DUSP6 regulates radiosensitivity in glioblastoma by modulating the recruitment of phosphorylated DNAPKcs at DNA double-strand breaks.

Glioblastoma (GBM) has poor median survival due to its resistance to chemoradiotherapy, which results in tumor recurrence. Recurrent GBMs currently lack effective treatments. DUSP6 is known to be pro-tumorigenic and is upregulated in GBM. We show that DUSP6 expression is significantly higher in recurrent GBM patient biopsies compared to expression levels in primary GBM biopsies. Importantly, although it has been reported to be a cytoplasmic protein, we found nuclear localization of DUSP6 in primary and recurrent patient samples and in parent and relapse populations of GBM cell lines generated from an in vitro radiation survival model. DUSP6 inhibition using BCI resulted in decreased proliferation and clonogenic survival of parent and relapse cells. Pharmacological or genetic inhibition of DUSP6 catalytic activity radiosensitized primary and, importantly, relapse GBM cells by inhibiting the recruitment of phosphorylated DNAPKcs (also known as PRKDC), subsequently downregulating the recruitment of phosphorylated histone H2AX (γH2AX) and 53BP1 (also known as TP53BP1). This resulted in decreased cell survival and prolonged growth arrest upon irradiation in vitro and significantly increased the progression-free survival in orthotopic mouse models of GBM. Our study highlights a non-canonical function of DUSP6, emphasizing the potential application of DUSP6 inhibitors in the treatment of recurrent GBM.

Outcomes of salvage re-irradiation in recurrent medulloblastoma correlate with age at initial diagnosis, primary risk-stratification, and molecular subgrouping.

PURPOSE: To report outcomes of salvage re-irradiation (re-RT) in recurrent/progressive medulloblastoma (MB). METHODS: Medical records of patients treated with curative-intent re-RT as multi-modality management for recurrent/progressive MB between 2008 and 2018 were analyzed retrospectively. RESULTS: A total of 28 patients (median age 18 years at index diagnosis) were included. Molecular subgrouping was done using real-time reverse transcriptase polymerase chain reaction (RT-PCR) based on the differential expression of select set of 12 protein coding genes and 9 microRNAs. Fifteen of 17 (88%) patients with sonic hedgehog (SHH)-MB developed isolated local recurrence within the index tumor-bed, while 5 of 7 (72%) patients with Group 4 MB developed localized relapse outside the posterior fossa. Diffuse neuraxial dissemination was seen in 2 patients with SHH-MB, and one each of Group 4 and wingless (WNT)-MB. Molecular subgrouping was not known in 3 patients. The dose and volume of re-RT was based on site and patterns of relapse, comprising unifocal in 18 (64%), multi-focal in 3 (11%), and repeat craniospinal irradiation (re-CSI) in 7 (25%) patients. Median interval from primary irradiation to re-RT was 49.5 months (range 24-98 months) with median cumulative biologically effective dose of 117 Gy (range 78-132 Gy). All patients received platinum-based salvage chemotherapy either before or after re-RT. One patient developed symptomatic radiation necrosis following re-CSI. At a median follow-up of 24 months (range 6-84 months), 2-year post-re-RT progression-free survival (PFS) and overall survival (OS) was 46% and 51% respectively. Younger age (< 18 years) at index diagnosis, primary risk stratification (standard-risk) and molecular subgrouping (Group 4) were associated with significantly better post-re-RT outcomes. CONCLUSION: Salvage re-RT provides good local control and encouraging survival outcomes with acceptable toxicity in selected patients with recurrent/progressive MB.

Systemic inflammatory biomarkers in primary central nervous system lymphoma versus high-grade glioma: exploratory, comparative and correlative analysis.

Aim: To assess systemic inflammatory biomarkers in non invasive differential diagnosis of primary central nervous system lymphoma (PCNSL) from high-grade glioma (HGG). Materials & methods: Patients with similar morphology (PCNSL or HGG) on conventional neuro-imaging were included. Systemic inflammatory indices were calculated from pretreatment complete blood counts and liver function tests and compared against histopathology as reference standard. Results: Mean values of absolute lymphocyte count and prognostic nutritional index were significantly different between PCNSL (n = 42) versus HGG (n = 16). Area under receiver operating characteristics curve for absolute lymphocyte count and prognostic nutritional index in the diagnosis of PCNSL was 0.70 and 0.72 respectively suggesting fair and acceptable diagnostic accuracy. Conclusion: Systemic inflammatory biomarkers complement established clinico-radiological features and aid in the differential diagnosis of PCNSL from HGG.

There exists a complex interplay between cancer and inflammation that can manifest as increased inflammatory biomarkers in blood. However, utility of systemic inflammatory biomarkers in the non invasive differential diagnosis of primary brain lymphoma from high-grade glioma is generally lacking. Two simple serum biomarkers, absolute lymphocyte count and prognostic nutritional index, easily derived from routine pretreatment blood tests have fair correlation and acceptable diagnostic accuracy in differentiating brain lymphoma from glioma in patients with similar morphology on MRI.

Nomograms based on preoperative multiparametric magnetic resonance imaging for prediction of molecular subgrouping in medulloblastoma: results from a radiogenomics study of 111 patients.

Background: Novel biological insights have led to consensus classification of medulloblastoma into 4 distinct molecular subgroups-wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4. We aimed to predict molecular subgrouping in medulloblastoma based on preoperative multiparametric magnetic resonance imaging (MRI) characteristics. Methods: A set of 19 MRI features were evaluated in 111 patients with histologic diagnosis of medulloblastoma for prediction of molecular subgrouping. MRI characteristics were correlated with molecular subgroups derived from tissue samples in 111 patients (WNT = 17, SHH = 44, Group 3 = 27, and Group 4 = 23). Multinomial logistic regression of imaging parameters was performed on a training cohort (TC) of 76 patients, representing two-thirds of randomly selected patients from each of 4 molecular subgroups, to generate binary nomograms. Validation of these nomograms was performed on the remaining 35 patients as the validation cohort (VC). Results: Medulloblastoma subgroups could be accurately predicted by preoperative MRI features in 74% of cases. Predictive accuracy was excellent for SHH (95%), acceptably high for Group 4 (78%), modest for Group 3 (56%) and worst for WNT (41%) subgroup medulloblastoma. SHH-specific nomogram was associated with excellent correlation between TC and VC, with area under the curve (AUC) of 0.939 and 0.991, respectively. AUC for Group 4 was acceptable at 0.851 and 0.788 in TC and VC, respectively; however, these values were consistently suboptimal in WNT and Group 3 medulloblastoma. Conclusion: The predictive accuracy of MRI-based nomograms was excellent for SHH and encouraging for Group 4 medulloblastoma. Further work is needed for Group 3 and WNT-pathway medulloblastoma.

Utility of flouro-deoxy-glucose positron emission tomography/computed tomography in the diagnostic and staging evaluation of patients with primary CNS lymphoma.

Aim: To prospectively assess the clinical utility of pretreatment flouro-deoxy-glucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in patients with primary central nervous system (CNS) lymphoma (PCNSL). Materials & methods: Patients with suspected/proven PCNSL underwent baseline whole-body 18F-FDG-PET/CT. Maximum standardized uptake value and tumor/normal tissue ratios were compared between CNS lymphoma and other histological diagnoses. Results: The mean maximum standardized uptake value (27.5 vs 18.2; p = 0.001) and mean tumor/normal tissue ratio (2.34 vs 1.53; p < 0.001) of CNS lymphoma was significantly higher than other histologic diagnoses. Five of 50 (10%) patients with biopsy-proven CNS lymphomas had pathologically increased FDG-uptake at extraneuraxial sites uncovering systemic lymphoma. Conclusion: Pretreatment whole-body 18F-FDG-PET/CT provides valuable complementary information in the diagnostic and staging evaluation of patients with PCNSL to guide therapeutic decision-making.

Impact of timing of radiation therapy on outcomes in atypical meningioma: A clinical audit.

BACKGROUND: The role of early adjuvant radiation therapy (RT) in patients with atypical meningioma remains controversial. The goal of this work was to report the impact of timing of RT on outcomes in atypical meningioma. METHODS AND MATERIALS: Patients of atypical meningioma were identified through electronic search of institutional database. Following surgery, RT was delivered either in upfront adjuvant setting (early adjuvant RT) or after recurrence/progression (salvage RT). RESULTS: There were 51 patients in the early adjuvant RT group and 30 patients in the salvage RT group. Six of 51 (12%) patients in the early adjuvant RT group recurred/progressed compared with 34 of 35 (97%) patients kept on observation after initial surgery. Thirty of these 34 patients received salvage RT, mostly after reexcision. Twelve of 30 (40%) patients recurred/progressed after salvage RT, compared with 6 of 51 (12%) patients after early adjuvant RT (P = .003). Post-RT 5-year progression-free survival was significantly better for early adjuvant RT compared to salvage RT (69% vs 28%, log-rank P < .001). CONCLUSIONS: Within the limitations of any retrospective analysis, upfront early adjuvant RT can significantly reduce the risk of local recurrence/progression in atypical meningiomas compared with initial observation. A sizeable proportion of patients who are observed initially recur/progress over time necessitating salvage therapy; however, reexcision followed by salvage RT may not be as effective as early adjuvant RT.