Publications by authors named "Clark C Chen"

218 Publications

Combined immunotherapy with controlled Interleukin-12 gene therapy and immune checkpoint blockade in recurrent glioblastoma: an open-label, multi-institutional phase 1 trial.

Neuro Oncol 2021 Nov 26. Epub 2021 Nov 26.

Northwestern Memorial Hospital, Chicago, IL.

Background: Veledimex (VDX)-regulatable interleukin-12 (IL-12) gene therapy in recurrent glioblastoma (rGBM) was reported to show tumor infiltration of CD8 + T cells, encouraging survival, but also up-regulation of immune checkpoint signaling, providing the rationale for a combination trial with immune checkpoint inhibition.

Methods: An open-label, multi-institutional, dose-escalation phase 1 trial in rGBM subjects (NCT03636477) accrued 21 subjects in 3 dose-escalating cohorts: 1- neo-adjuvant then ongoing nivolumab (1mg/kg) and VDX (10 mg) (n= 3); 2- neo-adjuvant then ongoing nivolumab (3 mg/kg) and VDX (10 mg) (n=3); and 3- neo-adjuvant then ongoing nivolumab (3 mg/kg) and VDX (20 mg) (n=15). Nivolumab was administered 7 (+/- 3) days before resection of the rGBM followed by peritumoral injection of IL-12 gene therapy. VDX was administered 3 hours before and then for 14 days after surgery. Nivolumab was administered every two weeks after surgery.

Results: Toxicities of the combination were comparable to IL-12 gene monotherapy and were predictable, dose-related and reversible upon withholding doses of VDX and/or nivolumab. VDX plasma pharmacokinetics demonstrate a dose-response relationship with effective brain tumor tissue VDX penetration and production of IL-12. IL-12 levels in serum peaked in all subjects at about Day 3 after surgery. Tumor IFNγ increased in post treatment biopsies. Median overall survival (mOS) for VDX 10 mg with nivolumab was 16.9 months and for all subjects was 9.8 months.

Conclusion: The safety of this combination immunotherapy was established and has led to an ongoing phase 2 clinical trial of immune checkpoint blockade with controlled IL-12 gene therapy (NCT04006119).
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http://dx.doi.org/10.1093/neuonc/noab271DOI Listing
November 2021

Disparities in access to surgery for glioblastoma multiforme at high-volume Commission on Cancer-accredited hospitals in the United States.

J Neurosurg 2021 Nov 12:1-10. Epub 2021 Nov 12.

1Department of Neurologic Surgery, Mayo Clinic, Rochester.

Objective: Although it has been shown that surgery for glioblastoma (GBM) at high-volume facilities (HVFs) may be associated with better postoperative outcomes, the use of such hospitals may not be equally distributed. The authors aimed to evaluate racial and socioeconomic differences in access to surgery for GBM at high-volume Commission on Cancer (CoC)-accredited hospitals.

Methods: The National Cancer Database was queried for patients with GBM that was newly diagnosed between 2004 and 2015. Patients who received no surgical intervention or those who received surgical intervention at a site other than the reporting facility were excluded. Annual surgical case volume was calculated for each hospital, with volume ≥ 90th percentile defined as an HVF. Multivariable logistic regression was performed to identify patient-level predictors for undergoing surgery at an HVF. Furthermore, multiple subgroup analyses were performed to determine the adjusted odds ratio of the likelihood of undergoing surgery at an HVF in 2016 as compared to 2004 for each patient subpopulation (by age, race, sex, educational group, etc.).

Results: A total of 51,859 patients were included, with 10.7% (n = 5562) undergoing surgery at an HVF. On multivariable analysis, Hispanic White patients (OR 0.58, 95% CI 0.49-0.69, p < 0.001) were found to have significantly lower odds of undergoing surgery at an HVF (reference = non-Hispanic White). In addition, patients from a rural residential location (OR 0.55, 95% CI 0.41-0.72, p < 0.001; reference = metropolitan); patients with nonprivate insurance status (Medicare [OR 0.78, 95% CI 0.71-0.86, p < 0.001], Medicaid [OR 0.68, 95% CI 0.60-0.78, p < 0001], other government insurance [OR 0.68, 95% CI 0.52-0.86, p = 0.002], or who were uninsured [OR 0.61, 95% CI 0.51-0.72, p < 0.001]); and lower-income patients ($50,354-$63,332 [OR 0.68, 95% CI 0.63-0.74, p < 0.001], $40,227-$50,353 [OR 0.84, 95% CI 0.76-0.92, p < 0.001]; reference = ≥ $63,333) were also found to be significantly associated with a lower likelihood of surgery at an HVF. Subgroup analyses revealed that elderly patients (age ≥ 65 years), both male and female patients and non-Hispanic White patients, and those with private insurance, Medicare, metropolitan residential location, median zip code-level household income in the first and second quartiles, and educational attainment in the first and third quartiles had increased odds of undergoing surgery at an HVF in 2016 compared to 2004 (all p ≤ 0.05). On the other hand, patients with other governmental insurance, patients with a rural residence, and those from a non-White racial category did not show a significant difference in odds of surgery at an HVF over time (all p > 0.05).

Conclusions: The present analysis from the National Cancer Database revealed significant disparities in access to surgery at an HVF for GBM within the United States. Furthermore, there was evidence that these racial and socioeconomic disparities may have widened between 2004 and 2016. The findings should assist health policy makers in the development of strategies for improving access to HVFs for racially and socioeconomically disadvantaged populations.
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http://dx.doi.org/10.3171/2021.7.JNS211307DOI Listing
November 2021

Fusion Genes Altered in Adult Malignant Gliomas.

Front Neurol 2021 4;12:715206. Epub 2021 Oct 4.

Department of Neurosurgery, University of Minnesota, Minneapolis, MN, United States.

Malignant gliomas are highly heterogeneous brain tumors in molecular genetic background. Despite the many recent advances in the understanding of this disease, patients with adult high-grade gliomas retain a notoriously poor prognosis. Fusions involving oncogenes have been reported in gliomas and may serve as novel therapeutic targets to date. Understanding the gene fusions and how they regulate oncogenesis and malignant progression will contribute to explore new approaches for personalized treatment. By now, studies on gene fusions in gliomas remain limited. However, some current clinical trials targeting fusion genes have presented exciting preliminary findings. The aim of this review is to summarize all the reported fusion genes in high-grade gliomas so far, discuss the characterization of some of the most popular gene fusions occurring in malignant gliomas, as well as their function in tumorigenesis, and the underlying clinical implication as therapeutic targets.
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http://dx.doi.org/10.3389/fneur.2021.715206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8520976PMC
October 2021

Statistical power or more precise insights into neuro-temporal dynamics? Assessing the benefits of rapid temporal sampling in fMRI.

Prog Neurobiol 2021 Sep 4:102171. Epub 2021 Sep 4.

Center for Magnetic Resonance Research, University of Minnesota, 2021 6th St SE, Minneapolis, MN, 55455, United States; Department of Neurosurgery, University of Minnesota, 500 SE Harvard St, Minneapolis, MN, 55455, United States. Electronic address:

Functional magnetic resonance imaging (fMRI), a non-invasive and widely used human neuroimaging method, is most known for its spatial precision. However, there is a growing interest in its temporal sensitivity. This is despite the temporal blurring of neuronal events by the blood oxygen level dependent (BOLD) signal, the peak of which lags neuronal firing by 4-6 seconds. Given this, the goal of this review is to answer a seemingly simple question - "What are the benefits of increased temporal sampling for fMRI?". To answer this, we have combined fMRI data collected at multiple temporal scales, from 323 to 1000 milliseconds, with a review of both historical and contemporary temporal literature. After a brief discussion of technological developments that have rekindled interest in temporal research, we next consider the potential statistical and methodological benefits. Most importantly, we explore how fast fMRI can uncover previously unobserved neuro-temporal dynamics - effects that are entirely missed when sampling at conventional 1 to 2 second rates. With the intrinsic link between space and time in fMRI, this temporal renaissance also delivers improvements in spatial precision. Far from producing only statistical gains, the array of benefits suggest that the continued temporal work is worth the effort.
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http://dx.doi.org/10.1016/j.pneurobio.2021.102171DOI Listing
September 2021

Targeted Liposomes Encapsulating miR-603 Complexes Enhance Radiation Sensitivity of Patient-Derived Glioblastoma Stem-Like Cells.

Pharmaceutics 2021 Jul 21;13(8). Epub 2021 Jul 21.

Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA.

Despite potential for clinical efficacy, therapeutic delivery of microRNAs (miRNA) remains a major translational barrier. Here, we explore a strategy for miRNA delivery in the treatment of glioblastoma, the most common form of adult brain cancer, that involves complexation of miRNA with polyethylenimine (PEI) and encapsulation in targeted liposomes. miRNA 603 (miR-603) is a master regulatory miRNA that suppresses glioblastoma radiation resistance through down-regulation of insulin-like growth factor 1 (IGF1) signaling. miR-603 was complexed with PEI, a cationic polymer, and encapsulated into liposomes decorated with polyethylene glycol (PEG) and PR_b, a fibronectin-mimetic peptide that specifically targets the αβ integrin that is overexpressed in glioblastomas. Cultured patient-derived glioblastoma cells internalized PR_b-functionalized liposomes but not the non-targeted liposomes. The integrin targeting and complexation of the miRNA with PEI were associated with a 22-fold increase in intracellular miR-603 levels, and corresponding decreases in IGF1 and IGF1 receptor (IGF1R) mRNA expression. Moreover, treatment of glioblastoma cells with the PR_b liposomes encapsulating miR-603/PEI sensitized the cells to ionizing radiation (IR), a standard of care treatment for glioblastomas. These results suggest that PR_b-functionalized PEGylated liposomes encapsulating miR-603/PEI complexes hold promise as a therapeutic platform for glioblastomas.
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http://dx.doi.org/10.3390/pharmaceutics13081115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8399469PMC
July 2021

Clinical outcomes as a function of the number of samples taken during stereotactic needle biopsies: a meta-analysis.

J Neurooncol 2021 Aug 12;154(1):1-11. Epub 2021 Jul 12.

Department of Neurosurgery, University of Minnesota, Minneapolis, MN, USA.

Background: Stereotactic needle biopsy remains the cornerstone for tissue diagnosis for tumors located in regions of the brain that are difficult to access through open surgery.

Objective: We perform a meta-analysis of the literature to examine the relation between number of samples taken during biopsy and diagnostic yield, morbidity and mortality.

Methods: We identified 2416 patients from 28 cohorts in studies published in PubMed database that studied stereotactic needle biopsies for tumor indications. Meta-analysis by proportions and meta-regression analyses were performed.

Results: On meta-analysis, the morbidity profile of the published needle biopsy studies clustered into three groups: studies that performed < 3 samples (n = 8), 3-6 samples (n = 13), and > 6 samples during biopsy (n = 7). Pooled estimates for biopsy related morbidity were 4.3%, 16.3%, and 17% for studies reporting < 3, 3-6, and > 6 biopsy samples, respectively. While these morbidity estimates significantly differed (p < 0.001), the diagnostic yields reported for studies performing < 3 biopsies, 3-6 samples, and > 6 samples were comparable. Pooled estimates of diagnostic yield for these three groups were 90.4%, 93.8%, and 88.1%, respectively. Mortality did not significantly differ between studies reporting differing number of samples taken during biopsy.

Conclusions: Our meta-analysis suggests that morbidity risk in needle biopsy is non-linearly associated with the number of samples taken. There was no association between the number of biopsies taken, and diagnostic yield or mortality.
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http://dx.doi.org/10.1007/s11060-021-03785-9DOI Listing
August 2021

Cumulative Intracranial Tumor Volume as a Prognostic Factor in Patients with Brain Metastases Undergoing Stereotactic Radiosurgery.

Acta Neurochir Suppl 2021 ;128:57-69

Department of Neurosurgery, University of Minnesota Medical School, Minneapolis, MN, USA.

Approximately 25-35% of all cancer patients suffer from brain metastases (BM), and many of them-in particular, those with a limited number of intracranial tumors-are treated with stereotactic radiosurgery (SRS). Accurate prediction of survival remains a key clinical challenge in this population. Several prognostic scales have been developed to facilitate this prognostication, including the Recursive Partitioning Analysis (RPA) classification, the modified Recursive Partitioning Analysis (mRPA) subclassifications, the Basic Score for Brain Metastases (BS-BM), the Score Index for Radiosurgery (SIR), the Graded Prognostic Assessment (GPA), and the diagnosis-specific Graded Prognostic Assessment (dsGPA). However, none of these scales include consideration of the cumulative intracranial tumor volume (CITV), which is defined as the sum of all intracranial tumor volumes. Since there is mounting evidence that the CITV carries significant prognostic value in SRS-treated patients with BM, this variable should be considered during survival prognostication, along with other pertinent clinical, pathological, and molecular characteristics.
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http://dx.doi.org/10.1007/978-3-030-69217-9_7DOI Listing
July 2021

Evidence-Based Recommendations for Seizure Prophylaxis in Patients with Brain Metastases Undergoing Stereotactic Radiosurgery.

Acta Neurochir Suppl 2021 ;128:51-55

Department of Neurosurgery, University of Minnesota Medical School, Minneapolis, MN, USA.

Symptomatic epilepsy is frequently encountered in patients with brain metastases (BM), affecting up to 25% of them. However, it generally remains unknown whether the risk of seizures in such cases is affected by stereotactic radiosurgery (SRS), which involves highly conformal delivery of high-dose irradiation to the tumor with a minimal effect on adjacent brain tissue. Thus, the role of prophylactic administration of antiepileptic drugs (AED) after SRS remains controversial. A comprehensive review and analysis of the available literature reveals that according to prospective studies, the incidence of seizures after SRS for BM varies from 8% to 22%, and there is no evidence that SRS increases the incidence of symptomatic epilepsy. Therefore, routine prophylactic administration of AED prior to, during, or after SRS in the absence of a seizure history is not recommended. Nevertheless, short-course administration of an AED may be judiciously considered (on the basis of class III evidence) for selected high-risk individuals.
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http://dx.doi.org/10.1007/978-3-030-69217-9_6DOI Listing
July 2021

Pattern of technology diffusion in the adoption of stereotactic laser interstitial thermal therapy (LITT) in neuro-oncology.

J Neurooncol 2021 Jul 13;153(3):417-424. Epub 2021 Jun 13.

Department of Neurological Surgery, University of Minnesota, 420 Delaware St SE, MMC 96, Room D-429, Minneapolis, MN, 55455, USA.

Purpose: Understanding factors that influence technology diffusion is central to clinical translation of novel therapies. We characterized the pattern of adoption for laser interstitial thermal therapy (LITT), also known as stereotactic laser ablation (SLA), in neuro-oncology using the National Inpatient Sample (NIS) database.

Methods: We identified patients age ≥ 18 in the NIS (2012-2018) with a diagnosis of primary or metastatic brain tumor that underwent LITT or craniotomy. We compared characteristics and outcomes for patients that underwent these procedures.

Results: LITT utilization increased ~ 400% relative to craniotomy during the study period. Despite this increase, the total number of LITT procedures performed for brain tumor was < 1% of craniotomy. After adjusting for this time trend, LITT patients were less likely to have > 2 comorbidities (OR 0.64, CI 0.51-0.79) or to be older (OR 0.92, CI 0.86-0.99) and more likely to be female (OR 1.35, CI 1.08-1.69), Caucasian compared to Black (OR 1.94, CI 1.12-3.36), and covered by private insurance compared to Medicare or Medicaid (OR 1.38, CI 1.09-1.74). LITT hospital stays were 50% shorter than craniotomy (IRR 0.52, CI 0.45-0.61). However, charges related to the procedures were comparable between LITT and craniotomy ($1397 greater for LITT, CI $-5790 to $8584).

Conclusion: For neuro-oncology indications, LITT utilization increased ~ 400% relative to craniotomy. Relative to craniotomy-treated patients, LITT-treated patients were likelier to be young, female, non-Black race, covered by private insurance, or with < 2 comorbidities. While the total hospital charges were comparable, LITT was associated with a shorter hospitalization relative to craniotomy.
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http://dx.doi.org/10.1007/s11060-021-03760-4DOI Listing
July 2021

A radiomics-based model for predicting local control of resected brain metastases receiving adjuvant SRS.

Clin Transl Radiat Oncol 2021 Jul 8;29:27-32. Epub 2021 May 8.

Department of Radiation Oncology, University of Minnesota, Minneapolis, MN, USA.

Purpose: Adjuvant radiosurgery to the cavities of surgically resected brain metastases provides excellent local tumor control while reducing the risk of deleterious cognitive decline associated with whole brain radiotherapy. A subset of these patients, however, will develop disease recurrence following radiosurgery. In this study, we sought to assess the predictive capability of radiomic-based models, as compared with standard clinical features, in predicting local tumor control.

Methods: We performed a retrospective chart review of patients treated with adjuvant radiosurgery for resected brain metastases at the "Institution" from 2009 to 2019. Shape, intensity and texture based radiomics features of the cavities were extracted from the pre-radiosurgery treatment planning MRI scans and trained using a gradient boosting technique with K-fold cross validation.

Results: In total, 71 cavities from 67 treated patients were included for analysis. The 6 and 12 month local control estimates were 86% and 76%, respectively. The 6 and 12 month overall survival was 78% and 55%, respectively. Thirty-six patients developed intracranial failures outside of the surgical cavity. The predictive model for local control trained on imaging features from the whole cavity achieved an area-under-the-curve (AUC) of 0.73 on the validation set versus an AUC of 0.40 for the clinical features.

Conclusions: Here we report a single institutional experience using radiomic-based predictive modeling of local tumor control following adjuvant Gamma Knife radiosurgery for resected brain metastases. We found the radiomics features to provide more robust predictive models of local control rates versus clinical features alone. Such techniques could potentially prove useful in the clinical setting and warrant further investigation.
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http://dx.doi.org/10.1016/j.ctro.2021.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164004PMC
July 2021

Macrophages/Microglia in the Glioblastoma Tumor Microenvironment.

Int J Mol Sci 2021 May 28;22(11). Epub 2021 May 28.

Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA.

The complex interaction between glioblastoma and its microenvironment has been recognized for decades. Among various immune profiles, the major population is tumor-associated macrophage, with microglia as its localized homolog. The present definition of such myeloid cells is based on a series of cell markers. These good sentinel cells experience significant changes, facilitating glioblastoma development and protecting it from therapeutic treatments. Huge, complicated mechanisms are involved during the overall processes. A lot of effort has been dedicated to crack the mysterious codes in macrophage/microglia recruiting, activating, reprogramming, and functioning. We have made our path. With more and more key factors identified, a lot of new therapeutic methods could be explored to break the ominous loop, to enhance tumor sensitivity to treatments, and to improve the prognosis of glioblastoma patients. However, it might be a synergistic system rather than a series of clear, stepwise events. There are still significant challenges before the light of truth can shine onto the field. Here, we summarize recent advances in this field, reviewing the path we have been on and where we are now.
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http://dx.doi.org/10.3390/ijms22115775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198046PMC
May 2021

Self‑renewal signaling pathways and differentiation therapies of glioblastoma stem cells (Review).

Int J Oncol 2021 Jul 20;59(1). Epub 2021 May 20.

Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China.

Glioblastoma multiforme (GBM) is a primary brain tumor with a high mortality rate and a median survival time of ~14 months from the initial diagnosis. Although progress has been made in the currently available therapies, the treatment of GBM remains palliative. GBM contains subsets of GBM stem cells (GSCs) that share numerous neural stem/progenitor cell characteristics, such as expression of stem cell markers, self‑renewal and multi‑lineage differentiation capacity, thus contributing to the heterogeneity and complexity of these tumors. GSCs are potentially associated with tumor initiation and they are considered as the driving force behind tumor formation, as they possess tumor‑propagating potential and exhibit preferential resistance to radiotherapy and chemotherapy. Targeting self‑renewal signaling pathways in cancer stem cells may effectively reduce tumor recurrence and significantly improve prognosis. The aim of the present review was to summarize the current knowledge on the self‑renewal signaling pathways of GSCs and discuss potential future targeting strategies for the design of differentiation therapies.
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http://dx.doi.org/10.3892/ijo.2021.5225DOI Listing
July 2021

State of Radiomics in Glioblastoma.

Neurosurgery 2021 07;89(2):177-184

Department of Neurosurgery, University of Minnesota, Minneapolis, Minnesota, USA.

Radiomics is an emerging discipline that aims to make intelligent predictions and derive medical insights based on quantitative features extracted from medical images as a means to improve clinical diagnosis or outcome. Pertaining to glioblastoma, radiomics has provided powerful, noninvasive tools for gaining insights into pathogenesis and therapeutic responses. Radiomic studies have yielded meaningful biological understandings of imaging features that are often taken for granted in clinical medicine, including contrast enhancement on glioblastoma magnetic resonance imaging, the distance of a tumor from the subventricular zone, and the extent of mass effect. They have also laid the groundwork for noninvasive detection of mutations and epigenetic events that influence clinical outcomes such as isocitrate dehydrogenase (IDH) and O6-methylguanine-DNA methyltransferase (MGMT). In this article, we review advances in the field of glioblastoma radiomics as they pertain to prediction of IDH mutation status and MGMT promoter methylation status, as well as the development of novel, higher order radiomic parameters.
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http://dx.doi.org/10.1093/neuros/nyab124DOI Listing
July 2021

Detection of Isocitrate Dehydrogenase Mutated Glioblastomas Through Anomaly Detection Analytics.

Neurosurgery 2021 07;89(2):323-328

Department of Computer Science and Engineering, University of Minnesota, Minneapolis, Minnesota, USA.

Background: The rarity of Isocitrate Dehydrogenase mutated (mIDH) glioblastomas relative to wild-type IDH glioblastomas, as well as their distinct tumor physiology, effectively render them "outliers". Specialized tools are needed to identify these outliers.

Objective: To carefully craft and apply anomaly detection methods to identify mIDH glioblastoma based on radiomic features derived from magnetic resonance imaging.

Methods: T1-post gadolinium images for 188 patients and 138 patients were downloaded from The Cancer Imaging Archive's (TCIA) The Cancer Genome Atlas (TCGA) glioblastoma collection, and from the University of Minnesota Medical Center (UMMC), respectively. Anomaly detection methods were tested on glioblastoma image features for the precision of mIDH detection and compared to standard classification methods.

Results: Using anomaly detection training methods, we were able to detect IDH mutations from features in noncontrast-enhancing regions in glioblastoma with an average precision of 75.0%, 69.9%, and 69.8% using three different models. Anomaly detection methods consistently outperformed traditional two-class classification methods from 2 unique learning models (67.9%, 67.6%). The disparity in performances could not be overcome through newer, popular models such as neural networks (67.4%).

Conclusion: We employed an anomaly detection strategy in the detection of IDH mutation in glioblastoma using preoperative T1 postcontrast imaging. We show these methods outperform traditional two-class classification in the setting of dataset imbalances inherent to IDH mutation prevalence in glioblastoma. We validate our results using an external dataset and highlight new possible avenues for radiogenomic rare event prediction in glioblastoma and beyond.
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http://dx.doi.org/10.1093/neuros/nyab130DOI Listing
July 2021

PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response.

Proc Natl Acad Sci U S A 2021 04;118(16)

Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455;

Precision medicine in oncology leverages clinical observations of exceptional response. Toward an understanding of the molecular features that define this response, we applied an integrated, multiplatform analysis of RNA profiles derived from clinically annotated glioblastoma samples. This analysis suggested that specimens from exceptional responders are characterized by decreased accumulation of microglia/macrophages in the glioblastoma microenvironment. Glioblastoma-associated microglia/macrophages secreted interleukin 11 (IL11) to activate STAT3-MYC signaling in glioblastoma cells. This signaling induced stem cell states that confer enhanced tumorigenicity and resistance to the standard-of-care chemotherapy, temozolomide (TMZ). Targeting a myeloid cell restricted an isoform of phosphoinositide-3-kinase, phosphoinositide-3-kinase gamma isoform (PI3Kγ), by pharmacologic inhibition or genetic inactivation disrupted this signaling axis by reducing microglia/macrophage-associated IL11 secretion in the tumor microenvironment. Mirroring the clinical outcomes of exceptional responders, PI3Kγ inhibition synergistically enhanced the anti-neoplastic effects of TMZ in orthotopic murine glioblastoma models. Moreover, inhibition or genetic inactivation of PI3Kγ in murine glioblastoma models recapitulated expression profiles observed in clinical specimens isolated from exceptional responders. Our results suggest key contributions from tumor-associated microglia/macrophages in exceptional responses and highlight the translational potential for PI3Kγ inhibition as a glioblastoma therapy.
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http://dx.doi.org/10.1073/pnas.2009290118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072253PMC
April 2021

Brain fMRI during orientation selective epidural spinal cord stimulation.

Sci Rep 2021 03 9;11(1):5504. Epub 2021 Mar 9.

Center for Magnetic Resonance Research (CMRR), Department of Radiology, University of Minnesota, 2021 6th St. SE, Minneapolis, MN, 55455, USA.

Epidural spinal cord stimulation (ESCS) is widely used for chronic pain treatment, and is also a promising tool for restoring motor function after spinal cord injury. Despite significant positive impact of ESCS, currently available protocols provide limited specificity and efficiency partially due to the limited number of contacts of the leads and to the limited flexibility to vary the spatial distribution of the stimulation field in respect to the spinal cord. Recently, we introduced Orientation Selective (OS) stimulation strategies for deep brain stimulation, and demonstrated their selectivity in rats using functional MRI (fMRI). The method achieves orientation selectivity by controlling the main direction of the electric field gradients using individually driven channels. Here, we introduced a similar OS approach for ESCS, and demonstrated orientation dependent brain activations as detected by brain fMRI. The fMRI activation patterns during spinal cord stimulation demonstrated the complexity of brain networks stimulated by OS-ESCS paradigms, involving brain areas responsible for the transmission of the motor and sensory information. The OS approach may allow targeting ESCS to spinal fibers of different orientations, ultimately making stimulation less dependent on the precision of the electrode implantation.
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http://dx.doi.org/10.1038/s41598-021-84873-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943775PMC
March 2021

Guidelines in the management of CNS tumors.

J Neurooncol 2021 Feb 21;151(3):345-359. Epub 2021 Feb 21.

Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA.

Introduction: Evidence-based, clinical practice guidelines in the management of central nervous system tumors (CNS) continue to be developed and updated through the work of the Joint Section on Tumors of the Congress of Neurological Surgeons (CNS) and the American Association of Neurological Surgeons (AANS).

Methods: The guidelines are created using the most current and clinically relevant evidence using systematic methodologies, which classify available data and provide recommendations for clinical practice.

Conclusion: This update summarizes the Tumor Section Guidelines developed over the last five years for non-functioning pituitary adenomas, low grade gliomas, vestibular schwannomas, and metastatic brain tumors.
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http://dx.doi.org/10.1007/s11060-020-03530-8DOI Listing
February 2021

GBP5 drives malignancy of glioblastoma via the Src/ERK1/2/MMP3 pathway.

Cell Death Dis 2021 02 19;12(2):203. Epub 2021 Feb 19.

Central Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China.

Guanylate binding proteins (GBPs), a family of interferon-inducible large GTPase, play a pivotal role in cell-autonomous immunity and tumor malignant transformation. Glioblastoma (GBM) is the most prevalent and lethal primary brain tumor in adults. Here we show that GBP5 was highly expressed in GBM cell lines and in clinical samples, especially in the mesenchymal subtype. The expression levels of GBP5 were negatively correlated with the prognosis of GBM patients. Overexpression of GBP5 promoted the proliferation, migration, and invasion of GBM cells in vitro and in vivo. In contrast, silencing GBP5 by RNA interference exhibited the opposite effects. Consequently, targeting GBP5 in GBM cells resulted in impaired tumor growth and prolonged survival time of mice with GBM tumors. We further identified that the Src/ERK1/2/MMP3 axis was essential for GBP5-promoted GBM aggressiveness. These findings suggest that GBP5 may represent a novel target for GBM intervention.
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http://dx.doi.org/10.1038/s41419-021-03492-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896088PMC
February 2021

Through the looking glass: A review of cranial window technology for optical access to the brain.

J Neurosci Methods 2021 04 15;354:109100. Epub 2021 Feb 15.

Department of Neurosurgery, University of Minnesota, 420 Delaware St SE, Mayo D429, MMC 96, Twin Cities, Minneapolis, MN, 55455, USA. Electronic address:

Deciphering neurologic function is a daunting task, requiring understanding the neuronal networks and emergent properties that arise from the interactions among single neurons. Mechanistic insights into neuronal networks require tools that simultaneously assess both single neuron activity and the consequent mesoscale output. The development of cranial window technologies, in which the skull is thinned or replaced with a synthetic optical interface, has enabled monitoring neuronal activity from subcellular to mesoscale resolution in awake, behaving animals when coupled with advanced microscopy techniques. Here we review recent achievements in cranial window technologies, appraise the relative merits of each design and discuss the future research in cranial window design.
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http://dx.doi.org/10.1016/j.jneumeth.2021.109100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100903PMC
April 2021

An integrated disease-specific graded prognostic assessment scale for melanoma: contributions of KPS, CITV, number of metastases, and BRAF mutation status.

Neurooncol Adv 2021 Jan-Dec;3(1):vdaa152. Epub 2020 Nov 12.

Department of Neurosurgery, University of Minnesota, Minneapolis, Minnesota, USA.

Background: Stereotactic radiosurgery (SRS) remains a mainstay therapy in the treatment of melanoma brain metastases (BM). While prognostic scales have been developed for melanoma patients who underwent SRS treatment for BM, the pertinence of these scales in the context of molecularly targeted therapies remains unclear.

Methods: Through a multi-institutional collaboration, we collated the survival patterns of 331 melanoma BM patients with known BRAF mutation status treated with SRS. We established a prognostic scale that was validated in an independent cohort of 174 patients. All patients with BRAF mutations in this series were treated with BRAF inhibitors. Prognostic utility was assessed using Net Reclassification Index (NRI > 0) and integrated discrimination improvement (IDI) metrics.

Results: In a multivariate Cox proportional hazards model, BRAF mutation status, KPS, number of metastases, and cumulative intracranial tumor volume (CITV) independently contributed to survival prognostication for melanoma patients with SRS-treated BM ( < .05 for all variables). These variables were incorporated into a prognostic scale using the disease-specific graded prognostic assessment (ds-GPA) framework. This integrated melanoma ds-GPA scale was validated in 2 independent cohorts collated through a multi-institutional collaboration. In terms of order of prognostic importance, BRAF mutation status exerted the greatest influence on survival, while KPS, the number of metastases, and CITV exhibited comparable, lesser impacts.

Conclusions: Optimal survival prognostication for SRS-treated patients with melanoma BM requires an integrated assessment of patient characteristics (KPS), tumor characteristics (CITV and number of metastases), and the mutational profile of the melanoma (BRAF mutation status).
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http://dx.doi.org/10.1093/noajnl/vdaa152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810198PMC
November 2020

The Rate of Symptomatic Ischemic Events after Passing Balloon Test Occlusion of the Major Intracranial Arteries: Meta-Analysis.

World Neurosurg 2021 02 30;146:e1182-e1190. Epub 2020 Nov 30.

Department of Neurosurgery, University of Minnesota, Minneapolis, Minnesota, USA. Electronic address:

Background: Balloon test occlusion is a widely used method for predicting tolerance of vessel occlusion in the treatment of aneurysms, fistulae, and head and neck neoplasms. However, the false-negative rate is variably reported due in part to the diversity of perfusion monitoring methods.

Objective: To evaluate the rate of symptomatic ischemic events after a negative balloon test occlusion and determine whether perfusion monitoring methods contribute to differences in these rates.

Methods: PubMed was systematically searched for studies between 1990 and 2020 that reported rates of ischemic outcomes of parental vessel occlusion in patients who passed balloon test occlusion. A generalized linear mixed model meta-analysis was performed. Results were expressed as the rate of symptomatic ischemic events after parental vessel occlusion without vessel bypass in patients who passed balloon test occlusion.

Results: Thirty-two studies met the inclusion criteria. The overall pooled rate of ischemic events after passing balloon test occlusion was 3.7% (95% confidence interval [CI]: 1.7-7.8). This rate was 3.8% (95% CI: 1.1-12.8) when monitored with angiography, 2.2% (95% CI: 0.4-10.2) when monitored by a form of computed tomography, and 5.3% (95% CI: 1.2-20.4) when monitored by 2 or more methods of perfusion assessment. The complication rate of balloon test occlusion was 0.8% (95% CI: 0.2-2.7).

Conclusions: Balloon test occlusion results in a low rate of subsequent ischemic events, without conclusive evidence of variation between methods of perfusion assessment. The choice of method should focus on reduction of complication risk, experience of the interventional team, and avoidance of prolonged test occlusion times.
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http://dx.doi.org/10.1016/j.wneu.2020.11.134DOI Listing
February 2021

Hemorrhagic Complications of Invasive Intracranial Pressure Monitor Placement in Acute Liver Failure: Outcomes of a Single-Center Protocol and Comprehensive Literature Review.

Neurocrit Care 2021 08 18;35(1):87-102. Epub 2020 Nov 18.

Division of Neurosurgery, McMaster University/Hamilton Health Sciences, 237, Barton Street East, Hamilton, ON, L8L 2X2, Canada.

Background: Elevated intracranial pressure due to cerebral edema is associated with very poor survival in patients with acute liver failure (ALF). Placing an intracranial pressure monitor (ICPm) aids in management of intracranial hypertension, but is associated with potentially fatal hemorrhagic complications related to the severe coagulopathy associated with ALF.

Methods: An institutional Acute Liver Failure Clinical Protocol (ALF-CP) was created to correct ALF coagulopathy prior to placing parenchymal ICP monitoring bolts. We aimed to investigate the frequency, severity, and clinical significance of hemorrhagic complications associated with ICPm bolt placement in the setting of an ALF-CP. All assessed patients were managed with the ALF-CP and had rigorous radiologic follow-up allowing assessment of the occurrence and chronology of hemorrhagic complications. We also aimed to compare our outcomes to other studies that were identified through a comprehensive review of the literature.

Results: Fourteen ALF patients were included in our analysis. There was no symptomatic hemorrhage after ICP monitor placement though four patients were found to have minor intraparenchymal asymptomatic hemorrhages after liver transplant when the ICP monitor had been removed, making the rate of radiographically identified clinically asymptomatic hemorrhage 28.6%. These results compare favorably to those found in a comprehensive review of the literature which revealed rates as high as 17.5% for symptomatic hemorrhages and 30.4% for asymptomatic hemorrhage.

Conclusion: This study suggests that an intraparenchymal ICPm can be placed safely in tertiary referral centers which utilize a protocol such as the ALF-CP that aggressively corrects coagulopathy. The ALF-CP led to advantageous outcomes for ICPm placement with a 0% rate of symptomatic and low rate of asymptomatic hemorrhagic complications, which compares well to results reported in other series. A strict ICPm placement protocol in this setting facilitates management of ALF patients with cerebral edema during the wait time to transplantation or spontaneous recovery.
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http://dx.doi.org/10.1007/s12028-020-01143-7DOI Listing
August 2021

Resective epilepsy surgery: assessment of randomized controlled trials.

Neurosurg Rev 2021 Aug 9;44(4):2059-2067. Epub 2020 Nov 9.

Department of Neurosurgery, University of Minnesota, 420 Delaware St SE, MMC 96, D-429 Mayo Memorial Building, Minneapolis, MN, 55455, USA.

Epilepsy is the most common form of chronic neurologic disease. Here, we review the available randomized controlled trials (RCTs) that examined the efficacy of resective epilepsy surgery in select patients suffering from medically intractable epilepsy (defined as persistent epilepsy despite two or more antiepileptic drugs [AEDs]). Three RCTs (two adult RCTs and one pediatric RCT) consistently supported the efficacy of resective surgery as treatment for epilepsy with semiology localized to the mesial temporal lobe. In these studies, 58-100% of the patients who underwent resective surgery achieved seizure freedom, in comparison to 0-13% of medically treated patients. In another RCT, the likelihood of seizure freedom after resective surgery was independent of the surgical approach (transSylvian [64%] versus subtemporal [62%]). Two other RCTs demonstrated that hippocampal resection is essential to optimize seizure control. But, no significant gain in seizure control was achieved beyond removing 2.5 cm of the hippocampus. Across RCTs, minor complications (deficit lasting < 3 months) and major complications (deficit > 3 months) ranged 2-5% and 5-11% respectively. However, nonincapacitating superior subquadrantic visual-field defects (not typically considered a minor or major complication) were noted in up to 55% of the surgical cohort. The available RCTs provide compelling support for resective surgery as a treatment for mesial temporal lobe epilepsy and offer insights toward optimal surgical strategy.
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http://dx.doi.org/10.1007/s10143-020-01432-xDOI Listing
August 2021

Effect of Vocimagene Amiretrorepvec in Combination With Flucytosine vs Standard of Care on Survival Following Tumor Resection in Patients With Recurrent High-Grade Glioma: A Randomized Clinical Trial.

JAMA Oncol 2020 12;6(12):1939-1946

Cleveland Clinic Foundation, Moffitt Cancer Center, Tampa, Florida.

Importance: New treatments are needed to improve the prognosis of patients with recurrent high-grade glioma.

Objective: To compare overall survival for patients receiving tumor resection followed by vocimagene amiretrorepvec (Toca 511) with flucytosine (Toca FC) vs standard of care (SOC).

Design, Setting, And Participants: A randomized, open-label phase 2/3 trial (TOCA 5) in 58 centers in the US, Canada, Israel, and South Korea, comparing posttumor resection treatment with Toca 511 followed by Toca FC vs a defined single choice of approved (SOC) therapies was conducted from November 30, 2015, to December 20, 2019. Patients received tumor resection for first or second recurrence of glioblastoma or anaplastic astrocytoma.

Interventions: Patients were randomized 1:1 to receive Toca 511/FC (n = 201) or SOC control (n = 202). For the Toca 511/FC group, patients received Toca 511 injected into the resection cavity wall at the time of surgery, followed by cycles of oral Toca FC 6 weeks after surgery. For the SOC control group, patients received investigators' choice of single therapy: lomustine, temozolomide, or bevacizumab.

Main Outcomes And Measures: The primary outcome was overall survival (OS) in time from randomization date to death due to any cause. Secondary outcomes reported in this study included safety, durable response rate (DRR), duration of DRR, durable clinical benefit rate, OS and DRR by IDH1 variant status, and 12-month OS.

Results: All 403 randomized patients (median [SD] age: 56 [11.46] years; 62.5% [252] men) were included in the efficacy analysis, and 400 patients were included in the safety analysis (3 patients on the SOC group did not receive resection). Final analysis included 271 deaths (141 deaths in the Toca 511/FC group and 130 deaths in the SOC control group). The median follow-up was 22.8 months. The median OS was 11.10 months for the Toca 511/FC group and 12.22 months for the control group (hazard ratio, 1.06; 95% CI 0.83, 1.35; P = .62). The secondary end points did not demonstrate statistically significant differences. The rates of adverse events were similar in the Toca 511/FC group and the SOC control group.

Conclusions And Relevance: Among patients who underwent tumor resection for first or second recurrence of glioblastoma or anaplastic astrocytoma, administration of Toca 511 and Toca FC, compared with SOC, did not improve overall survival or other efficacy end points.

Trial Registration: ClinicalTrials.gov Identifier: NCT02414165.
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http://dx.doi.org/10.1001/jamaoncol.2020.3161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596685PMC
December 2020

FHL1 promotes glioblastoma aggressiveness through regulating EGFR expression.

FEBS Lett 2021 01 28;595(1):85-98. Epub 2020 Oct 28.

Central Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou, China.

The four-and-a-half LIM domain protein 1 (FHL1) plays a key role in multiple cancers. Here, we characterized its role in glioblastoma (GBM), the most common and incurable form of brain cancer. Overexpression of FHL1 promotes growth, migration, and invasion of GBM cells in vivo and in vitro. In contrast, FHL1 silencing by RNAi exhibits the opposite effects. FHL1 interacts with the transcription factor SP1 to upregulate epidermal growth factor receptor (EGFR) expression and activate the downstream signaling cascades, including Src, Akt, Erk1/2, and Stat3, leading to GBM malignancy. FHL1 is highly expressed and positively correlated with EGFR levels in human GBM, particularly those of the classical subtype. Our results suggest that the FHL1-SP1-EGFR axis plays a tumor-promoting role, and highlight the translational potential of inhibiting FHL1 for GBM treatment.
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http://dx.doi.org/10.1002/1873-3468.13955DOI Listing
January 2021

Epidermal growth factor receptor as a molecular determinant of glioblastoma response to dopamine receptor D2 inhibitors.

Neuro Oncol 2021 03;23(3):400-411

Department of Neurosurgery, University of Minnesota, Minneapolis, Minnesota, USA.

Background: There are ongoing clinical trials exploring the efficacy of dopamine receptor D2 (DRD2) inhibition against glioblastomas, the most common primary brain tumor. Here we examine potential molecular determinants of this efficacy.

Methods: The Cancer Genome Atlas glioblastoma database and other published mRNA profiles were used to analyze the DRD2 and epidermal growth factor receptor (EGFR) expression pattern. In vitro and in vivo responses to DRD2 inhibitors were determined using patient-derived xenograft (PDX) glioblastoma models. Immunohistochemical studies were performed on clinically annotated glioblastoma samples derived from patients treated with ONC201.

Results: Analysis of clinical glioblastoma specimens derived from independent patient cohorts revealed an inverse correlation between EGFR and DRD2 mRNA expression, with implication that signaling mediated by these proteins shares overlapping functions. In independent panels of PDX glioblastoma lines, high EGFR expression was associated with poor in vitro and in vivo response to DRD2 inhibitors, including haloperidol and ONC201. Moreover, ectopic expression of a constitutively active EGFR, variant (v)III, suppressed glioblastoma sensitivity to ONC201. DRD2 expression positively correlated with expression of rate-limiting enzymes for dopamine synthesis as well as dopamine secretion, suggesting contribution of autocrine DRD2 signaling. Analysis of specimens from patients treated with ONC201 (n = 15) showed an inverse correlation between the intensity of EGFR staining and clinical response. The median overall survival for patients with high and low EGFR staining was 162 and 373 days, respectively (0.037).

Conclusions: High EGFR expression is a determinant of poor glioblastoma response to DRD2. This finding should inform future clinical trial designs.
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http://dx.doi.org/10.1093/neuonc/noaa188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992877PMC
March 2021

Combining oncolytic virus with FDA approved pharmacological agents for cancer therapy.

Expert Opin Biol Ther 2021 02 14;21(2):183-189. Epub 2020 Sep 14.

Department of Neurosurgery, University of Minnesota Medical School , Minneapolis, MN, USA.

Introduction: Oncolytic viruses (OVs) have been engineered to selectively replicate in cancer cells. While initially thought to exert its anti-cancer effects through direct cytolysis, it is increasingly appreciated that OVs interact with a multitude of cellular processes during its life cycle; FDA approved pharmacologic agents that modulate these cellular processes have been shown to augment the anti-neoplastic effects of OVs. Moreover, because of the release of tumor antigens as well as the innate immuno-stimulatory nature of viruses, OVs induce potent immune responses that augment the anti-tumor effects of FDA approved immunotherapies. There is mounting interest in OV as a platform for combinational anti-cancer therapy in this context.

Areas Covered: We will review pre-clinical and clinical data that demonstrate proof-of-principle and potential efficacy for OV-based combination therapies with FDA approved anti-cancer agents.

Expert Opinion: While the cytolytic activity of OV remains a key driver for its anti-neoplastic effects, understanding the virus-host interactions may afford opportunities for potential synergism with FDA approved therapeutics that target these interactions. Most intriguingly, the immune stimulatory effects of OVs renders combination with FDA approved immunotherapies more potent. While there are growing clinical trials employing such combination therapy, meaningful advances in this paradigm will require improved understanding of virus-host interactions.
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http://dx.doi.org/10.1080/14712598.2020.1811848DOI Listing
February 2021

Plasma Biomarker for Post-concussive Syndrome: A Pilot Study Using an Alternating Current Electro-Kinetic Platform.

Front Neurol 2020 14;11:685. Epub 2020 Jul 14.

Department of Neurosurgery, University of Minnesota, Minneapolis, MN, United States.

Technology platforms that afford biomarker discovery in patients suffering from traumatic brain injury (TBI) remain an unmet medical need. Here, we describe an observational pilot study to explore the utility of an alternating current electrokinetic (ACE) microchip device in this context. Blood samples were collected from participating subjects with and without minor TBI. Plasma levels of glial fibrillary acidic protein (GFAP), Tau, ubiquitin C-terminal hydrolase L1 (UCH-L1), and cell-free DNA (cfDNA) were determined in subjects with and without minor TBI using ACE microchip device followed by on-chip immunofluorescent analysis. Post-concussive symptoms were assessed using the Rivermead Post Concussion Symptoms Questionnaire (RPCSQ) at one-month follow-up. Highest levels of GFAP, UCH-L1, and Tau were seen in two minor TBI subjects with abnormality on head computed tomography (CT). In patients without abnormal head CT, Tau and GFAP levels discriminated between plasma from minor-TBI and non-TBI patients, with sensitivity and specificity of 64-72 and 50%, respectively. Plasma GFAP, UCH-L1, and Tau strongly correlated with the cumulative RPCSQ score. Plasma UCH-L1 and GFAP exhibited highest correlation to sensitivity to noise and light ( = 0.96 and 0.91, respectively, < 0.001). Plasma UCH-L1 and Tau showed highest correlation with headache ( = 0.74 and 0.78, respectively, < 0.001), sleep disturbance ( = 0.69 and 0.84, respectively, < 0.001), and cognitive symptoms, including forgetfulness ( = 0.76 and 0.74, respectively, < 0.001), poor concentration ( = 0.68 and 0.76, respectively, < 0.001), and time required for information processing ( = 0.77 and 0.81, respectively, < 0.001). cfDNA exhibited a strong correlation with depression ( = 0.79, < 0.01) and dizziness ( = 0.69, < 0.01). While cfDNA demonstrated positive correlation with dizziness and depression ( = 0.69 and 0.79, respectively, < 0.001), no significant correlation was observed between cumulative RPCSQ and cfDNA ( = 0.07, = 0.81). We provide proof-of-principle results supporting the utility of ACE microchip for plasma biomarker analysis in patients with minor TBI.
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http://dx.doi.org/10.3389/fneur.2020.00685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371973PMC
July 2020

Cost-effectiveness of stereotactic laser ablation (SLA) for brain tumors.

Int J Hyperthermia 2020 07;37(2):61-67

Department of Neurosurgery, University of Minnesota, Minneapolis, MN, USA.

Background: Stereotactic laser ablation(SLA) or laser interstitial thermal therapy (LITT) has been increasingly adopted as a treatment for primary and metastatic brain cancers. Here, we examined the published economic assessments of SLA, and review the current state of knowledge.

Methods: The PubMed database was queried for articles investigating the cost-effectiveness of LITT. 3068 articles were screened. Two studies that met the inclusion criteria were included in this review.

Results: Cost-effectiveness analysis(CEA) favored SLA( = 8) relative to craniotomy ( = 92) for brain metastases (Mean difference [MD]=-US$6522; 95% confidence interval (CI) -$11,911 to -$1133;  = 0.02). SLA ( = 19) was found to be cost equivalent to craniotomy ( = 248) (MD=-US$1669; 95%(CI) -$8192 to $4854,  = 0.62) for primary brain tumors in general. CEA favored SLA for a subset of primary brain cancers. SLA was found to be cost-effective for difficult to access high-grade gliomas(HGG). When compared to 'other' existing treatments, the cost per life-years gained (LYG) through SLA was ∼$29,340, a threshold below that set for new technology adaptation in the U.S. Factors contributing to these cost-effectiveness were: (1) SLA of HGGs was associated with three-months prolongation in survival; (2) SLA of brain metastasis was associated with (i) shorter average length of stay (SLA: 2.3 days; craniotomy: 4.7 days), (ii) decreased discharge to inpatient rehabilitation facility (IRF), skilled nursing facility (SNF), or home healthcare (SLA: 14.8%; craniotomy: 52%), (iii) lowered 30-day readmission (SLA: 0%; craniotomy: 14.1%).

Conclusion: There is limited data on the cost-effectiveness of SLA. In the available literature, SLA compared favorably to craniotomy in terms of cost-effectiveness as a treatment for primary and metastatic brain cancers.
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http://dx.doi.org/10.1080/02656736.2020.1774084DOI Listing
July 2020
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