Blood tests to detect circulating tumor cells (CTC) offer great potential to monitor disease status, gauge prognosis, and guide treatment decisions for patients with cancer. For patients with brain tumors, such as aggressive glioblastoma multiforme, CTC assays are needed that do not rely on expression of cancer cell surface biomarkers like epithelial cell adhesion molecules that brain tumors tend to lack. Here, we describe a strategy to detect CTC based on telomerase activity, which is elevated in nearly all tumor cells but not normal cells. This strategy uses an adenoviral detection system that is shown to successfully detect CTC in patients with brain tumors. Clinical data suggest that this assay might assist interpretation of treatment response in patients receiving radiotherapy, for example, to differentiate pseudoprogression from true tumor progression. These results support further development of this assay as a generalized method to detect CTC in patients with cancer.

Successful treatment of brain tumors such as glioblastoma multiforme (GBM) is limited in large part by the cumulative dose of Radiation Therapy (RT) that can be safely given and the blood-brain barrier (BBB), which limits the delivery of systemic anticancer agents into tumor tissue. Consequently, the overall prognosis remains grim. Herein, we report our pilot studies in cell culture experiments and in an animal model of GBM in which RT is complemented by PEGylated-gold nanoparticles (GNPs). GNPs significantly increased cellular DNA damage inflicted by ionizing radiation in human GBM-derived cell lines and resulted in reduced clonogenic survival (with dose-enhancement ratio of ∼1.3). Intriguingly, combined GNP and RT also resulted in markedly increased DNA damage to brain blood vessels. Follow-up in vitro experiments confirmed that the combination of GNP and RT resulted in considerably increased DNA damage in brain-derived endothelial cells. Finally, the combination of GNP and RT increased survival of mice with orthotopic GBM tumors. Prior treatment of mice with brain tumors resulted in increased extravasation and in-tumor deposition of GNP, suggesting that RT-induced BBB disruption can be leveraged to improve the tumor-tissue targeting of GNP and thus further optimize the radiosensitization of brain tumors by GNP. These exciting results together suggest that GNP may be usefully integrated into the RT treatment of brain tumors, with potential benefits resulting from increased tumor cell radiosensitization to preferential targeting of tumor-associated vasculature.

Background Glioblastoma is an aggressive and highly infiltrative brain cancer. Standard surgical resection is guided by enhancement on postcontrast T1-weighted (T1) magnetic resonance imaging (MRI), which is insufficient for delineating surrounding infiltrating tumor. Objective To develop imaging biomarkers that delineate areas of tumor infiltration and predict early recurrence in peritumoral tissue. Such markers would enable intensive, yet targeted, surgery and radiotherapy, thereby potentially delaying recurrence and prolonging survival. Methods Preoperative multiparametric MRIs (T1, T1-Gad, T2-weighted [T2], T2-fluid-attenuated inversion recovery [FLAIR], diffusion tensor imaging (DTI), and dynamic susceptibility contrast-enhanced [DSC]-MRI) from 31 patients were combined using machine learning methods, thereby creating predictive spatial maps of infiltrated peritumoral tissue. Cross validation was used in the retrospective cohort to achieve generalizable biomarkers. Subsequently, the imaging signatures learned from the retrospective study were used in a replication cohort of 34 new patients. Spatial maps representing likelihood of tumor infiltration and future early recurrence were compared to regions of recurrence on postresection follow-up studies with pathology confirmation. Results This technique produced predictions of early recurrence with a mean area under the curve (AUC) of 0.84, sensitivity of 91%, specificity of 93%, and odds ratio estimates of 9.29 (99% CI, 8.95–9.65) for tissue predicted to be heavily infiltrated in the replication study. Regions of tumor recurrence were found to have subtle, yet fairly distinctive multiparametric imaging signatures when analyzed quantitatively by pattern analysis and machine learning. Conclusion Visually imperceptible imaging patterns discovered via multiparametric pattern analysis methods were found to estimate the extent of infiltration and location of future tumor recurrence, paving the way for improved targeted treatment.

BACKGROUND AND PURPOSE:Early assessment of treatment response is critical in patients with glioblastomas. A combination of DTI and DSC perfusion imaging parameters was evaluated to distinguish glioblastomas with true progression from mixed response and pseudoprogression.

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Circulating tumor cells (CTC) are known to be present in the blood of glioblastoma (GBM) patients. Here we report that GBM-derived CTC possess a cancer stem cell (CSC)-like phenotype and contribute to local tumorigenesis and recurrence by the process of self-seeding. Genetic probes showed that mouse GBM-derived CTC exhibited Sox2/ETn transcriptional activation and expressed glioma CSC markers, consistent with robust expression of stemness-associated genes including SOX2, OCT4, and NANOG in human GBM patient-derived samples containing CTC. A transgenic mouse model demonstrated that CTC returned to the primary tumor and generated new tumors with enhanced tumorigenic capacity. These CTC were resistant to radiotherapy and chemotherapy and to circulation stress-induced cell apoptosis. Single-cell RNA-seq analysis revealed that Wnt activation induced stemness and chemoresistance in CTC. Collectively, these findings identify GBM-derived CTC as CSC-like cells and suggest that targeting Wnt may offer therapeutic opportunities for eliminating these treatment-refractory cells in GBM.

Older patients are more vulnerable to detrimental effects of Gamma Knife radiosurgery on hearing. We propose that cochlear dose volume histograms be created and used to reduce the percentage of the cochlear volume exposed to radiation doses greater than 5.3 Gy. This is the first report to suggest that the conformity index tumor coverage may be an important predictor of hearing outcomes.

ObjectFollowing resection of a brain metastasis, stereotactic radiosurgery (SRS) to the cavity is an emerging alternative to postoperative whole-brain radiation therapy (WBRT). This approach attempts to achieve local control without the neurocognitive risks associated with WBRT. The authors aimed to report the outcomes of a large patient cohort treated with this strategy.MethodsA retrospective review identified 91 patients without a history of WBRT who received Gamma Knife (GK) SRS to 96 metastasis resection cavities between 2007 and 2013. Patterns of intracranial control were examined in the 86 cases with post-GK imaging. Survival, local failure, and distant failure were estimated by the Kaplan-Meier method. Prognostic factors were tested by univariate (log-rank test) and multivariate (Cox proportional hazards model) analyses.ResultsCommon primary tumors were non–small cell lung (43%), melanoma (14%), and breast (13%). The cases were predominantly recursive partitioning analysis Class I (25%) or II (70%). Median preoperative metastasis diameter was 2.8 cm, and 82% of patients underwent gross-total resection. A median dose of 16 Gy was delivered to the 50% isodose line, encompassing a median treatment volume of 9.2 cm3. Synchronous intact metastases were treated in addition to the resection bed in 43% of cases. Patients survived a median of 22.3 months from the time of GK. Local failure developed in 16 cavities, for a crude rate of 18% and 1-year actuarial local control of 81%. Preoperative metastasis diameter ≥ 3 cm and residual or recurrent tumor at the time of GK were associated with local failure (p = 0.04 and 0.008, respectively). Distant intracranial failure occurred in 55 cases (64%) at a median of 7.3 months from GK. Salvage therapies included WBRT and additional SRS in 33% and 31% of patients, respectively. Leptomeningeal carcinomatosis developed in 12 cases (14%) and was associated with breast histology and infratentorial cavities (p = 0.024 and 0.012, respectively).ConclusionsThis study bolsters the existing evidence for SRS to the resection bed. Local control rates are high, but patients with larger preoperative metastases or residual/recurrent tumor at the time of SRS are more likely to fail at the cavity. While most patients develop distant intracranial failure, an SRS approach spared or delayed WBRT in the majority of cases. The risk of leptomeningeal carcinomatosis does not appear to be elevated with this strategy.