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

2026-03-25T03:09:31Z

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.

Artificial intelligence-powered H&E-based quantification of spatial tumor-infiltrating lymphocyte distribution identifies prognostic immune niches in colorectal cancer

2026-06-10T05:55:38Z

Title: Artificial intelligence-powered H&E-based quantification of spatial tumor-infiltrating lymphocyte distribution identifies prognostic immune niches in colorectal cancer Authors: Koh, Hyun-Hee; Lee, Seungeun; Oum, Chiyoon; Song, Sanghoon; Cho, Soo Ick; Pereira, Sergio; Ahn, Chang Ho; Kim, Jun Yong; Kim, Milim; Jung, Minsun Abstract: Purpose The prognostic significance of tumor-infiltrating lymphocytes (TILs) in colorectal cancer (CRC) is well established; however, existing approaches inadequately capture their spatial distribution. We investigated the prognostic implications of TIL spatial distribution in CRC using an artificial intelligence (AI)-based method. Methods A total of 202 patients with stage II-III CRC were included. TIL densities in intratumoral (iTIL) and stromal (sTIL) regions were quantified using AI-based analysis of hematoxylin and eosin (H&E)-stained images. Based on proximity to the tumor-stromal border (TSB), TILs were subclassified into core iTIL, bounding iTIL, bounding sTIL, and outermost sTIL. Immunoscore was calculated from CD3(+) and CD8(+) T-cell densities in the tumor center and invasive margin. Results Correlations between AI-based and pathologist assessments (iTIL: r = 0.57; sTIL: r = 0.70) were comparable to inter-pathologist correlations (iTIL: r = 0.47; sTIL: r = 0.70). In univariate Cox regression analysis, bounding iTIL, bounding sTIL, and outermost sTIL were significantly associated with recurrence-free survival (RFS), whereas core iTIL was not. Composite TIL and TSB scores were developed by incorporating the prognostically significant regions. In multivariable analysis, the TIL score (p = 0.001), TSB score (p < 0.001), and Immunoscore (p < 0.001) independently predicted RFS. In microsatellite instability-high tumors, only the TSB score remained prognostically significant. Conclusion AI-powered spatial analysis of TILs, particularly the TSB score, demonstrated prognostic performance comparable to conventional Immunoscore, thereby supporting the value of spatial immune profiling and AI-driven analysis of H&E-stained slides for improved risk stratification in CRC.

HER2 Positivity as a Prognostic Biomarker and Therapeutic Target in Advanced Biliary Tract Cancer: A Multi-institutional Analysis

2026-06-11T07:30:21Z

Title: HER2 Positivity as a Prognostic Biomarker and Therapeutic Target in Advanced Biliary Tract Cancer: A Multi-institutional Analysis Authors: Lee, Sunyoung S.; Seo, Dong Hyun; Chung, Taek; Fox, Daniel; Haro-Silerio, Jaime Ivan; Kim, Chang Gon; Yoo, Jeong Eun; Bhamidipati, Deepak; Lee, Sang Hun; Meric-Bernstam, Funda; Pant, Shubham; Choi, Hye Jin; Javle, Milind; Lee, Choong-kun Abstract: Purpose: This study aimed to evaluate the prognostic relevance of HER2 positivity and the clinical impact of anti-HER2 therapy in the management of advanced biliary tract cancers using integrated multi-institutional data.Experimental Design: This retrospective analysis included 388 patients with advanced biliary tract cancers and known HER2 status from Yonsei Cancer Center and MD Anderson Cancer Center between 2009 and 2023. HER2 positivity was defined as HER2 IHC 3+, IHC 2+ with in situ hybridization positivity, or ERBB2 amplification by next-generation sequencing. Clinical outcomes, including survival, and genomic profiling with curated oncogenic pathway enrichment were analyzed.Results: HER2 positivity was observed in 25.2% of the epidemiology analysis cohort (n = 309). In the survival analysis (n = 310), HER2-positive biliary tract cancers were associated with shorter overall survival [(OS); 13.7 vs. 17.1 months; HR, 1.25; 95% confidence interval (CI), 0.97-1.60] and significantly shorter first-line progression-free survival (5.1 vs. 7.4 months; HR, 1.91; 95% CI, 1.46-2.48) than HER2-negative biliary tract cancers. Anti-HER2 therapy significantly improved OS among HER2-positive patients (18.2 vs. 8.1 months; HR, 0.39; 95% CI, 0.21-0.62). Genomic analysis showed the strongest enrichment of angiogenesis pathway alterations in HER2-positive patients, whereas KRAS mutations were predominant in HER2-negative biliary tract cancers.Conclusions: HER2 is a clinically meaningful biomarker with prognostic and predictive relevance in advanced biliary tract cancers. Anti-HER2 therapy significantly improves survival in HER2-positive patients. These findings support routine HER2 testing, standardization of HER2 diagnostic criteria, and further prospective evaluation of HER2-targeted strategies for biliary tract cancers. See related commentary by Fitzpatrick and Harding, p. 1603Conclusions: HER2 is a clinically meaningful biomarker with prognostic and predictive relevance in advanced biliary tract cancers. Anti-HER2 therapy significantly improves survival in HER2-positive patients. These findings support routine HER2 testing, standardization of HER2 diagnostic criteria, and further prospective evaluation of HER2-targeted strategies for biliary tract cancers. See related commentary by Fitzpatrick and Harding, p. 1603

Phase IB/II Trial with Correlative Analyses of Doxorubicin plus Durvalumab Combination in Patients with Advanced Soft Tissue Sarcoma

2026-06-11T07:30:19Z

Title: Phase IB/II Trial with Correlative Analyses of Doxorubicin plus Durvalumab Combination in Patients with Advanced Soft Tissue Sarcoma Authors: Yun, Kum-Hee; Sim, Nam Suk; Shin, Su-Jin; Lee, Young Han; Baek, Wooyeol; Han, Yoon Dae; Park, Ji Woo; Kim, Sang Kyum; Cho, Iksung; Jung, Inkyung; Mesirov, Jill P.; Rha, Sun Young; Choi, Seo Hee; Yoon, Hong In; Kim, Seung Hyun; Kim, Hyo Song Abstract: Purpose: This open-label, phase IB/II study evaluated the efficacy and safety of standard-of-care doxorubicin combined with durvalumab [a programmed death 1 ligand (PD-L1) immune checkpoint inhibitor] in patients with advanced anthracycline-na & iuml;ve soft tissue sarcoma (STS) and identified patients who would most likely benefit from this combination treatment.Patients and Methods: This trial (NCT03802071) included patients with metastatic and/or recurrent STS not previously treated with anthracycline or a PD-1/PD-L1 inhibitor. Phase IB assessed the safety and tolerability of doxorubicin [level 1 (75 mg/m2); level -1 (60 mg/m2)] in combination with durvalumab 1,500 mg once every 3 weeks until documented disease progression or unacceptable toxicity. Phase II evaluated treatment efficacy, with the primary endpoint being the objective response rate (ORR).Results: As no dose-limiting toxicities were observed during the phase IB trial (n = 3), the recommended phase II dose was 75 mg/m2 of doxorubicin. Of 41 evaluable patients, 1 (2.4%) achieved a complete response and 12 (29.3%) achieved a confirmed partial response, yielding an ORR of 31.7%. Median progression-free survival (PFS) was 7.6 months, and median overall survival was 23.8 months. The most common treatment-related grade 3 to 4 adverse events were neutropenia (n = 23, 53.4%), thrombocytopenia (n = 6, 13.9%), and anemia (n = 5, 11.6%). In prespecified exploratory correlative analyses, absence of RTK-RAS pathway genetic alterations [hazard ratio (HR), 6.446; 95% confidence interval (CI), 1.934-21.486; P = 0.002] and high PD-1 expression (HR, 0.214; 95% CI, 0.071-0.649; P = 0.006) were identified as independent predictors of longer PFS.Conclusions: Doxorubicin plus durvalumab combination therapy exhibited promising efficacy in advanced STS, with acceptable toxicity profile.