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.

Unveiling the axonal connectivity between the precuneus and temporal pole: Structural evidence from the cingulum pathways.

Neuroimaging studies have consistently demonstrated concurrent activation of the human precuneus and temporal pole (TP), both during resting-state conditions and various higher-order cognitive functions. However, the precise underlying structural connectivity between these brain regions remains uncertain despite significant advancements in neuroscience research. In this study, we investigated the connectivity of the precuneus and TP by employing parcellation-based fiber micro-dissections in human brains and fiber tractography techniques in a sample of 1065 human subjects and a sample of 41 rhesus macaques. Our results demonstrate the connectivity between the posterior precuneus area POS2 and the areas 35, 36, and TG of the TP via the fifth subcomponent of the cingulum (CB-V) also known as parahippocampal cingulum. This finding contributes to our understanding of the connections within the posteromedial cortices, facilitating a more comprehensive integration of anatomy and function in both normal and pathological brain processes. PRACTITIONER POINTS: Our investigation delves into the intricate architecture and connectivity patterns of subregions within the precuneus and temporal pole, filling a crucial gap in our knowledge. We revealed a direct axonal connection between the posterior precuneus (POS2) and specific areas (35, 35, and TG) of the temporal pole. The direct connections are part of the CB-V pathway and exhibit a significant association with the cingulum, SRF, forceps major, and ILF. Population-based human tractography and rhesus macaque fiber tractography showed consistent results that support micro-dissection outcomes.

Glial fibrillary acidic protein, neurofilament light, matrix metalloprotease 3 and fatty acid binding protein 4 as non-invasive brain tumor biomarkers.

BACKGROUND: Gliomas are aggressive malignant tumors, with poor prognosis. There is an unmet need for the discovery of new, non-invasive biomarkers for differential diagnosis, prognosis, and management of brain tumors. Our objective is to validate four plasma biomarkers - glial fibrillary acidic protein (GFAP), neurofilament light (NEFL), matrix metalloprotease 3 (MMP3) and fatty acid binding protein 4 (FABP4) - and compare them with established brain tumor molecular markers and survival. METHODS: Our cohort consisted of patients with benign and malignant brain tumors (GBM = 77, Astrocytomas = 26, Oligodendrogliomas = 23, Secondary tumors = 35, Meningiomas = 70, Schwannomas = 15, Pituitary adenomas = 15, Normal individuals = 30). For measurements, we used ultrasensitive electrochemiluminescence multiplexed immunoassays. RESULTS: High plasma GFAP concentration was associated with GBM, low GFAP and high FABP4 were associated with meningiomas, and low GFAP and low FABP4 were associated with astrocytomas and oligodendrogliomas. NEFL was associated with progression of disease. Several prognostic genetic alterations were significantly associated with all plasma biomarker levels. We found no independent associations between plasma GFAP, NEFL, FABP4 and MMP3, and overall survival. The candidate biomarkers could not reliably discriminate GBM from primary or secondary CNS lymphomas. CONCLUSIONS: GFAP, NEFL, FABP4 and MMP3 are useful for differential diagnosis and prognosis, and are associated with molecular changes in gliomas.

Oral pimonidazole unveils clinicopathologic and epigenetic features of hypoxic tumour aggressiveness in localized prostate cancer.

BACKGROUND: Tumor hypoxia is associated with prostate cancer (PCa) treatment resistance and poor prognosis. Pimonidazole (PIMO) is an investigational hypoxia probe used in clinical trials. A better understanding of the clinical significance and molecular alterations underpinning PIMO-labeled tumor hypoxia is needed for future clinical application. Here, we investigated the clinical significance and molecular alterations underpinning PIMO-labeled tumor hypoxia in patients with localized PCa, in order to apply PIMO as a prognostic tool and to identify potential biomarkers for future clinical translation. METHODS: A total of 39 patients with localized PCa were recruited and administered oral PIMO before undergoing radical prostatectomy (RadP). Immunohistochemical staining for PIMO was performed on 37 prostatectomy specimens with staining patterns evaluated and clinical association analyzed. Whole genome bisulfite sequencing was performed using laser-capture of microdissected specimen sections comparing PIMO positive and negative tumor areas. A hypoxia related methylation molecular signature was generated by integrating the differentially methylated regions with previously established RNA-seq datasets. RESULTS: Three PIMO staining patterns were distinguished: diffuse, focal, and comedo-like. The comedo-like staining pattern was more commonly associated with adverse pathology. PIMO-defined hypoxia intensity was positively correlated with advanced pathologic stage, tumor invasion, and cribriform and intraductal carcinoma morphology. The generated DNA methylation signature was found to be a robust hypoxia biomarker, which could risk-stratify PCa patients across multiple clinical datasets, as well as be applicable in other cancer types. CONCLUSIONS: Oral PIMO unveiled clinicopathologic features of disease aggressiveness in localized PCa. The generated DNA methylation signature is a novel and robust hypoxia biomarker that has the potential for future clinical translation.

Meningioma transcriptomic landscape demonstrates novel subtypes with regional associated biology and patient outcome.

Meningiomas, although mostly benign, can be recurrent and fatal. World Health Organization (WHO) grading of the tumor does not always identify high-risk meningioma, and better characterizations of their aggressive biology are needed. To approach this problem, we combined 13 bulk RNA sequencing (RNA-seq) datasets to create a dimension-reduced reference landscape of 1,298 meningiomas. The clinical and genomic metadata effectively correlated with landscape regions, which led to the identification of meningioma subtypes with specific biological signatures. The time to recurrence also correlated with the map location. Further, we developed an algorithm that maps new patients onto this landscape, where the nearest neighbors predict outcome. This study highlights the utility of combining bulk transcriptomic datasets to visualize the complexity of tumor populations. Further, we provide an interactive tool for understanding the disease and predicting patient outcomes. This resource is accessible via the online tool Oncoscape, where the scientific community can explore the meningioma landscape.

Meningioma: International Consortium on Meningiomas (ICOM) consensus review on scientific advances & treatment paradigms for clinicians, researchers, and patients.

Meningiomas are the most common primary intracranial tumors in adults and are increasing in incidence due to the aging population and the rising availability of neuroimaging. While most exhibit non-malignant behaviour, a subset of meningiomas are biologically aggressive and lead to significant neurological morbidity and mortality. In recent years, meaningful advances in our understanding of the biology of these tumors have led to the incorporation of molecular biomarkers into their grading and prognostication. However, unlike other central nervous system tumors, a unified molecular taxonomy for meningiomas has not yet been established and remains an overarching goal of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy-Not Official WHO (cIMPACT-NOW) working group. There also remains clinical equipoise on how specific meningioma cases and patient populations should be optimally managed. To address these existing gaps, members of the International Consortium on Meningiomas (ICOM) including field-leading experts, have prepared a comprehensive consensus narrative review directed towards clinicians, researchers, and patients. Included in this manuscript are detailed overviews of proposed molecular classifications, novel biomarkers, contemporary treatment strategies, trials on systemic therapies, health-related quality of life studies, and management strategies for unique meningioma patient populations. In each section we discuss the current state of knowledge as well as ongoing clinical and research challenges to road map future directions for further investigation.

Metabologenomic characterization uncovers a clinically aggressive IDH mutant glioma subtype.

Mutations in the pivotal metabolic isocitrate dehydrogenase (IDH) enzymes are recognized to drive the molecular footprint of diffuse gliomas, and patients with IDH mutant gliomas have overall favorable outcomes compared to patients with IDH wild-type tumors. However, survival still varies widely among patients with IDH mutated tumors. Here, we aimed to characterize molecular signatures that explain the range of IDH mutant gliomas. By integrating matched epigenome-wide methylome, transcriptome, and global metabolome data in 154 patients with gliomas, we identified a group of IDH mutant gliomas with globally altered metabolism that resembled IDH wild-type tumors. IDH-mutant gliomas with altered metabolism have significantly shorter overall survival from their IDH mutant counterparts that is not fully accounted for by recognized molecular prognostic markers of CDKN2A/B loss and glioma CpG Island Methylator Phenotype (GCIMP) status. IDH-mutant tumors with dysregulated metabolism harbored distinct epigenetic alterations that converged to drive proliferative and stem-like transcriptional profiles, providing a window to target novel dependencies in gliomas.

The outcomes measured and reported in observational studies of incidental and untreated intracranial meningioma: A systematic review.

Background: The clinical management of patients with incidental intracranial meningioma varies markedly and is often based on clinician choice and observational data. Heterogeneous outcome measurement has likely hampered knowledge progress by preventing comparative analysis of similar cohorts of patients. This systematic review aimed to summarize the outcomes measured and reported in observational studies. Methods: A systematic literature search was performed to identify published full texts describing active monitoring of adult cohorts with incidental and untreated intracranial meningioma (PubMed, EMBASE, MEDLINE, and CINAHL via EBSCO, completed January 24, 2022). Reported outcomes were extracted verbatim, along with an associated definition and method of measurement if provided. Verbatim outcomes were de-duplicated and the resulting unique outcomes were grouped under standardized outcome terms. These were classified using the taxonomy proposed by the "Core Outcome Measures in Effectiveness Trials" (COMET) initiative. Results: Thirty-three published articles and 1 ongoing study were included describing 32 unique studies: study designs were retrospective n = 27 and prospective n = 5. In total, 268 verbatim outcomes were reported, of which 77 were defined. Following de-duplication, 178 unique verbatim outcomes remained and were grouped into 53 standardized outcome terms. These were classified using the COMET taxonomy into 9 outcome domains and 3 core areas. Conclusions: Outcome measurement across observational studies of incidental and untreated intracranial meningioma is heterogeneous. The standardized outcome terms identified will be prioritized through an eDelphi survey and consensus meeting of key stakeholders (including patients), in order to develop a Core Outcome Set for use in future observational studies.

The outcomes measured and reported in intracranial meningioma clinical trials: A systematic review.

Background: Meningioma clinical trials have assessed interventions including surgery, radiotherapy, and pharmacotherapy. However, agreement does not exist on what, how, and when outcomes of interest should be measured. To do so would allow comparative analysis of similar trials. This systematic review aimed to summarize the outcomes measured and reported in meningioma clinical trials. Methods: Systematic literature and trial registry searches were performed to identify published and ongoing intracranial meningioma clinical trials (PubMed, Embase, Medline, CINAHL via EBSCO, and Web of Science, completed January 22, 2022). Reported outcomes were extracted verbatim, along with an associated definition and method of measurement if provided. Verbatim outcomes were deduplicated and the resulting unique outcomes were grouped under standardized outcome terms. These were classified using the taxonomy proposed by the "Core Outcome Measures in Effectiveness Trials" (COMET) initiative. Results: Thirty published articles and 18 ongoing studies were included, describing 47 unique clinical trials: Phase 2 n = 33, phase 3 n = 14. Common interventions included: Surgery n = 13, radiotherapy n = 8, and pharmacotherapy n = 20. In total, 659 verbatim outcomes were reported, of which 84 were defined. Following de-duplication, 415 unique verbatim outcomes remained and were grouped into 115 standardized outcome terms. These were classified using the COMET taxonomy into 29 outcome domains and 5 core areas. Conclusions: Outcome measurement across meningioma clinical trials is heterogeneous. The standardized outcome terms identified will be prioritized through an eDelphi survey and consensus meeting of key stakeholders (including patients), in order to develop a core outcome set for use in future meningioma clinical trials.

Long-term neurocognitive and psychological outcomes in meningioma survivors: Individual changes over time and radiation dosimetry.

Background: This study investigates long-term changes in neurocognitive performance and psychological symptoms in meningioma survivors and associations with radiation dose to circumscribed brain regions. Methods: We undertook a retrospective study of meningioma survivors who underwent longitudinal clinical neurocognitive assessments. Change in neurocognitive performance or psychological symptoms was assessed using reliable change indices. Radiation dosimetry, if prescribed, was evaluated based on treatment-planning computerized tomography co-registered with contrast-enhanced 3D T1-weighted magnetic resonance imaging. Mixed effects analyses were used to explore whether incidental radiation to brain regions outside the tumor influences neurocognitive and psychological outcomes. Results: Most (range = 41%-93%) survivors demonstrated stable-albeit often below average-neurocognitive and psychological trajectories, although some also exhibited improvements (range = 0%-31%) or declines (range = 0%-36%) over time. Higher radiation dose to the parietal-occipital region (partial R2 = 0.462) and cerebellum (partial R2 = 0.276) was independently associated with slower visuomotor processing speed. Higher dose to the hippocampi was associated with increases in depression (partial R2 = 0.367) and trait anxiety (partial R2 = 0.236). Conclusions: Meningioma survivors experience neurocognitive deficits and psychological symptoms many years after diagnosis, and a proportion of them decline over time. This study offers proof of concept that incidental radiation to brain regions beyond the tumor site may contribute to these sequelae. Future investigations should include radiation dosimetry when examining risk factors that contribute to the quality of survivorship in this growing population.

Organelle resolved proteomics uncovers PLA2R1 as a novel cell surface marker required for chordoma growth.

Chordomas are clinically aggressive tumors with a high rate of disease progression despite maximal therapy. Given the limited therapeutic options available, there remains an urgent need for the development of novel therapies to improve clinical outcomes. Cell surface proteins are attractive therapeutic targets yet are challenging to profile with common methods. Four chordoma cell lines were analyzed by quantitative proteomics using a differential ultracentrifugation organellar fractionation approach. A subtractive proteomics strategy was applied to select proteins that are plasma membrane enriched. Systematic data integration prioritized PLA2R1 (secretory phospholipase A2 receptor-PLA2R1) as a chordoma-enriched surface protein. The expression profile of PLA2R1 was validated across chordoma cell lines, patient surgical tissue samples, and normal tissue lysates via immunoblotting. PLA2R1 expression was further validated by immunohistochemical analysis in a richly annotated cohort of 25-patient tissues. Immunohistochemistry analysis revealed that elevated expression of PLA2R1 is correlated with poor prognosis. Using siRNA- and CRISPR/Cas9-mediated knockdown of PLA2R1, we demonstrated significant inhibition of 2D, 3D and in vivo chordoma growth. PLA2R1 depletion resulted in cell cycle defects and metabolic rewiring via the MAPK signaling pathway, suggesting that PLA2R1 plays an essential role in chordoma biology. We have characterized the proteome of four chordoma cell lines and uncovered PLA2R1 as a novel cell-surface protein required for chordoma cell survival and association with patient outcome.

Corrigendum: Grade 3 Meningioma Survival and Recurrence Outcomes in an International Multicenter Cohort.

[This corrects the article DOI: 10.1055/s-0044-1779888.].

Differences in methylation profiles between long-term survivors and short-term survivors of IDH-wild-type glioblastoma.

Background: Patients with glioblastoma (GBM) have a median overall survival (OS) of approximately 16 months. However, approximately 5% of patients survive >5 years. This study examines the differences in methylation profiles between long-term survivors (>5 years, LTS) and short-term survivors (<1 year, STS) with isocitrate dehydrogenase (IDH)-wild-type GBMs. Methods: In a multicenter retrospective analysis, we identified 25 LTS with a histologically confirmed GBM. They were age- and sex-matched to an STS. The methylation profiles of all 50 samples were analyzed with EPIC 850k, classified according to the DKFZ methylation classifier, and the methylation profiles of LTS versus STS were compared. Results: After methylation profiling, 16/25 LTS and 23/25 STS were confirmed to be IDH-wild-type GBMs, all with +7/-10 signature. LTS had significantly increased O6-methylguanine methyltransferase (MGMT) promoter methylation and higher prevalence of FGFR3-TACC3 fusion (P = .03). STS were more likely to exhibit CDKN2A/B loss (P = .01) and higher frequency of NF1 (P = .02) mutation. There were no significant CpGs identified between LTS versus STS at an adjusted P-value of .05. Unadjusted analyses identified key pathways involved in both LTS and STS. The most common pathways were the Hippo signaling pathway and the Wnt pathway in LTS, and GPCR ligand binding and cell-cell signaling in STS. Conclusions: A small group of patients with IDH-wild-type GBM survive more than 5 years. While there are few differences in the global methylation profiles of LTS compared to STS, our study highlights potential pathways involved in GBMs with a good or poor prognosis.

Rate of pachymeningeal failure following adjuvant WBRT vs SRS in patients with brain metastases.

Background: Stereotactic radiosurgery (SRS) has supplanted whole brain radiotherapy (WBRT) as standard-of-care adjuvant treatment following surgery for brain metastasis (BrM). Concomitant with the adoption of adjuvant SRS, a new pattern of failure termed "Pachymeningeal failure" (PMF) has emerged. Methods: We reviewed a prospective registry of 264 BrM patients; 145 and 119 were treated adjuvantly with WBRT and SRS, respectively. The Cox proportional hazards model was used to identify variables correlating to outcomes. Outcomes were calculated using the cumulative incidence (CI) method. Univariate (UVA) and multivariate analyses (MVA) were done to identify factors associated with PMF. Results: CI of PMF was 2 % and 18 % at 12 months, and 2 % and 23 % at 24 months for WRBT and SRS, respectively (p < 0.001). The CI of classic leptomeningeal disease (LMD) was 3 % and 4 % at 12 months, and 6 % and 6 % at 24 months for WBRT and SRS, respectively (P = 0.67). On UVA, adjuvant SRS [HR 9.75 (3.43-27.68) (P < 0.001)]; preoperative dural contact (PDC) [HR 6.78 (1.64-28.10) (P = 0.008)]; GPA score [HR 1.64 (1.11-2.42) (P = 0.012)]; and lung EGFR/ALK status [HR 3.11 (1.02-9.45) (P = 0.045)]; were associated with PMF risk. On MVA, adjuvant SRS [HR 8.15 (2.69-24.7) (P < 0.001)]; and PDC [HR 6.28 (1.51-26.1) (P = 0.012)] remained associated with PMF. Conclusions: Preoperative dural contact and adjuvant SRS instead of adjuvant WBRT were associated with an increased risk of PMF. Strategies to improve pachymeningeal radiation coverage to sterilize at risk pachymeninges should be investigated.

Molecular prognostication in grade 3 meningiomas and p16/MTAP immunohistochemistry for predicting CDKN2A/B status.

Background: The World Health Organization 2021 classification introduces molecular grading criteria for anaplastic meningiomas, including TERT promoter (TERTp) mutations and CDKN2A/B homozygous deletion. Additional adverse prognostic factors include H3K27me3 and BAP1 loss. The aim of this study was to explore whether these molecular alterations stratified clinical outcomes in a single-center cohort of grade 3 meningiomas. Additionally, we examined whether p16 and MTAP immunohistochemistry can predict CDKN2A/B status. Methods: Clinical and histopathological information was obtained from the electronic medical records of grade 3 meningiomas resected at a tertiary center between 2007 and 2020. Molecular testing for TERTp mutations and CDKN2A/B copy-number status, methylation profiling, and immunohistochemistry for H3K27me3, BAP1, p16, and methylthioadenosine phosphorylase (MTAP) were performed. Predictors of survival were identified by Cox regression. Results: Eight of 15 cases demonstrated elevated mitotic index (≥20 mitoses per 10 consecutive high-power fields), 1 tumor exhibited BAP1 loss, 4 harbored TERTp mutations, and 3 demonstrated CDKN2A/B homozygous deletion. Meningiomas with TERTp mutations and/or CDKN2A/B homozygous deletion showed significantly reduced survival compared to anaplastic meningiomas with elevated mitotic index alone. Immunohistochemical loss of p16 and MTAP demonstrated high sensitivity (67% and 100%, respectively) and specificity (100% and 100%, respectively) for predicting CDKN2A/B status. Conclusions: Molecular alterations of grade 3 meningiomas stratify clinical outcomes more so than histologic features alone. Immunohistochemical loss of p16 and MTAP show promise in predicting CDKN2A/B status.

Grade 3 meningioma survival and recurrence outcomes in an international multicenter cohort.

OBJECTIVE: Grade 3 meningioma represents a rare meningioma subtype, for which limited natural history data are available. The objective of this study was to identify demographics and pathologic characteristics, clinical and functional status outcomes, and prognostic factors in an international cohort of grade 3 meningioma patients. METHODS: Clinical and histopathological data were collected for patients treated at 7 sites across North America and Europe between 1991 and 2022. RESULTS: A total of 103 patients (54% female, median age 65 [IQR 52, 72] years) were included. Sixty-seven (65%) patients had de novo grade 3 lesions, whereas 29 (28%) had malignant transformations of lower-grade meningiomas. All patients underwent initial resection of their tumor. Patients were followed for a median of 46 (IQR 24, 108) months, during which time there were 65 (73%) recurrences and 50 (49%) deaths. The 5-year overall survival (OS) and progression-free survival (PFS) rates were 66% (95% CI 56%-77%) and 37% (95% CI 28%-48%), respectively. Age ≥ 65 years and male sex were independent predictors of worse OS and PFS in multivariate regression analysis, while postoperative radiotherapy was independently associated with improved OS. Karnofsky Performance Status (KPS) remained stable relative to baseline over 5 years postdiagnosis among participants who were alive at the end of the follow-up period. CONCLUSIONS: This large multicenter study provides insight into the longitudinal outcomes of grade 3 meningioma, with respect to recurrence, survival, and functional status. This study affirms the survival benefit conferred by radiotherapy in this population and suggests good functional status outcomes for patients surviving to 5 years postoperatively.

Circulating Oncometabolite 2-hydroxyglutarate as a Potential Biomarker for Isocitrate Dehydrogenase (IDH1/2) Mutant Cholangiocarcinoma.

Isocitrate dehydrogenase (IDH) enzymes catalyze the decarboxylation of isocitrate to alpha-ketoglutarate (αKG). IDH1/2 mutations preferentially convert αKG to R-2-hydroxyglutarate (R2HG), resulting in R2HG accumulation in tumor tissues. We investigated circulating 2-hydroxyglutate (2HG) as potential biomarkers for patients with IDH-mutant (IDHmt) cholangiocarcinoma (CCA). R2HG and S-2-hydroxyglutarate (S2HG) levels in blood and tumor tissues were analyzed in a discovery cohort of patients with IDHmt glioma and CCA. Results were validated in cohorts of patients with CCA and clear-cell renal cell carcinoma. The R2HG/S2HG ratio (rRS) was significantly elevated in tumor tissues, but not in blood for patients with IDHmt glioma, while circulating rRS was elevated in patients with IDHmt CCA. There were overlap distributions of circulating R2HG and total 2HG in patients with both IDHmt and wild-type (IDHwt) CCA, while there was minimal overlap in rRS values between patients with IDHmt and IDHwt CCA. Using the rRS cut-off value of 1.5, the sensitivity of rRS was 90% and specificity was 96.8%. Circulating rRS is significantly increased in patients with IDHmt CCA compare with patients with IDHwt CCA. Circulating rRS is a sensitive and specific surrogate biomarker for IDH1/2 mutations in CCA. It can potentially be used as a tool for monitoring IDH-targeted therapy.

Endoscopic endonasal surgery for prolactinomas: prognostic factors for disease control and management of persistent disease.

Only a limited number of studies have focused on the results of the Endoscopic Endonasal Approach (EEA) for treatment of prolactinomas. We sought to assess the effectiveness of EEA for prolactinoma surgery, identify factors for disease remission, and present our approach for the management of persistent disease. Forty-seven prolactinomas operated over 10 years, with a mean follow-up of 59.9 months, were included. The primary endpoints were early disease remission and remission at last follow-up. Resistance/intolerance to DA were surgical indications in 76.7%. Disease remission was achieved in 80% of microprolactinomas and 100% of microprolactinomas enclosed by the pituitary. Early disease remission was correlated with female gender (p=0.03), lower preoperative PRL levels (p=0.014), microadenoma (p=0.001), lack of radiological hemorrhage (p=0.001), absence of cavernous sinus (CS) invasion (p<0.001), and extent of resection (EOR) (p<0.001). Persistent disease was reported in 48.9% of patients, with 47% of them achieving remission at last follow-up with DA therapy alone. Repeat EEA and/or radiotherapy were utilized in 6 patients, with 66.7% achieving remission. Last follow-up remission was achieved in 76.6%, with symptomatic improvement in 95.8%. Factors predicting last follow-up remission were no previous operation (p=0.001), absence of CS invasion (p=0.01), and EOR (p<0.001). Surgery is effective for disease control in microprolactinomas. In giant and invasive tumors, it may significantly reduce the tumor volume. A multidisciplinary approach may lead to long-term disease control in three-quarters of patients, with symptomatic improvement in an even greater proportion.

Pituitary metastases: a case series and scoping review.

PURPOSE: To understand the natural history and optimal treatment strategy for pituitary gland metastasis. METHODS: We performed both a retrospective chart review of patients treated at our institution and a scoping review of the topic. RESULTS: The retrospective review identified seven patients with an average age of 59.6 years. Primary histologies included breast cancer (4), melanoma (1), renal cell carcinoma (1), and sarcoma (1). Two patients had anterior pituitary endocrine dysfunction, one of whom was the only patient with visual symptoms. All patients were treated with radiosurgery and two also underwent surgical resection. Overall survival ranged from 6.5 to 117 months. Literature review identified 166 patients from 71 studies. The most common primary cancer was lung (27.7%), followed by breast (18.7%) and renal (14.5%) cancer. 107 presented with endocrine dysfunction, including 41 cases of diabetes insipidus and 55 cases of hypopituitarism. 110 presented with visual compromise. 107 patients received radiotherapy, 96 underwent surgical resection and 44 received systemic chemotherapy/immunotherapy. Surgery was significantly associated with an increased likelihood of vision improvement and a decreased likelihood of endocrine normalization. Radiographic regression predicted visual improvement. Median overall survival was 9.9 months (range: 0.2-96). CONCLUSIONS: This scoping review showed that both radiosurgery and surgical resection have been frequently used to treat pituitary metastases with good response. Vision improvement is more likely to happen following surgical resection, likely at the expense of endocrine dysfunction. Despite treatment and radiographic response, patient survival remains less than a year.