Hydroxyphenylpyruvate Dioxygenase Is a Metabolic Immune Checkpoint for UTX-deficient Colorectal Cancer.

BACKGROUND & AIMS: Aberrant epigenetic events mediated by histone methyltransferases and demethylases contribute to malignant progression of colorectal cancer (CRC). However, the role of the histone demethylase ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) in CRC remains poorly understood. METHODS: UTX conditional knockout mice and UTX-silenced MC38 cells were used to investigate UTX function in tumorigenesis and development of CRC. We performed time of flight mass cytometry to clarify the functional role of UTX in remodeling immune microenvironment of CRC. To investigate metabolic interaction between myeloid-derived suppressor cells (MDSCs) and CRC, we analyzed metabolomics data to identify metabolites secreted by UTX-deficient cancer cells and taken up by MDSCs. RESULTS: We unraveled a tyrosine-mediated metabolic symbiosis between MDSC and UTX-deficient CRC. Loss of UTX in CRC resulted in methylation of phenylalanine hydroxylase, preventing its degradation and subsequently increasing tyrosine synthesis and secretion. Tyrosine taken up by MDSCs was metabolized to homogentisic acid by hydroxyphenylpyruvate dioxygenase. Homogentisic acid modified protein inhibitor of activated STAT3 via carbonylation of Cys 176, and relieved the inhibitory effect of protein inhibitor of activated STAT3 on signal transducer and activator of transcription 5 transcriptional activity. This in turn, promoted MDSC survival and accumulation, enabling CRC cells to acquire invasive and metastatic traits. CONCLUSIONS: Collectively, these findings highlight hydroxyphenylpyruvate dioxygenase as a metabolic checkpoint to restrict immunosuppressive MDSCs and to counteract malignant progression of UTX-deficient CRC.

Magnetic resonance imaging with upconversion nanoprobes capable of crossing the blood-cerebrospinal fluid barrier.

The central nervous system (CNS) maintains homeostasis with its surrounding environment by restricting the ingress of large hydrophilic molecules, immune cells, pathogens, and other external harmful substances to the brain. This function relies heavily on the blood-cerebrospinal fluid (B-CSF) and blood-brain barrier (BBB). Although considerable research has examined the structure and function of the BBB, the B-CSF barrier has received little attention. Therapies for disorders associated with the central nervous system have the potential to benefit from targeting the B-CSF barrier to enhance medication penetration into the brain. In this study, we synthesized a nanoprobe ANG-PEG-UCNP capable of crossing the B-CSF barrier with high targeting specificity using a hydrocephalus model for noninvasive magnetic resonance ventriculography to understand the mechanism by which the CSF barrier may be crossed and identify therapeutic targets of CNS diseases. This magnetic resonance nanoprobe ANG-PEG-UCNP holds promising potential as a safe and effective means for accurately defining the ventricular anatomy and correctly locating sites of CSF obstruction.

Distinct macrophage polarization in acute and chronic gout.

Macrophage polarization mediates the development of inflammatory diseases. However, the polarization status at various stages of gout is not fully understood. Our study aimed to define the evolution of macrophage polarization in acute and chronic gout. Normal human synovium and synovium with tophi were collected for immunofluorescence (IF). Rat gouty joints were collected for joint thickness assessment and pathological evaluation. Tissue mRNA expression of inducible nitric oxide synthase (iNOS) and arginase-1 (Arg-1) were evaluated. Mouse peritoneal macrophages and THP-1 derived macrophages were stimulated by monosodium urate (MSU) crystals and were collected for detection of interleukin (IL) -1ß and IL-37 levels and iNOS/Arg-1 ratio. Arg-1 and IL-37 were highly expressed in normal synovium and synovium with tophi. In rat gouty joints, the inflammatory cell counts and ankle thickness began to increase at 2 h, peaked at 24 h, and was decreased spontaneously. An increase in macrophages preceded the neutrophils infiltration. Infiltration of M1 was positively related with the severity of arthritis. M2 appeared in an early stage (at 2 h) of inflammation. The number of M1 macrophages was comparable to that of M2 from 2 to 12 h and exceeded M2 number at 18 h and 24 h. The ratios of M2/M1 reversed at 48 h and remained reversed until 120 h. In mice gouty joints, iNOS/Arg-1 mRNA ratio was significantly higher than the that in control group at 8 h. The proportion of neutrophils and M1-macrophages reached peak at 4 h in mice model with peritoneal gout. Concentration of IL-1ß and ratio of iNOS/Arg-1 were increased at 6 h, peaked at 48 h, and were then decreased at 72 h in vitro, while the concentration of IL-37 peaked at 2 h and then decreased. In summary, altered macrophage polarization was observed in various stages of gouty inflammation. Macrophages in acute gout were polarized into M1 at early stage and into M2 at later stage while the macrophages in chronic gout mainly were only polarized towards M2. The number of M1 rose with the progression of inflammation. Early increase of M2 was observed, which might be generated directly from M0.

Targeting oxidative pentose phosphate pathway prevents recurrence in mutant Kras colorectal carcinomas.

Recurrent tumors originate from cancer stem cells (CSCs) that survive conventional treatments. CSCs consist of heterogeneous subpopulations that display distinct sensitivity to anticancer drugs. Such a heterogeneity presents a significant challenge in preventing tumor recurrence. In the current study, we observed that quiescent CUB-domain-containing protein 1 (CDCP1)+ CSCs are enriched after chemotherapy in mutant Kirsten rat sarcoma viral oncogene homolog (Kras) colorectal carcinomas (CRCs) and serve as a reservoir for recurrence. Mechanistically, glucose catabolism in CDCP1+ CSCs is routed to the oxidative pentose phosphate pathway (PPP); multiple cycling of carbon backbones in the oxidative PPP potentially maximizes NADPH reduction to counteract chemotherapy-induced reactive oxygen species (ROS) formation, thereby allowing CDCP1+ CSCs to survive chemotherapeutic attack. This is dependent on silent mating type information regulation 2 homolog 5 (Sirt5)-mediated inhibition of the glycolytic enzyme triosephosphate isomerase (TPI) through demalonylation of Lys56. Blocking demalonylation of TPI at Lys56 increases chemosensitivity of CDCP1+ CSCSs and delays recurrence of mutant Kras CRCs in vivo. These findings pinpoint a new therapeutic approach for combating mutant Kras CRCs.

A case of Lymphoplasmacyte-rich meningioma mimicking pachymeningitis.

BACKGROUND: Lymphoplasmacyte-rich meningioma (LPRM) is a rare form of meningioma characterized by prominent lymphoplasmacytic infiltrates into the tumor. Report of flat growth of LPRM mimicking pachymeningitis is rare in the literature. CASE PRESENTATION: A 55-year-old female who suffered from episodes of headache and seizures has been diagnosed with pachymeningitis for 4 years because post contrast brain MRI demonstrated enhanced carpet-like dura lesion in the left frontal lobe. The lesion kept unchanged on yearly follow-ups until a recent brain MRI found the lesion grew significantly into a mass. The lesion was resected and pathology suggested LPRM. CONCLUSION: LPRM may present as carpet-like growth pattern on MRI. Long-term follow-up in patients with pachymeningitis is necessary.

How I do it: Surgical Resection of a Recurrent Chondromyxoid Fibroma by Micro-Endoscopic Combination Technique.

BACKGROUND: The surgical resection of the tumor spreading into the cavernous sinus (CS) is complicated and challenging. METHOD: We report a left recurrent CS chondromyxoid fibroma occupying the clival-petrous apex-parasellar-suprasellar area, which was totally removed by the micro-endo combination technique via the middle cranial fossa extradural approach. CONCLUSION: This case demonstrates the value of the micro-endoscopic combination technique for complicated skull base surgery.

Paraganglioma of the cauda equina: A clinicopathologic study of 12 cases with demonstration of cytokeratin positivity.

Paragangliomas are rare neuroendocrine tumors originating from neural crest-derived paraganglion cells. Primary cauda equina paraganglioma (CEP) pose both diagnostic and surgical challenges. We report 12 cases of CEP to characterize the diagnostic and operative approach to these rare tumors. 12 cases with primary CEP were studied; 5 patients were male (41.7%) and 7 were female (56.3%). The median age was 44 years (range: 15-64 years). The most common symptom was lower back pain of variable duration. Radiologically, the lesions were intradural and extramedullary with well-defined margins, and ranged from 1 to 4.5 cm. in diameter (mean: 1.65 cm). 9 tumors were composed of sheets and nests of cells with a neuroendocrine pattern and intense vascularity and displayed a characteristic Zellballen pattern. Interestingly, CAM 5.2 was diffusely or focally positive with a dot-like or membrane pattern in 8/11 cases (72.7%). Similarly, CK was diffusely or focally positive with membrane and cytoplasmic staining or with a dot-like pattern in 7/11 (63.6%) and 2/11 cases (18.2%). None of the cases showed deletion of SDHB nor expression of GATA3. CEP can display aberrant keratin positivity, and this should be considered in the differential diagnosis of these lesions. This finding also raises the possibility that CEP may be an entirely different entity than non-spinal paragangliomas.

Supratentorial Extraventricular Ependymomas: Imaging Features and the Added Value of Apparent Diffusion Coefficient.

OBJECTIVE: To improve the understanding and the diagnosis of intracranial ependymal tumors. METHODS: The clinical, radiological and prognostic features of 48 supratentorial extraventricular ependymomas and 74 intraventricular ependymomas were summarized and compared. RESULTS: Supratentorial extraventricular ependymomas, most often located in the frontal lobe (33.3%) and classified as grade III (75.0%), had relatively large eccentric cysts (3.07 ± 2.03 cm), significant enhancement (84.8%), low apparent diffusion coefficient (ADC) values, and associated with higher mortality (41.3%). The majority of intraventricular lesions occurred in the fourth ventricle (86.5%) and classified as grade II (78.4%), had relatively small and multiple cystic changes (1.04 ± 0.87 cm), slight or moderate enhancement (76.9%), high ADC values and associated with lower mortality (20.7%). There were few significant differences between grade II and grade III tumors in these 2 groups, respectively. Young age, high grade and low ADC values are worse prognostic indicators for patients with supratentorial extraventricular ependymomas, but not for those with intraventricular ependymomas. CONCLUSIONS: Conventional radiological features, combined with clinical manifestations and quantitative information provided by diffusion-weighted imaging, may not only enhance the diagnosis and assist in determining prognosis but also provide a better pathophysiological understanding of intracranial ependymal tumors.

The role of carbonic anhydrase III and autophagy in type 2 diabetes with cardio-cerebrovascular disease.

Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases among the elderly people. The T2DM increases the risk of cardio-cerebrovascular disease (CCD), and the main pathological change of the CCD is atherosclerosis (AS). Meanwhile, the carbonic anhydrases (CAs) are involved in the formation and progression of plaques in AS. However, the exact physiological mechanism of carbonic anhydrase III (CAIII) has not been clear yet, and there are also no correlation study between CAIII protein and T2DM with CCD. The 8-week old diabetic mice (db/db-/- mice) and wild-type mice (wt mice) were feed by a normal diet till 32 weeks, and detected the carotid artery vascular opening angle using the method of biomechanics; The changes of cerebral cortex and myocardium were watched by the ultrastructure, and the autophagy were observed by electron microscope; The tissue structure, inflammation and cell injury were observed by Hematoxylin and eosin (HE) staining; The apoptosis of cells were observed by TUNEL staining; The protein levels of CAIII, IL-17, p53 were detected by immunohistochemical and Western Blot, and the Beclin-1, LC3, NF-κB were detected by Western Blot. All statistical analysis is performed using PRISM software. Compared with wt mice, db/db-/- mice' carotid artery open angle increased significantly. Electron microscope results indicated that autophagy in db/db-/- mice cerebral cortex and heart tissue decreased and intracellular organelle ultrastructure were damaged. HE staining indicated that, db/db-/- mice' cerebral cortex and heart tissue stained lighter, inflammatory cells infiltration, cell edema were obvious, myocardial fibers were disorder, and myocardial cells showed different degrees of degeneration. Compared with wt mice, TUNEL staining showed that there was obviously increase in db/db-/- mice cortex and heart tissue cell apoptosis. The results of immunohistochemistry and Western Blot indicated that CAIII, Beclin-1 and LC3II/I expression levels conspicuously decreased in cortex and heart tissue of db/db-/- mice, and the expression level of IL-17, NF-κB and p53 obviously increased. The carotid artery' vascular stiffness was increased and which was probably related with formation of AS in diabetic mice. And the autophagy participated in the occurrence and development of diabetic CCD. CAIII protein might somehow be involved in the regulation of autophagy probably through affecting cell apoptosis and inflammation, but the underlying mechanism remains to be further studied.

Comparison of non-invasive models for predicting liver damage in chronic hepatitis B patients.

INTRODUCTION: Inexpensive blood tests have been well established as alternatives to liver biopsies to evaluate liver fibrosis in CHB patients. Here, we aim to compare their diagnostic accuracy in assessing liver fibrosis and necroinflammation. PATIENTS AND METHODS: A retrospective study was performed to evaluate the predictive value of non-invasive models in chronic hepatitis B patients with liver fibrosis by the area under receiver operating characteristic curve (AUROC). The clinical data of 160 patients were collected from medical records. RESULTS: Of the 160 consecutive treatment-naïve CHB patients, 29 (16%) had significant fibrosis and 34 (21%) had severe necroinflammation. The AUROC of the gamma-glutamyl transpeptidase to platelet ratio (GPR) (0.761, 95% CI 0.671-0.850) for predicting significant fibrosis was significantly higher than that of the aspartate transaminase-to-platelet ratio index (APRI) (0.680, 95% CI 0.585-0.774, p=0.034), but comparable with the fibrosis index based on four factors (Fib-4) (0.746, 95% CI 0.656-0.836, p=0.703), while for predicting severe necroinflammation, the performance of the GPR (AUROC=0.869, 95% CI 0.800-0.937) was better than the APRI (AUROC=0.816, 95% CI 0.740-0.892, p=0.085) and Fib-4 (0.792, 95% CI 0.711-0.873, p=0.023). DISCUSSION: GPR is a satisfactory model to stage liver fibrosis and to grade necroinflammation activity, representing a convenient non-invasive alternative to liver biopsy in China.

EGb761 improves the cognitive function of elderly db/db-/- diabetic mice by regulating the beclin-1 and NF-κB signaling pathways.

To assess whether EGb761 could protect elderly diabetic mice with cognitive disorders and explore the role of beclin-1-mediated autophagy in these protective effects. Two-month-old male db/db-/- mice and wild-type C57/BL6 mice were randomly divided into six groups: db/db-/- control, db/db-/- 50 mg, db/db-/- 100 mg, wild-type (WT) control, WT 50 mg, and WT 100 mg. EGb761 (50 mg/kg or 100 mg/kg of bodyweight) was given by gavage once a day for 1 month from the age of 6 months. Y-maze and social choice tests were performed at 8th months. The blood pressure was measured. The imaging changes in the brain were measured using magnetic resonance imaging (MRI). The expression and distribution of beclin-1, LC3, and NF-κB were detected using immunohistochemistry staining and western blotting. Ultrastructure alterations in the hippocampus were observed using transmission electron microscopy. Compared with WT mice, the learning ability, memory and overall cognitive function of db/db-/- mice decreased (P < 0.05), and EGb761 could significantly improve the learning and memory function of db/db-/- mice (P < 0.05). EGb761 significantly improved systolic blood pressure in db/db-/- mice (P < 0.01). In addition, fMRI-bold showed a decline in the hippocampus of mice in the db/db-/- group compared with WT. EGb761 could improve these above changes. Immunohistochemistry staining and western blotting confirmed that EGb761 significantly increased beclin-1 and reduced LC3-II/I levels in the brains of db/db-/- mice (P < 0.05). NF-κB levels were obviously higher in the db/db-/- group than that in the WT group, and EGb761 significantly reduced NF-κB levels in db/db-/- mice (P < 0.05). There was a trend of increased autophagosomes in db/db-/- mice, but EGb761 did not change obviously the number of autophagosomes. Compared with normal aged WT mice, aging db/db-/- mice had more common complications of cerebral small vessel disease and cognitive dysfunction. EGb761 could significantly improve the cognitive function of aging db/db-/- mice via a mechanism that may involve the regulation of beclin-1, LC3, and NF-κB.

Multiple deep white matter lesions mimic multiple sclerosis as an unusual complication of left atrial myxoma.

We report the case of a patient who developed right hemiparesis with an acute onset 2 weeks before being transferred to our hospital. The brain MRI revealed multiple lesions in deep white matter; some were ovoid and perpendicular to the lateral ventricle, typical of cerebral demyelinating disease such as multiple sclerosis. The patient reported no history of hypertension, diabetes, dyslipidemia or other conventional vascular risk factors. The initial diagnosis was clinically isolated syndrome. However, low fever and petechiae in the extremities developed during hospitalization, which reminded us of cardioembolism. Echocardiography finally revealed a left atrial myxoma. The patient's symptom alleviated after resection of the tumor.

Isolation and phenotypic characterization of colorectal cancer stem cells with organ-specific metastatic potential.

BACKGROUND & AIMS: Migrating cancer stem cells (MCSCs) are believed to form metastases. We sought to identify markers of MCSCs from human colorectal cancers (CRCs) and determine their roles in organ-specific metastasis. METHODS: To identify colorectal MCSCs that contribute to organ-specific metastasis, we developed a model of liver or lung metastasis using primary tumor cells from patients with CRC who had liver and lung metastases. Distinct organ-specific metastatic cells were isolated by 6 cycles of selecting for cells that formed liver and lung tumors after subcutaneous injection into mice. Microarray analysis was used to identify markers of the organ-specific MCSCs. We then measured levels of these markers in CRC cell lines and 128 CRC samples. We characterized the functional roles of these markers in organ-specific metastasis. RESULTS: We identified CD110 and CDCP1 as cell surface markers of MCSCs from human colorectal tumors that metastasized to liver and lung. We observed a distinct pattern of CD110 and CDCP1 in a panel of primary colorectal tumor samples and their matched liver or pulmonary metastases, indicating that these proteins might serve as biomarkers of organ-specific metastasis. Functional studies showed that thrombopoietin attracts CD110(+) CSCs and increases their self-renewal to promote formation of liver metastases. CDCP1 promoted adhesion of CRC cells to the lung endothelium. CONCLUSIONS: We isolated MCSCs from primary human CRCs and found that the CD110(+) and CDCP1(+) subpopulations mediate organ-specific metastasis. These findings might be used to aid in selection of patients for postoperative adjuvant therapy.

The prognostic value of Foxp3+ tumor-infiltrating lymphocytes in patients with glioblastoma.

Forkhead box protein 3 (Foxp3) is known as a specific marker for regulatory T cells which contribute to immunosuppression in tumor microenvironment. However, existing studies regarding clinical significance of Foxp3+ tumor-infiltrating lymphocytes (TILs) in glioblastoma (GBM) remained discrepant. In this study, we aimed to explore whether this subtype of TILs correlated with prognosis in patients with GBM. Foxp3+ TILs as well as CD8+ ones were detected by immunohistochemistry on paraffin-embedded tumor samples from 62 patients. Staining for p53, MGMT and Ki-67 were also performed. The correlation of TIL subtypes with clinicopathologic features were analyzed. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method and compared using log-rank test. Independent prognostic factors for PFS and OS were determined through univariate and multivariate analysis. Significant correlation was found between Foxp3 and CD8 expression (P = 0.003), but not between TIL subtypes and clinicopathologic characteristics. Patients with higher density of Foxp3+ TILs showed relatively shorter PFS (P < 0.001) and OS (P = 0.003) whereas patients with higher density of CD8+ TILs obtained no significant differences in survival. Survival analysis based on molecular classifications further clarified these predictive values. Univariate and multivariate analysis revealed that frequency of Foxp3+ TILs was probably associated with both PFS (P = 0.002) and OS (P = 0.003). In conclusion, the results suggest that Foxp3 positive infiltrates could provide an independent predictive factor in GBM.

A universal multiple instance learning framework for whole slide image analysis.

BACKGROUND: The emergence of digital whole slide image (WSI) has driven the development of computational pathology. However, obtaining patch-level annotations is challenging and time-consuming due to the high resolution of WSI, which limits the applicability of fully supervised methods. We aim to address the challenges related to patch-level annotations. METHODS: We propose a universal framework for weakly supervised WSI analysis based on Multiple Instance Learning (MIL). To achieve effective aggregation of instance features, we design a feature aggregation module from multiple dimensions by considering feature distribution, instances correlation and instance-level evaluation. First, we implement instance-level standardization layer and deep projection unit to improve the separation of instances in the feature space. Then, a self-attention mechanism is employed to explore dependencies between instances. Additionally, an instance-level pseudo-label evaluation method is introduced to enhance the available information during the weak supervision process. Finally, a bag-level classifier is used to obtain preliminary WSI classification results. To achieve even more accurate WSI label predictions, we have designed a key instance selection module that strengthens the learning of local features for instances. Combining the results from both modules leads to an improvement in WSI prediction accuracy. RESULTS: Experiments conducted on Camelyon16, TCGA-NSCLC, SICAPv2, PANDA and classical MIL benchmark datasets demonstrate that our proposed method achieves a competitive performance compared to some recent methods, with maximum improvement of 14.6 % in terms of classification accuracy. CONCLUSION: Our method can improve the classification accuracy of whole slide images in a weakly supervised way, and more accurately detect lesion areas.

Clinically Available and Reproducible Prediction Models for IDH and CDKN2A/B Gene Status in Adult-type Diffuse Gliomas.

PURPOSE: Isocitrate dehydrogenase (IDH) and cyclin-dependent kinase inhibitor (CDKN) 2A/B status holds important prognostic value in diffuse gliomas. We aimed to construct prediction models using clinically available and reproducible characteristics for predicting IDH-mutant and CDKN2A/B homozygous deletion in adult-type diffuse glioma patients. MATERIALS AND METHODS: This retrospective, two-center study analysed 272 patients with adult-type diffuse glioma (230 for primary cohort and 42 for external validation cohort). Two radiologists independently assessed the patients' images according to the Visually AcceSAble Rembrandt Images (VASARI) feature set. Least absolute shrinkage and selection operator (LASSO) regression analysis was used to optimise variable selection. Multivariable logistic regression analysis was used to develop the prediction models. Calibration plots, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA) were used to validate the models. Nomograms were developed visually based on the prediction models. RESULTS: The interobserver agreement between the two radiologists for VASARI features was excellent (κ range, 0.813-1). For the IDH-mutant prediction model, the area under the curves (AUCs) was 0.88-0.96 in the internal and external validation sets, For the CDKN2A/B homozygous deletion model, the AUCs were 0.80-0.86 in the internal and external validation sets. The decision curves show that both prediction models had good net benefits. CONCLUSION: The prediction models which basing on VASARI and clinical features provided a reliable and clinically meaningful preoperative prediction for IDH and CDKN2A/B status in diffuse glioma patients. These findings provide a foundation for precise preoperative non-invasive diagnosis and personalised treatment approaches for adult-type diffuse glioma patients.

Methionine secreted by tumor-associated pericytes supports cancer stem cells in clear cell renal carcinoma.

Here, we identify a subset of vascular pericytes, defined by expression of platelet-derived growth factor receptor beta (PDGFR-ß) and G-protein-coupled receptor 91 (GPR91), that promote tumorigenesis and tyrosine kinase inhibitors (TKIs) resistance by functioning as the primary methionine source for cancer stem cells (CSCs) in clear cell renal cell carcinoma (ccRCC). Tumor-cell-derived succinate binds to GPR91 on pericyte to activate autophagy for methionine production. CSCs use methionine to create stabilizing N6-methyladenosine in ATPase-family-AAA-domain-containing 2 (ATAD2) mRNA, and the resulting ATAD2 protein complexes with SRY-box transcription factor 9 to assemble super enhancers and thereby dictate its target genes that feature prominently in CSCs. Targeting PDGFR-ß+GPR91+ pericytes with specific GRP91 antagonists reduce intratumoral methionine level, eliminate CSCs, and enhance TKIs sensitivity. These results unraveled the mechanisms by which PDGFR-ß+GPR91+ pericytes provide supportive niche for CSCs and could be used to develop targets for treating ccRCC.

Abundant infiltration of B cells and plasma cells in brain biopsy of a male patient with severe anti-NMDA receptor encephalitis: A case report.

RATIONALE: Anti-N-methyl-D-aspartate receptor (NMDAR) is the most common type of autoimmune encephalitis mediated by NMDAR antibodies. The pathological process remains unclear, especially in patients without tumors or infections. Autopsy and biopsy studies have rarely been reported because of the favorable prognosis. Pathological findings generally demonstrate mild-to-moderate inflammation. This case report presents severe anti-NMDAR encephalitis in a 43-year-old man without any identified triggers. The biopsy in this patient showed extensive inflammatory infiltration with evident B cell accumulation, which enriches the pathological study of male anti-NMDAR encephalitis patients without comorbidities. PATIENT CONCERNS: A 43-year-old previously healthy man presented with new-onset seizures with recurrent jerks. The initial autoimmune antibody test with serum and cerebrospinal fluid yielded negative results. After ineffective treatment for viral encephalitis, based on the imaging results indicating the possibility of diffuse glioma, the patient underwent a brain biopsy in the right frontal lobe to rule out malignancy. DIAGNOSIS: The immunohistochemical study showed extensive inflammatory cell infiltration, consistent with the pathological changes in encephalitis. Cerebrospinal fluid and serum samples were then retested and tested positive for IgG antibodies against NMDAR. Therefore, the patient was diagnosed with anti-NMDAR encephalitis. INTERVENTIONS: The patient was administered intravenous immunoglobulin (0.4 g/kg/d for 5 days), intravenous methylprednisolone (1 g/d for 5 days, 500 mg/d for 5 days, subsequently reduced to oral administration), and intravenous cyclophosphamide cycles. OUTCOMES: The patient developed refractory epilepsy 6 weeks later and required mechanical ventilation. Despite brief clinical improvement after extensive immunotherapy, the patient died from bradycardia and circulation. LESSONS: Anti-NMDAR encephalitis cannot be ruled out even if the initial autoantibody test result is negative. For progressive encephalitis of unknown etiology, it is necessary to recheck cerebrospinal fluid for anti-NMDAR antibodies.

Primary papillary epithelial tumor of the sella and posterior pituitary tumor show similar (epi)genetic features and constitute a single neuro-oncological entity.

BACKGROUND: "Primary papillary epithelial tumor of the sella (PPETS)" is a recently described rare tumor entity of the central nervous system (CNS) with stereotypic location in the sella. Comprehensive molecular investigations and epigenetic profiles of PPETS have not been performed to date. METHODS: We report a comprehensive clinical, histopathologic, and molecular assessment of 5 PPETS cases in comparison with a cohort composed of 7 choroid plexus papilloma (CPP), 7 central neurocytoma (CN), 15 posterior pituitary tumor (PPT) including 4 pituicytoma, 6 granular cell tumors of the sellar region (GCT), and 5 spindle cell oncocytoma. RESULTS: All PPETS had good outcomes. Immunohistochemically, PPETS tumors showed positive staining with TTF1, EMA, AE1/AE3, MAP2, and Vimentin, but were negatively stained with Syn, GFAP, CgA, and S100, and sporadically stained with Ki-67. In unsupervised hierarchical clustering and t-distributed stochastic neighbor embedding analyses of DNA-methylation data, PPETS and PPT tumors formed a distinct cluster irrespective of their histologic types. However, PPETS tumors did not cluster together with CPP and CN samples. Similar findings were obtained when our samples were projected into the reference cohort of the brain tumor classifier. Substantial fractions of the PPETS and PPT tumors shared broadly similar chromosomal copy number alterations. No mutations were detected using targeted next-generation sequencing. CONCLUSIONS: Though more cases are needed to further elucidate the molecular pathogenesis of these tumors, our findings indicate that PPETS and PPT tumors may constitute a single neurooncological entity.