Biliary duct invasion (BDI) is an underrecognized growth pattern of colorectal cancer (CRC) liver metastases that can mimic intrahepatic cholangiocarcinoma or intraductal papillary neoplasm of the bile duct. Its prevalence and clinicopathologic associations remain unclear. This study aimed to determine the prevalence of BDI and its clinicopathologic associations in surgically resected CRC liver metastases.

We retrospectively analyzed 133 consecutive patients who underwent hepatic resection for CRC liver metastases. Clinicopathologic variables, including age, sex, resection type, tumor differentiation, lymphovascular invasion (LVI), tumor budding, surgical margin status, and primary tumor characteristics, were compared between BDI-positive and BDI-negative cases. Categorical variables were analyzed using the chi-square, Fisher exact, or Fisher-Freeman-Halton exact test, as appropriate; continuous variables were analyzed using the Mann-Whitney U test.

BDI was identified in 19 of 133 cases (14.3%). Male sex showed the strongest numerical trend toward BDI (84.2% vs. 61.4%, P = 0.096), and LVI showed a nonsignificant numerical trend toward higher BDI rates (26.3% vs. 12.3%, P = 0.149). No clinicopathologic variable in the primary cohort analysis reached statistical significance after Bonferroni correction (α = 0.0050).

BDI occurs in approximately 14% of surgically resected CRC liver metastases in this cohort. Male sex and LVI show nonsignificant numerical trends toward higher BDI rates, but these findings should be interpreted cautiously given the limited sample size. Accurate histopathologic recognition of BDI and its distinction from intrahepatic cholangiocarcinoma remain important for correct pathologic diagnosis. Further prospective studies are warranted to clarify the clinicopathologic and prognostic significance of BDI.

Estrogen receptor alpha, encoded by the ESR1 gene, is a major oncogenic driver in hormone receptor-positive/HER2-negative breast cancers. While endocrine therapies are effective in treating this subgroup, patients with advanced or metastatic disease may develop resistance associated with acquired somatic ESR1 mutations. This mini review summarizes recent clinical and technological advances in understanding ESR1 mutations, newly approved targeted therapies, and the use of liquid biopsy companion diagnostics, with a focus on their implications for pathologists.

We conducted a narrative review of PubMed-indexed literature and relevant regulatory and guideline sources related to ESR1 in breast cancer, with an emphasis on recent peer-reviewed studies of ESR1 mutations and clinical trials of emerging therapies.

This review describes the molecular features of ESR1 alterations and estrogen receptor pathway biology, the mechanisms and key trial data for recently approved ER-targeted therapies for ESR1-mutated breast cancer. Additionally, it evaluates liquid biopsy testing platforms for detecting ESR1 mutations, discusses the advantages and limitations of liquid biopsy in detection of treatment resistance, and considers the evolving role of pathologists in breast cancer care.

Acquired ESR1 mutations are major drivers of endocrine therapy resistance. Next-generation sequencing and liquid biopsy have increasingly informed the clinical management of breast cancer in the past decade. Pathologists can play an important role in implementing molecular testing, interpreting complex biomolecular data, and helping to guide timely treatment decisions in the era of precision oncology.

EWSR1 fusions are recurrent genetic alterations in a wide spectrum of mesenchymal tumors and are often associated with specific clinicopathologic entities. However, the presence of an EWSR1 rearrangement does not always indicate a functional or disease-defining fusion.

We report a case of undifferentiated pleomorphic sarcoma with high-grade morphologic features harboring an EWSR1 rearrangement detected by fluorescence in situ hybridization. It was subsequently characterized by RNA sequencing as a likely nonfunctional fusion of EWSR1 exon 1 and NF2 intron 1. Histologically, the tumor was composed of pleomorphic spindle cells with brisk mitotic activity and lacked a specific line of differentiation. Immunohistochemically, the tumor showed diffuse cytoplasmic S100 positivity, with nuclear staining in a subset of tumor cells, while the overall immunophenotype did not support a specific line of differentiation. The EWSR1::NF2 fusion was inferred to have a tail-to-tail configuration, and additional KRAS and TP53 alterations were detected.

This case highlights that an EWSR1 rearrangement detected by fluorescence in situ hybridization should be interpreted cautiously and does not necessarily represent a functional or disease-defining fusion. Comprehensive molecular evaluation is important for the accurate interpretation and classification of sarcomas with atypical EWSR1 rearrangements.

The huge burden of type 1 diabetes mellitus (T1DM) has been a source of concern globally since the Industrial Revolution in the 18th–19th centuries. To this end, studies have shown that certain environmental changes that accompanied the Revolution may have increased the risk and burden of the disease in genetically predisposed individuals. However, documented studies that synthesize these environmental triggers are scarce. As a result, the current study was conceived to synthesize the environmental triggers of T1DM to boost public awareness. Relevant information was retrieved from reputable academic databases; namely, Scopus, PubMed, SpringerLink, and Embase. The results showed that chemical exposure, viral infection, gut microbiome disruption, vitamin and mineral deficiencies, inadequate or exclusive breastfeeding, as well as early exposure to infant feeding formulas could increase the risk and burden of T1DM in genetically predisposed individuals. As a consequence, these triggers could compromise the expression of certain genes involved in insulin synthesis and immune function, such as the human leukocyte antigen (HLA), insulin (INS), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and protein tyrosine phosphatase non-receptor type 22 (PTPN22) genes. This would result in a dysfunctional immune system in which immune cells, such as T-cells and B-cells and molecules, such as cytokines would attack self-tissues, thus causing autoimmunity of the pancreatic beta cells. Environmental triggers could also induce the T1DM pathophysiology by modifying the epigenome of the mentioned genes. Furthermore, some epigenetic changes could be reversed, which would infer that treatment procedures that would include the pathophysiology of the environmental triggers could be more effective.

Emerging evidence suggests that RNA-binding motif (RBM) proteins are involved in hepatocarcinogenesis and act either as oncogenes or tumor suppressors. The objective of this study was to investigate the role of RBM34, an RBM protein, in hepatocellular carcinoma (HCC).

We first examined the expression of RBM34 across cancers. The correlation of RBM34 with clinicopathological features and the prognostic value of RBM34 for HCC was then investigated. Functional enrichment analysis of RBM34-related differentially expressed genes (DEGs) was performed to explore its biological function. RNA sequencing (RNA-seq) was applied to identify downstream genes and pathways affected upon RBM34 knockout. The correlation of RBM34 with immune characteristics was also analyzed. The oncogenic function of RBM34 was examined in in vitro and in vivo experiments.

RBM34 was highly expressed in hepatocellular carcinoma and correlated with poor clinicopathological features and prognosis. RBM34 was positively associated with tumor immune cell infiltration, biomarkers of immune cells, and immune checkpoint expression. A positive correlation was also observed between RBM34, T cell exhaustion, and regulatory T cell marker genes. Knockout of RBM34 significantly inhibited cell proliferation, migration, and xenograft tumor growth, and sensitized HCC cells to sorafenib treatment. RBM34 inhibition reduced FGFR2 expression and affected PI3K-AKT pathway activation in HCC cells.

Our study suggests that RBM34 may serve as a new prognostic marker and therapeutic target of HCC.

Naringenin is an anti-inflammatory flavonoid that has been studied in chronic liver disease. The mechanism specific to its antifibrosis activity needs further investigation This study was to focused on the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) pathway in hepatic stellate cells and clarified the antifibrosis mechanism of naringenin.

The relationship between the cGAS-stimulator of interferon genes (STING) pathway and liver fibrosis was analyzed using the Gene Expression Omnibus database. Histopathology, immunohistochemistry, fluorescence staining, Western blotting and polymerase chain reaction were performed to assess gene and protein expression levels associated with the cGAS pathway in clinical liver tissue samples and mouse livers. Molecular docking was performed to evaluate the relationship between naringenin and cGAS, and western blotting was performed to study the expression of inflammatory factors downstream of cGAS in vitro.

Clinical database analyses showed that the cGAS-STING pathway is involved in the occurrence of chronic liver disease. Naringenin ameliorated liver injury and liver fibrosis, decreased collagen deposition and cGAS expression, and inhibited inflammation in carbon tetrachloride (CCl4)-treated mice. Molecular docking found that cGAS may be a direct target of naringenin. Consistent with the in vivo results, we verified the inhibitory effect of naringenin on activated hepatic stellate cells (HSCs). By using the cGAS-specific agonist double-stranded (ds)DNA, we showed that naringenin attenuated the activation of cGAS and its inflammatory factors affected by dsDNA. We verified that naringenin inhibited the cGAS-STING pathway, thereby reducing the secretion of inflammatory factors by HSCs to ameliorate liver fibrosis.

Interrupting the cGAS-STING pathway helped reverse the fibrosis process. Naringenin has potential as an antihepatic fibrosis drug.