Mechanism of neurodegeneration mediated by clonal inflammatory microglia.

Langerhans cell Histiocytosis (LCH) and Erdheim-Chester disease (ECD) are clonal myeloid disorders, associated with MAP-Kinase activating mutations and an increased risk of neurodegeneration. Surprisingly, we found pervasive PU.1 + microglia mutant clones across the brain of LCH and ECD patients with and without neurological symptoms, associated with microgliosis, reactive astrocytosis, and neuronal loss. The disease predominated in the grey nuclei of the rhombencephalon, a topography attributable to a local proliferative advantage of mutant microglia. Presence of clinical symptoms was associated with a longer evolution of the disease and a larger size of PU.1 + clones (p= 0.0003). Genetic lineage tracing of PU.1 + clones suggest a resident macrophage lineage or a bone marrow precursor origin depending on patients. Finally, a CSF1R-inhibitor depleted mutant microglia and limited neuronal loss in mice suggesting an alternative to MAPK inhibitors. These studies characterize a progressive neurodegenerative disease, caused by clonal proliferation of inflammatory microglia (CPIM), with a decade(s)-long preclinical stage of incipient disease that represent a therapeutic window for prevention of neuronal death.

Single-cell atlas of the human brain vasculature across development, adulthood and disease.

A broad range of brain pathologies critically relies on the vasculature, and cerebrovascular disease is a leading cause of death worldwide. However, the cellular and molecular architecture of the human brain vasculature remains incompletely understood1. Here we performed single-cell RNA sequencing analysis of 606,380 freshly isolated endothelial cells, perivascular cells and other tissue-derived cells from 117 samples, from 68 human fetuses and adult patients to construct a molecular atlas of the developing fetal, adult control and diseased human brain vasculature. We identify extensive molecular heterogeneity of the vasculature of healthy fetal and adult human brains and across five vascular-dependent central nervous system (CNS) pathologies, including brain tumours and brain vascular malformations. We identify alteration of arteriovenous differentiation and reactivated fetal as well as conserved dysregulated genes and pathways in the diseased vasculature. Pathological endothelial cells display a loss of CNS-specific properties and reveal an upregulation of MHC class II molecules, indicating atypical features of CNS endothelial cells. Cell-cell interaction analyses predict substantial endothelial-to-perivascular cell ligand-receptor cross-talk, including immune-related and angiogenic pathways, thereby revealing a central role for the endothelium within brain neurovascular unit signalling networks. Our single-cell brain atlas provides insights into the molecular architecture and heterogeneity of the developing, adult/control and diseased human brain vasculature and serves as a powerful reference for future studies.

Genome-wide loss of heterozygosity predicts aggressive, treatment-refractory behavior in pituitary neuroendocrine tumors.

Pituitary neuroendocrine tumors (PitNETs) exhibiting aggressive, treatment-refractory behavior are the rare subset that progress after surgery, conventional medical therapies, and an initial course of radiation and are characterized by unrelenting growth and/or metastatic dissemination. Two groups of patients with PitNETs were sequenced: a prospective group of patients (n = 66) who consented to sequencing prior to surgery and a retrospective group (n = 26) comprised of aggressive/higher risk PitNETs. A higher mutational burden and fraction of loss of heterozygosity (LOH) was found in the aggressive, treatment-refractory PitNETs compared to the benign tumors (p = 1.3 × 10-10 and p = 8.5 × 10-9, respectively). Within the corticotroph lineage, a characteristic pattern of recurrent chromosomal LOH in 12 specific chromosomes was associated with treatment-refractoriness (occurring in 11 of 14 treatment-refractory versus 1 of 14 benign corticotroph PitNETs, p = 1.7 × 10-4). Across the cohort, a higher fraction of LOH was identified in tumors with TP53 mutations (p = 3.3 × 10-8). A machine learning approach identified loss of heterozygosity as the most predictive variable for aggressive, treatment-refractory behavior, outperforming the most common gene-level alteration, TP53, with an accuracy of 0.88 (95% CI: 0.70-0.96). Aggressive, treatment-refractory PitNETs are characterized by significant aneuploidy due to widespread chromosomal LOH, most prominently in the corticotroph tumors. This LOH predicts treatment-refractoriness with high accuracy and represents a novel biomarker for this poorly defined PitNET category.

Transcript-specific enrichment enables profiling rare cell states via scRNA-seq.

Single-cell genomics technologies have accelerated our understanding of cell-state heterogeneity in diverse contexts. Although single-cell RNA sequencing (scRNA-seq) identifies many rare populations of interest that express specific marker transcript combinations, traditional flow sorting limits our ability to enrich these populations for further profiling, including requiring cell surface markers with high-fidelity antibodies. Additionally, many single-cell studies require the isolation of nuclei from tissue, eliminating the ability to enrich learned rare cell states based on extranuclear protein markers. To address these limitations, we describe Programmable Enrichment via RNA Flow-FISH by sequencing (PERFF-seq), a scalable assay that enables scRNA-seq profiling of subpopulations from complex cellular mixtures defined by the presence or absence of specific RNA transcripts. Across immune populations (n = 141,227 cells) and fresh-frozen and formalin-fixed paraffin-embedded brain tissue (n = 29,522 nuclei), we demonstrate the sorting logic that can be used to enrich for cell populations via RNA-based cytometry followed by high-throughput scRNA-seq. Our approach provides a rational, programmable method for studying rare populations identified by one or more marker transcripts.

Development and prospective validation of an artificial intelligence-based smartphone app for rapid intraoperative pituitary adenoma identification.

BACKGROUND: Intraoperative pathology consultation plays a crucial role in tumor surgery. The ability to accurately and rapidly distinguish tumor from normal tissue can greatly impact intraoperative surgical oncology management. However, this is dependent on the availability of a specialized pathologist for a reliable diagnosis. We developed and prospectively validated an artificial intelligence-based smartphone app capable of differentiating between pituitary adenoma and normal pituitary gland using stimulated Raman histology, almost instantly. METHODS: The study consisted of three parts. After data collection (part 1) and development of a deep learning-based smartphone app (part 2), we conducted a prospective study that included 40 consecutive patients with 194 samples to evaluate the app in real-time in a surgical setting (part 3). The smartphone app's sensitivity, specificity, positive predictive value, and negative predictive value were evaluated by comparing the diagnosis rendered by the app to the ground-truth diagnosis set by a neuropathologist. RESULTS: The app exhibits a sensitivity of 96.1% (95% CI: 89.9-99.0%), specificity of 92.7% (95% CI: 74-99.3%), positive predictive value of 98% (95% CI: 92.2-99.8%), and negative predictive value of 86.4% (95% CI: 66.2-96.8%). An external validation of the smartphone app on 40 different adenoma tumors and a total of 191 scanned SRH specimens from a public database shows a sensitivity of 93.7% (95% CI: 89.3-96.7%). CONCLUSIONS: The app can be readily expanded and repurposed to work on different types of tumors and optical images. Rapid recognition of normal versus tumor tissue during surgery may contribute to improved intraoperative surgical management and oncologic outcomes. In addition to the accelerated pathological assessments during surgery, this platform can be of great benefit in community hospitals and developing countries, where immediate access to a specialized pathologist during surgery is limited.

In tumor surgery, precise identification of abnormal tissue during surgical removal of the tumor is paramount. Traditional methods rely on the availability of specialized pathologists for a reliable diagnosis, which could be a limitation in many hospitals. Our study introduces a user-friendly smartphone app that quickly and precisely diagnoses pituitary tumors, powered by artificial intelligence (AI), which is the simulation of human intelligence in machines for tasks like learning, reasoning, problem-solving, and decision-making. Through data collection, app development, and validation, our findings demonstrate that the app can rapidly and accurately identify tumors in real-time. External validation further confirmed its effectiveness in detecting tumor tissue collected from a different source. This AI-driven app could contribute to elevating surgical precision, particularly in settings lacking immediate access to specialized pathologists.

Different patient versus provider perspectives on living with Cushing's disease.

CONTEXT: Patients with Cushing's disease (CD) face challenges living with and receiving appropriate care for this rare, chronic condition. Even with successful treatment, many patients experience ongoing symptoms and impaired quality of life (QoL). Different perspectives and expectations between patients and healthcare providers (HCPs) may also impair well-being. OBJECTIVE: To examine differences in perspectives on living with CD between patients and HCPs, and to compare care goals and unmet needs. DESIGN: Memorial Sloan Kettering Pituitary Center established an annual pituitary symposium for pituitary patients and HCPs. Through anonymous pre-program surveys distributed at the 2020 and 2022 symposia, patients and HCPs answered questions related to their own sense, or perception of their patients' sense, of hope, choice, and loneliness in the context of living with CD. PARTICIPANTS: From 655 participants over two educational events, 46 patients with CD and 116 HCPs were included. Median age of both groups was 51 years. 78.3% of the patients were female vs. 53.0% of the HCPs. RESULTS: More patients than HCPs reported they had no choices in their treatment (21.7% vs. 0.9%, P < 0.001). More patients reported feeling alone living with CD than HCPs' perception of such (60.9% vs. 45.5%, P = 0.08). The most common personal care goal concern for patients was 'QoL/mental health,' vs. 'medical therapies/tumor control' for HCPs. The most common CD unmet need reported by patients was 'education/awareness' vs. 'medical therapies/tumor control' for HCPs. CONCLUSIONS: CD patients experience long term symptoms and impaired QoL which may in part be due to a perception of lack of effective treatment options and little hope for improvement. Communicating experiences and care goals may improve long term outcomes for CD patients.

Sham surgery for the trialing of cell-based therapies to the CNS may not be necessary.

Sham surgery is often required for cell therapies adopting a randomized placebo-controlled double-blinded trial design. Using the case of dopamine neuron therapy for Parkinson's disease, we argue that alternative trial designs should be considered instead, for several reasons relating to ethics, patient burden, ease of unblinding, and cost.

NOVA1 acts as an oncogenic RNA-binding protein to regulate cholesterol homeostasis in human glioblastoma cells.

NOVA1 is a neuronal RNA-binding protein identified as the target antigen of a rare autoimmune disorder associated with cancer and neurological symptoms, termed paraneoplastic opsoclonus-myoclonus ataxia. Despite the strong association between NOVA1 and cancer, it has been unclear how NOVA1 function might contribute to cancer biology. In this study, we find that NOVA1 acts as an oncogenic factor in a GBM (glioblastoma multiforme) cell line established from a patient. Interestingly, NOVA1 and Argonaute (AGO) CLIP identified common 3' untranslated region (UTR) targets, which were down-regulated in NOVA1 knockdown GBM cells, indicating a transcriptome-wide intersection of NOVA1 and AGO-microRNA (miRNA) targets regulation. NOVA1 binding to 3'UTR targets stabilized transcripts including those encoding cholesterol homeostasis related proteins. Selective inhibition of NOVA1-RNA interactions with antisense oligonucleotides disrupted GBM cancer cell fitness. The precision of our GBM CLIP studies point to both mechanism and precise RNA sequence sites to selectively inhibit oncogenic NOVA1-RNA interactions. Taken together, we find that NOVA1 is commonly overexpressed in GBM, where it can antagonize AGO2-miRNA actions and consequently up-regulates cholesterol synthesis, promoting cell viability.

Treatment and outcomes of IDH1-mutant gliomas in elderly patients.

OBJECTIVE: Isocitrate dehydrogenase (IDH) mutations in both high- and low-grade gliomas are associated with an increase in survival compared with IDH-wild-type (IDHwt) tumors. A rare and understudied population is elderly individuals, ≥ 65 years of age, who have IDH1-R132H-mutant (IDHmt) gliomas. The objective of this paper was to characterize the institutions' experience with IDHmt gliomas in a patient population ≥ 65 years of age over the last 10 years. METHODS: A retrospective study of individuals ≥ 65 years of age with IDHmt gliomas treated between 2010 and 2020 at Memorial Sloan Kettering was performed. RESULTS: Twenty-five patients ≥ 65 years of age underwent resection or biopsy with a diagnosis of IDHmt glioma (52% WHO grade II, 32% WHO grade III, and 16% WHO grade IV). The most common presenting symptoms were seizure (28%) and motor or sensory deficits (24%). On preoperative MRI, 56% of tumors demonstrated contrast enhancement and 44% had no enhancement. Most patients underwent craniotomy for resection (n = 23, 92%), with subtotal resection achieved in the majority (16/23, 69.6%). Postoperative discharge location included home (64%), acute rehabilitation (16%), subacute rehabilitation (8%), and unknown (12%). Most patients received postoperative chemotherapy (72%) and radiation therapy (68%). The 2- and 5-year survival rates for the overall cohort were 83.1% (95% CI 69.3%-99.7%) and 69.7% (95% CI 53.2%-91.3%), respectively, with gross-total resection or near-total resection, contrast enhancement, and WHO grade significantly associated with survival. From the clinical sequencing data, no significant differences were identified between younger and older IDHmt cohorts. CONCLUSIONS: While IDH mutation in elderly patients may be rare, these patients have favorable survival relative to their IDHwt counterparts. Age at diagnosis should not be used in isolation to suggest a molecular IDHwt status or poor prognosis when guiding patient treatment decisions.

The medial transorbital approach in cranioendoscopic skull base tumor resections for locally advanced tumors.

BACKGROUND: Orbital structure preservation and avoidance of facial incisions without compromising oncological outcome are key to maintaining function and quality of life in locally advanced sinonasal tumor surgery. A transorbital approach at our institution has proven invaluable during cranioendoscopic skull base tumor resections and there are few descriptions of this in the literature. METHODS: An IRB-approved retrospective chart review was conducted at a tertiary cancer center for patients between 2020 and 2022 undergoing cranioendoscopic tumor resections utilizing a transorbital approach. Data collected included histopathology, sinus origin, disease extent, stage, operative details, length of stay, neo-adjuvant treatment and adjuvant treatment. Recurrence, survival, and complication rates were assessed. RESULTS: Four patients were identified for inclusion, including a SMARCB1-deficient carcinoma, esthesioneuroblastoma, squamous cell carcinoma and meningioma. All patients had resection of gross and microscopic disease with preservation of orbital contents. Post-operatively, one patient had mild diplopia on inferior gaze, all other patients had normal vision. Median follow-up was 9.5 months. One patient had recurrence of disease intracranially. CONCLUSIONS: The cranioendoscopic approach with a medial transorbital incision has multiple benefits. It avoids the need for a Weber-Ferguson incision with associated facial scar, allows for early intra-operative assessment for orbital invasion using tactile feedback and safe dissection of disease while protecting the globe and rectus muscles. This leads to preservation of eye function while ensuring an oncological resection. Other advantages include ligation of the anterior ethmoid artery and access for reconstruction of the medial orbital wall.

Virtual Surgical Planning and Three-Dimensional Models for Precision Sinonasal and Skull Base Surgery.

Sinonasal and skull base malignancies represent a rare, heterogenous group of pathologies with an incidence of 0.556 per 100,000 persons in the population. Given the numerous critical anatomic structures located adjacent to the sinonasal cavity and skull base, surgery for tumors in this region requires careful pre-operative planning with the assistance of radiological imaging and intraoperative image guidance technologies to reduce the risk of complications. Virtual surgical planning (VSP) and three-dimensional models (3DMs) are adjunctive technologies which assist clinicians to better visualize patient anatomy using enhanced digital radiological images and physical stereolithographic models based on patients' personal imaging. This review summarizes our institutional experience with VSP and 3DMs in sinonasal and skull base surgical oncology. A clinical case series is used to thematically illustrate the application of VSP and 3DMs in surgical ablation, reconstruction, patient communication, medical education, and interdisciplinary teamwork in sinonasal and skull base surgery.

Outcomes Following Early Postoperative Adjuvant Radiosurgery for Brain Metastases.

Importance: Adjuvant stereotactic radiosurgery (SRS) enhances the local control of resected brain metastases (BrM). However, the risks of local failure (LF) and potential for posttreatment adverse radiation effects (PTRE) after early postoperative adjuvant SRS have not yet been established. Objective: To evaluate whether adjuvant SRS delivered within a median of 14 days after surgery is associated with improved LF without a concomitant increase in PTRE. Design, Setting, and Participants: This prospective cohort study examines a clinical workflow (RapidRT) that was implemented from 2019 to 2022 to deliver SRS to surgical patients within a median of 14 days, ensuring all patients were treated within 30 days postoperatively. This prospective cohort was compared with a historical cohort (StanRT) of patients with BrM resected between 2013 and 2019 to assess the association of the RapidRT workflow with LF and PTRE. The 2 cohorts were combined to identify optimal SRS timing, with a median follow-up of 3.3 years for survivors. Exposure: Timing of adjuvant SRS (14, 21, and 30 days postoperatively). Main Outcomes and Measures: LF and PTRE, according to modified Response Assessment in Neuro-Oncology Brain Metastases criteria. Results: There were 438 patients (265 [60.5%] female patients; 23 [5.3%] Asian, 27 [6.2%] Black, and 364 [83.1%] White patients) with a mean (SD) age of 62 (13) years; 377 were in the StanRT cohort and 61 in the RapidRT cohort. LF and PTRE rates at 1 year were not significantly different between RapidRT and StanRT cohorts. Timing of SRS was associated with radiographic PTRE. Patients receiving radiation within 14 days had the highest 1-year PTRE rate (18.08%; 95% CI, 8.31%-30.86%), and patients receiving radiation between 22 and 30 days had the lowest 1-year PTRE rate (4.10%; 95% CI, 1.52%-8.73%; P = .03). LF rates were highest for patients receiving radiation more than 30 days from surgery (10.65%; 95% CI, 6.90%-15.32%) but comparable for patients receiving radiation within 14 days, between 15 and 21 days, and between 22 and 30 days (≤14 days: 5.12%; 95% CI, 0.86%-15.60%; 15 to ≤21 days: 3.21%; 95% CI, 0.59%-9.99%; 22 to ≤30 days: 6.58%; 95% CI, 3.06%-11.94%; P = .20). Conclusions and Relevance: In this cohort study of adjuvant SRS timing following surgical resection of BrM, the optimal timing for adjuvant SRS appears to be within 22 to 30 days following surgery. The findings of this study suggest that this timing allows for a balanced approach that minimizes the risks associated with LF and PTRE.

The treatment of aggressive prolactinomas with everolimus.

INTRODUCTION: Aggressive prolactinomas are life-limiting tumors without a standard of care treatment option after the oral alkylator, temozolomide, fails to provide tumor control. METHODS: We reviewed an institutional database of pituitary tumors for patients with aggressive prolactinomas who progressed following treatment with a dopamine receptor agonist, radiotherapy and temozolomide. Within this cohort, we identified four patients who were treated with everolimus and we report their response to this therapy. Treatment response was determined by a neuroradiologist, who manually performed volumetric assessment and determined treatment response by Response Assessments in Neuro-Oncology (RANO) criteria. RESULTS: Three of four patients who were treated with everolimus had a biochemical response to therapy and all patients derived a clinically meaningful benefit based upon suppression of tumor growth. While the best overall response as assessed by RANO criteria was stable disease for the four patients, a minor regression in tumor size was appreciated in two of the four patients. CONCLUSION: Everolimus is an active agent in the treatment of prolactinomas that warrants further investigation.

Dabrafenib as a diagnostic and therapeutic strategy for the non-surgical management of papillary craniopharyngioma.

PURPOSE: Papillary craniopharyngiomas can cause considerable morbidity due to mass effect and potential surgical complications. These tumors are known to harbor BRAF V600 mutations, which make them exquisitely sensitive to BRAF inhibitors. METHODS: The patient is a 59 year old man with a progressive suprasellar lesion that was radiographically consistent with a papillary craniopharyngioma. He was consented to an Institution Review Board-approved protocol, which permits sequencing of cell free DNA in plasma and the collection and reporting of clinical data. RESULTS: The patient declined surgical resection and was empirically treated with dabrafenib at 150 mg twice daily. Treatment response was demonstrated after 19 days, confirming the diagnosis. After achieving a near complete response after 6.5 months on drug, a decision was made to deescalate treatment to dabrafenib 75 mg twice daily with subsequent tumor stability for 2.5 months. CONCLUSION: Patients with a suspected papillary craniopharyngioma can be challenged with dabrafenib as a potentially effective diagnostic and therapeutic strategy, given that rapid regression with dabrafenib is only observed in tumors harboring a BRAF V600 mutation. Further work is needed to explore the optimal regimen and dose of the targeted therapy.

Advances in surgical approaches for refractory pituitary adenomas.

Refractory pituitary adenomas are difficult to control tumors that progress through optimal surgical, medical, and radiation management. Repeat surgery is a valuable tool to reduce tumor volume for more effective radiation and/or medical therapy, and to decompress critical neurovascular structures. Advances in surgical techniques and technologies, including minimally invasive cranial approaches, intraoperative MRI suites, and cranial nerve monitoring, have improved surgical outcomes and expanded indications. Today, repeat transsphenoidal surgery has similar complications rates to upfront surgery in historical cohorts. The decision to operate on refractory adenomas should be made with multidisciplinary teams, balancing the benefit of tumor reduction with the potential for complications, including cranial nerve injury, carotid injury, and cerebrospinal fluid leak.

Middle meningeal artery embolization using cone-beam computed tomography augmented guidance in patients with cancer.

PURPOSE: The purpose of this study was to evaluate the safety and efficacy of middle meningeal artery embolization (MMAE) performed under cone-beam computed tomography (CBCT) augmented guidance in patients with cancer. MATERIALS AND METHODS: Eleven patients with cancer (seven women, four men; median age, 75 years; age range: 42-87 years) who underwent 17 MMAEs under CBCT with a combination of particles and coils for chronic subdural hematoma (SDH) (n = 6), postoperative SDH (n = 3), or preoperative embolization of meningeal tumor (n = 2) from 2022 to 2023 were included. Technical success, fluoroscopy time (FT), reference dose (RD), kerma area product (KAP) were analyzed. Adverse events and outcomes were recorded. RESULTS: The technical success rate was 100% (17/17). Median MMAE procedure duration was 82 min (interquartile range [IQR]: 70, 95; range: 63-108 min). The median FT was 24 min (IQR: 15, 48; range: 21.5-37.5 min); the median RD was 364 mGy (IQR: 37, 684; range: 131.5-444.5 mGy); and the median KAP was 46.4 Gy.cm2 (9.6, 104.5; range: 30.2-56.6 Gy.cm2). No further interventions were needed. The adverse event rate was 9% (1/11), with one pseudoaneurysm at the puncture site in a patient with thrombocytopenia, which was treated by stenting. The median follow-up was 48 days (IQR; 14, 251; range: 18.5-91 days]. SDH reduced in 11 of 15 SDHs (73%) as evidenced by follow-up imaging, with a size reduction greater than 50% in 10/15 SDHs (67%) . CONCLUSION: MMAE under CBCT is a highly effective treatment option, but appropriate patient selection and careful consideration of potential risks and benefits is important for optimal patient outcomes.

Longitudinal Evaluation of Brain Plasticity in Low-Grade Gliomas: fMRI and Graph-Theory Provide Insights on Language Reorganization.

Language reorganization may represent an adaptive phenomenon to compensate tumor invasion of the dominant hemisphere. However, the functional changes over time underlying language plasticity remain unknown. We evaluated language function in patients with low-grade glioma (LGG), using task-based functional MRI (tb-fMRI), graph-theory and standardized language assessment. We hypothesized that functional networks obtained from tb-fMRI would show connectivity changes over time, with increased right-hemispheric participation. We recruited five right-handed patients (4M, mean age 47.6Y) with left-hemispheric LGG. Tb-fMRI and language assessment were conducted pre-operatively (pre-op), and post-operatively: post-op1 (4-8 months), post-op2 (10-14 months) and post-op3 (16-23 months). We computed the individual functional networks applying optimal percolation thresholding. Language dominance and hemispheric connectivity were quantified by laterality indices (LI) on fMRI maps and connectivity matrices. A fixed linear mixed model was used to assess the intra-patient correlation trend of LI values over time and their correlation with language performance. Individual networks showed increased inter-hemispheric and right-sided connectivity involving language areas homologues. Two patterns of language reorganization emerged: Three/five patients demonstrated a left-to-codominant shift from pre-op to post-op3 (type 1). Two/five patients started as atypical dominant at pre-op, and remained unchanged at post-op3 (type 2). LI obtained from tb-fMRI showed a significant left-to-right trend in all patients across timepoints. There were no significant changes in language performance over time. Type 1 language reorganization may be related to the treatment, while type 2 may be tumor-induced, since it was already present at pre-op. Increased inter-hemispheric and right-side connectivity may represent the initial step to develop functional plasticity.

Use of longitudinal functional MRI to demonstrate translocation of language function in patients with brain tumors.

OBJECTIVE: The ability of functional MRI (fMRI) to localize patient-specific eloquent areas has proved worthwhile in efforts to maximize resection while minimizing risk of iatrogenic damage in patients with brain tumors. Although cortical reorganization has been described, the frequency of its occurrence and the factors that influence incidence are not well understood. The authors investigated changes in language laterality between 2 fMRI studies in patients with brain tumors to elucidate factors contributing to cortical reorganization. METHODS: The authors analyzed 33 patients with brain tumors involving eloquent language areas who underwent 2 separate presurgical, language task-based fMRI examinations (fMRI1 and fMRI2). Pathology consisted of low-grade glioma (LGG) in 15, and high-grade glioma (HGG) in 18. The mean time interval between scans was 35 ± 38 months (mean ± SD). Regions of interest were drawn for Broca's area (BA) and the contralateral BA homolog. The laterality index (LI) was calculated and categorized as follows: > 0.2, left dominance; 0.2 to -0.2, codominance; and < -0.2, right dominance. Translocation of language function was defined as a shift across one of these thresholds between the 2 scans. Comparisons between the 2 groups, translocation of language function (reorganized group) versus no translocation (constant group), were performed using the Mann-Whitney U-test. RESULTS: Nine (27%) of 33 patients demonstrated translocation of language function. Eight of 9 patients with translocation had tumor involvement of BA, compared to 5/24 patients without translocation (p < 0.0001). There was no difference in LI between the 2 groups at fMRI1. However, the reorganized group showed a decreased LI at fMRI2 compared to the constant group (-0.1 vs 0.53, p < 0.01). The reorganized cohort showed a significant difference between LI1 and LI2 (0.50 vs -0.1, p < 0.0001) whereas the constant cohort did not. A longer time interval was found in the reorganized group between fMRI1 and fMRI2 for patients with LGG (34 vs 107 months, p < 0.002). Additionally, the reorganized cohort had a greater proportion of local tumor invasion into eloquent areas at fMRI2 than the constant group. Aphasia was present following fMRI2 in 13/24 (54%) patients who did not exhibit translocation, compared to 2/9 (22%) patients who showed translocation. CONCLUSIONS: Translocation of language function in patients with brain tumor is associated with tumor involvement of BA, longer time intervals between scans, and is seen in both LGG and HGG. The reduced incidence of aphasia in the reorganized group raises the possibility that reorganization supports the conservation of language function. Therefore, longitudinal fMRI is useful because it may point to reorganization and could affect therapeutic planning for patients.

Investigative needle core biopsies for multi-omics in Glioblastoma.

Glioblastoma (GBM) is a primary brain cancer with an abysmal prognosis and few effective therapies. The ability to investigate the tumor microenvironment before and during treatment would greatly enhance both understanding of disease response and progression, as well as the delivery and impact of therapeutics. Stereotactic biopsies are a routine surgical procedure performed primarily for diagnostic histopathologic purposes. The role of investigative biopsies - tissue sampling for the purpose of understanding tumor microenvironmental responses to treatment using integrated multi-modal molecular analyses ('Multi-omics") has yet to be defined. Secondly, it is unknown whether comparatively small tissue samples from brain biopsies can yield sufficient information with such methods. Here we adapt stereotactic needle core biopsy tissue in two separate patients. In the first patient with recurrent GBM we performed highly resolved multi-omics analysis methods including single cell RNA sequencing, spatial-transcriptomics, metabolomics, proteomics, phosphoproteomics, T-cell clonotype analysis, and MHC Class I immunopeptidomics from biopsy tissue that was obtained from a single procedure. In a second patient we analyzed multi-regional core biopsies to decipher spatial and genomic variance. We also investigated the utility of stereotactic biopsies as a method for generating patient derived xenograft models in a separate patient cohort. Dataset integration across modalities showed good correspondence between spatial modalities, highlighted immune cell associated metabolic pathways and revealed poor correlation between RNA expression and the tumor MHC Class I immunopeptidome. In conclusion, stereotactic needle biopsy cores are of sufficient quality to generate multi-omics data, provide data rich insight into a patient's disease process and tumor immune microenvironment and can be of value in evaluating treatment responses. One sentence summary: Integrative multi-omics analysis of stereotactic needle core biopsies in glioblastoma.

Integration of an enhanced recovery after surgery program for patients undergoing pituitary surgery.

Evidence-based enhanced recovery after surgery (ERAS) programs aim to improve patient outcomes and shorten hospital stays. The objective of this study is to describe the development, implementation, and evolution of an ERAS protocol to optimize the perioperative management for patients undergoing endoscopic skull base surgery for pituitary tumors. A systematic review of the literature was performed, best practices were discussed with stakeholders, and institutional guidelines were established and implemented. Key performance indicators (KPI) were measured and patient-reported outcome surveys were collected. The ERAS protocol was introduced successfully at our institution. We describe the process of initiation of the program and the perioperative management of our patients. We demonstrated the feasibility of integration of ERAS protocols for pituitary tumors with multidisciplinary engagement, with a particular emphasis on the use of data informatics and metrics to monitor outcomes. We expect that this approach will translate to improved quality of care for these often-complex patients.