Stereotactic radiosurgery for brain metastasis from cholangiocarcinoma.

OBJECTIVE: Accounting for approximately 15% of primary liver cancers and 3% of gastrointestinal malignancies, cholangiocarcinoma (CCA) poses a serious health concern given its high mortality rate. Managing brain metastases (BMs) from CCA is challenging because of their rarity and poor prognosis, with little guidance on treatment from the literature. In this study, the authors aimed to evaluate the safety and efficacy of stereotactic radiosurgery (SRS) in managing BMs from CCA. METHODS: This multicenter retrospective study included 13 CCA patients with 41 BMs treated with SRS from October 2006 to April 2022 at eight institutions affiliated with the International Radiosurgery Research Foundation. Inclusion criteria were a CCA diagnosis, an age over 18 years, no other malignancies, single-fraction SRS treatment for BMs, and at least one follow-up image. Data on demographics, tumor characteristics, treatment details, and outcomes were collected. The primary endpoints were local control (LC), intracranial progression-free survival (PFS), and overall survival (OS). The secondary endpoint was the development of adverse radiation effects (AREs). RESULTS: The median radiological follow-up was 5 months (range 1-18 months). At the last follow-up, LC was achieved in 39 (95.1%) of 41 BMs. New distant metastases were observed in 3 patients (23.1%), and the mean intracranial PFS was 9.4 months (95% CI 6.5-12.3 months). Six-month and 1-year OS rates were 38.5% and 11.5%, respectively, and the median OS was 6 months (95% CI 4.9-7.2 months). Concurrent immunotherapy was associated with a high risk of local failure (HR 29.665, 95% CI 1.799-489.206, p = 0.018), and the absence of systemic chemotherapy before SRS was linked to reduced OS (HR 6.658, 95% CI 1.173-37.776, p = 0.032). Regarding AREs, only 1 patient (7.7%) experienced right hemiparesis and was treated with corticosteroid therapy. CONCLUSIONS: SRS is an effective option for managing BMs in CCA patients, showing promise in LC and a high safety profile.

LC3-associated phagocytosis of neutrophils triggers tumor ferroptotic cell death in glioblastoma.

Necrosis in solid tumors is commonly associated with poor prognostic but how these lesions expand remains unclear. Studies have found that neutrophils associate with and contribute to necrosis development in glioblastoma by inducing tumor cell ferroptosis through transferring myeloperoxidase-containing granules. However, the mechanism of neutrophilic granule transfer remains elusive. We performed an unbiased small molecule screen and found that statins inhibit neutrophil-induced tumor cell death by blocking the neutrophilic granule transfer. Further, we identified a novel process wherein neutrophils are engulfed by tumor cells before releasing myeloperoxidase-containing contents into tumor cells. This neutrophil engulfment is initiated by integrin-mediated adhesion, and further mediated by LC3-associated phagocytosis (LAP), which can be blocked by inhibiting the Vps34-UVRAG-RUBCN-containing PI3K complex. Myeloperoxidase inhibition or Vps34 depletion resulted in reduced necrosis formation and prolonged mouse survival in an orthotopic glioblastoma mouse model. Thus, our study unveils a critical role for LAP-mediated neutrophil internalization in facilitating the transfer of neutrophilic granules, which in turn triggers tumor cell death and necrosis expansion. Targeting this process holds promise for improving glioblastoma prognosis.

Systematic Review of Cerebrospinal Fluid Biomarker Discovery in Neuro-Oncology: A Roadmap to Standardization and Clinical Application.

Effective diagnosis, prognostication, and management of CNS malignancies traditionally involves invasive brain biopsies that pose significant risk to the patient. Sampling and molecular profiling of cerebrospinal fluid (CSF) is a safer, rapid, and noninvasive alternative that offers a snapshot of the intracranial milieu while overcoming the challenge of sampling error that plagues conventional brain biopsy. Although numerous biomarkers have been identified, translational challenges remain, and standardization of protocols is necessary. Here, we systematically reviewed 141 studies (Medline, SCOPUS, and Biosis databases; between January 2000 and September 29, 2022) that molecularly profiled CSF from adults with brain malignancies including glioma, brain metastasis, and primary and secondary CNS lymphomas. We provide an overview of promising CSF biomarkers, propose CSF reporting guidelines, and discuss the various considerations that go into biomarker discovery, including the influence of blood-brain barrier disruption, cell of origin, and site of CSF acquisition (eg, lumbar and ventricular). We also performed a meta-analysis of proteomic data sets, identifying biomarkers in CNS malignancies and establishing a resource for the research community.

Estimating the risk of brain metastasis for patients newly diagnosed with cancer.

BACKGROUND: Brain metastases (BM) affect clinical management and prognosis but limited resources exist to estimate BM risk in newly diagnosed cancer patients. Additionally, guidelines for brain MRI screening are limited. We aimed to develop and validate models to predict risk of BM at diagnosis for the most common cancer types that spread to the brain. METHODS: Breast cancer, melanoma, kidney cancer, colorectal cancer (CRC), small cell lung cancer (SCLC), and non-small cell lung cancer (NSCLC) data were extracted from the National Cancer Database to evaluate for the variables associated with the presence of BM at diagnosis. Multivariable logistic regression (LR) models were developed and performance was evaluated with Area Under the Receiver Operating Characteristic Curve (AUC) and random-split training and testing datasets. Nomograms and a Webtool were created for each cancer type. RESULTS: We identify 4,828,305 patients from 2010-2018 (2,095,339 breast cancer, 472,611 melanoma, 407,627 kidney cancer, 627,090 CRC, 164,864 SCLC, and 1,060,774 NSCLC). The proportion of patients with BM at diagnosis is 0.3%, 1.5%, 1.3%, 0.3%, 16.0%, and 10.3% for breast cancer, melanoma, kidney cancer, CRC, SCLC, and NSCLC, respectively. The average AUC over 100 random splitting for the LR models is 0.9534 for breast cancer, 0.9420 for melanoma, 0.8785 for CRC, 0.9054 for kidney cancer, 0.7759 for NSCLC, and 0.6180 for SCLC. CONCLUSIONS: We develop accurate models that predict the BM risk at diagnosis for multiple cancer types. The nomograms and Webtool may aid clinicians in considering brain MRI at the time of initial cancer diagnosis.

When patients are diagnosed with cancer, it is unknown which patients have a significant risk of cancer spread to the brain. Cancer spread to the brain is important to diagnose since it changes how patients are treated and affects their prognosis. This study used a large national database of patients diagnosed with cancer and studied the characteristics that were associated with cancer spread to the brain. The results can be used by doctors to assess the risk of cancer spread to the brain and determine which patients with cancer may benefit most from brain imaging.

Regression of Multiple Intracranial Meningiomas With Cessation of Progesterone Agonist Therapy: A Case Report.

In this case report, we discuss a patient who experienced spontaneous regression of multiple intracranial meningiomas that were treated conservatively for 5 years after cessation of megestrol acetate, an exogenous progestin. In addition, we discuss the previous literature describing the relationship between exogenous progesterone medications and meningioma growth. This case, along with others reported, implies that cessation of progesterone therapy, when feasible, may alter the natural history of meningioma growth and thus impact treatment decisions.

Analysis of anemia and iron supplementation among glioblastoma patients reveals sex-biased association between anemia and survival.

The association between anemia and outcomes in glioblastoma patients is unclear. We analyzed data from 1346 histologically confirmed adult glioblastoma patients in the TriNetX Research Network. Median hemoglobin and hematocrit levels were quantified for 6 months following diagnosis and used to classify patients as anemic or non-anemic. Associations of anemia and iron supplementation of anemic patients with median overall survival (median-OS) were then studied. Among 1346 glioblastoma patients, 35.9% of male and 40.5% of female patients were classified as anemic using hemoglobin-based WHO guidelines. Among males, anemia was associated with reduced median-OS compared to matched non-anemic males using hemoglobin (HR 1.24; 95% CI 1.00-1.53) or hematocrit-based cutoffs (HR 1.28; 95% CI 1.03-1.59). Among females, anemia was not associated with median-OS using hemoglobin (HR 1.00; 95% CI 0.78-1.27) or hematocrit-based cutoffs (HR: 1.10; 95% CI 0.85-1.41). Iron supplementation of anemic females trended toward increased median-OS (HR 0.61; 95% CI 0.32-1.19) although failing to reach statistical significance whereas no significant association was found in anemic males (HR 0.85; 95% CI 0.41-1.75). Functional transferrin-binding assays confirmed sexually dimorphic binding in resected patient samples indicating underlying differences in iron biology. Anemia among glioblastoma patients exhibits a sex-specific association with survival.

Autologous cell immunotherapy (IGV-001) with IGF-1R antisense oligonucleotide in newly diagnosed glioblastoma patients.

Standard-of-care first-line therapy for patients with newly diagnosed glioblastoma (ndGBM) is maximal safe surgical resection, then concurrent radiotherapy and temozolomide, followed by maintenance temozolomide. IGV-001, the first product of the Goldspire™ platform, is a first-in-class autologous immunotherapeutic product that combines personalized whole tumor-derived cells with an antisense oligonucleotide (IMV-001) in implantable biodiffusion chambers, with the intent to induce a tumor-specific immune response in patients with ndGBM. Here, we describe the design and rationale of a randomized, double-blind, phase IIb trial evaluating IGV-001 compared with placebo, both followed by standard-of-care treatment in patients with ndGBM. The primary end point is progression-free survival, and key secondary end points include overall survival and safety.

Glioblastoma (GBM) is a fast-growing brain tumor that happens in about half of all gliomas. Surgery is the first treatment for patients with newly diagnosed GBM, followed by the usual radiation and chemotherapy pills named temozolomide. Temozolomide pills are then given as a long-term treatment. The outcome for the patient with newly diagnosed GBM remains poor. IGV-001 is specially made for each patient. The tumor cells are removed during surgery and mixed in the laboratory with a small DNA, IMV-001. This mix is the IGV-001 therapy that is designed to give antitumor immunity against GBM. IGV-001 is put into small biodiffusion chambers that are irradiated to stop the growth of any tumor cells in the chambers. In the phase IIb study, patients with newly diagnosed GBM are chosen and assigned to either the IGV-001 or the placebo group. A placebo does not contain any active ingredients. The small biodiffusion chambers containing either IGV-001 or placebo are surgically placed into the belly for 48 to 52 h and then removed. Patients then receive the usual radiation and chemotherapy treatment. Patients must be adults aged between 18 and 70 years. Patients also should be able to care for themselves overall, but may be unable to work or have lower ability to function. Patients with tumors on both sides of the brain are not eligible. The main point of this study is to see if IGV-001 helps patients live longer without making the illness worse compared with placebo. Clinical Trial Registration: NCT04485949 (ClinicalTrials.gov).

Development of a Treatment Planning Framework for Laser Interstitial Thermal Therapy (LITT).

PURPOSE: Develop a treatment planning framework for neurosurgeons treating high-grade gliomas with LITT to minimize the learning curve and improve tumor thermal dose coverage. METHODS: Deidentified patient images were segmented using the image segmentation software Materialize MIMICS©. Segmented images were imported into the commercial finite element analysis (FEA) software COMSOL Multiphysics© to perform bioheat transfer simulations. The laser probe was modeled as a cylindrical object with radius 0.7 mm and length 100 mm, with a constant beam diameter. A modeled laser probe was placed in the tumor in accordance with patient specific patient magnetic resonance temperature imaging (MRTi) data. The laser energy was modeled as a deposited beam heat source in the FEA software. Penne's bioheat equation was used to model heat transfer in brain tissue. The cerebrospinal fluid (CSF) was modeled as a solid with convectively enhanced conductivity to capture heat sink effects. In this study, thermal damage-dependent blood perfusion was assessed. Pulsed laser heating was modeled based on patient treatment logs. The stationary heat source and pullback heat source techniques were modeled to compare the calculated tissue damage. The developed bioheat transfer model was compared to MRTi data obtained from a laser log during LITT procedures. The application builder module in COMSOL Multiphysics© was utilized to create a Graphical User Interface (GUI) for the treatment planning framework. RESULTS: Simulations predicted increased thermal damage (10-15%) in the tumor for the pullback heat source approach compared with the stationary heat source. The model-predicted temperature profiles followed trends similar to those of the MRTi data. Simulations predicted partial tissue ablation in tumors proximal to the CSF ventricle. CONCLUSION: A mobile platform-based GUI for bioheat transfer simulation was developed to aid neurosurgeons in conveniently varying the simulation parameters according to a patient-specific treatment plan. The convective effects of the CSF should be modeled with heat sink effects for accurate LITT treatment planning.

Uptake of H-ferritin by Glioblastoma stem cells and its impact on their invasion capacity.

PURPOSE: Iron acquisition is key to maintaining cell survival and function. Cancer cells in general are considered to have an insatiable iron need. Iron delivery via the transferrin/transferrin receptor pathway has been the canonical iron uptake mechanism. Recently, however, our laboratory and others have explored the ability of ferritin, particularly the H-subunit, to deliver iron to a variety of cell types. Here, we investigate whether Glioblastoma (GBM) initiating cells (GICs), a small population of stem-like cells, are known for their iron addiction and invasive nature acquire exogenous ferritin, as a source of iron. We further assess the functional impact of ferritin uptake on the invasion capacity of the GICs. METHODS: To establish that H-ferritin can bind to human GBM, tissue-binding assays were performed on samples collected at the time of surgery. To interrogate the functional consequences of H-ferritin uptake, we utilized two patient-derived GIC lines. We further describe H-ferritin's impact on GIC invasion capacity using a 3D invasion assay. RESULTS: H-ferritin bound to human GBM tissue at the amount of binding was influenced by sex. GIC lines showed uptake of H-ferritin protein via transferrin receptor. FTH1 uptake correlated with a significant decrease in the invasion capacity of the cells. H-ferritin uptake was associated with a significant decrease in the invasion-related protein Rap1A. CONCLUSION: These findings indicate that extracellular H-ferritin participates in iron acquisition to GBMs and patient-derived GICs. The functional significance of the increased iron delivery by H-ferritin is a decreased invasion capacity of GICs potentially via reduction of Rap1A protein levels.

Comparison of first-line radiosurgery for small-cell and non-small cell lung cancer brain metastases (CROSS-FIRE).

INTRODUCTION: Historical reservations regarding stereotactic radiosurgery (SRS) for small-cell lung cancer (SCLC) brain metastases include concerns for short-interval and diffuse central nervous system (CNS) progression, poor prognoses, and increased neurological mortality specific to SCLC histology. We compared SRS outcomes for SCLC and non-small cell lung cancer (NSCLC) where SRS is well established. METHODS: Multicenter first-line SRS outcomes for SCLC and NSCLC from 2000 to 2022 were retrospectively collected (n = 892 SCLC, n = 4785 NSCLC). Data from the prospective Japanese Leksell Gamma Knife Society (JLGK0901) clinical trial of first-line SRS were analyzed as a comparison cohort (n = 98 SCLC, n = 814 NSCLC). Overall survival (OS) and CNS progression were analyzed using Cox proportional hazard and Fine-Gray models, respectively, with multivariable adjustment for cofactors including age, sex, performance status, year, extracranial disease status, and brain metastasis number and volume. Mutation-stratified analyses were performed in propensity score-matched retrospective cohorts of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) positive NSCLC, mutation-negative NSCLC, and SCLC. RESULTS: OS was superior for patients with NSCLC compared to SCLC in the retrospective dataset (median OS = 10.5 vs 8.6 months; P < .001) and in the JLGK0901 dataset. Hazard estimates for first CNS progression favoring NSCLC were similar in both datasets but reached statistical significance in the retrospective dataset only (multivariable hazard ratio = 0.82, 95% confidence interval = 0.73 to 0.92, P = .001). In the propensity score-matched cohorts, there were continued OS advantages for NSCLC patients (median OS = 23.7 [EGFR and ALK positive NSCLC] vs 13.6 [mutation-negative NSCLC] vs 10.4 months [SCLC], pairwise P values < 0.001), but no statistically significant differences in CNS progression were observed in the matched cohorts. Neurological mortality and number of lesions at CNS progression were similar for NSCLC and SCLC patients. Leptomeningeal progression was increased in patients with NSCLC compared to SCLC in the retrospective dataset only (multivariable hazard ratio = 1.61, 95% confidence interval = 1.14 to 2.26, P = .007). CONCLUSIONS: After SRS, SCLC histology was associated with shorter OS compared to NSCLC. CNS progression occurred earlier in SCLC patients overall but was similar in patients matched on baseline factors. SCLC was not associated with increased neurological mortality, number of lesions at CNS progression, or leptomeningeal progression compared to NSCLC. These findings may better inform clinical expectations and individualized decision making regarding SRS for SCLC patients.

Effects of Neuroanatomic Structural Distances on Pituitary Function After Stereotactic Radiosurgery: A Multicenter Study.

BACKGROUND: Delayed hypopituitarism is the most common complication after stereotactic radiosurgery (SRS) for pituitary adenomas. OBJECTIVE: To investigate the relationship between neuroanatomic structure distances from the radiation target and anterior pituitary function preservation after SRS through multicenter study. METHODS: We retrospectively reviewed the International Radiosurgery Research Foundation database from January 2002 to December 2021 for adult patients undergoing SRS for pituitary adenomas with >6 months of follow-up. Distances between centers or edges of hypothalamic-pituitary axis structures and SRS target volumes were measured using MRI. The primary outcome was anterior pituitary function preservation. Predictors were analyzed using multivariable logistic regression and area under the receiver operating curve (AUROC) curve analyses. RESULTS: Four hundred eighty-seven patients were categorized by preservation (n = 384) and no preservation (n = 103) of anterior pituitary function. The mean margin dose was 19.1(6.2) Gy. Larger distance from the center of the stalk to the tumor margin isodose was a positive predictor (adjusted odds ratio [aOR] = 1.162 [1.046-1.291], P = .005), while pre-SRS hypopituitarism (aOR = 0.646 [0.405-1.031], P = .067) and larger treatment volume (aOR = 0.965 [0.929-1.002], P = .061) were near negative predictors of the primary outcome. An interaction between the treatment volume and center stalk to margin isodose distance was found (aOR = 0.980 [0.961-0.999], P = .045). Center stalk to margin isodose distance had an AUROC of 0.620 (0.557-0.693), at 3.95-mm distance. For patients with treatment volumes of <2.34 mL, center stalk to margin isodose distance had an AUROC of 0.719 (0.614-0.823), at 2.95-mm distance. CONCLUSION: Achieving a distance between the center of the pituitary stalk and the tumor margin isodose ≥3.95 mm predicted anterior pituitary function preservation. For smaller treatment volumes <2.34 mL, the optimal distance was ≥2.95 mm. This may be modifiable during trans-sphenoidal resection to preserve pituitary function.

Stereotactic radiosurgery for Koos grade IV vestibular schwannoma in patients ≥ 65 years old: a multi-institutional retrospective study.

BACKGROUND: Surgery is the preferred treatment for large vestibular schwannomas (VS). Good tumor control and cranial nerve outcomes were described in selected Koos IV VS after single-session stereotactic radiosurgery (SRS), but outcomes in elderly patients have never been specifically studied. The aim of this study is to report clinical and radiological outcomes after single-session SRS for Koos IV VS in patients ≥ 65 years old. METHOD: This multicenter, retrospective study included patients ≥ 65 years old, treated with primary, single-session SRS for a Koos IV VS, and at least 12 months of follow-up. Patients with life-threatening or incapacitating symptoms were excluded. Tumor control rate, hearing, trigeminal, and facial nerve function were studied at last follow-up. RESULTS: One-hundred and fifty patients (median age of 71.0 (IQR 9.0) years old with a median tumor volume of 8.3 cc (IQR 4.4)) were included. The median prescription dose was 12.0 Gy (IQR 1.4). The local tumor control rate was 96.0% and 86.2% at 5 and 10 years, respectively. Early tumor expansion occurred in 6.7% and was symptomatic in 40% of cases. A serviceable hearing was present in 16.1% prior to SRS and in 7.4% at a last follow-up of 46.5 months (IQR 55.8). The actuarial serviceable hearing preservation rate was 69.3% and 50.9% at 5 and 10 years, respectively. Facial nerve function preservation or improvement rates at 5 and 10 years were 98.7% and 91.0%, respectively. At last follow-up, the trigeminal nerve function was improved in 14.0%, stable in 80.7%, and worsened in 5.3% of the patients. ARE were noted in 12.7%. New hydrocephalus was seen in 8.0% of patients. CONCLUSION: SRS can be a safe alternative to surgery for selected Koos IV VS in patients ≥ 65 years old. Further follow-up is warranted.

Stereotactic radiosurgery for Koos grade IV vestibular schwannoma: a multi-institutional study.

OBJECTIVE: Though stereotactic radiosurgery (SRS) is an established safe treatment for small- and medium-sized vestibular schwannomas (VSs), its role in the management of Koos grade IV VS is still unclear. In this retrospective multicenter study, the authors evaluated tumor control and the patient outcomes of primary, single-session SRS treatment for Koos grade IV VS. METHODS: This study included patients treated with primary, single-session SRS for Koos grade IV VS at 10 participating centers. Only those patients presenting with non-life-threatening or incapacitating symptoms and at least 12 months of clinical and neuroimaging follow-up were eligible for inclusion. Relevant data were collected, and the Kaplan-Meier method was used to perform time-dependent analysis for post-SRS tumor control, hearing preservation, and facial nerve function preservation. Univariate and multivariate analyses were performed for outcome measures using Cox regression analysis. RESULTS: Six hundred twenty-seven patients (344 females, median patient age 54 [IQR 22] years) treated with primary SRS were included in this study. The median tumor volume was 8.7 (IQR 5) cm3. Before SRS, serviceable hearing, facial nerve weakness (House-Brackmann grade > I), and trigeminal neuropathy were present in 205 (33%), 48 (7.7%), and 203 (32.4%) patients, respectively. The median prescription dose was 12 (IQR 1) Gy. At a median radiological follow-up of 38 (IQR 54) months, tumor control was achieved in 94.1% of patients. Early tumor expansion occurred in 67 (10.7%) patients and was associated with a loss of tumor control at the last follow-up (p = 0.001). Serviceable hearing preservation rates at the 5- and 10-year follow-ups were 65% and 44.6%, respectively. Gardner-Robertson class > 1 (p = 0.003) and cochlear dose ≥ 4 Gy (p = 0.02) were risk factors for hearing loss. Facial nerve function deterioration occurred in 19 (3.0%) patients at the last follow-up and was associated with margin doses ≥ 13 Gy (p = 0.03) and early tumor expansion (p = 0.04). Post-SRS, 33 patients developed hydrocephalus requiring shunting. Adverse radiation effects occurred in 92 patients and were managed medically or surgically in 34 and 18 cases, respectively. CONCLUSIONS: SRS is a safe and effective method of obtaining tumor control in patients with Koos grade IV VS presenting with non-life-threatening or debilitating symptoms, especially those with surgical comorbidities that contraindicate resection. To decrease the incidence of post-SRS facial palsy, a prescription dose < 13 Gy is recommended.

Preoperative validation of edema-corrected tractography in neurosurgical practice: translating surgeon insights into novel software implementation.

Background: Peritumoral edema alters diffusion anisotropy, resulting in false negatives in tractography reconstructions negatively impacting surgical decision-making. With supratotal resections tied to survival benefit in glioma patients, advanced diffusion modeling is critical to visualize fibers within the peritumoral zone to prevent eloquent fiber transection thereafter. A preoperative assessment paradigm is therefore warranted to systematically evaluate multi-subject tractograms along clinically meaningful parameters. We propose a novel noninvasive surgically-focused survey to evaluate the benefits of a tractography algorithm for preoperative planning, subsequently applied to Synaptive Medical's free-water correction algorithm developed for clinically feasible single-shell DTI data. Methods: Ten neurosurgeons participated in the study and were presented with patient datasets containing histological lesions of varying degrees of edema. They were asked to compare standard (uncorrected) tractography reconstructions overlaid onto anatomical images with enhanced (corrected) reconstructions. The raters assessed the datasets in terms of overall data quality, tract alteration patterns, and the impact of the correction on lesion definition, brain-tumor interface, and optimal surgical pathway. Inter-rater reliability coefficients were calculated, and statistical comparisons were made. Results: Standard tractography was perceived as problematic in areas proximal to the lesion, presenting with significant tract reduction that challenged assessment of the brain-tumor interface and of tract infiltration. With correction applied, significant reduction in false negatives were reported along with additional insight into tract infiltration. Significant positive correlations were shown between favorable responses to the correction algorithm and the lesion-to-edema ratio, such that the correction offered further clarification in increasingly edematous and malignant lesions. Lastly, the correction was perceived to introduce false tracts in CSF spaces and - to a lesser degree - the grey-white matter interface, highlighting the need for noise mitigation. As a result, the algorithm was modified by free-water-parameterizing the tractography dataset and introducing a novel adaptive thresholding tool for customizable correction guided by the surgeon's discretion. Conclusion: Here we translate surgeon insights into a clinically deployable software implementation capable of recovering peritumoral tracts in edematous zones while mitigating artifacts through the introduction of a novel and adaptive case-specific correction tool. Together, these advances maximize tractography's clinical potential to personalize surgical decisions when faced with complex pathologies.

Leveraging the CSF proteome toward minimally-invasive diagnostics surveillance of brain malignancies.

Background: Diagnosis and prognostication of intra-axial brain tumors hinges on invasive brain sampling, which carries risk of morbidity. Minimally-invasive sampling of proximal fluids, also known as liquid biopsy, can mitigate this risk. Our objective was to identify diagnostic and prognostic cerebrospinal fluid (CSF) proteomic signatures in glioblastoma (GBM), brain metastases (BM), and primary central nervous system lymphoma (CNSL). Methods: CSF samples were retrospectively retrieved from the Penn State Neuroscience Biorepository and profiled using shotgun proteomics. Proteomic signatures were identified using machine learning classifiers and survival analyses. Results: Using 30 µL CSF volumes, we recovered 755 unique proteins across 73 samples. Proteomic-based classifiers identified malignancy with area under the receiver operating characteristic (AUROC) of 0.94 and distinguished between tumor entities with AUROC ≥0.95. More clinically relevant triplex classifiers, comprised of just three proteins, distinguished between tumor entities with AUROC of 0.75-0.89. Novel biomarkers were identified, including GAP43, TFF3 and CACNA2D2, and characterized using single cell RNA sequencing. Survival analyses validated previously implicated prognostic signatures, including blood-brain barrier disruption. Conclusions: Reliable classification of intra-axial malignancies using low CSF volumes is feasible, allowing for longitudinal tumor surveillance.

Temporal radiographic and histological study of necrosis development in a mouse glioblastoma model.

Tumor necrosis is a poor prognostic marker in glioblastoma (GBM) and a variety of other solid cancers. Accumulating evidence supports that necrosis could facilitate tumor progression and resistance to therapeutics. GBM necrosis is typically first detected by magnetic resonance imaging (MRI), after prominent necrosis has already formed. Therefore, radiological appearances of early necrosis formation and the temporal-spatial development of necrosis alongside tumor progression remain poorly understood. This knowledge gap leads to a lack of reliable radiographic diagnostic/prognostic markers in early GBM progression to detect necrosis. Recently, we reported an orthotopic xenograft GBM murine model driven by hyperactivation of the Hippo pathway transcriptional coactivator with PDZ-binding motif (TAZ) which recapitulates the extent of GBM necrosis seen among patients. In this study, we utilized this model to perform a temporal radiographic and histological study of necrosis development. We observed tumor tissue actively undergoing necrosis first appears more brightly enhancing in the early stages of progression in comparison to the rest of the tumor tissue. Later stages of tumor progression lead to loss of enhancement and unenhancing signals in the necrotic central portion of tumors on T1-weighted post-contrast MRI. This central unenhancing portion coincides with the radiographic and clinical definition of necrosis among GBM patients. Moreover, as necrosis evolves, two relatively more contrast-enhancing rims are observed in relationship to the solid enhancing tumor surrounding the central necrosis in the later stages. The outer more prominently enhancing rim at the tumor border probably represents the infiltrating tumor edge, and the inner enhancing rim at the peri-necrotic region may represent locally infiltrating immune cells. The associated inflammation at the peri-necrotic region was further confirmed by immunohistochemical study of the temporal development of tumor necrosis. Neutrophils appear to be the predominant immune cell population in this region as necrosis evolves. This study shows central, brightly enhancing areas associated with inflammation in the tumor microenvironment may represent an early indication of necrosis development in GBM.

Stereotactic radiosurgery for Koos grade IV vestibular schwannoma in young patients: a multi-institutional study.

PURPOSE: Surgery is the treatment of choice for large vestibular schwannomas (VS). Stereotactic radiosurgery (SRS) has been suggested as an alternative to resection in selected patients. However, the safety and efficacy of SRS in Koos grade IV patients ≤ 45 years old has not been evaluated. The aim of this study is to describe the clinical and radiological outcomes of Koos grade IV in young patient managed with a single-session SRS. METHODS: This retrospective, multicenter analysis included SRS-treated patients, ≤ 45 years old presenting with non-life threatening or incapacitating symptoms due to a Koos Grade IV VS and with follow-up ≥ 12 months. Tumor control and neurological outcomes were evaluated. RESULTS: 176 patients [median age of 36.0 (IQR 9) and median tumor volume of 9.3 cm3 (IQR 4.7)] were included. The median prescription dose was 12 Gy (IQR 0.5). Median follow-up period was 37.5 (IQR 53.5) months. The 5- and 10-year progression-free survival was 90.9% and 86.7%. Early tumor enlargement occurred in 10.9% of cases and was associated with tumor progression at the last follow-up. The probability of serviceable hearing preservation at 5- and 10-years was 56.8% and 45.2%, respectively. The probability of improvement or preservation of facial nerve function was 95.7% at 5 and 10-years. Adverse radiation effects were noted in 19.9%. New-onset hydrocephalus occurred in 4.0%. CONCLUSION: Single-session SRS is a safe and effective alternative to surgical resection in selected patients ≤ 45 years old particularly those with medical co-morbidities and those who decline resection. Longer term follow up is warranted.

Comparative Efficacy of Treatments for Brain Metastases from Non-Small Cell Lung Cancer without an EGFR-Mutation/ALK-Rearrangement: A Systematic Review and Network Meta-Analysis.

INTRODUCTION: As many as 30% of patients with non-small cell lung cancer (NSCLC) will develop brain metastases (BMs) over the course of their illness. Here, we quantitatively compare the efficacy of the various emerging regimens for NSCLC BMs without a definitive targetable epidermal growth factor receptor mutation/ALK rearrangement. METHODS: We searched MEDLINE, EMBASE, Web of Science, ClinicalTrials.gov, CENTRAL, and references of key studies for randomized controlled trials (RCTs) published from inception until June 2020. Comparative RCTs that included ≥10 patients were included. We used a frequentist fixed or random-effects model for network meta-analysis. The outcomes of interest included intracranial progression-free survival (iPFS), overall survival (OS), and overall progression-free survival. RESULTS: In total, 18 studies representing 17 trials (n = 2726 patients) were identified. Immune checkpoint inhibitor regimens showed significant improvement in OS compared with chemotherapy alone, including pembrolizumab and chemotherapy (6 studies, hazard ratio [HR] 0.36, 95% confidence interval [CI] 0.21-0.62), atezolizumab alone (HR 0.54, 95% CI 0.33-0.89), and nivolumab and ipilimumab (HR 0.64, 95% CI 0.42-0.97). An improvement in overall PFS was seen with use of pembrolizumab and chemotherapy compared with chemotherapy alone (3 studies, HR 0.42, 95% CI 0.26-0.68). Studies evaluating checkpoint inhibitors did not report iPFS data, and we did not find improvement in iPFS or OS with the addition of any chemotherapy regimen to whole-brain radiation therapy. CONCLUSIONS: In this network meta-analysis, we demonstrate the promising survival benefit with use of checkpoint inhibitor-based regimens in NSCLC BMs without a targetable epidermal growth factor receptor mutation/ALK rearrangement. Moving forward, large-scale BM-focused RCTs are necessary to establish the iPFS benefit of immune checkpoint inhibitor-based immunotherapy in this patient population.

The Supraorbital Approach via an Eyebrow Incision: Analysis of Cosmetic Outcomes Using the Scar Cosmesis Assessment Rating Scale.

ABSTRACT: The supraorbital craniotomy through an eyebrow incision, referred to as the suprabrow approach, may be used to access intracranial lesions. Though offering good surgical exposure for anterior base cranial lesions, the suprabrow approach has a paucity of studies on its cosmetic outcomes. In this study, we aimed to assess the cosmetic outcomes of suprabrow approach using validated Scar Cosmesis Assessment Rating (SCAR) scale for the first time. Three patients underwent a suprabrow approach for resection of a suprasellar or frontal mass. Their postoperative courses were followed, with specific attention to the cosmetic outcome of their procedures. The SCAR scale was used to determine the cosmetic success of the approach. We found that all 3 patients scored ≤ 5 on the SCAR scale. All 3 resections were successful with no major postoperative complications. The only minor complication was transient hypoesthesia of the ipsilateral forehead that was noted in all 3 patients.This study quantified the positive cosmetic outcomes of a minimally invasive suprabrow approach. The suprabrow approach provides acceptable surgical exposure and access in an appropriately selected patient with anterior cranial base lesions and results in favorable cosmesis. Although transient hypoesthesia in the distribution of the ophthalmic branch of the trigeminal nerve occurs, the overall benefits of the approach and desirable cosmetic outcomes make the suprabrow approach a good technique to access intracranial lesions in appropriate cases.

5-Aminolevulinic acid for enhanced surgical visualization of high-grade gliomas: a prospective, multicenter study.

OBJECTIVE: Greater extent of resection (EOR) is associated with longer overall survival in patients with high-grade gliomas (HGGs). 5-Aminolevulinic acid (5-ALA) can increase EOR by improving intraoperative visualization of contrast-enhancing tumor during fluorescence-guided surgery (FGS). When administered orally, 5-ALA is converted by glioma cells into protoporphyrin IX (PPIX), which fluoresces under blue 400-nm light. 5-ALA has been available for use in Europe since 2010, but only recently gained FDA approval as an intraoperative imaging agent for HGG tissue. In this first-ever, to the authors' knowledge, multicenter 5-ALA FGS study conducted in the United States, the primary objectives were the following: 1) assess the diagnostic accuracy of 5-ALA-induced PPIX fluorescence for HGG histopathology across diverse centers and surgeons; and 2) assess the safety profile of 5-ALA FGS, with particular attention to neurological morbidity. METHODS: This single-arm, multicenter, prospective study included adults aged 18-80 years with Karnofsky Performance Status (KPS) score > 60 and an MRI diagnosis of suspected new or recurrent resectable HGG. Intraoperatively, 3-5 samples per tumor were taken and their fluorescence status was recorded by the surgeon. Specimens were submitted for histopathological analysis. Patients were followed for 6 weeks postoperatively for adverse events, changes in the neurological exam, and KPS score. Multivariate analyses were performed of the outcomes of KPS decline, EOR, and residual enhancing tumor volume to identify predictive patient and intraoperative variables. RESULTS: Sixty-nine patients underwent 5-ALA FGS, providing 275 tumor samples for analysis. PPIX fluorescence had a sensitivity of 96.5%, specificity of 29.4%, positive predictive value (PPV) for HGG histopathology of 95.4%, and diagnostic accuracy of 92.4%. Drug-related adverse events occurred at a rate of 22%. Serious adverse events due to intraoperative neurological injury, which may have resulted from FGS, occurred at a rate of 4.3%. There were 2 deaths unrelated to FGS. Compared to preoperative KPS scores, postoperative KPS scores were significantly lower at 48 hours and 2 weeks but were not different at 6 weeks postoperatively. Complete resection of enhancing tumor occurred in 51.9% of patients. Smaller preoperative tumor volume and use of intraoperative MRI predicted lower residual tumor volume. CONCLUSIONS: PPIX fluorescence, as judged by the surgeon, has a high sensitivity and PPV for HGG. 5-ALA was well tolerated in terms of drug-related adverse events, and its application by trained surgeons in FGS for HGGs was not associated with any excess neurological morbidity.