Natural history of a medulloblastoma: 30months of wait and see in a child with a cerebellar incidentaloma

Introduction: With the increasing use of neuroimaging studies, the discovery of incidental neoplastic lesions is becoming more frequent. However, standard procedures are lacking, and little is known about their optimal management. Case Report: We here present the case of a boy with a cerebellar mass incidentally discovered on a CT scan performed after head trauma. In another scan performed after another incident of head trauma 14months earlier, the lesion could be seen after retrospective examination. In view of the asymptomatic clinical and stable radiological status and the presumed diagnosis of a low-grade glioma, a watch-and-wait strategy was elected. After clinical and radiological progression was observed, the tumour was resected, 2½ years after the initial imaging study. Histological evaluation revealed a WNT pathway-activated classical medulloblastoma. Discussion: To our knowledge, this is the first description of such a long natural history and pre-symptomatic period of a medulloblastoma. The long period of stability followed by a period of accelerated tumour growth is compatible with increasing biological aggressiveness, possibly related to the stepwise accumulation of genetic change

Posterior hypothalamus-sparing surgery improves outcome after childhood craniopharyngioma

Objective: Quality of life (QoL) is frequently impaired in childhood-onset craniopharyngioma (CP) by hypothalamic syndrome. The debate, whether pretreatment hypothalamic involvement (HI) has apriori prognostic impact or surgical hypothalamic lesions (HL) determine outcome, is controversial. Design: Survival and outcome of CPs recruited between 2007 and 2014 in KRANIOPHARYNGEOM 2007 were analyzed with regard to reference-confirmed presurgical HI and surgical HL. Methods: Radiological findings, BMI and QoL were assessed at diagnosis and during follow-up. QoL was assessed using Pediatric Quality of Life (PEDQOL) questionnaire. Results: One hundred sixty-nine CPs were included presenting with no HI (n = 11), anterior (n = 49) and anterior + posterior (a + p) HI (n = 109) prior to surgery. The latter 109 were analyzed for postoperative HL (no lesion: n = 23, anterior HL: n = 29, a + pHL: n = 57). Progression-free survival (PFS) was higher after complete resection. The highest PFS was observed in CP with a + pHL, especially when compared between non-irradiated subgroups (P = 0.006). Overall survival (OS) rates were 1.0 in all subgroups. CP with a + pHL developed higher BMI (P ≤ 0.001) during follow-up compared between subgroups. 55/109 pts with a + pHI completed PEDQOL at diagnosis (48/109 at 3 years follow-up). QoL was worse for a + pHL patients in terms of physical, social and emotional functionality when compared with the anterior HL and no HL subgroup. BMI development and QoL during follow-up were similar for patients with anterior HL and without HL. Conclusions: Posterior hypothalamus-sparing surgical strategies are associated with higher QoL, decreased development of obesity and lower PFS in CP

Outcome of 11 children with ependymoblastoma treated within the prospective HIT-trials between 1991 and 2006

Ependymoblastoma is a rare malignant brain tumor of early childhood. Data on clinical behavior and optimal treatment strategies are scarce. We report on 11 consecutively treated children with centrally confirmed diagnosis of CNS ependymoblastoma, registered between February 1994 and October 2006 to the prospective GPOH-HIT multicenter brain tumor trials, and treated by multimodal regimens. Median age at diagnosis was 3.5years (range, 1.8-5.6years), and the median follow-up of survivors was 5.9years (range, 2.2-12.7years). Initial stage was M0 in 9, and M0/1 (no cerebrospinal fluid examination done) in 2 patients. Gross-total tumor resection was achieved in 7 patients, incomplete resection in 4 patients. Further primary therapy included chemotherapy in all patients, craniospinal radiotherapy in 5 patients and high-dose chemotherapy in 2 patients. Tumor response to chemotherapy was observed in 1 of 4 evaluable patients. Tumor progression occurred in 7 patients after a median time of 5.0months (range, 2.5-19.2months). Five-year progression-free survival was 36.4% (±14.5%), 5-year overall survival 30.3% (±15.9%). Of 4 survivors, 3 had gross-total tumor resection, and all were treated by either craniospinal radiotherapy and/or high-dose chemotherapy with autologous blood stem cell rescue. Prognosis of children with ependymoblastoma is poor, but sustained remissions have been achieved after multimodal treatment. Considerable diagnostic discrepancies between local and central pathologists underscore the importance of central review. Further studies are needed to improve survival of children with this rare malignant central nervous system tumo

Relapse patterns and outcome after relapse in standard risk medulloblastoma: a report from the HIT-SIOP-PNET4 study

The HIT-SIOP-PNET4 randomised trial for standard risk medulloblastoma (MB) (2001-2006) included 338 patients and compared hyperfractionated and conventional radiotherapy. We here report the long-term outcome after a median follow up of 7.8 years, including detailed information on relapse and the treatment of relapse. Data were extracted from the HIT Group Relapsed MB database and by way of a specific case report form. The event-free and overall (OS) survival at 10 years were 76 +/- 2 % and 78 +/- 2 % respectively with no significant difference between the treatment arms. Seventy-two relapses and three second malignant neoplasms were reported. Thirteen relapses (18 %) were isolated local relapses in the posterior fossa (PF) and 59 (82 %) were craniospinal, metastatic relapses (isolated or multiple) with or without concurrent PF disease. Isolated PF relapse vs all other relapses occurred at mean/median of 38/35 and 28/26 months respectively (p = 0.24). Late relapse, i.e. > 5 years from diagnosis, occurred in six patients (8 %). Relapse treatment consisted of combinations of surgery (25 %), focal radiotherapy (RT 22 %), high dose chemotherapy with stem cell rescue (HDSCR 21 %) and conventional chemotherapy (90 %). OS at 5 years after relapse was 6.0 +/- 4 %. In multivariate analysis; isolated relapse in PF, and surgery were significantly associated with prolonged survival whereas RT and HDSCR were not. Survival after relapse was not related to biological factors and was very poor despite several patients receiving intensive treatments. Exploration of new drugs is warranted, preferably based on tumour biology from biopsy of the relapsed tumour.Funding for this work was provided by: The Swedish Children's Cancer Foundation, The German Children's Cancer Foundation, Cancer Research UK, The French Ministry of Health, The French National Cancer Institute (INCa) and Associazione Bianca Garavaglia onlus (B. Arsizio, Milano)

Single-cell transcriptomics identifies potential cells of origin of MYC rhabdoid tumors

Rhabdoid tumors (RT) are rare and highly aggressive pediatric neoplasms. Their epigenetically-driven intertumoral heterogeneity is well described; however, the cellular origin of RT remains an enigma. Here, we establish and characterize different genetically engineered mouse models driven under the control of distinct promoters and being active in early progenitor cell types with diverse embryonic onsets. From all models only Sox2-positive progenitor cells give rise to murine RT. Using single-cell analyses, we identify distinct cells of origin for the SHH and MYC subgroups of RT, rooting in early stages of embryogenesis. Intra- and extracranial MYC tumors harbor common genetic programs and potentially originate from fetal primordial germ cells (PGCs). Using PGC specific Smarcb1 knockout mouse models we validate that MYC RT originate from these progenitor cells. We uncover an epigenetic imbalance in MYC tumors compared to PGCs being sustained by epigenetically-driven subpopulations. Importantly, treatments with the DNA demethylating agent decitabine successfully impair tumor growth in vitro and in vivo. In summary, our work sheds light on the origin of RT and supports the clinical relevance of DNA methyltransferase inhibitors against this disease

Local and systemic therapy of recurrent medulloblastomas in children and adolescents: results of the P-HIT-REZ 2005 study

SIMPLE SUMMARY: A medulloblastoma recurrence is usually associated with an unfavorable prognosis. The German P-HIT-REZ 2005 Study gathered data from patients with relapsed medulloblastomas treated in different, non-randomized therapy arms dependent on preconditions of the patients (previous treatment, comorbidities, relapse pattern), the decision of treating physicians, and the patients’/parents’ choice. A total of 93 evaluable patients with refractory or relapsed medulloblastoma were enrolled. The main aim of this study was to analyze the impact of patient and disease characteristics as well as local and systemic therapies on post-relapse progression-free (PFS) and overall survival (OS). In multivariate analysis, a short time until the first recurrence (<18 months) was the strongest predictor for a worse PFS and OS, which was mainly associated with molecular subgroup 3. Metastatic disease, at relapse, only had a significant impact on OS. Re-biopsy, at relapse, is highly recommended to investigate the histopathological and molecular genetic tumor characteristics and to exclude a secondary malignancy. ABSTRACT: Recurrent medulloblastomas are associated with survival rates <10%. Adequate multimodal therapy is being discussed as having a major impact on survival. In this study, 93 patients with recurrent medulloblastoma treated in the German P-HIT-REZ 2005 Study were analyzed for survival (PFS, OS) dependent on patient, disease, and treatment characteristics. The median age at the first recurrence was 10.1 years (IQR: 6.9–16.1). Median PFS and OS, at first recurrence, were 7.9 months (CI: 5.7–10.0) and 18.5 months (CI: 13.6–23.5), respectively. Early relapses/progressions (<18 months, n = 30/93) found mainly in molecular subgroup 3 were associated with markedly worse median PFS (HR: 2.34) and OS (HR: 3.26) in regression analyses. A significant survival advantage was found for the use of volume-reducing surgery as well as radiotherapy. Intravenous chemotherapy with carboplatin and etoposide (ivCHT, n = 28/93) showed improved PFS and OS data and the best objective response rate (ORR) was 66.7% compared to oral temozolomide (oCHT, n = 47/93) which was 34.8%. Intraventricular (n = 43) as well as high-dose chemotherapy (n = 17) at first relapse was not related to a significant survival benefit. Although the results are limited due to a non-randomized study design, they may serve as a basis for future treatment decisions in order to improve the patients’ survival

MRI and Molecular Characterization of Pediatric High-Grade Midline Thalamic Gliomas: The HERBY Phase II Trial

Background: Diffuse midline gliomas (DMG) are characterized by a high incidence of H3 K27 mutations and poorer outcome. The HERBY trial has provided one of the largest cohorts of pediatric DMGs with available radiologic, histologic-genotypic, and survival data. / Purpose: To define MRI and molecular characteristics of DMG. / Materials and Methods: This study is a secondary analysis of a prospective trial (HERBY; ClinicalTrials.gov identifier, NCT01390948) undertaken between October 2011 and February 2016. Among 121 HERBY participants, 50 had midline nonpontine-based tumors. Midline high-grade gliomas were reclassified into DMG H3 K27 mutant, H3 wild type with enhancer of zest homologs inhibitory protein overexpression, epidermal growth factor receptormutant, or not otherwise stated. The epicenter of each tumor and other radiologic characteristics were ascertained from MRI and correlated with the new subtype classification, histopathologic characteristics, surgical extent, and outcome parameters. Kaplan-Meier curves and log-rank tests were applied to determine and describe survival differences between groups. / Results: There were 42 participants (mean age, 12 years ± 4 [SD]; 23 girls) with radiologically evaluable thalamic-based DMG. Eighteen had partial thalamic involvement (12 thalamopulvinar, six anteromedial), 10 involved a whole thalamus, nine had unithalamic tumors with diffuse contiguous extension, and five had bithalamic tumors (two symmetric, three partial). Twenty-eight participants had DMG H3 K27 mutant tumors; there were no differences in outcome compared with other DMGs (n = 4). Participants who underwent major debulking or total or near-total resection had longer overall survival (OS): 18.5 months vs 11.4 months (P = .02). Enrolled participants who developed leptomeningeal metastatic dissemination before starting treatment had worse outcomes (event-free survival, 2.9 months vs 8.0 months [P = .02]; OS, 11.4 months vs 18.5 months [P = .004]). / Conclusion: Thalamic involvement of diffuse midline gliomas ranged from localized partial thalamic to holo- or bithalamic with diffuse contiguous spread and had poor outcomes, irrespective of H3 K27 subtype alterations. Leptomeningeal dissemination and less than 50% surgical resection were adverse risk factors for survival. / Clinical trial registration no. NCT0139094