Worries and anxiety in parents of adult survivors of childhood cancer: A report from the Swiss Childhood Cancer Survivor Study-Parents.

OBJECTIVE Having a child diagnosed with cancer is distressing for parents. We aimed to compare worries and anxiety in parents of adult childhood cancer survivors with parents of the Swiss general population (GP-parents), and to evaluate characteristics associated with worry in parents of survivors. METHODS We conducted a nationwide, population-based study in parents of survivors (survivors aged ≥20 years at study, ≤16 years at diagnosis, >5 years post diagnosis) and GP-parents (≥1 child aged ≥20 years at study). We used the Worry and Anxiety Questionnaire (WAQ), and computed the WAQ total score (worries; possible range 0-80) and caseness for generalized anxiety disorder (anxiety), cognitive, somatic, and any criteria. We used multilevel, multivariable linear regression to identify characteristics associated with worries in parents of survivors. RESULTS We included 787 parents of 513 survivors (41.0% fathers) and 478 GP-parents (42.3% fathers). Parents of survivors and GP-parents did not differ regarding worries (16.6 vs. 17.1, p = .977), anxiety (2.7% vs. 3.6%, p = .536), cognitive (p = .440), and somatic criteria (p = .067). Less parents of survivors met any criteria (17.7% vs. 24.0%, p = .039). Half of parents reported current cancer-related worries. Higher cancer-related worries were reported by mothers (β = 4.1; 95% CI: 2.0-6.2), parents with one child (β = 5.9; 95% CI: 2.0-9.7), currently experiencing disadvantages because of their child's former disease (β = 7.3; 95% CI: 4.0-10.6), or with support needs (β = 9.0; 95% CI: 3.9-14.2; p = .001). CONCLUSIONS It is encouraging that most parents of adult survivors report similar worries and anxiety as GP-parents, but cancer-related worries are still prevalent. Efforts should be made to empower parents to seek psycho-social support if required

Brain stem tumors in children less than 3 months: clinical and radiologic findings of a rare disease

Purpose Brain stem tumors in children < 3 months at diagnosis are extremely rare. Our aim is to study a retrospective cohort to improve the understanding of the disease course and guide patient management. Methods This is a multicenter retrospective analysis across the European Society for Pediatric Oncology SIOP-E HGG/DIPG Working Group linked centers, including patients with a brainstem tumor diagnosed between 2009 and 2020 and aged < 3 months at diagnosis. Clinical data were collected, and imaging characteristics were analyzed blindly and independently by two neuroradiologists. Results Five cases were identified. No patient received any therapy. The epicenter of two tumors was in the medulla oblongata alone and in the medulla oblongata and the pons in three. For patients with tumor in equal parts in the medulla oblongata and the pons (n = 3), the extension at diagnosis involved the spinal cord; for the two patients with the tumor epicenter in the medulla oblongata alone (n = 2), the extension at diagnosis included the pons (n = 2) and the spinal cord (n = 1). Biopsy was performed in one patient identifying a pilocytic astrocytoma. Two patients died. In one patient, autopsy revealed a high-grade glioma (case 3). Three survivors showed either spontaneous tumor regression (n = 2) or stable disease (n = 1). Survivors were followed up for 10, 7, and 0.6 years, respectively. One case had the typical imaging characteristics of a dorsal exophytic low-grade glioma. Conclusions No patient fulfilled the radiologic criteria defining a high-grade glioma. Central neuroradiological review and biopsy may provide useful information regarding the patient management

ETMR-01. Brain stem tumors in children less than three months: clinical and radiologic findings of a rare disease [Abstract]

BACKGROUND Brainstem gliomas account for 10-20% of all central nervous system pediatric neoplasms. Brain stem tumors in children less than three months old at diagnosis are extremely rare. Our aim is to study a retrospective cohort to improve the understanding of the disease course and guide patient management. METHODS This is a multicenter retrospective analysis across the European Society for Pediatric Oncology SIOP-E HGG/DIPG Working Group linked centers and included patients with a brainstem tumor diagnosed between 2009 and 2020 and aged less than 3 months at diagnosis. Clinical data was collected, and imaging characteristics were analyzed blindly and independently by two experienced neuroradiologists. RESULTS Five cases (female; n=4) were identified of which no patient received any therapy. The epicenter of 2 tumors was in the medulla oblongata alone and in the medulla oblongata and the pons in 3 cases. For patients with tumor in equal parts in the medulla oblongata and the pons (n=3) the extension at diagnosis involved the spinal cord; for the 2 patients with the tumor epicenter in the medulla oblongata alone (n=2) the extension at diagnosis included the pons (n=2) and the spinal cord (n=1). Biopsy was performed in one patient identifying a pilocytic astrocytoma. Two patients died rapidly. In one patient autopsy revealed a high-grade glioma (case 3). Three survivors showed either spontaneous tumor regression (n=2) or stable disease (n=1). The surviving patients were followed-up for 10, 7, and 0.6 years, respectively. One case had the typical imaging characteristics of a dorsal exophytic low-grade glioma. CONCLUSIONS No patient fulfilled the radiologic criteria defining a high-grade glioma. Central neuroradiological review and biopsy (if feasible) may provide useful information with regards to the patient’s management

Reirradiation as part of a salvage treatment approach for progressive non-pontine pediatric high-grade gliomas: preliminary experiences from the German HIT-HGG study group

Background and purpose: The aim of the present analysis was to assess the feasibility, toxicity, and the tumor control of reirradiation as a salvage treatment for progressive pediatric non-pontine high-grade gliomas (HGG). Patients and methods: The database of the Reference Center for Radiation Oncology of the German HIT (HIT = German acronym for brain tumor) treatment network for childhood brain tumors was screened for children who were reirradiated for progressive non-pontine HGG. Results: We identified eight patients (WHO grade III: n = 5; WHO grade IV: n = 3) who underwent reirradiation between April 2006 and July 2012. Median age was 13.5 years at primary diagnosis and 14.8 years at first progression. All patients initially underwent surgery (incomplete resection, n = 7; biopsy, n = 1) followed by radiochemotherapy. Relapses occurred inside (n = 2), at the margin (n = 4), and outside of the preirradiated area (n = 2). In all patients, reirradiation was tolerated well without significant acute toxicity. Temporary clinical improvement and tumor regression on magnetic resonance imaging (MRI) following reirradiation was reported (n = 3). However, all patients finally died by disease progression. Median survival time was 26.2 months from initial diagnosis and 11.4 months after first progression. Median time interval between initial radiotherapy and first reirradiation was 9.0 months. In six patients, all macroscopic tumor deposits were reirradiated. In these patients, median progression-free (overall) survival from the start of reirradiation was 2.4 (4.6) months. Conclusion: Our analysis, although based on a limited patient number, suggests that reirradiation of progressive non-pontine HGG is feasible in children. Benefit in terms of quality of life and/or survival needs to be assessed in a prospective and ideally in a randomized manner

Reirradiation as part of a salvage treatment approach for progressive non-pontine pediatric high-grade gliomas: preliminary experiences from the German HIT-HGG study group

Background and purpose: The aim of the present analysis was to assess the feasibility, toxicity, and the tumor control of reirradiation as a salvage treatment for progressive pediatric non-pontine high-grade gliomas (HGG). Patients and methods: The database of the Reference Center for Radiation Oncology of the German HIT (HIT = German acronym for brain tumor) treatment network for childhood brain tumors was screened for children who were reirradiated for progressive non-pontine HGG. Results: We identified eight patients (WHO grade III: n = 5; WHO grade IV: n = 3) who underwent reirradiation between April 2006 and July 2012. Median age was 13.5 years at primary diagnosis and 14.8 years at first progression. All patients initially underwent surgery (incomplete resection, n = 7; biopsy, n = 1) followed by radiochemotherapy. Relapses occurred inside (n = 2), at the margin (n = 4), and outside of the preirradiated area (n = 2). In all patients, reirradiation was tolerated well without significant acute toxicity. Temporary clinical improvement and tumor regression on magnetic resonance imaging (MRI) following reirradiation was reported (n = 3). However, all patients finally died by disease progression. Median survival time was 26.2 months from initial diagnosis and 11.4 months after first progression. Median time interval between initial radiotherapy and first reirradiation was 9.0 months. In six patients, all macroscopic tumor deposits were reirradiated. In these patients, median progression-free (overall) survival from the start of reirradiation was 2.4 (4.6) months. Conclusion: Our analysis, although based on a limited patient number, suggests that reirradiation of progressive non-pontine HGG is feasible in children. Benefit in terms of quality of life and/or survival needs to be assessed in a prospective and ideally in a randomized manner

Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas

Medulloblastoma is the most common malignant brain tumor in childhood. Molecular studies from several groups around the world demonstrated that medulloblastoma is not one disease but comprises a collection of distinct molecular subgroups. However, all these studies reported on different numbers of subgroups. The current consensus is that there are only four core subgroups, which should be termed WNT, SHH, Group 3 and Group 4. Based on this, we performed a meta-analysis of all molecular and clinical data of 550 medulloblastomas brought together from seven independent studies. All cases were analyzed by gene expression profiling and for most cases SNP or array-CGH data were available. Data are presented for all medulloblastomas together and for each subgroup separately. For validation purposes, we compared the results of this meta-analysis with another large medulloblastoma cohort (n = 402) for which subgroup information was obtained by immunohistochemistry. Results from both cohorts are highly similar and show how distinct the molecular subtypes are with respect to their transcriptome, DNA copy-number aberrations, demographics, and survival. Results from these analyses will form the basis for prospective multi-center studies and will have an impact on how the different subgroups of medulloblastoma will be treated in the future

WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma

TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6% +/- 8.7%, respectively (p < 0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89% +/- 2% vs. 57.4% +/- 1.8% (p < 0.01)). In contrast, beta-catenin mutation sensitized TP53 mutant cells to radiation (p < 0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5% +/- 1.5% in lithium treated cells vs. 56.6 +/- 3% (p < 0.01)) accompanied by increased number of.H2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33% +/- 8% for lithium treated cells vs. 27% +/- 3% for untreated controls (p = 0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.B.R.A.I.N Child Canada; Cancer Research UK; Brain Tumour Charity; Hungarian Brain Research Program [KTIA_13_NAP-A-V/3]; Janos Bolyai Scholarship of the Hungarian Academy of Sciences [TAMOP-4.2.2. A-11/1/KONV-2012-0025]; German Cancer Aid/Dr. Mildred Scheel Foundation for Cancer Research; Cure Childhood Cancer Foundation; St. Baldrick's Foundation; Southeastern Brain Tumor Foundation; Action Medical Research; [CZ.1.05/2.1.00/03.0101]; [CZ.1.07/2.3.00/20.0183

HGG-28. Oncogenic Tyrosine Kinase Gene Fusions in Supratentorial High Grade Gliomas of Young Children - Comparison of RNA- and DNA-Based Methods for their Reliable Detection

Abstract High-grade diffuse gliomas in early childhood are characterized by a more favorable outcome compared to older children. We have shown in previous studies that these tumors are characterized by stable genomes. The occurrence of tyrosine kinase gene fusions in high-grade gliomas of infancy may represent therapeutic targets. 50 glioblastomas (GBM) with supratentorial location occurring in children younger than four years were retrieved from the archives of the Brain Tumor Reference Center, Institute of Neuropathology, Bonn University. DNA and RNA were extracted from FFPE tumor samples. Gene fusions were identified on the DNA level by FISH using break-apart probes for ALK, NTRK1, -2, -3, ROS1 and MET and Molecular Inversion Probe (MIP) methodology. On the RNA level, fusion transcripts were detected by targeted RNA sequencing as well as Nanostring assay with fusion-specific probes. 37 supratentorial GBM occurred in the first year of life, 13 GBM between one and four years. 18 cases showed fusions of ALK to different partners; all occurred in the first year of life (18/37, 48.6%). Fusions of ROS1 were found in 5, MET in 3, NTRK1, -2, -3 in 10 cases. 12 cases showed no and two cases novel fusions. The different methods led to comparable results. Only recurrent fusions with known fusion partners were detectable with fusion sequence-specific Nanostring probes and library construction for targeted RNA sequencing failed in a fraction of cases. Break-apart FISH led to reliable results on the next day, and MIP technology represented the most sensitive method for analysis of FFPE samples. Gene fusions involving the tyrosine kinase genes ALK, MET, ROS1 and NTRK1, -2, -3 occurred in 72% of glioblastomas of young children; most frequent were ALK fusions occurring in infant GBM. DNA-based MIP technology represented the most robust and sensitive assay. A combination of RNA- and DNA-based methods to detect these fusions with high reliability is recommended.Abstract High-grade diffuse gliomas in early childhood are characterized by a more favorable outcome compared to older children. We have shown in previous studies that these tumors are characterized by stable genomes. The occurrence of tyrosine kinase gene fusions in high-grade gliomas of infancy may represent therapeutic targets. 50 glioblastomas (GBM) with supratentorial location occurring in children younger than four years were retrieved from the archives of the Brain Tumor Reference Center, Institute of Neuropathology, Bonn University. DNA and RNA were extracted from FFPE tumor samples. Gene fusions were identified on the DNA level by FISH using break-apart probes for ALK, NTRK1, -2, -3, ROS1 and MET and Molecular Inversion Probe (MIP) methodology. On the RNA level, fusion transcripts were detected by targeted RNA sequencing as well as Nanostring assay with fusion-specific probes. 37 supratentorial GBM occurred in the first year of life, 13 GBM between one and four years. 18 cases showed fusions of ALK to different partners; all occurred in the first year of life (18/37, 48.6%). Fusions of ROS1 were found in 5, MET in 3, NTRK1, -2, -3 in 10 cases. 12 cases showed no and two cases novel fusions. The different methods led to comparable results. Only recurrent fusions with known fusion partners were detectable with fusion sequence-specific Nanostring probes and library construction for targeted RNA sequencing failed in a fraction of cases. Break-apart FISH led to reliable results on the next day, and MIP technology represented the most sensitive method for analysis of FFPE samples. Gene fusions involving the tyrosine kinase genes ALK, MET, ROS1 and NTRK1, -2, -3 occurred in 72% of glioblastomas of young children; most frequent were ALK fusions occurring in infant GBM. DNA-based MIP technology represented the most robust and sensitive assay. A combination of RNA- and DNA-based methods to detect these fusions with high reliability is recommended