Pre-operative vs. post-operative stereotactic radiosurgery for operative metastatic brain tumors: study protocol for a phase III clinical trial.

BACKGROUND AND OBJECTIVES: Almost one third of cancer patients in the United States will develop brain metastases on an annual basis. Surgical resection is indicated in the setting of brain metastases for reasons, such as maximizing local control in select patients, decompression of mass effect, and/or tissue diagnosis. The current standard of care following resection of a brain metastasis has shifted from whole brain radiation therapy to post-operative stereotactic radiosurgery (SRS). However, there is a significant rate of local recurrence within one year of postoperative SRS. Emerging retrospective and prospective data suggest pre-operative SRS is a safe and potentially effective treatment paradigm for surgical brain metastases. This trial intends to determine, for patients with an indication for resection of a brain metastasis, whether there is an increase in the time to a composite endpoint of adverse outcomes; including the first occurrence of either: local recurrence, leptomeningeal disease, or symptomatic radiation brain necrosis - in patients who receive pre-operative SRS as compared to patients who receive post-operative SRS. METHODS: This randomized phase III clinical trial compares pre-operative with post-operative SRS for brain metastases. A dynamic random allocation procedure will allocate an equal number of patients to each arm: pre-operative SRS followed by surgery or surgery followed by post-operative SRS. EXPECTED OUTCOMES: If pre-operative SRS improves outcomes relative to post-operative SRS, this will establish pre-operative SRS as superior. If post-operative SRS proves superior to pre-operative SRS, it will remain a standard of care and halt the increasing utilization of pre-operative SRS. If there is no difference in pre- versus post-operative SRS, then pre-operative SRS may still be preferred, given patient convenience and the potential for a condensed timeline. DISCUSSION: Emerging retrospective and prospective data have demonstrated some benefits of pre-op SRS vs. post-op SRS. This study will show whether there is an increase in the time to the composite endpoint. Additionally, the study will compare overall survival; patient-reported outcomes; morbidity; completion of planned therapies; time to systemic therapy; time to regional progression; time to CNS progression; time to subsequent treatment; rate of radiation necrosis; rate of local recurrence; and rate of leptomeningeal disease. TRIAL REGISTRATION NUMBER: NCT03750227 (Registration date: 21/11/2018).

A clinical primer for the glymphatic system.

The complex and dynamic system of fluid flow through the perivascular and interstitial spaces of the CNS has new-found implications for neurological diseases. CSF movement throughout the CNS parenchyma is more dynamic than could be explained via passive diffusion mechanisms alone. Indeed, a semistructured glial-lymphatic (glymphatic) system of astrocyte-supported extracellular perivascular channels serves to directionally channel extracellular fluid, clearing metabolites and peptides to optimize neurological function. Clinical studies of the glymphatic network have to date proven challenging, with most data gleaned from rodent models and post-mortem investigations. However, increasing evidence suggests that disordered glymphatic function contributes to the pathophysiology of CNS ageing, neurodegenerative disease and CNS injuries, as well as normal pressure hydrocephalus. Unlocking such pathophysiology could provide important avenues towards novel therapeutics. We here provide a multidisciplinary overview of glymphatics and critically review accumulating evidence regarding its structure, function and hypothesized relevance to neurological disease. We highlight emerging technologies of relevance to the longitudinal evaluation of glymphatic function in health and disease. Finally, we discuss the translational opportunities and challenges of studying glymphatic science.

Presentation, imaging, patterns of care, growth, and outcome in sporadic and von Hippel-Lindau-associated central nervous system hemangioblastomas.

OBJECT: Hemangioblastoma is a relatively rare neoplasm occurring mostly in the cerebellum that may arise sporadically or in the context of von Hippel-Lindau (VHL) syndrome. Presentation, imaging, natural history, surgical patterns of care, and outcomes are incompletely defined for this uncommon lesion. We reviewed our large institutional series to help clarify these issues. METHODS: Retrospective analysis of consecutive, neurosurgically managed CNS hemangioblastomas at Mayo Clinic, 1988-2018. RESULTS: Two hundred and eighty five hemangioblastomas were treated in 184 unique patients (115 sporadic, 69 VHL). Compared to sporadic patients, VHL patients were younger (36.7 vs 51.7 years; p < 0.0001), were treated while asymptomatic more commonly (47.3 vs 4.2%; p < 0.0001), had smaller lesions (6.6 vs 13.9 mL; p < 0.0001), and harbored lesions with associated cysts less frequently (51.0 vs 75.0%; p = 0.0002). Macrocystic tumor architecture was associated with larger lesion size and greater symptom severity. Solid lesions later formed cysts at a median 130 months. Growth in both total volume and solid component accelerated after cyst formation (10.6 and 6.0 times median rate prior to cyst emergence). VHL patients died at a younger age (47.9 vs 74.5, p = 0.0017) and were more likely to die of direct disease sequelae. Though treatment-free survival time was significantly longer in sporadic cases, a substantial fraction (> 40%) developed tumor recurrence/progression requiring additional treatment. CONCLUSIONS: Hemangioblastoma presentation varies with etiology and clinical course is more complicated in VHL cases. Nodular lesions often develop cysts over time which is associated with accelerated tumor growth. Sporadic cases have a previously unappreciated but substantial risk of late recurrence/progression requiring treatment.

The role of single-fraction stereotactic radiosurgery for atypical meningiomas (WHO grade II): treatment results based on a 25-year experience.

PURPOSE: To clarify the role of stereotactic radiosurgery (SRS) for atypical meningiomas (AM). METHODS: A retrospective analysis of 68 patients with AM having SRS from 1995 until 2019. RESULTS: Nineteen patients (28%) had undergone prior external beam radiation therapy (EBRT) (median dose, 54 Gy). The median follow-up period was 52 months. Eighteen (26%), 17 (25%), and 33 (49%) patients received SRS as an upfront adjuvant (≤ 6 months), early salvage (7-18 months), or late salvage treatment (> 18 months), respectively. The 3-, 5-, and 10-year progression-free survivals (PFSs) were 52%, 35%, and 25%, respectively. The 3-, 5-, and 10-year disease-specific survivals were 85%, 78%, and 61%, respectively. Adverse radiation events (AREs) were observed in 12 patients (18%), with increased or new seizures being the most frequent complication (n = 7). Prior EBRT was associated with reduced PFS (HR 5.92, P < 0.01), reduced DSS (HR 5.84, P < 0.01), and an increased risk of ARE (HR 3.31, P = 0.04). Timing of SRS was correlated with reduced PFS for patients having early salvage treatment compared to upfront adjuvant (HR 3.17, P = 0.01) or late salvage treatment (HR 4.39, P < 0.01). CONCLUSION: PFS for patients with residual/recurrent AM remains poor despite SRS. Prior EBRT was associated with worse tumor control, higher tumor-related mortality, and an increased risk of ARE. Further study on the timing of SRS is needed to determine if upfront adjunctive SRS improves tumor control compared to salvage SRS.

The role of radiation and chemotherapy in adult patients with high-grade brainstem gliomas: results from the National Cancer Database.

INTRODUCTION: Surgical resection of high-grade brainstem gliomas is challenging and treatment mostly involves radiation and chemotherapy. In this study, we utilized registry data to determine prognostic features and impact of chemotherapy and radiation on overall survival. METHODS: The National Cancer Database was queried from 2006 to 2015 for adult cases with histologically confirmed high-grade brainstem glioma. Covariates including patient demographics, comorbidities, tumor characteristics and treatment parameters were captured. Multivariable Cox proportional hazards regression was performed to identify predictors of survival. RESULTS: A total of 422 patients were analyzed. Most patients (66.6%) underwent postoperative radiation with chemotherapy, 9.2% underwent radiation alone, while the remaining had no postoperative treatment (24.2%). Overall median survival was 9.8 months (95% CI 8.8-12). Survival was longer (p < 0.001) in the radiation + chemotherapy group (median: 14.2 months, 95% CI 11.7-17.1) compared to radiation alone (median: 5.7 months, 95% CI 3.7-12) and no postoperative treatment (median: 1.8 months, 95% CI 1.4-4) groups. In multivariable analysis, increasing age was associated with worse survival (HR: 1.87, 95% CI 1.47-2.37, p < 0.001), whereas radiation + chemotherapy was associated with lower mortality compared to radiation alone (HR: 0.67, 95% CI 0.46-0.98, p = 0.038). In subgroup analysis, postoperative chemotherapy with radiation was associated with significant survival benefit compared to radiation alone for grade IV (HR: 0.46, 95% CI 0.28-0.76, p = 0.003), but not for grade III tumors (HR: 0.87, 95% CI 0.48-1.58, p = 0.65). CONCLUSION: Analysis from a national registry illustrated the effectiveness of radiation with chemotherapy for adult patients with high-grade brainstem gliomas, particularly grade IV. Further research should identify specific patient profiles and molecular subgroups that are more likely to benefit from multimodality therapy.

Adjuvant radiation for WHO grade II and III intracranial meningiomas: insights on survival and practice patterns from a National Cancer Registry.

INTRODUCTION: WHO grades II (atypical) and III (malignant) meningiomas are associated with significant morbidity and mortality. The role of adjuvant radiotherapy (RT) in management remains controversial. The goal of this study was to evaluate the impact of adjuvant RT on 5-year survival in patients with atypical and malignant meningiomas. We secondarily aimed to assess contemporary practice patterns and the impact of sociodemographic factors on outcome. METHODS: We queried the National Cancer Database for patients ≥ 18 years of age with cranial atypical or malignant meningiomas from 2010 through 2015 who underwent surgical resection with or without adjuvant radiotherapy. Subjects with unknown WHO grade or radiation status and those not receiving any surgical procedure were excluded from analysis. RESULTS: The study includes 7486 patients, 6788 with atypical and 698 with malignant meningiomas. Overall 5-year survival was 76.9% (95% CI 75.5-78.3%) and 43.3% (95% CI 38.8-48.2%) among patients with WHO grades II and III meningiomas, respectively. Adjuvant RT correlated with improved survival in a multivariable model in patients with grade II tumors (HR 0.78; p = 0.029) regardless of the extent of resection. Age (HR 2.33; p < 0.001), male sex (HR 1.27; p < 0.001), Black race (HR 1.27; p = 0.011) and Charlson-Deyo Score ≥ 2 (1.35; p = 0.001) correlated with poorer survival whereas private insurance (HR 0.71; p < 0.001) correlated with improved survival. Adjuvant RT was also associated with improved 5-year survival among those with grade III tumors on univariate analysis (log-rank p = 0.006) but was underpowered for multivariable modeling. Utilization of adjuvant radiotherapy was only 28.4% and correlated with private insurance status. Academic institutions (25.3%) and comprehensive community cancer programs (21.4%) had lower radiotherapy utilization rates compared with integrated network cancer programs (30.5%) and community cancer programs (29.7%). CONCLUSIONS: Adjuvant RT may correlate with improved overall survival in patients with grades II and III intracranial meningiomas regardless of the extent of resection. There is poor utilization of adjuvant RT for patients with grades II and III meningiomas likely due to a paucity of quality data on the subject. These findings will be strengthened with prospective data evaluating the role of adjuvant RT.

Glioblastoma Recurrence Versus Treatment Effect in a Pathology-Documented Series.

OBJECTIVE: Patients diagnosed with glioblastoma (GBM) are treated with surgery followed by fractionated radiotherapy with concurrent and adjuvant temozolomide. Patients are monitored with serial magnetic resonance imaging (MRI). However, treatment-related changes frequently mimic disease progression. We reviewed a series of patients undergoing surgery for presumed first-recurrence GBM, where pathology reports were available for tissue diagnosis, in order to better understand factors associated with a diagnosis of treatment-related changes on final pathology. METHODS: Patient records at a single institution between 2005 and 2015 were retrospectively reviewed. Pathology reports were reviewed to determine diagnosis of recurrent GBM or treatment effect. Survival analysis was performed interrogating overall survival (OS) and progression-free survival (PFS). Correlation with radiation treatment plans was also examined. RESULTS: One-hundred-twenty-three patients were identified. One-hundred-sixteen patients (94%) underwent resection and seven underwent biopsy. Treatment-related changes were reported in 20 cases (16%). These patients had longer median OS and PFS from the time of recurrence than patients with true disease progression. However, there was no significant difference in OS from the time of initial diagnosis. Treatment effect was associated with surgery within 90 days of completing radiation. In patients receiving radiation at our institution (n = 53), larger radiation target volume and a higher maximum dose were associated with treatment effect. CONCLUSION: Treatment effect was associated with surgery nearer to completion of radiation, a larger radiation target volume, and a higher maximum point dose. Treatment effect was associated with longer PFS and OS from the time of recurrence, but not from the time of initial diagnosis.

Hypofractionated versus standard radiation therapy in combination with temozolomide for glioblastoma in the elderly: a meta-analysis.

BACKGROUND: There is no clear consensus regarding the optimal treatment for glioblastoma (GBM) in the elderly. Hypofractionated radiation therapy (hRT) has emerged as a viable and comparable radiation regime compared to standard radiation therapy (sRT), however the survival effect of temozolomide (TMZ) with hRT is uncertain. The aim of this meta-analysis was to evaluate survival outcomes of hRT + TMZ vs sRT + TMZ in this specific demographic. METHODS: Searches of 7 electronic databases from inception to January 2019 were conducted following the appropriate guidelines. Articles were screened against pre-specified criteria. The progression free survival (PFS) and overall survival (OS) metrics were then extracted and pooled by meta-analysis evaluating mean difference (MD). RESULTS: A total of 7 individual comparative studies describing hRT + TMZ vs sRT + TMZ (n = 917) respectively satisfied inclusion criteria. Meta-analysis by random-effects modelling indicated that compared to sRT + TMZ, hRT + TMZ resulted in comparable PFS (MD 0.3 months; 95% CI - 2.4 to 2.9; I2 = 91.7%; P-effect = 0.85) and significantly shorter OS (MD - 3.5 months; 95% CI - 6.3 to - 0.6; I2 = 98.9%; P-effect = 0.02). Subgroup analysis between age definitions of elderly of > 65 vs > 70 years old both demonstrated the same significant trend with no statistical difference between the groups. CONCLUSION: The combination of hRT + TMZ is feasible in well-selected elderly GBM cases, and appears to confer a statistically comparable PFS compared to sRT + TMZ. However, expectations that the OS with hRT + TMZ is comparable to that of sRT + TMZ in all elderly GBM presentations should be tempered. It is likely a specific subgroup of elderly GBM patients will benefit greatly from the addition of TMZ to hRT, and greater investigation is needed to identify their characteristics.

Brain Perfusion and Diffusion Abnormalities in Children Treated for Posterior Fossa Brain Tumors.

OBJECTIVE: To compare cerebral perfusion and diffusion in survivors of childhood posterior fossa brain tumor with neurologically normal controls and correlate differences with cognitive dysfunction. STUDY DESIGN: We analyzed retrospectively arterial spin-labeled cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) in 21 patients with medulloblastoma (MB), 18 patients with pilocytic astrocytoma (PA), and 64 neurologically normal children. We generated ANCOVA models to evaluate treatment effects on the cerebral cortex, thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala, nucleus accumbens, and cerebral white matter at time points an average of 5.7 years after original diagnosis. A retrospective review of patient charts identified 12 patients with neurocognitive data and in whom the relationship between IQ and magnetic resonance imaging variables was assessed for each brain structure. RESULTS: Patients with MB (all treated with surgery, chemotherapy, and radiation) had significantly lower global CBF relative to controls (10%-23% lower, varying by anatomic region, all adjusted P?

Radiation-induced brain injury: low-hanging fruit for neuroregeneration.

Brain radiation is a fundamental tool in neurooncology to improve local tumor control, but it leads to profound and progressive impairments in cognitive function. Increased attention to quality of life in neurooncology has accelerated efforts to understand and ameliorate radiation-induced cognitive sequelae. Such progress has coincided with a new understanding of the role of CNS progenitor cell populations in normal cognition and in their potential utility for the treatment of neurological diseases. The irradiated brain exhibits a host of biochemical and cellular derangements, including loss of endogenous neurogenesis, demyelination, and ablation of endogenous oligodendrocyte progenitor cells. These changes, in combination with a state of chronic neuroinflammation, underlie impairments in memory, attention, executive function, and acquisition of motor and language skills. Animal models of radiation-induced brain injury have demonstrated a robust capacity of both neural stem cells and oligodendrocyte progenitor cells to restore cognitive function after brain irradiation, likely through a combination of cell replacement and trophic effects. Oligodendrocyte progenitor cells exhibit a remarkable capacity to migrate, integrate, and functionally remyelinate damaged white matter tracts in a variety of preclinical models. The authors here critically address the opportunities and challenges in translating regenerative cell therapies from rodents to humans. Although valiant attempts to translate neuroprotective therapies in recent decades have almost uniformly failed, the authors make the case that harnessing human radiation-induced brain injury as a scientific tool represents a unique opportunity to both successfully translate a neuroregenerative therapy and to acquire tools to facilitate future restorative therapies for human traumatic and degenerative diseases of the central nervous system.

Aging-like changes in the transcriptome of irradiated microglia.

Whole brain irradiation remains important in the management of brain tumors. Although necessary for improving survival outcomes, cranial irradiation also results in cognitive decline in long-term survivors. A chronic inflammatory state characterized by microglial activation has been implicated in radiation-induced brain injury. We here provide the first comprehensive transcriptional profile of irradiated microglia. Fluorescence-activated cell sorting was used to isolate CD11b+ microglia from the hippocampi of C57BL/6 and Balb/c mice 1 month after 10 Gy cranial irradiation. Affymetrix gene expression profiles were evaluated using linear modeling and rank product analyses. One month after irradiation, a conserved irradiation signature across strains was identified, comprising 448 and 85 differentially up- and downregulated genes, respectively. Gene set enrichment analysis demonstrated enrichment for inflammation, including M1 macrophage-associated genes, but also an unexpected enrichment for extracellular matrix and blood coagulation-related gene sets, in contrast previously described microglial states. Weighted gene coexpression network analysis confirmed these findings and further revealed alterations in mitochondrial function. The RNA-seq transcriptome of microglia 24-h postradiation proved similar to the 1-month transcriptome, but additionally featured alterations in apoptotic and lysosomal gene expression. Reanalysis of published aging mouse microglia transcriptome data demonstrated striking similarity to the 1-month irradiated microglia transcriptome, suggesting that shared mechanisms may underlie aging and chronic irradiation-induced cognitive decline. GLIA 2015;63:754-767.

Controlling and monitoring stem cell safety in vivo in an experimental rodent model.

Adult stem cells have been investigated increasingly over the past years for multiple applications. Although they have a more favorable safety profile compared to pluripotent stem cells, they are still capable of self-renewal and differentiate into several cell types. We investigated the behavior of Oct4-positive (Oct4(+)) and Oct4-negative (Oct4(-) ) murine or rat bone marrow (BM)-derived stem cells in the healthy brain of syngeneic mice and rats. Engraftment of mouse and rat Oct4-positive BM-derived hypoblast-like stem cells (m/rOct4(+) BM-HypoSCs) resulted in yolk-sac tumor formation in the healthy brain which was monitored longitudinally using magnetic resonance imaging (MRI) and bioluminescence imaging (BLI). Contrast enhanced MRI confirmed the disruption of the blood brain barrier. In contrast, m/r Oct4-negative BM-derived multipotent adult progenitor cells (m/rOct4(-) BM-MAPCs) did not result in mass formation after engraftment into the brain. mOct4(+) BM-HypoSCs and mOct4(-) BM-MAPCs were transduced to express enhanced green fluorescent protein, firefly luciferase (fLuc), and herpes simplex virus-thymidine kinase to follow up suicide gene expression as a potential "safety switch" for tumor-forming stem cells by multimodal imaging. Both cell lines were eradicated efficiently in vivo by ganciclovir administration indicating successful suicide gene expression in vivo, as assessed by MRI, BLI, and histology. The use of suicide genes to prevent tumor formation is in particular of interest for therapeutic approaches where stem cells are used as vehicles to deliver therapeutic genes.

Targeting MET for glioma therapy.

Glioblastoma multiforme is the most common and most lethal of all primary brain tumors. Even with the standard therapy, life expectancy is still poor, with an average survival of approximately 14 months following initial diagnosis. Hence, there is an urgent need for novel treatment strategies that inhibit proliferation and angiogenesis in high-grade gliomas. One such strategy consists of inhibiting receptor tyrosine kinases, including MET and/or its ligand hepatocyte growth factor (HGF). Because of their widespread involvement in human cancer, HGF and MET have emerged as promising therapeutic targets, and some inhibitory agents that target them have already entered clinical trials. In this paper, the authors highlight recent evidence implicating HGF/MET pathway deregulation in glioblastoma multiforme, discuss therapeutic approaches to inhibit HGF/MET signaling, and summarize ongoing clinical trials targeting this pathway.

Clinical presentation, role of surgery and prognosis in spinal astrocytoma: Cohort study.

Spinal astrocytoma is a rare neoplasm with discouraging prognosis, which accounts for 6-8 % of total intramedullary spinal tumors. As this is a rare entity, details of the clinical and molecular features have not been fully unraveled. We evaluated the radiologic findings, perioperative clinical presentation, histopathological features and treatment response in a single institution series of 37 consecutive cases of spinal astrocytomas (WHO grades 1 to 4). We identified 8, 16, 8, and 5 patients with grade 1, 2, 3, and 4 lesions, respectively, from 1988 to 2017. Peak ages were youngest in grade 1, followed in order by grades 4, 3 and 2. Whereas all cases of grade 1 and 4 enhanced with contrast, less than half of the cases of grade 2 tumors enhanced (44 %). Grade 3 tumors had a higher rate of multiplicity at presentation (50 %). A concomitant brain lesion at presentation was present in 14 % and 43 % of grade 2 and 3 lesions, respectively. Progression-free and overall survival were worse in grades 3 and 4 compared to grade 2 lesions but no significant difference was observed between grade 3 and 4. Many patients (16-of-36) experienced new neurological deficits postoperatively regardless of grade. Most patients (88 %) required postoperative rehabilitation, and 61 % were not discharged to home. Discharge destination closely correlated with age (p = 0.002). These clinical findings may be useful in understanding the clinical phenotype and improving the management of this rare disease.

Safety of the immediate use of nonsteroidal anti-inflammatory drugs after adult craniotomy for tumor.

OBJECTIVE: Poor pain control has a negative impact on postoperative recovery and patient satisfaction. However, overzealous pain management, particularly with opioids, can confound serial neurological assessments, increase morbidity, and predispose patients to long-term dependence. Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in treating postoperative pain and can limit opioid intake, but their use has been limited in patients undergoing craniotomy for brain tumor resection due to concerns of an increased hemorrhage risk. Herein, the authors aim to 1) address the safety of NSAID use in the immediate postoperative setting and 2) determine whether NSAID administration decreases opioid use following craniotomy for tumor resection in adult patients. METHODS: The authors conducted a retrospective cohort study of patients 18 years and older with an estimated glomerular filtration rate ≥ 60 ml/min/body surface area who had undergone craniotomy for tumor resection at their institution between 2019 and 2021. NSAID use in the first 48 hours following surgery was recorded. Primary outcomes were postoperative hemorrhage requiring a return to the operating room before hospital discharge and within 30 days of surgery. Secondary outcomes were more-than-minimal hemorrhage that did not require reoperation, acute kidney injury, and total opioid use within 48 hours after craniotomy. RESULTS: Among 1765 reviewed patient records, 1182 were eligible for inclusion in this analysis. Amid these records were 114 patients (9.6%) who had received at least one dose of an NSAID within 48 hours of their craniotomy. Four (0.3%) patients experienced bleeding requiring a return to operating room, one of whom was from the NSAID-treated group (RR 3.12, 95% CI 0.33-29.77, p = 0.30). No significant difference in nonoperative intracranial hemorrhage (RR 1.34, 95% CI 0.54-3.35, p = 0.53), postoperative acute kidney injury, or clinically significant extracranial bleeding was found between the NSAID and no-NSAID groups. Patients in the NSAID group had significantly higher oral morphine equivalent use (median 68 vs 30, p < 0.001). CONCLUSIONS: Postoperative NSAID use following craniotomy for tumor resection was not associated with an increased risk of hemorrhage requiring a return to the operating room. The authors noted higher opioid use in the patients treated with NSAIDs, which may reflect underlying reasons for the decision to treat patients with NSAIDs in the immediate postoperative period. These data warrant further investigation of NSAIDs as a safe, opioid-sparing postoperative pain management strategy in patients with normal kidney function who are undergoing intracranial tumor resection.

The longitudinal risk of hemorrhage of melanoma brain metastases after Gamma Knife radiosurgery.

OBJECTIVE: The objective of this study was to analyze the hemorrhagic risk of melanoma brain metastases after Gamma Knife radiosurgery (GKRS). METHODS: A prospective institutional database was retrospectively queried to identify patients who underwent GKRS for melanoma brain metastases between 1990 and 2021. Lesional hemorrhage was defined as definite or possible based on radiologists' readings, and severity was graded according to Common Terminology Criteria for Adverse Events. RESULTS: Two hundred ninety-one patients with 1083 lesions treated in 419 sessions were identified. The mean (± SD) patient age was 60 ± 15 years, and 61% were male. The median follow-up period for overall survival (OS) was 11 (range 0-214) months with 581 patient-years. Definite/possible lesional hemorrhages occurred in 13% of lesions, with grade 3 hemorrhages observed in 4% of lesions. Surgical intervention was required in 2% of cases (5% of patients), and all resected lesions were pathologically consistent with melanoma. A decreased risk of definite/possible lesional hemorrhage was associated with a later time period between 2015 and 2021 (OR 0.45, 95% CI 0.266-0.75, p = 0.0021), increased marginal dose (OR 0.91, 95% CI 0.83-0.99, p = 0.037), antiplatelet use post-GKRS (OR 0.195, 95% CI 0.083-0.46, p < 0.001), and whole-brain radiotherapy (WBRT; OR 0.53, 95% CI 0.344-0.82, p = 0.0042). After 2015, more patients received anticoagulation, B-Raf proto-oncogene inhibitors, and immune checkpoint inhibitors, and fewer received bevacizumab (p < 0.001). The cumulative risk of lesional hemorrhage was 17%-20% at 36 months from GKRS, with 95%-96% of cases occurring within 12 months. The median patient OS was 11 (95% CI 9-13) months, and multivariate Cox regression analysis revealed that antiplatelet agents (hazard ratio [HR] 0.66, 95% CI 0.45-0.96, p = 0.031) and immune checkpoint inhibitors (HR 0.35, 95% CI 0.26-0.48, p < 0.001) were associated with longer OS, while WBRT (HR 1.36, 95% CI 1.02-1.81, p = 0.037) and definite/possible hemorrhage (HR 1.39, 95% CI 1.04-1.85, p = 0.024) were associated with shorter OS. CONCLUSIONS: The definite hemorrhage risk of melanoma brain metastases after GKRS was 17% in the first 3 years and 95% of the lesional hemorrhage occurred within the 1st year. Surgical intervention was needed in 5% of patients. Antiplatelet agents and immune checkpoint inhibitors were associated with improved OS, while definite/possible hemorrhage was associated with worse OS.

Proton versus photon craniospinal irradiation for adult medulloblastoma: A dosimetric, toxicity, and exploratory cost analysis.

Background: This study aimed to determine whether proton craniospinal irradiation (CSI) decreased the dose to normal tissue and resulted in less toxicity than photon CSI for adult patients. Methods: This single-institution retrospective analyzed differences in radiation doses, acute toxicity, and cost between proton and CSI for adult medulloblastoma patients. Results: Of 39 total patients, 20 were treated with photon CSI prior to 2015, and 19 were treated with proton CSI thereafter. Median age was 28 years (range 18-66). The molecular subtype was most commonly sonic hedgehog (68%). Patients most commonly received 36 Gy CSI in 20 fractions with a boost to 54-55.8 Gy (92%). Proton CSI delivered significantly lower mean doses to cochleae, lacrimal glands, lens, parotid glands, pharyngeal constrictors, esophagus, lungs, liver, and skin (all P < .001). Patients receiving proton CSI had significantly lower rates of acute dysphagia of any grade (5% versus 35%, P = .044) and decreased median weight loss during radiation (+1.0 versus -2.8 kg, P = .011). Weight loss was associated with acute hospitalization (P = .009). Median follow-up was 2.9 and 12.9 years for proton and photon patients, respectively, limiting late toxicity and outcome comparisons. At the last follow-up, 5 photon patients had died (2 of progressive disease, 3 without recurrence ages 41-63) and 21% had experienced major cardiovascular events. At 10 years, 89% were alive and 82% were recurrence free. Conclusions: This study demonstrates dosimetric improvements with proton CSI, potentially leading to decreased acute toxicity including dysphagia and weight loss during treatment.

Carcinoembryonic antigen-expressing oncolytic measles virus derivative in recurrent glioblastoma: a phase 1 trial.

Measles virus (MV) vaccine strains have shown significant preclinical antitumor activity against glioblastoma (GBM), the most lethal glioma histology. In this first in human trial (NCT00390299), a carcinoembryonic antigen-expressing oncolytic measles virus derivative (MV-CEA), was administered in recurrent GBM patients either at the resection cavity (Group A), or, intratumorally on day 1, followed by a second dose administered in the resection cavity after tumor resection on day 5 (Group B). A total of 22 patients received study treatment, 9 in Group A and 13 in Group B. Primary endpoint was safety and toxicity: treatment was well tolerated with no dose-limiting toxicity being observed up to the maximum feasible dose (2×107 TCID50). Median OS, a secondary endpoint, was 11.6 mo and one year survival was 45.5% comparing favorably with contemporary controls. Other secondary endpoints included assessment of viremia, MV replication and shedding, humoral and cellular immune response to the injected virus. A 22 interferon stimulated gene (ISG) diagonal linear discriminate analysis (DLDA) classification algorithm in a post-hoc analysis was found to be inversely (R = -0.6, p = 0.04) correlated with viral replication and tumor microenvironment remodeling including proinflammatory changes and CD8 + T cell infiltration in post treatment samples. This data supports that oncolytic MV derivatives warrant further clinical investigation and that an ISG-based DLDA algorithm can provide the basis for treatment personalization.

The dynamic impact of location and resection on the glioma CSF proteome.

While serial sampling of glioma tissue is rarely performed prior to recurrence, cerebrospinal fluid (CSF) is an underutilized longitudinal source of candidate glioma biomarkers for understanding therapeutic impacts. However, the impact of key variables to consider in longitudinal CSF samples, including anatomical location and post-surgical changes, remains unknown. To that end, pre- versus post-resection intracranial CSF samples were obtained at early (1-16 days; n=20) or delayed (86-153 days; n=11) timepoints for patients with glioma. Paired lumbar-versus-intracranial glioma CSF samples were also obtained (n=14). Using aptamer-based proteomics, we identify significant differences in the CSF proteome between lumbar, subarachnoid, and ventricular CSF. Our analysis of serial intracranial CSF samples suggests the early potential for disease monitoring and evaluation of pharmacodynamic impact of targeted therapies. Importantly, we found that resection had a significant, evolving longitudinal impact on the CSF proteome. Proteomic data are provided with individual clinical annotations as a resource for the field. One Sentence Summary: Glioma cerebrospinal fluid (CSF) accessed intra-operatively and longitudinally via devices can reveal impacts of treatment and anatomical location.