This study aimed to investigate the efficacy of radiation therapy and targeted therapy combined with or without immunotherapy for hepatocellular carcinoma (HCC) patients with lymph node metastases (LNM). A total of 132 HCC patients with LNM were enrolled in this study. Propensity score matching (PSM) and stabilized inverse probability of treatment weighting (sIPTW) were used to balance baseline variables between groups. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and clinical safety were compared between the two treatment arms. There were 61 patients in radiotherapy plus targeted therapy (RT) group, and 71 patients in radiation therapy, targeted therapy combined with immunotherapy (RTI) group. In the overall cohort, the median OS was 12.8 months in the RT group and 18.8 months in the RTI group (p = 0.003). Multivariate analysis identified that tumor thrombus status, distant metastasis, lymph node (LN) number, LN size and immunotherapy were independent prognostic factors for survival. Median PFS was 7.0 months in the RT group and 11.9 months in the RTI group (p = 0.001). The ORRs were 70.5

Purpose: To compare the outcomes of transarterial chemoembolization (TACE) alone with those of TACE combined with external beam radiation therapy (EBRT) in patients with hepatocellular carcinoma (HCC) in a multicenter randomized study. Methods and Materials: From 2017 to 2022, 74 HCC patients with tumors confined to the liver without vascular invasion were treated with either TACE only (TACE group, 39 patients) or TACE combined with EBRT (TACE + EBRT group, 35 patients). The primary outcome measured was overall survival (OS). Secondary outcomes included progression-free survival (PFS), local tumor control, and the assessment of treatment-related toxicity. Results: Due to slow accrual, the trial was closed prematurely after enrolling 74 patients. All patients received 2 cycles of TACE before randomization. The TACE and TACE + EBRT groups showed comparable patient and tumor characteristics. The TACE group underwent a median of 3 TACE cycles, and the TACE + EBRT group received 2 cycles of TACE, and a median of 5500 cGy in 15 fractions. For the TACE group, the median local control (LC) duration was 13.1 months, whereas for the TACE + EBRT group, the median LC was not achieved (P < .001). The PFS was recorded at 11.6 months in the TACE group compared with 15.4 months in the TACE + EBRT group (P = .072). The median OS reached 36.8 months for the TACE group and extended to 47.1 months for the TACE + EBRT group (P = .654). The incidence of toxicity was comparable between both groups. Conclusions: Although the number of patients enrolled in this clinical trial did not meet expectations. TACE combined with EBRT was shown to be more effective than TACE alone in improving LC without increasing toxicity, whereas PFS and OS were slightly improved. TACE + EBRT can be used as a standard treatment option for patients with inoperable but confined intrahepatic HCC. (c) 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Breast cancer (BC) remains one of the leading causes of cancer-related mortality among women worldwide, with distant metastasis being the primary contributor to poor prognosis. However, the molecular mechanisms driving BC metastasis are not yet fully understood. We integrated three public microarray datasets (GSE14776, GSE103357, and GSE32489) to identify the differentially expressed genes (DEGs) associated with breast cancer metastasis. Functional enrichment analysis, protein-protein interaction (PPI) network construction, and hub gene identification were performed using bioinformatics tools including DAVID, STRING, Cytoscape, and R. The prognostic significance of hub genes was assessed using Kaplan-Meier plotter and GEPIA. Expression validation was conducted through UALCAN, immunohistochemistry (IHC), and single-cell RNA sequencing (scRNA-seq) analysis from the GSE180286 dataset. A total of 295 co-DEGs were identified across the three datasets, enriched in pathways such as MAPK signaling, Rap1 signaling, and cell adhesion molecules. Twenty hub genes were identified from the PPI network, with eight showing strong prognostic value. Among them, PRC1 and POLR3H emerged as potential novel biomarkers. IHC confirmed the differential protein expression of PRC1, CDCA8, KIF14, and POLR3H. scRNA-seq analysis revealed that these hub genes were predominantly expressed in malignant epithelial and EMT (epithelial-mesenchymal transition) cells, particularly those from metastatic lymph node sites. This integrative analysis combining bulk and single-cell transcriptomic data identified key metastasis-associated genes in breast cancer. PRC1 and POLR3H, in particular, may serve as novel prognostic biomarkers and potential therapeutic targets.

Abstract Background: This study aimed to investigate the effect of radiotherapy on pancreatic cancer patients with liver metastasis only, and to establish a prognostic model. Methods: Pancreatic cancer patients with liver-only metastases were obtained from 2010 to 2019 in the Surveillance, Epidemiology, and End Results (SEER) database. Then they were divided into a radiotherapy group and a non-radiotherapy group. Cancer-specific survival (CSS) before and after propensity score matching(PSM) was compared between the two groups. The radiotherapy group was then divided into training and validation cohorts. The prognostic nomogram for 6-, and 12-mouth CSS was constructed based on the training set. In addition, 38 patients were recruited from our hospital as an external validation set. The calibration curves, receiver operating characteristic (ROC) curve, Harrell’s concordance index (C-index), decision curve analysis (DCA), and Kaplan-Meier analysis based on risk stratification were performed to evaluate and verify this model. Results: A total of 17453 patients with hepatic oligometastatic pancreatic cancer were included, of which 622 ( 3.6 % ) received radiotherapy and 16831 ( 96.4 % ) did not. Radiotherapy can significantly prolong survival time [median CSS: 8 months vs 5 months (HR, 0.716; 95%CI=0.655–0.783; p<0.001)]. After PSM, similar results can be obtained [median CSS: 8 months vs 7 months (HR, 0877; 95% CI=0.772–0.997; P=0.045)]. Independent prognostic factors in radiotherapy patients included age, race, histology, N staging, surgery, and chemotherapy. The ROC, C-index and Calibration curves showed good discrimination and calibration. DCA and KM curves further demonstrated the model's clinical applicability. Conclusion: Radiotherapy significantly improves survival compared to non-radiotherapy. Patients younger than 70 years old, non-black, with no lymph node metastasis, primary tumor surgery, and systemic chemotherapy have better prognosis. Finally, we developed and validated a model for prognostication and patient counseling.

Classical Hodgkin Lymphoma (CHL) is a rare malignant neoplasm of the lymphatic system. While CHL typically responds well to conventional treatments, some cases may experience relapse to other subtypes, with the development of secondary peripheral T-cell lymphoma (PTCL) being relatively uncommon. Herein, we report a rare case of nodal T follicular helper cell lymphomas,nos (nTFHL-NOS) secondary to CHL, accompanied by aberrant CD20 expression and clonal rearrangements of T-cell receptor (TCR) and immunoglobulin (IG). A 74-year-old male, was diagnosed with CHL, leaning toward the mixed cell type, 6 years ago. He received six cycles of the Adriamycin, Bleomycin, Vinblastine, Dacarbazine (ABVD) regimen, achieving complete clinical remission. The patient was admitted to our hospital due to the appearance of multiple skin nodules 66 months later. Histopathological analysis revealed nTFHL-NOS, with aberrant CD20 expression and clonal rearrangements of TCR and IG. The patient underwent two cycles of chemotherapy with brentuximab vedotin and the Gemcitabine-Oxaliplatin (G-mox) regimen, resulting in a reduction of the skin lesions to 2 cm × 1 cm. We discuss this rare case and review related literature.

Aim: To investigate radiotherapy efficacy and prognostic factors in patients with hepatocellular carcinoma (HCC) with cardiophrenic angle or superior diaphragmatic lymph node metastasis (LNM). Methods: We retrospectively analyzed 72 patients with HCC presenting with cardiophrenic angle or superior diaphragmatic LNM at Zhongshan Hospital of Fudan University from 2010 to 2023. Response rates, survival rates, local control rates, prognostic risk factors, and side effects of external beam radiation therapy (EBRT) were compared between patients with EBRT (EBRT group) and those without EBRT (non-EBRT group). Results: The overall response rates in the EBRT group and the non-EBRT group were 68.8% (22/32) and 7.5% (3/40), while median survival was 16.1 (95%CI: 8.09-24.12) and 5.9 months (95%CI: 3.05-7.76) respectively (HR = 2.87, P < 0.001). The survival was significantly prolonged with a daily dose > 4 Gy (P = 0.014). EBRT (P < 0.001) was identified as a factor correlated with the local control rate. Multivariate analysis revealed that tumor thrombosis, multiple intrahepatic tumors, a maximal intrahepatic tumor diameter ≥ 5 cm, abdominal LNM, and lack of EBRT were poor prognostic factors. Gastrointestinal (GI) bleeding in patients with bioequivalent dose 10 (BED10) ≤ 70 and > 70 were 0% (0/22) and 30.0% (3/10), respectively (P = 0.024). Conclusion: EBRT was a safe and effective treatment for HCC patients with cardiophrenic angle or superior diaphragmatic LNM and might prolong overall survival. Dose > 4 Gy per day and BED10 ≤ 70 would be recommended for LNM. Patients with tumor thrombosis, multiple intrahepatic tumors, a maximal intrahepatic tumor diameter ≥ 5 cm, abdominal LNM, and lack of EBRT had a poor prognosis.

Centrally located hepatocellular carcinoma (HCC) is difficult to be radically resected due to its special location close to major hepatic vessels. Thus, we aimed to assess whether stereotactic body radiation therapy (SBRT) can be an effective and safe approach for centrally located HCC. This retrospective study included 172 patients with centrally located HCC who were treated with SBRT. Overall survival (OS) was analyzed as the primary endpoint. Rates of progression-free survival (PFS), local control, intrahepatic relapse, extrahepatic metastasis and toxicities were analyzed as secondary endpoints. The OS rates of 1-, 3-, and 5-year were 97.7%, 86.7%, and 76.3%, respectively. The PFS/local control rates of 1-, 3-, and 5-year were 94.1%/98.2%, 76.8%/94.9%, and 59.3%/92.3%, respectively. The cumulative incidence of intrahepatic relapse/extrahepatic metastases of 1-, 3-, and 5-year were 3.7%/2.9%, 25.0%/7.4%, and 33.3%/9.8%, respectively. Both univariate and multivariate analyses revealed that patients received BED10 at 100 Gy or more had better OS. Radiation-related adverse events were mild to moderate according to Common Terminology Criteria for Adverse Events, and no toxicities over grade 3 were observed. Patients with centrally located HCC in our cohort who received SBRT had similar OS and PFS rates compared to those reported in literatures who received surgery with neoadjuvant or adjuvant intensity-modulated radiation therapy. These results indicate that SBRT is an effective and well-tolerated method for patients with centrally located HCC, suggesting that it may serve as a reasonable alternative treatment for these kind of patients.

Aim: The aim of this study was to compare the effects of conventionally fractionated radiotherapy (CFRT) and stereotactic body radiotherapy (SBRT) on peripheral lymphocyte subset levels in patients with hepatocellular carcinoma (HCC), and to assess the association between radiotherapy (RT)-induced lymphopenia and patient prognosis. Methods: A retrospective analysis was conducted on 137 HCC patients who underwent either CFRT or SBRT between July 2011 and January 2018. Variables were obtained within 1 week before RT, and 1 day and 2 months post-RT, respectively. Peripheral lymphocyte subsets, including CD4+, CD8+, CD19+, and NK cells, were measured using flow cytometry. Univariate and multivariate Cox regression analyses were conducted to investigate independent prognostic factors for overall survival (OS). Results: The one-year and two-year OS rates were 80.0% and 55.0%, respectively. Multivariate analysis identified tumor size > 4.5 cm, multiple tumors, and post-RT CD4+ T cell count < 231/μL and CD8+ T cell count < 179/μL as independent factors associated with inferior OS in HCC patients. Severe lymphopenia (< 0.5 × 109/L) occurred in 70.0% of patients following CFRT compared to 23.0% in SBRT patients. Patients who received SBRT exhibited higher total lymphocyte counts and subset levels 1 day and 2 months post-treatment compared to those receiving CFRT (P < 0.05). Logistic regression analysis identified the number of RT fractions as an independent factor for severe lymphopenia. Further analysis revealed that CD19+ B cells were predominantly depleted and recovered more slowly than other populations, whereas CD8+ T cells demonstrated rapid recovery. Among SBRT patients, higher levels of CD4+ and CD8+ T cells post-treatment were associated with longer OS (P < 0.05). Conclusion: SBRT may induce less severe lymphopenia than CFRT. Decreases in CD4+ and CD8+ T cell levels post-SBRT may independently predict worse OS in HCC patients.

Pre-clinical data suggest that type I interferon (IFN) responsiveness is essential for the antitumor effects of radiotherapy (RT). However, its clinical value remains unclear. This study aimed to explore this from a clinical perspective. In cohort 1, data from 152 hepatocellular carcinoma (HCC) patients who received RT were analyzed. Blood samples were taken 1 day before and 2 weeks after RT. RT was found to increase serum levels of IFN-β (a subtype of IFN-I) in HCC patients (3.42 ± 1.57 to 5.51 ± 2.11 pg/mL, p < 0.01), particularly in those with favorable responses. Higher post-RT serum IFN-β levels (≥ 4.77 pg/mL) were associated with better progression-free survival (HR = 0.58, p < 0.01). Cohort 2 included 46 HCC patients, including 23 who underwent preoperative RT and 23 matched control HCC who received surgical resection without RT. Formalin-fixed paraffin-embedded samples were obtained. Neoadjuvant RT significantly increased IFN-β expression in tumor tissues compared to direct surgery (8.13% ± 5.19% to 15.10% ± 5.89%, p < 0.01). Higher post-RT IFN-β (> median) indicated better disease-free survival (p = 0.049). Additionally, increased CD11c+MHCII+CD141+ antigen presenting cell subsets and CD103+CD39+CD8+ tumor-infiltrating lymphocytes were found in the higher IFN-β group (p = 0.02, p = 0.03), which may contribute to the favorable prognosis in higher IFN-β group. Collectively, these findings suggest that IFN-β response activated by radiation may serve as a prognostic biomarker for HCC patients undergoing RT.

Background and PurposeTo evaluate the different response patterns after Stereotactic Body Radiation Therapy (SBRT) and their predictive value in local control and progression of hepatocellular carcinoma (HCC).Materials and methodsSeventy-two HCC patients who were treated with SBRT during 2015–2020 were included in this retrospective study. The assessment was made using MRI, CT, and PET-CT. Local and systemic responses were determined according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria during follow up. Patients were categorized as early responders (complete response during 6 months after radiotherapy) or non-early responders (the rest of the patients). Prognostic factors were determined using multivariate logistic models.ResultsThe median follow-up was 24.0 months (range, 7.7–74.5 months). We found that 84.7%（61/72) of patients achieved a complete response. Early responses occurred in 45 patients (45/72, 62.5%), and they had 1-, 2-, and 5- year intrahepatic outfield-free survival (OutFFS) rates of 86.2%, 80.3%, and 76.3% vs. 55.3%, 44.7%, and 33.5% in non-early responses patients, whereas the 1-, 2-, and 5- year distant metastasis-free survival (DMFS) were 95.5%, 84.5% and 79.5% and 74.1%, 56.2% and 56.2%, respectively. The 1-, 2-, and 5-year overall survival (OS) were 97.7%, 92.1%, 79.1%, and 85.2%, 53.8%, and 40.3%, respectively. Multivariate analysis revealed that early tumor response was an independent predictor of OutFFS, DMFS, and OS.ConclusionsEarly complete tumor response within 6 months after radiotherapy predicted better intrahepatic outfield-free survival, distant metastasis-free survival, and overall survival outcomes. Confirmation is warranted for early response on SBRT to guide decision making.

Studies of the gut-liver axis have enhanced our understanding of the pathophysiology of various liver diseases and the mechanisms underlying the regulation of the effectiveness of therapies. Radiotherapy (RT) is an important therapeutic option for patients with unresectable hepatocellular carcinoma (HCC). However, the role of the microbiome in regulating the response to RT remains unclear. The present study characterizes the gut microbiome of patients responsive or non-responsive to RT and investigates the molecular mechanisms underlying the differences in patient response. We collected fecal samples for 16S rRNA sequencing from a prospective longitudinal trial of 24 HCC patients receiving RT. We used fecal microbiota transplantation (FMT), flow cytometry, and transcriptome sequencing to explore the effects of dysbiosis on RT. We also examined the role of stimulator of interferon genes (STING) in RT-associated antitumor immune responses mediated by gut microbiota in STING- (Tmem173-/-) and cGAS-knockout (Mb21d1-/-) mouse models. We propose that primary resistance to RT could be attributed to the disruption of the gut microbiome. Mechanistically, gut microbiome dysbiosis impairs antitumor immune responses by suppressing antigen presentation and inhibiting effector T cell functions through the cGAS-STING-IFN-I pathway. Cyclic-di-AMP - an emerging second messenger of bacteria - may act as a STING agonist and is thus a potential target for the prediction and modulation of responses to RT in HCC patients. Our study highlights the therapeutic potential of modulating the gut microbiome in HCC patients receiving RT and provides a new strategy for the radiosensitization of liver cancer.

Background: Our preclinical research reveals that radiotherapy (RT) promoted PD-L1 upregulation in tumor tissues and that higher PD-L1 after RT worsened the prognosis through immunosuppression. We sought to validate our experimental results in clinical cohorts and promote clinical application. Patients and methods: In cohort 1, formalin-fixed paraffin-embedded samples were obtained from 46 HCC patients, 23 of whom received preoperative RT and the other 23 received direct surgery. A prospectively collected database contained 122 HCC patients treated with liver RT were enrolled in cohort 2. Blood samples were taken a day before and two weeks after RT. Patients in cohort 2 were further divided into two groups, exploration (73 patients) and validation (49 patients) groups. Results: In cohort 1, RT increased the expression of PD-L1 in tumor tissues (p = 0.001), and PD-L1 levels were associated with decreased cytotoxic T-cell infiltration and a trend toward poor prognosis (p = 0.14). Moreover, PD-L1 expression in tumor tissue positively correlated with soluble (s) PD-L1 in serum (R = 0.421, p = 0.046). Then, in cohort 2, we revealed RT increased sPD-L1 in serum (p < 0.001), which was associated with the number of circulating CD8+ T cells (R = -0.24, p = 0.036), indicating poor survival. Furthermore, patients with higher rate of sPD-L1 increase after RT have better treatment response (p < 0.001), PFS (p = 0.032) and OS (p = 0.045). Conclusion: Higher post-RT serum sPD-L1, which may potentiate immune suppression effects, indicates a poor prognosis for HCC patients treated with RT.

Background and purposeThis study aims to evaluate whether dosimetric parameters affect the intrahepatic out-field recurrence or distant metastasis-free survival following the stereotactic body radiation therapy (SBRT) in patients with hepatocellular carcinoma (HCC).Materials and methodsA total of 76 patients with HCC who were treated with SBRT from January 2015 to May 2020 were included in this retrospective study. The main clinical endpoints considered were intrahepatic out-field free survival (OutFFS) and distant metastasis-free survival (DMFS). The target parameters and the liver were documented including tumor diameters, gross tumor volume (GTV), Liver minus GTV volume (LGV), and Liver minus GTV mean dose (LGD). Multivariable Cox regression with forward stepwise selection was performed to identify independent risk factors for OutFFS and DMFS. Maximally selected rank statistics were used to determine the most informative cut-off value for age and LGD.ResultsThe median follow-up was 28.2 months (range, 7.7–74.5 months). LGD higher than 12.54 Gy [HR, 0.861(0.747–0.993); p = 0.040] and age greater than 67-year-old [HR, 0.966(0.937–0.997); p = 0.030] are two independent predictors of OutFFS, previous TACE treatment [HR, 0.117(0.015–0.891); p = 0.038] was an independent predictor of DMFS.ConclusionsThe results of this study suggested that the higher the dose received by the normal liver (greater than 12.54 Gy) the better the intrahepatic out-field recurrence-free survival (RFS) rate. Further study is warranted to confirm and to better understand this phenomenon.

Background and purpose: This study aims to evaluate whether dosimetric parameters affect the intrahepatic outfield recurrence or distant metastasis-free survival following the stereotactic body radiation therapy (SBRT) in patients with hepatocellular carcinoma (HCC).Materials and methods: A total of 76 patients with HCC who were treated with SBRT from January 2015 to May 2020 were included in this retrospective study. The main clinical endpoints considered were intrahepatic outfield free survival (OutFFS) and distant metastasis-free survival (DMFS). The target parameters and the liver were documented including tumor diameters, gross tumor volume (GTV), Liver minus GTV volume (LGV), and Liver minus GTV mean dose (LGD). Multivariable Cox regression with forward stepwise selection was performed to identify independent risk factors for OutFFS and DMFS. Maximally selected rank statistics were used to determine the most informative cut-off value for age and LGD.Results: The median follow-up was 28.2 months (range, 7.7-74.5 months). LGD higher than 12.54 Gy [HR, 0.861 (0.747-0.993); p = 0.040] and age greater than 67-year-old [HR, 0.966(0.937-0.997); p = 0.030] are two independent predictors of OutFFS, previous TACE treatment [HR, 0.117(0.015-0.891); p = 0.038] was an independent predictor of DMFS.Conclusions: The results of this study suggested that the higher the dose received by the normal liver (greater than 12.54 Gy) the better the intrahepatic out-field recurrence-free survival (RFS) rate. Further study is warranted to confirm and to better understand this phenomenon.

Purpose To assess the efficacy and safety of different peri-operative regimens using the network meta-analysis for hepatocellular carcinoma (HCC) with portal/hepatic vein tumor thrombosis. The interested modalities included neoadjuvant three-dimensional radiotherapy (3D-CRT), post-operative intensity modulated radiation therapy (IMRT), post-operative transarterial chemoembolization (TACE), 3DCRT plus TACE and surgery alone. Methods PubMed and Cochrane Library electronic databases were systematically searched for eligible studies published up to March 2021. Data related to treatment efficacy including overall survival (OS) and disease-free survival (DFS) were extracted and compared using a Bayesian approach. Adverse events (AEs) were assessed and compared. Results Five studies published between 2009 and 2021 were enrolled in this network meta-analysis. The comparison showed that surgery with IMRT ranks relatively higher in prolonging OS in advanced HCC patients, followed by neoadjuvant 3DCRT and surgery plus TACE. Neoadjuvant 3DCRT and postoperative IMRT appear to be better choices than 3DCRT plus TACE in terms of OS. IMRT, TACE and neoadjuvant 3DCRT group were all superior to surgery alone in terms of DFS. The rate of AEs did not differ significantly. Conclusions Adjuvant IMRT showed more favorable treatment responses compared to other regimens in HCC patients as a peri-operative regimen.

Background Early screening and intervention therapies are crucial to improve the prognosis of hepatocellular carcinoma (HCC) patients with bone metastasis. We aimed to identify serum lncRNA as a prediction biomarker in HCC bone metastasis. Methods The expression levels of lnc34a in serum samples from 157 HCC patients were detected by quantitative real-time polymerase chain reaction (PCR). Univariate analysis and multivariate analysis were performed to determine statistically significant variables. Results Expression levels of lnc34a in serum from HCC patients with bone metastasis were significantly higher than those without bone metastasis. The high expressions of lnc34a, vascular invasion and Barcelona Clinic Liver Cancer (BCLC) stage were associated with bone metastasis by analysis. Moreover, lnc34a expression was specifically associated with bone metastasis rather than lung or lymph node metastasis in HCC. Conclusions High serum lnc34a expression was a independent risk factor for developing bone metastasis in HCC.

Purpose: To assess the efficacy and safety of stereotactic body radiation therapy using an abdominal compression technique and modified fractionation regimen (5-10 fractions) in patients with small-sized hepatocellular carcinoma. Methods: A total of 101 patients with small-sized hepatocellular carcinoma treated with stereotactic body radiation therapy using an abdominal compression technique and modified fractionation regimen were registered between June 2011 and June 2019 in our hospital. A total dose of 48 to 60 Gy was applied over 5 to 14 consecutive days. Liver motion was controlled by abdominal compression, and a helical intensity-modified radiation therapy-based stereotactic body radiation therapy administrated in tomotherapy platform. Results: The median follow-up period was 23.2 months (range: 4.1-99.2 months). Complete response and partial response were observed in 63 (62.4%) patients and in 24 (23.8%) patients, respectively. At the time of our analysis, the 1-, 3-, and 5-year local control rates after stereotactic body radiation therapy were 96.1%, 89.0%, and 89.0%, respectively. However, logistic regression analysis revealed no correlation between the biologically effective dose and 3-year local control rates. The 1-, 3-, and 5-year overall survival rates were 96.9%, 69.0%, and 64.3%, respectively. For patients who were treatment-naive, the 1-, 3-, and 5-year overall survival were 96.3%, 82.0%, and 82.0%, respectively. No patients experienced classic radiation-induced liver disease or nonclassic radiation-induced liver disease after stereotactic body radiation therapy completion. Conclusions: When using an abdominal compression technique and modified fractionation regimen (5-10 fractions) based on helical intensity-modified radiation therapy, stereotactic body radiation therapy led to a lower toxicity and comparative rate of local control and overall survival for patients who with small-sized hepatocellular carcinoma.

Liver damage upon exposure to ionizing radiation (IR), whether accidental or therapeutic, can contribute to liver dysfunction. Currently, radiotherapy (RT) is used for various cancers including hepatocellular carcinoma (HCC); however, the treatment dose is limited by radiation-induced liver disease (RILD) with a high mortality rate. Furthermore, the precise molecular mechanisms of RILD remain poorly understood. Here, we investigated RILD pathogenesis using various knockout mouse strains subjected to whole-liver irradiation. We found that hepatocytes released a large quantity of double-stranded DNA (dsDNA) after irradiation. The cGAS-STING pathway in non-parenchymal cells (NPCs) was promptly activated by this dsDNA, causing interferon (IFN)-I production and release and concomitant hepatocyte damage. Genetic and pharmacological ablation of the IFN-I signaling pathway protected against RILD. Moreover, clinically irradiated human peri-HCC liver tissues exhibited substantially higher STING and IFNβ expression than non-irradiated tissues. Increased serum IFNβ concentrations post-radiation were associated with RILD development in patients. These results delineate cGAS-STING induced type 1 interferon release in NPCs as a key mediator of IR-induced liver damage and described a mechanism of innate-immunity-driven pathology, linking cGAS-STING activation with amplification of initial radiation-induced liver injury.

e16672 Background: Accumulating data have shown that soluble (s)PD-1 and sPD-L1 are potential biomarkers for the curative efficacy of chemotherapy in several cancers. However, these markers have not been well established for outcomes in hepatocellular carcinoma (HCC) radiotherapy (RT). Therefore, this study aims to assess sPD-1/sPD-L1 levels before and after RT and their relationship to clinical characteristics and prognoses. Methods: Pre-treatment serum sPD-L1 and sPD-1 levels were measured with an enzyme-linked immunosorbent assay (ELISA) in 281 patients with HCC treated with RT. The association between serum sPD-L1 and sPD-1 levels and prognosis was assessed using survival analysis. Formalin-fixed paraffin-embedded samples were obtained from 40 patients with HCC who underwent surgery. The expression of PD-L1 was evaluated by immunohistochemical analysis. Results: Using multivariate analyses; sPD-L1 and sPD-1 levels were significant independent predictors of disease-free and overall survival. Patients with maximum tumor diameters ≥5 cm and Barcelona clinic liver cancer (BCLC) staging B and C had significantly higher median sPD-1/sPD-L1 serum concentrations compared to patients with smaller tumor sizes and earlier stages. There was a positive correlation (r = 0.377, p < 0.001) between sPD-L1 and sPD-1 levels. High pretreatment sPD-1/sPD-L1 levels were associated with poor prognoses, and increased sPD-1/sPD-L1 levels were associated with disease progression after RT. In post-irradiated tumor tissue, PD-L1 expression was significantly higher than matched, non-irradiated tissue. In addition, higher PD-L1 expression was correlated with decreased cytotoxic T-cell infiltration and poor survival. Therefore, sPD-1/sPD-L1 could be used as noninvasive biomarkers for evaluating HCC malignancy before RT and in predicting the response to RT in HCC patients. Conclusions: High pretreatment serum sPD-L1 and sPD-1 were associated with poor prognoses, and increased serum sPD-L1 levels were associated with the disease progression of HCC patients treated with RT. PD-L1/ PD-1 pathway may be explored as therapeutic targets and potential predictive biomarkers for HCC treated with RT.

Purpose. To investigate whether lymphocyte nadir induced by radiation is associated with survival and explore its underlying risk factors in patients with hepatocellular carcinoma (HCC).Methods. Total lymphocyte counts were collected from 184 HCC patients treated by radiotherapy (RT) with complete follow-up. Associations between gross tumor volumes (GTVs) and radiation-associated parameters with lymphocyte nadir were evaluated by Pearson/Spearman correlation analysis and multiple linear regression. Kaplan–Meier analysis, log-rank test, as well as univariate and multivariate Cox regression were performed to assess the relationship between lymphocyte nadir and overall survival (OS).Results. GTVs and fractions were negatively related with lymphocyte nadir (p<0.001andp=0.001, respectively). Lymphocyte nadir and Barcelona Clinic Liver Cancer (BCLC) stage were independent prognostic factors predicting OS of HCC patients (allp<0.001). Patients in the GTV ≤55.0 cc and fractions ≤16 groups were stratified by lymphocyte nadir, and the group with the higher lymphocyte counts (LCs) showed longer survival than the group with lower LCs (p<0.001andp=0.006, respectively). Patient distribution significantly differed among the RT fraction groups according to BCLC stage (p<0.001). However, stratification of patients in the same BCLC stage by RT fractionation showed that the stereotactic body RT (SBRT) group achieved the best survival. Furthermore, there were significant differences in lymphocyte nadir among patients in the SBRT group.Conclusions. A lower lymphocyte nadir during RT was associated with worse survival among HCC patients. Smaller GTVs and fractions reduced the risk of lymphopenia.