Treatment response as surrogate to predict risk for disease progression in pediatric medulloblastoma with persistent MRI lesions after first-line treatment.

BACKGROUND: This study aims at clarifying the impact of persistent residual lesions following first-line treatment for pediatric medulloblastoma. METHODS: Data on 84 pediatric patients with medulloblastoma and persistent residual lesions on centrally reviewed MRI at the end of first-line therapy were analyzed. RESULTS: Twenty patients (23.8%) had residual lesions in the tumor bed (R+/M0), 51 (60.7%) had distant lesions (R0/M+) and 13 (15.5%) had both (R+/M+). Overall response to first-line therapy was minor or partial (≥25% reduction, MR/PR) for 64 (76.2%) and stable disease (SD) for 20 patients (23.8%). Five-year post-primary-treatment progression-free (pptPFS) and overall survival (pptOS) were superior after MR/PR (pptPFS: 62.5±7.0%[MR/PR] vs. 35.9±12.8%[SD], p=0.03; pptOS: 79.7±5.9[MR/PR] vs. 55.5±13.9[SD], p=0.04). Further, R+/M+ was associated with a higher risk for progression (5-year pptPFS: 22.9±17.9%[R+,M+] vs. 72.4±12.0%[R+,M0]; p=0.03). Watch-and-wait was pursued in 58 patients, while n=26 received additional treatments (chemotherapy only, n=19; surgery only, n=2; combined, n=3; valproic acid, n=2), and their outcomes were not superior to watch-and-wait (5-year pptPFS: 58.5±7.7% vs. 51.6±10.7% p=0.71; 5-year pptOS: 76.3±6.9% vs. 69.8±9.7%, p=0.74). For the whole cohort, five-year pptPFS by molecular subgroup (58 cases) were WNT: 100%, SHH: 50.0±35.4%, Group-4, 52.5±10.5, Group-3 54.2±13.8%; (p=0.08). CONCLUSION: Overall response and extent of lesions can function as surrogate parameters to predict outcomes in pediatric MB patients with persistent lesions after first-line therapy. Especially in case of solitary persistent medulloblastoma MRI lesion, additional therapy was not beneficial. Therefore, treatment response, extent/kind of residual lesions and further diagnostic information needs consideration for indication of additional treatments for persisting lesions.

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.

Post-traumatic growth in parents of long-term childhood cancer survivors compared to the general population: A report from the Swiss childhood cancer survivor study-Parents.

OBJECTIVE: Post-traumatic growth (PTG) describes perceived positive changes following a traumatic event. We describe (i) PTG in parents of long-term childhood cancer survivors (CCS-parents) compared to parents of similar-aged children of the general population (comparison-parents), (ii) normative data for the Swiss population, and (iii) psychological, socio-economic, and event-related characteristics associated with PTG. METHODS: CCS-parents (aged ≤16 years at diagnosis, ≥20 years old at study, registered in the Childhood Cancer Registry Switzerland (ChCR), and the Swiss population responded to a paper-based survey, including the PTG-Inventory (total score 0-105). We carried out (i) t-tests, (ii) descriptive statistics, and (iii) multilevel regression models with survivor/household as the cluster variable. RESULTS: In total, 746 CCS-parents (41.7% fathers, response-rate = 42.3%) of 494 survivors (median time since diagnosis 24 (7-40) years), 411 comparison-parents (42.8% fathers, 312 households), and 1069 individuals of the Swiss population (40.7% male, response-rate = 20.1%) participated. Mean [M] total PTG was in CCS-parents M = 52.3 versus comparison-parents M = 50.4, p = 0.078; and in the Swiss population M = 44.5). CCS-parents showed higher 'relating-to-others' (18.4 vs. 17.3, p = 0.010), 'spiritual-change' (3.3 vs. 3.0, p = 0.038) and 'appreciation-of-life' (9.3 vs. 8.4, p = 0.027) than comparison-parents, but not in 'new-possibilities' and 'personal-strength'. Female gender, older age, higher post-traumatic stress, and higher resilience were positively associated with PTG. Individuals reporting events not typically classified as traumatic also reported growth. CONCLUSIONS: Our findings highlight that mothers and fathers can experience heightened growth many years after their child's illness. Being able to sensitively foreshadow the potential for new-possibilities and personal development may help support parents in developing a sense of hope.

Case report: Hepatotoxicity and nephrotoxicity induced by methotrexate in a paediatric patient, what is the role of precision medicine in 2023?

Methotrexate is an immunosuppressant and chemotherapeutic agent used in the treatment of a range of autoimmune disorders and cancers. Its main serious adverse effects, bone marrow suppression and gastrointestinal complications, arise from its antimetabolite effect. Nevertheless, hepatotoxicity and nephrotoxicity are two widely described adverse effects of methotrexate. Its hepatotoxicity has been studied mainly in the low-dose, chronic setting, where patients are at risk of fibrosis/cirrhosis. Studies of acute hepatoxicity of high dose methotrexate, such as during chemotherapy, are scarce. We present the case of a 14-year-old patient who received high-dose methotrexate and subsequently developed acute fulminant liver failure and acute kidney injury. Genotyping of MTHFR (Methylene tetrahydrofolate reductase gene), ABCB1 (codes for P-glycoprotein, intestinal transport and biliary excretion), ABCG2 (codes for BCRP, intestinal transporter and renal excretion) and SLCO1B1 (codes for OATP1B1, hepatic transporter) identified variants in all the genes analysed that predicted a reduced rate of methotrexate elimination and thus may have contributed to the clinical situation of the patient. Precision medicine involving pharmacogenomic testing could potentially avoid such adverse drug effects.

Pediatric Posterior Fossa ATRT: A Case Report, New Treatment Strategies and Perspectives.

Posterior fossa atypical teratoid rhabdoid tumor (ATRT) is a rare childhood tumor usually associated with a dismal prognosis. Although upfront surgical gross total resection (GTR) has classically been the first line of treatment, new multimodal treatments, including two-stage surgery, are showing promising results in terms of overall survival (OS) and complication rate. We present a case of a 9-month-old child treated with two-staged surgery and chemotherapy. When deemed risky, multimodal treatments, including staged surgeries, can be a safe alternative to reduce surgical mortality and morbidity. At 23 months old, the patient had normal global development and no major impact on quality of life. We, therefore, discuss the most recent advancements from a treatment perspective, including molecular targeting.

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 (ß = 4.1; 95% CI: 2.0-6.2), parents with one child (ß = 5.9; 95% CI: 2.0-9.7), currently experiencing disadvantages because of their child's former disease (ß = 7.3; 95% CI: 4.0-10.6), or with support needs (ß = 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.

[Precision medicine in the treatment of pediatric cancers]. / Médecine de précision dans le traitement des cancers pédiatriques.

Despite the progress in cure rates for pediatric cancers, several challenges remain, such as the management of diseases with poor prognosis. The efficacy of intensified chemotherapies is also accompanied by increased risks of severe acute and chronic toxicities. Thus, therapies specifically targeting tumor cells, or inhibiting oncogenic molecular aberrations, could provide more effective and less toxic treatments for pediatric cancers. Personalization of chemotherapies through pharmacogenetics and precision dosing could also improve the efficacy and toxicity of chemotherapies. In this review, we describe precision medicine strategies implemented or undergoing clinical evaluation in the treatment of pediatric cancers.

Malgré les progrès sur les taux de guérison des cancers pédiatriques, plusieurs défis restent à relever, comme la prise en charge des maladies à mauvais pronostic. L'efficacité des chimiothérapies intensives s'accompagne aussi de risques accrus de toxicités aiguës et chroniques graves. Ainsi, les thérapies ciblant spécifiquement les cellules tumorales, ou inhibant les aberrations moléculaires oncogéniques, pourraient offrir des traitements plus efficaces et moins toxiques pour les cancers pédiatriques. La personnalisation des chimiothérapies grâce à la pharmacogénétique et au dosage de précision pourrait également améliorer l'efficacité et la toxicité des chimiothérapies. Dans cet article de revue, nous décrivons les stratégies de médecine de précision implémentées ou en cours d'évaluation clinique dans le traitement des cancers pédiatriques.

Risk prediction in early childhood sonic hedgehog medulloblastoma treated with radiation-avoiding chemotherapy: Evidence for more than 2 subgroups.

BACKGROUND: The prognostic impact of clinical risk factors and DNA methylation patterns in sonic hedgehog (SHH)-activated early childhood desmoplastic/nodular medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN) were evaluated to better identify patients at risk for relapse. METHODS: One hundred and forty-four patients with DMB (n = 99) or MBEN (n = 45) aged <5 years and treated with radiation-sparing approaches, including intraventricular methotrexate in 132 patients were evaluated. RESULTS: Patients with DMB had less favorable 5-year progression-free survival than MBEN (5y-PFS, 71% [DMB] vs. 93% [MBEN]). Patients aged >3 years were associated with more unfavorable 5y-PFS (47% [>3 years] vs. 85% [<1 year] vs. 84% [1-3 years]). DNA methylation profiles available (n = 78) were reclassified according to the 2021 WHO classification into SHH-1 (n = 39), SHH-2 (n = 38), and SHH-3 (n = 1). Hierarchical clustering delineated 2 subgroups among SHH-2: SHH-2a (n = 19) and SHH-2b (n = 19). Patients with SHH-2b medulloblastoma were older, predominantly displayed DMB histology, and were more often located in the cerebellar hemispheres. Chromosome 9q losses were more frequent in SHH-2b, while few chromosomal alterations were observed in SHH-2a. SHH-2b medulloblastoma carried a significantly increased relapse risk (5y-PFS: 58% [SHH-2b] vs. 83% [SHH-1] vs. 95% [SHH-2a]). Subclassification of SHH-2 with key clinical and cytogenetic characteristics was confirmed using 2 independent cohorts (total n = 188). Gene mutation analysis revealed a correlation of SHH-2a with SMO mutations. CONCLUSIONS: These data suggest further heterogeneity within early childhood SHH-DMB/MBEN: SHH-2 splits into a very low-risk group SHH-2a enriched for MBEN histology and SMO mutations, and SHH-2b comprising older DMB patients with a higher risk of relapse.

How I treat recurrent pediatric high-grade glioma (pHGG): a Europe-wide survey study.

PURPOSE: As there is no standard of care treatment for recurrent/progressing pediatric high-grade gliomas (pHGG), we aimed to gain an overview of different treatment strategies. METHODS: In a web-based questionnaire, members of the SIOPE-BTG and the GPOH were surveyed on therapeutic options in four case scenarios (children/adolescents with recurrent/progressing HGG). RESULTS: 139 clinicians with experience in pediatric neuro-oncology from 22 European countries participated in the survey. Most respondents preferred further oncological treatment in three out of four cases and chose palliative care in one case with marked symptoms. Depending on the case, 8-92% would initiate a re-resection (preferably hemispheric pHGG), combined with molecular diagnostics. Throughout all case scenarios, 55-77% recommended (re-)irradiation, preferably local radiotherapy > 20 Gy. Most respondents would participate in clinical trials and use targeted therapy (79-99%), depending on molecular genetic findings (BRAF alterations: BRAF/MEK inhibitor, 64-88%; EGFR overexpression: anti-EGFR treatment, 46%; CDKN2A deletion: CDK inhibitor, 18%; SMARCB1 deletion: EZH2 inhibitor, 12%). 31-72% would administer chemotherapy (CCNU, 17%; PCV, 8%; temozolomide, 19%; oral etoposide/trofosfamide, 8%), and 20-69% proposed immunotherapy (checkpoint inhibitors, 30%; tumor vaccines, 16%). Depending on the individual case, respondents would also include bevacizumab (6-18%), HDAC inhibitors (4-15%), tumor-treating fields (1-26%), and intraventricular chemotherapy (4-24%). CONCLUSION: In each case, experts would combine conventional multimodal treatment concepts, including re-irradiation, with targeted therapy based on molecular genetic findings. International cooperative trials combining a (chemo-)therapy backbone with targeted therapy approaches for defined subgroups may help to gain valid clinical data and improve treatment in pediatric patients with recurrent/progressing HGG.

Pediatric oncologists' perspectives on the use of complementary medicine in pediatric cancer patients in Switzerland: A national survey-based cross-sectional study.

BACKGROUND: There is a widespread use of complementary therapies among pediatric cancer patients. Previous studies provided evidence that communication between pediatric oncologists (POs) and patients/families about the use of these therapies is often incomplete. Furthermore, nationwide studies on this topic are rare. AIMS: We assessed POs' perspectives on the use of complementary medicine (CM) in Switzerland, on the basis of an edited survey previously used in a nationwide study. METHODS AND RESULTS: A link to an online survey was sent by e-mail to each of the fifty-two eligible pediatric oncologists in all nine Swiss Pediatric Oncology Group (SPOG) centers. Eligible respondents were board-certified (Switzerland or abroad) POs currently working at a SPOG center. The survey was available for a total period of 2 months. We received 29 filled questionnaires (overall response rate: 56%). Most POs (59%) indicated that they ask more than 50% of their patients about CM use. Frequent reasons for not asking about the use of CM were i) forgetting to ask (55%), ii) lack of knowledge on the subject (31%), and iii) lack of time (24%). More than every second PO (55%) reported having a lack of knowledge on the subject. A majority of POs (66% to 76%) indicated interest in learning more about specific CM topics (cannabinoids, hypnosis and relaxation, music therapy, herbal medicine, acupuncture, meditation, and yoga). More information and specific training opportunities on the use of CM was deemed important by 76% to 97% of POs. CONCLUSION: POs working in Switzerland identify complementary therapies as an important subject. Swiss POs are willing to acquire more knowledge on CM. More training seems to be necessary in order to increase awareness about the topic, to enhance communication about complementary therapies and thus to improve patient care.

Neurological Symptom Improvement After Re-Irradiation in Patients With Diffuse Intrinsic Pontine Glioma: A Retrospective Analysis of the SIOP-E-HGG/DIPG Project.

Purpose: The aim of this study is to investigate the spectrum of neurological triad improvement in patients with diffuse intrinsic pontine glioma (DIPG) treated by re-irradiation (re-RT) at first progression. Methods: We carried out a re-analysis of the SIOP-E retrospective DIPG cohort by investigating the clinical benefits after re-RT with a focus on the neurological triad (cranial nerve deficits, ataxia, and long tract signs). Patients were categorized as "responding" or "non-responding" to re-RT. To assess the interdependence between patients' characteristics and clinical benefits, we used a chi-square or Fisher's exact test. Survival according to clinical response to re-RT was calculated by the Kaplan-Meier method. Results: As earlier reported, 77% (n = 24/31) of patients had any clinical benefit after re-RT. Among 25/31 well-documented patients, 44% (n = 11/25) had improvement in cranial nerve palsies, 40% (n = 10/25) had improvement in long-tract signs, and 44% (11/25) had improvement in cerebellar signs. Clinical benefits were observed in at least 1, 2, or 3 out of 3 symptoms of the DIPG triad, in 64%, 40%, and 24%, respectively. Patients irradiated with a dose ≥20 Gy versus <20 Gy may improve slightly better with regard to ataxia (67% versus 23%; p-value = 0.028). The survival from the start of re-RT to death was not different between responding and non-responding DIPG patients (p-value = 0.871). Conclusion: A median re-irradiation dose of 20 Gy provides a neurological benefit in two-thirds of patients with an improvement of at least one symptom of the triad. DIPG patients receiving ≥20 Gy appear to improve slightly better with regard to ataxia; however, we need more data to determine whether dose escalation up to 30 Gy provides additional benefits.

Pediatric high-grade gliomas and the WHO CNS Tumor Classification-Perspectives of pediatric neuro-oncologists and neuropathologists in light of recent updates.

Background: The WHO Classification of Tumors of the Central Nervous System has undergone major restructuring. Molecularly defined diagnostic criteria were introduced in 2016 (revised 4th edition) and expanded in 2021 (5th edition) to incorporate further essential diagnostic molecular parameters. We investigated potential differences between specialists in perception of these molecularly defined subtypes for pediatric high-grade gliomas (pedHGG). Methods: We designed a 22-question survey studying the impact of the revised 4th edition of the WHO classification on pedHGG. Data were collected and statistically analyzed to examine the spectrum of viewpoints and possible differences between neuro-oncologists and neuropathologists. Results: 465 participants from 53 countries were included; 187 pediatric neuro-oncologists (40%), 160 neuropathologists (34%), and 118 additional experts (26%). Neuro-oncologists reported issues with the introduction of molecularly defined tumor types, as well as the abolishment or renaming of established tumor entities, while neuropathologists did not to the same extent. Both groups indicated less relevant or insufficient diagnostic definitions were available in 2016. Reported issues were classified and assessed in the 2021 WHO classification and a substantial improvement was perceived. However, issues of high clinical relevance remain to be addressed, including the definition of clinical phenotypes for diffuse intrinsic pontine glioma and gliomatosis cerebri. Conclusions: Within the WHO classification of pediatric brain tumors, such as pedHGG, rapid changes in molecular characterization have been introduced. This study highlights the ongoing need for cross talk between pathologist and oncologist to advance the classification of pedHGG subtypes and ensure biological relevance and clinical impact.

Educational Attainment and Employment Outcome of Survivors of Pediatric CNS Tumors in Switzerland-A Report from the Swiss Childhood Cancer Survivor Study.

BACKGROUND: Childhood cancer survivors diagnosed with a central nervous system (CNS) tumor are at risk for educational and vocational challenges. This study compared educational attainment and employment outcome in survivors of CNS tumors to survivors of other malignancies. METHODS: The questionnaire-based Swiss Childhood Cancer Survivor Study (SCCSS) included cancer patients diagnosed between 1976 and 2010, aged ≤20 years, who survived ≥5 years after diagnosis. We classified participants aged ≥16 years into three groups: CNS tumor and non-CNS malignancy with and without CNS-directed treatment. We analyzed educational attainment, employment outcome and special schooling. Subgroup analyses included survivors aged ≥25 years. RESULTS: We analyzed 2154 survivors, including 329 (15%) CNS tumor survivors, 850 (40%) non-CNS tumor survivors with and 975 (45%) without CNS-directed treatment. Fewer CNS tumor survivors aged ≥25 years reached tertiary education (44%) compared to those without CNS-directed treatment (51%) but performed similar to survivors with CNS-directed treatment (42%). Among CNS tumor survivors, 36 (14%) received special schooling. Higher parental education was associated with higher levels in survivors. Employment outcome did not significantly differ between the three diagnostic groups. A higher proportion of CNS tumor survivors received disability pension or were unemployed. CONCLUSIONS: Our findings suggest that CNS tumor survivors need more time to achieve their highest educational level. This should influence clinical care of these survivors by offering vocational counseling.

Clinical and molecular characterization of isolated M1 disease in pediatric medulloblastoma: experience from the German HIT-MED studies.

PURPOSE: To evaluate the clinical impact of isolated spread of medulloblastoma cells into cerebrospinal fluid without additional macroscopic metastases (M1-only). METHODS: The HIT-MED database was searched for pediatric patients with M1-only medulloblastoma diagnosed from 2000 to 2019. Corresponding clinical and molecular data was evaluated. Treatment was stratified by age and changed over time for older patients. RESULTS: 70 patients with centrally reviewed M1-only disease were identified. Clinical data was available for all and molecular data for 45/70 cases. 91% were non-WNT/non-SHH medulloblastoma (Grp3/4). 5-year PFS for 52 patients ≥ 4 years was 59.4 (± 7.1) %, receiving either upfront craniospinal irradiation (CSI) or SKK-sandwich chemotherapy (CT). Outcomes did not differ between these strategies (5-year PFS: CSI 61.7 ± 9.9%, SKK-CT 56.7 ± 6.1%). For patients < 4 years (n = 18), 5-year PFS was 50.0 (± 13.2) %. M1-persistence occurred exclusively using postoperative CT and was a strong negative predictive factor (pPFS/OS < 0.01). Patients with additional clinical or molecular high-risk (HR) characteristics had worse outcomes (5-year PFS 42.7 ± 10.6% vs. 64.0 ± 7.0%, p = 0.03). In n = 22 patients ≥ 4 years with full molecular information and without additional HR characteristics, risk classification by molecular subtyping had an effect on 5-year PFS (HR 16.7 ± 15.2%, SR 77.8 ± 13.9%; p = 0.01). CONCLUSIONS: Our results confirm that M1-only is a high-risk condition, and further underline the importance of CSF staging. Specific risk stratification of affected patients needs attention in future discussions for trials and treatment recommendations. Future patients without contraindications may benefit from upfront CSI by sparing risks related to higher cumulative CT applied in sandwich regimen.

Refining M1 stage in medulloblastoma: criteria for cerebrospinal fluid cytology and implications for improved risk stratification from the HIT-2000 trial.

BACKGROUND: Medulloblastoma is the most common malignant paediatric brain tumour, and cerebrospinal fluid (CSF) dissemination (M1 stage) is a high-risk prognostic factor. Criteria for CSF evaluation and for differentiating M0 from M1 stage are not clearly defined, and the prognostic significance of M1 stage in this context is unknown. PATIENTS AND METHODS: CSF investigations from 405 patients with medulloblastoma of the prospective multicenter trial HIT-2000 (HIirnTumor-2000) were reviewed. Data from 213 patients aged ≥4 years were related to 5-year progression-free (5y-PFS) and overall survival. RESULTS: Patients with cytological tumour dissemination only (M1 stage only) aged ≥4 years (n = 18) and patients with radiologically detected metastases (M2/3, n = 85) showed a worse 5y-PFS than M0 patients (n = 110) without signs of metastatic disease (5y-PFS 61.1% and 59.6% vs 80.7%; p < 0.02 and p < 0.01, log rank). Patients with positive samples drawn early after surgery who turned negative within 14 days postoperatively (n = 9) and patients with atypical cells (n = 6) showed a 5y-PFS similar to M0 patients. No tumour cells were detected in samples containing <10 nucleated cells. Analysis of cytological criteria showed a better predictive value for tumour cell clusters than ≥2 individual tumour cells. CONCLUSION: Based on our results, we suggest that CSF medulloblastoma staging should be performed 14 days postoperatively by lumbar puncture, and specimens should contain at least 10 nucleated cells. Cytological tumour dissemination alone (M1 stage only) appears a high-risk prognostic factor associated with an outcome comparable to M2/M3 stage. Tumour cell clusters seem to have a greater impact on prognosis than single tumour cells. This should be validated further.

Cohort-based association study of germline genetic variants with acute and chronic health complications of childhood cancer and its treatment: Genetic Risks for Childhood Cancer Complications Switzerland (GECCOS) study protocol.

INTRODUCTION: Childhood cancer and its treatment may lead to various health complications. Related impairment in quality of life, excess in deaths and accumulated healthcare costs are relevant. Genetic variations are suggested to contribute to the wide inter-individual variability of complications but have been used only rarely to risk-stratify treatment and follow-up care. This study aims to identify germline genetic variants associated with acute and late complications of childhood cancer. METHODS AND ANALYSIS: The Genetic Risks for Childhood Cancer Complications Switzerland (GECCOS) study is a nationwide cohort study. Eligible are patients and survivors who were diagnosed with childhood cancers or Langerhans cell histiocytosis before age 21 years, were registered in the Swiss Childhood Cancer Registry (SCCR) since 1976 and have consented to the Paediatric Biobank for Research in Haematology and Oncology, Geneva, host of the national Germline DNA Biobank Switzerland for Childhood Cancer and Blood Disorders (BISKIDS).GECCOS uses demographic and clinical data from the SCCR and the associated Swiss Childhood Cancer Survivor Study. Clinical outcome data consists of organ function testing, health conditions diagnosed by physicians, second primary neoplasms and self-reported information from participants. Germline genetic samples and sequencing data are collected in BISKIDS. We will perform association analyses using primarily whole-exome or whole-genome sequencing to identify genetic variants associated with specified health conditions. We will use clustering and machine-learning techniques and assess multiple health conditions in different models. DISCUSSION: GECCOS will improve knowledge of germline genetic variants associated with childhood cancer-associated health conditions and help to further individualise cancer treatment and follow-up care, potentially resulting in improved efficacy and reduced side effects. ETHICS AND DISSEMINATION: The Geneva Cantonal Commission for Research Ethics has approved the GECCOS study.Research findings will be disseminated through national and international conferences, publications in peer-reviewed journals and in lay language online. TRIAL REGISTRATION NUMBER: NCT04702321.

Treatment of embryonal tumors with multilayered rosettes with carboplatin/etoposide induction and high-dose chemotherapy within the prospective P-HIT trial.

BACKGROUND: Embryonal tumors with multilayered rosettes (ETMR) are highly aggressive tumors occurring in early childhood. Published clinical data refer to retrospective, heterogeneously treated cohorts. Here, we describe the outcome of patients treated according to the prospective P-HIT trial and subsequent HIT2000-interim-registry. PATIENTS AND METHODS: Age-stratified treatment included carboplatin/etoposide induction, tandem high-dose chemotherapy ("CARBO/ETO + HDCT"), and response-stratified radiotherapy. Patients with centrally reviewed neuropathological and molecularly confirmed diagnosis of ETMR recruited within the P-HIT trial (2001-2011; n = 19), the HIT2000-interim-registry (2012-2014; n = 12), and earlier HIT trials (n = 4) were selected for analysis. RESULTS: Age-adjusted incidence rate was 1.35 per 1 million children (aged 1-4 years) in the years 2012-2014. Median age at diagnosis for 35 patients was 2.9 years. Metastases at diagnosis were detected in 9 patients. One patient died due to postoperative complications. For 30 patients with non-brainstem tumor location, 5-year progression-free survival (PFS) and overall survival (OS) were 35% and 47% after treatment with CARBO/ETO + HDCT (n = 17), compared to 0% and 8% with other treatments (n = 13, P[OS] = .011). All 4 patients with brainstem tumor died within 10 months after diagnosis. By multivariable analysis, supratentorial location: (HR [PFS]: 0.07 [95%CI: 0.01-0.38], P = .003), localized disease (M0): (HR [OS] M0, no residual tumor: 0.30 [95%CI: 0.009-1.09], P = .068; M0, residual tumor: 0.18 [95%CI: 0.04-0.76], P = .020), and CARBO/ETO + HDCT treatment (HR [OS]: 0.16 [95%CI: 0.05-054], P = .003) were identified as independent prognostic factors. Of 9 survivors, 6 were treated with radiotherapy (craniospinal 4; local 2). CONCLUSIONS: Our data indicate improved survival with intensified chemotherapy (CARBO/ETO + HDCT). However, despite intensive treatment, the outcome was poor. Thus, innovative therapies need to be evaluated urgently in an upfront setting.

Transitioning to molecular diagnostics in pediatric high-grade glioma: experiences with the 2016 WHO classification of CNS tumors.

BACKGROUND: Pediatric neuro-oncology was profoundly changed in the wake of the 2016 revision of the WHO Classification of Tumors of the Central Nervous System. Practitioners were challenged to quickly adapt to a system of tumor classification redefined by molecular diagnostics. METHODS: We designed a 22-question survey studying the impact of the revised WHO classification on pediatric high-grade glioma. The survey collected basic demographics, general attitudes, issues encountered, and opinions on pediatric subtypes. Participant answers were analyzed along socioeconomic lines utilizing the human development index (HDI) of the United Nations and membership in the group of seven (G7) world economic forum. RESULTS: Four hundred and sixty-five participants from 53 countries were included, 187 pediatric neurooncologists (40%), 160 neuropathologists (34%), and 118 other experts (26%). When asked about pediatric high-grade glioma entities, participants from very high development countries preferred treating a patient based on genetic findings. Participants from high and medium development countries indicated using traditional histology and tumor location as mainstays for therapeutic decisions. Non-G7 countries tended to regard the introduction of molecularly characterized tumor entities as a problem for daily routine due to lack of resources. CONCLUSIONS: Our findings demonstrate an overall greater reliance and favorability to molecular diagnostics among very high development countries. A disparity in resources and access to molecular diagnostics has left some centers unable to classify pediatric high-grade glioma per the WHO classification. The forthcoming edition should strain to abate disparities in molecular diagnostic availability and work toward universal adaptation.

The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets.

INFORM is a prospective, multinational registry gathering clinical and molecular data of relapsed, progressive, or high-risk pediatric patients with cancer. This report describes long-term follow-up of 519 patients in whom molecular alterations were evaluated according to a predefined seven-scale target prioritization algorithm. Mean turnaround time from sample receipt to report was 25.4 days. The highest target priority level was observed in 42 patients (8.1%). Of these, 20 patients received matched targeted treatment with a median progression-free survival of 204 days [95% confidence interval (CI), 99-not applicable], compared with 117 days (95% CI, 106-143; P = 0.011) in all other patients. The respective molecular targets were shown to be predictive for matched treatment response and not prognostic surrogates for improved outcome. Hereditary cancer predisposition syndromes were identified in 7.5% of patients, half of which were newly identified through the study. Integrated molecular analyses resulted in a change or refinement of diagnoses in 8.2% of cases. SIGNIFICANCE: The pediatric precision oncology INFORM registry prospectively tested a target prioritization algorithm in a real-world, multinational setting and identified subgroups of patients benefiting from matched targeted treatment with improved progression-free survival, refinement of diagnosis, and identification of hereditary cancer predisposition syndromes.See related commentary by Eggermont et al., p. 2677.This article is highlighted in the In This Issue feature, p. 2659.

Ketogenic diet treatment in diffuse intrinsic pontine glioma in children: Retrospective analysis of feasibility, safety, and survival data.

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is one of the most devastating diseases among children with cancer, thus novel strategies are urgently needed. AIMS: We retrospectively evaluated DIPG patients exposed to the carbohydrate restricted ketogenic diet (KD) with regard of feasibility, safety, and overall survival (OS). METHODS AND RESULTS: Searches of MEDLINE and Embase identified five hits meeting the search criteria (diagnosis of DIPG and exposure to KD). One additional case was identified by contact with experts. Individual patient data were extracted from publications or obtained from investigators. The inclusion criteria for analysis of the data were defined as DIPG patients who were exposed to the KD for ≥3 months. Feasibility, as described in the literature, was the number of patients able to follow the KD for 3 months out of all DIPG patients identified. OS was estimated by the Kaplan-Meier method. Five DIPG patients (males, n = 3; median age 4.4 years; range, 2.5-15 years) meeting the inclusion criteria were identified. Analysis of the available data suggested that the KD is generally relatively well tolerated. Only mild gastro-intestinal complaints, one borderline hypoglycemia (2.4 mmol/L) and one hyperketosis (max 7.2 mmol/L) were observed. Five out of six DIPG patients identified adhered for ≥3 months (median KD duration, 6.5 months; range, 0.25-2 years) to the diet. The median OS was 18.7 months. CONCLUSION: Our study provides evidence that it may be feasible for pediatric DIPG patients to adhere for at least 3 months to KD. In particular cases, diet modifications were done. The clinical outcome and OS appear not to be impacted in a negative way. KD might be proposed as adjuvant therapy when large prospective studies have shown feasibility and safety. Future studies might ideally assess the impact of KD on clinical outcome, quality of life, and efficacy.