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 cardiac and vascular late sequelae in long-term survivors of childhood cancer (CVSS)-study aimed to quantify the prevalence of cardiovascular risk factors (CVRF) and cardiovascular disease (CVD) in German childhood cancer survivors (CCS). In the CVSS-study (NCT02181049), 1002 CCS (age range 23–48 years) diagnosed with neoplasia prior to 15 years of age between 1980 and 1990 prospectively underwent a systematic, standardized clinical and laboratory cardiovascular screening, identical to the population-based Gutenberg Health Study (GHS) cohort. For 951 individuals, prevalences of CVRF and CVD were primarily compared to the GHS sample and to two further German population-based cohorts. Using log-binomial regression models, an increased risk for occurrence of arterial hypertension [relative risk (RR) 1.38, 95% confidence interval (95% CI 1.21–1.57)] and dyslipidaemia [RR 1.26 (95% CI 1.12–1.42)] was found. This indicates a premature occurrence compared to the general population of approximately 6 and 8 years, respectively [rate advancement period estimator, RAP_hypertension 5.75 (95% CI 3.5–8.0) and RAP_{dyslipidaemia} 8.16 (95% CI 4.4–11.9)]. Overall, no differences were observed for obesity and diabetes. Overt CVD was present in 4.5% (95% CI 3.0–6.6%) of CCS [RR 1.89 (95% CI 1.34–2.66), RAP_CVD 7.9 (95% CI 4.1–11.7)], of which the most frequent entities were congestive heart failure and venous thromboembolism. Prevalences of CVRF and CVD increased with age without reaching a plateau over time. This large CCS screening examination revealed consistently in comparison to three population samples a considerably increased risk for premature CVD. The findings in these young adult CCS indicate a high burden of cardiovascular morbidity and mortality in the long term. NCT02181049.

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^*; ${\eta }_{\text{p}}^2$ = 0.223], walking performance [F_{(1, 25)} = 4.270; p = 0.049^*; ${\eta }_{\text{p}}^2$ = 0.146], fatigue [F_{(1, 13)} = 8.353; p = 0.013^*; ${\eta }_{\text{p}}^2$ = 0.391], self-esteem [F_{(1, 6)} = 6.823; p = 0.040^*; ${\eta }_{\text{p}}^2$ = 0.532], and self-reported strength and endurance capacity [F_{(1, 6)} = 6.273; p = 0.046^*; ${\eta }_{\text{p}}^2$ = 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.

Background: Increasing survival rates after childhood cancer have raised the issue of long‐term mental health consequences in adulthood. This study determines mental health distress among long‐term survivors of pediatric cancer and compares it to control groups.Methods: Childhood cancer survivors (CCS; N = 951, aged 24‐49 years) were compared to three age‐matched control groups from the general population collected at three time points. The study compared the prevalence of clinically relevant symptoms of a wide range of common mental disorders (depression, somatic distress, suicidal ideation, generalized anxiety, panic, social anxiety, and sleep disturbances) using identical, validated questionnaires. CCS were identified by the German Childhood Cancer Registry. Controls were approached by a demographic consultation company (USUMA) which assured that the three samples were nationally representative.Results: Childhood cancer survivors reported higher education than controls and were less often married. All forms of common mental distress were increased among survivors. Twenty‐four percent of male (N = 526) and 41% of female survivors (N = 425) reported some form of clinically relevant mental health symptoms. Somatic distress as the leading complaint was highly frequent among CCS (OR: 10.98, CI 95%: 7.24‐16.64). Complaints by generalized anxiety (OR: 5.04, CI 95%: 2.61‐9.70), panic (OR: 3.28, CI 95%: 1.60‐6.70), depression (OR: 3.36, CI 95%: 2.22‐5.09), and suicidality (OR = 2.22; CI 95%: 1.38‐3.57) were also strongly increased. Female sex, low education, low income, and unemployment were associated with increased distress.Conclusions: Findings indicate a need to integrate psycho‐oncological screening and care into long‐term aftercare. Somatic distress, as cause and indicator of psychological distress, should receive stronger attention, especially tiredness, low energy, and pain.

Activation of the basal cell carcinoma pathway in a patient with CNS HGNET-BCOR diagnosis: consequences for personalized targeted therapy