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The relationship between tumor microenvironments (TMEs) of regional lymph node metastases (LNMs) and primary tumors in head and neck squamous cell carcinoma (HNSCC) remains unclear. This study compared tumor-infiltrating lymphocytes (TILs) and the immune phenotype (IP), characterized by spatial TIL distribution, between primary tumors and LNMs. Twenty-one HNSCC patients with regional LNM who received immune checkpoint inhibitors (ICIs) were included. A paired comparative analysis of TIL densities and IP between primary tumors and LNMs revealed no significant difference or correlation between TIL densities in primary tumors and LNMs. Their IPs were discordant in 12 patients (57.1%). Patients with high intratumoral TIL exhibited longer progression-free survival (PFS) than those with low intratumoral TIL in both primary tumors (median, 5.2 vs. 1.3 months, p = 0.003) and LNMs (median, 30.2 vs. 1.3 months, p = 0.012). Patients with inflamed IP exhibited longer PFS than those with non-inflamed IP in both primary tumors (median, 4.5 vs. 1.3 months, p = 0.043) and LNMs (median, 4.1 vs. 1.3 months, p = 0.037). Given the lack of correlation in TIL densities, the discrepancies in IP, and the predictive value of both TMEs, evaluating the TMEs of both primary tumors and LNMs may be beneficial for the precise use of ICIs in HNSCC. There was a significant discordance between the TME of primary tumors and LNMs, with implications in survival outcomes. Therefore, evaluating the TME of both the primary tumor and LNM could be beneficial for the precise use of ICIs in HNSCC. [ABSTRACT FROM AUTHOR]

Context Clinical implications of unilateral primary aldosteronism (PA) histopathology remain to be determined in various ethnic populations. Objective We examined the histopathology of unilateral PA using CYP11B2 immunostaining in relation to clinical phenotypes and postsurgical outcomes. Methods Patients consecutively operated for unilateral PA from 2010 to 2020 at 3 tertiary hospitals in South Korea were retrospectively enrolled. Adrenals with solitary aldosterone-producing adenomas and/or dominant aldosterone-producing nodules were classified as the classical and the others as the nonclassical groups. The classical group was subdivided into mixed or solitary group according to whether other aldosterone-producing lesions coexist or not. Results Of the 240 cases, 124 were solitary, 86 mixed, and 30 nonclassical. Baseline serum potassium concentration was lower in the solitary group than the mixed or nonclassical group. Plasma aldosterone concentration after saline loading was the highest in the solitary group (median 31.65 ng/dL), followed by the mixed group (median 25.40 ng/dL), and the lowest in the nonclassical group (median 14.20 ng/dL). Solitary and mixed groups showed higher lateralization indices and lower contralateral indices than the nonclassical group. The contralateral index was lower in the solitary group than the mixed group. At 6 to 12 months after adrenalectomy, fewer antihypertensive medications were required for the solitary and mixed groups than the nonclassical group. Conclusion The solitary group, followed by the mixed group, was associated with more severe hyperaldosteronism and more suppressed aldosterone production from the contralateral side than the nonclassical group. Histopathologic phenotypes were related to the clinical manifestations and may suggest postoperative prognosis. [ABSTRACT FROM AUTHOR]

BACKGROUND. Molecular characterization in pediatric papillary thyroid cancer (PTC), distinct from adult PTC, is important for developing molecularly targeted therapies for progressive radioiodine-refractory ([sup.131]I-refractory) PTC. METHODS. PTC samples from 106 pediatric patients (age range: 4.3-19.8 years; n = 84 girls, n = 22 boys) who were admitted to SNUH (January 1983-March 2020) were available for genomic profiling. Previous transcriptomic data from 125 adult PTC samples were used for comparison. RESULTS. We identified genetic drivers in 80 tumors: 31 with fusion oncogenes (RET in 21 patients, ALK in 6 patients, and NTRK1/3 in 4 patients); 47 with point mutations ([BRAF.sup.V600E] in 41 patients, [TERT.sup.C228T] in 2 patients [1 of whom had a coexisting [BRAF.sup.V600E]], and DICER1 variants in 5 patients); and 2 with amplifications. Fusion oncogene PTCs, which are predominantly detected in younger patients, were at a more advanced stage and showed more recurrent or persistent disease compared with [BRAF.sup.V600E] PTCs, which are detected mostly in adolescents. Pediatric fusion PTCs (in patients CONCLUSIONS. In pediatric patients with fusion oncogene PTC who have [sup.131]I-refractory advanced disease, selective fusiondirected therapy may restore radioiodine avidity and lead to a dramatic tumor response, underscoring the importance of molecular testing in pediatric patients with PTC. FUNDING. The Ministry of Science, ICT and Future Planning (NRF-2016R1A2B4012417 and 2019R1A2C2084332); the Korean Ministry of Health and Welfare (H14C1277); the Ministry of Education (2020R1A6A1A03047972); and the SNUH Research Fund (04-2015-0830). TRIAL REGISTRATION. Two patients received fusion-targeted therapy with larotrectinib (NCT02576431; NAVIGATE) or selpercatinib (LOXO-RET-18018)., Introduction Pediatric papillary thyroid cancers (PTCs) have distinct genetic alterations and a higher proportion of gene fusions compared with adult PTCs, in which point mutations predominate (1). Previous methods to [...]

Background: Thymic epithelial tumors (TET) are rare malignancies and lack well‐defined biomarkers for neoadjuvant therapy. This study aimed to evaluate the clinical utility of artificial intelligence (AI)‐powered tumor‐infiltrating lymphocyte (TIL) analysis in TET. Methods: Patients initially diagnosed with unresectable thymoma or thymic carcinoma who underwent neoadjuvant therapy between January 2004 and December 2021 formed our study population. Hematoxylin and eosin‐stained sections from the initial biopsy and surgery were analyzed using an AI‐powered spatial TIL analyzer. Intratumoral TIL (iTIL) and stromal TIL (sTIL) were quantified and their immune phenotype (IP) was identified. Results: Thirty‐five patients were included in this study. The proportion of patients with partial response to neoadjuvant therapy was higher in the group with nondesert IP in preneoadjuvant biopsy (63.6% vs. 17.6%, p = 0.038). A significant increase in both iTIL (median 22.18/mm2 vs. 340.69/mm2, p < 0.001) and sTIL (median 175.19/mm2 vs. 531.02/mm2, p = 0.004) was observed after neoadjuvant therapy. Patients with higher iTIL (>147/mm2) exhibited longer disease‐free survival (median, 29 months vs. 12 months, p = 0.009) and overall survival (OS) (median, 62 months vs. 45 months, p = 0.002). Patients with higher sTIL (>232.1/mm2) exhibited longer OS (median 62 months vs. 30 months, p = 0.021). Conclusions: Nondesert IP in initial biopsy was associated with a better response to neoadjuvant therapy. Increased infiltration of both iTIL and sTIL in surgical specimens were associated with longer OS in patients with TET who underwent resection followed by neoadjuvant therapy. [ABSTRACT FROM AUTHOR]

The frequency of CD4+CD8+ double-positive (DP) T cells is highly associated with a variety of diseases. Recently, we used high-throughput single-cell RNA sequencing to show that circulating DP T cells in cynomolgus monkeys comprise nine heterogeneous populations. To better understand the characteristics of DP T cells, we analyzed 7601 cells from a rhesus monkey and detected 14,459 genes. Rhesus monkey DP T cells comprised heterogeneous populations (naïve, Treg-, Tfh-, CCR9+ Th-, Th17-, Th2-, Eomes+ Tr1-, CTL-, PLZF+ innate- and Eomes+ innate-like cells) with multiple potential functions. We also identified two new subsets using aggregated scRNA-seq datasets from the rhesus and the cynomolgus monkey: CCR9+ Th-like cells expressing ICAM2 and ITGA1, and PLZF+ innate-like cells that display innate-associated gene signatures such as ZBTB16, TYROBP, MAP3K8, and KLRB1. Trajectory inference of cell differentiation status showed that most DP T cells in the rhesus monkey were found in the mid-to-late pseudotime, whereas DP T cells from the cynomolgus monkey were found in early pseudotime. This suggests that DP T cells in rhesus monkeys may exhibit more diverse differentiation states than those in cynomolgus monkeys. Thus, scRNA-seq and trajectory inference identified a more diverse subset of the circulating DP T cells than originally thought. [ABSTRACT FROM AUTHOR]

Sepsis represents a major cause of death in intensive care units. Here we show that administration of lysophosphatidylcholine (LPC), an endogenous lysophospholipid, protected mice against lethality after cecal ligation and puncture (CLP) or intraperitoneal injection of Escherichia coli. In vivo treatment with LPC markedly enhanced clearance of intraperitoneal bacteria and blocked CLP-induced deactivation of neutrophils. In vitro, LPC increased bactericidal activity of neutrophils, but not macrophages, by enhancing H[sub.2]O[sub.2] production in neutrophils that ingested E. coli. Incubation with an antibody to the LPC receptor, G2A, inhibited LPC-induced protection from CLP lethality and inhibited the effects of LPC in neutrophils. G2A-specific antibody also blocked the inhibitory effects of LPC on certain actions of lipopolysaccharides (LPS), including lethality and the release of tumor necrosis factor-[alpha] (TNF-[alpha]) from neutrophils. These results suggest that LPC can effectively prevent and treat sepsis and microbial infections., Author(s): Ji-Jing Yan [1, 4]; Jun-Sub Jung [1, 4]; Jung-Eun Lee [1, 4]; Jongho Lee [1, 4]; Sung-Oh Huh [1, 3, 4]; Hee-Sung Kim [1, 3]; Kyeong Cheon Jung [2]; [...]

Background: Despite an improved understanding of pheochromocytoma and extra-adrenal sympathetic parganglioma (PPGL), including diagnosis and management, some PPGLs are postoperatively diagnosed. Clinical characteristics and intraoperative haemodynamic instability (HI) in postoperatively diagnosed PPGL patients have been poorly defined. Thus, we investigated the clinical characteristics and HI in patients with postoperatively diagnosed PPGLs compared to patients with preoperatively diagnosed PPGLs. Methods: We obtained clinical and haemodynamic data from the electronic medical records of 256 patients with pathologically confirmed PPGLs at our institution from January 2005 to December 2019. We assessed the intraoperative HI (systolic blood pressure [SBP]>160 mmHg (min) or mean blood pressure [MBP]<60 mmHg (min)) over time. Results: Twenty-nine patients (11.3%) were diagnosed with PPGLs postoperatively. Hypertension (34.5% vs. 63.0%, P =0.006) and pheochromocytoma (17.2% vs. 81.1%, P <0.001) case rates were lower in postoperatively diagnosed patients than in preoperatively diagnosed patients. Preoperative SBP in the ward was similar between groups, but the use of α-blockers and β-blockers was more frequent in preoperatively diagnosed patients (89.0% vs. 3.4%, P <0.001; 36.3% vs. 6.9%, P =0.003). Considering intraoperative HI, postoperatively diagnosed patients demonstrated a similar percentage of time with SBP>160 mmHg (median [IQR]; 7.9% [2.5; 11.9] % vs. 4.6% [0.0; 11.9], P =0.088) but a significantly lower percentage of time with MBP<60 mmHg (0.0% [0.0; 3.0] vs. 5.6% [0.0, 12.6], P =0.002) compared with preoperatively diagnosed patients. Conclusions: Patients diagnosed with PPGLs postoperatively may have no further higher risk of intraoperative hypertension than those diagnosed preoperatively despite insufficient preoperative management for PPGLs. Further study will be needed to ascertain intrinsic tumour characteristics, and need for universal preoperative use of α- and β-blockers in PPGL patients postoperatively diagnosed or without typical symptoms related PPGLs. [ABSTRACT FROM AUTHOR]

Objective: Primary aldosteronism (PA) shows histological heterogeneity and clinical variability, including the coexistence of hypercortisolemia. Immunohistochemical analyses of steroidogenic enzymes in adrenal tissues have provided new insights into the pathogenesis of PA. However, a comprehensive analysis of the association between enzyme expression and clinical characteristics of PA has rarely been conducted. We aimed to investigate the correlation between clinical characteristics and steroidogenic enzyme expression in PA. Design: A retrospective case‐control study. Patients: Consecutive patients who underwent unilateral adrenalectomy for PA (n = 180). Patients with adrenal Cushing's syndrome (CS) (n = 29) and nonfunctioning adenoma (n = 6) as comparator groups. Measurements: A tissue microarray of adrenal adenomas was constructed and immunostained for CYP11B1, CYP11B2 and CYP17A1. The expression of the three enzymes was compared between PA and other adrenal diseases and between PA with and without mild autonomous cortisol excess (MACE). Results: Adrenal adenomas in PA showed lower CYP11B1, higher CYP11B2 and lower CYP17A1 expression than those in adrenal CS (p <.001). Nonfunctioning adenomas showed low expression of the three enzymes. PA with MACE showed higher CYP11B1 expression than PA without MACE. CYP11B1 expression was positively correlated with the severity of hypercortisolemia, and CYP11B2 was positively correlated with that of hyperaldosteronism. The expression of CYP11B1 and CYP11B2 had a negative correlation. Patients with absent clinical improvement after adrenalectomy had lower CYP11B2 expression than those with complete success. Conclusions: Variable expression of steroidogenic enzymes in adrenal adenoma underlies the clinical heterogeneity of PA and is associated with treatment outcomes. [ABSTRACT FROM AUTHOR]