The gut microbiota is increasingly recognized as a critical external regulator along the gut-liver axis, influencing hepatocarcinogenesis and modulating responses to immunotherapy. However, the specific microbial determinants, underlying mechanisms, and potential clinical applications remain incompletely elucidated.

Building on the observed association between gut microbiota and anti-programmed cell death protein-1 (PD-1) immunotherapeutic efficacy in patients with hepatocellular carcinoma (HCC), we leveraged a suite of clinically relevant murine HCC models to comprehensively characterize tumor-associated microbial signatures using 16S ribosomal RNA gene sequencing. By precisely manipulating microbial composition through a non-hepatotoxic antibiotic cocktail 3 (ABX-3), targeted microbial supplementation, human fecal microbiota transplant (FMT), and controlled Bacteroides thetaiotaomicron (B.th) repopulation following gut sterilization with ABX-5, we demonstrated a direct causal relationship between microbiota modulation and intrahepatic immune activation. Single-cell RNA sequencing of hepatic non-parenchymal cells, together with functional validation experiments, was performed to elucidate the underlying immune mechanisms.

Bacteroides-enriched gut microbiota derived from anti-PD-1-responsive patients with HCC significantly suppressed tumor growth in murine HCC models. In parallel, within our murine HCC system, ABX-3 administration, implemented as both a preventive and therapeutic intervention, attenuated tumor initiation and progression by selectively enriching Bacteroides within the gut microbial community. Functionally, ABX-3 enhanced the capacity of tumor antigen-specific T-cell receptor-I T cells to mount robust immune responses, culminating in targeted tumor regression following antigen-specific immunization. Among the Bacteroides species, B.th emerged as a critical mediator that potentiated αPD-1 immunotherapy in HCC by relieving Krüppel-like factor 2 (KLF2)-dependent suppression in dendritic cells (DCs). Mechanistically, the KLF2-toll-like receptor 9 (TLR9) signaling axis in DCs governed the activation of antigen-specific CD8⁺ T cells, thereby amplifying antitumor immunity within the HCC microenvironment.

B.th is identified as a key immunomodulatory species that enhances anti-PD-1 efficacy by reprogramming DCs through the KLF2/TLR9 signaling pathway. These findings reveal a novel microbiota-informed strategy to improve immunotherapeutic outcomes in HCC.

Cytokine-release syndrome (CRS) is a common toxicity of chimeric antigen receptor (CAR) T cells. CRS is often treated with corticosteroids such as dexamethasone. Dexamethasone is also used to treat multiple myeloma. To model CRS after CAR T-cell treatment of multiple myeloma (MM), three cell types are required: monocyte-lineage cells, CAR T cells, and MM cells. Some cytokines important in CRS, including interleukin (IL)-6, are released mainly by monocyte-lineage cells.

We added cells of an acute monocytic leukemia cell line (THP-1) to co-cultures of anti-B-cell maturation antigen (BCMA) CAR T cells (CAR-BCMA) and BCMA⁺ target cells. Addition of THP-1 cells to the co-cultures led to increased levels of IL-6 and monocyte chemoattractant protein-1 (MCP-1) in culture supernatants. We developed a murine CRS model. This model included engraftment of THP-1 into NOD-scid common γ-chain-deficient mice to provide a source of some cytokines associated with CRS, including IL-6 and MCP-1. The murine model also included engraftment of the bioluminescent BCMA⁺ MM cell line MM.1S-veff-Luc and an infusion of CAR-BCMA. We treated CRS with dexamethasone or vehicle control.

With this model, mice exhibited signs of CRS and had elevated serum cytokine levels after CAR T-cell infusion, and CAR-BCMA eliminated large burdens of MM.1S-veff-Luc. Dexamethasone administered 1, 3, and 5 days after CAR-BCMA ameliorated CRS. Dexamethasone was associated with faster elimination of MM burdens when either a dexamethasone-sensitive cell line (MM.1S-veff-Luc) or a dexamethasone-resistant cell line (MM.1R-veff-Luc) was used as the malignancy burden. Importantly, mice that received CAR-BCMA plus dexamethasone had higher levels of splenic CAR T cells when compared with mice that received CAR-BCMA without dexamethasone. When MM.1S-veff-Luc was treated, the median splenic CD3⁺CAR⁺ cell count for mice that received CAR-BCMA plus dexamethasone was 764 473 vs 327 888 for mice that received CAR-BCMA without dexamethasone (p=0.0021).Among four patients who received anti-BCMA CAR T cells and corticosteroids on a clinical trial, CAR⁺ cell levels continued to increase after initiation of corticosteroids in all patients.

In summary, our results should encourage further clinical research to design corticosteroid regimens that optimize treatment of CAR T-cell toxicities while maintaining anti-malignancy activity.

NCT03602612.

This review provides an updated and comprehensive overview of the diagnosis and management of splanchnic venous thrombosis (SVT), a rare but clinically important manifestation of venous thrombosis involving the portal, mesenteric, splenic, and hepatic veins. The aim of this article is to summarize and critically appraise recent advances in the evidence base for anticoagulant therapy, prognosis, and clinical decision-making across the diverse clinical settings in which SVT occurs, including the most important subgroups of liver disease, myeloproliferative neoplasms, and solid malignancy. The review integrates findings from prospective studies, meta-analyses, and registry data and highlights the evolving role of direct oral anticoagulants (DOACs) as an alternative to vitamin K antagonists and low-molecular-weight heparins. Meta-analyses demonstrate that anticoagulation increases the likelihood of vessel recanalization and improves survival in cirrhotic portal vein thrombosis (PVT) without increasing major bleeding. Pooled data suggest that DOACs achieve at least comparable efficacy to conventional anticoagulant drugs, with lower rates of thrombus growth and major bleeding, while low-dose rivaroxaban has proven effective for secondary prevention in chronic non-cirrhotic PVT. In cancer-associated SVT, anticoagulation reduces recurrence with acceptable bleeding risk, and in Budd-Chiari syndrome, DOACs show promising safety and efficacy in selected patients. Despite major progress in recent years, most evidence still remains observational, and randomized trials, pediatric data, and studies on long-term secondary prevention are urgently needed to further refine and standardize SVT management.

Head and neck squamous cell carcinoma (HNSCC) exhibits heterogeneous tumour-immune microenvironments that limit the utility of single biomarkers such as programmed death-ligand 1 (PD-L1) and tumour mutational burden (TMB) for guiding immune checkpoint inhibitor (ICI) therapy. This study developed and validated the Ecotype-Integrated Response Model for HNSCC (EIRM-HN), integrating single-cell states, spatial transcriptomic niches, and bulk transcriptomes to derive immune ecotypes that stratify ICI outcomes.

This retrospective multi-cohort study analysed 370 HNSCC cases (80 molecular, 210 immunotherapies, 80 control) profiled by single-cell RNA sequencing, spatial transcriptomics, and bulk RNA sequencing. Immune ecotypes were derived from integrated single-cell and spatial features, converted into weighted gene signatures, and projected into bulk ICI cohorts to train penalised Cox and logistic models and compare performance against PD-L1, tumour mutational burden, and published signatures, with external prognostic validation in the GSE65858 bulk cohort.

Among 210 ICI-treated patients, four ecotypes occurred at similar frequencies. The most suppressive ecotype showed low CD8⁺ T-cell abundance, high regulatory T-cell abundance, and increased stromal fraction, with median progression-free survival of 3.8 months and overall survival of 9.1 months, versus 9.8 and 20.3 months in the lymphoid-enriched ecotype. EIRM-HN achieved progression-free and overall survival concordance indices of 0.71 and 0.70, improving to 0.75 and 0.74 after adding clinical covariates, and exceeding PD-L1 and TMB. In GSE65858, overall survival concordance index was 0.67 with a hazard ratio of 1.89 for high- versus low-risk strata.

An ecotype-based, spatially anchored risk model integrating single-cell, spatial, and bulk transcriptomic data provides improved prognostic stratification of HNSCC relative to established biomarkers and generalises to an external bulk cohort.

Automated segmentation using artificial intelligence (AI) has the potential to rapidly perform three-dimensional (3-D) segmentation of small renal masses (SRM). The objective of this study was to test for clinically and statistically significant differences in time spent segmenting, accuracy, and reliability when comparing manual and automated segmentation of computed tomography (CT) scans with SRM.

Patients with a CT scan, SRM <4 cm, and renal neoplasm were identified through an institutional database. Of the 854 patients identified, 184 were excluded. Forty test cases were randomly selected. There were 630 cases for training (using nnU-Net) to which 488 cases from the KiTS23 open-source data set were added. Each of the test cases was segmented by a radiologist, a urologist, and the AI model. Time to segment and Dice coefficients were compared. Deidentified segmented CTs were provided to two independent radiologists who attempted to identify the segmentor and rated the acceptability of the segmented images on a five-point Likert scale.

There were 39 cases with complete timing data. The median time for the AI model to segment was one third of the radiologist's (152.4 s, interquartile range [IQR] 120.9-177.8 vs. 450 s, IQR 318.8-551.2) and about one-fifth of the urologist's (800.0 s, IQR 492.0-1538.0) (p<0.001). There was a high degree of inter-rater reliability (median Dice coefficients 0.86-0.90, p=0.09). The scoring radiologists were able to correctly identify the true segmentor in 61.6% of cases (p <0.001). The AI segmentations were scored highest among the three segmentors (median score 4.1/5, standard deviation [SD] 1.0) compared to 3.8 (SD 0.7) for the radiologist, and 3.3 (SD 0.7) for the urologist.

Automated segmentation of CT scans for patients with SRM was efficient, accurate, and acceptable in this study. This approach has the potential to greatly improve the clinical use of radiomics to assess medical images for these patients.

Multiple myeloma, the second most common hematologic malignancy, accounts for approximately 10% of all blood cancers. Therapeutic advances have transformed multiple myeloma from a uniformly fatal disease into a chronic, manageable condition. Autologous stem cell transplantation (ASCT) remains a cornerstone of frontline treatment, demonstrating superiority in progression-free survival (PFS) and minimal residual disease (MRD) negativity compared with chemotherapy alone or modern induction regimens without transplant. International guidelines continue to recommend ASCT as the standard of care for eligible patients. Maintenance therapy post ASCT further improves PFS and overall survival, although it carries a modestly increased risk of secondary malignancies. Meanwhile, novel immunotherapies, including chimeric antigen receptor T cells and bispecific antibodies, are reshaping treatment strategies, showing strong efficacy in relapsed/refractory multiple myeloma. Ongoing trials are evaluating their role in frontline settings, with the potential to complement or replace ASCT. The future of multiple myeloma management hinges on precision medicine, using MRD assessment, genomic profiling, and patient-specific risk stratification to guide therapy. As these personalized approaches are integrated alongside established therapies, the goal of achieving long-term remission and potentially a cure becomes increasingly attainable.

Immunotherapy has transformed the treatment of a variety of malignancies, including breast cancer. Given the unmet clinical need, immunotherapy was first studied in advanced-stage, triple-negative breast cancer (TNBC). The anti-PD-1 agent pembrolizumab plus chemotherapy is approved for both advanced and early TNBC, and data from randomized phase 3 trials in high-risk, early-stage, hormone receptor-positive breast cancer have demonstrated promising efficacy. Ongoing trials aim to identify the most appropriate patients for treatment, amount and timing of immunotherapy needed for optimal outcomes, and ideal combination of therapies to maximize survival while minimizing toxicity. The future of immunotherapy in breast cancer will continue to evolve with the advent of novel immunologic agents. In this review, we highlight pivotal trials that have informed current practice and ongoing trials that may inform the therapeutic landscape in the coming years.

Diethyl phthalate (DEP), a widely used plasticizer with endocrine-disrupting properties, has raised concerns regarding its potential carcinogenic effects. However, its precise role in colorectal cancer (CRC) development remains poorly understood.

The chemical structure of DEP was obtained from the PubChem database. Potential targets of DEP were identified through ChEMBL and STITCH databases and intersected with known CRC-related genes to screen for candidate biomarkers. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore the biological functions and signaling pathways involved. Molecular docking was conducted to predict the binding affinities between DEP and core targets. Finally, 200-ns molecular dynamics (MD) simulations using GROMACS were employed to evaluate the binding stability and dynamic behavior of the DEP-target complexes.

A total of 62 overlapping genes were identified between DEP targets and CRC-associated genes. GO and KEGG enrichment analyses indicated enrichment in epigenetic regulation, chromatin remodeling, and cancer-related signaling pathways, including Notch, TGF-β, and FoxO. Protein-protein interaction analysis identified EP300, EZH2, HDAC1, HDAC2, and KDM1A as key epigenetic regulators. Molecular docking predicted moderate binding affinities between DEP and these targets (-6.6 to -5.7 kcal·mol ⁻ ¹). Subsequent 200-ns MD simulations suggested that DEP formed stable complexes with HDAC1, KDM1A, and EZH2, moderate stability with EP300, and partial dissociation with HDAC2, consistent with hydrophobic and hydrogen-bonding interactions at the binding interfaces.

This study provides a theoretical framework for exploring the molecular mechanisms through which DEP may contribute to CRC development, emphasizing the value of network toxicology in cancer research. These findings may inform future investigations into the risks of DEP exposure and support public health policy and the development of targeted therapeutic strategies.

Head and neck squamous cell carcinoma (HNSCC) is a significant cause of morbidity and mortality worldwide, with limited treatment options for patients with locally advanced disease. CD47 immune checkpoint inhibitors have been used to block the CD47/SIRPa interaction that inhibits antigen-presenting cell phagocytosis, thereby enhancing antigen presentation to cytotoxic T-cells, and have shown promise in combination with anti-PD1 immunotherapy in tumors, including recurrent/metastatic HNSCC. We found that CD47 expression is associated with poor prognosis in HNSCC and explored the anti-tumor activity of an anti-CD47 fusion protein in combination with anti-PD1 and lymphatic-sparing radiotherapy in a locally advanced HNSCC model. In the 4MOSC1 syngeneic HPV-negative HNSCC mouse model, ALX301 (an engineered CD47-blocking SIRPα fusion for murine models) induced complete tumor regression when combined with anti-PD-1, and produced a partial tumor response as a monotherapy. An anti-PD1 immune checkpoint inhibitor in a CD47-null tumor background led to complete tumor regression confirming a key role for CD47 in tumor immunity. ALX301 treated mice demonstrated increased MHC-II expression on dendritic cells within the tumor and upregulation of CD86 co-stimulatory molecule on dendritic cells within the tumor, sentinel lymph nodes, and contralateral lymph nodes. Combination ALX301 and anti-PD1 treatment in an anti-PD1 resistant 4MOSC2 model demonstrated significant tumor regression, enhanced survivability, improved response with neoadjuvant radiotherapy, and greater retention of CD8 + T-cells within the tumor microenvironment. Notably, T-cell receptor sequencing revealed increased shared clonality between the tumor and sentinel lymph nodes of ALX301 treated mice. These data demonstrate that a combination of CD47 blockade and anti-PD1 therapy enhances tumor antigen presentation and immune cell infiltration, while further improving anti-tumor responses in combination with tumor-targeted radiotherapy. This study provides support for the rational design of combinatorial immunoradiotherapy, using anti-CD47 inhibitors and anti-PD1 therapy, in a clinical trial targeting locally advanced HPV-negative HNSCC.

BACKGROUND Angioleiomyoma is an uncommon benign soft-tissue tumor, typically found in the lower extremities. Angioleiomyoma is infrequently observed in the hand, and occurrences involving calcification are even less common. In patient with end-stage renal disease (ESRD) who receive hemodialysis, calcified angioleiomyoma can be challenging to distinguish diagnostically due to its resemblance to tumoral calcinosis. We report a unique case of calcified angioleiomyoma on the dorsum of the left hand in an ESRD patient undergoing long-term hemodialysis, focusing on clinical, imaging, and histopathological features. CASE REPORT A 46-year-old man, on maintenance hemodialysis for ESRD, presented with a painful, enlarging left-hand dorsal mass. Simple radiographs showed a well-defined soft-tissue mass with internal calcifications. Magnetic resonance imaging (MRI) revealed a well-circumscribed ovoid lesion with iso-intensity on the T1-weighted image and a heterogenous signal on the T2-weighted image, with no enhancement. He underwent complete marginal resection, and the histopathology confirmed angioleiomyoma with prominent dystrophic calcifications and positive smooth-muscle actin (SMA) immunostaining. No recurrence was seen at the 1-year follow-up. CONCLUSIONS This case highlights angioleiomyoma as a rare cause of painful hand nodules. Soft-tissue calcified masses must be differentiated from tumoral calcinosis and other benign tumors, especially in hemodialysis patients. Clinicopathologic and radiologic correlation are crucial for correct diagnosis and management.