AZD8055 enhances in vivo efficacy of afatinib in chordomas.

Chordomas are primary bone tumors that arise in the cranial base, mobile spine, and sacrococcygeal region, affecting patients of all ages. Currently, there are no approved agents for chordoma patients. Here, we evaluated the anti-tumor efficacy of small molecule inhibitors that target oncogenic pathways in chordoma, as single agents and in combination, to identify novel therapeutic approaches with the greatest translational potential. A panel of small molecule compounds was screened in vivo against patient-derived xenograft (PDX) models of chordoma, and potentially synergistic combinations were further evaluated using chordoma cell lines and xenograft models. Among the tested agents, inhibitors of EGFR (BIBX 1382, erlotinib, and afatinib), c-MET (crizotinib), and mTOR (AZD8055) significantly inhibited tumor growth in vivo but did not induce tumor regression. Co-inhibition of EGFR and c-MET using erlotinib and crizotinib synergistically reduced cell viability in chordoma cell lines but did not result in enhanced in vivo activity. Co-inhibition of EGFR and mTOR pathways using afatinib and AZD8055 synergistically reduced cell viability in chordoma cell lines. Importantly, this dual inhibition completely suppressed tumor growth in vivo, showing improved tumor control. Together, these data demonstrate that individual inhibitors of EGFR, c-MET, and mTOR pathways suppress chordoma growth both in vitro and in vivo. mTOR inhibition increased the efficacy of EGFR inhibition on chordoma growth in several preclinical models. The insights gained from our study potentially provide a novel combination therapeutic strategy for patients with chordoma. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Growth hormone secreting pituitary adenomas show distinct extrasellar extension patterns compared to nonfunctional pituitary adenomas.

PURPOSE: Patterns of extension of pituitary adenomas (PA) may vary according to PA subtype. Understanding extrasellar extension patterns in growth hormone PAs (GHPA) vis-a-vis nonfunctional PAs (NFPAs) may provide insights into the biology of GHPA and future treatment avenues. METHODS: Preoperative MR imaging (MRI) in 179 consecutive patients treated surgically for NFPA (n = 139) and GHPA (n = 40) were analyzed to determine patterns of extrasellar growth. Extension was divided into two principal directions: cranio-caudal (measured by infrasellar/suprasellar extension), and lateral cavernous sinus invasion (CSI) determined by Knosp grading score of 3-4. Suprasellar extension was defined as tumor extension superior to the tuberculum sellae- dorsum sellae line, and inferior extension as invasion through the sellar floor into the sphenoid sinus or clivus. Categorical analysis was performed using Fisher's exact test. RESULTS: GHPAs were overall more likely to remain purely intrasellar compared to NFPA (50% vs 26%, p < 0.001). GHPAs, however, were 7 times more likely to exhibit isolated infrasellar extension compared to NFPA (20% vs 2.8%, p = 0.001). Conversely, NFPAs were twice as likely to exhibit isolated suprasellar extension compared to GHPA (60% vs 28%, p < 0.001), as well as combined suprasellar/infrasellar extension (25% vs 3%, p = 0.011). There were no overall differences in CSI between the two subgroups. DISCUSSION: GHPA and NFPA demonstrate distinct extrasellar extension patterns on MRI. GHPAs show proclivity for inferior extension with bony invasion, whereas NFPAs are more likely to exhibit suprasellar extension through the diaphragmatic aperture. These distinctions may have implications into the biology and future treatment of PAs.

The role of frailty in the clinical management of neurofibromatosis type 1: a mixed-effects modeling study using the Nationwide Readmissions Database.

OBJECTIVE: Frailty embodies a state of increased medical vulnerability that is most often secondary to age-associated decline. Recent literature has highlighted the role of frailty and its association with significantly higher rates of morbidity and mortality in patients with CNS neoplasms. There is a paucity of research regarding the effects of frailty as it relates to neurocutaneous disorders, namely, neurofibromatosis type 1 (NF1). In this study, the authors evaluated the role of frailty in patients with NF1 and compared its predictive usefulness against the Elixhauser Comorbidity Index (ECI). METHODS: Publicly available 2016-2017 data from the Nationwide Readmissions Database was used to identify patients with a diagnosis of NF1 who underwent neurosurgical resection of an intracranial tumor. Patient frailty was queried using the Johns Hopkins Adjusted Clinical Groups frailty-defining indicator. ECI scores were collected in patients for quantitative measurement of comorbidities. Propensity score matching was performed for age, sex, ECI, insurance type, and median income by zip code, which yielded 60 frail and 60 nonfrail patients. Receiver operating characteristic (ROC) curves were created for complications, including mortality, nonroutine discharge, financial costs, length of stay (LOS), and readmissions while using comorbidity indices as predictor values. The area under the curve (AUC) of each ROC served as a proxy for model performance. RESULTS: After propensity matching of the groups, frail patients had an increased mean ± SD hospital cost ($85,441.67 ± $59,201.09) compared with nonfrail patients ($49,321.77 ± $50,705.80) (p = 0.010). Similar trends were also found in LOS between frail (23.1 ± 14.2 days) and nonfrail (10.7 ± 10.5 days) patients (p = 0.0020). For each complication of interest, ROC curves revealed that frailty scores, ECI scores, and a combination of frailty+ECI were similarly accurate predictors of variables (p > 0.05). Frailty+ECI (AUC 0.929) outperformed using only ECI for the variable of increased LOS (AUC 0.833) (p = 0.013). When considering 1-year readmission, frailty (AUC 0.642) was outperformed by both models using ECI (AUC 0.725, p = 0.039) and frailty+ECI (AUC 0.734, p = 0.038). CONCLUSIONS: These findings suggest that frailty and ECI are useful in predicting key complications, including mortality, nonroutine discharge, readmission, LOS, and higher costs in NF1 patients undergoing intracranial tumor resection. Consideration of a patient's frailty status is pertinent to guide appropriate inpatient management as well as resource allocation and discharge planning.

Robotic and robot-assisted skull base neurosurgery: systematic review of current applications and future directions.

OBJECTIVE: The utility of robotic instrumentation is expanding in neurosurgery. Despite this, successful examples of robotic implementation for endoscopic endonasal or skull base neurosurgery remain limited. Therefore, the authors performed a systematic review of the literature to identify all articles that used robotic systems to access the sella or anterior, middle, or posterior cranial fossae. METHODS: A systematic review of MEDLINE and PubMed in accordance with PRISMA guidelines performed for articles published between January 1, 1990, and August 1, 2021, was conducted to identify all robotic systems (autonomous, semiautonomous, or surgeon-controlled) used for skull base neurosurgical procedures. Cadaveric and human clinical studies were included. Studies with exclusively otorhinolaryngological applications or using robotic microscopes were excluded. RESULTS: A total of 561 studies were identified from the initial search, of which 22 were included following full-text review. Transoral robotic surgery (TORS) using the da Vinci Surgical System was the most widely reported system (4 studies) utilized for skull base and pituitary fossa procedures; additionally, it has been reported for resection of sellar masses in 4 patients. Seven cadaveric studies used the da Vinci Surgical System to access the skull base using alternative, non-TORS approaches (e.g., transnasal, transmaxillary, and supraorbital). Five cadaveric studies investigated alternative systems to access the skull base. Six studies investigated the use of robotic endoscope holders. Advantages to robotic applications in skull base neurosurgery included improved lighting and 3D visualization, replication of more traditional gesture-based movements, and the ability for dexterous movements ordinarily constrained by small operative corridors. Limitations included the size and angulation capacity of the robot, lack of drilling components preventing fully robotic procedures, and cost. Robotic endoscope holders may have been particularly advantageous when the use of a surgical assistant or second surgeon was limited. CONCLUSIONS: Robotic skull base neurosurgery has been growing in popularity and feasibility, but significant limitations remain. While robotic systems seem to have allowed for greater maneuverability and 3D visualization, their size and lack of neurosurgery-specific tools have continued to prevent widespread adoption into current practice. The next generation of robotic technologies should prioritize overcoming these limitations.

Clival paragangliomas: a report of two cases involving the midline skull base and review of the literature.

Head and neck paragangliomas are rare neuroendocrine tumors that arise from paraganglion cells of the parasympathetic nervous system. Paragangliomas arising from the midline skull base have only rarely been reported. Surgery is the mainstay of treatment and adjuvant radiation is often recommended. These tumors can rarely secrete metanephrines and normetanephrines which can complicate operative management. Here we present two cases of clival paragangliomas with unique clinical presentations and review the previous literature on skull base paragangliomas.

Tumor Treating Fields in Neuro-Oncological Practice.

Electric fields are known to produce biological effects. Depending on specific frequency, they can stimulate healing, directly damage tissues, or produce anti-mitotic activity. Frequencies of 100-300 KHz have been shown to disrupt mitosis and lead to cellular death. Growth of cancer cell lines, both in vitro and in vivo, was shown to be inhibited by application of the electric fields. In the clinical setting, electric fields are available for treatment of brain tumors, specifically glioblastoma (GBM), through a portable device producing so-called tumor treating fields (TTF). Clinical trials conducted in patients with recurrent and newly diagnosed GBM indicated that this novel treatment modality is active and associated with minimal toxicity. This manuscript will review the available evidence supporting the use of TTF in neuro-oncologic practice.

PD-1, PD-L1, PD-L2 expression in the chordoma microenvironment.

Chordomas are rare malignant tumors that are postulated to arise from remnants of the notochord. Currently, the interaction between chordomas and the host immune system is poorly understood. The checkpoint protein, PD-1 is expressed by circulating lymphocytes and is a marker of activation and exhaustion. Its ligands, PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273), are expressed on a variety of human cancers; however this pathway has not been previously reported in chordomas. We used flow cytometric and RT-PCR analysis in three established primary and recurrent chordoma cell lines (U-CH1, U-CH2, and JHC7) as well as immunohistochemical analysis of chordoma tissues from 10 patients to identify and localize expression of PD-1 pathway proteins. PD-1 ligands are not constitutively expressed by chordoma cells, but their expression is induced in the setting of pro-inflammatory cytokines in all cell lines examined. In paraffin embedded tissues, we found that tumor infiltrating lymphocytes expressed PD-1 in 3/6 cases. We also found that, although chordoma cells did not express significant levels of PD-L1, PD-L1 expression was observed on tumor-infiltrating macrophages and tumor infiltrating lymphocytes. Our study suggests that PD-1, PD-L1, and PD-L2 are present in the microenvironment of a subset of chordomas analyzed. Future studies are needed to evaluate the contribution of the PD-1 pathway to the immunosuppressive microenvironment of chordomas.

Extravascular optical coherence tomography: evaluation of carotid atherosclerosis and pravastatin therapy.

BACKGROUND AND PURPOSE: Extravascular optical coherence tomography (OCT), as a noninvasive imaging methodology with micrometer resolution, was evaluated in a murine model of carotid atherosclerosis by way of assessing the efficacy of pravastatin therapy. METHODS: An OCT device was engineered for extravascular plaque imaging. Wild-type mice and apolipoprotein E-deficient (ApoE(-/-)) mice were randomized to 3 treatment groups: (1) wild-type on a diet of standard rodent chow (n=13); (2) ApoE(-/-) on a high-fat, atherosclerotic diet (HFD; n=13); and (3) ApoE(-/-) on a HFD given daily pravastatin (n=13). Mice were anesthetized and the left common carotid was surgically exposed. Three-dimensional (3D; 2 spatial dimensions+time) and 4D (3 spatial dimensions+time) OCT images of the vessel lumen patency were evaluated. After perfusion, in situ OCT imaging was performed for statistical comparison with the in vivo results and final histology. RESULTS: Intraoperative OCT imaging positively identified carotid plaque in 100% of ApoE(-/-) mice on HFD. ApoE(-/-) mice on HFD had a significantly decreased lumen patency when compared with that in wild-type mice (P<0.001). Pravastatin therapy was found to increase lumen patency significantly in ApoE(-/-) mice on HFD (P<0.01; compared with ApoE(-/-) on HFD). The findings were confirmed with OCT imaging after perfusion and histology. CONCLUSIONS: OCT imaging offers the potential for real-time, detailed vessel lumen evaluation, potentially improving surgical accuracy and outcomes during cerebrovascular neurosurgical procedures. Pravastatin significantly increases vessel lumen patency in the ApoE(-/-) mouse on HFD.

Imaging changes following stereotactic radiosurgery for metastatic intracranial tumors: differentiating pseudoprogression from tumor progression and its effect on clinical practice.

Stereotactic radiosurgery has become standard adjuvant treatment for patients with metastatic intracranial lesions. There has been a growing appreciation for benign imaging changes following radiation that are difficult to distinguish from true tumor progression. These imaging changes, termed pseudoprogression, carry significant implications for patient management. In this review, we discuss the current understanding of pseudoprogression in metastatic brain lesions, research to differentiate pseudoprogression from true progression, and clinical implications of pseudoprogression on treatment decisions.

Pediatric Orbital and Skull Base Pathology.

Pediatric orbital and skull base pathologies encompass a spectrum of inflammatory, sporadic, syndromic, and neoplastic processes that require a broad and complex clinical approach for both medical and surgical treatment. Given their complexity and often multicompartment involvement, a multidisciplinary approach for diagnosis, patient and family counseling, and ultimately treatment provides the best patient satisfaction and clinical outcomes. Advances in minimally invasive surgical approaches, including endoscopic endonasal and transorbital approaches allows for more targeted surgical approaches through smaller corridors beyond more classic transcranial or transracial approaches.

Clinical Implications of Pituitary Adenomas Exhibiting Dual Transcription Factor Staining: A Case Series of 27 Patients.

OBJECTIVE: According to the 2017 World Health Organization classification of neuro-endocrine tumors, pituitary adenomas (PAs) are classified according to immunoexpression of the pituitary-specific transcription factors (TFs). A small subset of PAs exhibit multiple TF staining on immunohistochemistry and we present a series of 27 pathologically-confirmed cases of dual TF staining PAs (dsTF-PAs), and report clinically relevant implications. METHODS: A retrospective chart review of a multi-institutional database of patients with PAs surgically resected between 2008-2021 was performed. PAs expressing immunopositivity 2+ TFs. Patient demographics, neuro-imaging characteristics, histopathologic findings, and clinical data were collected. RESULTS: Twenty-seven patients had pathologically verified dsTF-PAs, of whom 17 were female (63%), with ages ranging from 20-84 years. Twenty-three (85.2%) patients harbored functional PAs, with acromegaly being the most common functional subtype (86.4%). The most common combination of TFs within a single tumor was PIT-1/SF-1 (85.2%). Six PAs exhibited Knosp cavernous sinus invasion grades of 3 or 4 and the Ki-67 labeling index was ≥3% in 6 patients (24.0%) and all stained for PIT-1/SF-1. Hormonal remission was achieved in 78% of functional dsTF-PAs. No PAs showed evidence of recurrence or progression over the mean follow-up period of 28.5 months. CONCLUSIONS: PAs exhibiting dsTF-PAs represent a small but clinically relevant diagnostic subset of PAs according to the 2021 World Health Organization criteria, as a majority are GH-producing. Precise classification using TF staining plays a key role in understanding the biology of these tumors. Favorable outcomes can be achieved in this subset of PAs with evolving TF classification.

Endoscopic Endonasal Transsphenoidal Resection of Pituitary Adenomas in Patients Presenting With Monocular Blindness.

BACKGROUND AND OBJECTIVES: Suprasellar tumors, particularly pituitary adenomas (PAs), commonly present with visual decline, and the endoscopic endonasal transsphenoidal approach (EETA) is the primary management for optic apparatus decompression. Patients presenting with complete preoperative monocular blindness comprise a high-risk subgroup, given concern for complete blindness. This retrospective cohort study evaluates outcomes after EETA for patients with PA presenting with monocular blindness. METHODS: Retrospective analysis of all EETA cases at our institution from June 2012 to August 2023 was performed. Inclusion criteria included adults with confirmed PA and complete monocular blindness, defined as no light perception, and a relative afferent pupillary defect secondary to tumor mass effect. RESULTS: Our cohort includes 15 patients (9 males, 6 females), comprising 2.4% of the overall PA cohort screened. The mean tumor diameter was 3.8 cm, with 6 being giant PAs (>4 cm). The mean duration of preoperative monocular blindness was 568 days. Additional symptoms included contralateral visual field defects (n = 11) and headaches (n = 10). Two patients presented with subacute PA apoplexy. Gross total resection was achieved in 46% of patients, reflecting tumor size and invasiveness. Postoperatively, 2 patients experienced improvement in their effectively blind eye and 2 had improved visual fields of the contralateral eye. Those with improvements were operated within 10 days of presentation, and no patients experienced worsened vision. CONCLUSION: This is the first series of EETA outcomes in patients with higher-risk PA with monocular blindness on presentation. In these extensive lesions, vision remained stable for most without further decline and improvement from monocular blindness was observed in a small subset of patients with no light perception and relative afferent pupillary defect. Timing from vision loss to surgical intervention seemed to be associated with improvement. From a surgical perspective, caution is warranted to protect remaining vision and we conclude that EETA is safe in the management of these patients.

Endoscopic Endonasal and Keyhole Surgery for Skull Base Meningiomas.

Traditionally, resection of anterior skull base meningiomas has been achieved by transcranial approaches; however, morbidity related (ie, brain retraction, sagittal sinus damage, optic nerve manipulation, and cosmetic healing) represent a limit of the approach. Minimally invasive techniques including supraorbital and endonasal endoscopic approaches (EEA) have gained consensus as surgical corridors provide direct access to the tumor via a midline approach in carefully selected patients . The supraorbital approach requires some retraction of the rectus gyrus, but it offers minimal risk of postoperative CSF leak or sinonasal morbidity compared to EEA.

From white to blue light: evolution of endoscope-assisted intracranial tumor neurosurgery and expansion to intraaxial tumors.

OBJECTIVE: Intraoperative use of the endoscope to assist in visualization of intracranial tumor pathology has expanded with increasing surgeon experience and improved instrumentation. The authors aimed to study how advancements in endoscopic technology have affected the evolution of endoscope use, with particular focus on blue light-filter modification allowing for discrimination of fluorescent tumor tissue following 5-ALA administration. METHODS: A retrospective analysis of patients undergoing craniotomy for tumor resection at a single institution between February 2012 and July 2021 was performed. Patients were included if the endoscope was used for diagnostic tumor cavity inspection or therapeutic assistance with tumor resection following standard craniotomy and microsurgical tumor resection, with emphasis on those cases in which blue light endoscopy was used. Medical records were queried for patient demographics, operative reports describing the use of the endoscope and extent of resection, associations with tumor pathology, and postoperative outcomes. Preoperative and postoperative MR images were reviewed for radiographic extent of resection. RESULTS: A total of 52 patients who underwent endoscope-assisted craniotomy for tumor were included. Thirty patients (57.7%) were men and the average age was 52.6 ± 16.1 years. Standard white light endoscopes were used for assistance with tumor resection in 28 cases (53.8%) for tumors primarily located in the ventricular system, parasellar region, and cerebellopontine angle. A blue light endoscope for detection of 5-ALA fluorescence was introduced into our practice in 2014 and subsequently used for assistance with tumor resection in 24 cases (46.2%) (intraaxial: n = 22, extraaxial: n = 2). Beyond the use of the surgical microscope as the primary visualization source, the blue light endoscope was used to directly perform additional tumor resection in 19/21 cases as a result of improved fluorescence detection as compared to the surgical microscope. No complications were associated with the use of the endoscope or with additional resection performed under white or blue light visualization. CONCLUSIONS: Endoscopic assistance to visualize intracranial tumors had previously been limited to white light, assisting mostly in the visualization of extraaxial tumors confined to intraventricular and cisternal compartments. Blue light-equipped endoscopes provide improved versatility and visualization of 5-ALA fluorescing tissue beyond the capability of the surgical microscope, thereby expanding its use into the realm of intraaxial tumor resections.

Anatomic Considerations Guiding Single Versus Multiportal Endoscopic Approaches for Resection of Juvenile Nasopharyngeal Angiofibroma: Cases Series With Graded Multicorridor Resections.

BACKGROUND: Juvenile nasopharyngeal angiofibromas (JNAs) are characterized by expansive and destructive growth, often invading the midline/paranasal sinuses, pterygopalatine fossa, and infratemporal fossa and can extend into the orbit, cavernous sinus, or intracranially. OBJECTIVE: To evaluete the major benefits of the extended endoscopic endonasal approach (EEA) for JNA resection as compared with more traditional and invasive transpalatal and transfacial approaches. When JNAs extend into lateral anatomic compartments, the optimal operative trajectory often requires additional approach strategies or surgical staging. METHODS: We retrospectively reviewed 8 cases of large JNAs arising in symptomatic adolescent boys (University of Pittsburgh Medical Center Stages II, III, and V) and discuss anatomic and tumor considerations guiding the decision of a pure EEA vs combined EEA and sublabial transmaxillary approach (Caldwell-Luc). RESULTS: A pure extended EEA was used in 6 JNA cases (UPMC Stages II-III); a multiportal EEA + Caldwell-Luc maxillotomy was used in 2 cases. One of the 2 patients (UPMC Stage V) previously treated with multiportal EEA + Caldwell-Luc maxillotomy underwent staged left temporal/transzygomatic craniotomy, obtaining gross total resection. Seven patients ultimately underwent complete removal without recurrence. One patient with a small residual JNA (UPMC II) underwent stereotactic radiosurgery without progression to date. CONCLUSION: JNAs with lateral extension into the infratemporal fossa often benefited from additional lateral exposure using a Caldwell-Luc maxillotomy. Cases with significant skull base and/or dural involvement may undergo staged surgical treatment; temporalis + transzygomatic craniotomy is often useful for second-stage approaches for residual tumor in these lateral infratemporal or intracranial regions. SRS should be considered for residual tumor if additional surgery is not warranted.

Validation of Myc-Associated Protein X (MAX) regulation in growth hormone secreting and nonfunctional pituitary adenoma.

INTRODUCTION: Many patients with growth hormone-secreting pituitary adenoma (GHPA) fail to achieve biochemical remission, warranting investigation into epigenetic and molecular signatures associated with tumorigenesis and hormonal secretion. Prior work exploring the DNA methylome showed Myc-Associated Protein X (MAX), a transcription factor involved in cell cycle regulation, was differentially methylated between GHPA and nonfunctional pituitary adenoma (NFPA). We aimed to validate the differential DNA methylation and related MAX protein expression profiles between NFPA and GHPA. METHODS: DNA methylation levels were measured in 52 surgically resected tumors (37 NFPA, 15 GHPA) at ~100,000 known MAX binding sites derived using ChIP-seq analysis from ENCODE. Findings were correlated with MAX protein expression using a constructed tissue microarray (TMA). Gene ontology analysis was performed to explore downstream genetic and signaling pathways regulated by MAX. RESULTS: GHPA had more hypomethylation events across all known MAX binding sites. Of binding sites defined using ChIP-seq analysis, 1,551 sites had significantly different methylation patterns between the two cohorts; 432 occurred near promoter regions potentially regulated by MAX, including promoters of TNF and MMP9. Gene ontology analysis suggested enrichment in genes involved in oxygen response, immune system regulation, and cell proliferation. Thirteen MAX binding sites were within coding regions of genes. GHPA demonstrated significantly increased expression of MAX protein compared to NFPA. CONCLUSION: GHPA have significantly different DNA methylation and downstream protein expression levels of MAX compared to NFPA. These differences may influence mechanisms involved with cellular proliferation, tumor invasion and hormonal secretion.

The role of STAT3 activation in modulating the immune microenvironment of GBM.

Glioblastoma multiforme (GBM) modulates the immune system to engance its malignant potential. Signal transducer and activator of transcription 3 (STAT3) activation is a regulatory node in modulating the immune microenvironment in several human tumors, including GBM. To investigate whether STAT3 inhibition might enhance anti-tumor responses, we inhibited STAT3 signaling using small interfering RNA against STAT3. We tested the human GBM cell lines U87, U251, and HS683, which are known to constitutively express high levels of phospho-STAT3. STAT3 inhibition resulted in enhanced expression of several pro-inflammatory cytokines and chemokines and supernatants from STAT3-silenced human GBM cell lines increased lipopolysaccharide-induced dendritic cell activation in vitro. We obtained comparable results when STAT3 activity was suppressed with specific small molecule inhibitors. Our results support the hypothesis that activated STAT3 contributes to the immunosuppressive microenvironment in GBM and support previous studies implicating STAT3 as a potential target for immunotherapy.

Intracranial Solitary Fibrous Tumor/Hemangiopericytoma Treated with Microsurgical Resection: Retrospective Cohort Analysis of a Single-Center Experience.

Objective: To provide benchmarks for further studies of solitary fibrous tumor/hemangiopericytoma (SFT/HPC) of the central nervous system (CNS), we investigated the association of baseline demographic, clinico-pathologic, and treatment factors with outcomes in those treated at our center. Methods: We conducted a retrospective, cohort analysis of patients treated for SFT/HPC at the University of Washington 1990-2020. Kaplan-Meier and univariable Cox analyses assessed relationships between baseline variables and local or global CNS recurrence, extraneural recurrence, progression-free survival (PFS) and overall survival (OS). Results: Among 34 eligible patients, median duration of follow-up was 79 months (range 13-318 months). Local and global CNS recurrence occurred at a median of 81 m (95% CI 48-151) and 81 m (95% CI 47-112), respectively. Extraneural metastases occurred at a median 248 m (95% CI 180-Not Reached) and only in grade 3 tumors. Median PFS and OS were 76 months (95% CI: 47-109 months) and 210 months (95% CI 131-306 months), respectively. Univariable Cox analyses showed that age at diagnosis was associated with local (p = 0.01) and global CNS relapse (p = 0.01), and PFS (p = 0.03). Gross total resection was associated with decreased local or global CNS relapse (p = 0.02) and improved PFS (p = 0.03); peri-operative radiation was associated with decreased local CNS relapse (p = 0.02). Conclusion: Following microsurgical resection of SFT/HPC, CNS relapse is common and associated with age, extent of resection, and adjuvant radiation. Extraneural relapse occurs in some patients. Delayed time-to-initial relapse justifies prolonged surveillance, but optimal approaches have not been defined.

Evaluating the predictive value of comorbidity indices in pituitary surgery: a mixed-effects modeling study using the Nationwide Readmissions Database.

OBJECTIVE: Although pituitary adenomas (PAs) are common intracranial tumors, literature evaluating the utility of comorbidity indices for predicting postoperative complications in patients undergoing pituitary surgery remains limited, thereby hindering the development of complex models that aim to identify high-risk patient populations. We utilized comparative modeling strategies to evaluate the predictive validity of various comorbidity indices and combinations thereof in predicting key pituitary surgery outcomes. METHODS: The Nationwide Readmissions Database was used to identify patients who underwent pituitary tumor operations (n = 19,653) in 2016-2017. Patient frailty was assessed using the Johns Hopkins Adjusted Clinical Groups (ACG) System. The Charlson Comorbidity Index (CCI) and Elixhauser Comorbidity Index (ECI) were calculated for each patient. Five sets of generalized linear mixed-effects models were developed, using as the primary predictors 1) frailty, 2) CCI, 3) ECI, 4) frailty + CCI, or 5) frailty + ECI. Complications of interest investigated included inpatient mortality, nonroutine discharge (e.g., to locations other than home), length of stay (LOS) within the top quartile (Q1), cost within Q1, and 1-year readmission rates. RESULTS: Postoperative mortality occurred in 73 patients (0.4%), 1-year readmission was reported in 2994 patients (15.2%), and nonroutine discharge occurred in 2176 patients (11.1%). The mean adjusted all-payer cost for the procedure was USD $25,553.85 ± $26,518.91 (Q1 $28,261.20), and the mean LOS was 4.8 ± 7.4 days (Q1 5.0 days). The model using frailty + ECI as the primary predictor consistently outperformed other models, with statistically significant p values as determined by comparing areas under the curve (AUCs) for most complications. For prediction of mortality, however, the frailty + ECI model (AUC 0.831) was not better than the ECI model alone (AUC 0.831; p = 0.95). For prediction of readmission, the frailty + ECI model (AUC 0.617) was not better than the frailty model alone (AUC 0.606; p = 0.10) or the frailty + CCI model (AUC 0.610; p = 0.29). CONCLUSIONS: This investigation is to the authors' knowledge the first to implement mixed-effects modeling to study the utility of common comorbidity indices in a large, nationwide cohort of patients undergoing pituitary surgery. Knowledge gained from these models may help neurosurgeons identify high-risk patients who require additional clinical attention or resource utilization prior to surgical planning.

5-Aminolevulinic acid-enhanced fluorescence-guided treatment of high-grade glioma using angled endoscopic blue light visualization: technical case series with preliminary follow-up.

OBJECTIVE: 5-Aminolevulinic acid (5-ALA)-enhanced fluorescence-guided resection of high-grade glioma (HGG) using microscopic blue light visualization offers the ability to improve extent of resection (EOR); however, few descriptions of HGG resection performed using endoscopic blue light visualization are currently available. In this report, the authors sought to describe their surgical experience and patient outcomes of 5-ALA-enhanced fluorescence-guided resection of HGG using primary or adjunctive endoscopic blue light visualization. METHODS: The authors performed a retrospective review of prospectively collected data from 30 consecutive patients who underwent 5-ALA-enhanced fluorescence-guided biopsy or resection of newly diagnosed HGG was performed. Patient demographic data, tumor characteristics, surgical technique, EOR, tumor fluorescence patterns, and progression-free survival were recorded. RESULTS: In total, 30 newly diagnosed HGG patients were included for analysis. The endoscope was utilized for direct 5-ALA-guided port-based biopsy (n = 9), microscopic to endoscopic (M2E; n = 18) resection, or exoscopic to endoscopic (E2E; n = 3) resection. All endoscopic biopsies of fluorescent tissue were diagnostic. 5-ALA-enhanced tumor fluorescence was visible in all glioblastoma cases, but only in 50% of anaplastic astrocytoma cases and no anaplastic oligodendroglioma cases. Gross-total resection (GTR) was achieved in 10 patients in whom complete resection was considered safe, with 11 patients undergoing subtotal resection. In all cases, endoscopic fluorescence was more avid than microscopic fluorescence. The endoscope offered the ability to diagnose and resect additional tumor not visualized by the microscope in 83.3% (n = 10/12) of glioblastoma cases, driven by angled lenses and increased fluorescence facilitated by light source delivery within the cavity. Mean volumetric EOR was 90.7% in all resection patients and 98.8% in patients undergoing planned GTR. No complications were attributable to 5-ALA or blue light endoscopy. CONCLUSIONS: The blue light endoscope is a viable primary or adjunctive visualization platform for optimization of 5-ALA-enhanced HGG fluorescence. Implementation of the blue light endoscope to guide resection of HGG glioma is feasible and ergonomically favorable, with a potential advantage of enabling increased detection of tumor fluorescence in deep surgical cavities compared to the microscope.