Yong Chen

Objective: There is still a lack of widely applicable biomarkers for immunotherapy in hepatocellular carcinoma (HCC). We aim to identify subtypes using computed tomography (CT) imaging features of HCC and assess their value in predicting prognosis and the effectiveness of immunotherapy. Materials and methods: We used unsupervised consensus clustering based on quantitative contrast-enhanced CT features to identify imaging subtypes and investigated their value in predicting prognosis and the effectiveness of immunotherapy in the discovery ( n = 103) and immunotherapy-treated ( n = 110) validation cohort. We also developed a gene-based classifier for imaging subtypes and tested their prognostic and biological relevance in two additional gene validation cohorts with publicly available gene expression data but without imaging data ( n = 551). Results: The imaging subtypes demonstrated significant correlations with overall survival across all cohorts ( p = 0.002, p < 0.001) and effectively predicted immunotherapy outcomes, with 1-year progression-free survival rates varying significantly ( p < 0.001). Imaging subtypes 1 and 3 with favorable and intermediate immunotherapy responses showed significant activation of B-cells, lymphocyte-mediated immunity, and immune response (adjusted p -value ≤ 0.047, false discovery rate ≤ 0.043). Imaging subtype 2 with poor immunotherapy responses displayed the least activated CD8+ T cells, the lowest cytolytic activity, and the highest infiltration of neutrophil and regulatory T cells. Additionally, type I and II interferon responses were significantly downregulated in imaging subtype 2. Conclusion: Unsupervised clustering of CT imaging features identified subtypes with significantly distinct prognosis and immune signatures. The imaging subtypes can serve as a marker for immunotherapy in HCC. Relevance statement: The imaging subtypes identified in this study demonstrate significant clinical relevance by providing a non-invasive approach to predict prognosis and immunotherapy response for HCC. Key Points: We identified three novel imaging subtypes using unsupervised consensus clustering of quantitative CT imaging features for HCC. Imaging subtypes were independent predictors of overall survival and the effectiveness of immunotherapy for HCC. The imaging subtypes can be used as a marker for immunotherapy in HCC.

Purpose Cancer-associated fibroblasts (CAFs), a crucial component of tumor microenvironment, play a critical role in tumorigenesis, progression, and conferring resistance to radiotherapy and chemotherapy. This study aimed to investigate the association between CAFs, CAF- related genes, and radioresistance in hepatocellular carcinoma (HCC). Methods CAFs were isolated from HCC tissues and subsequently utilized for co-culturing with HCC cells using CAFs-conditioned medium. An orthotopic HCC mouse model was established by co-implanting CAFs and HCC cells. Through integrative analysis of three RNA-sequencing datasets (TCGA-LIHC tumor vs. normal tissues, Huh7 radioresistant vs. parent cells, and CAF vs. control group), CAF-associated prognostic genes were identified using comprehensive bioinformatics approaches. Experimental validation was performed by real-time quantitative PCR, western blot, immunohistochemistry, cell viability assays, and colony formation assays. Results Our findings demonstrated that CAFs significantly enhance radioresistance in HCC. Based on 13 CAF-related prognostic genes, TCGA-LIHC patients were stratified into two distinct clusters via consensus clustering, exhibiting significant differences in overall survival, immune cell infiltration, and therapeutic response. A prognostic nomogram incorporating three hub genes and clinical characteristics was developed. Notably, SOX4 was upregulated in tumor tissues, radioresistant cells, and CAF-exposed HCC cells, correlating with poor prognosis. SOX4 knockdown suppressed HCC proliferation and reversed CAF-induced radioresistance. Additionally, a competitive endogenous RNA (ceRNA) network of LINC00665/miR-122-5p/SOX4 was constructed. Conclusion CAFs serve as crucial mediators of radioresistance in HCC, and CAF-related genes provide valuable prognostic and therapeutic insights. SOX4 emerges as a promising therapeutic target to improve radiotherapy efficacy in HCC. Clinical trial number Not applicable.

Radiation-induced liver disease (RILD) severely impairs the outcome of patients receiving irradiation (IR); however, its underlying mechanism remains unknown. GSDMD drives the progression of pyroptosis, and can be induced by IR in the gut and bone marrow, but its role in RILD remains unknown. Here we show that GSDMD is significantly upregulated and positively correlated with RILD severity in a mouse model. Hepatocytes are identified as critical pyroptotic cells in RILD thorough scRNA-seq, immunofluorescence and fluorescence-activated cell sorting analysis. Functional and mechanistic analysis using Gsdmd knockout (Gsdmd^∆Hep) mice and cell models. Mechanistically, GSDMD is indispensable for triggering hepatocyte pyroptosis and initiating the activation of transcription factor STAT5A, which subsequently promoted CXCL1 expression to recruit neutrophil into liver to accelerate the severity of RILD. We also discovered that pharmacological targeting GSDMD and its downstream CXCL1 effectively alleviated RILD. Together, our study demonstrates that GSDMD as therapeutic targets to improve RILD.

This study aimed to investigate the incidence of post radiation nasopharyngeal necrosis (PRNN) in primary NPC after intensity modulated radiation therapy (IMRT) and identify the predictors of risk. Data of 5798 NPC patients who received IMRT-based treatment between April 2009 and December 2015 were retrospectively reviewed. PRNN was diagnosed by MRI or nasopharyngoscopy. Dosimetric factors were selected by the least absolute shrinkage and selection operator logistic regression and applied to Cox proportional hazards modeling with clinical predictors. Among the 5798 patients, 53 developed PRNN—an incidence rate of 0.89%. Age > 55 years, diabetes, LDH > 170 U/L, and tumor volume of nasopharynx > 60.5 cm3,were independently associated with risk of PRNN(all p < 0.05. Dosimetric analysis showed that D0.5ccEQD2 of 80.20 Gy might be the dose constraint for nasopharynx (sensitivity = 62.3%, 33 out of 53; specificity = 84.2%, 4897 out of 5925). Besides, the RTOG dose constraints of V110% (V77.0) should be less than 0.2% in case of increasing risk of PRNN(HR = 2.28, 95% CI: 1.26–4.41, p = 0. 01). Nasopharyngeal necrosis is rare after primary IMRT. The independent risk factors for this rare complication include age > 55 years, diabetes mellitus, LDH > 170 U/L, tumor volume of nasopharynx > 60.5 cm3, D0.5ccEQD2 > 80.20 Gy, and V77.0 < 0.2% to the planning treatment volume of nasopharynx. High radiation dose may lead to devastating nasopharyngeal necrosis after primary IMRT. Real world analysis will provide valuable information for prevention. The aged, diabetes mellitus, large tumor volume, D0.5ccEQD2 > 80.20 Gy and V77.0 < 0.2% to planning treatment volume increased the risk of nasopharyngeal necrosis. This real-world study provided valuable information for prevention of PRNN. Compared with RTOG protocol, D0.5ccEQD2 > 80.20 Gy is a reliable evidence-based new complement to dose constraint, especially for T3-4 disease, who received high prescribe dose in China.

Background: Induction chemotherapy (IC) with docetaxel, cisplatin, and fluorouracil (TPF), combined with concurrent chemoradiotherapy (CCRT), has been shown to improve survival in patients with locally advanced nasopharyngeal carcinoma (LA-NPC) . Our previous study demonstrated that adjusting the number of IC cylces based on TNM stage and Epstein-Barr virus DNA (EBV-DNA) load after IC did not compromise efficacy while reducing toxicity. However, due to the small sample size, there is a need for further confirmation of the long-term outcomes . Methods: This retrospective analysis evaluated the clinical data and survival outcomes of patients with stage III–IVaLA-NPC treated with TPF IC followed by CCRT. Patients in the conventional treatment group received three standard cycles of TPF IC an d CCRT, while those in the experimental group had IC cycles determined by EBV-DNA clearance . If EBV-DNA was undetectable after a certain IC course, subsequent IC was stopped, and CCRT commenced. Propensity score matching (PSM) was performed at a ratio of 1:4 to balance baseline characteristics. Survival outcomes between the two groups were compared. Results: A total of 730 patients were included , and 481 patients were successfully matched into 106 pairs . The median followed-up duration was 116months. The 5-year survival outcomes before and after matching, respectively, were as follows: distant metastasis-free survival (89 .3%vs.87.6%, P=0.52/ 87.9% vs . 87.6%, P=0.886), local recurrence-free survival (90 .3%vs. 81.9%, P=0.015/88 .8% vs . 81.9%, P=0.069),progression-free survival (81 . 1%vs . 68.7%, P=0.003/78.5%vs .68.7%, P=0.033), and overall survival (85 .9% vs . 85.3%, P=0.795 / 84.4%vs.85.3%, P=0.870) . Conclusions: This study addresses an important clinical question about the use of EBV-DNA as a marker for optimizing IC in LA-NPC patients, and presents promising findings that could enhance patient outcomes.The results provides a valuable foundation for future research but requires further confirmation through well-designed prospective trials. Trial registration : This is a retrospective study without registration for prospective clinical trial.

Background: Mecapegfilgrastim, a long‐acting granulocyte‐colony stimulating factor has been approved for reducing the incidence of infection, particularly febrile neutropenia (FN), in China.Objective: We conducted a multicenter prospective observational study to examine the safety and effectiveness of mecapegfilgrastim in preventing neutropenia in gastrointestinal patients receiving the chemotherapy, including S‐1/capecitabine‐based regimens or the fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI)/fluorouracil, leucovorin, and oxaliplatin (FOLFOX)/fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) regimens.Method: Five hundred and sixty‐one gastrointestinal patients from 40 sites across China, between May 2019 and November 2021, were included. The administration of mecapegfilgrastim was prescribed at the discretion of local physicians.Results: The most common adverse drug reactions (ADRs) of any grade for all patients was increased white blood cells (2.9%). Grade 3/4 ADRs were observed for anemia (0.2%), decreased white blood cells (0.2%), and decreased neutrophil count (0.2%). Among the 116 patients who received S‐1/capecitabine‐based chemotherapy throughout all cycles, ADRs of any grade included anemia (1.7%), myalgia (0.9%), and increased alanine aminotransferase (0.9%). No grade 3/4 ADRs were observed. In 414 cycles of patients who underwent S‐1/capecitabine‐based regimens, only one (0.2%) cycle experienced grade 4 neutropenia. In the FOLFIRINOX, FOLFOXIRI, and FOLFOX chemotherapy regimens, grade 4 neutropenia occurred in one (2.7%) of 37 cycles, four (4.7%) of 85 cycles, and two (1.2%) of 167 cycles, respectively.Conclusion: In a real‐world setting, mecapegfilgrastim has proven effective in preventing severe neutropenia in gastrointestinal patients following chemotherapy. This includes commonly used moderate or high‐risk FN regimens or regimens containing S1/capecitabine, all of which have demonstrated favorable efficacy and safety profiles.

Radiotherapy causes DNA damage by direct ionization and indirect generation of reactive oxygen species (ROS) thereby destroying cancer cells. However, ionizing radiation (IR) unexpectedly elicits metastasis and invasion of cancer cells by inducing cancer stem cells' (CSCs) properties. As BMI1 is a crucial gene that causes radioresistance and an unfavorable prognosis of hepatocellular carcinoma (HCC), BMI1 inhibitor PTC-209 has been encapsulated in a ROS-responsive liposome (LP(PTC-209)) to be temporally and spatially delivered to radioresistant HCC tissue. The ROS generated during IR was not only considered to directly cause tumor cell death but also be used as a stimulator to trigger ROS-responsive drug release from LP(PTC-209). The PTC-209 released into resistant HCC tissue under radiotherapy further led to cancer stem cell (CSC) differentiation and then recovered radiosensitivity of HCC tumor. The suppression of the radioresistant performance of LP(PTC-209) has been proved on radiosensitive and radioresistant Hepa1-6 CSC tumor models, respectively. Our study clarified the relationship between radiotherapy and cancer stemness and provided insights to achieve complete suppression of radioresistant HCC tumor by inhibiting cancer stemness.

Objectives: The aim of this study was to compare the metastatic patterns of synchronous bone metastasis (SBM) and metachronous bone metastasis (MBM) in nasopharyngeal carcinoma (NPC). Methods: This study included bone metastases in NPC patients from 2005 to 2016 in a Chinese hospital. Cohort 1 was collected from 2005 to 2010 for discovery, and Cohort 2 from 2011 to 2016 for validation. The chi‐squared test, Wilcoxon rank sum test, and Kaplan–Meier technique were used to compare site, time, and survival between cohorts 1 and 2. Prognostic factors were analyzed using univariate or multivariate Cox regression. Results: Cohort 1 had 112 individuals with SBM and 394 with MBM, and cohort 2 had 328 with SBM and 307 with MBM. The thoracic vertebra was the most frequently affected site of metastasis. Patients with SBM more often had metastasis to the cervical vertebrae compared with patients with MBM (34.5% vs. 22.3%, p < 0.05). Patients with SBM had better overall survival (42.2 months, 95% CI: 33.9–50.7) than patients with MBM (24.9 months, 95% CI: 22.2–28.7). Age at bone metastasis detection, metastasis to other organs, and more bone metastasis locations were associated with worse prognosis. The majority of MBMs occurred at 7 to 18 months after NPC diagnosis. Conclusion: Radiotherapy does not modify the metastatic patterns of NPC bone metastases. Patients with SBM tend to have metastasis to the cervical vertebra, which is close to the nasopharynx. Paying more attention to bone metastases during follow‐up in the first 2 years after an NPC diagnosis.

Objectives: To explore the efficacy of induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) in stage II nasopharyngeal carcinoma (NPC) treated with intensity‐modulated radiotherapy (IMRT).Methods: Totally, 450 eligible patients with staged II NPC on the basis of the 8th edition of the AJCC/UICC TNM staging system were eventually included from January 2010 to September 2020. The one‐to‐one propensity score‐matched (1:1 PSM) analysis was employed to balance variables. We conducted univariate and multivariate analysis of survival to identify prognostic factors and demonstrated the findings in the matching cohort.Results: In total, 141 pairs were selected by 1:1 PSM. IC + CCRT group in the matched data decreased 5‐year progression‐free survival (PFS, 75.5% vs. 88.0%, p = 0.032) and distant metastasis‐free survival (DMFS, 86.0% vs. 96.5%, p = 0.009). There was no significant difference in 5‐year overall survival (OS, 93.8% vs. 95.6%, p = 0.192) and locoregional relapse‐free survival (LRRFS, 87.1% vs. 94.3%, p = 0.169) compared with RT/CCRT. Multivariate analysis indicated that IC + CCRT was associated with significantly poor PFS (p = 0.024) and DMFS (p = 0.010). High neutrophil‐to‐lymphocyte ratio (>4.1) was negatively associated with OS (p = 0.034), PFS (p = 0.017) and DMFS (p = 0.001).Conclusion: Adding IC to CCRT or IMRT alone has decreased PFS and DMFS, therefore, IC should not be recommended in stage II NPC patients. No significant differences in OS and LRRFS were observed in stage II disease.