The Utility of Spectroscopic MRI in Stereotactic Biopsy and Radiotherapy Guidance in Newly Diagnosed Glioblastoma.

Current diagnostic and therapeutic approaches for gliomas have limitations hindering survival outcomes. We propose spectroscopic magnetic resonance imaging as an adjunct to standard MRI to bridge these gaps. Spectroscopic MRI is a volumetric MRI technique capable of identifying tumor infiltration based on its elevated choline (Cho) and decreased N-acetylaspartate (NAA). We present the clinical translatability of spectroscopic imaging with a Cho/NAA ≥ 5x threshold for delineating a biopsy target in a patient diagnosed with non-enhancing glioma. Then, we describe the relationship between the undertreated tumor detected with metabolite imaging and overall survival (OS) from a pilot study of newly diagnosed GBM patients treated with belinostat and chemoradiation. Each cohort (control and belinostat) were split into subgroups using the median difference between pre-radiotherapy Cho/NAA ≥ 2x and the treated T1-weighted contrast-enhanced (T1w-CE) volume. We used the Kaplan-Meier estimator to calculate median OS for each subgroup. The median OS was 14.4 months when the difference between Cho/NAA ≥ 2x and T1w-CE volumes was higher than the median compared with 34.3 months when this difference was lower than the median. The T1w-CE volumes were similar in both subgroups. We find that patients who had lower volumes of undertreated tumors detected via spectroscopy had better survival outcomes.

Three-dimensional analysis of biplanar glenoid deformities: What are they and can they be virtually reconstructed with anatomic total shoulder arthroplasty implants?

BACKGROUND: Descriptions of glenoid deformities in glenohumeral osteoarthritis (GHOA) have focused on the axial plane. Less is known regarding arthritic glenoids with higher amounts of superior inclination and little evidence exists to guide management of inclination or combined version-inclination deformity when performing anatomic total shoulder arthroplasty (aTSA). We hypothesized that biplanar deformities (BD) would be present in a higher proportion of GHOA patients than previously appreciated, and these deformities would be difficult to adequately reconstruct with contemporary aTSA implants. METHODS: A retrospective query was performed of GHOA patients indicated for TSA 2012-2017 with a computed tomography (CT) scan within three months of surgery. Images were uploaded to three-dimensional software for automated measurements. Glenoids with superior inclination ≥10˚, retroversion ≥20˚ were considered to have BD. Walch classification was determined, C-type glenoids were excluded. Rotator-cuff muscle cross-sectional area (CSA) was measured and fatty infiltration graded. Glenoids with BD were virtually planned for aTSA with correction to neutral inclination and version, then 5˚ superior inclination and 10˚ retroversion. RESULTS: Two-hundred sixty-eight shoulders in 250 patients were included; average age 65 years, 67% male. There were no differences in inclination between Walch types (p=0.25). Twenty-nine shoulders with BD were identified (11%). These deformities were not associated with age (p=0.47) or gender (p=0.50) but were skewed towards Walch B-type, specifically B2 (p=0.03). Acromial index and posterior humeral head subluxation were higher in BD patients (p=0.04, p<0.001, respectively). Biplanar deformities had similar cuff CSA compared to those without but were less frequently associated with fatty infiltration of the subscapularis (p=0.05). When correcting to neutral version and inclination, 41% BD could not be reconstructed. Of those that could, 94% required augmented implants. When correcting to 5˚ superior inclination and 10˚ retroversion, 10% could not be reconstructed. Of those that could, 58% required augmented implants. With partial correction, augment use was predicted by retroversion >26˚ (p=0.009). Inclination did not predict augment use (p=0.90). Final implant position commonly involved unseating in the posterosuperior quadrant and cancellous exposure in the anteroinferior quadrant. CONCLUSIONS: This retrospective CT-based study of 268 shoulders with GHOA found a 11% prevalence of BD. These deformities were commonly associated with Walch B2 wear patterns. Virtual aTSA planning showed a high failure rate (41%) when correcting to neutral version and inclination. Posteriorly augmented implants were frequently required, and often still involved unseating in the posterosuperior quadrant, increased cancellous exposure in the anteroinferior quadrant, and vault perforation.

Predictors of pain development for contralateral asymptomatic degenerative rotator cuff tears based on features of an ipsilateral painful cuff tear: a prospective longitudinal cohort study.

BACKGROUND: Prior rotator cuff disease natural history studies have focused on tear-related factors that predict disease progression within a given shoulder. The purpose of this study was to examine both patient- and tear-related characteristics of a painful rotator cuff tear that predict future pain development and functional impairment in a shoulder with a contralateral asymptomatic cuff tear. METHODS: This was a prospective longitudinal cohort study of patients aged ≤65 years who underwent surgery for a painful degenerative rotator cuff tear and possessed an asymptomatic contralateral tear. Patients were followed up prospectively by shoulder ultrasound, physical examination, and functional score assessment. The primary outcome was change in the American Shoulder and Elbow Surgeons (ASES) score at 2 years. Secondary outcomes included the Western Ontario Rotator Cuff Index (WORC) score, Patient-Reported Outcomes Measurement Information System (PROMIS) score, Hospital Anxiety Depression Scale (HADS) depression and anxiety scores, and Veterans RAND-12 (VR-12) mental component score (MCS). RESULTS: Sixty-five patients were included, with a mean follow-up period of 37 months (range, 24-42 months). In 17 patients (26%), contralateral shoulder pain developed at a median of 15.2 months (interquartile range [IQR], 10.5 months). No difference in age, sex, Charlson Comorbidity Index, or occupational demand was noted between patients in whom pain developed and those in whom pain did not develop. In the presenting painful shoulder, there was no difference in baseline tear size, muscle degeneration, or biceps pathology between groups. The mean baseline tear length (8.6 mm vs. 3.8 mm, P = .0008) and width (8.4 mm vs. 3.2 mm, P = .0004) were larger in asymptomatic shoulders in which pain subsequently developed compared with those in which pain did not develop. However, there was no difference in mean tear enlargement (P = .51 for length and P = .90 for width). There were no differences in baseline ASES, WORC, Patient-Reported Outcomes Measurement Information System (PROMIS), or HADS depression and anxiety scores between shoulders in which pain developed and those in which pain did not develop; however, patients in whom pain developed reported a lower baseline VR-12 MCS (53.3 vs. 57.6, P = .04). Shoulders in which pain developed had higher visual analog scale pain scores (2.9 [standard deviation (SD), 2.5] vs. 0.6 [SD, 1.0]; P = .016), lower ASES scores 75 [SD, 33] vs. 100 [SD, 11.6]; P = .001), and significant changes in all WORC scales with pain onset compared with those that remained asymptomatic. The study showed no significant difference in changes in the HADS anxiety and depression scores but found a significant increase in the VR-12 MCS in patients in whom pain developed (7.1 [interquartile range, 12.6] vs. -1.9 [interquartile range, 8.7]; P = .036). CONCLUSION: In one-quarter of patients with painful cuff tears, pain developed in a contralateral asymptomatic cuff tear that resulted in a measurable decline in function within 3 years. Our analysis showed that only the baseline tear size of the asymptomatic shoulder was predictive of pain development. There were no tear-related features of the presenting painful rotator cuff tear or indices of mental health and physical function or occupational demand that were predictive of future pain development at short-term follow-up.

Volumetric Analysis of Spheno-Orbital Meningiomas: Prognostic Correlation and a Compartmentalized Approach.

BACKGROUND AND OBJECTIVES: Spheno-orbital meningiomas arise from the arachnoid villi cap cells at the sphenoid ridge and have the ability to spread through soft tissue extension and cranial bone invasion. Owing to their orbital hyperostosis and intraorbital soft tissue extension, they commonly present with ophthalmologic manifestations. This study aims to investigate the correlation between tumor volume with the presenting symptoms and postoperative outcomes. METHODS: This retrospective study analyzed patients who underwent surgical resection of spheno-orbital meningiomas. Tumor volumes in different compartments were measured using preoperative and postoperative imaging. Linear and logistic regression analyses were used to identify correlations between tumor volumes and presenting symptoms preoperatively and postoperative outcomes. RESULTS: Sixty-six patients were included in this study, of whom 86.4% had proptosis, 80.3% had decreased visual acuity (VA), 30.3% had visual field defects, and 13.6% had periorbital edema. Preoperatively, proptosis linearly correlated with intraosseous tumor volume (coefficient = 0.6, P < .001), while the decrease in baseline VA correlated with the intraorbital tumor volume (coefficient = 0.3, P = .01). The odds of periorbital edema were found to increase with an increase in intraosseous tumor volume with an adjusted odds ratio of 1.4 (95% CI, 1.1-1.7, P = .003), while the odds of visual field defects were found to increase with an increase in intraorbital tumor volume with an adjusted odds ratio of 2.7 (95% CI, 1.3-5.6, P = .01). Postoperatively, the volume of intraosseous tumor resected linearly correlated with the improvement in proptosis (coefficient = 0.7, P < .001), while the volume of intraorbital tumor resected linearly correlated with improvement in VA (coefficient = 0.5, P < .001) and with a larger effect size in patients presenting with moderate-to-severe decrease in VA preoperatively (coefficient = 0.8). CONCLUSION: Underscoring the importance of each tumor compartment relative to the patient's symptomatology serves as a valuable guide in implementing a compartmentalized resection approach tailored to the surgical objectives.

Rationale for the Development of a Novel Clinical Grading Scale for Postoperative Facial Nerve Function: Results of a Multidisciplinary International Working Group.

OBJECTIVE: The objective of the current study was to present the results of an international working group survey identifying perceived limitations of existing facial nerve grading scales to inform the development of a novel grading scale for assessing early postoperative facial paralysis that incorporates regional scoring and is anchored in recovery prognosis and risk of associated complications. STUDY DESIGN: Survey. SETTING: A working group of 48 multidisciplinary clinicians with expertise in skull base, cerebellopontine angle, temporal bone, or parotid gland surgery. RESULTS: House-Brackmann grade is the most widely used system to assess facial nerve function among working group members (81%), although more than half (54%) agreed that the system they currently use does not adequately estimate the risk of associated complications, such as corneal injury, and confidence in interrater and intrarater reliability is generally low. Simplicity was ranked as the most important attribute of a novel postoperative facial nerve grading system to increase the likelihood of adoption, followed by reliability and accuracy. There was widespread consensus (91%) that the eye is the most critical facial region to focus on in the early postoperative setting. CONCLUSIONS: Members were invited to submit proposed grading systems in alignment with the objectives of the working group for subsequent validation. From these data, we plan to develop a simple, clinically anchored, and reproducible staging system with regional scoring for assessing early postoperative facial nerve function after surgery of the skull base, cerebellopontine angle, temporal bone, or parotid gland.

Revision of failed reverse total shoulder arthroplasty with reverse: short-term clinical outcomes.

BACKGROUND: The prevalence of failed reverse total shoulder arthroplasty (rTSA) is increasing. This can often present a challenging clinical situation with substantial bone loss and limited reconstruction options. This study reports a single tertiary referral center's experience with revision of failed rTSA managed with revision rTSA of bone-interfacing components. METHODS: After institutional review board approval, all revision shoulder arthroplasty cases performed at a single institution between 2012 and 2020 were reviewed. Cases in which rTSA was revised to a new rTSA construct with revision of at least 1 bone-interfacing implant (humeral stem and/or baseplate) with a minimum 2-year follow-up were identified. Characteristics of revision cases-including indications, bony stock, revised components, and use of bone graft-were collected. All patients were contacted for patient-reported outcome measures at a minimum of 2 years after surgery. In addition, the incidence and indication for any reoperation after revision were determined. RESULTS: Thirty-three patients with an average age of 66 years (range: 46-82 years), with 19 (58%) being female, met the inclusion criteria and had a mean follow-up of 4.2 years (range: 2-8 years). The most common indication for revision rTSA included humeral component loosening (33%; 11/33), baseplate loosening (27%; 9/33), and instability (21%; 7/33). Prerevision infectious workup demonstrated no cases of periprosthetic shoulder infection. Thirteen cases had massive bone loss-5 treated with humeral allograft prosthetic composite, 5 with glenoid bone grafting, and 3 with custom glenoid implant. In total, 10 of 33 cases (30%) required reoperation at a mean of 13 months (range: 1-44 months) for instability (4), humeral loosening (2), infection (1), baseplate loosening (1), or periprosthetic fracture (1). The reoperation rate for patients with revised baseplates only, humerus only, or combined was 23% (3/13), 28% (5/18), and 27% (3/11), respectively. Overall, the visual analog scale pain score improved from 6.5 preoperatively to 2.0 (P < .001), and the American Shoulder and Elbow Surgeons score improved from 30.7 to 67.5 (P < .001). However, the postoperative Single Assessment Numeric Evaluation score averaged only 51.2% (range: 2-100%). CONCLUSION: This study demonstrates that failed rTSA can be salvaged with a revision rTSA. However, patient expectations for functional improvements should be tempered, and a high reoperation rate should be expected.

Label- and slide-free tissue histology using 3D epi-mode quantitative phase imaging and virtual H&E staining.

Histological staining of tissue biopsies, especially hematoxylin and eosin (H&E) staining, serves as the benchmark for disease diagnosis and comprehensive clinical assessment of tissue. However, the process is laborious and time-consuming, often limiting its usage in crucial applications such as surgical margin assessment. To address these challenges, we combine an emerging 3D quantitative phase imaging technology, termed quantitative oblique back illumination microscopy (qOBM), with an unsupervised generative adversarial network pipeline to map qOBM phase images of unaltered thick tissues (i.e., label- and slide-free) to virtually stained H&E-like (vH&E) images. We demonstrate that the approach achieves high-fidelity conversions to H&E with subcellular detail using fresh tissue specimens from mouse liver, rat gliosarcoma, and human gliomas. We also show that the framework directly enables additional capabilities such as H&E-like contrast for volumetric imaging. The quality and fidelity of the vH&E images are validated using both a neural network classifier trained on real H&E images and tested on virtual H&E images, and a user study with neuropathologists. Given its simple and low-cost embodiment and ability to provide real-time feedback in vivo, this deep learning-enabled qOBM approach could enable new workflows for histopathology with the potential to significantly save time, labor, and costs in cancer screening, detection, treatment guidance, and more.

Clinical and descriptive characteristics associated with high-grade meningioma in a large clinical series.

PURPOSE: We studied 571 patients with intracranial meningioma for clinical characteristics and tumor location associated with high grade meningioma (WHO II/III). MATERIALS AND METHODS: Patients were participants in a multicentre epidemiologic study of risk factors for primary brain tumors including meningioma recruited from September 2005 to November 2019. We included patients 18 or older with a recent diagnosis of a primary intracranial meningioma of any subtype (ICD9/10: 9530-0, 9531-0, 9532-0, 9537-0, 9533-0, 9534-0, 9530-0, 9538-1, 9538-3) who were enrolled at neuro-oncology and neuro-surgery clinics in the southeastern U.S. RESULTS: The median patient age was 58 years (IQR: 48-68) and the majority of patients were female (n = 415; 72.7%) and Caucasian (n = 516; 90.4%). Most patients were symptomatic (n = 460; 80.6%) and their tumours more commonly occurred in a non-skull base location (n = 298; 52.2%). A total of 86 patients (15.0%) had a WHO grade II/III meningioma. Compared to patients with WHO grade I tumours, patients with WHO II/III meningiomas were over 3-times more likely to be male (odds ratio (OR): 3.25; 95% confidence interval (CI): 1.98, 5.35) adjusting for age, race, symptomatic presentation, and skull-based location. Moreover, a WHO grade II/III meningioma was substantially less likely to be observed in asymptomatic patients (OR: 0.15, 95% CI: 0.04, 0.42), and in patients with a skull-based tumour (OR: 0.40, 95% CI: 0.24, 0.66), adjusting for other factors. Male gender, symptomatic tumour, and a non-skull base location were independently associated with WHO grade II/III meningioma. CONCLUSION: These findings may shed additional light on the underlying pathogenesis of meningioma.

Immune microenvironment remodeling after radiation of a progressing brain metastasis.

Radiation is commonly used in the treatment of many cancers. However, its effects on anti-tumor immune responses are incompletely understood. Here, we present a detailed immunological analysis of two tumors from a patient with multiple non-small cell lung cancer metastases to the brain. One tumor was resected without treatment; the second was irradiated to a total dose of 30 Gy and resected following further progression. Comprehensive single-cell analysis reveals a substantially reduced immune cell fraction in the irradiated tumor, including the depletion of tissue-resident macrophages and infiltration of pro-inflammatory monocytes. Despite the presence of similar somatic mutations in both tumors, radiation is associated with the depletion of exhausted, tumor-resident T cell clones and their replacement by circulating clones unlikely to contribute to tumor-specific immunity. These results provide insight into the local effects of radiation on anti-tumor immunity and raise important considerations for the combination of radiation and immunotherapy.

Using Brain Tumor MRI Structured Reporting to Quantify the Impact of Imaging on Brain Tumor Boards.

Multidisciplinary tumor boards (TB) are an essential part of brain tumor care, but quantifying the impact of imaging on patient management is challenging due to treatment complexity and a lack of quantitative outcome measures. This work uses a structured reporting system for classifying brain tumor MRIs, the brain tumor reporting and data system (BT-RADS), in a TB setting to prospectively assess the impact of imaging review on patient management. Published criteria were used to prospectively assign three separate BT-RADS scores (an initial radiology report, secondary TB presenter review, and TB consensus) to brain MRIs reviewed at an adult brain TB. Clinical recommendations at TB were noted and management changes within 90 days after TB were determined by chart review. In total, 212 MRIs in 130 patients (median age = 57 years) were reviewed. Agreement was 82.2% between report and presenter, 79.0% between report and consensus, and 90.1% between presenter and consensus. Rates of management change increased with increasing BT-RADS scores (0-3.1%, 1a-0%, 1b-66.7%, 2-8.3%, 3a-38.5%, 3b-55.9, 3c-92.0%, and 4-95.6%). Of 184 (86.8%) cases with clinical follow-up within 90 days after the tumor board, 155 (84.2%) of the recommendations were implemented. Structured scoring of MRIs provides a quantitative way to assess rates of agreement interpretation alongside how often management changes are recommended and implemented in a TB setting.

Immune niches in brain metastases contain TCF1+ stem-like T cells, are associated with disease control and are modulated by preoperative SRS.

The CD8+ T-cell response is prognostic for survival outcomes in several tumor types. However, whether this extends to tumors in the brain, an organ with barriers to T cell entry, remains unclear. Here, we analyzed immune infiltration in 67 brain metastasis (BrM) and found high frequencies of PD1+ TCF1+ stem-like CD8+ T-cells and TCF1- effector-like cells. Importantly, the stem-like cells aggregate with antigen presenting cells in immune niches, and niches were prognostic for local disease control. Standard of care for BrM is resection followed by stereotactic radiosurgery (SRS), so to determine SRS's impact on the BrM immune response, we examined 76 BrM treated with pre-operative SRS (pSRS). pSRS acutely reduced CD8+ T cells at 3 days. However, CD8+ T cells rebounded by day 6, driven by increased frequency of effector-like cells. This suggests that the immune response in BrM can be regenerated rapidly, likely by the local TCF1+ stem-like population.

Complications Are Infrequent After Humeral Shaft Fractures Due to Low-Energy Gunshot Injuries.

OBJECTIVE: To describe humerus shaft fractures after low-energy gunshot wound (GSW) and compare with blunt injuries. We hypothesized that nerve injury, infection, and fracture union would be similar. DESIGN: Retrospective. SETTING: Urban Level 1 trauma center. PATIENTS/PARTICIPANTS: Four hundred three patients were treated for a humeral shaft fracture over 18 years. Sixty-two patients sustained injury due to GSW. INTERVENTION: Primary open reduction and internal fixation was pursued in 59%, including 32% after GSW. MAIN OUTCOME MEASUREMENTS: Rates of nerve injury, infection, and fracture union. RESULTS: Patients with GSW were younger with a mean age of 30 years, more likely male (90%), with isolated injuries (84%), and less likely to have simple fractures (84%). Both groups experienced high rates of union (98% of GSW fractures vs. 99% of closed high-energy fractures). Deep infection occurred in 1 patient (1.6%) after GSW. Rates of deep infection in the closed and open blunt trauma fracture groups were similarly low at 1% and 4.5%, respectively. Nerve injury on presentation after GSW was more common than after low-energy and high-energy closed fractures (47% vs. 13% and 27%), but similar to blunt open fracture (52%). Despite higher rates of nerve injury, nerve recovery occurred at similarly high rates after both GSW and blunt injuries (78% vs. 86%). CONCLUSIONS: Nerve injuries are more common after GSW, but most recover without intervention. Infection is uncommon after GSW, and secondary unplanned operations are rare. Initial nonoperative care of most GSW humerus fractures, even with radial nerve injury at the time of presentation, seems appropriate. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Artificial neural networks predict the need for permanent cerebrospinal fluid diversion following posterior fossa tumor resection.

Background: Resection of posterior fossa tumors (PFTs) can result in hydrocephalus that requires permanent cerebrospinal fluid (CSF) diversion. Our goal was to prospectively validate a machine-learning model to predict postoperative hydrocephalus after PFT surgery requiring permanent CSF diversion. Methods: We collected preoperative and postoperative variables on 518 patients that underwent PFT surgery at our center in a retrospective fashion to train several statistical classifiers to predict the need for permanent CSF diversion as a binary class. A total of 62 classifiers relevant to our data structure were surveyed, including regression models, decision trees, Bayesian models, and multilayer perceptron artificial neural networks (ANN). Models were trained using the (N = 518) retrospective data using 10-fold cross-validation to obtain accuracy metrics. Given the low incidence of our positive outcome (12%), we used the positive predictive value along with the area under the receiver operating characteristic curve (AUC) to compare models. The best performing model was then prospectively validated on a set of 90 patients. Results: Twelve percent of patients required permanent CSF diversion after PFT surgery. Of the trained models, 8 classifiers had an AUC greater than 0.5 on prospective testing. ANNs demonstrated the highest AUC of 0.902 with a positive predictive value of 83.3%. Despite comparable AUC, the remaining classifiers had a true positive rate below 35% (compared to ANN, P < .0001). The negative predictive value of the ANN model was 98.8%. Conclusions: ANN-based models can reliably predict the need for ventriculoperitoneal shunt after PFT surgery.

Development and validation of a prognostic gene expression signature for lower-grade glioma following surgery and adjuvant radiotherapy.

BACKGROUND AND PURPOSE: Standard of care for lower-grade glioma (LGG) is maximal safe resection and risk-adaptive adjuvant therapy. While patients who benefit the most from adjuvant chemotherapy have been elucidated in prospective randomized studies, comparable insights for adjuvant radiotherapy (RT) are lacking. We sought to identify and validate patterns of gene expression that are associated with differential outcomes among LGG patients treated by RT from two large genomics databases. MATERIALS AND METHODS: Patients from The Cancer Genome Atlas (TCGA) with LGG (WHO grade II-III glioma) treated by surgery and adjuvant RT were randomized 1:1 to a discovery cohort or an internal validation cohort. Using the discovery cohort only, associations between tumor RNA-seq expression and progression-free survival (PFS) as well as overall survival (OS) were evaluated with adjustment for clinicopathologic covariates. A Genomic Risk Score (GRS) was then constructed from the expression levels of top genes also screened for involvement in glioma carcinogenesis. The prognostic value of GRS was further assessed in the internal validation cohort of TCGA and a second distinct database, compiled by the Chinese Glioma Genome Association (CGGA). RESULTS: From TCGA, 289 patients with LGG received adjuvant RT alone (38 grade II, 30 grade III) or chemoradiotherapy (CRT) (51 grade II, 170 grade III) between 2009 and 2015. From CGGA, 178 patients with LGG received adjuvant RT alone (40 grade II, 13 grade III) or CRT (41 grade II, 84 grade III) between 2004 and 2016. The genes comprising GRS are involved in MAP kinase activity, T cell chemotaxis, and cell cycle transition: MAP3K15, MAPK10, CCL3, CCL4, and ADAMTS1. High GRS, defined as having a GRS in the top third, was significantly associated with poorer outcomes independent of age, sex, glioma histology, WHO grade, IDH mutation, 1p/19q co-deletion, and chemotherapy status in the discovery cohort (PFS HR 1.61, 95% CI 1.10-2.36, P = 0.014; OS HR 2.74, 95% CI 1.68-4.47, P < 0.001). These findings were replicated in the internal validation cohort (PFS HR 1.58, 95% CI 1.05-2.37, P = 0.027; OS HR 1.84, 95% CI 1.13-3.00, P = 0.015) and the CGGA external validation cohort (OS HR 1.72, 95% CI 1.27-2.34, P < 0.001). Association between GRS and outcomes was observed only among patients who underwent RT, in both TCGA and CGGA. CONCLUSION: This study successfully identified an expression signature of five genes that stratified outcomes among LGG patients who received adjuvant RT, with two rounds of validation leveraging independent genomics databases. Expression levels of the highlighted genes were associated with PFS and OS only among patients whose treatment included RT, but not among those with omission of RT, suggesting that expression of these genes may be predictive of radiation treatment response. While additional prospective studies are warranted, interrogation of these genes may be considered in the multidisciplinary management of LGG.

Adjuvant Radiotherapy in Grade II, Atypical Meningioma of the Skull Base.

Introduction Atypical meningiomas (AM) are meningiomas that are more aggressive than their grade-I counterparts and have a higher rate of recurrence. The effect of adjuvant radiotherapy (ART) on AM of the skull base is not defined. Methods A retrospective review of all AM's of the skull base primarily resected at our institution from 1996 to 2018 was completed. ART was defined as radiotherapy (RT) that occurred within 6 months of initial resection, regardless of Simpson's grade. Minimum time length of follow-up after resection was 2 years. Statistical analysis was performed using SAS. Results There were a total of 59 skull base-located (SBL) AMs resected at our institution from 1996 to 2018. The average age of our cohort was 53.2 years. Gross total resection, defined as Simpson's grades I to III resection, was achieved in 36 (61%) of cases. Thirty-five of 59 (59%) patients received ART. Recurrence was observed in 14 patients (24%), and mean time to recurrence was 63.8 months. Patients who received ART had a lower observed rate of recurrence (8 vs. 46%); however, time to recurrence was not significantly different between the two populations. Conclusion We observe that AM in the skull base location have higher recurrence rates than we would expect from grade-I meningioma. These data suggest that ART may offer benefit to the overall observed frequency of recurrence of SBL AM; however, the time to recurrence between patients who received ART and those who did not was not statistically significant in survival analysis.

Congress of neurological surgeons systematic review and evidence-based guidelines update on the role of neuropathology in the management of progressive glioblastoma in adults.

TARGET POPULATION: These recommendations apply to adult patients with progressive or recurrent glioblastoma (GBM). QUESTION: For adult patients with progressive glioblastoma does testing for Isocitrate Dehydrogenase (IDH) 1 or 2 mutations provide new additional management or prognostic information beyond that derived from the tumor at initial presentation? RECOMMENDATION: Level III: Repeat IDH mutation testing is not necessary if the tumor is histologically similar to the primary tumor and the patient's clinical course is as expected. QUESTION: For adult patients with progressive glioblastoma does repeat testing for MGMT promoter methylation provide new or additional management or prognostic information beyond that derived from the tumor at initial presentation and what methods of detection are optimal? RECOMMENDATION: Level III: Repeat MGMT promoter methylation is not recommended. QUESTION: For adult patients with progressive glioblastoma does EGFR amplification or mutation testing provide management or prognostic information beyond that provided by histologic analysis and if performed on previous tissue samples, does it need to be repeated? RECOMMENDATION: Level III: In cases that are difficult to classify as glioblastoma on histologic features EGFR amplification testing may help in classification. If a previous EGFR amplification was detected, repeat testing is not necessary. Repeat EGFR amplification or mutational testing may be recommended in patients in which target therapy is being considered. QUESTION: For adult patients with progressive glioblastoma does large panel or whole genome sequencing provide management or prognostic information beyond that derived from histologic analysis? RECOMMENDATION: Level III: Primary or repeat large panel or whole genome sequencing may be considered in patients who are eligible or interested in molecularly guided therapy or clinical trials. QUESTION: For adult patients with progressive glioblastoma should immune checkpoint biomarker testing be performed to provide management and prognostic information beyond that obtained from histologic analysis? RECOMMENDATION: Level III: The current evidence does not support making PD-L1 or mismatch repair (MMR) enzyme activity a component of standard testing. QUESTION: For adult patients with progressive glioblastoma are there meaningful biomarkers for bevacizumab responsiveness and does their assessment provide additional information for tumor management and prognosis beyond that learned by standard histologic analysis? RECOMMENDATION: Level III: No established Bevacizumab biomarkers are currently available based upon the inclusion criteria of this guideline.

Distinct phenotypic states and spatial distribution of CD8+ T cell clonotypes in human brain metastases.

Metastatic disease in the brain is difficult to control and predicts poor prognosis. Here, we analyze human brain metastases and demonstrate their robust infiltration by CD8+ T cell subsets with distinct antigen specificities, phenotypic states, and spatial localization within the tumor microenvironment. Brain metastases are densely infiltrated by T cells; the majority of infiltrating CD8+ T cells express PD-1. Single-cell RNA sequencing shows significant clonal overlap between proliferating and exhausted CD8+ T cells, but these subsets have minimal clonal overlap with circulating and other tumor-infiltrating CD8+ T cells, including bystander CD8+ T cells specific for microbial antigens. Using spatial transcriptomics and spatial T cell receptor (TCR) sequencing, we show these clonally unrelated, phenotypically distinct CD8+ T cell populations occupy discrete niches within the brain metastasis tumor microenvironment. Together, our work identifies signaling pathways within CD8+ T cells and in their surrounding environment that may be targeted for immunotherapy of brain metastases.

Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on the Management of Progressive Glioblastoma in Adults: Update of the 2014 Guidelines.

BACKGROUND: The Institute of Medicine best practice recommendation to review guidelines every 5 years is followed by the Congress of Neurological Surgeons Guidelines Committee. The aim of this work was to provide an updated literature review and evidence-based recommendations on the topic of diagnosis and treatment of patients with progressive glioblastoma (pGBM). OBJECTIVE: To review the literature published since the last guidelines on pGBM dated 2014, with literature search ending in June 2012. METHODS: PubMed, Embase, and Cochrane were searched for the period July 1, 2012, to March 31, 2019, using search terms and search strategies to identify pertinent abstracts. These were then screened using published exclusion/inclusion criteria to identify full-text review articles. Evidence tables were constructed using data derived from full-text reviews and recommendations made from the evidence derived. RESULTS: From the total 8786 abstracts identified by the search, 237 full-text articles met inclusion/exclusion criteria and were included in this update. Two new level II recommendations derived from this work. For the diagnosis of patients with GBM, the use of diffusion-weighted images is recommended to be included in the magnetic resonance images with and without contrast used for surveillance to detect pGBM. For the treatment of patients with pGBM, repeat cytoreductive surgery is recommended to improve overall survival. An additional 21 level III recommendations were provided. CONCLUSION: Recent published literature provides new recommendations for the diagnosis and treatment of pGBM. The Central Nervous System Guidelines Committee will continue to pursue timely updates to further improve the care of patients with diagnosis.https://www.cns.org/guidelines/browse-guidelines-detail/guidelines-management-of-progressive-glioblastoma.

Final Report on Clinical Outcomes and Tumor Recurrence Patterns of a Pilot Study Assessing Efficacy of Belinostat (PXD-101) with Chemoradiation for Newly Diagnosed Glioblastoma.

Glioblastoma (GBM) is highly aggressive and has a poor prognosis. Belinostat is a histone deacetylase inhibitor with blood-brain barrier permeability, anti-GBM activity, and the potential to enhance chemoradiation. The purpose of this clinical trial was to assess the efficacy of combining belinostat with standard-of-care therapy. Thirteen patients were enrolled in each of control and belinostat cohorts. The belinostat cohort was given a belinostat regimen (500-750 mg/m2 1×/day × 5 days) every three weeks (weeks 0, 3, and 6 of RT). All patients received temozolomide and radiation therapy (RT). RT margins of 5-10 mm were added to generate clinical tumor volumes and 3 mm added to create planning target volumes. Median overall survival (OS) was 15.8 months for the control cohort and 18.5 months for the belinostat cohort (p = 0.53). The recurrence volumes (rGTVs) for the control cohort occurred in areas that received higher radiation doses than that in the belinostat cohort. For those belinostat patients who experienced out-of-field recurrence, tumors were detectable by spectroscopic MRI before RT. Recurrence analysis suggests better in-field control with belinostat. This study highlights the potential of belinostat as a synergistic therapeutic agent for GBM. It may be particularly beneficial to combine this radio-sensitizing effect with spectroscopic MRI-guided RT.