The role of laser interstitial thermal therapy in enhancing progression-free survival of difficult-to-access high-grade gliomas: A multicenter study

Surgical extent-of-resection has been shown to have an impact on high-grade glioma (HGG) outcomes; however, complete resection is rarely achievable in difficult-to-access (DTA) tumors. Controlled thermal damage to the tumor may have the same impact in DTA-HGGs. We report our multicenter results of laser interstitial thermal therapy (LITT) in DTA-HGGs. We retrospectively reviewed 34 consecutive DTA-HGG patients (24 glioblastoma, 10 anaplastic) who underwent LITT at Cleveland Clinic, Washington University, and Wake Forest University (May 2011–December 2012) using the NeuroBlate® System. The extent of thermal damage was determined using thermal damage threshold (TDT) lines: yellow TDT line (43°C for 2 min) and blue TDT line (43°C for 10 min). Volumetric analysis was performed to determine the extent-of-coverage of tumor volume by TDT lines. Patient outcomes were evaluated statistically. LITT was delivered as upfront in 19 and delivered as salvage in 16 cases. After 7.2 months of follow-up, 71% of cases demonstrated progression and 34% died. The median overall survival (OS) for the cohort was not reached; however, the 1-year estimate of OS was 68 ± 9%. Median progression-free survival (PFS) was 5.1 months. Thirteen cases who met the following two criteria—(1) <0.05 cm(3) tumor volume not covered by the yellow TDT line and (2) <1.5 cm(3) additional tumor volume not covered by the blue TDT line—had better PFS than the other 21 cases (9.7 vs. 4.6 months; P = 0.02). LITT can be used effectively for treatment of DTA-HGGs. More complete coverage of tumor by TDT lines improves PFS which can be translated as the extent of resection concept for surgery

Genomic predictors of patterns of progression in glioblastoma and possible influences on radiation field design

We present a retrospective investigation of the role of genomics in the prediction of central versus marginal disease progression patterns for glioblastoma (GBM). Between August 2000 and May 2010, 41 patients with GBM and gene expression and methylation data available were treated with radiotherapy with or without concurrent temozolomide. Location of disease progression was categorized as within the high dose (60 Gy) or low dose (46 Gy) volume. Samples were grouped into previously described TCGA genomic groupings: Mesenchymal (m), classical (c), proneural (pn), and neural (n); and were also classified by MGMT-Methylation status and G-Cimp methylation phenotype. Genomic groupings and methylation status were investigated as a possible predictor of disease progression in the high dose region, progression in the low dose region, and time to progression. Based on TCGA category there was no difference in OS (p = 0.26), 60 Gy progression (PN: 71 %, N: 60 %, M: 89 %, C: 83 %, p = 0.19), 46 Gy progression (PN: 57 %, N: 40 %, M: 61 %, C: 50 %, p = 0.8) or time to progression (PN: 9 months, N:15 months, M: 9 months, C: 7 months, p = 0.58). MGMT methylation predicted for improved OS (median 25 vs. 13 months, p = 0.01), improved DFS (median 13 vs. 8 months, p = 0.007) and decreased 60 Gy (p = 0.003) and 46 Gy (p = 0.006) progression. There was a cohort of MGMT methylated patients with late marginal disease progression (4/22 patients, 18 %). TCGA groups demonstrated no difference in survival or progression patterns. MGMT methylation predicted for a statistically significant decrease in in-field and marginal disease progression. There was a cohort of MGMT methylated patients with late marginal progression. Validations of these findings would have implications that could affect radiation field size

Multi-Omics Analysis of Brain Metastasis Outcomes Following Craniotomy

Background: The incidence of brain metastasis continues to increase as therapeutic strategies have improved for a number of solid tumors. The presence of brain metastasis is associated with worse prognosis but it is unclear if distinctive biomarkers can separate patients at risk for CNS related death. Methods: We executed a single institution retrospective collection of brain metastasis from patients who were diagnosed with lung, breast, and other primary tumors. The brain metastatic samples were sent for RNA sequencing, proteomic and metabolomic analysis of brain metastasis. The primary outcome was distant brain failure after definitive therapies that included craniotomy resection and radiation to surgical bed. Novel prognostic subtypes were discovered using transcriptomic data and sparse non-negative matrix factorization. Results: We discovered two molecular subtypes showing statistically significant differential prognosis irrespective of tumor subtype. The median survival time of the good and the poor prognostic subtypes were 7.89 and 42.27 months, respectively. Further integrated characterization and analysis of these two distinctive prognostic subtypes using transcriptomic, proteomic, and metabolomic molecular profiles of patients identified key pathways and metabolites. The analysis suggested that immune microenvironment landscape as well as proliferation and migration signaling pathways may be responsible to the observed survival difference. Conclusion: A multi-omics approach to characterization of brain metastasis provides an opportunity to identify clinically impactful biomarkers and associated prognostic subtypes and generate provocative integrative understanding of disease

The Protective Action Encoding of Serotonin Transients in the Human Brain

The role of serotonin in human brain function remains elusive due, at least in part, to our inability to measure rapidly the local concentration of this neurotransmitter. We used fast-scan cyclic voltammetry to infer serotonergic signaling from the striatum of fourteen brains of human patients with Parkinson's disease. Here we report these novel measurements and show that they correlate with outcomes and decisions in a sequential investment game. We find that serotonergic concentrations transiently increase as a whole following negative reward prediction errors, while reversing when counterfactual losses predominate. This provides initial evidence that the serotonergic system acts as an opponent to dopamine signaling, as anticipated by theoretical models. Serotonin transients on one trial were also associated with actions on the next trial in a manner that correlated with decreased exposure to poor outcomes. Thus, the fluctuations observed for serotonin appear to correlate with the inhibition of over-reactions and promote persistence of ongoing strategies in the face of short-term environmental changes. Together these findings elucidate a role for serotonin in the striatum, suggesting it encodes a protective action strategy that mitigates risk and modulates choice selection particularly following negative environmental events

Intracranial approach for sub-second monitoring of neurotransmitters during DBS electrode implantation does not increase infection rate

Introduction Currently, sub-second monitoring of neurotransmitter release in humans can only be performed during standard of care invasive procedures like DBS electrode implantation. The procedure requires acute insertion of a research probe and additional time in surgery, which may increase infection risk. We sought to determine the impact of our research procedure, particularly the extended time in surgery, on infection risk. Methods We screened 602 patients who had one or more procedure codes documented for DBS electrode implantation, generator placement, programming, or revision for any reason performed at Wake Forest Baptist Medical Center between January 2011 through October 2020 using International Classification of Diseases (ICD) codes for infection. During this period, 116 patients included an IRB approved 30-minute research protocol, during the Phase 1 DBS electrode implantation surgery, to monitor sub-second neurotransmitter release. We used Fisher's Exact test (FET) to determine if there was a significant change in the infection rate following DBS electrode implantation procedures that included, versus those that did not include, the neurotransmitter monitoring research protocol. Results Within 30-days following DBS electrode implantation, infection was observed in 1 (0.21%) out of 486 patients that did not participate in the research procedure and 2 (1.72%) of the 116 patients that did participate in the research procedure. Notably, all types of infection observed were typical of those expected for DBS electrode implantation. Conclusion Infection rates are not statistically different across research and non-research groups within 30-days following the research procedure (1.72% vs. 0.21%; p = 0.0966, FET). Our results demonstrate that the research procedures used for sub-second monitoring of neurotransmitter release in humans can be performed without increasing the rate of infection