Recent integrative genomic approaches have defined molecular subgroups of medulloblastoma that are genetically and clinically distinct. Sonic hedgehog (Shh) medulloblastomas account for one-third of all cases and comprise the majority of infant and adult medulloblastomas. To discern molecular heterogeneity among Shh-medulloblastomas, we analyzed transcriptional profiles from four independent Shh-medulloblastoma expression datasets (n = 66). Unsupervised clustering analyses demonstrated a clear distinction between infant and adult Shh-medulloblastomas, which was reliably replicated across datasets. Comparison of transcriptomes from infant and adult Shh-medulloblastomas revealed deregulation of multiple gene families, including genes implicated in cellular development, synaptogenesis, and extracellular matrix maintenance. Furthermore, metastatic dissemination is a marker of poor prognosis in adult, but not in pediatric Shh-medulloblastomas. Children with desmoplastic Shh-medulloblastomas have a better prognosis than those with Shh-medulloblastomas and classic histology. Desmoplasia is not prognostic for adult Shh-medulloblastoma. Cytogenetic analysis of a large, non-overlapping cohort of Shh-medulloblastomas (n = 151) revealed significant over-representation of chromosome 10q deletion (P < 0.001) and MYCN amplification (P < 0.05) in pediatric Shh cases compared with adults. Adult Shh-medulloblastomas harboring chromosome 10q deletion, 2 gain, 17p deletion, 17q gain, and/or GLI2 amplification have a much worse prognosis as compared to pediatric cases exhibiting the same aberrations. Collectively, our data demonstrate that pediatric and adult Shh-medulloblastomas are clinically, transcriptionally, genetically, and prognostically distinct.

Initial progression of TKI-treated cancers occurred predominantly in original disease sites. Consolidation SBRT was judged feasible in a subset of patients following maximum TKI response and may have prevented oligoprogression in most of these. In addition, we hypothesize that consolidation SBRT for residual disease could delay subsequent metastatic reseeding.

Our data support the evolving literature which suggests that GTR alone provides suboptimal disease control in MPE. In our patients, RT resulted in control of residual, metastatic and/or recurrent disease. Routine adjuvant RT may improve outcomes in pediatric MPE.

Genotype-based selection of patients for targeted therapies has had a substantial impact on the treatment of non-small cell lung cancers (NSCLCs). Tyrosine kinase inhibitors (TKIs) directed at cancers driven by oncogenes, such as epidermal growth factor receptor mutations or anaplastic lymphoma kinase rearrangements, often achieve dramatic responses and result in prolonged survival compared with chemotherapy. However, TKI resistance invariably develops. Disease progression can be limited to only one or a few sites and might not be symptomatic, raising the important question of whether this type of oligoprogression warrants a change in systemic therapy or consideration of local treatment. Recent clinical observations suggest a growing role for stereotactic body radiation therapy (SBRT) in the treatment of oligoprogressive and perhaps even oligopersistent disease (primary and/or metastases) in oncogene-driven NSCLC. SBRTmight allow patients to continue with existing TKI treatments longer and delay the need to switch to other systemic options. We review the current data with regard to the use of SBRT for metastatic NSCLC and particularly oncogene-driven disease. Although there is great promise in the marriage of targeted therapies with SBRT, prospective data are urgently needed. In the meantime, such strategies are being used in carefully selected patients, with risk-adapted SBRT dose-fractionation regimens used to optimize the therapeutic index. The Oncologist 2016; 21:964-973 Implications for Practice: Stereotactic body radiation therapy (SBRT) or SBRT-like treatments are increasingly being used for oligoprogression in patients with oncogene-driven non-small cell lung cancer.This approach allows patients to extend the duration of tyrosine kinase inhibitor therapy and has the potential to prolong survival times. Careful patient selection and risk-adapted radiation dosing is of critical importance to minimize toxicity and preserve patient quality of life.

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Medulloblastoma (MB) represents approximately 4% of adult brain tumours, and as such is a poorly studied disease. Although many adult MB are treated using paediatric MB protocols, the reported outcomes are inferior to those observed in children. It remains unclear whether biologic differences underlie these clinical observations. We investigated the molecular characteristics of 31 adult MB. Twelve and 19 adult MB were respectively examined using Affymetrix-HG-U133-plus-2.0-genechips and immunohistochemical analyses. 26/31 (84%) of adult MB examined by gene expression and/or immunohistochemical analysis showed evidence of sonic hedgehog (SHH) pathway activation. A comparison of adult and paediatric MB showed that most adult tumours cluster within the SHH-active subgroup of paediatric MB. The preponderance of SHH activity in adult MB tumours was also shown by positive SFRP1 immunostaining in 16/19 adult paraffin-embedded adult MB tumour blocks. A smaller proportion of adult tumours exhibited evidence of WNT pathway activation, as confirmed by nuclear β-catenin staining (9.7%; 3/31). Notably, we found PTCH1 gene mutation in 4/8 samples tested. Similar to children, adult MB has abnormalities in developmental signalling pathways including SHH and WNT. Importantly, we found a preponderance of SHH pathway activation amongst MB tumours in adults. This SHH signature does not appear to correlate with a long-term favourable outcome. Differences in molecular profiles exist between adult and paediatric SHH-driven MB and further investigations are needed to better characterize age-related molecular profiles in this subgroup.

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