Clonal hematopoiesis of indeterminate potential is rare in pediatric patients undergoing autologous stem cell transplantation.

Clonal hematopoiesis of indeterminate potential (CHIP) describes recurrent somatic gene mutations in the blood of healthy individuals, associated with higher risk for hematological malignancies and higher all-cause mortality by cardiovascular disease. CHIP increases with age and is more common in adult patients after chemotherapy or radiation for cancer. Furthermore, in some adult patients undergoing autologous stem cell transplantation (ASCT) or thereafter, CHIP has been identified. In children and adolescents, it remains unclear how cellular stressors such as cytotoxic therapy influence the incidence and expansion of CHIP. We conducted a retrospective study on 33 pediatric patients mostly with solid tumors undergoing ASCT for presence of CHIP. We analyzed CD34+ selected peripheral blood stem cell grafts after several cycles of chemotherapy, prior to cell infusion, by next-generation sequencing including 18 "CHIP-genes". Apart from a somatic variant in TP53 in one patient no other variants indicative of CHIP were identified. As a CHIP-unrelated finding, germline variants in CHEK2 and in ATM were identified in two and four patients, respectively. In conclusion, we could not detect "typical" CHIP variants in our cohort of pediatric cancer patients undergoing ASCT. However, more studies with larger patient numbers are necessary to assess if chemotherapy in the pediatric setting contributes to an increased CHIP incidence and at what time point.

Body image in adolescent survivors of childhood cancer: The role of chronic health conditions.

BACKGROUND: Cancer and its treatment may impair the body image of childhood cancer survivors during adolescence. We compared the body image between adolescent cancer survivors and their siblings, and determined whether survivors' body image is associated with socio-demographic characteristics, clinical characteristics and chronic health conditions. PROCEDURE: As part of the nationwide Swiss Childhood Cancer Survivor Study, we sent questionnaires to adolescents (aged 16-19 years), who survived >5 years after having been diagnosed with childhood cancer between 1989 and 2010. Siblings received the same questionnaire. We assessed the level of agreement with three body image statements referring to body satisfaction and preferences for changes. Chronic health conditions were classified into cardiovascular, pulmonary, endocrine, musculoskeletal, renal/digestive, neurological and hearing or vision impairment. We used ordered logistic regression models to identify determinants of a more negative body image. RESULTS: Our study included 504 survivors (48% female) with a median age at study of 17.7 years (interquartile range: 16.8-18.6) and 136 siblings. Survivors and siblings reported overall comparable levels of agreement with body image statements (all p > .05). Female survivors (all odds ratio [ORs] ≥1.7), survivors treated with haematopoietic stem cell transplantation (HSCT; all ORs ≥2.2), and survivors with ≥2 chronic health conditions (all ORs ≥1.4) reported a more negative body image. This was particularly pronounced for survivors suffering from musculoskeletal or endocrine conditions. CONCLUSION: Female survivors, survivors treated with HSCT or with chronic health conditions are at risk of body image concerns during adolescence. Increased awareness among clinicians and targeted psychosocial support could mitigate such concerns.

Targeting Telomere Biology in Acute Lymphoblastic Leukemia.

Increased cell proliferation is a hallmark of acute lymphoblastic leukemia (ALL), and genetic alterations driving clonal proliferation have been identified as prognostic factors. To evaluate replicative history and its potential prognostic value, we determined telomere length (TL) in lymphoblasts, B-, and T-lymphocytes, and measured telomerase activity (TA) in leukocytes of patients with ALL. In addition, we evaluated the potential to suppress the in vitro growth of B-ALL cells by the telomerase inhibitor imetelstat. We found a significantly lower TL in lymphoblasts (4.3 kb in pediatric and 2.3 kb in adult patients with ALL) compared to B- and T-lymphocytes (8.0 kb and 8.2 kb in pediatric, and 6.4 kb and 5.5 kb in adult patients with ALL). TA in leukocytes was 3.2 TA/C for pediatric and 0.7 TA/C for adult patients. Notably, patients with high-risk pediatric ALL had a significantly higher TA of 6.6 TA/C compared to non-high-risk patients with 2.2 TA/C. The inhibition of telomerase with imetelstat ex vivo led to significant dose-dependent apoptosis of B-ALL cells. These results suggest that TL reflects clonal expansion and indicate that elevated TA correlates with high-risk pediatric ALL. In addition, telomerase inhibition induces apoptosis of B-ALL cells cultured in vitro. TL and TA might complement established markers for the identification of patients with high-risk ALL. Moreover, TA seems to be an effective therapeutic target; hence, telomerase inhibitors, such as imetelstat, may augment standard ALL treatment.

SARS-CoV-2 Infection During Induction Chemotherapy in a Child With High-risk T-Cell Acute Lymphoblastic Leukemia.

The clinical course of SARS-CoV-2 infection (COVID-19) in children with hematologic malignancies is unclear. We describe the diagnosis, treatment and outcome of a 4-year-old boy with high-risk acute lymphoblastic leukemia and COVID-19. Regardless of immunosuppressive induction chemotherapy his symptoms remained moderate. He received only supportive treatment. Seroconversion occurred in a similar period as in immunocompetent adults. Despite prolonged myelosuppression he did neither acquire secondary infections nor did the treatment delay caused by the infection have a measurable negative impact on the residual disease of acute lymphoblastic leukemia. Intriguingly, residual leukemia even decreased even though he did not receive any antileukemic therapy.

Parental occupational exposure to pesticides and risk of childhood cancer in Switzerland: a census-based cohort study.

BACKGROUND: Pesticide exposure is a suspected risk factor for childhood cancer. We investigated the risk of developing childhood cancer in relation to parental occupational exposure to pesticides in Switzerland for the period 1990-2015. METHODS: From a nationwide census-based cohort study in Switzerland, we included children aged < 16 years at national censuses of 1990 and 2000 and followed them until 2015. We extracted parental occupations reported at the census closest to the birth year of the child and estimated exposure to pesticides using a job exposure matrix. Cox proportional hazards models, adjusted for potential confounders, were fitted for the following outcomes: any cancer, leukaemia, central nervous system tumours (CNST), lymphoma, non-CNS solid tumours. RESULTS: Analyses of maternal (paternal) exposure were based on approximately 15.9 (15.1) million-person years at risk and included 1891 (1808) cases of cancer, of which 532 (503) were leukaemia, 348 (337) lymphomas, 423 (399) CNST, and 588 (569) non-CNS solid tumours. The prevalence of high likelihood of exposure was 2.9% for mothers and 6.7% for fathers. No evidence of an association was found with maternal or paternal exposure for any of the outcomes, except for "non-CNS solid tumours" (High versus None; Father: adjusted HR [95%CI] =1.84 [1.31-2.58]; Mother: 1.79 [1.13-2.84]). No evidence of an association was found for main subtypes of leukaemia and lymphoma. A post-hoc analysis on frequent subtypes of "non-CNS solid tumours" showed positive associations with wide CIs for some cancers. CONCLUSION: Our study suggests an increased risk for solid tumours other than in the CNS among children whose parents were occupationally exposed to pesticides; however, the small numbers of cases limited a closer investigation of cancer subtypes. Better exposure assessment and pooled studies are needed to further explore a possible link between specific childhood cancers types and parental occupational exposure to pesticides.

Micronucleus formation in human cancer cells is biased by chromosome size.

Chromosomal instability is one of the hallmarks of cancer and caused by chromosome missegregation during mitosis, a process frequently associated with micronucleus formation. Micronuclei are formed when chromosomes fail to join a daughter nucleus during cell division and are surrounded by their own nuclear membrane. Although it has been commonly assumed that the gain or loss of specific chromosomes is random during compromised cell division, recent data suggest that the size of chromosomes can impact on chromosome segregation fidelity. To test whether chromosome missegregation rates scale with chromosome size in primary human cancer cells, we assessed chromosome sequestration into micronuclei in patient-derived primary NCH149 glioblastoma cells, which display high-level numerical chromosome instability (CIN), pronounced spontaneous micronucleus formation but virtually no structural CIN. The cells were analyzed by interphase fluorescence in situ hybridization using chromosome-specific painting probes for all chromosomes. Overall, 33% of early passage NCH149 cells harbored micronuclei. Entrapment within a micronucleus clearly correlated with chromosome size with larger chromosomes being significantly more frequently missegregated into micronuclei than smaller chromosomes in primary glioblastoma cells. These findings extend the concept that chromosome size determines segregation fidelity by implying that size-specific micronucleus entrapment occurs in primary human cancer cells as well.

Marker chromosomes can arise from chromothripsis and predict adverse prognosis in acute myeloid leukemia.

Metaphase karyotyping is an established diagnostic standard in acute myeloid leukemia (AML) for risk stratification. One of the cytogenetic findings in AML is structurally highly abnormal marker chromosomes. In this study, we have assessed frequency, cytogenetic characteristics, prognostic impact, and underlying biological origin of marker chromosomes. Given their inherent gross structural chromosomal damage, we speculated that they may arise from chromothripsis, a recently described phenomenon of chromosome fragmentation in a single catastrophic event. In 2 large consecutive prospective, randomized, multicenter, intensive chemotherapy trials (AML96, AML2003) from the Study Alliance Leukemia, marker chromosomes were detectable in 165/1026 (16.1%) of aberrant non-core-binding-factor (CBF) karyotype patients. Adverse-risk karyotypes displayed a higher frequency of marker chromosomes (26.5% in adverse-risk, 40.3% in complex aberrant, and 41.2% in abnormality(17p) karyotypes, P < .0001 each). Marker chromosomes were associated with a poorer prognosis compared with other non-CBF aberrant karyotypes and led to lower remission rates (complete remission + complete remission with incomplete recovery), inferior event-free survival as well as overall survival in both trials. In multivariate analysis, marker chromosomes independently predicted poor prognosis in the AML96 trial ≤60 years. As detected by array comparative genomic hybridization, about one-third of marker chromosomes (18/49) had arisen from chromothripsis, whereas this phenomenon was virtually undetectable in a control group of marker chromosome-negative complex aberrant karyotypes (1/34). The chromothripsis-positive cases were characterized by a particularly high degree of karyotype complexity, TP53 mutations, and dismal prognosis. In conclusion, marker chromosomes are indicative of chromothripsis and associated with poor prognosis per se and not merely by association with other adverse cytogenetic features.

Pax5 loss imposes a reversible differentiation block in B-progenitor acute lymphoblastic leukemia.

Loss-of-function mutations in hematopoietic transcription factors including PAX5 occur in most cases of B-progenitor acute lymphoblastic leukemia (B-ALL), a disease characterized by the accumulation of undifferentiated lymphoblasts. Although PAX5 mutation is a critical driver of B-ALL development in mice and humans, it remains unclear how its loss contributes to leukemogenesis and whether ongoing PAX5 deficiency is required for B-ALL maintenance. Here we used transgenic RNAi to reversibly suppress endogenous Pax5 expression in the hematopoietic compartment of mice, which cooperates with activated signal transducer and activator of transcription 5 (STAT5) to induce B-ALL. In this model, restoring endogenous Pax5 expression in established B-ALL triggers immunophenotypic maturation and durable disease remission by engaging a transcriptional program reminiscent of normal B-cell differentiation. Notably, even brief Pax5 restoration in B-ALL cells causes rapid cell cycle exit and disables their leukemia-initiating capacity. These and similar findings in human B-ALL cell lines establish that Pax5 hypomorphism promotes B-ALL self-renewal by impairing a differentiation program that can be re-engaged despite the presence of additional oncogenic lesions. Our results establish a causal relationship between the hallmark genetic and phenotypic features of B-ALL and suggest that engaging the latent differentiation potential of B-ALL cells may provide new therapeutic entry points.