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BACKGROUND AND OBJECTIVES: Despite growing interest in how patient frailty affects outcomes (eg, in neuro-oncology), its role after transsphenoidal surgery for Cushing disease (CD) remains unclear. We evaluated the effect of frailty on CD outcomes using the Registry of Adenomas of the Pituitary and Related Disorders (RAPID) data set from a collaboration of US academic pituitary centers. METHODS: Data on consecutive surgically treated patients with CD (2011-2023) were compiled using the 11-factor modified frailty index. Patients were classified as fit (score, 0-1), managing well (score, 2-3), and mildly frail (score, 4-5). Univariable and multivariable analyses were conducted to examine outcomes. RESULTS: Data were analyzed for 318 patients (193 fit, 113 managing well, 12 mildly frail). Compared with fit and managing well patients, mildly frail patients were older (mean ± SD 39.7 ± 14.2 and 48.9 ± 12.2 vs 49.4 ± 8.9 years, P < .001) but did not different by sex, race, and other factors. They had significantly longer hospitalizations (3.7 ± 2.0 and 4.5 ± 3.5 vs 5.3 ± 3.5 days, P = .02), even after multivariable analysis (ß = 1.01, P = .007) adjusted for known predictors of prolonged hospitalization (age, Knosp grade, surgeon experience, American Society of Anesthesiologists grade, complications, frailty). Patients with mild frailty were more commonly discharged to skilled nursing facilities (0.5% [1/192] and 4.5% [5/112] vs 25% [3/12], P < .001). Most patients underwent gross total resection (84.4% [163/193] and 79.6% [90/113] vs 83% [10/12]). No difference in overall complications was observed; however, venous thromboembolism was more common in mildly frail (8%, 1/12) than in fit (0.5%, 1/193) and managing well (2.7%, 3/113) patients (P = .04). No difference was found in 90-day readmission rates. CONCLUSION: These results demonstrate that mild frailty predicts CD surgical outcomes and may inform preoperative risk stratification. Frailty-influenced outcomes other than age and tumor characteristics may be useful for prognostication. Future studies can help identify strategies to reduce disease burden for frail patients with hypercortisolemia.
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BACKGROUND AND OBJECTIVES: To address the lack of a multicenter pituitary surgery research consortium in the United States, we established the Registry of Adenomas of the Pituitary and Related Disorders (RAPID). The goals of RAPID are to examine surgical outcomes, improve patient care, disseminate best practices, and facilitate multicenter surgery research at scale. Our initial focus is Cushing disease (CD). This study aims to describe the current RAPID patient cohort, explore surgical outcomes, and lay the foundation for future studies addressing the limitations of previous studies. METHODS: Prospectively and retrospectively obtained data from participating sites were aggregated using a cloud-based registry and analyzed retrospectively. Standard preoperative variables and outcome measures included length of stay, unplanned readmission, and remission. RESULTS: By July 2023, 528 patients with CD had been treated by 26 neurosurgeons with varying levels of experience at 9 academic pituitary centers. No surgeon treated more than 81 of 528 (15.3%) patients. The mean ± SD patient age was 43.8 ± 13.9 years, and most patients were female (82.2%, 433/527). The mean tumor diameter was 0.8 ± 2.7 cm. Most patients (76.6%, 354/462) had no prior treatment. The most common pathology was corticotroph tumor (76.8%, 381/496). The mean length of stay was 3.8 ± 2.5 days. The most common discharge destination was home (97.2%, 513/528). Two patients (0.4%, 2/528) died perioperatively. A total of 57 patients (11.0%, 57/519) required an unplanned hospital readmission within 90 days of surgery. The median actuarial disease-free survival after index surgery was 8.5 years. CONCLUSION: This study examined an evolving multicenter collaboration on patient outcomes after surgery for CD. Our results provide novel insights on surgical outcomes not possible in prior single-center studies or with national administrative data sets. This collaboration will power future studies to better advance the standard of care for patients with CD.
Subject(s)
Adenoma , Pituitary ACTH Hypersecretion , Pituitary Neoplasms , Registries , Humans , Female , Male , Adult , Pituitary ACTH Hypersecretion/surgery , Middle Aged , Adenoma/surgery , Treatment Outcome , Pituitary Neoplasms/surgery , Retrospective Studies , Cohort Studies , Neurosurgical Procedures/methods , Surgeons/statistics & numerical data , Prospective Studies , Length of Stay/statistics & numerical data , United States/epidemiology , AgedABSTRACT
BACKGROUND: Congenital optic canal stenosis causing compressive optic neuropathy is a rare disorder that presents unique diagnostic and treatment challenges. Endoscopic endonasal optic nerve decompression (EOND) has been described for optic nerve compression in adults and adolescents but has never been reported for young children without pneumatized sphenoid sinuses. The authors describe preoperative and intraoperative considerations for three patients younger than 2 years of age with congenital optic canal stenosis due to genetically confirmed osteopetrosis or chondrodysplasia. OBSERVATIONS: Serial ophthalmological examinations, with a particular focus on object tracking ability, fundoscopic examination, and visual evoked potential trends in preverbal children, are important for detecting progressive optic neuropathy. The lack of pneumatization of the sphenoid sinus presents unique challenges and requires the surgical creation of a sphenoid sinus with the use of neuronavigation to determine the limits of bony exposure given the lack of easily identifiable anatomical landmarks such as the opticocarotid recess. There were no perioperative complications. LESSONS: EOND for congenital optic canal stenosis is safe and technically feasible even given the lack of pneumatization of the sphenoid sinus in young patients. The key operative step is surgically creating the sphenoid sinus through careful bony removal with the aid of neuronavigation. https://thejns.org/doi/10.3171/CASE23559.
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BACKGROUND AND OBJECTIVE: Cushing disease (CD) affects mortality and quality of life along with limited long-term remission, underscoring the need to better identify recurrence risk. The identification of surgical or imaging predictors for CD remission after transsphenoidal surgery has yielded some inconsistent results and has been limited by single-center, single-surgeon, or meta-analyses studies. We sought to evaluate the multicenter Registry of Adenomas of the Pituitary and Related Disorders (RAPID) database of academic US pituitary centers to assess whether robust nonhormonal recurrence predictors could be elucidated. METHODS: Patients with treated CD from 2011 to 2023 were included. The perioperative and long-term characteristics of CD patients with and without recurrence were assessed using univariable and multivariable analyses. RESULTS: Of 383 patients with CD from 26 surgeons achieving postoperative remission, 288 (75.2%) maintained remission at last follow-up while 95 (24.8%) showed recurrence (median time to recurrence 9.99 ± 1.34 years). Patients with recurrence required longer postoperative hospital stays (5 ± 3 vs 4 ± 2 days, P = .002), had larger average tumor volumes (1.76 ± 2.53 cm3 vs 0.49 ± 1.17 cm3, P = .0001), and more often previously failed prior treatment (31.1% vs 14.9%, P = .001) mostly being prior surgery. Multivariable hazard prediction models for tumor recurrence found younger age (odds ratio [OR] = 0.95, P = .002) and Knosp grade of 0 (OR = 0.09, reference Knosp grade 4, P = .03) to be protective against recurrence. Comparison of Knosp grade 0 to 2 vs 3 to 4 showed that lower grades had reduced risk of recurrence (OR = 0.27, P = .04). Other factors such as length of stay, surgeon experience, prior tumor treatment, and Knosp grades 1, 2, or 3 failed to reach levels of statistical significance in multivariable analysis. CONCLUSION: This multicenter study centers suggests that the strongest predictors of recurrence include tumor size/invasion and age. This insight can help with patient counseling and prognostication. Long-term follow-up is necessary for patients, and early treatment of small tumors may improve outcomes.
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The landscape of the cranial neurosurgery has changed tremendously in past couple of decades. The main frontiers including introduction of neuro-endoscopy, minimally invasive skull base approaches, SRS, laser interstitial thermal therapy and use of tubular retractors have revolutionized the management of intracerebral hemorrhages, deep seated tumors other intracranial pathologies. Introduction of these novel techniques is based on smaller incisions with maximal operative corridors, decreased blood loss, shorter hospital stays, decreased post-operative pain and cosmetically appealing scars that improves patient satisfaction and clinical outcomes. The sophisticated tools like neuroendoscopy have improved light source, and better visualization around the corners. Advanced navigated tools and channel-based retractors help us to target deeply seated lesions with increased precision and minimal disruption of the surrounding neurovascular tissues. Advent of stereotactic radiosurgery has provided us alternative feasible, safe and effective options for treatment of patients who are otherwise not medically stable to undergo complex cranial surgical interventions. This paper review advances in treatment of intracranial pathologies, and how the neurosurgeons and other medical providers at the University of Missouri-Columbia (UMC) are optimizing these treatments for their patients.
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Neurosurgical Procedures , Humans , Neurosurgical Procedures/methods , Neurosurgical Procedures/trends , Radiosurgery/methods , Radiosurgery/trends , Cerebral Hemorrhage/surgery , Brain Neoplasms/surgery , Neuroendoscopy/methods , Neuroendoscopy/trendsABSTRACT
PURPOSE: Outcomes for patients with glioblastoma (GBM) remain poor despite multimodality treatment with surgery, radiation, and chemotherapy. There are few immunotherapy options due to the lack of tumor immunogenicity. Several clinical trials have reported promising results with cancer vaccines. To date, studies have used data from a single tumor site to identify targetable antigens, but this approach limits the antigen pool and is antithetical to the heterogeneity of GBM. We have implemented multisector sequencing to increase the pool of neoantigens across the GBM genomic landscape that can be incorporated into personalized peptide vaccines called NeoVax. PATIENTS AND METHODS: In this study, we report the findings of four patients enrolled onto the NeoVax clinical trial (NCT0342209). RESULTS: Immune reactivity to NeoVax neoantigens was assessed in peripheral blood mononuclear cells pre- and post-NeoVax for patients 1 to 3 using IFNγ-ELISPOT assay. A statistically significant increase in IFNγ producing T cells at the post-NeoVax time point for several neoantigens was observed. Furthermore, a post-NeoVax tumor biopsy was obtained from patient 3 and, upon evaluation, revealed evidence of infiltrating, clonally expanded T cells. CONCLUSIONS: Collectively, our findings suggest that NeoVax stimulated the expansion of neoantigen-specific effector T cells and provide encouraging results to aid in the development of future neoantigen vaccine-based clinical trials in patients with GBM. Herein, we demonstrate the feasibility of incorporating multisector sampling in cancer vaccine design and provide information on the clinical applicability of clonality, distribution, and immunogenicity of the neoantigen landscape in patients with GBM.
Subject(s)
Antigens, Neoplasm , Cancer Vaccines , Glioblastoma , Precision Medicine , Vaccines, Subunit , Humans , Glioblastoma/immunology , Glioblastoma/therapy , Glioblastoma/genetics , Glioblastoma/pathology , Cancer Vaccines/immunology , Cancer Vaccines/administration & dosage , Cancer Vaccines/therapeutic use , Vaccines, Subunit/immunology , Vaccines, Subunit/administration & dosage , Vaccines, Subunit/therapeutic use , Precision Medicine/methods , Antigens, Neoplasm/immunology , Female , Male , Middle Aged , Brain Neoplasms/immunology , Brain Neoplasms/therapy , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Adult , Aged , Immunotherapy/methods , Protein Subunit VaccinesABSTRACT
BACKGROUND: Trials of surgical evacuation of supratentorial intracerebral hemorrhages have generally shown no functional benefit. Whether early minimally invasive surgical removal would result in better outcomes than medical management is not known. METHODS: In this multicenter, randomized trial involving patients with an acute intracerebral hemorrhage, we assessed surgical removal of the hematoma as compared with medical management. Patients who had a lobar or anterior basal ganglia hemorrhage with a hematoma volume of 30 to 80 ml were assigned, in a 1:1 ratio, within 24 hours after the time that they were last known to be well, to minimally invasive surgical removal of the hematoma plus guideline-based medical management (surgery group) or to guideline-based medical management alone (control group). The primary efficacy end point was the mean score on the utility-weighted modified Rankin scale (range, 0 to 1, with higher scores indicating better outcomes, according to patients' assessment) at 180 days, with a prespecified threshold for posterior probability of superiority of 0.975 or higher. The trial included rules for adaptation of enrollment criteria on the basis of hemorrhage location. A primary safety end point was death within 30 days after enrollment. RESULTS: A total of 300 patients were enrolled, of whom 30.7% had anterior basal ganglia hemorrhages and 69.3% had lobar hemorrhages. After 175 patients had been enrolled, an adaptation rule was triggered, and only persons with lobar hemorrhages were enrolled. The mean score on the utility-weighted modified Rankin scale at 180 days was 0.458 in the surgery group and 0.374 in the control group (difference, 0.084; 95% Bayesian credible interval, 0.005 to 0.163; posterior probability of superiority of surgery, 0.981). The mean between-group difference was 0.127 (95% Bayesian credible interval, 0.035 to 0.219) among patients with lobar hemorrhages and -0.013 (95% Bayesian credible interval, -0.147 to 0.116) among those with anterior basal ganglia hemorrhages. The percentage of patients who had died by 30 days was 9.3% in the surgery group and 18.0% in the control group. Five patients (3.3%) in the surgery group had postoperative rebleeding and neurologic deterioration. CONCLUSIONS: Among patients in whom surgery could be performed within 24 hours after an acute intracerebral hemorrhage, minimally invasive hematoma evacuation resulted in better functional outcomes at 180 days than those with guideline-based medical management. The effect of surgery appeared to be attributable to intervention for lobar hemorrhages. (Funded by Nico; ENRICH ClinicalTrials.gov number, NCT02880878.).
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Cerebral Hemorrhage , Humans , Basal Ganglia Hemorrhage/mortality , Basal Ganglia Hemorrhage/surgery , Basal Ganglia Hemorrhage/therapy , Bayes Theorem , Cerebral Hemorrhage/mortality , Cerebral Hemorrhage/surgery , Cerebral Hemorrhage/therapy , Minimally Invasive Surgical Procedures/methods , Treatment Outcome , NeuroendoscopyABSTRACT
Recent clinical trials have highlighted the limited efficacy of T cell-based immunotherapy in patients with glioblastoma (GBM). To better understand the characteristics of tumor-infiltrating lymphocytes (TIL) in GBM, we performed cellular indexing of transcriptomes and epitopes by sequencing and single-cell RNA sequencing with paired V(D)J sequencing, respectively, on TILs from two cohorts of patients totaling 15 patients with high-grade glioma, including GBM or astrocytoma, IDH-mutant, grade 4 (G4A). Analysis of the CD8+ TIL landscape reveals an enrichment of clonally expanded GZMK+ effector T cells in the tumor compared with matched blood, which was validated at the protein level. Furthermore, integration with other cancer types highlights the lack of a canonically exhausted CD8+ T-cell population in GBM TIL. These data suggest that GZMK+ effector T cells represent an important T-cell subset within the GBM microenvironment and may harbor potential therapeutic implications. SIGNIFICANCE: To understand the limited efficacy of immune-checkpoint blockade in GBM, we applied a multiomics approach to understand the TIL landscape. By highlighting the enrichment of GZMK+ effector T cells and the lack of exhausted T cells, we provide a new potential mechanism of resistance to immunotherapy in GBM. This article is featured in Selected Articles from This Issue, p. 897.
Subject(s)
CD8-Positive T-Lymphocytes , Glioblastoma , Lymphocytes, Tumor-Infiltrating , Humans , Glioblastoma/immunology , Glioblastoma/therapy , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Brain Neoplasms/immunology , Tumor Microenvironment/immunologyABSTRACT
Vestibular schwannomas (VS) are benign tumors that lead to significant neurologic and otologic morbidity. How VS heterogeneity and the tumor microenvironment (TME) contribute to VS pathogenesis remains poorly understood. In this study, we perform scRNA-seq on 15 VS, with paired scATAC-seq (n = 6) and exome sequencing (n = 12). We identify diverse Schwann cell (SC), stromal, and immune populations in the VS TME and find that repair-like and MHC-II antigen-presenting SCs are associated with myeloid cell infiltrate, implicating a nerve injury-like process. Deconvolution analysis of RNA-expression data from 175 tumors reveals Injury-like tumors are associated with larger tumor size, and scATAC-seq identifies transcription factors associated with nerve repair SCs from Injury-like tumors. Ligand-receptor analysis and in vitro experiments suggest that Injury-like VS-SCs recruit myeloid cells via CSF1 signaling. Our study indicates that Injury-like SCs may cause tumor growth via myeloid cell recruitment and identifies molecular pathways that may be therapeutically targeted.
Subject(s)
Neuroma, Acoustic , Humans , Neuroma, Acoustic/genetics , Neuroma, Acoustic/metabolism , Neuroma, Acoustic/pathology , Ecosystem , Multiomics , Schwann Cells/metabolism , Signal Transduction/physiology , Single-Cell Analysis , Tumor MicroenvironmentABSTRACT
Introduction A low subfrontal dural opening technique that limits brain manipulation was assessed in patients who underwent frontotemporal approaches for anterior fossa lesions. Methods A retrospective review was performed for cases using a low subfrontal dural opening including characterization of demographics, lesion size and location, neurological and ophthalmological assessments, clinical course, and imaging findings. Results A low subfrontal dural opening was performed in 23 patients (17F, 6M), median age of 53 years (range 23-81) with a median follow-up duration of 21.9 months (range 6.2-67.1). Lesions included 22 meningiomas (nine anterior clinoid, 12 tuberculum sellae, and one sphenoid wing), one unruptured internal carotid artery aneurysm clipped during a meningioma resection, and one optic nerve cavernous malformation. Maximal possible resection was achieved in all cases including gross total resection in 16/22 (72.7%), near total in 1/22 (4.5%), and subtotal in 5/22 (22.7%) in which tumor involvement of critical structures limited complete resection. Eighteen patients presented with vision loss; 11 (61%) improved postoperatively, three (17%) were stable, and four (22%) worsened. The mean ICU stay and time to discharge were 1.3 days (range 0-3) and 3.8 days (range 2-8). Conclusion A low sub-frontal dural opening for approaches to the anterior fossa can be performed with minimal brain exposure, early visualization of the optico-carotid cistern for cerebrospinal fluid release, minimizing need for fixed brain retraction, and Sylvian fissure dissection. This technique can potentially reduce surgical risk and provide excellent exposure for anterior skull base lesions with favorable extent of resection, visual recovery, and complication rates.
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The central nervous system (CNS) antigen-presenting cell (APC) that primes antitumor CD8+ T-cell responses remains undefined. Elsewhere in the body, the conventional dendritic cell 1 (cDC1) performs this role. However, steady-state brain parenchyma cDC1 are extremely rare; cDCs localize to the choroid plexus and dura. Thus, whether the cDC1 play a function in presenting antigen derived from parenchymal sources in the tumor setting remains unknown. Using preclinical glioblastoma (GBM) models and cDC1-deficient mice, we explored the presently unknown role of cDC1 in CNS antitumor immunity. We determined that, in addition to infiltrating the brain tumor parenchyma itself, cDC1 prime neoantigen-specific CD8+ T cells against brain tumors and mediate checkpoint blockade-induced survival benefit. We observed that cDC, including cDC1, isolated from the tumor, the dura, and the CNS-draining cervical lymph nodes harbored a traceable fluorescent tumor antigen. In patient samples, we observed several APC subsets (including the CD141+ cDC1 equivalent) infiltrating glioblastomas, meningiomas, and dura. In these same APC subsets, we identified a tumor-specific fluorescent metabolite of 5-aminolevulinic acid, which fluorescently labeled tumor cells during fluorescence-guided GBM resection. Together, these data elucidate the specialized behavior of cDC1 and suggest that cDC1 play a significant role in CNS antitumor immunity.
Subject(s)
Dendritic Cells , Neoplasms , Animals , Mice , CD8-Positive T-Lymphocytes , Antigens, Neoplasm , BrainABSTRACT
OBJECTIVE: For patients with surgically accessible solitary metastases or oligometastatic disease, treatment often involves resection followed by postoperative stereotactic radiosurgery (SRS). This strategy has several potential drawbacks, including irregular target delineation for SRS and potential tumor "seeding" away from the resection cavity during surgery. A neoadjuvant (preoperative) approach to radiation therapy avoids these limitations and offers improved patient convenience. This study assessed the efficacy of neoadjuvant SRS as a new treatment paradigm for patients with brain metastases. METHODS: A retrospective review was performed at a single institution to identify patients who had undergone neoadjuvant SRS (specifically, Gamma Knife radiosurgery) followed by resection of a brain metastasis. Kaplan-Meier survival and log-rank analyses were used to evaluate risks of progression and death. Assessments were made of local recurrence and leptomeningeal spread. Additionally, an analysis of the contemporary literature of postoperative and neoadjuvant SRS for metastatic disease was performed. RESULTS: Twenty-four patients who had undergone neoadjuvant SRS followed by resection of a brain metastasis were identified in the single-institution cohort. The median age was 64 years (range 32-84 years), and the median follow-up time was 16.5 months (range 1 month to 5.7 years). The median radiation dose was 17 Gy prescribed to the 50% isodose. Rates of local disease control were 100% at 6 months, 87.6% at 12 months, and 73.5% at 24 months. In 4 patients who had local treatment failure, salvage therapy included repeat resection, laser interstitial thermal therapy, or repeat SRS. One hundred thirty patients (including the current cohort) were identified in the literature who had been treated with neoadjuvant SRS prior to resection. Overall rates of local control at 1 year after neoadjuvant SRS treatment ranged from 49% to 91%, and rates of leptomeningeal dissemination from 0% to 16%. In comparison, rates of local control 1 year after postoperative SRS ranged from 27% to 91%, with 7% to 28% developing leptomeningeal disease. CONCLUSIONS: Neoadjuvant SRS for the treatment of brain metastases is a novel approach that mitigates the shortcomings of postoperative SRS. While additional prospective studies are needed, the current study of 130 patients including the summary of 106 previously published cases supports the safety and potential efficacy of preoperative SRS with potential for improved outcomes compared with postoperative SRS.
Subject(s)
Brain Neoplasms , Meningeal Neoplasms , Radiosurgery , Humans , Adult , Middle Aged , Aged , Aged, 80 and over , Radiosurgery/adverse effects , Neoadjuvant Therapy/adverse effects , Brain Neoplasms/surgery , Meningeal Neoplasms/surgery , Salvage Therapy , Retrospective Studies , Treatment OutcomeABSTRACT
BACKGROUND: Choroid plexus papillomas are benign tumors of the choroid plexus. Although typically focal, they can metastasize. Rarely, patients may present with numerous cystic lesions throughout the craniospinal axis. OBSERVATIONS: The authors present three cases of pathologically confirmed fourth ventricular World Health Organization (WHO) grade 1 choroid plexus papillomas presenting with numerous cystic lesions throughout the craniospinal axis. Two cases were treated with only resection of the fourth ventricular mass; one was treated with a partial cyst fenestration. During follow-up, there was only mild interval growth of the cystic lesions over time, and all patients remained asymptomatic from their cystic lesions. The authors summarize five additional cases of cystic dissemination in the published literature and discuss hypotheses for the pathophysiology of this rare presentation. LESSONS: Choroid plexus papillomas may present with numerous, widely disseminated cystic lesions within the craniospinal axis. Thus, the authors recommend preoperative and routine imaging of the entire neuroaxis in patients with choroid plexus tumors, regardless of WHO grade. Although the role of adjuvant therapy and cyst fenestration in the treatment of these lesions remains unclear, watchful waiting may be indicated, especially in asymptomatic patients, because the lesions often demonstrate slow, if any, growth over time.
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OBJECTIVE: To identify factors, including the use of intraoperative magnetic resonance imaging (iMRI), impacting overall survival (OS) and progression-free survival (PFS) after resections of newly diagnosed intracranial grade II ependymomas performed across 4 different institutions. METHODS: Analyses of a multicenter mixed retrospective/prospective database assessed the impact of patient, treatment, and tumor characteristics on OS and PFS. iMRI workflow and logistics were also outlined. RESULTS: Forty-three patients were identified (mean age 25.4 years, mean follow-up 52.8 months). The mean OS was 52.8 ± 44.7 months. Univariate analyses failed to identify prognostic factors associated with OS, likely due to relatively shorter follow-up time for this less aggressive glioma subtype. The mean PFS was 43.7 ± 39.8 months. Multivariate analyses demonstrated that gross-total resection was associated with prolonged PFS compared to both subtotal resection (STR) (P = 0.005) and near-total resection (P = 0.01). Infratentorial location was associated with improved PFS compared to supratentorial location (P = 0.04). Log-rank analyses of Kaplan-Meier survival curves showed that increasing extent of resection (EOR) led to improved OS specifically for supratentorial tumors (P = 0.02) and improved PFS for all tumors (P < 0.001). Thirty cases (69.8%) utilized iMRI, of which 12 (27.9%) involved additional resection after iMRI. Of these, 8/12 (66.7%) resulted in gross-total resection, while 2/12 (16.7%) were near-total resection and 2/12 (16.7%) were subtotal resection. iMRI was not an independent prognosticator of PFS (P = 0.72). CONCLUSIONS: Greater EOR and infratentorial location were associated with increased PFS for grade II ependymomas. Greater EOR was associated with longer OS only for supratentorial tumors. A longer follow-up is needed to establish prognostic factors for this cohort, including use of iMRI.
Subject(s)
Brain Neoplasms , Ependymoma , Supratentorial Neoplasms , Humans , Adult , Retrospective Studies , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/surgery , Ependymoma/diagnostic imaging , Ependymoma/surgery , Supratentorial Neoplasms/diagnostic imaging , Supratentorial Neoplasms/surgery , Disease-Free Survival , Magnetic Resonance Imaging/methodsABSTRACT
BACKGROUND: Recent investigations of the meninges have highlighted the importance of the dura layer in central nervous system immune surveillance beyond a purely structural role. However, our understanding of the meninges largely stems from the use of pre-clinical models rather than human samples. METHODS: Single-cell RNA sequencing of seven non-tumor-associated human dura samples and six primary meningioma tumor samples (4 matched and 2 non-matched) was performed. Cell type identities, gene expression profiles, and T cell receptor expression were analyzed. Copy number variant (CNV) analysis was performed to identify putative tumor cells and analyze intratumoral CNV heterogeneity. Immunohistochemistry and imaging mass cytometry was performed on selected samples to validate protein expression and reveal spatial localization of select protein markers. RESULTS: In this study, we use single-cell RNA sequencing to perform the first characterization of both non-tumor-associated human dura and primary meningioma samples. First, we reveal a complex immune microenvironment in human dura that is transcriptionally distinct from that of meningioma. In addition, we characterize a functionally diverse and heterogenous landscape of non-immune cells including endothelial cells and fibroblasts. Through imaging mass cytometry, we highlight the spatial relationship among immune cell types and vasculature in non-tumor-associated dura. Utilizing T cell receptor sequencing, we show significant TCR overlap between matched dura and meningioma samples. Finally, we report copy number variant heterogeneity within our meningioma samples. CONCLUSIONS: Our comprehensive investigation of both the immune and non-immune cellular landscapes of human dura and meningioma at single-cell resolution builds upon previously published data in murine models and provides new insight into previously uncharacterized roles of human dura.
Subject(s)
Meningeal Neoplasms , Meningioma , Animals , Endothelial Cells/pathology , Humans , Immunity , Meningeal Neoplasms/genetics , Meningeal Neoplasms/pathology , Meninges/pathology , Meningioma/genetics , Meningioma/pathology , Mice , Tumor MicroenvironmentABSTRACT
BACKGROUND: Many factors impact survival in patients with glioblastoma, including age, Karnofsky Performance Status, postoperative chemoradiation, IDH1/2 mutation status, MGMT promoter methylation status, and extent of resection. High-throughput next-generation sequencing is a widely available diagnostic tool, but the independent impact of tumors harboring specific mutant genes on survival and the efficacy of extent of resection are not clear. METHODS: We utilized a widely available diagnostic platform (FoundationOne CDx) to perform high-throughput next-generation sequencing on 185 patients with newly diagnosed glioblastoma in our tertiary care center. We performed multivariate analysis to control for clinical parameters with known impact on survival to elucidate the independent prognostic value of prevalent mutant genes and the independent impact of gross total resection. RESULTS: When controlling for factors with known prognostic significance including IDH1/2 mutation and after multiple comparisons analysis, CDKN2B and EGFR mutations were associated with reduced overall survival while PTEN mutation was associated with improved overall survival. Gross total resection, compared to other extent of resection, was associated with improved overall survival in patients with tumors harboring mutations in CDKN2A, CDKN2B, EGFR, PTEN, TERT promoter, and TP53. All patients possessed at least one of these 6 mutant genes. CONCLUSIONS: This study verifies the independent prognostic value of several mutant genes in glioblastoma. Six commonly found mutant genes were associated with improved survival when gross total resection was achieved. Thus, even when accounting for known predictors of survival and multiple mutant gene comparisons, extent of resection continues to be strongly associated with survival.
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OBJECTIVE: Colloid cysts of the third ventricle are histologically benign lesions that can cause obstructive hydrocephalus and death. Historically, colloid cysts have been removed by open microsurgical approaches. More recently, minimally invasive endoscopic and port-based techniques have offered decreased complications and length of stay, with improved patient satisfaction. METHODS: A single-center retrospective analysis of patients with colloid cysts who underwent surgery at a large tertiary care hospital was performed. The cohort was assessed based on the surgical approach, comparing endoscopic resection to open microsurgical resection. The primary endpoint was rate of perioperative complications. Univariate analysis was used to assess several procedure-related variables and the cost of treatment. Multivariate analysis was used to assess predictors of perioperative complications. Total inpatient cost for each case was extracted from the health system financial database. RESULTS: The study included 78 patients with colloid cysts who underwent resection either via an endoscopic approach (n = 33) or through a craniotomy (n = 45) with an interhemispheric-transcallosal or transcortical-transventricular approach. Nearly all patients were symptomatic, and half had obstructive hydrocephalus. Endoscopic resection was associated with reduced operative time (3.2 vs 4.9 hours, p < 0.001); lower complication rate (6.1% vs 33.1%, p = 0.009); reduced length of stay (4.1 vs 8.9 days, p < 0.001); and improved discharge to home (100% vs 75.6%, p = 0.008) compared to microsurgical resection. Coagulated residual cyst wall remnants were more common after endoscopic resection (63.6% vs 19.0%, p < 0.001) although this was not associated with a significantly increased rate of reoperation for recurrence. The mean follow-up was longer in the microsurgical resection group (3.1 vs 4.9 years, p = 0.016). The total inpatient cost of endoscopic resection was, on average, one-half (47%) that of microsurgical resection. When complications were encountered, the total inpatient cost of microsurgical resection was 4 times greater than that of endoscopic resection where no major complications were observed. The increased cost-effectiveness of endoscopic resection remained during reoperation. CONCLUSIONS: Endoscopic resection of colloid cysts of the third ventricle offers a significant reduction in perioperative complications when compared to microsurgical resection. Endoscopic resection optimizes nearly all procedure-related variables compared to microsurgical resection, and reduces total inpatient cost by > 50%. However, endoscopic resection is associated with a significantly increased likelihood of residual coagulated cyst wall remnants that could increase the rate of reoperation for recurrence. Taken together, endoscopic resection represents a safe and effective minimally invasive approach for removal of colloid cysts.
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OBJECTIVE: Pilocytic astrocytomas (PAs) have a generally favorable prognosis; however, progression or recurrence after resection is possible. The prognostic value of histopathological qualifiers (defined below) or BRAF alterations is not well understood. The aim of this study was to identify the prognostic value of genetic and histopathological features of pediatric PAs. METHODS: Patients treated for a WHO grade I PA at a single institution were analyzed for histopathological and genetic features and outcomes. "Histopathological qualifier" refers to designations such as "WHO grade I PA with increased proliferative index." BRAF alterations include gene fusions and point mutations. Patients with neurofibromatosis type 1 were excluded. RESULTS: A total of 222 patients were analyzed (51% female, mean age 9.6 years). Tumors were located in the cerebellum/fourth ventricle (51%), optic pathway/hypothalamus (15%), brainstem (12%), and cerebral cortex (11%). BRAF alterations were screened for in 77 patients and identified in 56 (73%). Histopathological qualifiers were present in 27 patients (14%). Resection was performed in 197 patients (89%), 41 (21%) of whom displayed tumor progression or recurrence after resection. Tumor progression or recurrence was not associated with histopathologic qualifiers (p = 0.36) or BRAF alterations (p = 0.77). Ki-67 proliferative indices were not predictive of progression or recurrence (p = 0.94). BRAF alterations, specifically KIAA1549 fusions, were associated with cerebellar/fourth ventricular tumor location (p < 0.0001) and younger patient age (p = 0.03). Patients in whom gross-total resection was achieved had lower rates of progression and recurrence (p < 0.0001). CONCLUSIONS: Histopathological features/qualifiers and BRAF alterations were not associated with tumor recurrence/progression in pediatric PAs. The extent of resection was the only factor analyzed that predicted outcome.
Subject(s)
Astrocytoma , Brain Neoplasms , Cerebellar Neoplasms , Child , Humans , Female , Male , Brain Neoplasms/genetics , Brain Neoplasms/surgery , Brain Neoplasms/pathology , Proto-Oncogene Proteins B-raf/genetics , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/surgery , Astrocytoma/genetics , Astrocytoma/surgery , Astrocytoma/pathologyABSTRACT
Despite some success in secondary brain metastases, targeted or immune-based therapies have shown limited efficacy against primary brain malignancies such as glioblastoma (GBM). Although the intratumoral heterogeneity of GBM is implicated in treatment resistance, it remains unclear whether this diversity is observed within brain metastases and to what extent cancer cell-intrinsic heterogeneity sculpts the local immune microenvironment. Here, we profiled the immunogenomic state of 93 spatially distinct regions from 30 malignant brain tumors through whole-exome, RNA, and T-cell receptor sequencing. Our analyses identified differences between primary and secondary malignancies, with gliomas displaying more spatial heterogeneity at the genomic and neoantigen levels. In addition, this spatial diversity was recapitulated in the distribution of T-cell clones in which some gliomas harbored highly expanded but spatially restricted clonotypes. This study defines the immunogenomic landscape across a cohort of malignant brain tumors and contains implications for the design of targeted and immune-based therapies against intracranial malignancies. SIGNIFICANCE: This study describes the impact of spatial heterogeneity on genomic and immunologic characteristics of gliomas and brain metastases. The results suggest that gliomas harbor significantly greater intratumoral heterogeneity of genomic alterations, neoantigens, and T-cell clones than brain metastases, indicating the importance of multisector analysis for clinical or translational studies.This article is highlighted in the In This Issue feature, p. 1.
Subject(s)
Brain Neoplasms/pathology , Glioblastoma/secondary , Receptors, Antigen, T-Cell/genetics , Brain Neoplasms/genetics , Brain Neoplasms/immunology , Genomics , Glioblastoma/genetics , Glioblastoma/immunology , Humans , Immunotherapy , Neoplasm Metastasis , Tumor Microenvironment , Exome SequencingABSTRACT
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.