Desmoid tumor (DT) is a rare, locally invasive soft tissue tumor that does not metastasize but has a high recurrence rate after surgery. DTs can be divided into three types: abdominal wall, intra-abdominal and extra-abdominal DTs. The primary treatment options for abdominal wall DT include active surveillance (AS) and surgical resection. However, many patients experience progression during AS, whereas surgical resection carries a high risk of recurrence. Therefore, an effective, noninvasive and safe local treatment method is currently needed in clinical practice.

This study included all patients with abdominal wall DT treated by high-intensity focused ultrasound (HIFU) at the Oncology Department of the Second Affiliated Hospital of Zhejiang University School of Medicine from July 2015 to May 2023. Thermal ablation of the abdominal wall DT was conducted using focused ultrasound beams. Following tumor ablation, treatment outcomes were evaluated for all patients.

A total of 55 abdominal wall DT cases underwent HIFU treatment, including 46 and 9 initial and recurrent tumors, respectively. The median follow-up time was 58 months. The median ablation rate for all patients after 1 month of HIFU treatment was 61%. The objective response rate (ORR) and disease control rate (DCR) were 82% (45/55) and 98% (54/55), respectively. Based on disease course, ORRs were 87% and 56% in treatment-naïve patients and re-treated patients, respectively.

HIFU demonstrates a high DCR for abdominal wall DT with few side effects, representing an effective treatment, especially for treatment-naïve patients.

BACKGROUND Primary clear cell carcinoma of the colon is an exceptionally rare condition. It is still uncertain whether this carcinoma represents a separate biological category or simply a variant of typical colorectal cancer. From a diagnostic standpoint, the presence of clear cell morphology introduces significant challenges, as similar features can be observed in various other carcinomas, including renal, ovarian, and endometrial carcinoma. Typically, primary colorectal tumors demonstrate positivity for markers such as CK20 and CDX2, supporting intestinal origin. CASE REPORT We present a case of primary clear cell carcinoma of the sigmoid colon, with no adenoma component, in a 69-year-old woman. The tumor was detected on routine bowel screening colonoscopy, and the patient underwent anterior resection of a pT3N2b sigmoid tumor with prophylactic oophorectomy and salpingectomy. In contrast to the positivity for intestinal-origin markers typically seen in primary colorectal tumors, in this case, the histopathological and immunohistochemical analyses revealed that the tumor was positive for AMACR, CK7, and PAX 8 and negative for WT1, ER, PR, P16, CD10, CDX2, and CK20. These results were consistent with colonic clear cell carcinoma. CONCLUSIONS Specific data on colorectal clear cell carcinoma in Ireland and worldwide are limited. In academic literature, few cases have been documented. The presence of clear cell morphology in colon tumors presents significant diagnostic challenges, necessitating careful radiological and histopathological evaluation, which should be correlated with the patient's clinical history. This case was documented due to the extreme rarity of this condition and the diagnostic difficulties it poses, particularly in distinguishing clear cell carcinoma of the colon from conventional adenocarcinoma.

High mammographic breast density is a strong independent risk factor for sporadic breast cancer, yet involved mechanisms remain poorly defined. The extracellular compartment plays a critical role in the intercellular communication during tumor initiation and progression. Although several mechanosensitive pathways have been described, the role of platelets (PLTs) in stiffness-driven signaling in the breast is unknown.

Extracellular soluble proteins were sampled in situ from live breast tissue using microdialysis. A total of 108 postmenopausal women were included: women with nondense or dense breasts, women with dense breasts randomized to low-dose acetylsalicylic acid (ASA; 160 mg/day) or no treatment, and patients with estrogen receptor-positive (ER⁺) breast cancer. Breast density was assessed by magnetic resonance imaging. High-dimensional proteomic profiling of 1,158 proteins was performed using proximity extension assays. To investigate stiffness-dependent PLT responses, cells were cultured in a 3D in vitro system with tunable matrix stiffness generated by cross-linked hyaluronic acid, modeling nondense and dense breast tissue.

Dense breast tissue exhibited a distinct extracellular proteomic signature enriched for proteins associated with platelet activation, along with alterations in several immunomodulatory pathways. Several PLT-associated proteins were also elevated in ER⁺ breast cancers, supporting their clinical relevance. Post hoc exploratory proteomic analysis of samples from women treated with low-dose ASA did not reveal modulation of these proteins, suggesting that stiffness-induced PLT activation may occur via mechanotransduction rather than biochemical pathways in vivo. Consistently, in the 3D in vitro model, increased matrix stiffness representative of dense breasts promoted a procoagulant PLT phenotype without corresponding changes in classical activation markers.

Tissue stiffness is a critical regulator of PLT mechanotransduction in dense breast tissue, contributing to a microenvironment permissive for cancer progression. These findings highlight PLT mechanobiology as a potential target for breast cancer prevention and therapy.

EudraCT: 2017-000317-22.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive precursor cell hematological malignancy with a dismal prognosis, necessitating prompt and accurate diagnosis. However, its blastoid morphology and immunophenotype may lead to diagnostic confusion with a broad spectrum of hematological neoplasms. This systematic review delineates the critical morphological, immunophenotypic, and molecular features required to distinguish BPDCN from its mimics across common sites of involvement (skin, bone marrow, and lymph nodes). We reinforce the diagnostic criteria for BPDCN and provide an in-depth analysis of its differential diagnosis, structuring it into two groups: (A) hematological neoplasms with blastoid morphology (e.g., ALL/LBL, blastoid MCL, AML, myeloid sarcoma), and (B) myeloid malignancies with pDC-associated markers (e.g., AML with pDC-like phenotype, AML with pDC expansion, mature pDC proliferation). We emphasize the integration of immature and lineage-specific markers, and molecular data (e.g., ZRSR2, MYB/MYBL1, NPM1, FLT3, RUNX1, DNMT3, CCND1 status) to resolve diagnostic dilemmas. The aim is to provide a comprehensive diagnostic review and guide to standardize the workup and facilitate the early initiation of appropriate treatment for this challenging disease.

Selective inhibition of the immunoproteasome offers a therapeutic avenue for diseases where dysregulated proteasomal activity plays a role such as multiple myeloma. The development of noncovalent inhibitors avoids the off-target toxicity issues often associated with covalent inhibitors. This study provides a comprehensive investigation into the binding mechanisms and inhibitory activities of noncovalent inhibitors for the β1i and β5i subunits of the immunoproteasome. The computational methods (MD simulations, Binding Pose Metadynamics, Induced fit docking, pharmacophore modeling, and virtual screening) and experimental assays have provided valuable insights into inhibitor binding, which could be further exploited to optimize inhibitor potency and selectivity.

Thyroid cancer represents the most prevalent malignancy of the endocrine system, with its incidence exhibiting a significant rise in recent years. Diagnostic methods have undergone profound evolution over the past century, progressing from basic clinical examination to a sophisticated and technology-centered approach. Initially, the diagnosis of thyroid neoplasms relied on physical examination and palpation, with definitive diagnoses being stated after postoperative histopathological analysis. The mid-twentieth century brought the emergence of imaging techniques, including radionuclide scanning and, later, high-resolution ultrasound, which revolutionized non-invasive detection, enabling earlier and more precise identification of thyroid lesions. The subsequent introduction of fine-needle aspiration (FNA) cytology fundamentally transformed diagnostic algorithms, optimizing preoperative risk stratification and reducing the number of unnecessary surgical interventions. This review outlines the historical development of thyroid cancer diagnostics and highlights major clinical practice milestones.

The complex nonlinear dynamics of tumor-immune interactions drive tumor heterogeneity and complicate treatment strategies. While bifurcation and multistability analyses of mathematical models can uncover critical system dynamics, few studies have explored bifurcation-particularly cusp bifurcation-in high-dimensional tumor-immune systems, as most existing analyses are limited to simplified two-dimensional models. In this study, we extend the tumor-immune model proposed by Anderson et al. (2024a) to incorporate combination therapy with immune checkpoint inhibitors (ICIs) and C-C chemokine receptor type 2 (CCR2) antagonists. By combining linear algebra methods, Sotomayor's theorem, projection singularity analysis, numerical simulation, and continuation techniques, we explicitly identify transcritical and saddle-node bifurcations, conduct a systematic cusp bifurcation analysis as a classical two-parameter problem, and derive explicit quantitative conditions. Calibration against four independent murine datasets demonstrates the model's ability to reproduce tumor growth dynamics across multiple tumor datasets. Bifurcation analysis characterizes the multiplicity of tumorous equilibria, and reveals the emergence of monostable and bistable regimes. In particular, the saddle-node bifurcation curve partitions the two-parameter space under combination therapy into monostable and bistable regions. Notably, a dose-dependent inverse correlation between ICIs and CCR2 antagonists emerges along this bifurcation boundary. Our results demonstrate that effective tumor control depends not only on treatment intensity but also on the patient's initial tumor burden. The corresponding critical thresholds are determined by bifurcation structure and the stable manifold (or characteristic space) of the saddle point, respectively. These findings provide theoretical guidance for treatment design under different tumor states. Importantly, the identification of a stable low-tumor state-being clinically acceptable and controllable-highlights the potential for sustained tumor control as an alternative therapeutic objective to complete tumor eradication.

Glioblastoma remains the most aggressive malignant brain tumor, with limited survival despite advances in surgery, radiotherapy, and chemotherapy. Current diagnostic modalities are insufficient for early detection and precise monitoring of disease progression, prompting interest in liquid biopsy-based biomarkers. Exosomal microRNAs (miRNAs) have been highlighted as significant biomarkers due to their stability and involvement in tumor progression. This narrative review evaluates current evidence regarding the diagnostic, prognostic, and therapeutic significance of exosomal and extracellular vesicle-associated miRNAs in brain tumors, particularly gliomas. Data were collected from PubMed and Google Scholar, and eight original articles published between 2016 and 2026 were included after careful screening. The findings demonstrated dysregulated expression of exosomal miRNAs, including miR-29b, miR-210, miR-301a, miR-454-3p, and miR-2276-5p, which were significantly associated with tumor grade, recurrence, survival, and treatment response. The majority of studies reported strong diagnostic performance, with receiver operating characteristic/area under the curve values ranging from 0.80 to 0.93, while mechanistic analyses implicated these miRNAs in oncogenic pathways, including PTEN/AKT signaling, hypoxia-mediated progression, autophagy regulation, and angiogenesis. Overall, exosomal miRNAs demonstrate considerable potential as noninvasive biomarkers for prognostication and therapeutic targeting, while their dynamic preoperative alterations further suggest utility in disease monitoring.

BCL6 is a master transcriptional regulator of germinal center (GC) B cells. BCL6 is frequently translocated at the major translocation cluster (MTC) within intron 1 of the BCL6 locus, a hotspot commonly rearranged in diffuse large B cell lymphomas (DLBCLs). BCL6 amplifications are associated with therapeutic resistance and poor survival outcomes in hematological and solid cancers. However the mechanisms suppressing genome instability at the BCL6-MTC preventing BCL6 rearragements remain unclear. Here, transcriptome analysis and genome-wide mapping of histone H3 lysine 4 trimethylation (H3K4me3) in hydroxyurea (HU)-treated Raji cells (a Burkitt's lymphoma model) revealed the induced expression of MBD1, encoding the DNA CpG methylation-binding protein. Functional studies using shRNA silencing and ectopic overexpression demonstrated that MBD1 suppresses BCL6 transcription whose promoter harbors conserved CpG methylation sites, suggesting a DNA methylation-dependent regulation of BCL6 trasncription by MBD1. Conversely, BCL6 repressed MBD1 expression by binding to its promoter. MBD1-depleted Raji cells exhibited increased genomic instability at the BCL6-MTC upon HU treatment, heightened sensitivity to DNA replication inhibitors (HU, gemcitabine, and etoposide), and reduced tumorigenicity in xenograft mouse models. We propose that MBD1 prevents genomic instability at the BCL6-MTC to suppress DLBCL formation. Moreover, MBD1 promotes genomic stability and cell viability during DNA replication stress. MBD1 thus represents a potential therapeutic target for cancers exhibiting resistance to chemotherapies targeting DNA replication.

Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer, characterized by high invasiveness, poor prognosis, and limited therapeutic options. Cancer-associated fibroblasts (CAFs), as a core component of the tumor microenvironment (TME), have been shown to promote the malignant progression of NSCLC, but the specific regulatory mechanisms remain incompletely understood. This study aims to investigate the role of CAFs and their metabolic products, particularly lactate, in the progression of NSCLC. CAFs and normal fibroblasts (NFs) were cultured, and the conditioned media (CM) were collected and used to treat NSCLC cells. Cell proliferation was assessed using CCK-8 and EdU assays, while cell migration was evaluated through transwell assays. The expression of E-cadherin and N-cadherin was detected by immunofluorescence (IF). Additionally, lactate levels, gene expression, and lactylation levels were assessed using a lactate detection kit, RT-qPCR, Western blot (WB), and chromatin immunoprecipitation (ChIP). The CM from CAFs enhanced the proliferation, migration, and epithelial-mesenchymal transition (EMT) of NSCLC cells. Our experiments revealed that the metabolites from CAFs, particularly lactate, had a promoting effect on NSCLC. In lactate-treated NSCLC cells, the expression levels of stemness genes were significantly upregulated, accompanied by increased lactylation levels of H3K18. In in vivo experiments, tumors from the lactate treatment group exhibited higher growth rates and increased expression of stemness genes. Furthermore, human NSCLC tumor tissues showed significant upregulation of stemness genes. This study demonstrates that lactate derived from CAFs promotes the expression of stemness genes by mediating H3K18 lactylation in the promoters of these genes in NSCLC cells, thereby accelerating the malignant phenotype formation of NSCLC cells. These findings provide new insights into the role of CAFs in the TME and identify potential therapeutic targets for NSCLC.