Distal pancreatectomy with celiac axis resection (DP-CAR) is an established procedure for the resection of celiac-trunk-infiltrating carcinomas of the pancreatic corpus or cauda. In contrast, total pancreatectomy with celiac axis resection (TP-CAR) remains a controversial procedure, which is sporadically mentioned in the literature. This study aimed to compare perioperative and survival outcomes following TP-CAR with those of the established DP-CAR operation.

Laslo et al. recently reported a guided denoising diffusion implicit model for spatial tumor growth prediction on magnetic resonance imaging (MRI) in pediatric diffuse midline glioma. Their proof-of-principle study demonstrates the feasibility of generative artificial intelligence (AI) for producing patient-specific tumor growth maps as an early step toward informing personalized radiotherapy planning in data-limited pediatric neuro-oncology settings. However, the external validation cohort comprised only 13 patients, and growth-region prediction performance, measured using the continuous Dice coefficient (cDICE; median ≈ 0.22; range 0.071-0.376), was considerably weaker than full-tumor performance (cDICE median ≈ 0.81; range 0.439-0.877). In this Matters Arising, we provide a focused methodological commentary on several issues that should be considered when interpreting the translational implications of this work.

Metastasis remains the principal cause of cancer mortality, with the lungs representing one of the most frequent and clinically challenging sites. The tumor microenvironment, particularly tumor-associated macrophages (TAMs), plays a pivotal role in establishing and maintaining metastatic niches. Yet, how host ketone bodies influence the immune microenvironment to govern metastatic progression is poorly defined.

Nuclear receptor coactivator 3 (NCOA3) is associated with various cancers, but its function and mechanism in glioblastoma multiforme (GBM) are still unclear. Bioinformatics analysis, in vitro cell experiments (NCOA3 silencing (si-NCOA3) or NCOA3 small-molecule inhibitor SI-2), in vivo animal models, and metabolic level detection were used to elucidate the activity of NCOA3 in GBM. The data revealed that GBM tissues had NCOA3 overexpression, which was linked with poor prognosis. It regulates pathways related to glycolysis, the cell cycle, and immunosuppression. Functionally, si-NCOA3/SI-2 suppressed GBM cell proliferation and migration. In vivo, sh-NCOA3/SI-2 demonstrated anti-glioma effects. Metabolically, treatment with si-NCOA3/SI-2 reduced glucose uptake, pyruvate and lactate production, ATP levels, and glycolysis-related enzyme expression in GBM cells. Combination therapy with SI-2 and TMZ enhanced GBM cell sensitivity to TMZ. Single-cell RNA sequencing revealed high NCOA3 expression in glioma stem cells (GSCs). si-NCOA3 inhibited GSCs proliferation and self-renewal while reducing the expression of Nestin and SOX2. NCOA3 is an oncogene in GBM. In mechanism, NCOA3 promotes GBM progression by enhancing the Warburg effect. In addition, NCOA3 is also highly expressed in GSCs and significantly promotes their proliferation and self-renewal ability. NCOA3 may represent a promising therapeutic target for GBM.

Cutaneous T-cell lymphoma (CTCL) and classic Hodgkin lymphoma (cHL) are distinct lymphoid neoplasms with differing cells of origin and immunophenotypes. Morphological overlap between these entities can pose significant diagnostic challenges, particularly in patients with a concurrent or prior lymphoma diagnosis.

Clear cell renal cell carcinoma (ccRCC) exhibits substantial molecular and clinical heterogeneity, contributing to variable disease progression and therapeutic outcomes. We previously identified a de-clear cell differentiation (DCCD) tumor state characterized by loss of canonical clear-cell features and aggressive clinical behavior. This study aimed to translate DCCD-associated biology into a prognostic framework and investigate its underlying molecular basis. Using TCGA-KIRC as the training cohort, we developed a five-gene prognostic signature comprising COL7A1, IGFN1, AJAP1, SMIM24, and ADGRV1, which consistently stratified patient survival across multiple public and institutional cohorts. Comparison with SSIGN, Leibovich, and ClearCode34-like models demonstrated that the DCCD signature provided complementary prognostic information. High-risk tumors exhibited enhanced proliferative and invasive programs, increased IL6-JAK-STAT3 pathway activity, and an immune-excluded microenvironment. Associations with treatment response were also observed in retrospective therapeutic cohorts. Integrated analyses of bulk and single-cell transcriptomics, spatial transcriptomics, tissue microarrays, CPTAC proteomics, and molecular interaction networks identified SMIM24 as an epithelial-associated factor linked to favorable outcomes and preserved metabolic programs. Functional experiments showed that SMIM24 overexpression suppressed migration, invasion, three-dimensional spheroid invasion, and clonogenic growth in ccRCC cells, accompanied by reduced JAK1 and STAT3 phosphorylation and decreased PD-L1 expression. Pharmacological activation of STAT3 with Colivelin partially restored PD-L1 expression in SMIM24-overexpressing cells. Collectively, these findings support the reproducibility of the DCCD-associated prognostic framework and identify SMIM24 as a candidate suppressor of ccRCC aggressiveness and PD-L1 expression, potentially acting in part through reduced STAT3 activation.

Lung cancer progression is governed not only by tumour-intrinsic genetic alterations but also by dynamic communication between tumour cells and the surrounding microenvironment. An important component of this communication is the tumour secretome, comprising soluble factors and extracellular vesicles (EVs), which contribute to the regulation of tumour growth, invasion, immune evasion, and therapeutic resistance. Through these mechanisms, secretome components and EVs promote phenotypic plasticity, microenvironmental remodelling, and adaptive responses to hypoxia, immune surveillance, and therapeutic stress. Importantly, secretome-derived factors and EVs are released into accessible biofluids, including blood, bronchoalveolar lavage fluid, and pleural effusions, highlighting their potential as minimally invasive biomarkers. In this review, we examine the lung tumour secretome, including both soluble secreted factors and EVs, with an emphasis on their contributions to tumour progression, metastasis, immune modulation, and resistance to targeted therapies, immunotherapy, and radiation. We discuss methodological advances and persistent technical challenges in EV isolation, characterisation, and molecular profiling that influence reproducibility and interpretation. We further evaluate emerging clinical applications, including liquid biopsy, treatment monitoring, and therapeutic targeting, and consider their integration within precision oncology frameworks. Finally, we highlight key barriers to clinical translation and outline priorities for future research, including methodological standardisation, prospective clinical validation, and the development of strategies to target tumour-derived secretory signalling selectively.

Patients with unresectable pancreatic ductal adenocarcinoma (PDAC) frequently experience impaired treatment continuity, and many cannot reach second-line treatment. We evaluated whether pretreatment geriatric nutritional risk index (GNRI) could identify patients at risk of impaired treatment continuity, treatment-related adverse events, and shorter survival.

R-CHOP-treated diffuse large B-cell lymphoma (DLBCL) shows heterogeneous outcomes. High-risk relapsed/refractory (R/R) patients, especially activated B-cell (ABC) and double-/triple-hit subtypes, have poor prognosis, highlighting an urgent need to uncover the underlying aggressive molecular mechanisms. Epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) properties drive its invasion, metastasis, and drug resistance. This study investigated the regulatory role and mechanism of Hedgehog (Hh) pathway key factor GLI1 in DLBCL. Immunohistochemistry detected GLI1, Bmi1, and SOX2 expression in DLBCL tissues. DLBCL cell lines (HBL-1, SUDHL-2) were treated with pan-GLI inhibitor GANT61, or transfected with GLI1 overexpression/silencing plasmids combined with Bmi1 intervention. CCK-8, flow cytometry, RT-qPCR, Western blot, Co-IP, tumor sphere, and immunofluorescence assays were performed. In vivo xenograft experiments were conducted to verify GANT61's anti-tumor effect. GLI1 was aberrantly activated in DLBCL tissues and positively correlated with Bmi1/SOX2. GANT61 inhibited DLBCL cell proliferation, induced G0/G1 arrest and apoptosis, reversed EMT, and reduced CSC-related molecules. Co-IP confirmed GLI1-Bmi1 interaction. GLI1 overexpression enhanced proliferation, EMT, and CSC properties, while GLI1 silencing exerted opposite effects. Bmi1 inhibitor reversed GLI1's pro-tumor effects, and Bmi1 agonist partially restored GLI1 silencing-induced inhibition. In vivo, GANT61 significantly reduced tumor volume/weight in HBL-1 xenografts with good tolerability. GLI1 modulates EMT-like plasticity and stem cell traits in DLBCL via direct protein interaction with Bmi1, confirming a functional regulatory connection between these two molecules that forms the core Hh-GLI1-Bmi1 regulatory pathway. Targeting this axis provides a novel therapeutic strategy for DLBCL. Key words: Hedgehog signaling pathway; Diffuse large B-cell lymphoma (DLBCL); Epithelial-mesenchymal transition (EMT); Cancer stem cell properties; GLI1-Bmi1 axis; GANT61; Xenograft model.

Transcription factor SNAI1 guides plasticity and invasiveness in cancer. Using a complete SNAI1 knockout in mesenchymal, triple-negative breast cancer cells, unbiased genome-wide transcriptomic analysis revealed a marked under-expression of integrin-based adhesion and endocytic components. Utilizing this knockout cell model, complementary breast cancer cell models and functional screening of multiple differentially expressed genes, we found that the pioneering transcription factor FOXA1, whose expression is repressed by SNAI1, associates with several key mediators of the cellular phenotype. FOXA1 represses the small GTPase ARF6 and its exchange factor PSD4. In addition, some of the integrin and matrix metalloproteinase genes are regulated by the transcriptional FOXA1 signal. Accordingly, SNAI1 knockout cells presented poor adhesion to collagen type I or fibronectin, formed defective invadopodia and focal adhesions with weakened FAK/SRC signaling. SNAI1 knockout cells performed ineffective receptor-mediated internalization, including nanoparticle and extracellular vesicle (EV) uptake, exhibited reduced lysosomal content, lacked multivesicular bodies enriched in intraluminal vesicles and showed decreased EV secretion. Gain-of-function experiments demonstrated that SNAI1 has an impact on the PSD4/ARF6 signaling module, using FOXA1 as an intermediate factor to regulate EV release by tumor cells. We propose that the SNAI1-FOXA1 transcriptional mechanism operates at the level of membrane and vesicular trafficking control, which interlinks cell plasticity, adhesion and invasiveness through the extracellular environment, with the associated process of EV secretion.

Mefatinib, a novel second-generation epidermal growth factor (EGFR) tyrosine kinase inhibitor that has shown promising antitumor activity in targeting non-small cell lung cancer (NSCLC) with common and uncommon EGFR-activating mutations. In this phase III, randomized, double-blind trial in China, 336 eligible patients with advanced nonsquamous NSCLC harboring EGFR L858R or exon 19 deletion (ex19del) were assigned (2:1) to receive either mefatinib (60 mg daily, n = 223) or gefitinib (250 mg daily, n = 113). The primary endpoint was progression-free survival (PFS), assessed by an independent review committee (IRC). The trial is registered with chinadrugtrials.org.cn (CTR20192297). After a median follow-up of 15.9 months for mefatinib and 18.5 months for gefitinib, mefatinib demonstrated a significantly longer median IRC-assessed PFS compared to gefitinib (13.7 vs. 9.7 months; hazard ratio [HR] = 0.68; 95% confidence intervals [CI]: 0.53-0.87; p = 0.002). The 30-month overall survival rate was 60.2% for mefatinib and 54.3% for gefitinib. Patients with EGFR ex19del had comparable PFS for both treatment arms (p > 0.100), whereas patients with EGFR L858R had significantly longer median PFS when treated with mefatinib than gefitinib (13.7 vs 8.3 months HR = 0.55 [95% CI: 0.38-0.78]; p = 0.001). Patients with EGFR L858R had a 30-month overall survival rate of 56.6% with mefatinib and 43.7% with gefitinib. Treatment-related adverse events ≥grade 3 were reported in 45.7% of the mefatinib group and 24.8% of the gefitinib group. No new safety signals were observed for mefatinib. Mefatinib demonstrated superior efficacy to gefitinib with a similar tolerability profile in the first-line treatment of EGFR-mutated advanced NSCLC.

Cancer stem cells (CSCs) are tumor cell subsets with self-renewal, multilineage differentiation, and tumor-initiating capacity that sustain cancer initiation, progression, metastasis, and relapse. Targeting CSCs therefore represents a promising route to improve the durability of cancer treatment. However, translation of this approach into routine care has been slow because of the biological complexity and clinical constraints. This review discusses current concepts of CSC origin and plasticity, the criteria used to define CSCs across different tumor types, and the marker systems as well as high-resolution technologies that are used to track CSC states. Developmental pathways, growth factor and cytokine cascades, as well as microenvironmental and stress responses that control CSC maintenance and therapy resistance are explored with a focus on their tractability as drug targets. We then discuss mechanisms through which CSCs escape chemotherapy, radiotherapy, and targeted agents. We review current efforts to use these pathways in designing small molecules, antibodies, cellular therapies, and vaccines aimed at CSC compartments. Heterogeneity within and between tumors, dynamic interconversion between CSC and non-CSC states, and support from specialized niches are considered as major barriers for clinical trial design, biomarker development, and response assessment. Emerging single-cell, spatial, and lineage tracing approaches, together with organoid and ex vivo platforms, are reviewed as tools that can bridge preclinical models and patient samples and guide the development of CSC-directed combination regimens. The goal is to outline translational principles that can guide future strategies for integrating CSC-focused interventions with established therapies to improve long-term disease control.

Nucleoporins (NUPs) constitute the nuclear pore complex (NPC) and are essentially involved in nuclear transport, chromatin organization, and context-dependent gene regulation. However, the role of NUPs in neuroendocrine (tumor)biology and related diagnostic potential is poorly defined. In this study, we comparatively analyzed immunohistochemical expression patterns of NUP98 and NUP153 (sharing structural and functional similarities) across a large variety of human tissues and tumors (total N > 600), with a focus on neuroendocrine neoplasms (NENs (n = 361)). While both NUPs showed a nuclear rim accentuated staining pattern, NUP98 exhibited ubiquitous and NUP153 a striking cell- and tissue/tumor-type-dependent immunoreactivity. More specifically, NUP153 immunoreactivity was consistently detectable in neuroendocrine tissues (e.g., pancreatic islets) and retained in neuroendocrine tumors (NETs) of the pancreas, lung, appendix, and small intestine, but almost completely absent in neuroendocrine carcinomas (NECs) and non-neuroendocrine carcinomas. Loss of NUP153 staining correlated with poorer clinical outcomes in pancreatic NETs. Further analyses revealed that NUP153 messenger ribonucleic acid (mRNA) and total protein levels were not significantly different between NETs and non-neuroendocrine carcinomas, as evaluated by quantitative real-time polymerase chain reaction and targeted proteomics. Differential isoform usage was ruled out by polymerase chain reaction and sequencing as another possible explanation for the discriminative immunohistochemical findings. Finally, a high density of post-translational modifications (PTMs) within the antigen sequence could be discovered and indicated PTM-dependent detection as the likely cause of differential staining. Collectively, our findings suggest that NUP153 is a differentiation-dependent and PTM-sensitive immunohistochemical marker in NENs with diagnostic and prognostic potential. It also emphasizes the importance of orthogonal molecular analyses for correct interpretation of IHC stainings.

Although immune checkpoint inhibition has proven highly effective in patients with metastatic or advanced squamous cell carcinomas, such as oral cancer, the role of innate immune responses in regulating oral cancer progression remains poorly understood. In this study, we examined the impact of innate immune responses in an orthotopic oral squamous cell carcinoma model (NR-S1-Luc cells) using bioluminescence imaging. In severe combined immunodeficiency mice lacking adaptive immune cells, CD11b+ Ly6Ghi Ly6Chi (Ly-6G+) myeloid cells accumulated more prominently than CD11b+ Ly6Gint Ly6Chi (Ly-6C+) cells within NR-S1-Luc tumors. Although Ly-6G+ myeloid cells were predominant in orthotopic NR-S1 tumors, in vivo depletion of Ly-6G+ cells did not alter tumor growth. Treatment with a Toll-like receptor 3 (TLR3) agonist (poly I:C) significantly inhibited tumor growth, accompanied by enhanced inflammation and upregulation of Ly-6C expression on Ly-6G+ myeloid cells. Moreover, depletion of Ly-6G+ cells partially impaired this TLR3-mediated effect. Transcriptomic analysis of Ly-6G+ myeloid cells from NR-S1-Luc tumor-bearing mice revealed that poly I:C treatment induced functional reprogramming of these cells, accompanied by broad alterations in immune-related and metabolic pathways within the orthotopic oral tumor microenvironment. Collectively, these findings suggest that tumor-infiltrating Ly-6G+ myeloid cells are functionally plastic and can be reprogrammed by TLR3 stimulation, thereby contributing to the regulation of tumor progression.

In this study, we engineered pH/glutathione dual-responsive nanoparticles (LP/CC-Cu-Cur NPs) based on a poly-γ-glutamic acid (γ-PGA)/chitosan (CS) core-shell architecture for synergistic chemo/chemodynamic therapy of glioma. The nanoparticles feature a core of CC-Cu-Cur NPs, formed via Cu2+-coordinated self-assembly of caffeic acid-grafted CS and curcumin (Cur), encapsulated within a phenylboronic acid-conjugated γ-PGA shell through pH-sensitive borate ester bonds. Surface modification with lactoferrin conferred brain-penetrating and glioma-targeting capabilities. The resulting spherical nanoparticles had a uniform size of 235.89 nm, a zeta potential of -22.66 mV, and high Cur loading (6.02%) and encapsulation efficiency (83.09%). Upon exposure to the acidic tumor microenvironment, the nanoparticle shell detaches, reversing surface charge from negative to positive, thereby enhancing cellular uptake and mitochondrial targeting. Intracellular glutathione then triggers core degradation, releasing Cur and Cu2+. Cur induces mitochondrial apoptosis, while Cu2+ catalyzes a Fenton-like reaction, converting endogenous hydrogen peroxide into highly cytotoxic reactive oxygen species. In vitro, the nanoparticles showed enhanced blood-brain barrier penetration, efficient lysosomal escape, and potent cytotoxicity against GL-261 cells (IC50 = 18.34 μg/mL) via a synergistic action of Cu2+ and Cur (CI = 0.28). In vivo, LP/CC-Cu-Cur NPs achieved superior brain accumulation and antitumor efficacy, highlighting their potential as a promising strategy for glioma therapy.

Acquired resistance limits the durability of programmed cell death protein-1 (PD-1) blockade in lung adenocarcinoma, yet the tumor-intrinsic programs and immune circuits that drive acquired resistance relapse remain poorly defined. The purpose of this study was to identify tumor-intrinsic mediators of acquired resistance and determine how they remodel antitumor immunity.

A woman in her early 20s at 30 weeks of gestation presented with elevated blood pressure, transaminitis, progressive dyspnoea, orthopnoea, exertional chest pain and peripheral oedema, raising concern for preeclampsia-associated cardiopulmonary disease or peripartum cardiomyopathy. Transthoracic echocardiography showed preserved left ventricular systolic function, normal left-sided filling pressures, right ventricular dilatation and an estimated right atrial pressure of 15 mmHg; N-terminal pro-brain natriuretic peptide was 57 pg/mL. Cross-sectional imaging revealed a large multi-cystic anterior mediastinal mass occupying the left hemithorax, displacing the heart and abutting/compressing major cardiopulmonary structures. Labour was induced at 34 weeks after clinical stabilisation. Three months postpartum, the patient re-presented with worsening dyspnoea and haemoptysis and underwent complete surgical resection. Pathology confirmed mature cystic teratoma and cardiopulmonary symptoms resolved after resection.

Antenatally detected cystic abdominal masses in neonates pose a diagnostic challenge, particularly in female infants where ovarian pathology is common but heterogeneous. We report a term female neonate with a large intra-abdominal cyst detected antenatally and persisting postnatally. Imaging revealed a well-defined, unilocular, avascular cyst without solid components, initially suggestive of an enteric duplication cyst. Postnatal imaging was non-specific as to the origin of the lesion. Given the size and persistence of the lesion, surgical exploration was undertaken. Intraoperatively, the mass was found to arise from the right adnexa, and histopathological examination confirmed a serous cystadenoma of the ovary. This rare diagnosis highlights the limitations of imaging in distinguishing benign abdominal cysts from uncommon ovarian neoplasms and underscores the importance of a structured diagnostic approach and timely surgical intervention in selected cases.

Although B-cell lymphomas are the most common malignancies in people living with HIV, T-cell lymphomas, such as anaplastic large cell lymphoma (ALCL), have also been described in people living with HIV, with frequent extranodal involvement and a poor prognosis when associated with a lack of anaplastic lymphoma kinase (ALK) expression. We present a case of a man in his late 30s with a 2 year history of HIV and adequate antiretroviral therapy (ART) adherence who presented with worsening oppressive low back pain radiating to the abdomen and constitutional symptoms. Imaging revealed retroperitoneal lymphadenopathy and biopsy showed CD30+and ALK-negative large atypical anaplastic lymphocytes consistent with ALK-negative ALCL. As expected in ALK-negative ALCL, the patient deteriorated quickly and died hours after starting chemotherapy. This case highlights the importance of including HIV-associated malignancies, including T-cell lymphomas, in our differential diagnosis to allow prompt initiation of targeted therapy in case of a rapidly progressing malignancy.

Many patients with N-methyl-D-aspartate receptor (NMDAR) encephalitis show persistent neurological or psychiatric symptoms, despite immunotherapy. The neuroanatomical basis of these symptoms remains uncertain. Morphological complexity analysis with fractal dimensionality has emerged as a sensitive neuroimaging method in related conditions, but remains unexplored in autoimmune encephalitis. We aimed to characterise morphological brain complexity, symptom trajectories from peak illness to the post-acute stage, and the relationship between structural brain changes and post-acute outcomes in patients with NMDAR encephalitis.