This study aimed to investigate the effects of cephaeline on oral squamous cell carcinoma (OSCC) cell lines, with a focus on cancer stem cell (CSC) regulation and its interaction with cisplatin.

The SCC4, SCC9, and SCC25 cell lines were utilized. Cell viability was assessed using the MTT assay, while CSC content was evaluated using the tumorsphere formation assay and the aldehyde dehydrogenase enzymatic activity assay. Tumorsphere formation was monitored daily, and aldehyde dehydrogenase activity was measured by flow cytometry. Immunofluorescence staining was conducted to assess histone acetylation status (H3K9ac) and NFκB signaling. Additionally, the combined impact of cephaeline and cisplatin on OSCC cells was assessed through the MTT assay.

Cisplatin treatment did not significantly affect tumorsphere formation, whereas a single dose of cephaeline disrupted tumorsphere formation in SCC4 and SCC9 and reduced the population of aldehyde dehydrogenase-positive cells. Cephaeline also inhibited the NFκB pathway and increased H3 histone acetylation levels. Notably, cephaeline sensitized OSCC cells to cisplatin.

Cephaeline is a promising therapeutic agent for OSCC by disrupting CSC populations through NFκB inhibition and histone H3 acetylation. This study is the first to demonstrate that combining cephaeline with cisplatin could serve as a potential treatment strategy for oral cancer.

Biliary tract cancer (BTC) is an aggressive malignancy associated with a poor prognosis, yet effective molecular therapeutic targets remain scarce. Chromosome 16 open reading frame 74 (C16orf74) has been implicated in tumor progression; however, its specific role in BTC remains unclear. This study aimed to investigate the prognostic significance of C16orf74 in extrahepatic cholangiocarcinoma (eCCA) and to evaluate its potential as a therapeutic target.

We evaluated C16orf74 protein expression in 146 resected eCCA specimens using immunohistochemistry. Functional analyses in BTC cell lines included reverse transcription-polymerase chain reaction, cell proliferation assays, and migration and invasion assays, followed by the evaluation of downstream Akt/mTOR signaling. The in vivo antitumor efficacy of a C16orf74-targeting dimer-blocking (DB) peptide was assessed using a murine xenograft model.

High C16orf74 expression occurred in 45.2% of the tumors and was associated with worse overall survival (5-year survival rate: 27.2% vs. 52.2%). Although this association only trended toward significance following false discovery rate adjustment in the univariate analysis, high C16orf74 expression remained an independent predictor of worse survival in the multivariate analysis. In vitro, the DB peptide inhibited cellular migration and invasion and induced dose-dependent cytotoxicity in C16orf74-high cell lines; these effects were accompanied by decreased Akt phosphorylation. In vivo, DB peptide treatment suppressed tumor growth in the TFK-1 xenograft model.

High C16orf74 expression is associated with a poor prognosis in patients with resected eCCA. Furthermore, targeting C16orf74 with a DB peptide demonstrates substantial antitumor activity. Therefore, C16orf74 represents a promising prognostic biomarker and a potential therapeutic target for eCCA.

Plexiform fibromyxoma (PF) is a rare benign mesenchymal tumor of the stomach that can be difficult to distinguish from gastrointestinal stromal tumor (GIST) due to overlapping clinical and imaging features. The risk of hemorrhagic complications following biopsy in PF has not been well established.

A 76-year-old man was followed for a small gastric submucosal lesion that showed gradual enlargement over time. Endoscopic ultrasound (EUS)-guided biopsy was performed to obtain a definitive diagnosis, and the initial histopathological diagnosis suggested GIST. Although the patient remained asymptomatic, magnetic resonance imaging performed two months after biopsy revealed cystic enlargement of the lesion. The lesion subsequently enlarged rapidly, forming a 15-cm cystic mass associated with abdominal pain. EUS-guided drainage was performed; however, progressive anemia developed, requiring repeated blood transfusions. Surgical resection was ultimately performed. Histopathological examination revealed PF, and the cystic lesion was diagnosed as a chronic expanding hematoma, likely caused by biopsy-related capsular injury.

PF can mimic GIST and may lead to severe delayed hemorrhagic complications following biopsy. Careful consideration should be given to invasive diagnostic procedures for gastric submucosal lesions, even when lesions are small and asymptomatic.

Neuroendocrine prostate cancer (NEPC) is characterized by strong immune evasion and profound metabolic reprogramming. A high regulatory T cell (Treg)/CD8⁺ T cell ratio and an increased proportion of M2/M1 tumor-associated macrophages (TAMs) in the NEPC tumor microenvironment (TME) are associated with poorer progression-free survival, a phenomenon linked to lipid accumulation within the TME. Understanding the regulatory mechanisms governing both the metabolic and immune landscapes of NEPC is critical.

To investigate these mechanisms, prostate cancer cell lines and patient samples were analyzed using immunohistochemistry, flow cytometry, PCR, western blotting, and mass spectrometry. The interleukin (IL)-8/CXCR2 signaling pathway was targeted for intervention in two tumor-bearing mouse models.

Data revealed that IL-8/CXCR2 signaling drives the accumulation of free fatty acids and very-long-chain polyunsaturated fatty acids, leading to ferroptosis in tumor-infiltrating CD8⁺ T cells. This, in turn, promotes Treg cell infiltration and an M2 macrophage-dominant immune landscape. Mechanistically, IL-8/CXCR2 signaling upregulates the AKT-mTOR-FAS pathway while activating the mTOR-MYC-ELOVL5 axis via Rictor acetylation. In preclinical studies using NSG and B57BL/6 mouse models, CXCR2 inhibition restored CD8⁺ T cell antitumor activity and enhanced TAM phagocytosis, significantly reducing tumor growth.

These findings highlight CXCR2 as a promising immunotherapeutic target for NEPC and underscore its relevance in translational medicine.

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide and is characterized by an immunosuppressive tumor microenvironment (TME). While adaptive immunity contributes to tumor control, growing evidence underscores the role of innate lymphocytes, particularly natural killer (NK) cells, in early antitumor surveillance. However, tumor-infiltrating NK cells often exhibit defective maturation and impaired effector functions, whereas the signals regulating NK cell differentiation and activity in CRC remain poorly defined. Interleukin-27 (IL-27) has emerged as a regulator of antitumor immunity, yet its role in modulating NK cell responses in intestinal tumors is largely unexplored.

We employed an orthotopic transplantation model of genetically engineered colorectal tumor organoids Apc^-/-Kras^G12D/+Trp53^R172H/-Smad4^-/- (AKPS) to investigate NK cell heterogeneity, maturation, and function during CRC progression. Tumor-infiltrating innate lymphocytes were analyzed using single-cell RNA sequencing, flow cytometry, immunofluorescence, and functional assays. In vitro co-culture systems and in vivo IL-27 blockade were used to assess the impact of tumor-derived IL-27 on NK cell transcriptional programs and effector activity.

Single-cell transcriptomic profiling revealed marked heterogeneity among tumor-infiltrating NK cells, identifying subsets with different maturation states and functional capacities. Among innate lymphocytes, AKPS tumors were dominated by NK cells displaying reduced activating receptors and diminished cytotoxic and cytokine-producing potential. Phenotypic and adoptive transfer analyses demonstrated that the TME favors persistence of immature CD27⁺ NK cell subsets while limiting differentiated NK cells. Mechanistically, tumor-derived IL-27 emerged as a critical regulator sustaining NK cell infiltration and activation; IL-27 blockade reduced NK cell accumulation, interferon-γ production, and immature subset frequency. The clinical relevance of these findings was supported by analysis of human CRC single-cell datasets, which revealed elevated IL-27 signaling in intratumoral NK cells, as well as by the ability of patient-derived organoids to enhance NK-cell cytotoxicity, which was reduced by IL-27 blockade.

Our study identifies IL-27 as a critical modulator of NK cell differentiation and function in CRC, highlighting its role in sustaining NK cell-mediated immune surveillance within the tumor microenvironment. These findings provide mechanistic insight into NK cell dysfunction in CRC and suggest IL-27 signaling as a promising therapeutic target to restore innate antitumor immunity.

Although chromosome 14q deletion (14q-) is present in up to 40% of clear cell renal cell carcinoma (ccRCC) cases, its immunologic and molecular impact remains unclear. Because TRAF3 and NFΚBIA, key regulators of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, are located on 14q, we hypothesize that 14q- in ccRCC promotes increased inflammation and unique determinants of immune checkpoint blockade (ICB) response.

We collected data from 825 patients with ccRCC from publicly available sources, our own independent retrospective study, and the Oncology Research Information Exchange Network. These data include bulk RNA-sequencing (RNA-seq), single-cell RNA-seq (scRNA-seq), and whole exome sequencing (WES). We also include reverse phase protein array from DepMap cell lines (n=277). Next, we performed multiplex immunofluorescence for spatial analysis of immune cells on 23 patient slides with paired WES and ICB response. Finally, progression-free survival, 14q- status (assessed in bulk RNA-seq or whole exome sequencing), and kidney inflammatory marker EDNRB expression were assessed in two independent ICB immunotherapy trials.

14q- status is associated with increased NF-κB-target transcription and p65 phosphorylation. Tumor scRNA-seq revealed increased expression of CCL20, an NF-κB target and lymphotactic protein. Simultaneously, single-cell and bulk RNA-seq demonstrated higher effector CD8+T cell infiltration in 14q- tumors compared with controls. We investigated myeloid panel mIF images from 14q- tumors and found dendritic cells (DCs) significantly aggregate with tumor cells in ICB responders compared with non-responders. Cell-cell communication analysis on DCs and tumor cells from a 14q- responder revealed tumor-derived EDN1 is uniquely interacting with EDNRB on DCs. In two ICB trials, 14q- combined with elevated EDNRB expression correlated with significantly improved progression-free survival.

This is the first evidence that 14q- in ccRCC is associated with an antitumor inflammatory phenotype, possibly driven by aberrant NF-κB activation. Furthermore, 14q- with high EDNRB expression (EDNRB+) may serve as a predictive biomarker for ICB response in ccRCC. Finally, our results indicate patients with 14q-/EDNRB- may respond poorly to immunotherapy and new treatment options should be explored for this cohort.

CDC73 alterations are associated with three main parathyroid lesions according to the World Health Organization (WHO) classification of tumors of the endocrine system. These include hyperparathyroidism-jaw tumor (HPT-JT) syndrome-associated adenomas, atypical parathyroid tumors (APTs), and parathyroid carcinomas (PCs). The loss of nuclear parafibromin expression, which serves as a surrogate marker for the underlying CDC73 alteration, encompasses these tumors under the term parafibromin-deficient parathyroid tumors. They have distinct morphologic features of more abundant eosinophilic cytoplasm with perinuclear clearing surrounding a large nucleus as well as prominent dilated branching "hemangiopericytoma-like" vasculature and a thick capsule as well as variably sized cystic spaces. These tumors include cases that show unequivocal histologic features fulfilling the criteria for PCs with growing data indicating a higher rate of recurrence or metastasis compared with parafibromin intact PCs. More importantly, the loss of parafibromin expression can be used in clinical practice to recognize APTs that fall short of a conclusive diagnosis of PCs, but clinically behave akin to them. Moreover, recognizing these tumors can lead to an underlying germline mutation and a diagnosis of HPT-JT, which impacts long-term treatment and surveillance for patients and close family.

Parathyroid disease typically presents with parathyroid hyperfunction as result of neoplasia or a consequence of non-neoplastic systemic disease. Given the parathyroid gland is a hormonally active organ with broad physiologic implications and serologically accessible markers for monitoring, the diagnosis of parathyroid disease is predominantly a clinical pathologic correlation. We provide the current pathological correlates of parathyroid disease and discuss preoperative, intraoperative, and postoperative pathology consultative practice for optimal patient care.

Thyroid carcinoma originating in struma ovarii comprises a small minority of all cases of struma ovarii. Given the rarity of this diagnosis, literature to guide evaluation and management is limited. The most common carcinoma originating from struma ovarii is papillary thyroid carcinoma. Treatment includes surgery, including a fertility sparing approach if disease is confined to the ovary, with consideration of total thyroidectomy and radioactive iodine ablation for high-risk pathologic features or disease spread beyond the ovary. This review discusses the histopathologic findings, molecular pathology, clinical implications and management, and prognosis of thyroid carcinomas originating in struma ovarii.

The use of intraoperative consultation for indeterminate thyroid lesions is not advocated but is still requested by some surgeons. Obscured cytomorphology and nonrepresentative sampling limit the specificity of intraoperative assessment. Formalin fixation of thyroid glands before sectioning also minimizes artifacts introduced by fresh sectioning. Inking of thyroid may vary based on institutional preferences and information desired by clinical teams. Sectioning may occur in the conventional transverse method or the modified transverse vertical method to more thoroughly evaluate the lesion's periphery. Gross examination of thyroid lesions should always consider possible high-grade features, such as necrosis or extrathyroidal extension.