Paediatric and adolescent medulloblastoma and CNS-PNET in Norway 1974 – 2013: Survival, regional differences, and late effects

Medulloblastoma (MB) and supratentorial primitive neuroectodermal tumor (CNS-PNET) are embryonal brain tumours, and they account for about 15%–20% and 2.5%, respectively, of malignant brain tumors in children and adolescents. The aim of the thesis was two-fold. First, to investigate whether there within Norway were re-gional differences in survival for patients with MB and CNS-PNET in the time period 1974–2013, and if so try and identify possible explanations for such differences. The second aim was to determine frequency and severity of undesirable late effects in MB and CNS-PNET survivors, and evaluate rehabilitation need. We performed a retrospective study of patients diagnosed with MB or CNS-PNET in Norway between 1974 and 2013. Second, a clinical follow-up study focusing on late effects and rehabilitation need for MB and CNS-PNET survivors in South-Eastern Norway Regional Health Authority was performed. At the time of analysis, 46% of all Norwegian patients were alive. In univariable analysis, five-year OS, but not five-year event-free survival (EFS), for MB/CNS-PNET altogether was significantly better at University Hospital Of North Norway, St. Olavs Hospi-tal Trondheim University Hospital, and Haukeland University Hospital, compared to Oslo University Hospital (68% vs 54%). We were not able to identify any possible explanations for these regional survival differences within Norway. In the clinical follow-up study, a high burden of unwanted late effects was found in paediatric, adolescent, and adult MB and CNS-PNET survivors, in the vast majority of cases leading to unmet rehabilitation needs. It is im-portant to note that several late effects do not occur until years or even decades following completion of anti-neoplastic treatment and these patients will therefore need life-long follow-up and rehabilitation

Neuropsychological functioning in survivors of childhood medulloblastoma/CNS-PNET: The role of secondary medical complication

To investigate the long-term cognitive consequences of malignant pediatric brain tumor and its treatment, and factors explaining variability in cognitive functioning among survivors. Method: A geographical cohort of survivors of pediatric medulloblastoma (MB) and supratentorial primitive neuroectodermal tumor (CNS-PNET), treated between 1974 and 2013, was invited to participate. Of the 63 surviving patients, 50 (79%) consented to participation. The participants were tested with a battery of neuropsychological tests covering a wide age range. Verbal cognition, nonverbal cognition, processing speed, attention, memory, executive functioning, and manual dexterity were assessed. The participants were between 5:5 and 51:11 years of age at time of assessment. Assessments took place on average 19 years after primary tumor resective surgery. Results: One participant had a severe intellectual disability. For the rest, IQ varied from 52 to 125, with a mean score of 88.0 (SD 19.7). Twenty-eight (56%) of the participants had full-scale IQ scores in the age-average range or above. Gender, age at operation, time since operation, the presence of secondary medical complications, and treatment variables explained 46% of the variability in IQ scores, F(4,44) =  9.5, p<.001. The presence of endocrine insufficiency in combination with either epilepsy and/or hydrocephalus was associated with lowered IQ, lowered processing speed, and memory impairments. Conclusion: Patients treated for childhood MB and CNS-PNET have a lifelong risk of medical sequelae, including impaired cognitive functioning. This study adds to the literature by demonstrating the importance of following neuropsychological functioning closely, especially processing speed, learning, and memory, in survivors who have multiple secondary medical complications

Outcomes in adulthood after neurosurgical treatment of brain tumors in the first 3 years of life: long-term follow-up of a single consecutive institutional series of 97 patients

Abstract Background Long-term outcome for children who underwent surgery for brain tumors in the first 3 years of life is not well-known. Methods We performed a retrospective study on surgical morbidity, mortality rate, academic achievement, and work participation in children below 3 years of age who underwent primary tumor resection for a brain tumor in the period from 1973 to 1998. Gross motor function and activities of daily life were scored according to the Barthel Index. Long-term survivors were defined as with a survival from primary diagnosis of 20 years or more. Findings Ninety-seven consecutive children were included. No patient was lost to follow-up. Gross total resection was achieved in 67 children during the primary procedure, 25 had subtotal resections, and 5 had only partial resection. The 20-year survival figures for the 46 children with high-grade tumors was 33%, and the corresponding figures for 51 patients treated for low-grade tumors was 82%. Five of the 57 20-year-survivors died 21, 29, 30, 30, and 41 years, respectively, following primary surgery. Fifty of the 52 long-term survivors had a Barthel Index (BI) of 100, while the remaining two had a BI of 40. Twelve patients were long-term survivors after treatment for HG tumors (26%), while 40 of the 51 patients treated for LG tumors (78%) were alive. Thirty-two of the 52 long-term survivors were in full-time work and 29 of them after treatment for LG tumors. Another 10 were in part-time work, while the last 10 individuals had no working capacity. Conclusion Survival is better for patients with low-grade tumors compared with those with high-grade tumors. The functional level of long-term survivors is affected by adjuvant therapy and radiotherapy in particular. Neurosurgical intervention in itself is safe and plausible for pediatric brain tumor patients below 3 years of age. However, there should be a focus on potential late affects, and survivors should be followed by knowledgeable clinical staff for the neoplastic disease as well as for potential side effects. In this consecutive series, a 33% 20-year survival for children treated for HG tumors and 82% for patients with LG tumors was observed. The patients with LG tumors who had been treated with surgical resection without any adjuvant therapy showed a good clinical outcome as adults, and two-thirds of them were in full-time work

Unmet rehabiliation needs in 86% of Norwegian paediatric embryonal brain tumour survivors

Aim To study incidence, types and degrees of late effects in a geographical cohort of paediatric medulloblastoma and central nervous system primitive neuroectodermal tumour (CNS‐PNET) survivors, and identify the need for rehabilitation. Methods Between 1974 and 2013, 63 patients survived treatment for paediatric medulloblastoma and CNS‐PNET at Oslo University Hospital, Norway. Of these, 50 accepted invitation and were included in this study. Results Median follow‐up was 20 years (range 3.2‐41), and 96% of participants had developed late effects. Cognitive impairment was found in 72%, reduced hearing in 68%, endocrine deficits in 66%, epilepsy in 32% and another 30% had been diagnosed with one or more second primary neoplasms. Radiotherapy significantly increased risk of secondary primary neoplasms and endocrinological deficits, chemotherapy risk of ototoxicity and endocrinological deficits, and epilepsy was found significantly more often in CNS‐PNET than medulloblastoma patients. Epilepsy was the main cause of cognitive impairments (full‐scale IQ) in our study. 86% of participants had an unmet rehabilitation need. Conclusion Significant late effects and unmet rehabilitation needs were documented in the large majority of survivors after treatment for paediatric medulloblastoma and CNS‐PNET

Taste and smell function in long-term survivors after childhood medulloblastoma/CNS-PNET

Abstract Purpose To investigate taste and smell function in survivors, with a minimum of 2 years since treatment of childhood medulloblastoma (MB)/central nervous system supratentorial primitive neuroectodermal tumor (CNS-PNET). Methods This cross-sectional study included 40 survivors treated ≤ 20 years of age. Taste strips with four concentrations of sweet, sour, salt, and bitter were used to assess taste function in all participants. Score from 0 to 16; ≥ 9 normogeusia, &lt; 9 hypogeusia, and complete ageusia which equals no sensation. No sensation of a specific taste quality equals ageusia of that quality. Thirty-two participants conducted smell testing using three subtests of Sniffin’ sticks: threshold, discrimination, and identification. Together they yield a TDI-score from 1 to 48; functional anosmia ≤ 16.00, hyposmia &gt; 16.00– &lt; 30.75, normosmia ≥ 30.75– &lt; 41.50, and ≥ 41.50 hyperosmia. Results were compared with normative data. Survivors rated their taste and smell function using a numerical rating scale (NRS) score 0–10. Results Forty survivors with a mean time since treatment of 20.5 years, 13 (32.5%) were diagnosed with hypogeusia, nine (22.5%) of these being ageusic to one or more taste qualities. Seventeen (53%) of 32 participants were diagnosed with hyposmia. The mean scores of the olfactory subtests, and TDI score were significantly lower than normative data ( P  &lt; 0.0001). The mean NRS scores of smell and taste function were 7.9 ± 1.5 and 8 ± 1.3, respectively. Conclusion Our study showed impaired taste and smell function in survivors of childhood MB/CNS-PNET using objective measurements. However, subjective ratings did not reflect objective findings

Identification of novel genetic variants associated with cardiorespiratory fitness

Introduction Low maximal oxygen uptake (VO2max) is a strong and independent risk factor for all-cause and cardiovascular disease (CVD) mortality. For other CVD risk factors, numerous genetic association studies have been performed, revealing promising risk markers and new therapeutic targets. However, large genomic association studies on VO2max are still lacking, despite the fact that VO2max has a large genetic component. Methods We performed a genetic association study on 123.545 single-nucleotide polymorphisms (SNPs) and directly measured VO2max in 3470 individuals (exploration cohort). Candidate SNPs from the exploration cohort were analyzed in a validation cohort of 718 individuals, in addition to 7 wild-card SNPs. Sub-analyses were performed for each gender. Validated SNPs were used to create a genetic score for VO2max. In silico analyses and genotype-phenotype databases were used to predict physiological function of the SNPs. Results In the exploration cohort, 41 SNPs were associated with VO2max (p < 5.0 ∗ 10−4). Six of the candidate SNPs were associated with VO2max also in the validation cohort, in addition to three wild-card SNPs (p < 0.05, in men, women or both). The cumulative number of high-VO2max-SNPs correlated negatively with CVD risk factors, e.g. waist-circumference, visceral fat, fat %, cholesterol levels and BMI. In silico analysis indicated that several of the VO2max-SNPs influence gene expression in adipose tissue, skeletal muscle and heart. Conclusion We discovered and validated new SNPs associated with VO2max and proposed possible links between VO2max and CVD. Studies combining several large cohorts with directly measured VO2max are needed to identify more SNPs associated with this phenotype

Bone mineral density and nutrition in long-term survivors of childhood brain tumors

Background and aims Childhood cancer survivors are at risk of unwanted late effects. The primary aim of this study was to assess bone mineral density Z-scores (BMDz) in long-term survivors of childhood medulloblastoma (MB) or central nervous system supratentorial primitive neuroectodermal tumor (CNS-PNET). Secondary aims were to describe nutrient intake, vitamin D status, physical activity and explore potential risk factors for decreased BMDz. Methods All MB and CNS-PNET survivors treated at Oslo University Hospital from 1974 to 2013 were invited to participate in a cross-sectional study. Dual-energy x-ray absorptiometry (Lunar Prodigy) assessed BMDz lumbar spine, BMDz total body, and lean body mass. Decreased BMDz was defined as a combination of low BMDz −1 to −1.99 and very low BMDz ≤−2. Lean body mass index (LMI) was calculated by dividing lean body mass by the squared height. Nutrient intake was assessed by a 3-day food record. Serum 25(OH)D was analyzed. Physical activity was reported by a questionnaire. Descriptive statistics and multivariable Cox regression analyses were applied. Results Fifty survivors with a median age of 25.5 years (5.5–51.9) and a median follow-up time of 19.5 years (3.2–40.5) were included. Mean BMDz lumbar spine was −0.8 (SD 1.1, 95% CI: −1.1 to −0.4), and BMDz total body was −0.6 (SD 1.1, 95% CI: −0.9 to −0.3). Decreased BMDz was detected in 48% of the lumbar spine and 34% of the total body measurements. In all, 62% had low calcium, and 69% had low vitamin D intake. 26% of participants had serum 25(OH)D < 50 nmol/L, and 62% reported an inactive lifestyle. Male sex, higher age at diagnosis, and lower LMI were potential risk factors for decreased BMDz. Conclusions Long-term survivors of childhood MB and CNS-PNET had decreased BMDz, and risk factors were male sex, higher age at diagnosis, and lower LMI. Inadequate calcium and vitamin D intake, an inactive lifestyle, and a high prevalence of 25(OH)D ≤ 50 nmol/L were detected

Identification of novel genetic variants associated with cardiorespiratory fitness

Introduction: Low maximal oxygen uptake (VO) is a strong and independent risk factor for all-cause and cardiovascular disease (CVD) mortality. For other CVD risk factors, numerous genetic association studies have been performed, revealing promising risk markers and new therapeutic targets. However, large genomic association studies on VO are still lacking, despite the fact that VO has a large genetic component. Methods: We performed a genetic association study on 123.545 single-nucleotide polymorphisms (SNPs) and directly measured VO in 3470 individuals (exploration cohort). Candidate SNPs from the exploration cohort were analyzed in a validation cohort of 718 individuals, in addition to 7 wild-card SNPs. Sub-analyses were performed for each gender. Validated SNPs were used to create a genetic score for VO. In silico analyses and genotype-phenotype databases were used to predict physiological function of the SNPs. Results: In the exploration cohort, 41 SNPs were associated with VO (p < 5.0 ∗ 10). Six of the candidate SNPs were associated with VO also in the validation cohort, in addition to three wild-card SNPs (p < 0.05, in men, women or both). The cumulative number of high-VO SNPs correlated negatively with CVD risk factors, e.g. waist-circumference, visceral fat, fat %, cholesterol levels and BMI. In silico analysis indicated that several of the VO-SNPs influence gene expression in adipose tissue, skeletal muscle and heart. Conclusion: We discovered and validated new SNPs associated with VO and proposed possible links between VO and CVD. Studies combining several large cohorts with directly measured VO are needed to identify more SNPs associated with this phenotype

Long-term outcome of posterior fossa medulloblastoma in patients surviving more than 20 years following primary treatment in childhood

The aim of the study was to analyze the long-term outcome (>20 years) after treatment of posterior fossa medulloblastoma (MB) in childhood. We analyzed data from patients treated for posterior fossa MB between 1974 (introduction of the first international treatment protocol in Norway) and 1987 (when use of radiotherapy was abandoned in children under 4 years of age). Out of 47 children, 24 survived >20 years. At the time of analysis, 16 patients (median age 41 years, range 32–52) were alive (median follow-up 34 years, range 30–42), while 8 patients died 22–41 years (median 31 years) after primary treatment: one late death (after 22 years) was due to tumor recurrence whilst other 7 deaths (after 23 to 41 years) were related to the detrimental effects of the treatment (secondary tumors, stroke, severe epilepsy and depression). Observed 20- and 30-year survival rates were 51% and 44%, respectively. Despite successful treatment of MB in childhood and satisfactory tumor control during the first 20 years following primary treatment, our data indicates that even long-term survivors may die from tumor recurrence. However, the main factors causing late mortality and morbidity in long-term survivors seem to be the complications related to radiotherapy given in childhood

Molecular pathological insights reveal a high number of unfavorable risk patients among children treated for medulloblastoma and CNS-PNET in Oslo 2005–2017

Background An unexplained regional difference in survival was observed in previous publications on outcome for children treated for medulloblastoma and supratentorial primitive neuroectodermal tumor (CNS-PNET) in Norway. We aimed now to reevaluate and perform a retrospective molecular-based risk stratification of all embryonal brain tumors (excluding atypical teratoid rhabdoid tumors [ATRT]) in pediatric patients, who underwent surgery and treatment at Oslo University Hospital between 2005 and 2017. Procedure Specimens from all patients <20 years of age with initial diagnosis of medulloblastoma or CNS-PNET were reviewed. Molecular analyses comprised NanoString gene expression, molecular inversion probe profiling, Sanger sequencing, and 850K-methylation analysis. Whole chromosomal aberration signatures were assessed in standard-risk non-WNT/non-SHH medullobastomas for molecular risk stratification. Results We identified 53 non-ATRT embryonal tumors among which 33 were medulloblastomas. Molecular genetic parameters including whole chromosomal aberration signatures allowed classification of 17 medulloblastomas as molecular high risk. These patients had a significantly worse 5-year overall survival than the remaining 16 medulloblastoma patients (52.9% vs. 87.1% p = 0.036). Five patients in our cohort had tumors that are considered as new entities in the 2021 classification of tumors of the central nervous system. Five tumors were re-classified as nonembryonal tumors after review. Conclusion Molecular-based risk stratification of standard-risk non-WNT/non-SHH medulloblastoma enabled superior identification of medulloblastomas with dismal prognosis. Our cohort demonstrated a significantly increased fraction of standard-risk non-WNT/non-SHH medulloblastoma with molecular high-risk profile compared to other studies, which might have contributed to previously reported unfavorable outcome data