[Clinicopathologic characteristics and survival analysis of primary large B-cell lymphoma of the central nervous system].

Objective: To retrospectively analyze the clinical and pathologic characteristics, response to treatment, survival, and prognosis of patients with primary large B-cell lymphoma of the central nervous system (PCNSLBCL) . Methods: Clinical and pathologic data of 70 patients with PCNSLBCL admitted to Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from December 2010 to November 2022 were collected for retrospective analysis. Survival analysis was performed using the Kaplan-Meier method and log-rank test, and prognosis analysis was conducted using the Cox proportional hazards model. Results: Among 70 patients with PCNSLBCL, complete remission (CRs) were achieved in 49 (70.0% ) and partial remission in 4 (5.7% ) after the first-line induction therapy; the overall remission rate was 75.7%. The 2-year progression-free survival (PFS) rate was 55.8% and the median progression-free survival (mPFS) time was 35.9 months, whereas the 2-year overall survival (OS) rate was 79.1% with a median OS time not reached. After CR induced by first-line therapy, cumulative incidence of relapse (CIR) was lower in patients who had received auto-HSCT than in those who had not received consolidation therapy (P=0.032), whose 2-year PFS rate was 54.4% and mPFS time was 35.9 months; comparatively, the 2-year PFS rate in patients having received oral maintenance of small molecule drugs reached 84.4% with a mPFS time of 79.5 months (P=0.038). Multivariant analysis demonstrated that Class 3 in the Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic model is an independent adverse prognostic factor of OS in patients with PCNSLBCL (HR=3.127, 95% CI 1.057-9.253, P=0.039) . Conclusions: In patients with PCNSLBCL achieving CR after the first-line induction therapy, auto-HSCT as consolidation therapy would lead to a decreased CIR, and PFS time could be prolonged by oral maintenance of small molecule drugs. Class 3 MSKCC prognostic model is independently associated with poorer OS.

Clinical features, MRI, molecular alternations, and prognosis of astrocytoma based on WHO 2021 classification of central nervous system tumors: A single-center retrospective study.

BACKGROUND: The diagnosis of glioma has advanced since the release of the WHO 2021 classification with more molecular alterations involved in the integrated diagnostic pathways. Our study aimed to present our experience with the clinical features and management of astrocytoma, IDH mutant based on the latest WHO classification. METHODS: Patients diagnosed with astrocytoma, IDH-mutant based on the WHO 5th edition classification of CNS tumors at our center from January 2009 to January 2022 were included. Patients were divided into WHO 2-3 grade group and WHO 4 grade group. Integrate diagnoses were retrospectively confirmed according to WHO 2016 and 2021 classification. Clinical and MRI characteristics were reviewed, and survival analysis was performed. RESULTS: A total of 60 patients were enrolled. 21.67% (13/60) of all patients changed tumor grade from WHO 4th edition classification to WHO 5th edition. Of these, 21.43% (6/28) of grade II astrocytoma and 58.33% (7/12) of grade III astrocytoma according to WHO 4th edition classification changed to grade 4 according to WHO 5th edition classification. Sex (p = 0.042), recurrent glioma (p = 0.006), and Ki-67 index (p < 0.001) of pathological examination were statistically different in the WHO grade 2-3 group (n = 27) and WHO grade 4 group (n = 33). CDK6 (p = 0.004), FGFR2 (p = 0.003), and MYC (p = 0.004) alterations showed an enrichment in the WHO grade 4 group. Patients with higher grade showed shorter mOS (mOS = 75.9 m, 53.6 m, 26.4 m for grade 2, 3, and 4, respectively, p = 0.01). CONCLUSIONS: Patients diagnosed as WHO grade 4 according to the 5th edition WHO classification based on molecular alterations are more likely to have poorer prognosis. Therefore, treatment should be tailored to their individual needs. Further research is needed for the management of IDH-mutant astrocytoma is needed in the future.

Primary diffuse large B-cell lymphoma of the central nervous system identified with CSF biomarkers.

BACKGROUND: Diagnosis of primary diffuse large B-cell lymphoma of the central nervous system (PCNSL) is challenging and often delayed. MRI imaging, CSF cytology and flow cytometry have a low sensitivity and even brain biopsies can be misleading. We report three cases of PCNSL with various clinical presentation and radiological findings where the diagnosis was suggested by novel CSF biomarkers and subsequently confirmed by brain biopsy or autopsy. CASE PRESENTATIONS: The first case is a 79-year-old man with severe neurocognitive dysfunction and static ataxia evolving over 5 months. Brain MRI revealed a nodular ventriculitis. An open brain biopsy was inconclusive. The second case is a 60-year-old woman with progressive sensory symptoms in all four limbs, evolving over 1 year. Brain and spinal MRI revealed asymmetric T2 hyperintensities of the corpus callosum, corona radiata and corticospinal tracts. The third case is a 72-year-old man recently diagnosed with primary vitreoretinal lymphoma of the right eye. A follow-up brain MRI performed 4 months after symptom onset revealed a T2 hyperintense fronto-sagittal lesion, with gadolinium uptake and perilesional edema. In all three cases, CSF flow cytometry and cytology were negative. Mutation analysis on the CSF (either by digital PCR or by next generation sequencing) identified the MYD88 L265P hotspot mutation in all three cases. A B-cell clonality study, performed in case 1 and 2, identified a monoclonal rearrangement of the immunoglobulin light chain lambda (IGL) and kappa (IGK) gene. CSF CXCL-13 and IL-10 levels were high in all three cases, and IL-10/IL-6 ratio was high in two. Diagnosis of PCNSL was later confirmed by autopsy in case 1, and by brain biopsy in case 2 and 3. CONCLUSIONS: Taken together, 5 CSF biomarkers (IL-10, IL-10/IL-6 ratio, CXCL13, MYD88 mutation and monoclonal IG gene rearrangements) were strongly indicative of a PCNSL. Using innovative CSF biomarkers can be sensitive and complementary to traditional CSF analysis and brain biopsy in the diagnosis of PCNSL, potentially allowing for earlier diagnosis and treatment.

NTRK-fused central nervous system tumours: clinicopathological and genetic insights and response to TRK inhibitors.

Background Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are found in 1% of gliomas across children and adults. TRK inhibitors are promising therapeutic agents for NTRK-fused gliomas because they are tissue agnostic and cross the blood-brain barrier (BBB). Methods We investigated twelve NGS-verified NTRK-fused gliomas from a single institute, Seoul National University Hospital. Results The patient cohort included six children (aged 1-15 years) and six adults (aged 27-72 years). NTRK2 fusions were found in ten cerebral diffuse low-grade and high-grade gliomas (DLGGs and DHGGs, respectively), and NTRK1 fusions were found in one cerebral desmoplastic infantile ganglioglioma and one spinal DHGG. In this series, the fusion partners of NTRK2 were HOOK3, KIF5A, GKAP1, LHFPL3, SLMAP, ZBTB43, SPECC1L, FKBP15, KANK1, and BCR, while the NTRK1 fusion partners were TPR and TPM3. DLGGs tended to harbour only an NTRK fusion, while DHGGs exhibited further genetic alterations, such as TERT promoter/TP53/PTEN mutation, CDKN2A/2B homozygous deletion, PDGFRA/KIT/MDM4/AKT3 amplification, or multiple chromosomal copy number aberrations. Four patients received adjuvant TRK inhibitor therapy (larotrectinib, repotrectinib, or entrectinib), among which three also received chemotherapy (n = 2) or proton therapy (n = 1). The treatment outcomes for patients receiving TRK inhibitors varied: one child who received larotrectinib for residual DLGG maintained stable disease. In contrast, another child with DHGG in the spinal cord experienced multiple instances of tumour recurrence. Despite treatment with larotrectinib, ultimately, the child died as a result of tumour progression. An adult patient with glioblastoma (GBM) treated with entrectinib also experienced tumour progression and eventually died. However, there was a successful outcome for a paediatric patient with DHGG who, after a second gross total tumour removal followed by repotrectinib treatment, showed no evidence of disease. This patient had previously experienced relapse after the initial surgery and underwent autologous peripheral blood stem cell therapy with carboplatin/thiotepa and proton therapy. Conclusions Our study clarifies the distinct differences in the pathology and TRK inhibitor response between LGG and HGG with NTRK fusions.

What Changed in CNS5? A Mini-Review on General Changes and Adult Diffuse Gliomas.

The fifth edition of the WHO classification of tumors of the central nervous system (WHO CNS5) was published in 2021 which is the sixth version of the international standard for the diagnostics of CNS tumors. Regular updates of the consortium to inform molecular and practical approaches to CNS tumor taxonomy (cIMPACT-NOW) shaped the WHO CNS5 which continues the trend of incorporating the molecular characteristics of tumors into the histological and immunohistochemical findings. The various updates can be classified into general changes across all tumors and specific changes within the tumor groups. This mini-review highlights the general changes and the major changes in adult diffuse gliomas.

RésuméLa cinquième édition de la classification OMS des tumeurs du système nerveux central (WHO CNS5) a été publiée en 2021, soit la sixième version de la norme internationale pour le diagnostic des tumeurs du SNC. Mises à jour régulières du consortium pour informer les chercheurs moléculaires et pratiques les approches de la taxonomie des tumeurs du SNC (cIMPACT-NOW) ont façonné le CNS5 de l'OMS, qui poursuit la tendance à incorporer la méthodologie moléculaire caractéristiques des tumeurs dans les résultats histologiques et immunohistochimiques. Les différentes mises à jour peuvent être classées en modifications générales dans toutes les tumeurs et les changements spécifiques au sein des groupes de tumeurs. Cette mini-revue met en évidence les changements généraux et les changements majeurs dans gliomes diffus de l'adulte.

ACT001 inhibits primary central nervous system lymphoma tumor growth by enhancing the anti-tumor effect of T cells.

Primary central nervous system lymphoma (PCNSL) is a group of malignant brain tumors with a poor prognosis, and new therapeutic approaches for this tumor urgently need to be investigated. Formulated from a long-standing anti-inflammatory drugs, ACT001 has demonstrated in clinical research to be able to pass through the blood-brain barrier (BBB) and affect the central nervous system. The effects of ACT001 on PCNSL cell apoptosis, proliferation and immune-related indexes were detected by flow cytometry, and the efficacy of ACT001 was verified in vivo by constructing a mouse PCNSL tumor model. ACT001 significantly inhibited PCNSL cell proliferation and induced apoptosis in vitro. In addition, ACT001 can significantly inhibit the PD-1/PD-L1 expression and restore the function of T cells, so that the immune system cannot allow tumor cells to escape. In vivo experiments show that co-infusion of ACT001 and T cells effectively inhibits PCNSL tumor growth in NSG mice. Our work describes the inhibitory effect of ACT001 on the PCNSL cell line and demonstrated the inhibitory effect of ACT001 on immune checkpoints.

Patient's HLA Genotype Is Associated With the Risk of Central Nervous System Dissemination and Clinical Disease Presentation in Diffuse Large B-cell Lymphoma.

BACKGROUND/AIM: Central nervous system (CNS) involvement in aggressive B-cell lymphoma, either as a primary or secondary event to systemic disease, portends a poor prognosis. This study sought to identify patients at high risk for CNS relapse by analyzing their human leukocyte antigen (HLA) genotypes. PATIENTS AND METHODS: We retrospectively examined the HLA genotypes of 164 patients with systemic lymphoma, primary CNS lymphoma, and CNS relapse of systemic lymphoma. Patient records were analyzed, and HLA typing was performed by the Finnish Red Cross Blood Service. After excluding patients who received CNS prophylaxis, 131 patients were included in the final analysis. RESULTS: A strong association was found between the HLA-A*31 genotype and CNS disease (p=0.001). Additionally, various HLA genotypes were linked to lactate dehydrogenase levels, extranodal disease, International Prognostic Index score, and disease stage. CONCLUSION: The patient's genetic constitution, rather than solely disease-related factors, plays a role in the tropism of lymphoma for the CNS. If confirmed in a larger study, defining the HLA genotype of a lymphoma patient could provide valuable information for predicting CNS relapse.

Neuroradiological, genetic and clinical characteristics of histone H3 K27-mutant diffuse midline gliomas in the Kansai Molecular Diagnosis Network for CNS Tumors (Kansai Network): multicenter retrospective cohort.

This study aims to elucidate the clinical and molecular characteristics, treatment outcomes and prognostic factors of patients with histone H3 K27-mutant diffuse midline glioma. We retrospectively analyzed 93 patients with diffuse midline glioma (47 thalamus, 24 brainstem, 12 spinal cord and 10 other midline locations) treated at 24 affiliated hospitals in the Kansai Molecular Diagnosis Network for CNS Tumors. Considering the term "midline" areas, which had been confused in previous reports, we classified four midline locations based on previous reports and anatomical findings. Clinical and molecular characteristics of the study cohort included: age 4-78 years, female sex (41%), lower-grade histology (56%), preoperative Karnofsky performance status (KPS) scores ≥ 80 (49%), resection (36%), adjuvant radiation plus chemotherapy (83%), temozolomide therapy (76%), bevacizumab therapy (42%), HIST1H3B p.K27M mutation (2%), TERT promoter mutation (3%), MGMT promoter methylation (9%), BRAF p.V600E mutation (1%), FGFR1 mutation (14%) and EGFR mutation (3%). Median progression-free and overall survival time was 9.9 ± 1.0 (7.9-11.9, 95% CI) and 16.6 ± 1.4 (13.9-19.3, 95% CI) months, respectively. Female sex, preoperative KPS score ≥ 80, adjuvant radiation + temozolomide and radiation ≥ 50 Gy were associated with favorable prognosis. Female sex and preoperative KPS score ≥ 80 were identified as independent good prognostic factors. This study demonstrated the current state of clinical practice for patients with diffuse midline glioma and molecular analyses of diffuse midline glioma in real-world settings. Further investigation in a larger population would contribute to better understanding of the pathology of diffuse midline glioma.

Comparative Study on the Clinicopathologic and Molecular Characteristics of Primary and Secondary Diffuse Large B-cell Lymphoma in the Central Nervous System.

BACKGROUND/AIM: Diffuse large B-cell lymphoma of the central nervous system (CNS-DLBCL) is an aggressive B-cell lymphoma with clinical and molecular heterogeneity. Primary CNS-DLBCL (PCNSL) affects the brain, eyes, leptomeninges, or spinal cord without systemic involvement. Secondary CNS-DLBCL (SCNSL) manifests concurrently with systemic lymphoma or as an isolated CNS relapse with poor prognosis. MATERIALS AND METHODS: Next-generation sequencing (NGS) was used to identify genomic alterations in 32 PCNSL and 9 SCNSL cases. Single nucleotide variants and copy number variations in addition to the clinicopathologic data and proposed risk predictive values were compared to aid in diagnostic differentiation between the two types of lymphomas. RESULTS: The MCD genotype, characterized by mutations in MYD88 and CD79B, is the most common alteration in PCNSL and is associated with lower survival rates. The frequency of MYD88 mutation was significantly higher in PCNSL compared to SCNSL (75.0% vs. 33.3%; p=0.042). Recurrent copy number loss of 6p21 occurred in 56.1% of cases, more often in PCNSL (65.6%) than in SCNSL (22.2%) (p=0.028). Diagnostic positive predictive values (PPV) of MYD88 mutation and 6p21 loss for PCNSL were 89% and 91%, respectively. PPV of both alterations was 93% for the diagnosis of PCNSL. CONCLUSION: MYD88 mutation and 6p21 loss were significantly higher in PCNSL than in SCNSL, and novel risk prediction models based on these distinct genomic profiles can aid in the clinical differentiation of PCNSL and SCNSL.

BRAF V600E-mutant colorectal cancer with CNS metastases treated successfully with encorafenib, binimetinib and cetuximab.

This report describes a case of BRAF V600E-mutated colorectal cancer with CNS metastases in which treatment with encorafenib, binimetinib and cetuximab was effective. There is limited information on the ability of encorafenib, binimetinib and cetuximab to enter the CNS.The patient was a 53-year-old man was diagnosed with ascending colon cancer (cT3N3M1c stage IVc). BRAF V600E mutation was confirmed. FOLFOX was started, but CNS metastases soon appeared. Encorafenib, binimetinib and cetuximab were administered and had a favorable effect on the CNS lesions. The patient initially responded well, but his disease progressed 2 months later. Further research is needed to improve management strategies for BRAF V600E-mutated colorectal cancer with CNS metastases.

[Box: see text].

Novel insights toward diagnosis and treatment of glioneuronal and neuronal tumors in young adults.

Aim: Glioneuronal and neuronal tumors are rare primary central nervous system malignancies with heterogeneous features. Due to the rarity of these malignancies diagnosis and treatment remains a clinical challenge. Methods: Here we performed a narrative review aimed to investigate the principal issues concerning the diagnosis, pathology, and clinical management of glioneuronal tumors. Results: Diagnostic criteria have been recently overturned thanks to a better characterization on a histological and molecular biology level. The study of genomic alterations occurring within these tumors has allowed us to identify potential therapeutic targets including BRAF, FGFR, and PDGFRA. Conclusion: Techniques allowing molecular sequencing DNA methylation assessment of the disease are essential diagnostic tools. Targeting agents should be included in the therapeutic armamentarium after loco-regional treatment failure.

[Box: see text].

Primary central nervous system lymphomas in immunocompromised patients require specific response criteria.

PURPOSE: Immunosuppression is a well-established risk factor for primary central nervous system lymphomas (PCNSLs), which present in this context distinct radiological characteristics. Our aim was to describe the radiological evolution of treated PCNSL in immunocompromised patients and suggest adapted MRI response criteria. METHODS: We conducted a multicenter retrospective study of patients from the French LOC, K-Virogref and CANCERVIH network databases and enrolled adult immunocompromised patients with newly diagnosed PCNSL. RESULTS: We evaluated the baseline, intermediate, end-of-treatment and follow-up MRI data of 31 patients (9 living with HIV, 16 with solid organ transplantation and 6 with an autoimmune disease under chronic immunosuppressive therapy). At baseline, 23/30 (77%) patients had necrotic lesions with ring enhancement and 28% of the lesions were hemorrhagic. At the end of the first-line treatment, 12/28 (43%) patients could not be classified according to the IPCG criteria. Thirteen of 28 (46%) patients still harbored contrast enhancement, and 11/28 (39%) patients had persistent large necrotic lesions with a median diameter of 15 mm. These aspects were not associated with a pejorative outcome and progressively diminished during follow-up. Six patients relapsed; however, we failed to identify any neuroimaging risk factors on the end-of-treatment MRI. CONCLUSION: In immunocompromised patients, PCNSLs often harbor alarming features on end-of-treatment MRI, with persistent contrast-enhanced lesions frequently observed. However, these aspects seemed to be related to the necrotic and hemorrhagic nature of the lesions and were not predictive of a pejorative outcome. Specific response criteria for this population are thereby proposed.

Targeting GPC2 on Intraocular and CNS Metastatic Retinoblastomas with Local and Systemic Delivery of CAR T Cells.

PURPOSE: Retinoblastoma is the most common intraocular malignancy in children. Although new chemotherapeutic approaches have improved ocular salvage rates, novel therapies are required for patients with refractory intraocular and metastatic disease. Chimeric antigen receptor (CAR) T cells targeting glypican-2 (GPC2) are a potential new therapeutic strategy. EXPERIMENTAL DESIGN: GPC2 expression and its regulation by the E2F1 transcription factor were studied in retinoblastoma patient samples and cellular models. In vitro, we performed functional studies comparing GPC2 CAR T cells with different costimulatory domains (4-1BB and CD28). In vivo, the efficacy of local and systemic administration of GPC2 CAR T cells was evaluated in intraocular and leptomeningeal human retinoblastoma xenograft models. RESULTS: Retinoblastoma tumors, but not healthy retinal tissues, expressed cell surface GPC2, and this tumor-specific expression was driven by E2F1. GPC2-directed CARs with 4-1BB costimulation (GPC2.BBz) were superior to CARs with CD28 stimulatory domains (GPC2.28z), efficiently inducing retinoblastoma cell cytotoxicity and enhancing T-cell proliferation and polyfunctionality. In vivo, GPC2.BBz CARs had enhanced persistence, which led to significant tumor regression compared with either control CD19 or GPC2.28z CARs. In intraocular models, GPC2.BBz CAR T cells efficiently trafficked to tumor-bearing eyes after intravitreal or systemic infusions, significantly prolonging ocular survival. In central nervous system (CNS) retinoblastoma models, intraventricular or systemically administered GPC2.BBz CAR T cells were activated in retinoblastoma-involved CNS tissues, resulting in robust tumor regression with substantially extended overall mouse survival. CONCLUSIONS: GPC2-directed CAR T cells are effective against intraocular and CNS metastatic retinoblastomas.

Impact of HMGB1 on cancer development and therapeutic insights focused on CNS malignancy.

The present study explores the complex roles of High Mobility Group Box 1 (HMGB1) in the context of cancer development, emphasizing glioblastoma (GBM) and other central nervous system (CNS) cancers. HMGB1, primarily known for its involvement in inflammation and angiogenesis, emerges as a multifaceted player in the tumorigenesis of GBM. The overexpression of HMGB1 correlates with glioma malignancy, influencing key pathways like RAGE/MEK/ERK and RAGE/Rac1. Additionally, HMGB1 secretion is linked to the maintenance of glioma stem cells (GSCs) and contributes to the tumor microenvironment's (TME) vascular leakiness. Henceforth, our review discusses the bidirectional impact of HMGB1, acting as both a promoter of tumor progression and a mediator of anti-tumor immune responses. Notably, HMGB1 exhibits tumor-suppressive roles by inducing apoptosis, limiting cellular proliferation, and enhancing the sensitivity of GBM to therapeutic interventions. This dualistic nature of HMGB1 calls for a nuanced understanding of its implications in GBM pathogenesis, offering potential avenues for more effective and personalized treatment strategies. The findings underscore the need to explore HMGB1 as a prognostic marker, therapeutic target, and a promising tool for stimulating anti-tumor immunity in GBM.

CBTRUS Statistical Report: American Brain Tumor Association & NCI Neuro-Oncology Branch Adolescent and Young Adult Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2016-2020.

Recent analyses have shown that, whereas cancer survival overall has been improving, it has not improved for adolescents and young adults ages 15-39 years (AYA). The clinical care of AYA with primary brain and other central nervous system (CNS) tumors (BT) is complicated by the fact that the histopathologies of such tumors in AYA differ from their histopathologies in either children (ages 0-14 years) or older adults (ages 40+ years). The present report, as an update to a 2016 publication from the Central Brain Tumor Registry of the United States and the American Brain Tumor Association, provides in-depth analyses of the epidemiology of primary BT in AYA in the United States and is the first to provide biomolecular marker-specific statistics and prevalence by histopathology for both primary malignant and non-malignant BT in AYA. Between 2016 and 2020, the annual average age-specific incidence rate (AASIR) of primary malignant and non-malignant BT in AYA was 12.00 per 100,000 population, an average of 12,848 newly diagnosed cases per year. During the same period, an average of 1,018 AYA deaths per year were caused by primary malignant BT, representing an annual average age-specific mortality rate of 0.96 per 100,000 population. When primary BT were categorized by histopathology, pituitary tumors were the most common (36.6%), with an AASIR of 4.34 per 100,000 population. Total incidence increased with age overall; when stratified by sex, the incidence was higher in females than males at all ages. Incidence rates for all primary BT combined and for non-malignant tumors only were highest for non-Hispanic American Indian/Alaska Native individuals, whereas malignant tumors were more frequent in non-Hispanic White individuals, compared with other racial/ethnic groups. On the basis of histopathology, the most common molecularly defined tumor was diffuse glioma (an AASIR of 1.51 per 100,000). Primary malignant BT are the second most common cause of cancer death in the AYA population. Incidence rates of primary BT overall, as well as specific histopathologies, vary significantly by age. Accordingly, an accurate statistical assessment of primary BT in the AYA population is vital for better understanding the impact of these tumors on the US population and to serve as a reference for afflicted individuals, for researchers investigating new therapies, and for clinicians treating these patients.

A multicenter proof-of-concept study on deep learning-based intraoperative discrimination of primary central nervous system lymphoma.

Accurate intraoperative differentiation of primary central nervous system lymphoma (PCNSL) remains pivotal in guiding neurosurgical decisions. However, distinguishing PCNSL from other lesions, notably glioma, through frozen sections challenges pathologists. Here we sought to develop and validate a deep learning model capable of precisely distinguishing PCNSL from non-PCNSL lesions, especially glioma, using hematoxylin and eosin (H&E)-stained frozen whole-slide images. Also, we compared its performance against pathologists of varying expertise. Additionally, a human-machine fusion approach integrated both model and pathologic diagnostics. In external cohorts, LGNet achieved AUROCs of 0.965 and 0.972 in distinguishing PCNSL from glioma and AUROCs of 0.981 and 0.993 in differentiating PCNSL from non-PCNSL lesions. Outperforming several pathologists, LGNet significantly improved diagnostic performance, further augmented to some extent by fusion approach. LGNet's proficiency in frozen section analysis and its synergy with pathologists indicate its valuable role in intraoperative diagnosis, particularly in discriminating PCNSL from glioma, alongside other lesions.

Clinical, pathological, and molecular features of central nervous system tumors with BCOR internal tandem duplication.

Central nervous system tumor with BCOR internal tandem duplication (CNS tumor with BCOR-ITD) constitutes a molecularly distinct entity, characterized by internal tandem duplication within exon 15 of the BCOR transcriptional co-repressor gene (BCOR-ITD). The current study aimed to elucidate the clinical, pathological, and molecular attributes of CNS tumors with BCOR-ITD and explore their putative cellular origin. This study cohort comprised four pediatric cases, aged 23 months to 13 years at initial presentation. Magnetic resonance imaging revealed large, well-circumscribed intra-CNS masses localized heterogeneously throughout the CNS. Microscopically, tumors were composed of spindle to ovoid cells, exhibiting perivascular pseudorosettes and palisading necrosis, but lacking microvascular proliferation. Immunohistochemical staining showed diffuse tumor cell expression of BCOR, CD56, CD99, vimentin, and the stem cell markers PAX6, SOX2, CD133 and Nestin, alongside focal positivity for Olig-2, S100, SOX10, Syn and NeuN. Molecularly, all cases harbored BCOR-ITDs ranging from 87 to 119 base pairs in length, including one case with two distinct ITDs. Notably, the ITDs were interrupted by unique 1-3 bp insertions in all cases. In summary, CNS tumors with BCOR-ITD exhibit characteristic clinical, pathological, and molecular features detectable through BCOR immunohistochemistry and confirmatory molecular analyses. Their expression of stem cell markers raises the possibility of an origin from neuroepithelial stem cells rather than representing true embryonal neoplasms.

Distinct roles of TREM2 in central nervous system cancers and peripheral cancers.

Glioblastomas (GBM) are incurable central nervous system (CNS) cancers characterized by substantial myeloid cell infiltration. Whether myeloid cell-directed therapeutic targets identified in peripheral non-CNS cancers are applicable to GBM requires further study. Here, we identify that the critical immunosuppressive target in peripheral cancers, triggering receptor expressed on myeloid cells-2 (TREM2), is immunoprotective in GBM. Genetic or pharmacological TREM2 deficiency promotes GBM progression in vivo. Single-cell and spatial sequencing reveals downregulated TREM2 in GBM-infiltrated myeloid cells. TREM2 negatively correlates with immunosuppressive myeloid and T cell exhaustion signatures in GBM. We further demonstrate that during GBM progression, CNS-enriched sphingolipids bind TREM2 on myeloid cells and elicit antitumor responses. Clinically, high TREM2 expression in myeloid cells correlates with better survival in GBM. Adeno-associated virus-mediated TREM2 overexpression impedes GBM progression and synergizes with anti-PD-1 therapy. Our results reveal distinct functions of TREM2 in CNS cancers and support organ-specific myeloid cell remodeling in cancer immunotherapy.