Faculty Bibliography

Treatment-resistant glioma stem cells are thought to propagate and drive growth of malignant gliomas, but their markers and our ability to target them specifically are not well understood. We demonstrate that podoplanin (PDPN) expression is an independent prognostic marker in gliomas across multiple independent patient cohorts comprising both high- and low-grade gliomas. Knockdown of PDPN radiosensitized glioma cell lines and glioma-stem-like cells (GSCs). Clonogenic assays and xenograft experiments revealed that PDPN expression was associated with radiotherapy resistance and tumor aggressiveness. We further demonstrate that knockdown of PDPN in GSCs in vivo is sufficient to improve overall survival in an intracranial xenograft mouse model. PDPN therefore identifies a subset of aggressive, treatment-resistant glioma cells responsible for radiation resistance and may serve as a novel therapeutic target.

BACKGROUND/UNASSIGNED:Hyperglycemia has been associated with worse survival in glioblastoma. Attempts to lower glucose yielded mixed responses which could be due to molecularly distinct GBM subclasses. METHODS/UNASSIGNED:Clinical, laboratory, and molecular data on 89 IDH-wt GBMs profiled by clinical next-generation sequencing and treated with Stupp protocol were reviewed. IDH-wt GBMs were sub-classified into RTK I (Proneural), RTK II (Classical) and Mesenchymal subtypes using whole-genome DNA methylation. Average glucose was calculated by time-weighting glucose measurements between diagnosis and last follow-up. RESULTS/UNASSIGNED:= .02). Methylation clustering did not identify unique signatures associated with high or low glucose levels. Metabolomic analysis of 23 tumors showed minimal variation across metabolites without differences between molecular subclasses. CONCLUSION/UNASSIGNED:Higher average glucose values were associated with poorer OS in RTKI and Mesenchymal IDH-wt GBM, but not RTKII. There were no discernible epigenetic or metabolomic differences between tumors in different glucose environments, suggesting a potential survival benefit to lowering systemic glucose in selected molecular subtypes.

PURPOSE/OBJECTIVE:To provide guidance to clinicians regarding therapy for patients with brain metastases from solid tumors. METHODS:ASCO convened an Expert Panel and conducted a systematic review of the literature. RESULTS:Thirty-two randomized trials published in 2008 or later met eligibility criteria and form the primary evidentiary base. RECOMMENDATIONS/CONCLUSIONS:Surgery is a reasonable option for patients with brain metastases. Patients with large tumors with mass effect are more likely to benefit than those with multiple brain metastases and/or uncontrolled systemic disease. Patients with symptomatic brain metastases should receive local therapy regardless of the systemic therapy used. For patients with asymptomatic brain metastases, local therapy should not be deferred unless deferral is specifically recommended in this guideline. The decision to defer local therapy should be based on a multidisciplinary discussion of the potential benefits and harms that the patient may experience. Several regimens were recommended for non-small-cell lung cancer, breast cancer, and melanoma. For patients with asymptomatic brain metastases and no systemic therapy options, stereotactic radiosurgery (SRS) alone should be offered to patients with one to four unresected brain metastases, excluding small-cell lung carcinoma. SRS alone to the surgical cavity should be offered to patients with one to two resected brain metastases. SRS, whole brain radiation therapy, or their combination are reasonable options for other patients. Memantine and hippocampal avoidance should be offered to patients who receive whole brain radiation therapy and have no hippocampal lesions and 4 months or more expected survival. Patients with asymptomatic brain metastases with either Karnofsky Performance Status ≤ 50 or Karnofsky Performance Status < 70 with no systemic therapy options do not derive benefit from radiation therapy.Additional information is available at www.asco.org/neurooncology-guidelines.

OBJECTIVE:Patients with non-small cell lung cancer (NSCLC) metastatic to the brain are living longer. The risk of new brain metastases when these patients stop systemic therapy is unknown. The authors hypothesized that the risk of new brain metastases remains constant for as long as patients are off systemic therapy. METHODS:A prospectively collected registry of patients undergoing radiosurgery for brain metastases was analyzed. Of 606 patients with NSCLC, 63 met the inclusion criteria of discontinuing systemic therapy for at least 90 days and undergoing active surveillance. The risk factors for the development of new tumors were determined using Cox proportional hazards and recurrent events models. RESULTS:The median duration to new brain metastases off systemic therapy was 16.0 months. The probability of developing an additional new tumor at 6, 12, and 18 months was 26%, 40%, and 53%, respectively. There were no additional new tumors 22 months after stopping therapy. Patients who discontinued therapy due to intolerance or progression of the disease and those with mutations in RAS or receptor tyrosine kinase (RTK) pathways (e.g., KRAS, EGFR) were more likely to develop new tumors (hazard ratio [HR] 2.25, 95% confidence interval [CI] 1.33-3.81, p = 2.5 × 10-3; HR 2.51, 95% CI 1.45-4.34, p = 9.8 × 10-4, respectively). CONCLUSIONS:The rate of new brain metastases from NSCLC in patients off systemic therapy decreases over time and is uncommon 2 years after cessation of cancer therapy. Patients who stop therapy due to toxicity or who have RAS or RTK pathway mutations have a higher rate of new metastases and should be followed more closely.

OBJECTIVE:Isocitrate dehydrogenase (IDH) mutation status is recommended used for diagnosis and prognostication of glioblastoma patients. We studied efficacy and safety of stereotactic radiosurgery (SRS) for patients with recurrent IDH-wt glioblastoma. METHODS:Consecutive patients treated with SRS for IDH-wt glioblastoma were pooled for this retrospective observational international multi-institutional study from institutions participating in the International Radiosurgery Research Foundation. RESULTS:) for IDH-wt glioblastoma. All patients had histories of surgery and chemotherapy with temozolomide, and 98% underwent fractionated radiation therapy. MGMT status was available for 42 patients, of which half of patients had MGMT mutant glioblastomas. During median post-SRS imaging follow-up of 6 months, 52% of patients experienced tumor progression. Median post-SRS progression free survival was 4 months. SRS prescription dose of > 14 Gy predicted longer progression free survival [HR 0.357 95% (0.164-0.777) p = 0.009]. Fifty-percent of patients died during post-SRS clinical follow-up that ranged from 1 to 33 months. SRS treatment volume of > 5 cc emerged as an independent predictor of shorter post-SRS overall survival [HR 2.802 95% CI (1.219-6.444) p = 0.02]. Adverse radiation events (ARE) suggestive of radiation necrosis were diagnosed in 6/55 (10%) patients and were managed conservatively in the majority of patients. CONCLUSIONS:SRS prescription dose of > 14 Gy is associated with longer progression free survival while tumor volume of > 5 cc is associated with shorter overall survival after SRS for IDH-wt glioblastomas. AREs are rare and are typically managed conservatively.

OBJECTIVE:Molecular profiles, such as isocitrate dehydrogenase (IDH) mutation and O6-methylguanine-DNA methyltransferase (MGMT) methylation status, have important prognostic roles for glioblastoma patients. The authors studied the efficacy and safety of stereotactic radiosurgery (SRS) for glioblastoma patients with consideration of molecular tumor profiles. METHODS:For this retrospective observational multiinstitutional study, the authors pooled consecutive patients who were treated using SRS for glioblastoma at eight institutions participating in the International Radiosurgery Research Foundation. They evaluated predictors of overall and progression-free survival with consideration of IDH mutation and MGMT methylation status. RESULTS:Ninety-six patients (median age 56 years) underwent SRS (median dose 15 Gy and median treatment volume 5.53 cm3) at 147 tumor sites (range 1 to 7). The majority of patients underwent prior fractionated radiation therapy (92%) and temozolomide chemotherapy (98%). Most patients were treated at recurrence (85%), and boost SRS was used for 12% of patients. The majority of patients harbored IDH wild-type (82%) and MGMT-methylated (62%) tumors. Molecular data were unavailable for 33 patients. Median survival durations after SRS were similar between patients harboring IDH wild-type tumors and those with IDH mutant tumors (9.0 months vs 11 months, respectively), as well as between those with MGMT-methylated tumors and those with MGMT-unmethylated tumors (9.8 vs. 9.0 months, respectively). Prescription dose > 15 Gy (OR 0.367, 95% CI 0.190-0.709, p = 0.003) and treatment volume > 5 cm3 (OR 1.036, 95% CI 1.007-1.065, p = 0.014) predicted overall survival after controlling for age and IDH status. Treatment volume > 5 cm3 (OR 2.215, 95% CI 1.159-4.234, p = 0.02) and absence of gross-total resection (OR 0.403, 95% CI 0.208-0.781, p = 0.007) were associated with inferior local control of SRS-treated lesions in multivariate models. Nine patients experienced adverse radiation events after SRS, and 7 patients developed radiation necrosis at 59 to 395 days after SRS. CONCLUSIONS:Post-SRS survival was similar as a function of IDH mutation and MGMT promoter methylation status, suggesting that molecular profiles of glioblastoma should be considered when selecting candidates for SRS. SRS prescription dose > 15 Gy and treatment volume ≤ 5 cm3 were associated with longer survival, independent of age and IDH status. Prior gross-total resection and smaller treatment volume were associated with superior local control.

PURPOSE/OBJECTIVE(S): Healthcare data often exist in silos and in unstructured formats that limit interoperability and require tedious manual extraction. Our institution has adopted a flexible and scalable big data platform built on Hadoop that integrates data from Epic/Clarity as well as Aria and allows users to leverage modern data science tools to facilitate access. We hypothesize that a data analytics and visualization dashboard can be built using open-source tools that will (1) allow non-technical users to explore de-identified clinical data within our institutional big data platform and (2) connect with repositories of molecular data to demonstrate potential methods of integrating clinical and basic science data. MATERIALS/METHODS: De-identified patient-level radiation oncology data from the institutional big data platform (Hadoop) were extracted with the python packages pyodbc and pandas. For the purposes of this dashboard, radiation oncology specific clinical data elements were queried including the date of first radiation treatment, treatment location, treatment modality (SBRT, external beam, SRS, TBI, LDR/HDR brachytherapy), ICD10 codes, anatomic treatment site, number of fractions, treatment prescription, and dose per fraction. A python client connection with the publicly accessible instance of cBioPortal for Cancer Genomics was established using the Bravado library. Data transformation and cleaning was performed in python using panda's data frames. A web-based dashboard to facilitate user-defined visualizations was implemented using the Dash python library and interactive visualizations of subsets of extracted data were generated in real-time using the plotly plotting library.
RESULT(S): We developed a web-based dashboard that gives users without extensive programming expertise the ability to explore de-identified clinical data extracted from Hadoop. As proof of principle, the dashboard was used to visualize the clinical impact of the COVID-19 pandemic on radiation oncology patient volumes, revealing a significant decline in new radiation treatments in April and May of 2020 (-54% and -36% compared to 2019) during the initial COVID-19 surge. Furthermore, the dashboard allows users to interact with the cBioPortal for Cancer Genomics repository, which currently houses clinical and molecular data from 301 publicly available studies spanning 869 different cancer types. This interface with cBioPortal illustrates the potential for future integration of clinically meaningful sequencing results with clinical outcomes data.
CONCLUSION(S): We built an interactive web-based dashboard to enable general users' easy access to de-identified clinical data stored within the institutional big data platform. Additional data sources, including external molecular data can be connected to the dashboard allowing for future integration.
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PURPOSE/OBJECTIVE(S): Despite maximal surgical resection, radiotherapy, chemotherapy and re-treatment at re-occurrence, median overall survival time of glioblastoma (WHO grade IV, IDH wild-type) is estimated to be ~16 months. In glioma, DNA methylation states are the most predictive marker of overall survival and response to therapy. Our understanding of how epigenetic states, such as DNA methylation, are "mis-repaired" after DNA damage repair is scant, hampering our ability to understand how treatment associated DNA methylation alterations may drive tumor resistance and growth. MATERIALS/METHODS: Three different patient derived glioma stem cell (GSC) lines, in duplicates, were treated with 20 Gy in 10 fractions and allowed to recover prior to DNA methylation analysis with 850K methylation arrays. To analyze the methylation array data, we used RnBeads (version 2.4.0) and R (version 3.6.1) packages. We further focused our analysis to various genomic regions, including CpG islands, promoters, gene bodies and CTCF motifs to understand how methylation alterations may differ between these and other genomic contexts.
RESULT(S): We found differential methylation (pre-treatment vs. radiation treatment) changes among the genomic regions examined. Interestingly, we found differential methylation changes at CTCF motifs, which play important DNA-methylation dependent roles in gene expression and chromatin architecture regulation. Hierarchical clustering, PCA and MDS analysis amongst CpG islands, promoters, gene bodies and CTCF domains did not reveal strong inter-sample differences that segregated the samples on the basis of treatment status, suggesting radiation associated methylation alterations are context dependent.
CONCLUSION(S): Radiation treatment is associated with wide-spread alterations of DNA methylation states in this patient derived glioblastoma model. Such alterations may drive gene expression changes, or genomic architecture alterations, that lead to treatment resistance in the recurrent setting. AUTHOR DISCLOSURE: A.S. Modrek: None. R. Ezhilarasan: None. M. Snuderl: None. E.P. Sulman: None.
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