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Objective: To examine as secondary analyses the effect the FAMily-Oriented Support (FAMOS) family therapy program on reducing parent-reported medical traumatic stress in the sub-sample of pediatric cancer survivors, age 2-5 years. Methods: The FAMOS study was a national multicenter randomized controlled trial with all four pediatric oncology departments in Denmark (Clinicaltrials.gov [NCT02200731]). Families were randomized in parallel design (1:1) to intervention or usual care. The FAMOS program includes seven home-based psychotherapeutic sessions and is based on family systems therapy to address the individuals in the family system using cognitive behavioral, problem-solving and goal-setting techniques. Questionnaires were completed by parents at baseline, 6, and 12 months. In linear mixed-effects models, the effect of FAMOS on reducing children's trauma-related behavior after 6 and 12 months was examined in 62 children (31 in the intervention and 29 in the control group, respectively). It was also examined if a trauma-related behavior effect was mediated through reduced symptoms of depression in mothers and fathers, respectively. Results: On average, children in the intervention group experienced significantly larger decreases in trauma-related behaviors at 6 and 12 months than the control group (predicted mean difference -3.89, p =. 02 and -6.24, p =. 003, respectively). The effect on trauma-related behavior was partly mediated through reduced symptoms of depression in mothers, but not fathers. Conclusions: Adding to previously reported positive effects of the FAMOS intervention on parents' symptoms of post-traumatic stress and depression, significant improvements were found in young children's trauma related-behavior. Further research is needed to develop therapy for children with cancer.

Minimal residual disease (MRD) constitutes the most important prognostic factor in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Flow cytometry is widely used in MRD assessment, yet little is known regarding the effect of different immunophenotypic subsets on outcome. In this study of 200 BCP-ALL patients, we found that a CD34 positive, CD38 dim positive, nTdT dim positive immunophenotype on the leukemic blasts was associated with poor induction therapy response and predicted an MRD level at the end of induction therapy (EOI) of ≥0.001. CD34 expression was strongly and positively associated with EOI MRD, whereas CD34 negative patients had a low relapse risk. Further, CD34 expression increased from diagnosis to relapse. CD34 is a stemness-associated cell-surface molecule, possibly involved in cell adhesion/migration or survival. Accordingly, genes associated with stemness were overrepresented amongst the most upregulated genes in CD34 positive leukemias, and protein-protein interaction (PPI) networks showed an overrepresentation of genes associated with cell migration, cell adhesion and negative regulation of apoptosis. The present work is the first to demonstrate a CD34 negative immunophenotype as a good prognostic factor in ALL, whereas high CD34 expression associates with poor therapy response and an altered gene expression profile reminiscent of migrating cancer stem-like cells.

Introduction: Evidence-based knowledge is needed to reduce psychological symptoms in families of young children with cancer after treatment ends. Objective: To evaluate the effect of a psychotherapeutic intervention, FAMily-Oriented Support (FAMOS) on parents of young children after cancer treatment. Methods: All families of children aged 0-6 years who had been treated for cancer at one of the four paediatric oncology departments in Denmark were invited to participate after ending intensive medical treatment. The families were randomly assigned 1:1 to up to seven sessions of FAMOS, a cognitive-behavioural manualised home intervention, for 6 months or to usual psychosocial care. The primary outcome was parents’ symptoms of posttraumatic stress disorder (PTSD) at 6 and 12 months after enrolment. The secondary outcomes were parents’ symptoms of depression and anxiety. Results: We enrolled 109 families (204 parents). Parents in the intervention group did not show a statistically significant decrease in symptoms of PTSD as compared with the control group at 6 months (predicted mean difference, −0.10; 95% confidence interval [CI] −0.19, 0.01), but a statistically significant decrease was seen at 12 months (predicted mean difference, −0.15; 95% CI −0.28, −0.02), and they had significantly lower symptoms of depression at both 6 and 12 months. Differences in reductions in symptoms of anxiety were not statistically significant. Conclusions: The FAMOS intervention reduced parents’ symptoms of PTSD and depression. Next step is to also report on psychological effects in the children and siblings (clinicaltrials.gov: NCT02200731).

Background: The classic Bernard-Soulier syndrome (BSS) is a rare inherited thrombocytopenia (IT) associated with severe thrombocytopenia, giant platelets, and bleeding tendency caused by homozygous or compound heterozygous variants in GP1BA, GP1BB, or GP9. Monoallelic BSS (mBSS) associated with mild asymptomatic macrothrombocytopenia caused by heterozygous variants in GP1BA or GP1BB may be a frequent cause of mild IT. Objective: We aimed to examine the frequency of mBSS in a consecutive cohort of patients with IT and to characterize the geno- and phenotype of mBSS probands and their family members. Additionally, we set out to examine if thrombopoietin (TPO) levels differ in mBSS patients. Patients/Methods: We screened 106 patients suspected of IT using whole exome- or whole genome sequencing and performed co-segregation analyses of mBSS families. All probands and family members were phenotypically characterized. Founder mutation analysis was carried out by certifying that the probands were unrelated and the region around the variant was shared by all patients. TPO was measured by solid phase sandwich ELISA. Results: We diagnosed 14 patients (13%) with mBSS associated with heterozygous variants in GP1BA and GP1BB. Six unrelated probands carried a heterozygous variant in GP1BA (c.58T>G, p.Cys20Gly) and shared a 2.0 Mb region on chromosome 17, confirming that it is a founder variant. No discrepancy of TPO levels between mBSS patients and wild-type family members (P >.05) were identified. Conclusion: We conclude that the most frequent form of IT in Denmark is mBSS caused by the Copenhagen founder variant.

OBJECTIVES: Survival among children diagnosed with acute lymphoblastic leukaemia (ALL) has increased considerably. However, morbidity in survivors constitutes a potential increasing burden not limited to secondary health care. Our objectives were to compare health care utilisation, including both primary and secondary health care, between childhood ALL survivors and matched references up to 15 years after curative treatment. Moreover, to increase knowledge on survivors' health service seeking behaviour as time from treatment elapsed. DESIGN AND SETTING: A Danish population-based matched cohort study linking multiple nationwide registries. PARTICIPANTS: 675 cases, diagnosed with childhood (1.0-17.9 years) ALL between 1994 and 2015, and 6750 matched references sampled randomly from the source population (matched on age, gender and geographical region). PRIMARY OUTCOME MEASURES: Repeated consultations in general practice and hospital (outpatient and inpatient) estimated as yearly rates from 2.5 years after diagnosis and onwards. We compared cases and references with yearly incidence rate ratios (IRRs) from negative binomial regression models. RESULTS: Survivors of childhood ALL had a mean number of yearly daytime contacts in general practice of 4.75 (95% CI 4.41 to 5.11) the first year, corresponding to an IRR of 1.85 (95% CI 1.71 to 2.00); decreasing to 1.16 (1.01 to 1.34) after 15 years, and without significant impact of gender (p=0.894) or age (p=0.399). For hospital contacts, ALL survivors had a mean number of yearly contacts of 14.21 (13.38-15.08) the first year, corresponding to an IRR of 31.50 (28.29-35.07); decreasing to 2.42 (1.59-3.68) after 15 years. No differences were found across calendar time. CONCLUSIONS: ALL survivors used significantly more health care services across sectors than the reference population. Decreasing use over 15 years illustrated the dynamics of health care needs; this knowledge may inform the future organisation of integrated foll

Objectives To investigate health care utilisation including both primary and secondary health care 6 months before the diagnosis of a relapse or a second malignant neoplasm (SMN) in survivors of childhood acute lymphoblastic leukaemia (ALL). Design and setting A Danish population-based matched cohort study linking multiple nationwide registries. Participants Participants were recruited from a total of 622 childhood ALL 2.5-year event-free survivors diagnosed between 1994 and 2015. Cases were survivors developing a relapse or an SMN and references were survivors still in first remission. Each case was matched with five references on age, sex, treatment protocol and risk group. Primary outcome measures Consultations in general practice and hospital the last 6 months before relapse or SMN. Cases and references were compared with monthly incidence rate ratios (IRRs) from negative binomial regression models. Results Of the 622 childhood ALL survivors, 60 (9.6%) developed a relapse (49) or an SMN (11) and 295 matched references were identified. Health care utilisation in general practice increased among cases the last month before the event compared with references with an IRR of 2.71 (95% CI 1.71 to 4.28). Data showed a bimodal structure with a significantly increased number of visits 4, 5 and 6 months before the event. Hospital health care utilisation increased 2 months before the event in cases with an IRR of 5.01 (3.78 to 6.63) the last month before the event and an IRR of 1.94 (1.32 to 2.85) the second-last month comparing cases and references. Conclusions Survivors of childhood ALL developing a relapse or an SMN have a short period of increased health care utilisation before diagnosis. At hospital, this might be explained by pre-diagnostic examinations. In general practice, data suggest a bimodal structure with children later developing a relapse having more contacts also half a year before the relapse, suggesting that there could be early warnings.