Cortical Microhemorrhage Presentation of Small Vessel Primary Angiitis of the Central Nervous System.

OBJECTIVE: Primary angiitis of the central nervous system (PACNS) is a rare vasculitis restricted to the brain, spinal cord, and leptomeninges. This study aimed to describe the imaging characteristics of patients with small vessel PACNS (SV-PACNS) using 7 T magnetic resonance imaging (MRI). METHODS: This ongoing prospective observational cohort study included patients who met the Calabrese and Mallek criteria and underwent 7 T MRI scan. The MRI protocol includes T1-weighted magnetization-prepared rapid gradient echo imaging, T2 star weighted imaging, and susceptibility-weighted imaging. Two experienced readers independently reviewed the neuroimages. Clinical data were extracted from the electronic patient records. The findings were then applied to a cohort of patients with large vessel central nervous system (CNS) vasculitis. RESULTS: We included 21 patients with SV-PACNS from December 2021 to November 2023. Of these, 12 (57.14%) had cerebral cortical microhemorrhages with atrophy. The pattern with microhemorrhages was described in detail based on the gradient echo sequence, leading to the identification of what we have termed the "coral-like sign." The onset age of patients with coral-like sign (33.83 ± 9.93 years) appeared younger than that of patients without coral-like sign (42.11 ± 14.18 years) (P = 0.131). Furthermore, the cerebral lesions in patients with cortical microhemorrhagic SV-PACNS showed greater propensity toward bilateral lesions (P = 0.03). The coral-like sign was not observed in patients with large vessel CNS vasculitis. INTERPRETATION: The key characteristics of the coral-like sign represent cerebral cortical diffuse microhemorrhages with atrophy, which may be an important MRI pattern of SV-PACNS. ANN NEUROL 2024;96:194-203.

Machine learning-based pathomics signature of histology slides as a novel prognostic indicator in primary central nervous system lymphoma.

PURPOSE: To develop and validate a pathomics signature for predicting the outcomes of Primary Central Nervous System Lymphoma (PCNSL). METHODS: In this study, 132 whole-slide images (WSIs) of 114 patients with PCNSL were enrolled. Quantitative features of hematoxylin and eosin (H&E) stained slides were extracted using CellProfiler. A pathomics signature was established and validated. Cox regression analysis, receiver operating characteristic (ROC) curves, Calibration, decision curve analysis (DCA), and net reclassification improvement (NRI) were performed to assess the significance and performance. RESULTS: In total, 802 features were extracted using a fully automated pipeline. Six machine-learning classifiers demonstrated high accuracy in distinguishing malignant neoplasms. The pathomics signature remained a significant factor of overall survival (OS) and progression-free survival (PFS) in the training cohort (OS: HR 7.423, p < 0.001; PFS: HR 2.143, p = 0.022) and independent validation cohort (OS: HR 4.204, p = 0.017; PFS: HR 3.243, p = 0.005). A significantly lower response rate to initial treatment was found in high Path-score group (19/35, 54.29%) as compared to patients in the low Path-score group (16/70, 22.86%; p < 0.001). The DCA and NRI analyses confirmed that the nomogram showed incremental performance compared with existing models. The ROC curve demonstrated a relatively sensitive and specific profile for the nomogram (1-, 2-, and 3-year AUC = 0.862, 0.932, and 0.927, respectively). CONCLUSION: As a novel, non-invasive, and convenient approach, the newly developed pathomics signature is a powerful predictor of OS and PFS in PCNSL and might be a potential predictive indicator for therapeutic response.

Effectiveness of tofacitinib monotherapy for patients with IgG4-RD or idiopathic retroperitoneal fibrosis.

OBJECTIVES: To explore the effectiveness of tofacitinib for immunoglobulin G4-related disease (IgG4-RD) and idiopathic retroperitoneal fibrosis (IRF), and investigate the expression of JAKs in the lesion of these diseases. METHODS: Clinical data of patients with IgG4-RD or IRF who were administered with tofacitinib monotherapy were collected. IgG4-RD responder index (IgG4-RD RI) was assessed. The expression of JAK1, JAK2, JAK3, and TYK2 were analysed with immunohistochemistry staining in three salivary glands specimens of IgG4-RD and one retroperitoneal tissue of IRF. RESULTS: Two patients with IRF and two patients with IgG4-RD used tofacitinib monotherapy. Two patients with IRF achieved complete remission with diminished retroperitoneal mass and decreased CRP, as IgG4-RD RI decreased from 6 to 1 in both of them. One with IgG4-RD achieved complete remission with alleviated enlargement of pancreas and IgG4 level decreased from 13.7 g/L to 2.4 g/L, as IgG4-RD RI decreased from 12 to 1. One with IgG4-RD achieved partial response with IgG4 level decreased from 77.1g/L to 25.8g/L as IgG4-RD RI from 18 to 6. JAK1, JAK2, JAK3, and TYK2 expression were detected in biopsy tissues. The staining intensity of the JAK family on the lesion from one IRF patient was similar to those from IgG4-RD patients. CONCLUSIONS: Tofacitinib is a potentially effective treatment for IgG4-RD and IRF and it is reasonable to conduct clinical trial to validate its efficacy. The JAKs were expressed in the inflammatory lesions of IgG4-RD and IRF and they may share a common pathogenesis pathway that is independent of IgG4 production.

The expression level of Neuronal Calcium Sensor 1 can predict the prognosis of cytogenetically normal AML.

Acute myeloid leukemia (AML) is malignant clonal expansion of myeloid blasts with high heterogeneity and numerous molecular biomarkers have been found to judge the prognosis in some specific classifications of AML. Furthermore, as for patients with cytogenetically normal acute myeloid leukemia (CN-AML), we need to find more new biomarkers to predict the patients' outcomes. Recently, the expression level of Neuronal Calcium Sensor 1 (NCS1) has been associated with the prognosis of breast cancer and hepatocellular carcinoma, but nothing related has been reported about hematological malignancies. Therefore, we make this study to explore the relationship between the NCS1 expression level and CN-AML. We analyzed the relation between survival and NCS1 RNA expression through 75 CN-AML patients from Cancer Genome Atlas (TCGA) database and 433 CN-AML patients (3 independent datasets) from Gene Expression Omnibus (GEO) database. Additionally, we compared the NCS1 RNA expression between 138 leukemia stem cells positive (LSCs+) samples and 89 leukemia stem cells negative (LSCs-) samples from 78 AML patients from GSE76004 dataset. In our study, CN-AML patients with high expression level of NCS1 have longer EFS or OS. In addition, the NCS1 expression level in leukemia stem cells was low (p = 0.00039). According to these findings, we concluded that the high expression of NCS1 can predict favorable prognosis in CN-AML patients. Furthermore, our work put forward that NCS1 expresses lower in LSCs+, which might be an important mechanism to explain the aggressiveness of AML.

The sinuous, wave-like intratumoral-wall sign is a sensitive and specific radiological biomarker for oligodendrogliomas.

OBJECTIVES: The purpose of this study was to investigate the clinical utility of the sinuous, wave-like intratumoral-wall (SWITW) sign on T2WI in diagnosing isocitrate dehydrogenase (IDH) mutant and 1p/19q codeleted (IDHmut-Codel) oligodendrogliomas, for which a relatively conservative resection strategy might be sufficient due to a better response to chemoradiotherapy and favorable prognosis. METHODS: Imaging data from consecutive adult patients with diffuse lower-grade gliomas (LGGs, histological grades 2-3) in Beijing Tiantan Hospital (December 1, 2013, to October 31, 2021, BTH set, n = 711) and the Cancer Imaging Archive (TCIA) LGGs set (n = 117) were used to develop and validate our findings. Two independent observers assessed the SWITW sign and some well-reported discriminative radiological features to establish a practical diagnostic strategy. RESULTS: The SWITW sign showed satisfying sensitivity (0.684 and 0.722 for BTH and TCIA sets) and specificity (0.938 and 0.914 for BTH and TCIA sets) in defining IDHmut-Codels, and the interobserver agreement was substantial (κ 0.718 and 0.756 for BTH and TCIA sets). Compared to calcification, the SWITW sign improved the sensitivity by 0.28 (0.404 to 0.684) in the BTH set, and 81.0% (277/342) of IDHmut-Codel cases demonstrated SWITW and/ or calcification positivity. Combining the SWITW sign, calcification, low ADC values, and other discriminative features, we established a concise and reliable diagnostic protocol for IDHmut-Codels. CONCLUSIONS: The SWITW sign was a sensitive and specific imaging biomarker for IDHmut-Codels. The integrated protocol provided an explicable, efficient, and reproducible method for precise preoperative diagnosis, which was essential to guide individualized surgical plan-making. KEY POINTS: • The SWITW sign was a sensitive and specific imaging biomarker for IDHmut-Codel oligodendrogliomas. • The SWITW sign was more sensitive than calcification and an integrated strategy could improve diagnostic sensitivity for IDHmut-Codel oligodendrogliomas. • Combining SWITW, calcification, low ADC values, and other discriminative features could make a precise preoperative diagnosis for IDHmut-Codel oligodendrogliomas.

Autonomic dysfunction-dominant phenotype in a Chinese family with biallelic GGC repeat expansions in NOTCH2NLC.

The GGC repeat expansions in the NOTCH2NLC gene are associated with multiple neurodegenerative disorders. Herein, we report the clinical phenotype in a family with biallelic GGC expansions in NOTCH2NLC. Autonomic dysfunction was a prominent clinical manifestation in three genetically confirmed patients without dementia, parkinsonism, and cerebellar ataxia for > 12 years. A 7-T brain magnetic resonance imaging in two patients revealed a change in the small cerebral veins. The biallelic GGC repeat expansions may not modify the disease progression in neuronal intranuclear inclusion disease. Autonomic dysfunction-dominant may expand the clinical phenotype of NOTCH2NLC.

Nonhematogenic circulating aneuploid cells confer inferior prognosis and therapeutic resistance in gliomas.

Aneuploidy is the hallmark of malignancy. Our previous study successfully detected nonhematogenic circulating aneuploidy cells (CACs) in types of gliomas. The current prospective clinical study aims to further precisely subcategorize aneuploid CACs, including CD31- circulating tumor cells (CTCs) and CD31+ circulating tumor endothelial cells, and thoroughly investigate the clinical utilities of these different subtypes of cells. Co-detection and analysis of CTCs and circulating tumor-derived endothelial cells (CTECs) expressing CD133, glial fibrillary acidic protein (GFAP), or epidermal growth factor receptor variant III (EGFR vIII) were performed by integrated subtraction enrichment and immunostaining fluorescence in situ hybridization (SE-iFISH) in 111 preoperative primary diffuse glioma patients. Aneuploid CACs could be detected in most de novo glioma patients. Among detected CACs, 45.6% were CD31- /CD45- aneuploid CTCs and the remaining 54.4% were CD31+ /CD45- aneuploid CTECs. Positive detection of CTECs significantly correlated with disruption of the blood-brain barrier. The median number of large CTCs (L CTCs, >5 µm, 2) in low-grade glioma (WHO grade 2) was less than high-grade glioma (WHO grades 3 and 4) (3, p = 0.044), but this difference was not observed in small CTCs (S CTCs, ≤5 µm), CTECs or CACs (CTCs + CTECs). The numbers of CTCs, CTECs, or CACs in patients with contrast-enhancing (CE) lesions considerably exceeded that of non-CE lesions (p < 0.05). Receiver operating characteristic curves demonstrated that CD31+ CTECs, especially L CTECs, exhibited a close positive relationship with CE lesions. Survival analysis revealed that the high number of CD31- CTCs could be an adverse factor for compromised progression-free survival and overall survival. Longitudinal surveillance of CD31- CTCs was suitable for evaluating the therapeutic response and for monitoring potential emerging treatment resistance.

The PI3K/AKT/mTOR signaling pathway is aberrantly activated in primary central nervous system lymphoma and correlated with a poor prognosis.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a specific subtype of non-Hodgkin lymphoma that is highly invasive and confined to the central nervous system (CNS). The vast majority of PCNSLs are diffuse large B-cell lymphomas (DLBCLs). PCNSL is a highly heterogeneous disease, and its pathogenesis has not yet been fully elucidated. Further studies are needed to guide individualized therapy and improve the prognosis. METHODS: In this study, we detected 1) the expression of p-AKT, p-mTOR, p-S6 and p-4E-BP1 by immunohistochemistry (IHC) and Western blotting, 2) the mRNA expression by real-time qPCR and 3) the deletion of PTEN gene by immunofluorescence in situ hybridization (FISH) in order to investigate the activation status of the PI3K/AKT/mTOR signaling pathway in PCNSL. Samples of reactive hyperplasia lymphnods were used as the control group. The correlations between the clinical characteristics and prognosis of PCNSL patients and the expression of p-AKT, p-mTOR, p-S6 and p-4E-BP1 and the deletion of PTEN were assessed. RESULTS: The IHC results showed that the positive expression rates of p-AKT, p-mTOR, p-S6 and p-4E-BP1 in PCNSL were significantly higher in the PCNSL group than in the control group (P < 0.05). The relative mRNA expression level of MTOR in PCNSL samples was significantly increased (P = 0.013). Correlation analysis revealed that the expression of p-mTOR was correlated with that of p-AKT, p-S6, p-4E-BP1. PTEN deletion was found in 18.9% of PCNSL samples and was correlated with the expression of p-AKT (P = 0.031). Correlation analysis revealed that the PCNSL relapse rate in the p-mTOR-positive group was 64.5%, significantly higher than that in the negative group (P = 0.001). Kaplan-Meier survival analysis showed inferior progression-free survival (PFS) in the p-mTOR- and p-S6-positive groups (P = 0.002 and 0.009, respectively), and PTEN deletion tended to be related to shorter overall survival (OS) (P = 0.072). Cox regression analysis revealed p-mTOR expression as an independent prognostic factor for a shorter PFS (hazard ratio (HR) =7.849, P = 0.046). CONCLUSIONS: Our results suggest that the PI3K/AKT/mTOR signaling pathway is aberrantly activated in PCNSL and associated with a poor prognosis, which might indicate new therapeutic targets and prognostic factors.

Cellular senescence: a promising therapeutic target in colorectal cancer.

Colorectal cancer is one of the most malignant cancers worldwide, and efforts have been made to elucidate the mechanism of colorectal carcinogenesis. Cellular senescence is a physiological process in cell life, but it is also found in cancer initiation and progression. Lines of evidence show that senescence may influence the development and progression of colorectal carcinogenesis. Here, the authors review the characteristics of senescence and the recent findings of a relationship between senescence and colorectal cancer.

Cancer is a leading cause of death worldwide; out of the top ten most common cancers in 2020, the incidence and mortality rate of colorectal cancer (CRC) ranked third and second, respectively. Based on statistics, it was estimated that more than 1.9 million CRC cases occurred in 2020. In terms of CRC, a prominent risk factor is age, and studies suggest that the aging process plays a role in CRC initiation and progression. This review discusses how aging contributes to CRC carcinogenesis and summarizes recent findings on potential therapeutics.

Combining MGMT promoter pyrosequencing and protein expression to optimize prognosis stratification in glioblastoma.

Pyrosequencing (PSQ) represents the golden standard for MGMT promoter status determination. Binary interpretation of results based on the threshold from the average of several CpGs tested would neglect the existence of the "gray zone". How to define the gray zone and reclassify patients in this subgroup remains to be elucidated. A consecutive cohort of 312 primary glioblastoma patients were enrolled. CpGs 74-81 in the promoter region of MGMT were tested by PSQ and the protein expression was assessed by immunohistochemistry (IHC). Receiver operating characteristic curves were constructed to calculate the area under the curves (AUC). Kaplan-Meier plots were used to estimate the survival rate of patients compared by the log-rank test. The optimal threshold of each individual CpG differed from 5% to 11%. Patients could be separated into the hypomethylated subgroup (all CpGs tested below the corresponding optimal thresholds, n = 126, 40.4%), hypermethylated subgroup (all CpGs tested above the corresponding optimal thresholds, n = 108, 34.6%), and the gray zone subgroup (remaining patients, n = 78, 25.0%). Patients in the gray zone harbored an intermediate prognosis. The IHC score instead of the average methylation levels could successfully predict the prognosis for the gray zone (AUC for overall survival, 0.653 and 0.519, respectively). Combining PSQ and IHC significantly improved the efficiency of survival prediction (AUC: 0.662, 0.648, and 0.720 for PSQ, IHC, and combined, respectively). Immunohistochemistry is a robust method to predict prognosis for patients in the gray zone defined by PSQ. Combining PSQ and IHC could significantly improve the predictive ability for clinical outcomes.

Genetic manipulation of primary human natural killer cells to investigate the functional and oncogenic roles of PRDM1.

Extra-nodal natural killer/T-cell lymphoma, nasal type (ENKTCL) is a highly aggressive lymphoma, where the tumor suppressor gene (TSG) PRDM1 is frequently lost/inactivated. We employed two different CRISPR/Cas9 approaches to generate PRDM1-/- primary NK cells to study its role in NK-cell homeostasis. PRDM1-/- NK cells showed a marked increase in cloning efficiency, higher proliferation rate and less apoptosis compared with their wild type counterparts. Gene expression profiling demonstrated a marked enrichment in pathways associated with proliferation, cell cycle, MYC, MYB and TCR/NK signaling in PRDM1-/- NK cells, but pathways associated with normal cellular functions including cytotoxic functions were down-regulated, suggesting that the loss of PRDM1 shifted NK cells toward proliferation and survival rather than the performance of its normal functions. We were also able to further modify a PRDM1 deleted clone to introduce heterozygous deletions of common TSG in ENKTCL such as TP53, DDX3X, or PTPN6. We have established an in vitro model to elucidate the major pathways through which PRDM1 mediates its homeostatic control of NK-cells. This approach can be applied to the study of other relevant genetic lesions and oncogenic collaborations in lymphoma pathogenesis.

Supratentorial high-grade astrocytoma with leptomeningeal spread to the fourth ventricle: a lethal dissemination with dismal prognosis.

PURPOSE: Leptomeningeal spread to the fourth ventricle (LSFV) from supratentorial high-grade astrocytoma (HGA) is rarely investigated. The incidence and prognostic merit of LSFV were analyzed in this study. METHODS: A consecutive cohort of 175 patients with pathologically diagnosed HGA according to the 2016 WHO classification of brain tumors was enrolled. LSFV was defined as radiological occupation in the fourth ventricle at the moment of initial progression. Clinical, radiological, and pathological data were analyzed to explore the difference between HGA patients with and without LSFV. RESULTS: There were 18 of 175 (10.3%) HGAs confirmed with LSFV. The difference of survival rate between patients with LSFV or not was significant in both overall survival (OS) (14.5 vs. 24 months, P = 0.0007) and post progression survival (PPS) (6.0 vs. 11.5 months, P = 0.0004), while no significant difference was observed in time to progression (TTP) (8.5 months vs. 9.5 months P = 0.6795). In the Cox multivariate analysis, LSFV was confirmed as an independent prognostic risk factor for OS (HR 2.06, P = 0.010). LSFV was correlated with younger age (P = 0.044), ventricle infringement of primary tumor (P < 0.001) and higher Ki-67 index (P = 0.013) in further analysis, and the latter two have been validated in the Logistic regression analysis (OR 18.16, P = 0.006; OR 4.04, P = 0.012, respectively). CONCLUSION: LSFV was indicative of end-stage for supratentorial HGA patients, which shortened patients' PPS and OS instead of TTP. It's never too cautious to alert this lethal event when tumor harbored ventricle infringement and higher Ki-67 index in routine clinical course.

Inflammatory myofibroblastic tumors of the nasal cavity and paranasal sinus: a clinicopathologic study of 25 cases and review of the literature.

Inflammatory myofibroblastic tumor (IMT) is rare in nasal cavity and paranasal sinus. The aim of this study was to describe the clinicopathological features of sinonasal IMT and analyze the relationship between the clinicopathological features and the prognosis. A retrospective study of 25 IMT patients between 2001 and 2012 was performed. Data on clinical features, treatment, and follow-up were recorded. The histological characters were observed. Overall survival (OS) and event-free survival (EFS) were estimated using the Kaplan-Meier method. Clinically, the most common symptoms were nasal obstruction, facial pain, and toothache. Twenty patients received follow-ups 6-120 months after initial diagnosis. Fifteen (75 %) developed recurrence 1 or more times. One patient had left cervical lymph node metastasis (5 %). Five patients died of the tumor (25 %). Histologically, the IMTs composed of bland spindle cells admixed with a prominent infiltrate of plasma cells and lymphocytes and showed obvious atypia in recurrent cases. Histology with necrosis, mitosis (≥1/10 HPF), ganglion-like cells, histological pattern I or II and relapse (≥4 times) was significantly associated with poor OS and EFS. IMT of the nasal cavity and paranasal sinuses exhibits relatively bland histologic appearances, but can shows strongly aggressive behavior and relatively poor outcomes. Multiple relapse, necrosis, frequent mitosis, the presence of ganglion-like cells, and histological pattern might be associated with poor clinical outcomes.

Wild-type K-ras has a tumour suppressor effect on carcinogen-induced murine colorectal adenoma formation.

K-ras mutations are found in ~40% of human colorectal adenomas and carcinomas and contribute to colorectal tumour formation at an early stage. Wild-type K-ras has been reported to be deleted in some tumours, but the consequences of changes in wild-type K-ras copy number for experimental colorectal carcinogenesis have not been investigated. To characterize the effects of K-ras copy number changes on formation of carcinogen-induced colorectal neoplasms in mice, wild-type (K-ras(+/+) ) and heterozygous K-ras exon 1 knockout (K-ras(+/-) ) mice were given 10 weekly treatments of 1, 2-dimethylhydrazine (DMH) to induce colorectal tumours. Colorectal expression levels of K-ras 4A and 4B transcripts in K-ras(+/-) mice were ~50% decreased compared with K-ras(+/+) mice. One year after DMH treatment, survival of K-ras(+/-) mice decreased from 88 to 82% compared with wild-type mice. Colorectal adenomas significantly increased from 0.52 ± 0.15 in K-ras(+/+) mice to 0.87 ± 0.14 in K-ras(+/-) mice (mean ± SEM per mouse, P < 0.01); total tumour volume increased 2.13-fold (P < 0.05). Comparing K-ras(+/+) with K-ras(+/-) murine adenomas, Ki-67-positive proliferating tumour cells significantly increased from 7.77 ± 0.64% to 9.15 ± 0.92% and cleaved caspase-3-positive apoptotic tumour cells decreased from 1.40 ± 0.37% to 0.80 ± 0.22% (mean ± SEM, P < 0.05 for both). No K-ras or B-raf mutations were detected in the adenomas. Immunohistochemical studies showed no significant changes in extracellular signal regulating kinase/mitogen-activated protein kinase (Erk/MapK) or PI3K/Akt pathway activation in the adenomas. In conclusion, the data collectively show that a 50% reduction in K-ras gene dosage and RNA expression promoted experimental colorectal tumourigenesis, consistent with wild-type K-ras having a tumour suppressor effect on carcinogen-induced murine colorectal adenoma formation.

Recurrent laryngeal inflammatory myofibroblastic tumor with positive anaplastic lymphoma kinase mimicking recurrent respiratory papillomatosis: a case report.

Inflammatory myofibroblastic tumor (IMT) of the larynx is an unusual lesion, particularly in the pediatric age group. Laryngeal IMTs in children follow a benign clinical course with reports of only rare recurrences and no metastases. Although anaplastic lymphoma kinase (ALK) has been associated with IMTs, there is only one pediatric laryngeal IMT reported to be ALK-positive with immunohistochemical staining. Here, we present a case of a 10-year-old boy with a laryngeal IMT that recurred four times and was misdiagnosed as recurrent respiratory papillomatosis after the initial three operations. ALK positivity was demonstrated by both immunohistochemical staining and fluorescence in situ hybridization. To the best of our knowledge, this case report is the first to describe a laryngeal IMT that recurred multiple times and was confirmed to be ALK-positive at the molecular level.

Computational pathology-based weakly supervised prediction model for MGMT promoter methylation status in glioblastoma.

Introduction: The methylation status of oxygen 6-methylguanine-DNA methyltransferase (MGMT) is closely related to the treatment and prognosis of glioblastoma. However, there are currently some challenges in detecting the methylation status of MGMT promoters. The hematoxylin and eosin (H&E)-stained histopathological slides have always been the gold standard for tumor diagnosis. Methods: In this study, based on the TCGA database and H&E-stained Whole slide images (WSI) of Beijing Tiantan Hospital, we constructed a weakly supervised prediction model of MGMT promoter methylation status in glioblastoma by using two Transformer structure models. Results: The accuracy scores of this model in the TCGA dataset and our independent dataset were 0.79 (AUC = 0.86) and 0.76 (AUC = 0.83), respectively. Conclusion: The model demonstrates effective prediction of MGMT promoter methylation status in glioblastoma and exhibits some degree of generalization capability. At the same time, our study also shows that adding Patches automatic screening module to the computational pathology research framework of glioma can significantly improve the model effect.

Single-cell analysis of tumor microenvironment and cell adhesion reveals that interleukin-1 beta promotes cancer cell proliferation in breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC), which is so called because of the lack of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2) receptors on the cancer cells, accounts for 10%-15% of all breast cancers. The heterogeneity of the tumor microenvironment is high. However, the role of plasma cells controlling the tumor migration progression in TNBC is still not fully understood. METHODS: We analyzed single-cell RNA sequencing data from five HER2 positive, 12 ER positive/PR positive, and nine TNBC samples. The potential targets were validated by immunohistochemistry. RESULTS: Plasma cells were enriched in TNBC samples, which was consistent with validation using data from The Cancer Genome Atlas. Cell communication analysis revealed that plasma cells interact with T cells through the intercellular adhesion molecule 2-integrin-aLb2 complex, and then release interleukin 1 beta (IL1B), as verified by immunohistochemistry, ultimately promoting tumor growth. CONCLUSION: Our results revealed the role of plasma cells in TNBC and identified IL1B as a new prognostic marker for TNBC.

Cavernous Malformation From Cranial Nerves: A Systematic Review With a Novel Classification and Patient-Level Analysis.

BACKGROUND AND OBJECTIVES: Cavernous malformations (CMs) occurring in the cranial nerve (CN) are extremely rare, and there is currently no comprehensive review on CN CMs, leading to a lack of sufficient understanding of CN CMs. We aimed to systematically review all published CN CM cases; summarize the epidemiology, clinical manifestations, treatment, and prognosis of CN CMs; and identify factors influencing the prognosis of CN CMs. METHODS: This systematic review identified all cases potentially diagnosed with CN CM through a systematic search of PubMed, SCOPUS, Web of Science, and Cochrane databases. This represents the most comprehensive systematic review to date. We classified CN CMs based on their anatomic origins. Patient characteristics, disease manifestations, treatment approaches, and prognosis were summarized descriptively. Further analysis was conducted to identify factors influencing the prognosis of CN CMs. RESULTS: The final analysis included 108 articles (127 individual patient cases). The optic nerve (49/128, 38.3%) is the most commonly affected nerve. Notably, CN CMs can be categorized into 3 types: Intraneural, Perineural, and Extraneural. Preoperative nerve function status and novel classification were associated with the prognosis of CN CMs (P = .001; P < .001). The postoperative neurological deterioration rate for the Intraneural type was 19/37 (51.4%); for the Extraneural type, it was 13/69 (18.8%); and for the Perineural type, it was 1/22 (4.5%) (P < .001). CONCLUSION: We reviewed all the published CN CMs to date, offering a comprehensive description of CN CMs for the first time and identifying prognostic factors. The classification of CN CMs proposed in this study could serve as guidance for the selection of intraoperative treatment regimens. The findings of this systematic review are expected to provide a foundation for clinical decision-making in this crucial rare disease and lay the groundwork for developing relevant clinical guidelines.

Dystonia, spastic tetraplegia, and ataxia due to a novel mutation in the dynamin domain of OPA1.

Movement disorders manifest in various hereditary neurodegenerative diseases. We reported a young man who presented with progressive upper limb dystonia, spastic tetraplegia, and ataxia. Whole-exome sequencing (WES) revealed a novel variant, c.2357A > G, in the dynamin domain of OPA1. No mtDNA deletion was detected in muscle by long-range PCR. Atrophy and decreased glucose metabolism of the basal ganglia were discovered. Decreased mtDNA copy number, fragmented mitochondria, slightly impaired oxidative phosphorylation, and increased autophagy were detected in mutant fibroblasts. Evident oxidative phosphorylation impairment and mtDNA deletions were not involved in the pathogenicity of this mutation unlike mutations in the GTPase domain of OPA1.

Zanubrutinib delays selinexor resistance evolution in biopsy sample-derived primary central nervous system lymphoma models.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive lymphoma of the brain with poor prognosis. The scarcity of cell lines established using PCNSL makes it difficult to conduct preclinical studies on new drugs. We aimed to explore the effect of selinexor combined with zanubrutinib in PCNSL using established PCNSL cells and an orthotopic PCNSL model. Primary PCNSL cells were successfully cultured. Selinexor inhibited proliferation, induced G1 phase arrest, and promoted apoptosis, however, induced drug resistance in PCNSL. Selinexor combined with zanubrutinib had a synergistic effect on PCNSL and prevented the onset of selinexor resistance in PCNSL by inhibiting AKT signaling. Moreover, selinexor combined with zanubrutinib notably slowed tumor growth and prolonged survival compared to that of the control. Overall, the addition of zanubrutinib to selinexor monotreatment had a synergistic effect in vitro and prolonged survival in vivo.