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Spatial immunophenotyping of tumor-associated macrophages predicts prognostic outcomes in clear cell renal cell carcinoma

Fri, 01 May 2026 00:00:00 GMT

Title: Spatial immunophenotyping of tumor-associated macrophages predicts prognostic outcomes in clear cell renal cell carcinoma Authors: Uh, Jisu; Kim, Jisup; Shin, Su Jin; Ko, Jiwon; Go, Heounjeong Abstract: Introduction Clear cell renal cell carcinoma (ccRCC), the most common kidney cancer subtype, has high rates of metastasis and recurrence. Its tumor microenvironment (TME), particularly tumor-associated macrophages (TAMs) and tumor-infiltrating lymphocytes (TILs), influences immune evasion and tumor progression. This study evaluated the prognostic significance of TAM and TIL subsets based on their phenotypes and spatial distribution within the TME. Materials and Methods This retrospective study included 643 ccRCC patients who underwent surgery at Asan Medical Center between 2011 and 2013. Multiplex immunofluorescence staining was performed on tissue microarrays from central and peripheral tumor regions. Markers for M1/M2 macrophages and T cells were quantified using automated imaging software, and optimal cutoffs were defined using maximally selected rank statistics, with additional sensitivity analyses performed to assess robustness. Survival outcomes were assessed with Cox regression, and group comparisons used appropriate statistical tests. Results High central density of M2-like TAMs (CD68+CD206+) was associated with poor overall, metastasis-free, and progression-free survival (PFS) (P < 0.05). In contrast, high central density of M1-like TAMs (CD68+iNOS+) was associated with favorable PFS (P = 0.034). M2-like TAMs were more abundant than M1-like across all tumor regions. Peripheral CD3+ TILs were more frequent than in the center. Exploratory analyses showed weak correlations between immune cell densities and response to tyrosine kinase inhibitor therapy. Conclusion Distinct phenotypes and spatial distributions of TAMs were associated with prognostic outcomes in ccRCC. Central M2-like TAMs were associated with poor outcomes, while central M1-like TAMs were linked to favorable prognosis. TILs did not demonstrate independent prognostic value.

Loss of ABCA3 disrupts lipid balance and leads to AMPK-dependent suppression of SREBP1 in glioblastoma stem cells

Wed, 01 Apr 2026 00:00:00 GMT

Title: Loss of ABCA3 disrupts lipid balance and leads to AMPK-dependent suppression of SREBP1 in glioblastoma stem cells Authors: Kim, Jun-Kyum; Park, Min Gi; Ham, Seok Won; Yoon, Seunghyun; Kim, Sua; Jang, Junseok; Kim, Hyejin; Hong, Nayoung; Park, Jong Min; Park, Cheol Gyu; Park, Min Ji; Choi, Sang-Hun; Kim, Jung Yun; Jeon, Hee-Young; Seo, Sunyoung; Lee, Seon Yong; Lee, Yeri; Cho, Hee Jin; Gwak, Minseo; Kim, Eun-Jung; Eun, Kiyoung; Shin, Yong Jae; Nam, Do-Hyun; Kim, Se Hoon; Yoo, Seung Jun; Kim, Hyunggee Abstract: Malignant cancers exhibit distinct lipid metabolic features that support tumor initiation and progression. Glioblastoma (GBM) is an aggressive brain tumor driven by GBM stem cells (GSCs), which are responsible for tumor development and therapy resistance. However, effective treatments targeting vulnerable metabolic pathways in GSCs have not yet been developed. Here, we demonstrate that the ATP-binding cassette transporter A3 (ABCA3) maintains lipid metabolic balance in GSCs. ABCA3 is highly expressed in GSCs, where lipid biosynthesis is particularly active. Knocking down ABCA3 significantly reduces cell growth, self-renewal, viability, and tumor growth after intracranial implantation. These changes are caused by a profound disruption of lipid metabolic balance, as demonstrated by RNA sequencing and liquid chromatography-time-of-flight mass spectrometry, which revealed widespread alterations in lipid metabolism genes and lipid composition. Mechanistically, ABCA3 knockdown inhibits sterol regulatory element-binding protein 1 (SREBP1) signaling by accumulating acylcarnitines (ACs) caused by phospholipid breakdown. The increased ACs induce the production of mitochondrial reactive oxygen species, which activate adenosine monophosphate-activated protein kinase (AMPK), resulting in the inhibition of SREBP1 signaling and reduced GSC fitness. Overall, these findings suggest that ABCA3 maintains lipid metabolic balance in GSCs, and disrupting this function triggers AMPK-dependent suppression of SREBP1 signaling.

Adequacy Criteria for Thyroid Fine-Needle Aspiration in the Era of the Bethesda Reporting System

Wed, 01 Apr 2026 00:00:00 GMT

Title: Adequacy Criteria for Thyroid Fine-Needle Aspiration in the Era of the Bethesda Reporting System Authors: Kwak, Jin Young; Cho, Sangwoo; Lee, Hye Sun; Yoon, Jung Hyun; Ali, Syed Z.; Hong, Soon Won Abstract: Purpose: There is a lack of consensus and data validating lower cell counts for sample adequacy of thyroid fine-needle aspiration (FNA). We investigated less stringent adequacy thresholds under the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) and evaluated malignancy risks for "nondiagnostic" nodules by ultrasound features. Materials and Methods: A total of 2459 nodules with initial FNA were included. We built 11 new adequacy criteria based on the number of cell groups and total follicular epithelial cells. Diagnostic performance of each criterion was compared with the original criterion using the general estimating equation. Nondiagnostic nodules under each criterion were categorized by the American College of Radiology Thyroid Imaging Reporting and Data System (ACR TIRADS), and malignancy rates of each ACR TIRADS category were compared. Results: Malignancy rates of nondiagnostic nodules were under 3.5% across all criteria, and showed no significant differences compared with the original. More than 40 cells, regardless of cell group, or more than three cell groups showed no significant difference in diagnostic accuracy and false negative rates compared with the original criterion. Malignancy rates of nondiagnostic nodules were above 28.6% for ACR TIRADS 5, and below 5% for ACR TIRADS 1 to 4, in all criteria. Conclusion: Less stringent thresholds for sample adequacy can show comparable diagnostic performances to the original criterion of the TBSRTC. Given their markedly higher malignancy rates, nondiagnostic ACR TIRADS 5 nodules may warrant more active management than lower category nodules.

Consensus position statements for the standardized application of histological grading and staging systems in MASH clinical trials

Wed, 01 Apr 2026 00:00:00 GMT

Title: Consensus position statements for the standardized application of histological grading and staging systems in MASH clinical trials Authors: Lackner, Carolin; Gouw, Annette S. H.; Alves, Venancio Avancini Ferreira; Arola, Johanna; Bedossa, Pierre; Behling, Cynthia; Brunt, Elisabeth M.; Burt, Alastair; Clouston, Andrew; Cummings, Oscar; Goodman, Zachary D.; Guido, Maria; Guy, Cynthia; Hubscher, Stefan G.; Hytiroglou, Prodromos; Kleiner, David; Pai, Rish; Paradis, Valerie; Park, Young Nyun; Rastogi, Archana; Schirmacher, Peter; Wee, Aileen; Yano, Hirohisa; Yeh, Matthew; Avian, Alexander; Tiniakos, Dina G. Abstract: Background & Aims: Assessment of histologic disease activity (grading) and fibrosis (staging) is a prerequisite for patient selection and evaluation of treatment response in clinical trials of metabolic dysfunction-associated steatohepatitis (MASH). The lack of universally accepted definitions of histological components required for metabolic dysfunction-associated steatotic liver disease (MASLD) grading and staging, inconsistent histologic interpretations, and the absence of guidelines on how to apply currently used scoring systems, contribute to high interobserver variation and influence supervised machine learning algorithms. Methods: The International MASLD Pathology Group (IMPG), comprising 25 expert liver pathologists and one statistician, was established to develop guidance for the histological assessment of liver biopsies in MASH clinical trials and to define standards for liver biopsy processing, as well as to refine criteria for histological MASLD grading and staging. Statements were generated by three IMPG working subgroups and evaluated through a Delphi consensus procedure. Results: The IMPG working groups issued a total of 278 primary statements, which were evaluated in the first Delphi round, yielding 162 statements with 80% or higher agreement. The remaining 116 statements were discussed and either revised or not further considered. The resulting 33 revised statements were evaluated in a second Delphi round, yielding 192 final statements with 80% or higher agreement. Conclusion: For the first time, the IMPG statements provide guidelines to promote consensus among liver pathologists on the histopathological evaluation and scoring of liver biopsies for MASH clinical trials. Furthermore, they may inform the development of supervised machine learning algorithms for quantitative histology assessments of MASLD. (c) 2025 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.