% of WT-S. Blood pressure measurements revealed arterial hypertension in 15 (40.5%) WT-S (newly diagnosed
n
=10). In 24.3% both CKD ≥ stage II and arterial hypertension were determined.
Conclusion
Even though WT-S are believed to carry a low risk for end-stage renal disease, in this study, a remarkable number of WT-S presented with previously unidentified subclinical signs of renal function impairment and secondary morbidity. Therefore, it is important to continue regular follow-up, especially after transition into adulthood.
Background The CVSS (Cardiac and Vascular Late Sequelae in Long-Term Survivors of Childhood Cancer) study aimed to investigate the prevalence of different stages of heart failure (HF) in childhood ...cancer survivors (CCSs) compared with the general population. Methods and Results A total of 1002 CCSs (age range, 23-48 years) diagnosed with neoplasia before an age of 15 years underwent a comprehensive cardiovascular screening. An age- and sex-matched sample from the population-based GHS (Gutenberg Health Study) served as a comparison group. Although prevalence of HF was significantly higher in CCSs, prevalence of different HF stages varied strongly by specific tumor history. Compared with the population, the prevalence ratio was 2.6 (95% CI, 2.4-2.8) for HF stage A and 4.6 (95% CI, 4.1-5.1) for the composite of HF stage B to D in an age- and sex-adjusted Poisson regression model. Multivariable linear regression, adjusting for tumor entities, age, sex, and cardiovascular risk factors, revealed a lower left ventricular ejection fraction in patients with history of bone tumors (
-4.30 95% CI, -5.70 to -2.80), soft tissue sarcoma (
-1.60 95% CI, -2.90 to -0.30), and renal tumors (
-1.60 95% CI, -2.80 to -0.29) compared with the population. The same model for the diastolic marker, ratio of the peak early diastolic filling velocity/lateral mitral annular early diastolic velocity, showed an association only with cardiovascular risk factors but not with tumor entities. Conclusions The prevalence of HF stage A to D was significantly higher among long-term CCSs compared with the population and varied strongly by tumor entity. Systolic dysfunction was primarily associated with tumor entities, whereas diastolic dysfunction was associated with a higher burden of cardiovascular risk factors in CCSs.
Objectives
Long‐term survivors of childhood cancer are at increased risk for sequelae such as poor mental health (MH) or impaired health‐related quality of life (HrQoL). We aimed to evaluate early ...adverse effects on MH and HrQoL in young childhood cancer survivors (YCCS) before school entry.
Methods
In a nationwide prospective cohort study, children with cancer other than brain tumors diagnosed at preschool age and completed cancer treatments were identified from the German Childhood Cancer Registry. The comparison group was children of the same age without a cancer diagnosis who participated in the prospective population‐based health survey ikidS. MH problems and HrQoL were assessed by parental versions of the Strengths and Difficulties Questionnaire (SDQ) and the questionnaire for health‐related quality of life in children (KINDL), respectively. Associations between cancer and MH as well as HrQoL were analyzed by multivariable linear regression.
Results
Of 382 YCCS contacted, 145 were enrolled (mean age 6.6 years) and 124 analyzed. Compared to children without a cancer diagnosis (3683 contacted, 2003 enrolled, 1422 analyzed), YCCS had more MH problems (13% vs. 3%) and slightly worse HrQoL (median 78.7 vs. 80.2 points). In the adjusted analysis, YCCS had higher SDQ scores (2.2 points, 95% confidence interval CI 1.3, 3.0) and lower KINDL scores (−2.4 points, 95% CI −3.7, −1.1) compared to children without cancer diagnosis.
Conclusion
Already at preschool age, YCCS may be at increased risk of MH problems and impaired HrQoL. This could have impacts on subsequent school performance and educational attainment. Follow‐up health care for YCCS may include early screening for MH problems and reasons for HrQoL deficits.
Cancer-related fatigue (CRF) is one of the most common and distressing symptoms in paediatric oncology. Based on previous studies, physical activity interventions are considered to be effective in ...reducing CRF in adult cancer patients.
The aim of this systematic review is to investigate whether physical activity interventions can reduce CRF in paediatric patients undergoing cancer treatment.
A systematic literature search was conducted in PubMed and Sport-Discus in October 2021 to identify intervention studies examining the effects of physical activity on CRF in cancer patients ≤ 21 years of age. Their methodological quality was assessed using the JBI Critical Appraisal Tool.
A total of 20 studies (seven randomized-controlled, six quasi-experimental and seven single-arm intervention trials) were included in the review. Nine studies reported significant positive effects of physical activity interventions on CRF in group comparison or within groups. Eleven trials reported no significant changes in CRF.
Physical activity as a therapeutic intervention in paediatric oncology may have the potential to reduce CRF in childhood cancer patients undergoing cancer treatment. Further high-quality studies with large samples are needed to verify these results and to assess the interdependence of dose and response of physical activity interventions.
Due to sensitive neuroimaging techniques, cerebrovascular complications such as cerebral microbleeds (CMB) and cerebral cavernous malformations (CCM) are increasingly recognized as considerable late ...effects after treatment for pediatric brain tumor. The aim of this study was to analyze CMB in a cohort of patients after cranial irradiation therapy for medulloblastoma or other pediatric brain tumors using susceptibility-weighted magnetic resonance imaging (SWI).
Forty former pediatric brain tumor patients were enrolled in this prospective cross-sectional study and examined by cranial MRI including SWI sequences. Cerebral microbleeds, clinical symptoms and disability were evaluated.
Thirty-six (90%) of the examined individuals (mean follow-up age 22.2 y; mean follow-up time 13.5 y) were affected by CMB. Longer follow-up time and higher craniospinal irradiation doses correlated with higher total lesion count (p < 0.01). Thirteen patients (32.5%) presented with clinical symptoms. Individuals with CMB were more severely disabled than patients without CMB (p < 0.05).
Cerebrovascular sequelae occur frequently after treatment for pediatric brain tumor. In this study, a remarkable part of pediatric brain tumor patients presents with CMB. As a sign of vascular damage, they can cause clinical symptoms and may correspond to neurocognitive decline. Further studies are needed to standardize MRI protocols and to improve quality of long-term follow-up.
Objective:
In cancer patients, the impairment in muscle function is a frequently observed phenomenon. However, comprehensive evaluation of the effect of exercise training on muscle function in ...childhood cancer patients (CCPs) is sparse and therefore investigated in the MUCKI trial.
Study Design:
In the randomized controlled MUCKI trial, CCPs during intensive cancer treatment and aged 4–18 years were recruited. Eligible patients were enrolled soon after diagnosis as long as they were physically and mentally able to participate in exercise testing and training. Patients of the exercise group (
n
= 16) participated in average 2.7 ± 1.2 times per week in a combined resistance and endurance training with moderate exercise intensity, for a time period of 8.0 ± 2.1 weeks, while patients of the control group (
n
= 17) received usual care. Leg strength was evaluated as the primary endpoint. Secondary endpoints were 6-min walk performance, arm strength, body composition, fatigue, and health-related quality of life.
Results:
Comparisons of pre- and post-intervention results were evaluated by baseline and stratification criteria adjusted analysis and showed positive effects for the exercise group regarding leg strength
F
(1, 20)
= 5.733;
p
= 0.027
*
;
η
p
2
= 0.223, walking performance
F
(1, 25)
= 4.270;
p
= 0.049
*
;
η
p
2
= 0.146, fatigue
F
(1, 13)
= 8.353;
p
= 0.013
*
;
η
p
2
= 0.391, self-esteem
F
(1, 6)
= 6.823;
p
= 0.040
*
;
η
p
2
= 0.532, and self-reported strength and endurance capacity
F
(1, 6)
= 6.273;
p
= 0.046
*
;
η
p
2
= 0.511. No significant differences were found for the other parameters.
Conclusion:
Within one of the first randomized controlled trials, the present study provides evidence for a positive effect of combined training in CCPs during intensive cancer treatment. Further research is needed to confirm these results and to evaluate their clinical impact.
Clinical Trial Registration Number:
NCT02612025.
The insulin-like growth factor (IGF) pathway plays an important role in several brain tumor entities. However, the lack of inhibitors crossing the blood-brain barrier remains a significant obstacle ...for clinical translation. Here, we targeted the IGF pathway using ceritinib, an off-target inhibitor of the IGF1 receptor (IGF1R) and insulin receptor (INSR), in a pediatric patient with an unclassified brain tumor and a
(
) germline mutation. Pathway analysis of the tumor revealed activation of the sonic hedgehog (SHH), the wingless and integrated-1 (WNT), the IGF, and the Notch pathway. The proliferation of the patient tumor cells (225ZL) was inhibited by arsenic trioxide (ATO), which is an inhibitor of the SHH pathway, by linsitinib, which is an inhibitor of IGF1R and INSR, and by ceritinib. 225ZL expressed INSR but not IGF1R at the protein level, and ceritinib blocked the phosphorylation of INSR. Our first personalized treatment included ATO, but because of side effects, we switched to ceritinib. After 46 days, we achieved a concentration of 1.70 µM of ceritinib in the plasma, and after 58 days, MRI confirmed that there was a response to the treatment. Ceritinib accumulated in the tumor at a concentration of 2.72 µM. Our data suggest ceritinib as a promising drug for the treatment of IGF-driven brain tumors.
•Vascular late sequelae after radiochemotherapy in former pediatric brain tumor former pediatric Medulloblastoma.•Premature cerebral vascular changes imaged through high resolution MRI.•Follow-up ...time after RCT predicts premature cerebral atherosclerotic lesions.•A tendency to dose dependency of vessel wall alterations is observed.
While survival times after treatment of medulloblastoma are increasing, little is known about radiochemotherapy (RCT)-induced cerebrovascular changes. High resolution vessel wall imaging (VWI) sequences are an emerging tool for the evaluation of cerebrovascular diseases. We performed VWI in medulloblastoma long-term survivors to screen for late sequelae of RCT.
Twenty-two pediatric medulloblastoma survivors (mean age 25.8 years (10–53 years); 16.3 years (mean) post primary RCT (range 1–45 years)) underwent 2D VWI–MRI. Vessel wall thickening, contrast enhancement and luminal narrowing were analyzed. The findings were correlated with the patients’ radiation protocols.
Vessel wall changes were observed the intracranial internal carotid artery (ICA) and the vertebrobasilar circulation (VBC) in 14 of 22 patients (63.6%). In multivariate analysis, time after RCT (OR = 1.38, p < 0.05) was strongest independent predictor for development of vessel wall alterations. The dose of radiation was not a relevant predictor.
With longer follow-up time intracranial vessel wall changes are observed more frequently in medulloblastoma survivors. Thus VWI is a useful tool to monitor vessel wall alterations of cranially irradiated patients, creating the prerequisite for further treatment of late sequelae.
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