Risk Factors and Predictive Nomogram for Survival in Elderly Patients with Brain Glioma.

OBJECTIVE: To determine the factors that contribute to the survival of elderly individuals diagnosed with brain glioma and develop a prognostic nomogram. METHODS: Data from elderly individuals (age ≥65 years) histologically diagnosed with brain glioma were sourced from the Surveillance, Epidemiology, and End Results (SEER) database. The dataset was randomly divided into a training cohort and an internal validation cohort at a 6:4 ratio. Additionally, data obtained from Tangdu Hospital constituted an external validation cohort for the study. The identification of independent prognostic factors was achieved through the least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis, enabling the construction of a nomogram. Model performance was evaluated using C-index, ROC curves, calibration plot and decision curve analysis (DCA). RESULTS: A cohort of 20 483 elderly glioma patients was selected from the SEER database. Five prognostic factors (age, marital status, histological type, stage, and treatment) were found to significantly impact overall survival (OS) and cancer-specific survival (CSS), with tumor location emerging as a sixth variable independently linked to CSS. Subsequently, nomogram models were developed to predict the probabilities of survival at 6, 12, and 24 months. The assessment findings from the validation queue indicate a that the model exhibited strong performance. CONCLUSION: Our nomograms serve as valuable prognostic tools for assessing the survival probability of elderly glioma patients. They can potentially assist in risk stratification and clinical decision-making.

Prognosis of Pneumonia in Head and Neck Squamous Cell Carcinoma Patients Who Received Concurrent Chemoradiotherapy.

Concurrent chemoradiotherapy (CCRT) is the standard treatment for patients with locally advanced squamous cell carcinoma of the head and neck (HNSCC). Pneumonia is a significant complication in these patients. This study aims to identify pneumonia risk factors and their impact on survival in HNSCC patients undergoing CCRT. Data from the Chang Gung Research Database (CGRD) were retrospectively reviewed for patients treated between January 2007 and December 2019. Of 6959 patients, 1601 (23.01%) developed pneumonia, resulting in a median overall survival (OS) of 1.2 years compared to 4.9 years in the non-pneumonia group (p < 0.001). The pneumonia group included older patients with advanced tumors, more patients with diabetes mellitus (DM), more patients with invasive procedures, longer chemotherapy and radiotherapy durations, and lower body weight. The 2-year, 5-year, and 10-year OS rates were significantly lower in the pneumonia group. Multivariate analysis identified alcohol consumption, DM, gastrostomy, nasogastric tube use, longer chemotherapy, and a 2-week radiotherapy delay as independent risk factors. Understanding these risks can lead to early interventions to prevent severe pneumonia-related complications. A better understanding of the risks of pneumonia enables early and aggressive interventions to prevent severe complications.

Advances and prospects of biomarkers for immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) activate anti-cancer immunity by blocking T cell checkpoint molecules such as programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). Although ICIs induce some durable responses in various cancer patients, they also have disadvantages, including low response rates, the potential for severe side effects, and high treatment costs. Therefore, selection of patients who can benefit from ICI treatment is critical, and identification of biomarkers is essential to improve the efficiency of ICIs. In this review, we provide updated information on established predictive biomarkers (tumor programmed death-ligand 1 [PD-L1] expression, DNA mismatch repair deficiency, microsatellite instability high, and tumor mutational burden) and potential biomarkers currently under investigation such as tumor-infiltrated and peripheral lymphocytes, gut microbiome, and signaling pathways related to DNA damage and antigen presentation. In particular, this review aims to summarize the current knowledge of biomarkers, discuss issues, and further explore future biomarkers.

Reducing tension step by step in epicanthus and lower eyelid incision for treating cilial entropion in children: A case series analysis.

OBJECTIVE: To evaluate the surgical outcomes of a modified technique for treating congenital cilial entropion in children, which involves reducing tension step by step in the epicanthus and lower eyelid incision. METHODS: The observational group consisted of 153 pediatric patients (81 males and 72 females) who were treated using the modified technique, whereas the control group included 124 patients (68 males and 56 females) who were treated using the rotating suture surgery. All the participants were bilateral. Surgical outcomes were classified as good, fair, or poor, and the recurrence rate, scar condition, inferior eyelid position, and patient satisfaction were also assessed. RESULTS: The mean follow-up period was 9.13 ± 3.50 months (range: 3-14 months) for the observational group and 6.93 ± 4.51 months (range: 3-14 months) for the control group. In the observational group, surgical success with "good" outcomes was achieved in 300 eyes (98.04%), compared to 224 eyes (90.32%) in the control group. No recurrence occurred in the observational group, whereas the recurrence rate in the control group was 4.43%. Postoperative scar formation was mild in the observational group. The average scar score was 1.27 ± 0.96 in the observational group and 2.70 ± 0.99 in the control group, with a statistically significant difference (P < 0.001). Neither overcorrection nor postoperative ectropion was observed in both groups. CONCLUSION: The modified technique effectively corrected medial entropion and trichiasis in the lower eyelid, resulting in stable postoperative outcomes, mild scar formation, quick recovery, flexible eyelid motility, and stable ocular surface. Therefore, it can be widely applied to children with congenital entropion and trichiasis.

Synthesis and Characterization of Sulfonamide-Containing Naphthalimides as Fluorescent Probes.

A tumor-targeting fluorescent probe has attracted increasing interest in fluorescent imaging for the noninvasive detection of cancers in recent years. Sulfonamide-containing naphthalimide derivatives (SN-2NI, SD-NI) were synthesized by the incorporation of N-butyl-4-ethyldiamino-1,8-naphthalene imide (NI) into sulfonamide (SN) and sulfadiazine (SD) as the tumor-targeting groups, respectively. These derivatives were further characterized by mass spectrometry (MS), nuclear magnetic resonance spectroscopy (1H NMR), Fourier transform infrared spectroscopy (FT-IR), ultraviolet-visible spectroscopy (UV), and a fluorescence assay. In vitro properties, including cell cytotoxicity and the cell uptake of tumor cells, were also evaluated. Sulfonamide-containing naphthalimide derivatives possessed low cell cytotoxicity to B16F10 melanoma cells. Moreover, SN-2NI and SD-NI can be taken up highly by B16F10 cells and then achieve good green fluorescent images in B16F10 cells. Therefore, sulfonamide-containing naphthalimide derivatives can be considered to be the potential probes used to target fluorescent imaging in tumors.

Tannic acids and proanthocyanidins in tea inhibit SARS-CoV-2 variants infection.

The COVID-19 pandemic has caused hundreds million cases and millions death as well as continues to infect human life in the world since late of 2019. The breakthrough infection caused from mutation of SARS-CoV-2 is rising even the vaccinated population has been increasing. Currently, the severe threat posed by SARS-CoV-2 has been alleviated worldwide, and the situation has transitioned to coexisting with the virus. The dietary food with antiviral activities may improve to prevent virus infection for living with COVID-19 pandemic. Teas containing enriched phenolic ingredients such as tannins have been reported to be antitumor agents as well as be good inhibitors for coronavirus. This study developed a highly sensitive and selective ultra-high performance liquid chromatography-high resolution mass spectrometric method for quantification of tannic acids, a hydrolysable tannin, and proanthocyanidins, a condense tannin, in teas with different levels of fermentation. The in vitro pseudoviral particles (Vpp) infection assay was used to evaluate the inhibition activities of various teas. The results of current research demonstrate that the tannins in teas are effective inhibitors against infection of SARS-CoV-2 and its variants.

The risk of free flap revision and subsequent medical costs in patients with hypopharyngeal cancer.

BACKGROUND: Few studies have examined the preoperative risks and healthcare costs related to free flap revision in hypopharyngeal cancer (HPC) patients. METHODS: A 20-year retrospective case-control study was conducted using the Chang Gung Research Database, focusing on HPC patients who underwent tumor excision and free flap reconstruction from January 1, 2001, to December 31, 2019. The impacts of clinical variables on the need for re-exploration due to free flap complications were assessed using logistic regression. The direct and indirect effects of these complications on medical costs were evaluated by causal mediation analysis. RESULTS: Among 348 patients studied, 43 (12.4%) developed complications requiring re-exploration. Lower preoperative albumin levels significantly increased the risk of complications (OR 2.45, 95% CI 1.12-5.35), especially in older and previously irradiated patients. Causal mediation analysis revealed that these complications explained 11.4% of the effect on increased hospitalization costs, after controlling for confounders. CONCLUSIONS: Lower preoperative albumin levels in HPC patients are associated with a higher risk of microvascular free flap complications and elevated healthcare costs, underscoring the need for enhanced nutritional support before surgery in this population.

Salvage radiofrequency ablation followed by external beam radiotherapy for inoperable recurrent differentiated thyroid cancer.

PURPOSE: The treatment of recurrent thyroid cancer with critical organ invasion is challenging. The combination of radiofrequency ablation (RFA) and external beam radiation therapy (EBRT) has been proposed as an effective option. This study evaluates outcomes for inoperable residual/recurrent differentiated thyroid cancer (rDTC) patients treated with RFA followed by EBRT. MATERIALS AND METHODS: Patients with rDTC treated with RFA followed by EBRT were retrospectively studied. RFA was performed using a free-hand, 'moving-shot' technique under US or CT guidance. For lesions invading critical structures intolerant to 'en bloc' high-temperature RFA, limited-field EBRT using 6- or 10-MV photons was used for adjuvant treatment at a dose of 66 Gy in 33 daily fractions. Toxicities and outcomes were reviewed. RESULTS: Between April 2020 and January 2022, 11 patients with 14 rDTC lesions underwent RFA followed by EBRT. Five patients had metastatic lesions at rDTC diagnosis. With a median follow-up period of 33.7 months, all patients maintained locoregional control, while achieving a 2-year survival rate of 90.9%. This combined treatment achieved a volume reduction ratio of 92.1% ± 5.1%. The mean nadir thyroglobulin level in patients without initial distant metastases after treatment was 1.40 ± 0.81 ng/ml. Regarding treatment-related complications, one patient (9%) experienced temporary hoarseness after RFA, grade 2 radiation dermatitis occurred in 3 patients (27.2%), and grade 2 dysphagia was noted in 4 patients (36.4%). No grade 3 or greater toxicities occurred. CONCLUSIONS: Salvage RFA followed by EBRT is feasible, effective and safe for patients with rDTC.

A Joint Model Based on Post-Treatment Longitudinal Prognostic Nutritional Index to Predict Survival in Nasopharyngeal Carcinoma.

BACKGROUND: a low PNI in patients with NPC is linked to poor survival, but prior studies have focused on single-timepoint measurements. Our study aims to employ joint modeling to analyze longitudinal PNI data from each routine visit, exploring its relationship with overall survival. METHODS: In this retrospective study using data from the Chang Gung Research Database (2007-2019), we enrolled patients with NPC undergoing curative treatment. We analyzed the correlation between patient characteristics, including the PNI, and overall survival. A joint model combining a longitudinal sub-model with a time-to-event sub-model was used to further evaluate the prognostic value of longitudinal PNI. RESULTS: A total of 2332 patient were enrolled for the analysis. Separate survival analyses showed that longitudinal PNI was an independent indicator of a reduced mortality risk (adjusted HR 0.813; 95% CI, 0.805 to 0.821). Joint modeling confirmed longitudinal PNI as a consistent predictor of survival (HR 0.864; 95% CI, 0.850 to 0.879). An ROC analysis revealed that a PNI below 38.1 significantly increased the risk of 90-day mortality, with 90.0% sensitivity and 89.6% specificity. CONCLUSIONS: Longitudinal PNI data independently predicted the overall survival in patients with NPC, significantly forecasting 90-day survival outcomes. We recommend routine PNI assessments during each clinic visit for these patients.

The Value of the Nutritional Indicators in Predicting Free Flap Failure From a Multicentre Database.

OBJECTIVE: Nutritional and inflammatory statuses have been associated with complications in microvascular-free flaps during head and neck surgeries. This study aimed to evaluate the potential of nutritional indicators in predicting postoperative free flap complications. STUDY DESIGN: We conducted a 20-year retrospective, case-control study within a defined cohort. SETTING: The study involved head and neck cancer patients from the Chang Gung Research Database who underwent simultaneous tumor ablation and free flap wound reconstruction between January 1, 2001, and December 31, 2019. METHODS: We employed logistic regression and stratified analysis to assess the risk of free flap complications and the subsequent need for flap revision or redo in relation to nutritional indicators and other clinical variables. RESULTS: Of the 8066 patients analyzed, 687 (8.5%) experienced free flap complications. Among these, 197 (2.4%) had free flap failures necessitating a redo of either a free flap or a pedicled flap. Beyond comorbidities such as chronic obstructive pulmonary disease, end-stage renal disease, and a history of prior radiotherapy, every 10-unit decrease in the preoperative prognostic nutritional index (PNI) was consistently associated with an increased risk of both free flap complications and failure. The covariate-adjusted odds ratios were 1.90 (95% confidence interval [CI]: 1.42-2.54) and 1.89 (95% CI: 1.13-3.17), respectively. CONCLUSION: A lower preoperative PNI suggests a higher likelihood of microvascular free flap complications in head and neck surgeries. Further randomized controlled trial designs are required to establish causality.

PPM1G promotes cell proliferation via modulating mutant GOF p53 protein expression in hepatocellular carcinoma.

The serine/threonine protein phosphatase family involves series of cellular processes, such as pre-mRNA splicing. The function of one of its members, protein phosphatase, Mg2+/Mn2+ dependent 1G (PPM1G), remains unclear in hepatocellular carcinoma (HCC). Our results demonstrated that PPM1G was significantly overexpressed in HCC cells and tumor tissues compared with the normal liver tissues at both protein and RNA levels. High PPM1G expression is associated with shorter overall survival (p < 0.0001) and disease-free survival (p = 0.004) in HCC patients. Enhanced expression of PPM1G increases the cell proliferation rate, and knockdown of PPM1G led to a significant reduction in tumor volume in vivo. Further experiments illustrated that upregulated-PPM1G expression increased the protein expression of gain-of-function (GOF) mutant p53. Besides, the immunoprecipitation analysis revealed a direct interaction between PPM1G and GOF mutant p53. Collectively, PPM1G can be a powerful prognostic predictor and potential drug-target molecule.

Expression and clinical significance of hypoxia-induced long non-coding RNA TCONS_I2_00001955 in breast cancer.

BACKGROUND: Long non-coding RNAs (lncRNAs) have been found to play important roles in occurrence, development, and metastasis of various tumors. We aimed to screen long non-coding RNAs (lncRNAs) that promote invasion and metastasis of breast cancer cells under hypoxia, and investigate the relationship between lncRNA expression and clinicopathological features and prognosis in invasive breast cancer. METHODS: LncRNA microarray was used to screen the differentially expressed lncRNAs in MCF7, MDA-MB-231, and SKBR3 breast cancer cell lines cultured under normoxia and hypoxia, respectively. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to verify the microarray results. CCK8 and Transwell experiments were performed to identify the lncRNA that promote proliferation, migration, and invasion of breast cancer cells. Expression of the lncRNA and HIF-1α in invasive breast cancer was detected by RNAscope and immunohistochemistry, respectively. Correlation between the lncRNA expression and baseline characteristics was analyzed. Prognostic value of the lncRNA was evaluated using univariate and multivariate Cox regression. RESULTS: Expression of lncRNA TCONS_I2_00001955 in all the three breast cancer cells was increased under hypoxia. Overexpression of TCONS_I2_00001955 significantly enhanced proliferation, migration, and invasion of SKBR3 cells. Positive expression of TCONS_I2_00001955 was associated with recurrence, metastasis, and high expression of HIF-1α (P < 0.05), and it was an independent risk factor for poor disease-free survival of breast cancer. CONCLUSION: Hypoxia-induced lncRNA TCONS_I2_00001955 was associated with aggressive feature and poor prognosis of breast cancer.

Targeting ALK averts ribonuclease 1-induced immunosuppression and enhances antitumor immunity in hepatocellular carcinoma.

Tumor-secreted factors contribute to the development of a microenvironment that facilitates the escape of cancer cells from immunotherapy. In this study, we conduct a retrospective comparison of the proteins secreted by hepatocellular carcinoma (HCC) cells in responders and non-responders among a cohort of ten patients who received Nivolumab (anti-PD-1 antibody). Our findings indicate that non-responders have a high abundance of secreted RNase1, which is associated with a poor prognosis in various cancer types. Furthermore, mice implanted with HCC cells that overexpress RNase1 exhibit immunosuppressive tumor microenvironments and diminished response to anti-PD-1 therapy. RNase1 induces the polarization of macrophages towards a tumor growth-promoting phenotype through activation of the anaplastic lymphoma kinase (ALK) signaling pathway. Targeting the RNase1/ALK axis reprograms the macrophage polarization, with increased CD8+ T- and Th1- cell recruitment. Moreover, simultaneous targeting of the checkpoint protein PD-1 unleashes cytotoxic CD8+ T-cell responses. Treatment utilizing both an ALK inhibitor and an anti-PD-1 antibody exhibits enhanced tumor regression and facilitates long-term immunity. Our study elucidates the role of RNase1 in mediating tumor resistance to immunotherapy and reveals an RNase1-mediated immunosuppressive tumor microenvironment, highlighting the potential of targeting RNase1 as a promising strategy for cancer immunotherapy in HCC.

Intelligent carboxymethyl cellulose composite films containing Garcinia mangostana shell anthocyanin with improved antioxidant and antibacterial properties.

In this study, anthocyanin from Garcinia mangostana shell extract (Mse) was used as pH indicator to prepare intelligent carboxymethyl cellulose (CMC) based composite films. The structure and properties of the CMC-based composite films were characterized and discussed in detail. Results showed that the CMC-based composite films with Mse had excellent mechanical, antibacterial and antioxidant abilities. Especially, the carboxymethyl cellulose/corn starch/Garcinia mangostana shell extract (CMC/Cst/Mse) composite film had best mechanical properties (20.62 MPa, 4.06 % EB), lowest water vapor permeability (1.80 × 10-12 g·cm/(cm2·s·Pa)), excellent ultraviolet (UV) blocking performance, and the best antibacterial and antioxidant abilities. The pH sensitivity of composite films which had Mse obviously changed with time when the fish freshness was monitored at 25 °C. Given the good pH sensitivity of the composite films, it had significant potential for application of intelligent packaging film as a food packaging material to indicate the freshness of fish.

Comparison of contraction-type and noncontraction-type lymphatic vessels in lymphaticovenous anastomosis for cancer-related unilateral lower limb lymphedema: a retrospective cohort propensity-score-matched outcome analysis.

BACKGROUND: Contraction-type lymphatic vessels (LV) are considered suboptimal for lymphaticovenous anastomosis (LVA). However, despite these pathological changes, their functionality and link to outcomes have not been fully elucidated. The aim of this study was to determine the impact on outcomes when contraction-type LVs were used for LVA compared to the noncontraction-type (normal + ectatic) counterpart for treating lower limb lymphedema. STUDY DESIGN: Eighty-three patients with gynecologic cancer-related unilateral lower-limb lymphedema who underwent LVA as their primary treatment were enrolled in this study. The study group included 20 patients who used only contraction-type LVs. An additional 63 patients (control group) received noncontraction-type LVs only. Patients with a history of LVA, liposuction, or excisional therapy were excluded. Patient characteristics, intraoperative findings, functional parameters, and pre-LVA and post-LVA volume changes were recorded and matched using propensity scores. The primary endpoint was the volume change at 6/12 months after LVA. RESULTS: After matching, 20 patients were included in each group. All parameters were matched, except that the study group still had a significantly inferior indocyanine green (ICG)-positive ratio, lymph flow-positive ratio, and washout-positive ratios ( P <0.001, P =0.003, and P <0.001, respectively) when compared to the control group after matching. However, at 1-year follow-up, the postoperative percentage volume reduction was comparable between the groups ( P= 0.619). CONCLUSION: The use of contraction-type LVs for LVA is encouraged when no other LVs are available.

Clinical Value of Endoscopic Esophageal Screening in Head and Neck Squamous Cell Carcinoma Patients.

OBJECTIVE: To investigate the clinical benefit of routine esophageal screening in newly diagnosed head and neck squamous cell carcinoma (HNSCC) patients. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary medical center. METHODS: This retrospective study selected newly diagnosed HNSCC patients from the Chang Gung Research Database between January 2007 and December 2019. Patients who underwent endoscopic esophageal examinations within 2 months of the initial diagnosis of HNSCC were included in the screening group. The clinical outcomes of the screening and nonscreening groups were analyzed. RESULTS: In total, 13,627 HNSCC patients were included, comprising 1032 females and 12,640 males (mean age 55.0 years), and the esophageal screening group included 7033 (51.4%) patients. The prevalence rate of esophageal tumors was 4.5%. Hypopharyngeal cancer patients were the most likely to have (13.4%) second primary esophageal tumors. The American Joint Committee on Cancer stage of the esophageal tumor was lower in the esophageal screening group than in the nonesophageal screening group. The oral, oropharyngeal, and hypopharyngeal cancer patients in the esophageal screening group had better survival outcomes than their counterparts in the nonesophageal screening group. CONCLUSION: Endoscopic esophageal screening of newly diagnosed HNSCC patients can detect esophageal tumors at an early stage and improve overall survival. Esophageal screening could be a routine survey in HNSCC patients, particularly those with lifestyle risk factors and in countries with a high prevalence of esophageal cancer.

Development of an online calculator for the prediction of seizure freedom following pediatric hemispherectomy using the Hemispherectomy Outcome Prediction Scale (HOPS).

OBJECTIVES: Although hemispheric surgeries are among the most effective procedures for drug-resistant epilepsy (DRE) in the pediatric population, there is a large variability in seizure outcomes at the group level. A recently developed HOPS score provides individualized estimation of likelihood of seizure freedom to complement clinical judgement. The objective of this study was to develop a freely accessible online calculator that accurately predicts the probability of seizure freedom for any patient at 1-, 2-, and 5-years post-hemispherectomy. METHODS: Retrospective data of all pediatric patients with DRE and seizure outcome data from the original Hemispherectomy Outcome Prediction Scale (HOPS) study were included. The primary outcome of interest was time-to-seizure recurrence. A multivariate Cox proportional-hazards regression model was developed to predict the likelihood of post-hemispheric surgery seizure freedom at three time points (1-, 2- and 5- years) based on a combination of variables identified by clinical judgment and inferential statistics predictive of the primary outcome. The final model from this study was encoded in a publicly accessible online calculator on the International Network for Epilepsy Surgery and Treatment (iNEST) website (https://hops-calculator.com/). RESULTS: The selected variables for inclusion in the final model included the five original HOPS variables (age at seizure onset, etiologic substrate, seizure semiology, prior non-hemispheric resective surgery, and contralateral fluorodeoxyglucose-positron emission tomography [FDG-PET] hypometabolism) and three additional variables (age at surgery, history of infantile spasms, and magnetic resonance imaging [MRI] lesion). Predictors of shorter time-to-seizure recurrence included younger age at seizure onset, prior resective surgery, generalized seizure semiology, FDG-PET hypometabolism contralateral to the side of surgery, contralateral MRI lesion, non-lesional MRI, non-stroke etiologies, and a history of infantile spasms. The area under the curve (AUC) of the final model was 73.0%. SIGNIFICANCE: Online calculators are useful, cost-free tools that can assist physicians in risk estimation and inform joint decision-making processes with patients and families, potentially leading to greater satisfaction. Although the HOPS data was validated in the original analysis, the authors encourage external validation of this new calculator.

The Impact of Clinical Prognosis of Viral Hepatitis in Head and Neck Cancer Patients Receiving Concurrent Chemoradiotherapy.

This study evaluated the clinical characteristics of head and neck cancer (HNC) patients with hepatitis B (HBV) or hepatitis C (HCV) who underwent concurrent chemoradiotherapy (CCRT) and examined the prognostic impact of antiviral therapies. In a 19-year retrospective analysis of 8224 HNC patients treated with CCRT, 29.8% (2452) were diagnosed with HBV or HCV, of whom 714 received antiviral therapy. For non-metastatic HNC patients on CCRT, factors such as gender, Charlson Comorbidity Index (CCI), liver cirrhosis markers (Fibrosis-4, APRI), and initial tumor stage were significant determinants of their overall survival. However, the presence of HBV or HCV and the administration of antiviral treatments did not yield distinct survival outcomes. In summary, antiviral therapy for HBV or HCV did not affect the 5-year survival rates of non-metastatic HNC patients undergoing CCRT, while gender, tumor stage, CCI, and liver cirrhosis were notable prognostic indicators.

CD45- erythroid progenitor cells promote lymph node metastasis in gastric cancer by inducing a hybrid epithelial/mesenchymal state in lymphatic endothelial cells.

BACKGROUND AND AIMS: Specific mechanisms of lymph node (LN) metastasis in early-stage gastric cancer (GC) have not been elucidated. The role of anemia, a vital clinical feature of GC, in LN metastasis is also unclear. Since the number of erythroid progenitor cells (EPCs) is increased in chronic anemia, we investigated its association with LN metastasis in GC. METHODS: Flow cytometry and immunofluorescence analyses were performed to sort and study EPCs from the circulation and tumors of patients with stage I-III GC. The effect of these EPCs on the activation of T and B cells and on the functions of lymphatic endothelial cells (LECs) was determined, and their ability to promote LN metastasis was evaluated using a footpad-popliteal LN metastasis model based on two human adenocarcinoma GC cell lines in nude mice. The prognostic value of EPCs was also analyzed. RESULTS: The proportion of CD45- EPCs was higher in the mononuclear cells in the circulation, tumors, and LNs of GC patients with LN metastasis (N+) than in those of GC patients without LN metastasis (N0). In N+ patients, CD45- EPCs were more abundant in metastatic LNs than in non-metastatic LNs. Lymphatic vessel endothelial hyaluronan receptor 1 immunoreactivity in tumors revealed that CD45- EPCs were positively associated with nodal stages and lymph vessel density. Furthermore, CD45- EPCs increased LEC proliferation and migration through their S100A8/A9 heterodimer-induced hybrid epithelial/mesenchymal (E/M) state; however, they did not influence the invasion and tubulogenesis of LECs or T and B cell proliferation. CD45- EPCs promoted LN metastasis in vivo; the S100A8/A9 heterodimer mimicked this phenomenon. Finally, CD45- EPCs predicted the overall and disease-free survival of stage I-III GC patients after radical resection. CONCLUSIONS: The CD45- EPCs accumulated in GC tissues and metastatic LNs and promoted LN metastasis via the S100A8/9-induced hybrid E/M state of LECs, which was the specific mechanism of LN metastasis in the early stages of GC.