Enrichment of infection-associated bacteria in the low biomass brain bacteriota of Alzheimer's disease patients.

Alzheimer's disease (AD) is a neurodegenerative disease accompanied by neuroimmune inflammation in the frontal cortex and hippocampus. Recently, the presence of bacteria in AD-affected brains has been documented, prompting speculation about their potential role in AD-associated neuroinflammation. However, the characterization of bacteriota in human brains affected by AD remains inconclusive. This study aimed to investigate potential associations between specific bacteria and AD pathology by examining brain tissues from AD-associated neurodegenerative regions (frontal cortex and hippocampus) and the non-AD-associated hypothalamus. Employing 16S rRNA gene sequencing, 30 postmortem brain tissue samples from four individuals with normal brain histology (N) and four AD patients were analyzed, along with three blank controls. A remarkably low biomass characterized the brain bacteriota, with their overall structures delineated primarily by brain regions rather than the presence of AD. While most analyzed parameters exhibited no significant distinction in the brain bacteriota between the N and AD groups, the unique detection of Cloacibacterium normanense in the AD-associated neurodegenerative regions stood out. Additionally, infection-associated bacteria, as opposed to periodontal pathogens, were notably enriched in AD brains. This study's findings provide valuable insights into potential link between bacterial infection and neuroinflammation in AD.

Clinical Practice Recommendations for the Use of Next-Generation Sequencing in Patients with Solid Cancer: A Joint Report from KSMO and KSP.

In recent years, next-generation sequencing (NGS)-based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing.

A selective ER-phagy exerts neuroprotective effects via modulation of α-synuclein clearance in parkinsonian models.

The endoplasmic reticulum (ER) is selectively degraded by ER-phagy to maintain cell homeostasis. α-synuclein accumulates in the ER, causing ER stress that contributes to neurodegeneration in Parkinson's disease (PD), but the role of ER-phagy in α-synuclein modulation is largely unknown. Here, we investigated the mechanisms by which ER-phagy selectively recognizes α-synuclein for degradation in the ER. We found that ER-phagy played an important role in the degradation of α-synuclein and recovery of ER function through interaction with FAM134B, where calnexin is required for the selective FAM134B-mediated α-synuclein clearance via ER-phagy. Overexpression of α-synuclein in the ER of the substantia nigra (SN) resulted in marked loss of dopaminergic neurons and motor deficits, mimicking PD characteristics. However, enhancement of ER-phagy using FAM134B overexpression in the SN exerted neuroprotective effects on dopaminergic neurons and recovered motor performance. These data suggest that ER-phagy represents a specific ER clearance mechanism for the degradation of α-synuclein.

Proteomic analysis predicts anti-angiogenic resistance in recurred glioblastoma.

BACKGROUND: Recurrence is common in glioblastoma multiforme (GBM) because of the infiltrative, residual cells in the tumor margin. Standard therapy for GBM consists of surgical resection followed by chemotherapy and radiotherapy, but the median survival of GBM patients remains poor (~ 1.5 years). For recurrent GBM, anti-angiogenic treatment is one of the common treatment approaches. However, current anti-angiogenic treatment modalities are not satisfactory because of the resistance to anti-angiogenic agents in some patients. Therefore, we sought to identify novel prognostic biomarkers that can predict the therapeutic response to anti-angiogenic agents in patients with recurrent glioblastoma. METHODS: We selected patients with recurrent GBM who were treated with anti-angiogenic agents and classified them into responders and non-responders to anti-angiogenic therapy. Then, we performed proteomic analysis using liquid-chromatography mass spectrometry (LC-MS) with formalin-fixed paraffin-embedded (FFPE) tissues obtained from surgical specimens. We conducted a gene-ontology (GO) analysis based on protein abundance in the responder and non-responder groups. Based on the LC-MS and GO analysis results, we identified potential predictive biomarkers for anti-angiogenic therapy and validated them in recurrent glioblastoma patients. RESULTS: In the mass spectrometry-based approach, 4957 unique proteins were quantified with high confidence across clinical parameters. Unsupervised clustering analysis highlighted distinct proteomic patterns (n = 269 proteins) between responders and non-responders. The GO term enrichment analysis revealed a cluster of genes related to immune cell-related pathways (e.g., TMEM173, FADD, CD99) in the responder group, whereas the non-responder group had a high expression of genes related to nuclear replisome (POLD) and damaged DNA binding (ERCC2). Immunohistochemistry of these biomarkers showed that the expression levels of TMEM173 and FADD were significantly associated with the overall survival and progression-free survival of patients with recurrent GBM. CONCLUSIONS: The candidate biomarkers identified in our protein analysis may be useful for predicting the clinical response to anti-angiogenic agents in patients with recurred GBM.

Expression of Inflammatory Markers in the Muscles of Patients with Idiopathic Inflammatory Myopathy According to the Presence of Interstitial Lung Disease.

BACKGROUND: Several studies have identified factors associated with the development of interstitial lung disease (ILD) in patients with idiopathic inflammatory myopathies (IIMs). However, few have assessed the association between ILD and muscle biopsy findings, including inflammatory marker expressions analyzed using immunohistochemistry (IHC). METHODS: Muscle biopsies from patients who were newly diagnosed with IIMs between 2000 and 2017 were reviewed. ILD was diagnosed based on chest computed tomography findings at the time of diagnosis of IIMs. IHC staining was performed for CD3, CD4, CD8, CD20, CD68, CD163, MX1, MHC class I, and HLA-DR. The factors associated with the presence of ILD were evaluated by logistic regression analysis. RESULTS: Of the 129 patients with IIM, 49 (38%) had ILD. In the muscle biopsy findings, CD4 expression, MX1 expression on immune cells, and expression of MHC class I and HLA-DR on myofibers were more common in patients with ILD than those without. In the logistic regression analysis, the HLA-DR expression on myofibers was significantly associated with the risk of ILD (OR, 2.39; 95% CI, 1.24-4.90, p = 0.012) after adjusting for pathologic findings, clinical features, and autoantibodies. CONCLUSION: The expression of HLA-DR on myofibers was associated with the presence of ILD in patients with IIM.

GPCR19 Regulates P2X7R-Mediated NLRP3 Inflammasomal Activation of Microglia by Amyloid ß in a Mouse Model of Alzheimer's Disease.

Amyloid ß (Aß) and/or ATP activate the NLRP3 inflammasome (N3I) via P2X7R in microglia, which is crucial in neuroinflammation in Alzheimer's disease (AD). Due to polymorphisms, subtypes, and ubiquitous expression of P2X7R, inhibition of P2X7R has not been effective for AD. We first report that taurodeoxycholate (TDCA), a GPCR19 ligand, inhibited the priming phase of N3I activation, suppressed P2X7R expression and P2X7R-mediated Ca++ mobilization and N3I oligomerization, which is essential for production of IL-1ß/IL-18 by microglia. Furthermore, TDCA enhanced phagocytosis of Aß and decreased the number of Aß plaques in the brains of 5x Familial Alzheimer's disease (5xFAD) mice. TDCA also reduced microgliosis, prevented neuronal loss, and improved memory function in 5xFAD mice. The pleiotropic roles of GPCR19 in P2X7R-mediated N3I activation suggest that targeting GPCR19 might resolve neuroinflammation in AD patients.

Clinical Implications of the Mitotic Index as a Predictive Factor for Malignant Transformation of Atypical Meningiomas.

OBJECTIVE: Intracranial atypical meningiomas have a poor prognosis and high rates of recurrence. Moreover, up to one-third of the recurrences undergo high-grade transformation into malignant meningiomas. We aimed to investigate the clinical factors that can predict the propensity of malignant transformation from atypical to anaplastic meningiomas. METHODS: Between 2001 and 2018, all patients with atypical meningioma, in whom the tumors had undergone malignant transformation to anaplastic meningioma, were included. The patients' medical records documenting the diagnosis of atypical meningioma prior to malignant transformation were reviewed to identify the predictors of transformation. The control group comprised 56 patients with atypical meningiomas who were first diagnosed between January 2017 and December 2018 and had no malignant transformation. RESULTS: Nine patients in whom the atypical meningiomas underwent malignant transformation were included. The median time interval from diagnosis of atypical meningioma to malignant transformation was 19 months (range, 7-78). The study group showed a significant difference in heterogeneous enhancement (77.8% vs. 33.9%), bone invasion (55.6% vs. 12.5%), mitotic index (MI; 14.8±4.9 vs. 3.5±3.9), and Ki-67 index (20.7±13.9 vs. 9.5±7.1) compared with the control group. In multivariate analysis, increased MI (odds ratio, 1.436; 95% confidence interval, 1.127-1.900; p=0.004) was the only significant factor for predicting malignant transformation. CONCLUSION: An increased MI within atypical meningiomas might be used as a predictor of malignant transformation. Tumors at high risk for malignant transformation might require more attentive surveillance and management than other atypical meningiomas.

Posterior Fossa Teratomas in Adults : A Systematic Review.

OBJECTIVE: The occurrence of posterior fossa teratomas in adulthood is extremely rare. In this study, we aimed to report our experience with two cases of posterior fossa mature teratoma in adults who underwent surgical resection. We also performed a systematic review of published papers available to date. METHODS: We retrospectively reviewed the electronic medical records of patients who had onset of posterior fossa teratomas in adulthood at our institute between 1995 and 2020. We evaluated the clinical, radiographic, and pathological features of mature teratomas at the posterior fossa in adulthood. Furthermore, we searched the PubMed, EMBASE, and Web of Science database and reviewed published articles. RESULTS: We found 507 articles on database review; of them, 102 were duplicates and 389 were excluded based on the inclusion criteria. Finally, 16 cases of posterior fossa from the web search and related articles. Subsequently, we added two cases that underwent surgery at our institute. We analyzed a total of 18 cases of mature teratomas. Headache was the most common (55.6%) symptom. The teratomas showed heterogeneous signals on magnetic resonance imaging. Thirteen patients (72.2%) had lesion at midline, five patients (27.8%) had calcification. Surgical resection was performed in all patients. No studies reported recurrence after resection. CONCLUSION: The occurrence of posterior fossa teratomas in adulthood is difficult to diagnose at the initial stage. Radiographic diagnosis alone can lead to misdiagnosis. Pathological confirmation is essential. Surgical resection is a curative option for posterior fossa teratomas in adulthood.

Intracranial solitary fibrous tumor/hemangiopericytoma: tumor reclassification and assessment of treatment outcome via the 2016 WHO classification.

PURPOSE: As per the 2016 World Health Organization (WHO) guidelines on the classification of central nervous system tumors, solitary fibrous tumors (SFTs) and hemangiopericytomas (HPCs) constitute a single disease entity, known as SFT/HPC. This study provides a clinical analysis of these tumors and describes the treatment outcomes of SFT/HPCs. METHODS: This retrospective study included 76 patients with histopathologically proven SFT/HPC. Reclassification according to the 2016 WHO guideline was done for patients who were diagnosed with SFT or HPC based on the 2007 WHO classification. Recurrence-free survival (RFS) and overall survival (OS) were evaluated for all patients and subgroups. RESULTS: The median follow-up period was 77.9 months. The median RFS and OS were 126.5 and 136.8 months, respectively. The 1-, 5-, 10-, and 15-year RFS rates were 93%, 72%, 40%, and 40%, respectively. The 1-, 5-, 10- and 15-year OS rates were 97%, 89%, 54%, and 35%, respectively. In multivariable analyses, stereotactic radiosurgery (SRS; p = 0.009, hazard ratio [HR] 6.986), female sex (p = 0.023, HR 1.76), and age over 45 (p = 0.037, HR 2.74) were associated with shorter RFS. Patients who underwent SRS as initial treatment had a shorter OS than that of patients who underwent primary resection (p < 0.001, HR 12.86). CONCLUSIONS: High-grade tumors tended to have worse OS and occur extracranial metastases earlier than low-grade tumors. The median RFS was not different between grade II and III tumors. Male sex, younger age, and GTR were associated with a better RFS. A history of SRS before tumor resection was associated with a shorter RFS and OS.

Survival outcome and prognostic factors in anaplastic oligodendroglioma: a single-institution study of 95 cases.

The aim of this study was to evaluate prognostic factors including surgical, radiographic, and histopathologic analyses in anaplastic oligodendroglioma (AO) patients. We reviewed the electronic records of 95 patients who underwent surgery and were diagnosed with AO for 20 years. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Univariate and multivariable analyses included clinical, histopathological, and radiographic prognostic factors. Subgroup analysis was performed in isocitrate dehydrogenase (IDH1/2)-mutant and 1p/19q-codeleted patients. The median PFS and OS were 24.7 months and 50.8 months, respectively. The 1-, 3-, 5-, and 10-year PFS were 75.8%, 42.9%, 32.4%, and 16.4%, respectively. Furthermore, the 1-, 3-, 5-, and 10-year OS were 98.9%, 76.9%, 42.9%, and 29.7%, respectively. The median PFS and OS of the IDH1/2-mutant and 1p/19q-codeleted patients were 54.2 and 57.8 months, respectively. In univariate analyses, young age, frontal lobe, weak enhancement, gross total resection (GTR), low Ki-67 index, 1p/19q codeletion, and IDH1/2 mutations were associated with a favorable outcome. In multivariable analyses, IDH1/2 mutation was related to better PFS and OS. In subgroup analysis, GTR was associated with favorable outcomes.

Predictive factors for high-grade transformation in benign meningiomas.

OBJECTIVE: Although they are generally slow-growing benign tumors, meningiomas may recur after surgery with transformation into atypical meningiomas. The purpose of this study was to investigate the radiological and histopathological factors that predict the risk of tumor progression from a benign to an atypical meningioma. PATIENTS AND METHODS: All patients treated for recurrent meningiomas in whom the tumor showed histopathologically confirmed high-grade transformation (HGT) from a benign to an atypical meningioma between 2001 and 2017 were included. To evaluate the predictors of transformation, patient medical records documenting the diagnosis of a benign meningioma at the first surgery prior to second surgery with HGT were reviewed. Each patient was matched with four age- and sex-matched controls who were treated for a benign meningioma. The control group comprised all patients without any recurrence for at least 60 months. RESULTS: Fourteen patients with benign meningioma underwent HGT and were included. The median time interval of transformation was 63 months (range, 19-132 months). Multivariate analysis indicated that an increased mitotic index (odds ratio [OR], 10.409; 95 % confidence interval [CI], 1.297-83.549; P = 0.027) was a significant predictor of transformation. Prominent peritumoral edema (OR, 33.822; 95 % CI, 0.935-223.688; P = 0.054) did not reach the statistical significance. CONCLUSION: An increased mitotic index may be used as the predictor for HGT of benign meningiomas. Although these tumors with a high risk for transformation do not meet the diagnostic criteria for atypical meningiomas, they may require more attentive observation and management than other benign meningiomas.

Clinicopathological features of programmed cell death-1 and programmed cell death-ligand-1 expression in the tumor cells and tumor microenvironment of angioimmunoblastic T cell lymphoma and peripheral T cell lymphoma not otherwise specified.

The expression patterns of programmed cell death-1 (PD-1) and programmed cell death-ligand-1 (PD-L1) and their clinicopathological implications were investigated in peripheral T cell lymphoma (PTCL) including angioimmunoblastic T cell lymphoma (AITL) and PTCL-not otherwise specified (PTCL-NOS). PTCL-NOS was further classified into nodal PTCL with follicular helper T cell (Tfh) phenotype ("PTCL-Tfh_new") and "PTCL-NOS_new". PD-1 and PD-L1 expression on tumor cells and reactive immune cells was evaluated using immunohistochemistry. PD-1 and PD-L1 expression on tumor cells (PD-1T and PD-L1T, respectively) was interpreted as positive when more than 5% of tumor cells expressed PD-1 or PD-L1. For PD-1 and PD-L1 on tumor cells and/or reactive immune cells (PD-1T + IC and PD-L1T + IC, respectively), a cutoff of 10% of cells was used. PD-1T, PD-L1T, and PD-L1T + IC expressions tended to be higher in AITLs than in PTCLs-NOS. PD-1T, PD-1T + IC, PD-L1T, and PD-L1T + IC expressions tended to be higher in PTCLs with Tfh phenotype including AITLs and "PTCL-Tfh_new" than in PTCLs without Tfh phenotype. The serum LDH level was significantly elevated in patients with PTCL positive for PD-L1T (P = 0.006) and PD-L1T + IC (P < 0.001). Patients with PTCL who were positive for combined expression of PD-1T/PD-L1T + IC presented at older ages (P = 0.010), nodal diseases (P = 0.001), higher IPI (P = 0.060), and elevated LDH (P = 0.030). Combined PD-1T/PD-L1T + IC positivity was related to shorter overall survival in patients with AITL (P = 0.051). Combined PD-1T/PD-L1T + IC positivity was a significant poor prognostic factor in patients with stage IV AITL, independent of B symptoms and performance status (HR = 6.282 [CI, 1.655-23.844], P = 0.007). In summary, the PD-1/PD-L1 pathway could be a potential prognostic and therapeutic biomarker for PTCL.

Exosomal PD-L1 promotes tumor growth through immune escape in non-small cell lung cancer.

Programmed cell death protein-1/programmed cell death ligand-1 (PD-1/PD-L1) pathway blockade is a promising new cancer therapy. Although PD-1/PD-L1 treatment has yielded clinical benefits in several types of cancer, further studies are required to clarify predictive biomarkers for drug efficacy and to understand the fundamental mechanism of PD-1/PD-L1 interaction between host and tumor cells. Here, we show that exosomes derived from lung cancer cells express PD-L1 and play a role in immune escape by reducing T-cell activity and promoting tumor growth. The abundance of PD-L1 on exosomes represented the quantity of PD-L1 expression on cell surfaces. Exosomes containing PD-L1 inhibited interferon-gamma (IFN-γ) secretion by Jurkat T cells. IFN-γ secretion was restored by PD-L1 knockout or masking on the exosomes. Both forced expression of PD-L1 on cells without PD-L1 and treatment with exosomes containing PD-L1 enhanced tumor growth in vivo. PD-L1 was present on exosomes isolated from the plasma of patients with non-small cell lung cancer, and its abundance in exosomes was correlated with PD-L1 positivity in tumor tissues. Exosomes can impair immune functions by reducing cytokine production and inducing apoptosis in CD8+ T cells. Our findings indicate that tumor-derived exosomes expressing PD-L1 may be an important mediator of tumor immune escape.

High tumoral PD-L1 expression and low PD-1+ or CD8+ tumor-infiltrating lymphocytes are predictive of a poor prognosis in primary diffuse large B-cell lymphoma of the central nervous system.

We investigated the clinicopathological role of the PD-1/PD-L1 pathway in primary diffuse large B-cell lymphoma of the central nervous system (PCNS-DLBCL) arising in the immune-privileged site. PD-L1 immunostaining of ≥30% of tumor cells was defined as tPD-L1+, and PD-L1 immunostaining of ≥30% of total cellularity, including tumor and non-tumoral cells, as tmPD-L1+ . PD-1+ and CD8+ tumor-infiltrating lymphocytes (TILs) were enumerated. Thirty-five cases (35.7%) were tPD-L1+ and 47 cases (48%) were tmPD-L1+ . The number of TILs was greater in tmPD-L1+ cases than in tmPD-L1- cases (CD8+, P= .050; PD-1+, P= .019). tPD-L1+ and tmPD-L1+ cases tended to have a poor performance status. In contrast, the numbers of CD8+ and PD-1+ TILs tended to be higher in patients with a good performance status and MYC/BCL2 negativity. Patients with tPD-L1+ had a worse overall survival (P= .026), and those with increased CD8+ or PD-1+ TILs tended to have a better overall survival (P= .081 and 0.044, respectively). Tumoral PD-L1 expression and the number of PD-1+ TILs were independent prognostic factors. tPD-L1+ patients with a small number of CD8+ or PD-1+ TILs had the worst prognosis, and tPD-L1- patients with a large number of CD8+ or PD-1+ TILs had the best prognosis. In validation group, increased CD8+ or PD-1+ TILs were significantly associated with a prolonged survival, but PD-L1 had no prognostic significance. In conclusion, PD-L1 is frequently expressed in tumor cells and the immune microenvironment of PCNS-DLBCL and is correlated with increased TILs. PD-L1 and CD8+ and PD-1+ TILs have potential as prognostic biomarkers and therapeutic targets in PCNS-DLBCL.

Detection of chromosome structural variation by targeted next-generation sequencing and a deep learning application.

Molecular testing is increasingly important in cancer diagnosis. Targeted next generation sequencing (NGS) is widely accepted method but structural variation (SV) detection by targeted NGS remains challenging. In the brain tumor, identification of molecular alterations, including 1p/19q co-deletion, is essential for accurate glial tumor classification. Hence, we used targeted NGS to detect 1p/19q co-deletion using a newly developed deep learning (DL) model in 61 tumors, including 19 oligodendroglial tumors. An ensemble 1-dimentional convolution neural network was developed and used to detect the 1p/19q co-deletion. External validation was performed using 427 low-grade glial tumors from The Cancer Genome Atlas (TCGA). Manual review of the copy number plot from the targeted NGS identified the 1p/19q co-deletion in all 19 oligodendroglial tumors. Our DL model also perfectly detected the 1p/19q co-deletion (area under the curve, AUC = 1) in the testing set, and yielded reproducible results (AUC = 0.9652) in the validation set (n = 427), although the validation data were generated on a completely different platform (SNP Array 6.0 platform). In conclusion, targeted NGS using a cancer gene panel is a promising approach for classifying glial tumors, and DL can be successfully integrated for the SV detection in NGS data.

Tumor-infiltrating immune cell subpopulations and programmed death ligand 1 (PD-L1) expression associated with clinicopathological and prognostic parameters in ependymoma.

Ependymomas are biologically and clinically heterogeneous tumors of the central nervous system that have variable clinical outcomes. The status of the tumor immune microenvironment in ependymoma remains unclear. Immune cell subsets and programmed death ligand 1 (PD-L1) expression were measured in 178 classical ependymoma cases by immunohistochemistry using monoclonal antibodies that recognized tumor-infiltrating lymphocyte subsets (TILs; CD3, CD4, CD8, FOXP3, and CD20), tumor-associated macrophages (TAMs; CD68, CD163, AIF1), indoleamine 2,3-dioxygenase (IDO)+ cells and PD-L1-expressing tumor cells. Increases in CD3+ and CD8+ cell numbers were associated with a prolonged PFS. In contrast, increased numbers of FOXP3+ and CD68+ cells and a ratio of CD163/AIF1+ cells were significantly associated with a shorter PFS. An increase in the IDO+ cell number was associated with a significantly longer PFS. To consider the quantities of TILs, TAMs, and IDO+ cells together, the cases were clustered into 2 immune cell subgroups using a k-means clustering analysis. Immune cell subgroup A, which was defined by high CD3+, low CD68+ and high IDO+ cell counts, predicted a favorable PFS compared to subgroup B by univariate and multivariate analyses. We found six ependymoma cases expressing PD-L1. All these cases were supratentorial ependymoma, RELA fusion-positive (ST-RELA). PD-L1 expression showed no prognostic significance. This study showed that the analysis of tumor-infiltrating immune cells could aid in predicting the prognosis of ependymoma patients and in determining therapeutic strategies to target the tumor microenvironment. PD-L1 expression in the ST-RELA subgroup suggests that this marker has a potential added value for future immunotherapy treatments.

Prognostic implications of tumor-infiltrating macrophages, M2 macrophages, regulatory T-cells, and indoleamine 2,3-dioxygenase-positive cells in primary diffuse large B-cell lymphoma of the central nervous system.

Primary diffuse large B-cell lymphoma of the central nervous system (CNS-DLBCL) is an aggressive disease with a poor prognosis. The status of the tumor immune microenvironment in CNS-DLBCL remains unclear. We investigated the prognostic implications of tumor-associated macrophages (TAMs), regulatory T-cells (Tregs), and indoleamine 2,3-dioxygenase (IDO)+ cells in primary CNS-DLBCL (n = 114) by immunohistochemical analysis. The numbers of tumor-infiltrating immune cells, including CD68+ TAMs, CD163+ or CD204+ M2 macrophages, FOXP3+ Tregs, and IDO+ cells were all significantly lower in CNS-DLBCL versus systemic DLBCL (n = 165; all P < 0.001), but with little difference in the ratio of CD163+/CD68+ or CD204+/CD68+ cells. An increase in CD68+ cell numbers was significantly associated with prolonged progression-free survival (PFS) and overall survival in patients with CNS-DLBCL (P = 0.004 and 0.021, respectively). In contrast, an increase in CD204+ cell numbers or a higher ratio of CD204+/CD68+ cells was related to a shorter PFS (P = 0.020 and 0.063, respectively). An increase in IDO+ cell numbers was associated with a significantly longer PFS (P = 0.019). In combination, the status of low IDO+ cell numbers combined with low CD68+ cell numbers, high CD204+ cell numbers, or a high CD204+/CD68+ cell ratio all predicted poor PFS in multivariate analyses. This study showed that an increase in CD204+ cell numbers, suggestive of M2 macrophages, was associated with poor clinical outcome in CNS-DLBCL, whereas increased CD68+ or IDO+ cell numbers were related to a favorable prognosis. The analysis of tumor-infiltrating immune cells could help in predicting the prognosis of CNS-DLBCL patients and determining therapeutic strategies targeting tumor microenvironment.

Association of PD-L1 Expression with Tumor-Infiltrating Immune Cells and Mutation Burden in High-Grade Neuroendocrine Carcinoma of the Lung.

INTRODUCTION: The immune microenvironment of high-grade neuroendocrine carcinoma of the lung, including programmed death ligand 1 (PD-L1) expression, has not been well characterized. METHODS: On the basis of immunohistochemistry (IHC) results, PD-L1 expression on tumor cells (TCs) and tumor-infiltrating immune cells (ICs) was scored as follows: TC0 and IC0 were defined as PD-L1 expression less than 1%, TC1 and IC1 as at least 1% but less than 10%, TC2 and IC2 as 10% or more but less than 50%, and TC3 and IC3 as 50% or more. Phosphatase and tensin homolog (PTEN) IHC was scored as either lost or retained expression. The Ion AmpliSeq Comprehensive Cancer Panel (ThermoFisher Scientific, Waltham, MA) was used to identify mutations in all coding exons of 409 cancer-related genes. RESULTS: A total of 192 patients with large cell neuroendocrine carcinoma (LCNEC) (n = 72) and SCLC (n = 120) were studied. The prevalence of PD-L1 expression on TCs was 15.1% (29 of 192). IC infiltration and PD-L1 expression on ICs were observed in 34.4% of patients (66 of 192) and 31.3% of patients (60 of 192), respectively. The prevalence of IC infiltration and PD-L1 expression on IC were more strongly correlated with LCNEC than with SCLC (57.6% versus 23.3%, p < 0.01; 45.8% versus 22.5%, p < 0.01) and high nonsynonymous mutations (p = 0.05 and .04). PTEN loss was found in 9.5% of patients (18 of 189) and showed no correlation with PD-L1 expression. Progression-free survival was better in patients with IC infiltration than in those without IC infiltration (median 11.3 versus 6.8 months [p < 0.01]) and in patients with PD-L1 expression of IC1/2/3 than in those with expression of IC0 (median 11.3 versus 7.0 months [p = 0.03]). CONCLUSION: These findings suggest that the PD-1/PD-L1 pathway is activated in the microenvironment of pulmonary high-grade neuroendocrine carcinoma and correlated with a higher mutation burden.

Immunoglobulin G4-Related Disease Mimicking an Anterior Mediastinal Tumor.

Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated collection of disorders that were once thought to be unrelated but are increasingly being recognized as a single entity. The tumor-like swelling of the involved organ, a storiform pattern of fibrosis, and a serologic elevation of IgG4 can lead to the diagnosis of IgG4-RD. The usual organs affected are the pancreas, biliary tract, and salivary and lacrimal glands. There have been few reports of intrathoracic cases, which usually have pulmonary lesions. We here report a case of IgG4-RD of the anterior mediastinum in the form of a mass, a rare entity, the second such patient described in the literature to date.