BACKGROUND AND AIMS: The endoscopic grading of gastric intestinal metaplasia (EGGIM) has not been comprehensively validated. Microvascular (MV) pattern abnormalities are critical for diagnosing gastric neoplastic transformation. The present study aims to validate the diagnostic accuracy of EGGIM for identifying high-risk GIM patients and to develop a modified EGGIM model incorporating microvascular pattern, evaluating its diagnostic performance for risk stratification of GC development in GIM patients. METHODS: All patients underwent EGGIM scoring and microvascular pattern evaluation. Targeted or random biopsies were performed at the antrum, incisura, and corpus, followed by operative link on gastric intestinal metaplasia assessment (OLGIM). The sensitivity, specificity, positive likelihood ratios (PLR), and positive predictive values (PPV) of both EGGIM and the modified EGGIM model for assessing GC risk in GIM patients were validated. RESULTS: A total of 144 patients were enrolled. The area under curve (AUC) of the receiver operating characteristic of EGGIM for diagnosing OLGIM III-IV was 0.885 (95% CI 0.837-0.943). At the cutoff value ≥4, the sensitivity, specificity, PLR, and PPV were 90.90%, 73%, 3.36, and 50%, respectively. Altered microvascular pattern was identified as a risk factor for high-risk GC development in GIM ( < 0.001; odds ratio [OR] = 4.696; 95% CI 2.792-7.896). The modified EGGIM model achieved an AUC of 0.921 (95% CI 0.873-0.968) for identifying OLGIM III-IV; at the cutoff value ≥ 2.5, the sensitivity, specificity, PLR, and PPV were 97%, 66.70%, 2.91, and 46.4%, respectively. After incorporating MV, the AUC of the EGGIM score increased from 0.885 to 0.921, suggesting improved diagnostic performance. CONCLUSIONS: Microvascular pattern serves as a significant independent predictor for OLGIM III-IV. The modified EGGIM demonstrated good diagnostic performance for OLGIM III-IV, suggesting its potential as a non-invasive endoscopic tool for assessing the risk stratification of GC development.

Ga-containing agents show great promise in tumor theranostics due to their unique physicochemical and biological features. Recent studies have extensively explored Ga-containing radiopharmaceuticals, therapeutic compounds, and multifunctional formulations, clarifying their interactions with the tumor microenvironment and antitumor mechanisms. Clinically, Ga imaging agents, especially Ga-labeled probes, have become standard tools for precise diagnosis of prostate cancer, neuroendocrine tumors, and other malignancies, while Ga therapeutic agents act by interfering with DNA metabolism, regulating tumor immunity, and inhibiting angiogenesis. This review summarizes the current research status of Ga-containing agents in tumor diagnosis and therapy, covering imaging/therapeutic mechanisms and clinical applications, and clarifies their advantages and limitations. To promote their clinical translation, future efforts should focus on AI-assisted multimodal imaging, personalized theranostics, intelligent targeted delivery systems and standardized multicenter clinical promotion.

OBJECTIVE: The rising incidence of cancer in Malaysia underscores the necessity for specialized oncology social work services. Implementing a localized plan for these services would strengthen medical social workers' knowledge and skills, ultimately enhancing support for cancer patients and their families. METHODS: A total of 171 medical social work officers in public health facilities participated in a self-report survey. Additionally, five medical social work officers who directly work with cancer patients participated in in-depth interviews, and 30 primary caregivers of cancer patients participated in a focus group discussion. These participants provided perspectives on the requirements for Oncology Social Work Services in government health facilities in Malaysia. FINDINGS: The establishment of oncology social work services that incorporate the four scopes of practice defined by the Association of Oncology Social Work (AOSW) within Malaysia's public health system is essential and creates opportunities for generalist medical social work officers to specialize in this critical field. CONCLUSION: Implementing a standardized oncology social work framework improve efficiency and enhancing clinical practice and discipline-specific responsibilities in psychosocial oncology.

OBJECTIVE: The internalization into gastric epithelial cells may play a critical role in pathogenicity and evasion of antibacterial agents. However, many issues remain elusive. This review aimed to summarize the researches on internalization and its associated intervention strategies. METHODS: This descriptive review systematically analyzed studies in this field. RESULT: BabA and SabA mediate internalization, correlating with invasion into normal and inflammatory/neoplastic tissues, respectively. invades gastric epithelial cells via zipper-like (spiral strains) and trigger (coccoid strains) pathways, rather than the single zipper-like mechanism conventionally recognized. Post-internalization, reside in autophagosomes containing large and small vacuoles, distinct from the intracellular localization of and spp. It proliferates within 12-24 h independent of virulence factors and is subsequently cleared. VacA⁺ strains exhibit lower intracellular clearance rates and a linear decline compared with VacA⁻ strains. Multiple toxins and molecular targets cooperatively mediate autophagy suppression via multipathway regulation. Probiotics, natural medicines, polymeric compounds and sonodynamic therapy represent promising interventions with translational potential. Critical knowledge gaps remain regarding the direct association between internalization and eradication failure, invasion into non-gastric cancer cells, and the undefined intracellular survival time window of wild-type strains. CONCLUSION: Unlike other bacteria, invades gastric epithelial cells via two pathways and evades intracellular immunity through specific toxins. However, knowledge gaps persist. Future research should focus on these gaps and promote the translational application of potential interventions.

Radiotherapy resistance remains a major obstacle in nasopharyngeal carcinoma (NPC). Stress granules (SGs), dynamic cytoplasmic ribonucleoprotein condensates, have been linked to therapy resistance, but their role in NPC radioresistance remains unclear. Here, we show that SGs are key mediators of NPC radioresistance. Radioresistant NPC cells displayed markedly enhanced SG formation in a dose- and time-dependent manner, whereas pharmacological inhibition with ISRIB or genetic disruption of G3BP1 significantly sensitized cells to irradiation in vitro and in vivo. Integrated transcriptomic and proteomic analyses identified heterogeneous nuclear ribonucleoprotein D (HNRNPD) as a critical SG-associated RNA-binding protein upregulated in resistant cells and associated with poor prognosis. Functionally, HNRNPD promoted radioresistance by suppressing apoptosis, whereas its depletion restored radiosensitivity. Mechanistically, HNRNPD underwent RNA-dependent phase separation through its C-terminal intrinsically disordered region and interacted with G3BP1 to facilitate SG assembly. Irradiation promoted cytoplasmic accumulation of HNRNPD, while the p37 isoform preferentially bound G3BP1 and functionally drove SG formation. HNRNPD further bound GRAMD4 mRNA via its RRM1 domain and sequestered it in SG-associated compartments, thereby repressing GRAMD4 translation, suppressing mitochondrial apoptosis, and promoting survival. Restoration of GRAMD4 abrogated HNRNPD-induced radioresistance. Together, these findings establish the HNRNPD-SG-GRAMD4 axis as a key determinant of NPC radioresistance and a potential therapeutic target for radiosensitization.

Breast cancer is associated mostly with women; however, breast cancer also appears in men, which dictates the need to know about gender-specific differences in the pathology and treatment. Male breast cancer constitutes less than 1 % of all cases and is usually diagnosed when the patient is older, with bigger tumors and at later stages than breast cancer in women. The most widespread subtype in both genders is invasive ductal carcinoma. The effect of hormone receptor positivity is very prominent in the treatment of men, and the risk factors include the BRCA2 mutations and the hormonal imbalance. The management approach, such as surgery, chemotherapy, radiotherapy, and hormonal therapy, is like that of women, and it may vary in treatment effectiveness because of hormonal and biological differences. The prognostic data in males are scarce, with generally worse outcomes, most likely because of delayed diagnosis and low rates of clinical trial representation. Men with breast cancer also face special psychosocial obstacles with regard to stigma and support. The use of artificial intelligence (AI) and machine learning are emerging options that have the potential to improve detectability and personalized treatment in both genders. The current review draws similarities between breast cancer in males and females to promote gender-specific interventions and better outcomes.

Lymph node metastasis (LNM) is a pivotal determinant of poor prognosis in ovarian cancer (OC), yet how tumor-intrinsic programs remodel the microenvironment to enable spread remains unclear.Here, we identify the transcription factor mesenchymal homeobox 1 (MEOX1) as an upstream coordinator, whose overexpression associates with LNM, increased lymphatic density, and poor survival based on integrative analyses of public datasets and our 113-patient cohort. In an in vivo LNM model, MEOX1 overexpression enhances tumor burden, lymphatic vessel density, and LNM, whereas tumor-conditioned medium does not directly activate lymphatic endothelial cells (LECs), implicating stromal intermediates. Spatial transcriptomic and immunostaining analyses confirmed cancer-associated fibroblast (CAF)-LEC proximity and vascular endothelial growth factor-C (VEGF-C) localization within CAFs, supporting a CAF-dependent lymphangiogenic route. Mechanistically, MEOX1 binds the sphingosine kinase 1 (SPHK1) promoter to activate sphingosine-1-phosphate (S1P) synthesis, driving a dual autocrine-paracrine program: sphingosine-1-phosphate receptor 3 (S1PR3)-dependent signaling promotes tumor proliferation/migration, while S1P/S1PR1 reprograms fibroblasts into VEGF-C-secreting, alpha-smooth muscle actin (α-SMA)-positive CAFs that stimulate lymphangiogenesis and LNM; SPHK1 inhibition blunts these phenotypes, whereas S1P supplementation restores them. These findings provide novel insights into lymphatic metastasis and demonstrate that metastatic competence depends not only on intrinsic tumor aggressiveness but also on the acquired ability to construct a pro-dissemination niche.

Ovarian cancer (OC) remains a major cause of gynecologic cancer mortality, with progress in targeted therapy limited by an incomplete understanding of post-transcriptional oncogenic drivers. Dysregulated RNA splicing-particularly intron retention (IR)-is increasingly recognized as a key driver of tumor progression. Here, integrated transcriptomic and proteomic analyses identify SNRPF, a core spliceosomal component, as a potent oncogenic driver in OC. SNRPF is highly expressed in tumor specimens, and its overexpression predicts poor patient survival. Silencing SNRPF suppresses proliferation, invasion, and xenograft growth. IR-focused analysis reveals that SNRPF depletion induces intron 6 retention in DDX24, disrupting the Helicase_C domain and generating premature termination codons that activate nonsense-mediated decay (NMD), thereby reducing DDX24 protein abundance and markedly impairing its oncogenic function. DDX24 depletion similarly promotes intron 2 retention in E2F4, causing NMD-mediated downregulation. Notably, E2F4 directly binds the SNRPF promoter, forming a self-sustaining "SNRPF-DDX24-E2F4" axis linking splicing and transcriptional regulation. Antisense oligonucleotide-mediated inhibition of SNRPF disrupts this feedback loop, downregulates DDX24 and E2F4 via IR, and significantly impairs tumor growth in vitro, in vivo, and in patient-derived xenografts. These findings define a splicing-transcription coupling mechanism in OC and position SNRPF as a promising therapeutic target.

Nephrolithiasis is increasingly prevalent worldwide. Although metabolic dysregulation has emerged as an important feature of the disease, the specific metabolic programs within tubular epithelial cells that drive stone formation remain poorly understood. Here, we use single-cell transcriptomics to profile mouse models of nephrolithiasis and identify a marked suppression of gluconeogenesis in renal proximal tubular epithelial cells, driven by downregulation of the rate-limiting enzyme glucose-6-phosphatase (G6PC) and associated with lactate accumulation. We further show that loss of G6PC or lactate accumulation is sufficient to activate TGF-β/SMAD3 signaling, driving epithelial-mesenchymal transition (EMT) and a profibrotic epithelial program associated with enhanced crystal deposition. Mechanistically, lactate induces lactylation of the transcription factor SNAIL1 at lysine 206, facilitating its nuclear localization and transcriptional activation of TGF-β. Together, these findings establish a G6PC-lactate-SNAIL1 axis linking metabolic dysregulation to epithelial remodeling during nephrolithiasis.

This review article summarizes the development of tumor-infiltrating lymphocyte (TIL) based immunotherapy, from the pioneering work of Rosenberg, Spiess and Lafreniere to the 2024 regulatory approval of lifileucel, the first cell therapy authorized for the treatment of solid tumors. A key advantage of TIL therapy over the chimeric antigen receptor (CAR) T-cell technology is its polyclonal T-cell receptor repertoire, which enables more effective recognition of heterogeneous tumor cell populations. The therapeutic approach is based on the ex vivo expansion and activation of lymphocytes isolated from a patient's own tumor, followed by their reinfusion after lymphodepleting conditioning. The review details the major technological advances in the field, with particular emphasis on the significance of "young TIL" protocols, which preserve proliferative capacity and prevent terminal differentiation by shortening culture duration. Current challenges are also discussed, including the need for more precise selection of tumor-reactive T cells, improved tumor homing and infiltration, and reduction of treatment-associated systemic toxicities. Next-generation strategies, including modified cytokines and genetically engineered TILs, aim to replace high-dose IL-2 and intensive chemotherapy, thereby reducing side effects. Overall, the approval of lifileucel validates the clinical relevance of TIL therapy. Fine-tuning the technology through standardized manufacturing and modulation of the tumor microenvironment promises to expand its application to other solid malignancies, fundamentally reshaping cancer treatment. By addressing the limitations of earlier methods, modern TIL therapy serves not as a final solution, but as a transitional foundation for more precise and controllable cellular immunotherapies. Orv Hetil. 2026; 167(19): 740-745.

AIMS: Heart failure (HF) and acute myocardial infarction (AMI) may contribute to cancer development through shared and disease-related pathophysiological pathways. We investigated the mid-term risk of incident cancer in patients with HF or AMI using a large, real-world dataset. METHODS: Adults with a first hospitalization for acute HF or AMI between October 2015 and October 2024 were included from the TriNetX Global Collaborative Research Network. Patients with prior or concurrent cancer were excluded. Each cohort was matched 1:1 with controls without HF or AMI using propensity score matching. The primary end-point was any new cancer diagnosis occurring during follow-up, starting 6 months after the index hospitalization. RESULTS: After matching, 120 783 patients with HF and 7896 patients with AMI were included. Over a median follow-up of 13 months in the HF cohort and 16 months in the AMI cohort (after the 6-month landmark), both groups showed an higher incidence of cancer compared with controls (HF: HR 2.80 [95% CI, 2.69; 2.91]; AMI: HR 2.02 [95% CI, 1.71; 2.39]; both P < .001). In both cohorts, the excess risk was more pronounced for haematologic than for solid malignancies (HF: HR: 6.78 vs 2.53; AMI: HR: 4.45 vs 1.77). HF with preserved ejection fraction was associated with a slightly higher cancer incidence than HF with reduced or mildly reduced ejection fraction (HR 1.10 [95% CI, 1.04; 1.17], P = .002), whereas no difference was observed between ST and non-ST segment elevation AMI. CONCLUSIONS: In this large, real-world cohort, both HF and AMI were associated with an increased incidence of cancer, particularly haematologic malignancies. HF was associated with a greater excess risk than AMI. These findings are hypothesis-generating and warrant further investigation.

OBJECTIVE: KIF15, a kinesin-12 family motor protein, has emerged as a recurrently upregulated factor in multiple human malignancies and has been implicated in diverse oncogenic processes. This review aims to provide a comprehensive synthesis of the molecular biology of KIF15, its oncogenic and non-oncogenic functions, the regulatory mechanisms governing its expression and activity, and its therapeutic potential across human disease contexts. METHODS: A comprehensive literature review was conducted using PubMed, Web of Science, and Scopus to identify studies addressing KIF15 structure, mitotic and non-mitotic functions, cancer-associated mechanisms, pharmacological targeting, and germline disease associations. RESULTS: KIF15 is frequently upregulated across multiple solid tumors-including lung, breast, prostate, pancreatic, gastric, colorectal, and hepatocellular cancers-and elevated expression is commonly associated with adverse clinical outcomes. Mechanistically, KIF15 activates mitogen-activated protein kinase kinase-extracellular signal-regulated kinase (MEK-ERK), phosphoinositide 3-kinase-protein kinase B (PI3K-AKT), and epidermal growth factor receptor (EGFR) signaling, androgen receptor (AR) and its splice variant androgen receptor splice variant 7 (AR-V7) to confer enzalutamide resistance, supports glycolytic reprogramming via phosphoglycerate kinase 1 (PGK1) deubiquitination, and maintains cancer stem cells (CSCs) phenotypes through reactive oxygen species (ROS) suppression. KIF15 additionally mediates adaptive resistance to kinesin-5 (Eg5, also known as KIF11), inhibitors via protein regulator of cytokinesis 1 (PRC1)-dependent antiparallel microtubule bundling. Beyond oncology, germline KIF15 variants have been associated with increased genetic susceptibility to idiopathic pulmonary fibrosis. Several KIF15-directed preclinical probes and proof-of-concept inhibitors have been reported, and dual Eg5/KIF15 inhibition has shown synergistic antitumor effects in experimental models. CONCLUSIONS: KIF15 functions as a context-dependent regulator of mitotic adaptation and tumor progression, with reported roles in mitogenic signaling, metabolic reprogramming, and therapeutic resistance across multiple cancer types. Its chemical tractability and non-redundant role in drug-resistant spindle maintenance position it as a compelling candidate for combination anticancer strategies.

Hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR + /HER2 -) breast cancer (BC) is the most frequently diagnosed subtype of BC, accounting for approximately 70% of cases. The introduction of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) has significantly improved clinical outcomes and transformed the therapeutic landscape of HR + /HER2 - in both the metastatic and early settings.Hepatotoxicity associated with CDK4/6i is increasingly recognized as a clinically relevant adverse event. Most cases are asymptomatic, occur early during treatment, and resolve with dose modification or management according to the Summary of Product Characteristics (SmPC). However, variability in monitoring and management persists in clinical practice. Key issues, such as corticosteroid use, treatment continuation and reintroduction of the CDK4/6i (either the same compound or another among the three globally approved agents) after liver toxicity recovery, remain insufficiently addressed by current evidence, despite the need for routine clinical decision-making.To address these gaps, a Spanish multidisciplinary panel of hepatologists and medical oncologists developed expert consensus recommendations on liver toxicity in patients with HR + /HER2 - BC receiving CDK4/6i. This consensus provides practical guidance on the classification, monitoring and management of liver-related adverse events during CDK4/6i therapy and promotes proactive collaboration between oncology and hepatology teams to support treatment continuity and optimize patient outcomes.

The prognostic values of cuproptosis-related genes (CRGs) in gastric cancer with lymph node metastasis (GCLM), especially in the tumor immune microenvironment (TIME), remain unclear. We analyzed the expression, mutation, immunity, drug sensitivity, and prognostic value of CRGs in GCLM using TCGA and GEO cohorts. Consensus clustering was performed to identify CRG subtypes, with differences characterized by multi-omics analysis. A CRG-based prognostic risk score and immune score were constructed for individualized assessment, and the role of CRGs was validated through in vitro and in vivo experiments. Consensus clustering revealed that CRGs were significantly enriched in biological processes related to mitosis and energy metabolism, as well as in immune-related and cancer-associated pathways. Four distinct CRG subtypes were identified, showing marked differences in expression profiles, prognosis, genetic alterations, TIME, and chemotherapeutic drug sensitivity. We developed an exploratory CRG-based prognostic risk score for preliminary individualized assessment, and the functional relevance of CRGs in GCLM was further validated through in vitro experiments. Among these, FDX1, LIAS, DLAT, MTF1, and GLS were identified as key determinants of overall survival in patients with GCLM, with FDX1 emerging as a potential independent prognostic factor. Notably, upregulation of FDX1 significantly suppressed lymph node metastasis of gastric cancer cells in a mouse popliteal lymph node metastasis model. Our data uncovers FDX1 might be a potential favorable prognostic factors in GCLM patients. These findings may improve our understanding of CRGs in GCLM and provide new in-sights for assessing prognosis and developing more effective treatment strategies.

BACKGROUND: GTPase, IMAP family genes (GIMAPFGs) are extensively used for diagnosis and treatment in cancer, their prognostic significance and therapeutic potential in hepatocellular carcinoma (HCC) remain insufficiently explored. METHODS: GIMAPFGs associated with HCC prognosis were identified using Cox regression analysis. a prognostic model was constructed through multivariate Cox regression, the model was validated on an independent dataset. followed by an analysis of its biological function. We analyzed variations in tumor immune cell infiltration according to the prognostic signature. Meanwhile, single-cell analysis demonstrated the expression of GIMAPFGs in HCC. RESULTS: A prognostic risk model was developed using 2 GIMAPFGs (GIMAP1 and GIMAP8) and its prognostic significance was confirmed with an independent external HCC dataset, establishing it as an independent risk factor for HCC patients. This characteristic is also associated with the immune microenvironment of HCC. CONCLUSIONS: This novel GIMAPFGs signature provides a valuable tool for patient stratification and offer a new therapeutic approach for HCC.

The century-old vision of a "magic bullet" in oncology is being realized through the paradigm of precision theranostics, which formally integrates targeted delivery, cytotoxic action, and non-invasive imaging into a unified clinical feedback loop. This review synthesizes the cutting-edge convergence of three interdependent pillars: antibody-drug conjugates (ADCs), which act as Trojan horses delivering potent cytotoxic payloads; radioimmunotherapy (RIT), which harnesses the power of radionuclides for crossfire-mediated cytotoxicity; and advanced molecular imaging, which orchestrates patient stratification and early response assessment. We dissect the mechanistic innovations in ADC design, the renaissance of RIT with novel isotopes and targets, and the pivotal role of immuno-PET in enabling an "image-to-treat" paradigm. Furthermore, we explore the synergistic frontier of rationally combining ADCs and RIT to overcome resistance through multi-mechanistic attacks, leveraging radiation for payload activation, and priming the tumor microenvironment. Despite challenges in toxicity management, radiopharmaceutical supply, and regulatory frameworks, the integration of these modalities, guided by artificial intelligence and functional imaging, heralds a new era of dynamic, personalized, and adaptive cancer therapy. This integrative approach promises to convert tumor heterogeneity from a fundamental obstacle into a targetable vulnerability; however, this promise must be tempered by clinical examples in which heterogeneity undermined otherwise promising targeted approaches (for example, subclonal RAS mutations limiting benefit from anti-EGFR monoclonal antibodies in colorectal cancer). We therefore emphasize lesion-level imaging and adaptive, imaging-guided sequencing as realistic, evidence-based mechanisms by which theranostics can reduce the impact of intratumoral heterogeneity and improve the chance of durable benefit.

PURPOSE: The sensitivity of bladder cancer detection using a single biomarker from single sample type is limited. This study aimed to investigate whether a combined approach utilizing multiple biomarkers from different clinical samples could improve detection sensitivity. METHODS: A total of 85 patients with bladder cancer and 30 healthy individuals were enrolled in this study. Urine and blood samples were collected for the isolation of urine-derived epithelial cells (UDECs) and circulating tumor cells (CTCs). These cells were then analyzed via PD-L1 assay and fluorescence in situ hybridization (FISH) targeting chromosomes 7 and 8. In parallel, matched urine samples from patients underwent conventional urine exfoliation cytology testing (UEC). All data were analyzed in conjunction with pathological information using specialized statistical software. RESULTS: Analysis of CTCs demonstrated a significantly higher bladder cancer detection rate (78.6%) compared to UEC (36.7%). The combination of UDEC-FISH and CTC analysis utilizing urine and blood samples achieved a higher detection rate (94.1%) than the combination of UDEC-FISH with UEC performed on the same urine sample (79.8%). Furthermore, combined analysis of three markers of CTC, UEC, and UDEC-FISH (96.5%) or CTC, UEC, and UDEC-PD-L1 (90.6%) yielded significantly higher detection rates than any single biomarker analysis alone. CONCLUSION: Integrating multiple biomarkers from distinct sample types significantly enhances the detection sensitivity for bladder cancer.

INTRODUCTION: Pyoderma gangrenosum (PG) is a rare, autoinflammatory skin disorder characterized by painful ulcers, with scarce treatment options. Adalimumab is a recently approved tumor necrosis factor-alpha inhibitor for PG, for which real-world data remain limited. This study evaluated the long-term safety and effectiveness of adalimumab in patients with PG. METHODS: This multicenter, prospective, open-label, single-arm, postmarketing observational study enrolled patients with PG who were prescribed adalimumab and were monitored for 52 weeks. The primary outcome was safety, assessed as the incidence proportion of infections reported as adverse drug reactions (ADRs). Secondary outcomes included other safety measures and effectiveness, estimated using the Physician Global Assessment (PGA), Investigator Inflammation Assessment, and Verbal Rating Scale (VRS) for pain. Relapse rates after remission and changes in PG subtype during the observation period were also examined. RESULTS: Sixty-seven patients with PG were enrolled in the study. The mean age was 61.9 years, and 77.6% of the patients had comorbidities, including diabetes mellitus (19.4%), ulcerative colitis (16.4%), and hypertension (14.9%); 59.7% were concomitantly receiving systemic steroids. The PG subtypes among the enrolled patients were ulcerative (n = 62), pustular (n = 2), vegetative (n = 2), and bullous (n = 1). The incidence proportions of infections reported as ADRs and serious ADRs were 14.9% and 9.0%, respectively. The proportions of patients with a PGA score (total lesions) of 0/1 at weeks 12, 26, and 52 were 36.0%, 46.2%, and 57.7%, respectively, and with a VRS score of 0 at weeks 26 and 52 were 45.7% and 52.4%, respectively. No relapses occurred among patients who discontinued treatment due to symptom improvement. CONCLUSIONS: This real-world study demonstrated no new safety concerns with adalimumab and demonstrated its effectiveness, including pain relief, across a heterogeneous PG population. These findings support its use as a standard treatment for PG, including in patients receiving concomitant systemic steroid therapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04750213.

Lactylation, as a novel post-translational modification, plays a key role in gene transcription and protein expression, serving as an important link between cellular metabolism and functional regulation. Ferroptosis is a regulatory form of cell death characterized by iron-dependent lipid peroxidation, and its abnormal regulation is closely associated with the onset and progression of various diseases, including tumors, degenerative diseases, and ischemia-reperfusion injury. Recent studies have shown that lactylation can regulate ferroptosis-related pathways and key targets through multiple mechanisms, regulate ferroptosis and thereby influence disease progression. This review first comprehensively summarizes the mechanisms of lactylation and ferroptosis, then systematically reviews the regulatory mechanisms and roles of lactylation in ferroptosis, and finally, we summarize the role of lactylation-regulated ferroptosis in various diseases and its potential as a therapeutic target. The aim is to deepen our understanding of the regulatory mechanisms and roles of lactylation in ferroptosis and to lay the foundation for the development of precision treatment strategies for related diseases.

Alectinib serves as an indispensable treatment for ALK (ALK receptor tyrosine kinase)-positive non-small-cell lung cancer (NSCLC), yet its hepatotoxicity and dermatotoxicity pose significant clinical concerns due to poorly understood mechanisms. This study demonstrated that alectinib-induced dermatotoxicity was secondary to hepatotoxicity. Integrated multi-omics analysis revealed that alectinib triggered excessive macroautophagic/autophagic degradation of hepatic BTD (biotinidase), causing systemic biotin deficiency that drove both hepatocyte apoptosis and skin barrier dysfunction. Mechanistically, we discovered increased phosphorylation of NBR1 at Ser656, a previously uncharacterized site, which conferred protein stability and contributed to selective BTD degradation. Importantly, exogenous biotin supplementation concurrently mitigated alectinib-induced hepatotoxicity and dermatotoxicity, providing a strategy for safer clinical application. These results uncovered a novel paradigm in drug-induced multi-organ toxicity, in which dysregulated inter-organ crosstalk served as a central mechanistic element.

INTRODUCTION: Fusion genes represent one of the most specific molecular alterations in human cancer and have long served as important diagnostic and therapeutic biomarkers. Advances in next-generation sequencing have driven a rapid expansion in fusion gene discovery. Clinical translation has lagged however, particularly in solid tumors. This review critically examines the role of fusion genes in molecular diagnostics, focusing on opportunities, limitations and clinical implementation. AREAS COVERED: We summarize the biological mechanisms underlying fusion gene formation insofar as they influence diagnostic detection and interpretation. Current technologies for fusion detection in clinical practice are evaluated and major diagnostic pitfalls discussed. Prostate cancer is presented as a diagnostic case study to illustrate both the promise and limitations of fusion gene - based biomarkers. EXPERT OPINION: Despite their biological appeal and tumor specificity, fusion genes remain underutilized in routine diagnostics due to interpretive complexity and limited clinical validation. In our view, fusion genes are most likely to deliver sustained diagnostic value when incorporated into targeted, standardized and context-aware diagnostic frameworks rather than pursued as isolated biomarkers. Over the next five years, fusion gene diagnostics are expected to become more selective, integrative and clinically disciplined, with emphasis shifting from discovery toward validated clinical utility.

PURPOSE: The aim of this study was to describe and compare the structure and organization of orthopaedic and traumatology residency training across European countries. METHODS: A descriptive, cross-sectional survey (31 items) of national teaching experts across Europe (≥10 years of experience in training residents) focused on: specialty integration, training model (time-based/competency-based/hybrid), program duration and duty hours was conducted from October 2023 to February 2025. Standardized extraction by three blinded reviewers was done and the answers were transformed into a consensus dataset. RESULTS: Responses were obtained from 33/40 countries (82.5%). In 31/33 countries (94%), orthopaedic surgery and musculoskeletal traumatology form a unified specialty. Only 9/33 (27%) countries delineate fixed elective-orthopaedics versus trauma blocks during the course of the residency. Training models were predominantly hybrid-having both features of competency and time-based learning criteria (26/33; 78%), with 7/33 (21%) time-based and none fully competency-based. Program length was mostly 5 years (16/33; 48%) or 6 years (11/33; 33%) long. Extremes ranged from 2 to 8 years. Average weekly hours varied from 37 to 70+, with nearly half of countries reporting practice that exceeds the European Working Time Directive 48-h limit via legal exceptions or weak enforcement by hospital. Flexible (less than full time training) pathways exist in 19 (58%) countries (unrestricted in 8; restricted in 11), but remain unavailable in 14 (42%). CONCLUSIONS: European orthopaedic and trauma training programs show great similarity in terms of training duration and being a unified specialty. However, there still is a relevant difference in training models, duty hours and flexibility of prolonged training duration. There is a clear movement toward competency-based training in most of the European countries. LEVEL OF EVIDENCE: Level IV.

TL1A is a proinflammatory cytokine in the tumor necrosis factor (TNF) superfamily that signals via DR3 on T helper cells, innate lymphoid cells, and fibroblasts. Dysregulated TL1A signaling has been hypothesized to affect multiple immune-mediated diseases, with clinical proof of concept demonstrated in ulcerative colitis and Crohn's disease. We characterized the binding affinity, specificity, structure, pharmacodynamics, pharmacokinetics, and toxicity profiles of SPY002 and SPY072, two novel extended half-life monoclonal antibodies that inhibit TL1A. SPY002 and SPY072 demonstrated selective, high-affinity binding to human TL1A (K ≈ 31-35 pM) and potent functional inhibition of DR3 signaling. Based on Fc modifications, SPY002 and SPY072 showed attenuated Fc effector function and increased FcRn binding at acidic pH (5.8). Both antibodies exhibited enhanced PK profiles in nonhuman primates, resulting in predicted human half-lives that support quarterly or biannual dosing. In toxicity studies, no drug-related adverse effects were observed with either antibody at exposures >10 times those anticipated in clinical trials. In a rat collagen-induced arthritis model, anti-TL1A antibody treatment effectively reduced arthritis severity, with similar efficacy to the TNF antagonist etanercept. In humanized mouse Imiquimod-induced psoriasis and 2,4,6‑trinitrobenzene sulfonic acid colitis models, anti-TL1A demonstrated similar efficacy to anti-IL-23 and anti-TNF antibodies. These findings characterize two novel extended half-life TL1A antibodies and support the ongoing Phase 2 clinical development of SPY002 and SPY072 for immune-mediated diseases such as inflammatory bowel disease and rheumatic diseases.

The development of multifunctional electro-spun nanofibrous mats has been explored as an effective platform for implantable localized cancer treatment because they provide a supportive matrix to regenerate tissues and deliver encapsulated anticancer drugs to suppress the proliferation of cancer cells. However, conventionally designed nanofibrous scaffolds present several critical challenges, particularly delayed and uncontrolled release of drug molecules due to inefficient crosslinks. Herein, we report a robust approach with the synthesis of a new phenyl diboronic acid crosslinker bearing an acid-cleavable Schiff base linkage to develop dual acidic pH-responsive degradable e-spun nanofibrous mats. The dual smart mats crosslinked with both acid-labile imine and boronic ester linkages, being structurally stable in a physiological pH, rapidly degrade through their acid-catalyzed hydrolysis in an acidic environment, leading to the enhanced release of encapsulated anticancer drugs. Furthermore, doxorubicin-loaded mats have desired antitumoral activity and hemocompatibility, while empty ones are biocompatible. These results demonstrate the great potential of dual acidic pH-responsive degradable e-spun nanofibrous mats as implantable localized drug delivery scaffolds for cancer chemotherapy.