Background Real-world evaluations associating surgical quality indicators with outcomes in esophageal squamous cell carcinoma (ESCC) remain limited. This study assessed processes of care, perioperative outcomes, and long-term survival within a high-volume ESCC surgical program under a standardized quality framework. Methods We analyzed 2952 patients undergoing esophagectomy (June 2018-September 2023) under standardized clinical pathways. The primary endpoint was overall survival (OS); secondary endpoints included preoperative positron emission tomography-computed tomography (PET-CT) use, neoadjuvant therapy adherence, lymph node yield, R0 resection rate, complications, length of hospitalization stay, and 30- and 90-day mortality. OS was estimated by the Kaplan-Meier method; multivariable Cox regression assessed associations between selected quality indicators and OS, adjusted for clinical confounders and calendar period. Results The 1-, 3-, and 5-year OS rates were 95.7%, 85.2%, and 76.4%. PET-CT was performed in 83.1%; 76.0% of indicated patients received neoadjuvant therapy. Median lymph node yield was 34; R0 resection rate was 95.6%. Complications declined from 18.9% to 15.6%; median length of hospitalization stay was 8 days; 30- and 90-day mortality were 0.3% and 0.6%. Higher lymph node yield (per 10-node increase: hazard ratio [HR] 0.88 [95% CI: 0.81, 0.96]), R0 resection (HR, 0.40 [95% CI: 0.29, 0.55]), and neoadjuvant therapy adherence (HR, 0.67 [95% CI: 0.50, 0.88]) were associated with improved OS after adjustment. Conclusions Within a unified quality framework, this ESCC cohort shows favorable performance on quality indicators, low perioperative risk, and durable survival. Higher lymph node yield, R0 resection, and neoadjuvant therapy adherence are associated with improved survival after adjustment. Together, the predefined quality indicators may inform multicenter quality benchmarking, though causal inference remains limited.
As global populations age, older adults constitute the majority of cancer patients. Their response to immunotherapy is heavily influenced by immunosenescence, a systemic remodeling of both innate and adaptive immunity with aging. Although age-related immune decline theoretically impairs antitumor responses, clinical data frequently show that older patients derive survival benefits comparable to younger cohorts. This review examines this paradox by analyzing how the aged immune system acts as a double-edged sword. We discuss how a constricted naive T cell repertoire and a suppressive tumor microenvironment create barriers, while the accumulation of antigen-experienced, exhausted T cells provides a vast reservoir for checkpoint blockade reinvigoration. We also delineate the unique clinical safety profile in this demographic, examining how localized tissue aging drives organ-specific immune-related adverse events. Beyond immune checkpoint inhibitors (ICIs), we evaluate the distinct biological barriers immunosenescence creates for chimeric antigen receptor T cell therapy, cancer vaccines, and oncolytic viruses. Finally, we propose a transition toward precision geriatric immuno-oncology. This framework relies on biological age rather than chronological age, combining comprehensive geriatric assessment with multi-omics biomarkers to promisingly define an individual's immunological age. We emphasize the potential of novel interventions, including senolytics and mitochondria-targeted platforms, to reverse immune exhaustion and optimize treatment efficacy for this growing demographic.
Objective Selinexor is a first-in-class XPO1 inhibitor approved for the treatment of relapsed or refractory multiple myeloma (RRMM). However, its overall response remains limited, suggesting that additional mechanisms underlying Selinexor sensitivity require further investigation. Methods Nucleus-cytoplasm fractionation-based proteomic analysis is used to identify XPO1-transported proteins under Selinexor treatment. Protein-protein interactome and ubiquitination assays, mitochondrial function assessments, and the combined anti-tumor effects of specific inhibitors in vivo and in vitro are employed to define the regulatory machinery of the protein of interest in Selinexor sensitivity. Results The RING finger-containing E3 ligase, RNF5, is a cargo of XPO1 and its nuclear-cytoplasmic transport is correlated with poor clinical therapeutic response. RNF5 catalyzes K29-linked polyubiquitination of DNAJA1, which strengthens the interaction between DNAJA1 and HSP70, and consequently antagonizes the interaction between HSP70 and HSF1, therefore activates mitochondrial unfolded pprotein response (UPRmt) pathway to protect mitochondria function and MM survival. Thus, administration of RNF5 inhibitor inh-02 and DNAJA1 inhibitor 116-9e disrupts UPRmt balance and sensitizes MM cells to Selinexor. Conclusion Our study elucidates the mechanism of the XPO1-RNF5-DNAJA1 axis in regulating sensitivity of Selinexor, and sheds light on developing new strategies to improve the efficacy of treating RRMM patients.
Background Chronic gastric inflammation contributes to the multistep development of gastric cancer (GC), but the relevance of inflammatory proteins to gastric carcinogenesis and whether inflammatory proteins can serve as indicators for GC risk remains unclear. Methods Inflammatory proteins were profiled in a case-control study of the national Upper Gastrointestinal Cancer Early Detection program (UGCED, n = 200, including 63 GCs) and a nested case-control study of the Mass Intervention Trial in Linqu county, Shandong Province (MITS, n = 300, including 150 GCs). Samples were collected 0–12 years before GC diagnosis (n = 500 plasma and n = 166 tissue), with a subgroup obtained paired samples at diagnosis (n = 33). We examined circulating inflammatory proteins associated with GC risk, with external validation conducted in the UK Biobank Pharma Proteomics Project (UKB-PPP, n = 48,011, including 138 incident GCs). Results Our two-stage study identified 9 inflammatory proteins consistently associated with GC risk. Five upregulated proteins (A2M, AFM, BTD, MAP2K7, and TF) indicated short-term GC risk up to 6 years pre-diagnosis, while four proteins (ADH1B, EZR, FN1 and HDGF) presented long-term risk. A higher overall inflammatory-protein-score (O-IPS) integrating 9 proteins was associated with increased GC risk across UGCED (OR = 2.35, 95% CI: 1.59–3.47, per unit increase), MITS (OR = 1.72, 95% CI: 1.30–2.27), and UKB (HR = 1.33, 95% CI: 1.13–1.56). O-IPS was also higher at GC diagnosis than at pre-diagnostic baseline (P = 0.0016). Integrating key proteins improved discrimination in MITS (AUC: 0.800 vs 0.513, DeLong’s P = 4.58×10−5) and UKB (0.758 vs 0.704, P = 0.0023). Favourable lifestyle might potentially modify the association between O-IPS and GC risk (P-for-interaction = 0.066). Conclusions Circulating inflammatory proteins demonstrates informative markers for GC risk across different time horizons and enhance risk prediction, supporting potential application in precision prevention.
Background Pancreatic ductal adenocarcinoma (PDAC) is characterized by early metastasis and metabolic reprogramming, yet the epigenetic drivers linking these features remain poorly defined. This study investigates the role of CDK13, overexpressed in PDAC, in orchestrating these processes. Methods We utilized transcriptomic (RNA-seq), phosphoproteomic, and chromatin accessibility (ATAC-seq) profiling in PDAC cell lines and clinical specimens. Functional assays included gene knockdown/overexpression, site-directed mutagenesis, ChIP-qPCR, luciferase reporter assays, and in vivo metastatic models. Results CDK13 was overexpressed in PDAC and promoted tumor migration, invasion, and hepatic metastasis. Mechanistically, CDK13 phosphorylated the histone demethylase KDM2A at Ser692, triggering an H3K36me2-to-H3K36me1 switch at an intronic enhancer of NUP93—a nuclear pore component. This epigenetic activation upregulated NUP93, which facilitated nuclear translocation of phosphorylated STAT3. Nuclear p-STAT3 bound the HMGCR promoter to drive cholesterol biosynthesis. Genetic or pharmacological disruption of CDK13, KDM2A, or NUP93 suppressed cholesterol accumulation and metastatic progression in vitro and in vivo. Conclusions Our findings reveal an epigenetic-metabolic circuit wherein CDK13-mediated nuclear pore reprogramming via KDM2A phosphorylation and NUP93 activation drives cholesterol metabolism and metastasis in PDAC. This work suggests that co-targeting CDK13 and NUP93 may offer a promising therapeutic avenue for metastatic PDAC.
Epstein-Barr virus (EBV)-associated lung carcinoma (EBVaLC) is a rare group of non-small cell lung cancer (NSCLC). It predominantly affects young, non-smoking Asian patients and is characterized by variable lymphocytic infiltration in the tumor microenvironment. However, due to its rarity, the clinical characteristics of EBVaLC remain incompletely characterized. EBV infection is detected in the vast majority of tumor tissues and is recognized as the principal etiological agent of EBVaLC, which encompasses a small proportion of lung squamous cell carcinomas (LUSC) and rare lung adenocarcinomas (LUAD). Nevertheless, the mechanisms underlying EBV-induced carcinogenesis remain incompletely understood. Definitive diagnosis relies on histopathological examination and EBV-encoded small RNA (EBER) in situ hybridization. However, EBVaLC is frequently misdiagnosed as conventional LUSC in clinical practice. In this review, we use the term “EBV-associated lung carcinoma (EBVaLC)” to encompass the entire spectrum of EBV-positive lung malignancies, summarize the current diagnostic approach for EBVaLC, and integrate clinical and biological insights into EBVaLC, with particular emphasis on how mechanistic insights form other EBV-driven malignancies—especially EBV-mediated reprogramming of latently infected B lymphocytes—may illuminate its pathogenesis.
Glioblastoma and other malignant gliomas are characterized by high heterogeneity that drives their aggressiveness and contributes to poor clinical outcomes. Understanding the mechanisms behind glioma malignancy, as well as the crosstalk between these tumors and their microenvironment, may hold transformative clinical relevance. Recent findings show that glioblastoma cells interact in bidirectional and multimodal crosstalk with the neuronal compartment of the microenvironment. While the knowledge on these complex interactions is still limited, it is now clear that dynamic communications include responses to neuronal activity-dependent molecules, synaptic signaling, and remodeling of neural circuits. Together, these direct and indirect dialogues promote glioma cells proliferation and invasion, effectively hijacking neuronal activity to fuel tumor aggressiveness. This review focuses on the bidirectional interaction between neurons and malignant glioma cells, highlighting its clinical relevance and potential to guide the development of novel precision therapies specifically targeting the glioma-neuron crosstalk.
Cancer is a disease of dysregulated multicellular coordination in which transformed cells evade homeostatic constraints to proliferate, invade, and metastasize. Increasing evidence places the nervous system, spanning central and peripheral circuits, within the tumor microenvironment as an active organizer rather than a bystander. Neuronal inputs shape malignant phenotypes through multiple interaction modalities, including paracrine neurotransmitters, neuropeptides, and neurotrophic factors, synapse-like neuron–tumor coupling, tumor-intrinsic bioelectric excitability, nerve-guided invasion/perineural spread, and tumor-driven neuronal remodeling. Through these pathways, neuronal inputs and activity can directly reprogram tumor growth, invasion, stem-like states, and therapy response, while indirectly rewiring immune surveillance, stromal activation, vascular dynamics, and metabolic ecosystems to create permissive niches for progression. Crucially, neuronal signaling is not a unidirectional growth license but a context-encoded control layer whose net effect can flip with receptor/transport configuration, cellular state, and neuroimmune wiring, fueling proliferation, invasion, and immune exclusion in some niches while reinforcing antigen presentation, effector fitness, and tissue-resident cytotoxicity in others. Here, we synthesize a pan-cancer framework for neuro–tumor crosstalk, emphasizing shared mechanistic logic across organ contexts and across primary tumors and metastases within the same neuronal ecological niches. By integrating neuronal signaling with microenvironmental rewiring, this review clarifies how circuit activity and neuroregulatory programs become selectable components of tumor evolution and highlights emerging opportunities to therapeutically target neuro–tumor axes in cancer. Accordingly, translation should move beyond blanket “denervation logic” toward program-selective neural intervention and therapeutic reprogramming guided by niche-resolved biomarkers.
Background Cancer remains a major public health issue globally, with a growing burden due to population aging and lifestyle changes. This study provides the estimates of cancer burden in China for 2024. Methods Cancer data of year 2019 from 919 population-based cancer registries across China submitted to the National Cancer Center were selected, with 106 registries providing continuous data from 2010 to 2019 being used to predict the burden of cancer in 2024. The Segi’s world standard population was used to estimate the age-standardized rates. Joinpoint regression analysis was used to evaluate the trends from 2000 to 2019 by calculating the annual percentage changes (APC) and average annual percentage changes (AAPC). Results In 2024, an estimated 5,150,000 new cancer cases and 2,580,000 cancer deaths occurred in China. The age-standardized incidence rate (ASIR) was 207.70 per 100,000 population and the age-standardized mortality rate (ASMR) was 90.90 per 100,000 population. Lung cancer was the most diagnosed cancer, followed by thyroid, colorectal, breast, and liver cancers. Collectively these top five cancers accounted for 59.13 % of all new cases. The leading cause of cancer death was lung cancer, followed by liver cancer, colorectal cancer, stomach cancer, and esophageal cancer, which together comprised of 66.75 % of all cancer deaths. The age-specific incidence rates increased with age for most cancer sites in men, but for cancers of breast, thyroid, ovarian, and cervix in women, the rates increased significantly in young and middle ages. The age-specific mortality rate increased with age and showed a higher level in men than in women. From 2000 to 2019, the ASIR for all cancers combined increased significantly (AAPC = 1.6 %), while the ASMR decreased (AAPC = −1.4 %). Cancers of the esophagus, stomach, and liver showed declining incidence and mortality trends, whereas thyroid, prostate, and cervical cancers exhibited significant increases in incidence. Conclusions The cancer burden in China continued to be substantial, characterized by a coexistence of cancer patterns of both developing and developed countries. The results highlight the necessity for targeted policies within the “Healthy China 2030" initiative to address sex and age disparities, as well as evolving cancer patterns.
Night shift work (NSW) has been known for its linkage with circadian disruption, while the NSW carcinogenic potential is well documented. However, there has been little research on the NSW-associated biological pathways and small molecules that may be implicated with the early stages of carcinogenicity. Metabolomics platforms are novel exposomics tools that act as intermediate biological layers of information linking NSW schedules with the downstream endogenous response in humans. To this extent, we conducted a scoping review to answer the question: how does NSW impact the endogenous human metabolome using metabolomics tools? Thus, this work critically reviewed human studies on the association between NSW and the associated endogenous biological response. Online databases were screened, and 13 original publications were included in the analysis; eight studies were conducted in occupational settings, and the remaining studies were well-controlled laboratory experiments simulating NSW. This work summarized the consistent reporting of the most frequently reported metabolites and associated biological pathways enriched in actual NSW, or in simulated NSW conditions of occupational and experimental laboratory studies, respectively. Further research is warranted to better understand the complex metabolic changes associated with NSW, informing strategies to mitigate early-stage carcinogenic effects, ultimately improving health and well-being of shift workers.
Premalignant lesions provide a crucial window of opportunity for cancer chemoprevention. Green tea, particularly its major catechin, epigallocatechin-3-gallate (EGCG), has demonstrated potential as a chemopreventive agent. Notably, a green tea ointment (Sinecatechins, or Veregen®) is the first and only botanical drug derived from green tea approved by the U.S. Food and Drug Administration for the treatment of HPV-related epithelial lesions. This approval underscores its clinical translational relevance, even though these lesions are caused by HPV types 6 and 11, which are considered low risk for malignancy. This review summarizes current mechanistic and clinical evidence supporting the role of green tea in suppressing the progression of premalignant lesions, with a specific focus on its ability to modulate the epithelial-mesenchymal transition (EMT). We first review the major constituents, bioavailability, and bioactivities of green tea, followed by the role of EMT in various stages of cancer progression, from early carcinogenesis to premalignant progression, and ultimately to cancer invasion and metastasis. EMT as a potential therapeutic as well as chemopreventive target is also discussed. We then summarize the association of the EMT pathway with the chemopreventive effect of green tea on premalignant lesions in several organ systems, including oral, cervical, colorectal, prostate, and skin. Although the existing in vitro, in vivo, and small-scale human studies are encouraging, definitive, large-scale, randomized, and prospective clinical trials that measure EMT-associated biomarkers are necessary to confirm the efficacy of green tea-based interventions as a strategy for managing premalignant lesions and EMT modulation.
The recognition of tumor innervation has evolved from a histological curiosity into a foundational principle of cancer neuroscience. The bidirectional crosstalk between nerves and cancer cells is profoundly paradoxical, exerting complex, context-dependent, and often opposing effects on tumor dynamics, thereby influencing cancer progression and patient prognosis. Through synthesizing the established knowledge of tumor innervation with the broader hallmarks of cancer, this paper seeks to delineate the reciprocal interplay and key messengers between cancer cells and nerves, assess its prognostic value, and evaluate current and emerging therapeutic strategies. Our synthesis establishes tumor innervation as an integrative component of cancer pathogenesis, where cancer cells promote neurogenesis and axonogenesis as well as recruit peripherial nerves, while nerves reciprocally disrupt key cellular homeostatic processes, contributing to canonical cancer hallmarks. While increased nerve characteristics and stress hormones are robust prognostic markers for aggressive disease and poor survival, exosomes provide complementary diagnostic value. Stress-mediated signaling through adrenergic and glucocorticoid receptors presents a druggable axis, yet monotherapies face limitations of efficacy and resistance. CAP has evolved as a promising solution, either as a standalone treatment or an adjuvant, by impairing neurogenesis and axonogenesis, remodeling tumor microenvironment for nerve recruitment blockage, and targeting cancer hallmarks. Collectively, cancer innervation has emerged as an innovative cancer hallmark, and the concept of reciprocal reprogramming, whereby cancer cells reprogram neural cells to fuel progression while nerves reciprocally reprogram the hallmarks of cancer, provides a unifying framework for understanding this bidirectional crosstalk. Leveraging this framework may advance precision medicine through targeted disruption of the tumor-nerve axis.
Despite the PACIFIC trial transforming unresectable stage III non-small cell lung cancer (NSCLC) management, survival gains remain modest and heterogeneous. Current consolidation strategies are fragmented, with redundant “me-too” designs, underuse of dynamic biomarkers, and little consensus on optimal sequencing of chemoradiotherapy (CRT), surgery, and next-generation systemic agents. We synthesise emerging evidence across immune checkpoint inhibitors (ICIs), genotype-directed tyrosine kinase inhibitors (TKIs), antibody-drug conjugates (ADCs), bispecific antibodies, and advanced radiotherapy techniques, identifying critical gaps: lack of head-to-head CRT-first vs systemic-first comparisons, inconsistent central nervous system (CNS) management, unclear optimal integration of stereotactic body radiotherapy (SBRT) boosts, and minimal integration of dynamic biomarkers such as circulating tumour DNA (ctDNA) to guide escalation or de-escalation. We further examine the potential of early ADC integration to maximise initial tumour eradication, the role of salvage and planned surgery within trimodality strategies, and the need for harmonised CNS management. Finally, we address the economic sustainability of intensification, advocating value-based pricing, outcome-linked reimbursement, and biomarker-driven duration limits.
Objective This study aimed to systematically estimate the global incidence levels and distribution characteristics of anatomical subsites of colon cancer across different ages, sexes and geographic regions in 2022. Methods Colon cancer cases in 2022 were obtained from the International Agency for Research on Cancer (IARC)’s GLOBOCAN database. Cases with anatomical subsites of colon cancer were obtained from Volume XII of Cancer Incidence in Five Continents (CI5). Age-standardized incidence rates (ASRs) and the proportional distribution of anatomical subsites were calculated by age group, sex, world region and Human Development Index (HDI). Data from 2003 to 2017 were obtained from CI5 Volumes X, XI, and XII, and temporal trends were analyzed using Joinpoint regression. Results Globally, the ASR for proximal colon cancer was higher than that for distal colon cancer (5.59 vs 5.11 per 100,000 person-years) in all populations. As HDI level increases, the ASRs for all anatomical subsites generally increased among people aged 50 years and above. Sigmoid colon cancer had the highest ASR globally. Appendiceal cancer accounted for over 65% of cases in the 0–14 years age group, but declined sharply with age. More countries had an increasing trend for proximal colon cancer incidence than for distal colon cancer (19 countries vs 13 countries), and the upward trend was more pronounced among individuals aged 0–49 years. Conclusions The global distribution of colon cancer anatomical subsites exhibits age-specific and geographical disparities. The rising incidence of early-onset proximal and distal colon cancers indicates the need for tailored screening strategies and resource allocation.
