Minimally invasive treatment for high-risk gastrointestinal stromal tumor (GIST) remains controversial for the concerns including intra-operative rupture and tumor spillage. This study aimed to compare the long-term oncological outcomes in the high-risk GIST patients receiving laparoscopic and open surgery. We conducted a retrospective study on patients with high-risk GISTs of the stomach undergoing curative resection by laparoscopic or open approach from 2002 to 2024 at a single medical center. Propensity score matching was applied to adjust for tumor size and tumor location between these two groups at a 1:1 ratio. We evaluated the peri-operative and long-term oncological outcomes. There were 184 patients with high-risk GISTs of the stomach recruited. The clinical demographics including age and gender were similar between the laparoscopic and open groups. The mean tumor size was significantly larger in the open group (13.4 ± 7.4cm versus 5.7 ± 3.5cm, p < 0.001). After matching, 34 patients in each group were analyzed with comparable tumor sizes and locations. The laparoscopic group was associated with a shorter hospital stay (9.7 ± 2.3days versus 12.4 ± 4.0days, p = 0.013). Otherwise, the operation time, blood loss, and the ratio of receiving adjuvant target therapy were similar between groups. Kaplan-Meier RFS analysis showed no difference between the open and laparoscopic groups either in 10-year RFS (82.7% versus 73.6%, p = 0.739) or 10-year OS (90.0% versus 96.9%, p = 0.588). Multivariate analysis showed the surgical approach was not a significant risk factor affecting RFS or OS. Laparoscopic resection is a safe and feasible surgical approach in selected gastric high-risk GIST patients, providing comparable oncologic outcomes to open surgery with a shorter hospital stay.

Background/Objectives: Thymomas are the most common tumors of the anterior mediastinum. While early-stage disease often has a favorable prognosis, therapeutic options in advanced stages remain limited. Moreover, the molecular profile of thymomas is still poorly characterized. In the present study, we explored the presence of targetable mutations and programmed death-ligand 1 (PD-L1) expression in a cohort of surgically resected thymomas. Furthermore, we investigated the correlation between PD-L1 expression, histological subtype, and risk of recurrence in patients who underwent curative-intent thymectomy. Methods: Mutational profiling was performed using a DNA-based NGS Cancer Panel of 16 genes. PD-L1 expression was evaluated via Tumor Proportion Score (TPS), and thymomas with TPS ≥ 50% were identified as high expressors. The associations with histological subtype and disease-free survival (DFS) were analyzed using logistic regression, Cox proportional hazards models, and Kaplan–Meier survival curves. Results: In our study, 2/37 (5.4%) of tested neoplasms (type AB and B2 thymoma) reported as a PIK3CA mutation; no other targetable mutations were observed. Moreover, high PD-L1 expression (≥50%) was reported in (15/37) 40.5% of patients and was significantly associated with aggressive histological subtypes (B2 and B3) (p &lt; 0.001). Logistic regression analysis showed that high PD-L1 expression was a significant predictor of aggressive histology (McFadden’s R2 = 0.268, p &lt; 0.001), with an odds ratio of 15.5 (95% CI: 2.9–83.4; p = 0.001). During follow-up, 5/37 (13.5%) of patients experienced disease recurrence; however, no significant difference in DFS was found between high and low PD-L1 expression groups. Conclusions: Our data confirm the presence of PIK3CA mutations in thymomas and encourage the exploration the potential role of molecular target therapy in this setting. Moreover, we underlined that high PD-L1 expression level is associated with more aggressive thymoma subtypes and may have a role as a prognostic biomarker. These findings support the need for further studies on the potential role of molecular and predictive pathology in thymic epithelial tumors.

Risk of infection for different B-cell targeting agents in treating systemic lupus erythematosus: A systematic review and network meta-analysis.

Abstract Thrombotic microangiopathy (TMA) is a pathological condition characterized by microangiopathic hemolytic anemia, thrombocytopenia and ischemic organ dysfunction due to microvascular endothelial damage and thrombosis. It affects approximately 0.8-14% of kidney transplant recipients, and may manifest as either a recurrent or de novo disease. While systemic manifestations are commonly anticipated, kidney-limited TMA can also occur and is not rare. Histopathologic examination of allograft biopsies shows morphologic features indicating endothelial injury, and repeated episodes of TMA may result in coexisting acute and chronic lesions within the same patient. In transplant recipients, multiple triggers contribute to endothelial damage, including ischemia-reperfusion injury, antibody-mediated rejection, immunosuppressive agents (calcineurin and mTOR inhibitors) and infections. The risk is particularly important in individuals with genetic variants that dysregulate the alternative complement pathway. In de novo TMA, environmental triggers and transplant-related stressors play a central role, whereas genetic predisposition is the primary factor in recurrent cases. Notably, these mechanisms often overlap and may act synergistically. Recurrent atypical hemolytic uremic syndrome can successfully be managed with terminal complement inhibitors, and prophylactic use of eculizumab in the peri-transplant period has significantly reduced recurrence rates. Management of de novo TMA begins with the identification and removal of precipitating factors. In cases where no clear trigger is found, or when the disease proves refractory to conventional therapy, terminal complement inhibition may be an effective therapeutic option. The prognosis of recurrent TMA has improved substantially with the advent of complement targeting therapies but research is still needed to optimize management strategies.

BackgroudUreteritis and cystitis is a rare immune-related adverse event (irAE) of immune checkpoint inhibitors (ICIs), challenging to distinguish from urinary tract infection (UTI), easily leading to missed diagnosis. We aim to describe clinical features, radiological characteristics and treatment of patients who suffer from ICI-related ureteritis and cystitis (ICI-UC).MethodsThis was a single centre case series of patients diagnosed with solid tumor who received ICIs treatment and subsequently suffered from ICI-UC. All clinical demographic data, laboratory parameters, imaging characteristics, and treatment information were collected.ResultsBetween Mar 1st, 2020 and Mar 31th 2025, 12 of 1239 patients treated at Peking Union Medical College Hospital with ICIs were confirmed to have ICI-related ureteritis and cystitis (0.96%), 10 males and 2 females. Only 1 patient received anti-programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte associated protein-4 (CTLA-4) dual immunotherapy, the other 11 patients received PD-1/PD-ligand 1 plus chemotherapy or/and target therapy. The median time to onset was 83 days (range 28–442 days). All patients (100%) exhibited significant urinary tract irritation symptoms. 12 patients demonstrated characteristic imaging abnormalities, including hydroureteronephrosis, irregular ureteral wall thickening, bladder wall thickening with irregular margins, or/and conspicuous renal fascia. Spontaneous remission was observed in 2 patients, while 10 patients received steroids and all showed rapid improvement of symptom after treatment.The median time from symptom onset to the initiation of steroids was 24 days, and the median prednisone dose was 0.60 mg/kg/day. Six patients (6/10, 60%) experienced disease recurrence during the corticosteroid tapering phase, and two patients who failed steroid tapering were successfully treated with a combination of corticosteroid and JAK inhibitor therapy.ConclusionThis pioneering cohort study provides the first systematic investigation of ICI-UC, establishing its incidence and comprehensively characterizing clinical and imaging features. Through cohort analysis, we propose a novel severity grading system with corresponding treatment algorithms, while additionally exploring the therapeutic potential of JAK inhibitors for steroid-dependent cases.

Editorial: Brain metastasis and systemic target therapy: implications for neurosurgeons

Role of 18F-FDG PET/CT for Evaluation of Prognostic Target Therapy Response in HER2 Positive Breast Cancer Patients: Comparative study

Clinical Outcomes of Targeted Therapies Following HIF-2α Inhibition in Metastatic Renal Cell Carcinoma: A Real-World Analysis.

ABSTRACT Hemophilic arthropathy (HA), a major complication of hemophilia, is a chronic osteoarthropathy driven by repeated joint bleeding. Although traditional therapies such as coagulation factor replacement, physical rehabilitation, and surgery can manage symptoms, they cannot fundamentally repair established joint damage or break the pathological cascades. This review systematically summarizes therapeutic frontiers in HA, including regenerative medicine, molecular targeting, and gene therapy. Regenerative medicine aims to restore joint function through tissue repair using mesenchymal stem cells and their exosomes, as well as multifunctional biomaterials such as nanocarriers and hydrogels for targeted delivery and microenvironment modulation. Molecular targeting offers precision treatment by interfering with key pathological pathways using monoclonal antibodies that either improve coagulation or target pro‐inflammatory factors. Non‐coding RNAs are also being explored for their roles in regulating inflammation and cartilage degradation. Gene therapy, a paradigm shift from symptomatic care to fundamental repair, enables continuous endogenous production of coagulation factors, thereby preventing bleeding and delaying HA progression. The successful translation of these therapies into clinical practice requires overcoming challenges such as optimizing cell survival in hostile environments, standardizing biomaterial production, managing immune responses to vectors, and reducing costs. Future research should focus on interdisciplinary strategies, personalized treatment plans, and long‐term follow‐up studies to achieve synergistic effects and ensure safety. These innovative approaches promise to significantly improve joint function and quality of life for HA patients, ultimately working toward a functional cure.

Bcl-xL plays an important role in tumors from different origins, including melanoma, and for this reason it has been widely targeted with small-molecule BH3 mimetics, which unfortunately show several adverse effects. To overcome this limitation, selective Bcl-xL proteolysis-targeting chimera degraders have been developed. Among these, DT2216, a candidate in phase I/II clinical trials, has demonstrated antitumoral activity in preclinical cancer models from different origins, not including melanoma. By using several established and patient-derived BRAF wild type and mutated melanoma cells, we performed western blot analysis and MTT assay to study DT2216 effect on Bcl-xL protein levels and cell viability, respectively. Combination studies were performed on BRAF mutated melanoma cells treated with DT2216 and Dabrafenib/Trametinib or on wild type melanoma cells treated with DT2216 and Trametinib or S63845. Combination index was calculated to study drug interactions. Apoptotic induction was studied through western blot (PARP-1 cleavage), cytofluorimetric (subG1 peak in the cell cycle) and live-cell fluorescent imaging of activated caspases 3/7 analyses. Group differences were analysed with a two-sided paired or unpaired Student's t-test. To investigate the effect of the combination treatment in vivo, A375luc melanoma cells were inoculated in xenograft mice, then treated with Dabrafenib/Trametinib or DT2216, alone or in combination, for three weeks. Differences between groups, were analysed with Mann-Whitney test. DT2216 induced the specific and long-lasting degradation of Bcl-xL protein, and reduced cell viability, in a concentration-dependent manner. Of note, a positive correlation between Bcl-xL degradation and sensitivity to DT2216 was observed, being cells with higher degradation the most sensitive to DT2216. In combination studies, DT2216 was able to enhance the activity of target therapy regardless BRAF mutational status. Moreover, the Mcl-1 specific inhibitor, S63845, potentiated the efficacy of DT2216 in melanoma cells in which DT2216 determined an increase of Mcl-1 protein. Interestingly, DT2216 also increased the activity of target therapy in melanoma cells resistant to Dabrafenib and Trametinib. Finally, experiments in a xenograft mouse melanoma model highlighted DT2216 potentiating effect of target therapy, not only inducing a significant reduction of tumor growth, but also showing a longer disease control. Our findings provide new insights for combination therapy including Bcl-xL degradation for melanoma treatment.

Sirolimus to treat chronic uveitis in PTEN hamartoma tumor syndrome: experience of a target therapy customized on specific disease pathway.

The clinical benefit of PD-1/PD-L1-based immunotherapy in gastric signet ring cell carcinoma (GSRCC) remains unclear. This study evaluated the efficacy of first-line immunotherapy in advanced GSRCC. This single-center retrospective cohort study assessed the clinical response of patients with advanced GC diagnosed from November 2019 to January 2025 after receiving first-line immunotherapy combined with chemotherapy and/or target therapy, concurrently comparing therapeutic outcomes in GSRCC and non-GSRCC cohorts. This study included 230 patients, with objective response rate (ORR) achieving 43.9%. Among the 150 non-GSRCC patients, the ORR was 50.7%, compared to 31.3% in the 80 GSRCC patients. Non-GSRCC patients had longer median progression-free survival (PFS: 10.0 vs 7.9 months; p = 0.002) and overall survival (OS: 17.4 vs 15.3 months; p = 0.039). Peritoneal metastasis was independently associated with rapid progression and poor survival (HR 2.63, 95% CI 1.52-5.53; p = 0.001). Among GSRCC patients, those with peritoneal metastasis had significantly shorter PFS (6.6 vs 13.6 months; p < 0.001) and OS (11.0 vs 19.4 months; p = 0.001). The findings suggest that GSRCC is associated with resistance to immunotherapy in advanced GC. Furthermore, peritoneal metastasis is significantly associated with poor prognosis in GSRCC patients.

Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD+ salvage pathway and a promising therapeutic target in cancer. Resistance to NAMPT inhibitors, such as FK866, remains a key limitation to their clinical translation. While acquired resistance in cancer cell lines has been linked to target mutations, increased drug efflux, and metabolic reprogramming, innate resistance mechanisms have been poorly studied. Addressing this gap is crucial for identifying patient subgroups that are most likely to benefit from NAMPT-targeted therapies.Advanced castration resistance prostate cancer (CRPC) lacks effective targeted treatments. Among its heterogeneous subtypes, stem cell-like CRPC (CRPC-SCL) is characterized by independence from androgen receptor (AR) signaling, dependency on YAP/TAZ, and mesenchymal traits. In this study, we identify the YAP/nicotinamide N-methyltransferase (NNMT) axis as a key regulator of innate sensitivity to FK866 in stem-like mesenchymal CRPC cells.Using genetic and pharmacological models, we show that YAP or NNMT silencing rescues PC3 cells from FK866-induced apoptosis, endoplasmic reticulum stress, and NAD(H) depletion. Metabolomic profiling confirmed that NNMT activity depletes nicotinamide, sensitizing cells to FK866. We further validated NNMT upregulation across clinical CRPC-SCL datasets, where it strongly correlates with mesenchymal and therapy-resistant phenotypes. Murine prostate cancer cells with mesenchymal/stemness phenotypes (DVL3-SCM), that exhibit NNMT overexpression and high aggressiveness in vivo, also show increased sensitivity to FK866 compared with their parental counterparts (DVL3-PAR).In conclusion, we identify the YAP/NNMT axis as a determinant of innate sensitivity to NAMPT inhibition in prostate cancer. These findings support the use of NNMT as a predictive biomarker for NAD+-targeting therapies and provide mechanistic insight into a metabolic vulnerability of the CRPC-SCL subtype. Targeting the YAP/NNMT/NAMPT axis may represent a novel strategy for treating stem-like/mesenchymal, therapy-resistant prostate cancers.

Target therapy is effective for epidermal growth factor receptor (EGFR) mutation in non-small cell lung cancer (NSCLC). However, resistance often occurs after treatment for several months. Macrophages have difficulty in devouring resistant cells. Ganoderma immunomodulatory protein (GMI) exhibits anti-tumour and immunomodulatory activities. This study aimed to investigate whether GMI overcomes Osimertinib (Tagrisso) and Gefitinib (Iressa) resistance via enhancing macrophage polarization. GMI attenuated signal transducer and activator of transcription 3 (STAT3) phosphorylation and downstream CD47 expression in parental and resistant cells via Western blot and RT-qPCR. Overexpressed STAT3 restored GMI-induced apoptosis and GMI-reduced transcription of CD47 in HCC827 and H1975 lung cancer cells. Phospho-STAT3 inhibitor (W1131) also reduced the expression of CD47 in NSCLC cells. The interaction between GMI and W1131 was effective in reducing phosphorylated STAT3 and CD47. ImageXpress Pico analysis revealed that GMI enhanced phagocytotic activity of macrophages toward tumour cells with Red CMTPX and Green CMFDA dyes. The results showed that GMI enhanced macrophage phagocytosis of lung cancer cells by inhibiting STAT3 and reducing CD47 expression. In addition, GMI enhanced M1 inhibition of M2 polarization but had no effect on M1 differentiation. This is the first study to demonstrate that GMI enhances macrophage phagocytosis and modulates the STAT3-CD47 axis to overcome EGFR-TKI resistance in NSCLC, highlighting its potential as a novel adjunct immunotherapeutic agent.

Background: Acute kidney injury (AKI) frequently progresses to chronic kidney disease (CKD) through the AKI-to-CKD transition; however, effective treatment strategies remain challenging due to the complex and multifactorial pathophysiology of this process. This study aims to develop a multifunctional nanoplatform for kidney-specific targeting, reactive oxygen species (ROS) scavenging, and anti-fibrotic drug delivery to mitigate AKI-to-CKD progression. Methods: Reduced graphene oxide (rGO) was conjugated with hyaluronic acid (HA) to form HA/rGO nanoparticles, enabling CD44-mediated renal targeting and ROS-responsive drug release. Paricalcitol, a hydrophobic anti-fibrotic agent, was loaded onto HA/rGO to form P/HA/rGO. The physicochemical characteristics, ROS-scavenging capacity, and oxidative stress-responsive drug release were evaluated. In vitro cytoprotection was assessed using HK-2 cells under oxidative stress. In vivo studies using ischemia/reperfusion (IR) injury mouse models assessed biodistribution, renal targeting, and therapeutic efficacy after systemic administration of P/HA/rGO. Results: HA/rGO nanoparticles demonstrated potent antioxidant activity and significantly protected HK-2 cells from ROS-induced cytotoxicity. P/HA/rGO exhibited a high paricalcitol loading efficiency (93%) and released 26% of the drug over 30 days under oxidative conditions. P/HA/rGO selectively accumulated in IR-injured kidneys via HA-CD44 interactions, decreased serum NGAL and cystatin C levels, and effectively attenuated tubular injury, fibrosis, inflammation, and apoptosis compared to vehicle-treated controls. Conclusion: The P/HA/rGO nanoplatform enables kidney-targeted delivery of paricalcitol with ROS-scavenging and ROS-responsive release properties, providing a promising therapeutic strategy to suppress the AKI-to-CKD transition via integrated targeting and microenvironment-responsive therapy.

Engineering tactics for organelle targeting behavior and PDT efficiency by fine structural regulation.

PLGA-integrated micro/nanoparticles for cargo delivery and nanomedicine of lung cancer.

Next-generation nanocarriers for therapeutic oligonucleotides: Precision targeting and stimuli-responsive cancer therapy.

Alzheimer's disease continues to be a debilitating disorder, profoundly affecting the quality of life, despite decades of extensive research. The impermeability of the blood-brain barrier, multifactorial etiology of the disease and the repeated failures of single target therapy are the major contributors of this therapeutic stagnation. If there is a silver lining, it lies in the growing advancement of multi-targeted therapeutic approaches that address the complex pathophysiology of Alzheimer's disease. In this context, carbon dots have emerged as highly promising, ultrasmall and biocompatible nanomaterials capable of traversing the blood-brain barrier and targeting various pathophysiologies of the disease. These include but are not limited to inhibition of abnormal protein aggregation, scavenging of reactive oxygen species and attenuation of neuroinflammatory processes. This review aims to critically synthesize the current body of research on carbon dots with particular emphasis on their mechanistic insights, surface chemistry driven targeting strategies and ligand free transportation mechanisms. The indulgence of photodynamic therapy in targeting carbon dots has also been touched upon. The key regulatory hurdles and translational gaps have been addressed that hinder their journey from bench to bedside. This review highlights the potential of carbon dots as intelligent nanoplatforms by integrating the molecular and pharmacological perspectives.

P0434 Periodontal Inflammation Predicts the Clinical Course of Inflammatory Bowel Disease: A RealWorld Longitudinal Cohort Study