Neoadjuvant therapy has become the standard of care for locally advanced esophageal cancer; however, a subset of patients still faces the dilemma of treatment failure, characterized by clinical progression or failure to achieve R0 resection. The predominant recurrence patterns are distant metastasis and locoregional recurrence. This failure is a multidimensional consequence of patient characteristics, treatment modalities, and hospital volume. To address this clinical challenge, this article systematically explores individualized breakthrough strategies. The first is the perioperative "intensification and salvage" strategy, encompassing the re-evaluation of salvage surgery at high-volume centers, the intensification and conversion of systemic therapies (e.g., novel agents like bispecific ADCs), the individualized application of precision radiotherapy, and the standardized intervention of postoperative adjuvant immunotherapy (e.g., PD-1 inhibitors). The second strategy is molecular residual disease (MRD)-guided precision adjuvant therapy, utilizing liquid biopsy technologies such as ctDNA to implement an adaptive management model-intensifying treatment for MRD-positive patients while de-escalating or observing for MRD-negative ones. In the future, the clinical management of esophageal cancer will shift from passive "post-failure salvage" to proactive "whole-process prediction and adaptive management," aiming to further optimize treatment pathways and improve patient prognosis.

Objective: To investigate the diagnostic value of plasma circulating tumor DNA (ctDNA) methylation of glutathione S-transferase P1 (GSTP1) and secreted frizzled-related protein 2 (SFRP2) for early hepatocellular carcinoma (HCC), and to evaluate a multimodal model integrating smoking history, nodule size, alpha-fetoprotein (AFP), and protein induced by vitamin K absence-Ⅱ (PIVKA-Ⅱ). Methods: This single-center retrospective case-control study enrolled 180 patients with HCC or liver cirrhosis at the Affiliated Hospital of Shaanxi University of Chinese Medicine from May 2023 to December 2024, with patients with cirrhosis serving as disease controls. The training set included 63 HCC patients and 63 cirrhosis patients, and the validation set included 26 HCC patients and 28 cirrhosis patients. Baseline clinical data, tumor biomarkers, liver function parameters, coagulation indices, imaging characteristics, and plasma ctDNA GSTP1/SFRP2 methylation levels detected by methylation-specific quantitative PCR (MS-qPCR) were collected. Logistic regression was used to identify independent risk factors and construct a multimodal diagnostic model. Model performance was evaluated using receiver operating characteristic (ROC) curves, calibration curves, confusion matrix analysis, and decision curve analysis (DCA). Result: GSTP1 methylation was higher in the HCC group than in the cirrhosis group [0.87 (0.75, 0.97) vs. 0.76 (0.54, 0.86); U=-3.842, P<0.001], and SFRP2 methylation was also higher [0.83 (0.70, 0.94) vs. 0.71 (0.60, 0.83); U=-3.423, P<0.001]. Multivariate logistic regression identified smoking history (OR=18.84, 95%CI: 2.82-126.10), nodule diameter (OR=33.40, 95%CI: 2.50-446.58), AFP (OR=40.03, 95%CI: 7.39-216.95), PIVKA-Ⅱ (OR=6.18, 95%CI: 1.34-28.39), and GSTP1/SFRP2 methylation (OR=1.50/2.54) as independent risk factors for HCC. The multimodal model achieved AUCs of 0.962 and 0.955 in the training and validation sets, respectively, with positive predictive accuracies of 0.891 and 0.868, outperforming single-factor diagnostic methods. In conclusion, GSTP1 and SFRP2 methylation levels were significantly higher in the HCC group than in the cirrhosis group, and both were independent risk factors for HCC, indicating potential for early diagnosis. The multimodal model integrating ctDNA methylation and clinicoradiological indicators achieved AUCs of 0.962 and 0.955 in the training and validation sets, with positive predictive accuracies of 0.891 and 0.868, respectively. Conclusion: DCA showed greater net benefit than any single indicator, suggesting that this model could improve diagnostic performance for early HCC and provide a new strategy for liver cancer screening.

Objective: To assess the disease burden of esophageal cancer attributable to smoking in China and globally from 1990 to 2021 and to explore the causal association between smoking and esophageal cancer. Methods: Data on smoking-attributable esophageal cancer deaths and disability-adjusted life years (DALYs) in China and globally from 1990 to 2021 were extracted from the Global Burden of Disease (GBD) 2021 database. Joinpoint regression models were used to analyze temporal trends in the age-standardized mortality rate (ASMR) and age-standardized DALY rate (ASDR). The lifetime smoking index from the UK Biobank was used as the exposure, and summary-level data for esophageal cancer from a genome-wide association study (GWAS) were used as the outcome. Mendelian randomization (MR) analysis was performed to investigate the causal relationship between smoking and esophageal cancer. Cochran's Q test was applied to assess heterogeneity among instrumental variables (IVs); MR-Egger regression and MR-PRESSO were used to evaluate horizontal pleiotropy of IVs; and leave-one-out analysis together with funnel plots were conducted to examine the stability of the results. Results: From 1990 to 2021, the absolute numbers of smoking-attributable esophageal cancer deaths and DALYs increased in both China and globally, whereas the ASMR and ASDR decreased significantly. Joinpoint analysis showed that the declines in ASMR and ASDR in China (AAPC:-1.49% and -1.87%, respectively) were faster than the corresponding global declines (-1.23% and -1.57%). The decrease was significantly more rapid in females than in males (all P<0.001). MR analysis confirmed a causal association between smoking and esophageal cancer (OR=1.004, 95%CI: 1.002-1.006, P<0.001). Cochran's Q test indicated no heterogeneity (P>0.05), and MR-Egger regression and MR-PRESSO showed no evidence of horizontal pleiotropy among the IVs (all P>0.05). Leave-one-out analysis and funnel plots demonstrated the robustness of the causal estimate. Conclusion: The disease burden of esophageal cancer attributable to smoking remains substantial in both China and globally, with declining trends in age-standardized rates; notably, the decline in China has outpaced the global average. Smoking is a causal risk factor for esophageal cancer, and males represent a high-risk group.

Objective: To explore the prognostic impact of hypomethylating agents (HMA) versus hydroxyurea plus best supportive care (HU/BSC) in patients with intermediate-and high-risk chronic myelomonocytic leukemia (CMML), and to analyze the patterns of clonal evolution and dynamic changes of inflammatory cytokines in patients with disease progression before and after HMA treatment. Methods: A total of 63 patients diagnosed with intermediate-and high-risk CMML admitted to the Department of Hematology, the Second Hospital of Tianjin Medical University between October 20 2017 and May 8 2025 were retrospectively enrolled. All patients were followed up every 3 months via outpatient and inpatient visits after discharge, with the last follow-up conducted on February 28, 2026. According to treatment regimens, the patients were divided into HMA group (n=31) and HU/BSC group (n=32). Treatment response, disease progression and survival outcomes were compared between the 2 groups. The Kaplan-Meier method was used to plot the survival curves of overall survival (OS) and progression-free survival (PFS). Bone marrow DNA was collected from patients with disease progression before and after treatment with HMA (n=20) and HU/BSC (n=13). Next-generation sequencing was used to detect 325 mutated genes related to hematological malignancies, and the clonal evolution of gene mutations in patients receiving the 2 treatment regimens before and after disease progression was investigated. Bone marrow supernatant specimens were collected from patients with disease progression treated with HMAs (n=8) and HU/BSC (n=8), and enzyme-linked immunosorbent assay (ELISA) was used to measure the expression levels of 21 inflammatory cytokines including IL-6 and IFN-γ. The differences in inflammatory cytokine expression before and after disease progression were compared. Results: The median follow-up duration for all patients [M(Q₁,Q₃)] was 21 (10, 40) months. The median OS was 22.0 months (95%CI: 11.8-32.2) in the HMA group and 36.0 months (95%CI: 23.6-48.4) in the HU/BSC group, with no statistically significant difference between groups (P=0.208). The median PFS was 18.0 months (95%CI: 10.8-25.2) and 26.0 months (95%CI: 19.9-21.1) respectively, and the difference was also not statistically significant (P=0.108). Among patients with disease progression after HMA treatment, newly acquired mutations were predominantly enriched in RAS pathway genes, accounting for 25% (5/20). Clonal expansion of SF3B1, TP53 and RUNX1 was observed, and the mutational burden of each gene accounted for 10% (2/20). Compared with baseline levels, the concentrations of TNF-α [113.6 (104.1, 147.1) pg/ml vs 25.7 (20.2, 41.3) pg/ml, P<0.001] and IL-8 [77.5 (54.6, 115.8) pg/ml vs 7.0 (2.6, 9.2) pg/ml, P=0.003] were significantly increased after disease progression, while the level of IFN-γ [341.5 (221.2, 460.7) pg/ml vs 732.7 (389.0, 852.4) pg/ml, P=0.013] was markedly decreased. Conclusions: Compared with HU/BSC regimen, HMA failed to significantly improve OS and PFS in patients with intermediate-and high-risk CMML. Disease progression after HMA treatment may be closely associated with newly emerging mutations in the RAS pathway, clonal expansion of pre-existing mutations such as TP53, as well as the upregulation of TNF-α and IL-8 and downregulation of IFN-γ.

Objective: To analyze the clinical and genetic characteristics of pheochromocytoma and paraganglioma (PPGL), as well as genotype-phenotype correlations in children and adolescents. Methods: A retrospective analysis was performed on clinical data and germline genetic testing results of 93 pediatric and adolescent patients (age≤18 years) diagnosed with PPGL at Peking Union Medical College Hospital between January 2010 and February 2025. According to germline variant results, enrolled patients were divided into four subgroups(6 cases with variants of uncertain pathogenic significance or benign variants and 3 cases with incomplete genetic testing were excluded. A total of 84 cases were included for analysis): SDHB-mutant group(carring pathogenic or likely pathogenic SDHB variants,n=41), VHL group (carring pathogenic or likely pathogenic VHL variants, n=9), other-gene variant group (carrying pathogenic or likely pathogenic variants in alternative genes,n=8), and wild-type group (no definite pathogenic variants detected, n=26). Clinical manifestations, germline mutation spectrum, long-term prognosis, and genotype-related phenotypic discrepancies were statistically compared across groups. Results: Among the 93 patients, 54 were male and 39 were female; the mean onset age was (13.7±3.7) years, with the follow-up duration of 2.5 (1.0, 7.0) years. Follow-up was terminated in February 2026. Tumor classification included 56 paragangliomas, 34 pheochromocytomas, and 3 composite tumors with both lesions. Eighty-four patients received surgical resection. Ki-67 index≥5% was confirmed in 54% (27/50) of available pathological specimens. Postoperative tumor recurrence occurred in 21 cases, distant metastasis developed in 36 cases, and 12 patients presented with concurrent recurrence and metastasis. Germline pathogenic or likely pathogenic variants were identified in 64 patients (68.8%, 64/93), among which definite pathogenic/likely pathogenic mutations accounted for 58 cases (62.4%, 58/93): 41 with SDHB variants, 9 with VHL variants, and 8 with rare alternative-gene variants (2 cases each for SDHD and RET, 1 case apiece for SDHA, SDHC, MAX, and FH). In the SDHB-mutant group, paraganglioma accounted for 85.4% (35/41), all tumors were solitary (100.0%, 41/41), and metastatic rate reached 53.7% (22/41). In the VHL-mutant group, pheochromocytoma constituted 66.7% (6/9), multifocal lesions were seen in 77.8% (7/9), and metastatic rate was only 11.1% (1/9). Conclusions: PPGL in children and adolescents presents a strong hereditary predisposition; SDHB and VHL germline variants lead to distinctly divergent clinical phenotypes. SDHB mutations are characterized by solitary paragangliomas with high metastatic risk, whereas VHL mutations are associated with multiple pheochromocytomas featuring low metastatic risk.

Globally, especially in the Asia-Pacific region, chronic hepatitis B infection has led to an undesirable escalating morbidity and mortality with acute-on chronic liver failure, end-staged liver cirrhosis and hepatocellular carcinoma. This has happened despite the past four-decades of major scientific advances made in screening methods, vaccination strategies, highly effective low-cost anti-viral therapies and surveillance strategies for early detection of hepatocellular carcinoma. To address this health threat, APASL has formed a Viral Elimination Taskforce to unite key opinion leaders from its member countries and regions. The ongoing shifts in hepatitis B epidemiology, socioeconomic changes, and advancements in technology are taken into consideration. With the conjoint efforts of all the members of the APASL Viral Elimination Taskforce, these clinical practice guidelines have been formulated aiming to facilitate healthcare professionals, policy makers and patients in making practical and cost-effective management decisions for chronic hepatitis B infection. Altogether, it provides recommendations in thirteen major areas related to screening, vaccination, treatment and HCC surveillance. The implementation of these clinical practice guidelines represents major APASL effort toward elimination of the disease burden due to chronic hepatitis B infection in Asia-Pacific region.

High-grade serous ovarian carcinoma (HGSC) demonstrates poor prognosis with approximately 80% recurrence rates and significant chemotherapy resistance. Conventional checkpoint inhibitors show limited efficacy (10-15%), necessitating alternative immunotherapeutic approaches. Engineered T lymphocytes, particularly CAR-T and TCR-T cells, have emerged as promising strategies for HGSC. This literature review examines the promising role of engineered T lymphocytes in immunotherapy for HGSC. A comprehensive literature search was conducted across PubMed, Scopus, and Cochrane Library databases for peer-reviewed studies published between 2015 and 2025. Search terms included "engineered T lymphocytes," "CAR-T cells," "TCR-T cells," "ovarian cancer immunotherapy". CAR-T cells demonstrate promising preclinical antitumor activity in HGSC, with high-avidity T-cell clones showing robust efficacy. Engineered T lymphocytes demonstrate promising approaches across disease contexts. In high-grade serous ovarian carcinoma, Engineered T lymphocytes orchestrate tumor cell apoptosis through coordinated granzyme/perforin and Fas/FasL signaling, enabling rapid cytotoxic elimination of multiple tumor targets.

Natural killer (NK) cells are vital for anti-tumor immunity, yet their effector functions are frequently constrained within the tumor microenvironment. Integrin β3 (ITGB3) has been implicated in breast cancer progression and stemness, but whether ITGB3 expression in malignant cells influences NK cell states and contributes to immune evasion remains unclear.

Single-cell RNA sequencing data were utilized to profile the transcriptomic and metabolic divergence of NK cells between ITGB3⁺ and ITGB3⁻ tumor microenvironments. Cell-cell communication and pseudotime trajectory analyses were performed to identify key signaling axes. The SCIPAC framework was employed to map single-cell subsets to the bulk TCGA-BRCA cohort for clinical correlation. The mechanistic findings were validated through in vitro co-culture assays and NKG2A blocking experiments using MDA-MB-231 and BT-474 cell lines.

NK cells associated with ITGB3⁺ tumor microenvironments displayed enhanced cytotoxic and inflammatory transcriptional programs, together with metabolic remodeling and stronger clinical associations with advanced TNM stages. Cell-cell communication analysis revealed intensified predicted interactions between ITGB3⁺ malignant cells and NK cells, with enrichment of MHC-I-related signaling and HLA-E-KLRC1/KLRC2 interactions. KLRC1 encodes the inhibitory receptor NKG2A, whereas KLRC2 encodes the activating receptor NKG2C. Therefore, these inferred interactions do not by themselves define the net functional direction of HLA-E signaling. Although KLRC2 was transcriptionally enriched in NK cells from the ITGB3⁺ tumor microenvironment, NKG2A blockade reversed ITGB3-associated suppression of NK-derived IFN-γ secretion, supporting a functional contribution of the inhibitory NKG2A branch.

ITGB3 expression in malignant cells is associated with a primed but functionally constrained NK cell state in breast cancer. Increased malignant-cell HLA-E expression and restoration of IFN-γ production following NKG2A blockade support a functional contribution of the inhibitory NKG2A branch, without excluding concurrent activating signaling through NKG2C.

Right-hemisphere gliomas have traditionally been regarded as less eloquent than left-sided lesions, influencing surgical decision-making and anesthetic approach. However, these tumors produce diverse non-motor manifestations affecting cognition, behavior, and socio-emotional functioning with important consequences for quality of life. This review aimed to characterize these manifestations and their implications for functional eloquence.

Following PRISMA guidelines, PubMed, Scopus, and Embase were searched using predefined terms for right-hemisphere gliomas and their manifestations. Eligible studies included patients with supratentorial right-hemisphere gliomas reporting motor and/or non-motor clinical manifestations. Studies were excluded if the clinical presentation was incompletely described or if glioma pathology lacked histopathological confirmation. Extracted data included tumor location, histopathology, clinical manifestations, neuropsychological assessments, and functional outcomes.

A total of 372 patients from 88 studies were included. Median age was 42 years (range, 11-87), with slight male predominance (49% vs. 48% female). Preoperative non-motor manifestations were common and heterogeneous, most frequently compromising cognition and executive performance (43%), followed by vision and visuospatial deficits (28.4%) and language deficits (24%). Postoperatively, the most common deficits involved language (46%), followed by vision and visuospatial deficits (40%), and cognition and executive dysfunction (23.1%). Analyses relating extent of resection to postoperative deficits were considered exploratory because reporting of extent of resection and postoperative outcome assessment were incomplete and heterogeneous.

Right-hemisphere gliomas carry a substantial and under-recognized burden of non-motor manifestations that challenge conventional definitions of functional eloquence and support the expansion of functional assessment and surgical planning encompassing right-hemisphere cognitive and behavioral networks.

β-Lapachone exhibits potent anticancer activity although its clinical application remains limited by toxicity and mechanisms of resistance. Therefore, structural modifications have been explored to improve its pharmacological profile. This study evaluated the cytotoxic, genotoxic, and toxicological effects of the oxime derivative β-lapachone oxime (Oxβ-Lp), together with its predicted pharmacokinetic properties and potential molecular interactions. Oxβ-Lp displayed cytotoxic activity against all tested cancer cell lines (NCI-H460, PC9, K562, and HepG2) after 72 h of exposure, with the greatest potency and selectivity observed in NCI-H460 non-small cell lung cancer cells (IC₅₀ = 1.88 µM; SI = 13.1). Mechanistic analyses demonstrated reduced cell viability, mitochondrial membrane depolarization, DNA damage, and induction of apoptosis, without significant cell cycle arrest. In Allium cepa, Oxβ-Lp did not alter the mitotic index or induce micronucleus formation but promoted chromosomal aberrations and DNA strand breaks. The Artemia salina assay indicated high acute toxicity (LC₅₀ = 16.80 µg/mL). Molecular docking suggested a potential interaction between Oxβ-Lp and NQO1, with binding energies comparable to those of dicoumarol and similar interaction patterns within the catalytic site. Overall, these findings demonstrate that Oxβ-Lp exhibits selective cytotoxicity against NCI-H460 cells and promotes apoptosis associated with mitochondrial dysfunction and DNA damage. Although the molecular mechanisms underlying its biological activity require further investigation, Oxβ-Lp represents a promising scaffold for developing novel anticancer agents.