Gwangil Kim

The 2021 WHO Classification of Tumors of the Central Nervous System incorporates integrated molecular diagnostics into the classification of diffuse gliomas; however, access to comprehensive molecular testing remains limited in some settings. This study retrospectively evaluated grade‐associated patterns of PCR‐based loss of heterozygosity (LOH) and microsatellite instability (MSI) in a historical, morphology‐defined cohort of diffuse astrocytic gliomas from the pre‐IDH era. LOH and MSI analyses were performed using 14 LOH and 5 MSI microsatellite markers in 40 archival diffuse astrocytic gliomas, including 12 diffuse astrocytomas, NOS (WHO grade 2), 15 anaplastic astrocytomas, NOS (WHO grade 3), and 13 glioblastomas, NOS (WHO grade 4), collected between 1997 and 2002 prior to the availability of IDH immunohistochemistry. LOH‐high (LOH‐H) was defined as LOH involving three or more of the seven microsatellite markers examined at each locus, and MSI‐high (MSI‐H) as instability at two or more of the five markers. LOH was detected in 77.5% of tumors. LOH‐H at 10q23 ( PTEN ) correlated significantly with WHO grade (8.3%, 40.0%, and 61.5% in grades 2, 3, and 4, respectively; p = 0.022) and distinguished high‐grade from low‐grade tumors ( p = 0.015). LOH‐H at either 10q23 or 17p13 ( TP53 ) was observed in 67.9% of high‐grade tumors compared with 25.0% of grade 2 tumors ( p = 0.013). MSI and MSI‐H rates were 17.5% and 10.0%, respectively. Three of the four MSI‐H tumors lacked concurrent LOH‐H; given the small number of MSI‐H tumors, this observation is preliminary and should not be interpreted as evidence of distinct genomic instability pathways. LOH‐H at 10q23, alone or in combination with 17p13, was associated with higher morphology‐based WHO grade, whereas 17p13 LOH alone showed no significant grade association. Because IDH mutation status could not be determined, these findings should not be extrapolated to contemporary WHO‐defined astrocytic gliomas; whether these findings apply to molecularly defined gliomas would require validation.

Background & Aims: Nab-paclitaxel plus gemcitabine-cisplatin (Gem/Cis/nab-P) had promising efficacy in phase II trials for advanced biliary tract cancer (BTC) but failed to demonstrate superiority in phase III. We investigated Gem/Cis/nab-P efficacy and identified molecular subgroups with clinical benefit. Approach & Results: This prospective observational cohort study (NCT04871321) enrolled 119 patients with advanced BTC who received Gem/Cis/nab-P from July 2021 to December 2022. Of these, 108 were included in genomic and transcriptomic analyses of pretreatment tumor samples that met quality control criteria. Among 119 patients, 39.5% had intrahepatic cholangiocarcinoma, 37.0% extrahepatic cholangiocarcinoma, and 23.5% gallbladder cancer. Most patients had metastatic disease (68.9%). At a median follow-up of 23.7 months, the median progression-free survival was 8.3 months and median overall survival 19.8 months. Grade ≥3 treatment-related adverse events occurred in 70 patients (58.8%), and dose reduction was required in 99.2%. Frequent genetic alterations were TP53 (53.7%), KRAS (29.6%), and CDKN2A (20.4%), with TP53 mutations being significantly associated with worse outcomes. Transcriptomic analysis identified four molecular subtypes: cholangiocyte-like, stromal, metabolic, and inflammatory-proliferative. The cholangiocyte-like subtype, marked by increased cholangiocyte markers, had the most favorable prognosis. Stromal and metabolic subtypes showed moderate outcomes, characterized by a fibroblast-rich stroma with activated angiogenesis and enriched metabolic pathways, respectively. The inflammatory-proliferative subtype had the worst prognosis, with cell cycle and inflammatory activation, and an exhausted immune microenvironment. Conclusions: This study demonstrated the clinical activity of Gem/Cis/nab-P in advanced BTC and highlighted that biology-driven patient stratification based on genomic and transcriptomic features may provide important prognostic information.

Introduction: The development of targeted therapies and immune checkpoint inhibitors for advanced hepatocellular carcinoma (HCC) reinforces the need for individualized treatment. However, precision medicine is hindered by the lack of mandatory tissue biopsy for genomic profiling in HCC. Liquid biopsy enables genomic profiling of circulating tumor DNA (ctDNA), which could compensate for the lack of tissue-based analysis. This study evaluated the concordance between ctDNA and tumor tissue genomic profiling and its feasibility in advanced HCC treated with atezolizumab plus bevacizumab (atezo/bev). Methods: This cohort study prospectively collected pretreatment plasma samples from 130 patients with advanced HCC who underwent tissue-based sequencing before systemic therapy from June 2020 to October 2022. Tumor tissue sequencing was performed using the Oncomine Comprehensive Assay, and ctDNA sequencing was conducted using Guardant360. Results: ctDNA variants revealed 72.6% (69/95; 95% CI, 62.9–80.6%) sensitivity and 75.0% (69/92; 95% CI, 65.3–82.7%) positive predictive value compared to tumor tissue. With an interval of ≤30 days between ctDNA and tumor tissue sampling, the sensitivity increased to 96.3% (26/27; 95% CI, 81.7–99.3%). In patients treated with first-line atezo/bev, maximum variant allele frequency (maxVAF) of ctDNA was significantly correlated with poor survival outcomes even after adjustment for clinicogenomic variables. Conclusion: In advanced HCC, ctDNA-based genotyping demonstrated clinically acceptable concordance with tissue-based profiling, providing a reliable alternative when tissue samples are limited. Additionally, ctDNA maxVAF demonstrated independent prognostic value in patients treated with first-line atezo/bev. Liquid biopsy using ctDNA can help address challenges associated with limited tissue-based genomic profiling in advanced HCC.

IgG4–related disease (IgG4–RD) is an autoimmune condition marked by IgG4–positive plasma cell infiltration, causing inflammation, fibrosis, and tumor–like lesions, especially in the lacrimal gland (LG). Current diagnostic criteria, based primarily on serum IgG4 levels, face limitations in predicting clinical outcomes and treatment responses. To address this, we conducted a multiplex immaunohistochemical analysis of LG tissues to assess immune checkpoint interactions and immune cell distribution in relation to mass size, fibrosis, and treatment response. Our findings revealed that PD–L1 (Programmed Death–Ligand 1), an immune checkpoint molecule, plays a key role in shaping an immunosuppressive environment that varies by clinical group. In non–responsive patients, increased co–expression of PD–L1 and CD11c+ dendritic cells (DCs) suggested a link to treatment resistance. Spatial analysis highlighted more active immune responses in non–fibrotic areas, while fibrotic regions exhibited stabilized immune interactions driven by PD–L1 expression. These results indicate that PD–L1 contributes to immune regulation and disease progression in IgG4–RD and emphasize its potential as a therapeutic target. This study provides new insights into the immunological landscape of IgG4–RD and paves the way for the development of personalized treatment strategies.

We investigated the role of the epithelium of nodules in Hurley stage I hidradenitis suppurativa (HS) by using spatial transcriptomics to analyse the profiles of epithelial cells and dermal-infiltrating immune cells. Compared with epidermal cysts, genes related to bacterial response, inflammatory mediators and neutrophil degranulation pathways were upregulated in the epithelial cells of early-stage HS nodules. Our analysis of dermal-infiltrating immune cells surrounding the epithelium of nodules revealed significantly elevated levels of B-cell-related genes. Similarly to the sinus tract formation observed in moderate-to-severe HS, we propose that the production of inflammatory mediators in early-stage HS may involve the activation of keratinocytes and their interaction with dermal-infiltrating immune cells.