Martin Mynarek

Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma.

Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate ‘enhancer hijacking’ as an efficient mechanism driving oncogene activation in a childhood cancer.

Recent developments and current concepts in medulloblastoma

Medulloblastoma is the most common malignant brain tumor of childhood. While prognosis has significantly improved in the last decades with multimodal therapy including surgery, radiotherapy, and chemotherapy, one third of patients still succumb to their disease. Further research is needed to find more efficient treatment strategies for prognostically unfavorable patient groups and to minimize long-term sequelae of tumor treatment. This review gives a summary of the current state of treatment concepts including an outlook on the near future. We describe recent advances in the understanding of molecular mechanisms, their potential impact on risk stratification in upcoming clinical trials, and perspectives for the clinical implementation of targeted therapies.

Intraventricular methotrexate as part of primary therapy for children with infant and/or metastatic medulloblastoma: Feasibility, acute toxicity and evidence for efficacy

BACKGROUND To assess feasibility, acute toxicity, and efficacy of intraventricular methotrexate administered as part of the primary therapy in medulloblastoma. METHODS From 2001 to 2007, 240 patients < 22 years from 61 treatment centres were registered. Patients received 2-3 cycles of intraventricular methotrexate with systemic chemotherapy in three different treatment arms of the prospective multicentre trial HIT2000 (150 children > 4 years with metastatic, 59 < 4 years with non-metastatic, 31 < 4 years with metastatic medulloblastoma). RESULTS 211 patients received an intraventricular access device with a subcutaneous reservoir for the application of chemotherapy. Reservoir-associated complications were documented in 57 (27%) patients, mostly due to infection (n = 32) and reservoir malfunction (n = 19), requiring removal in 39 (18%) patients. Acute neurotoxicity likely associated with intraventricular MTX was observed in 9/202 documented patients. Toxicity was usually mild, apart from one therapy-associated death due to toxic oedema followed by seizures. Of 519 treatment cycles including intraventricular methotrexate, 226 (43%) were reduced or omitted, most frequently due to the absence of an intraventricular device. Survival rates were higher in patients receiving ⩾ 75% of the scheduled intraventricular methotrexate dose compared to those receiving < 75% in both univariate and multivariate models (event-free survival (EFS), 61.5 versus 46.2%, p = 0.004; OS, 75.5% versus 60.4%, p = 0.015; hazard ratio: EFS 1.723, p = 0.016; OS 1.648, p = 0.051). CONCLUSION Intraventricular methotrexate therapy was feasible and mostly well tolerated. Infections were the most frequent complication. A higher cumulative dose of intraventricular methotrexate was associated with better survival. Further evaluation of efficacy and late effects is warranted.

Postponed Is Not Canceled: Role of Craniospinal Radiation Therapy in the Management of Recurrent Infant Medulloblastoma—An Experience From the HIT-REZ 1997 & 2005 Studies

PURPOSE To evaluate the efficacy of craniospinal irradiation (CSI) in the management of recurrent infant medulloblastoma after surgery and chemotherapy alone. METHODS AND MATERIALS Seventeen pediatric medulloblastoma patients registered in the HIT-REZ 1997 and 2005 studies underwent CSI as salvage treatment at first recurrence. All patients had achieved complete remission after first-line treatment consisting of surgery and chemotherapy. Eleven patients showed metastatic disease at relapse. Five patients underwent surgery prior to radiation therapy, which resulted in complete resection in 1 case. In 1 patient, complete resection of the residual tumor was performed after CSI. Eleven patients received chemotherapy prior, 6 patients during and 8 patients after CSI. All patients received CSI with a median total dose of 35.2 Gy, and all but 1 received a boost to the posterior fossa (median total dose, 55.0 Gy). Metastases were boosted with an individual radiation dose, depending on their location and extent. RESULTS During a median follow-up time of 6.2 years since recurrence, 11 patients showed progressive disease and died. Median progression-free (overall) survival was 2.9 ± 1.1 (3.8 ± 0.8) years. Progression-free survival (PFS) rates at 1, 3, and 5 years were 88% ± 8%, 46% ± 12%, and 40% ± 12%, respectively. Overall survival (OS) rates at 1, 3, and 5 years were 94% ± 6%, 58% ± 12%, and 39% ± 12%, respectively. For 11 patients with classic medulloblastoma, 3-year (and 5-year) PFS and OS were 62% ± 15% and 72% ± 14% (52% ± 16% and 51% ± 16%), respectively. On univariate analysis, metastatic disease was not associated with poorer progression-free and overall survival. CONCLUSIONS Our results suggest that salvage treatment of relapsed medulloblastomas consisting of CSI and chemotherapy offers a second chance for cure, even for patients with classic histological findings. Metastatic disease at relapse did not have an impact on survival. However, this may be explained by the small number of patients.

Evaluation of age-dependent treatment strategies for children and young adults with pineoblastoma: analysis of pooled European Society for Paediatric Oncology (SIOP-E) and US Head Start data

Background Pineoblastoma is a rare pineal region brain tumor. Treatment strategies have reflected those for other malignant embryonal brain tumors. Patients and Methods Original prospective treatment and outcome data from international trial groups were pooled. Cox regression models were developed considering treatment elements as time-dependent covariates. Results Data on 135 patients with pineoblastoma aged 0.01-20.7 (median 4.9) years were analyzed. Median observation time was 7.3 years. Favorable prognostic factors were age ≥4 years (hazard ratio [HR] for progression-free survival [PFS] 0.270, P < .001) and administration of radiotherapy (HR for PFS 0.282, P < .001). Metastatic disease (HR for PFS 2.015, P = .006), but not postoperative residual tumor, was associated with unfavorable prognosis. In 57 patients <4 years old, 5-year PFS/overall survival (OS) were 11 ± 4%/12 ± 4%. Two patients survived after chemotherapy only, while 3 of 16 treated with craniospinal irradiation (CSI) with boost, and 3 of 5 treated with high-dose chemotherapy (HDCT) and local radiotherapy survived. In 78 patients aged ≥4 years, PFS/OS were 72 ± 7%/73 ± 7% for patients without metastases, and 50 ± 10%/55 ± 10% with metastases. Seventy-three patients received radiotherapy (48 conventionally fractionated CSI, median dose 35.0 [18.0-45.0] Gy, 19 hyperfractionated CSI, 6 local radiotherapy), with (n = 68) or without (n = 6) chemotherapy. The treatment sequence had no impact; application of HDCT had weak impact on survival in older patients. Conclusion Survival is poor in young children treated without radiotherapy. In these patients, combination of HDCT and local radiotherapy may warrant further evaluation in the absence of more specific or targeted treatments. CSI combined with chemotherapy is effective for older non-metastatic patients.

Refining medulloblastoma subgroups

Medulloblastoma is currently deemed to be composed of four molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGrp3), and group 4 (MBGrp4). Reports from retrospective data collection have shown distinct clinical and biological characteristics and outcomes for the four subgroups, with the MBWNT subgroup having an excellent prognosis and patients in the MBGrp3 subgroup having very poor prognosis across several studies. However, substantial heterogeneity in clinical and molecular features still exists in these subgroups. On the basis of preclinical data, further stratification of medulloblastoma into distinct molecular subgroups beyond the four that are generally accepted have been attempted. However, most of the molecular subgrouping of medulloblastoma has been generated from large cohorts without taking clinical and therapeutic information of the treated patients into account. In The Lancet Oncology, Edward Schwalbe and colleagues report their retrospective analysis of 428 paediatric patients with molecularly defined medulloblastoma with more comprehensive clinical annotations, which aimed to identify a deeper molecular substructure of the four subgroups with further clinical relevance. The limitations of this study, mainly its retrospective nature and the restriction of the survival analyses to patients aged between 3–16 years, have been carefully addressed by the authors. The strength of the study is the high number of patients analysed with integration of clinical information into their substratification algorithm. Schwalbe and colleagues identified seven robust and primarily molecularly defined subgroups, characterised by distinct clinical and biological features. Their findings suggest that the MBSHH subgroup could be robustly divided into an infant group (younger than 3 years) and a group of older children (aged 3 years and older). A further subdivision has previously been suggested, but could not be confirmed in a validation cohort to date. The reported age cutoff between 4 and 5 years provides a molecular rationale for the decision making on primary chemotherapy versus primary radiotherapy in paediatric patients with MBSHH medulloblastoma. Moreover, in future trials, the combination of age and other parameters, rather than a sharp age cutoff, might finally be used for therapy stratification within the MBSHH subgroup. This study corroborates the assumption that MBGrp3 and MBGrp4 medulloblastomas share a somewhat similar biological profile. The authors also show a split in both subgroups (high-risk and low-risk groups), which was associated with significantly different outcomes. Although MBGrp3 and MBGrp4 have both been reported to have poor-to-intermediate risk profiles, the authors propose chromosome 13 loss as a predictor for favourable risk and MYC amplification as a predictor of very high risk. A hypothesis on the molecular mechanism leading to a better outcome in the case of chromosome 13 loss would be an interesting subject for further molecular studies. Taken together, these new findings suggest the potential for further individualisation of therapy for patients with MBGrp3 and MBGrp4 medulloblastoma in future studies. Rather than reporting on single prognostic biological parameters, such as MYC amplification or chromosome 11 loss, the authors present distinctive new subgroups based on methylation profiling, which reveal high correlation with individual parameters for which prognostic impact has been described previously. This integrative approach could help to simplify therapy stratification algorithms for clinical trials in an era in which knowledge about medulloblastoma biology can become too complex for viable clinical decision making. From a clinical perspective, the number of subgroups should ideally remain within a frame allowing their clinical application—eg, for stratification in the context of future clinical trials. The risk stratification proposal by Schwalbe and colleagues is compatible with this aim. However, the predictive value of the reported findings for upfront risk assessment remains to be proven in a clinical setting. In summary, the reported refinements resulting in seven subgroups add to existing concepts of risk stratification and to the understanding of the underlying biology of medulloblastoma. While the very first prospective molecularly informed medulloblastoma trials are still ongoing (NCT01878617, NCT02066220), the findings by Schwalbe and colleagues represent a substantial refinement of the four-subgroup consensus achieved in 2012. The new insights obtained from molecular information combined with clinical and pathological findings could serve to improve risk-adapted treatment strategies towards individualised and thereby better therapies in future. Li vi ng A rt E nt er pr ise s/ Sc ie nc e Ph ot o Li br ar y

Reply to letter that comments on 'Intraventricular methotrexate as part of primary therapy for children with infant and/or metastatic medulloblastoma: Feasibility, acute toxicity and evidence for efficacy'.

We would like to thank the readers for their appreciated comment on our recent article. The primary aim of our retrospective analysis was to assess the feasibility and toxicity e potentially related with intraventricular methotrexate (i.vc. MTX). In addition, we performed several explorative analyses in order to test whether the i.vc. MTX may have an effect on survival. The additional impact of intravenous methotrexate, in terms of doses, leucovorin rescue, etc., was not assessable in this analysis due to the nature of our data retrieved from different trials. As stated in the Discussion, we agree that there might have been a positive selection of those patients who received >75% of scheduled i.vc. MTX and that there are other factors which had an influence on our results, e.g. tumour size, extend of resection, treatment centre, molecular findings, and treatment components (including high-dose methotrexate). However, to reduce the bias of positive selection concerning systemic chemotherapy, the amount of administered i.vc. MTX