Radiotherapy For Hepatocellular Carcinoma Research Articles

Perioperative Tislelizumab plus intensity modulated radiotherapy in resectable hepatocellular carcinoma with macrovascular invasion: a phase II trial

Hepatocellular carcinoma (HCC) patients with macrovascular invasion (MVI) have dismal prognosis and there are no standard perioperative therapies. This phase 2 trial (ChiCTR2000036385) aimed to investigate the activity and safety of perioperative tislelizumab plus intensity modulated radiotherapy (IMRT) for resectable HCC with MVI. Thirty treatment-naïve patients with MVI received 3 cycles of tislelizumab intravenously (200 mg, every three weeks) and concurrent IMRT (45 Gray in 15 fractions). Primary endpoints were the overall response rate (ORR) and overall survival (OS). Secondary endpoints were the proportion of patients with a complete or major pathological response (pCR or MPR), recurrence-free survival (RFS) and safety. Of patients enrolled, 15 (50%) underwent curative surgery followed by adjuvant tislelizumab. The ORR was 30.0% (90% CI 16.6%-46.5%) and the median OS was 18.7 months. Of the 15 patients underwent surgical resection, 10 (66.7%) achieved pCR or MPR and 8 (53.3%) remained recurrence-free. The median RFS were not reached with a median follow-up of 21.77 months (95% CI 12.50-31.03) post-surgery. 4 (13.3%) patients experienced grade 3 treatment-related adverse events. The most common events were thrombocytopenia, leukopenia, and anemia. The trial has met the pre-specified endpoints, and these results support further studies of perioperative immunotherapy plus radiotherapy in HCC.

Quercetin regulates sensitivity to X-ray radiation of hepatocellular carcinoma through miR-216a-3p

Hepatocellular carcinoma (HCC) is a highly aggressive liver cancer with limited therapeutic options, and enhancing radiosensitivity remains a key challenge in improving treatment outcomes. Quercetin (Que) can inhibit the progression of hepatocellular carcinoma (HCC); however, its effect on HCC radiosensitivity remains unclear. This research investigates the role of Que in regulating HCC growth and radiosensitivity, aiming to provide a scientific foundation for enhancing the clinical efficacy of radiation therapy in HCC. The CCK-8 assay was used to determine the optimal treatment conditions for Que and X-rays. Changes in cell growth, cycle arrest, invasion, migration, the relative proportion of JC-1 red and green fluorescence (mitochondrial membrane potential), and the levels of ROS, MDA, SOD, and GSH-Px (oxidative stress) were assessed using flow cytometry, Transwell assays, JC-1 staining, Western blot, and ELISA, respectively, under Que, X-ray, and co-treatment conditions. The effect of miR-216a-3p knockdown on the action of Que was also explored, and the potential pathways by which Que regulates HCC growth and radiosensitivity were investigated in conjunction with in vivo subcutaneous transplantation tumor experiments. The in vitro treatment parameters for Que and X-rays were 100 µM and 4 Gy. Que combined with X-ray therapy enhanced HCC cell radiosensitivity, reduced proliferation, invasion, and migration, and promoted oxidative stress and apoptosis. Que was found to upregulate miR-216a-3p in HCC cells. Rescue experiments with miR-216a-3p knockdowns demonstrated that Que regulates HCC cell radiosensitivity via miR-216a-3p. In vivo research further showed that Que increased tumor sensitivity to X-rays by upregulating miR-216a-3p, thereby inhibiting HCC growth. In conclusion, Que has been shown to enhance HCC radiosensitization by upregulating miR-216a-3p and inhibiting HCC progression. Que may be a promising agent for increasing the radiosensitivity of HCC.

AdipoRon Alleviates Liver Injury by Protecting Hepatocytes from Mitochondrial Damage Caused by Ionizing Radiation

Radiation liver injury is a common complication of hepatocellular carcinoma radiotherapy. It is mainly caused by irreversible damage to the DNA of hepatocellular cells directly by radiation, which seriously interferes with metabolism and causes cell death. AdipoRon can maintain lipid metabolism and stabilize blood sugar by activating adiponectin receptor 1 (AdipoR1). However, the role of AdipoRon/AdipoR1 in the regulation of ionizing radiation (IR)-induced mitochondrial damage remains unclear. In this study, we aimed to elucidate the roles of AdipoRon/AdipoR1 in IR-induced mitochondrial damage in normal hepatocyte cells. We found that AdipoRon treatment rescued IR-induced liver damage in mice and mitochondrial damage in normal hepatocytes in vivo and in vitro. AdipoR1 deficiency exacerbated IR-induced oxidative stress, mitochondrial dynamics, and biogenesis disorder. Mechanistically, the absence of AdipoR1 inhibits the activity of adenosine monophosphate-activated protein kinase α (AMPKα), subsequently leading to disrupted mitochondrial dynamics by decreasing mitofusin (MFN) and increasing dynamin-related protein 1 (DRP1) protein expression. It also controls mitochondrial biogenesis by suppressing the peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC1α) and transcription factor A (TFAM) signaling pathway, ultimately resulting in impaired mitochondrial function. To sum up, AdipoRon/AdipoR1 maintain mitochondrial function by regulating mitochondrial dynamics and biogenesis through the AdipoR1-AMPKα signaling pathway. This study reveals the significant role of AdipoR1 in regulating IR-induced mitochondrial damage in hepatocytes and offers a novel approach to protecting against damage caused by IR.

Sequencing microsphere selective internal radiotherapy after external beam radiotherapy for hepatocellular carcinoma: proof of concept of a synergistic combination.

This study aims to explore the synergistic effects of combining Stereotactic Body Radiation Therapy (SBRT) and Selective Internal Radiation Therapy (SIRT) in that specific sequence for treating hepatocellular carcinoma (HCC), particularly in patients at high risk of radiation-induced liver disease (RILD). We analyzed a case of a patient with HCC who was treated with SBRT at our institution. A virtual 90Y dose distribution was added using our in-house -BLINDED FOR REVIEW- model to keep a minimum dose to the healthy liver tissue. BED and EUD metrics were calculated to harmonize the dose distributions of SBRT and SIRT. Our radiation biology-based models suggest that the combination of SBRT and SIRT could maintain effective tumor control while reducing the dose to normal liver tissue. Specifically, an SBRT plan of 10 Gy x 3 fractions combined with SIRT yielded comparable tumor control probability to an SBRT-only plan of 10 Gy x 5 fractions. The combination of SBRT and SIRT is a promising treatment strategy for HCC patients at high risk of RILD. While the LQ model and associated formalisms provide a useful starting point, further studies are needed to account for factors beyond these models. Nonetheless, the potential for significant dose reduction to normal tissue suggests that this combination therapy could offer substantial clinical benefits. This article presents a proposal to combine SBRT and SIRT, in this specific order, for HCC, discussing its advantages. A framework for future research into optimizing combination therapy for HCC is provided, utilizing a novel HCC vascular model to simulate 90Y doses.

Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma in Child-Pugh Class C As Bridge Therapy Before Liver Transplantation

Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma in Child-Pugh Class C As Bridge Therapy Before Liver Transplantation

Long-term outcomes of more than a decade treating patients with stereotactic body radiation therapy for hepatocellular carcinoma

Purpose/Objective(s)To evaluate if stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC) has a durable effect on tumor control and can be delivered safely. Materials/MethodsPatients included in this retrospective study have been treated at our institution from January 2008 to December 2022. Eligibility criteria were diagnosis of HCC, BCLC stage 0-A-B, non-cirrhotic liver or liver with cirrhosis Child-Pugh class A, and a maximum of three lesions with a cumulative diameter of ≤ 6 cm. Patients with relapses after surgery, thermal ablation or TACE or patients awaiting transplant were also candidates for SBRT. SBRT was delivered in 6 fractions of 8 or 9 Gy. The primary endpoint was local (target) control (LC). Secondary endpoints were time to progression (TTP), overall survival (OS), response rate (RR) and toxicity. ResultsA total of 52 patients received SBRT at our institution and 51 were included in this study. One patient objected and was excluded. Median follow-up was 2.1 years for LC and 2.3 years for OS. Median tumor size was 26 mm. LC rates at 1, 2, and 5 years were 100 %, 95 % and 95 % respectively. Median TTP was 45.6 months. Median OS was 7.1 years. RR was 96 %. No patients in this study have experienced SBRT related CTC AE grade ≥ 3 toxicity. ConclusionSBRT resulted in excellent long-term local control rates and absence of severe toxicity in a group of HCC patients. The reported outcomes compare favorably with other local therapies. SBRT should be considered as one of the available local treatment options for HCC.

Determining the gross tumor volume for hepatocellular carcinoma radiotherapy based on multi-phase contrast-enhanced magnetic resonance imaging

PurposeThe aim of this study was to quantitatively analyze of the differences in determining the gross tumor volume (GTV) for hepatocellular carcinoma (HCC) radiotherapy using multi-phase contrast-enhanced magnetic resonance imaging (CE-MRI) and provide a reference for determining the GTV for radiotherapy of HCC. MethodsThis retrospective study analyzed 99 HCC patients (145 lesions) who underwent MR simulation. T1-weighted imaging (T1WI), contrast-enhanced T1WI (CE-T1WI) at 15 s, 45 s, 75 s, 150 s, and 20 min after contrast agent injection were performed, comprising a total of six imaging sequences. The GTVs identified on different sequences were grouped and fused in various combinations. The internal GTV (IGTV), which was the reference structure, was obtained by the fusion of all six sequences. Mean signal intensity (SI), volume, shape, and fibrous capsule (FC) thickness among GTVs were compared. Results(1) The mean SI value of GTV-T1WI, GTV-15s-GTV-20min in patients with transarterial chemoembolization (TACE) was lower by 14.09 % (GTV-T1WI) to 31.31 % (GTV-15s) compared with that in patients without TACE. Except for GTV-T1WI, the differences in SI values between the two groups for other GTVs were statistically significant (p < 0.05). (2) The volumes of GTV-T1WI, GTV-15s-GTV-20min ranged from 32.66-34.99 cm3. The volume differences between GTV-45s and the other GTVs were statistically significant (p < 0.05), excluding the GTV-T1WI. (3) Compared with the IGTV, the change trend of GTV volume reduction rate is consistent with that of dice similarity coefficients (DSC). (4) In the CE-T1WI sequences (except for CE-T1WI-15s), FC measurement was possible in 39.31 % of lesions (57/145), with the largest mean thickness observed at 75 s. ConclusionAlthough single-phase CE-MRI introduces uncertainty in HCC GTV determination, combining different phases CE-MRI can enhance accuracy. The CE-T1WI-45s should be routinely included as a necessary scanning sequence

The Role of Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma Patients: A Literature Review

Background: Globally, hepatocellular carcinoma (HCC) is the most prevalent kind of primary liver cancer. Treatment options for HCC include radiotherapy, immunotherapy, surgery, targeted therapy, transarterial chemoembolization, and hepatic arterial infusion chemotherapy. Limited efficacy was observed since 70-80% of cases are diagnosed late and unresectable. Growing evidence reported that SBRT is a viable option for locoregional treatments like radiofrequency ablation (RFA) or transarterial chemoembolization (TACE) for patients who did not respond to those treatments. Methods: A thorough search of electronic databases including PubMed, Cochrane Library, and Embase was conducted for studies on Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma published in English over the past 10 years. The review process followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to ensure a systematic approach. Inclusion criteria encompassed studies focusing on SBRT use in HCC treatment, with extracted data synthesized to provide a comprehensive overview of current evidence. Any discrepancies during the review were resolved through consultation with a third reviewer when necessary. Results: In comparison to conventional radiation therapy, Stereotactic Body Radiation Therapy (SBRT) offers precise administration of the high dose of radiotherapy, given in fewer fractions, and may be used in conjunction with other therapy modalities. Global guidelines, including in Indonesia, have proposed the implementation of SBRT. Local control was reportedly achieved in around 90–95% of HCC patients. Multimodal therapies, combined with TACE, showed superior results regarding the local control and overall survival. SBRT may eventually become the definitive treatment for early-stage HCC patients and has a critical role as a transitional therapy for patients awaiting liver transplantation. Improved outcomes and quality of life were also observed in patients with portal vein thrombosis (PVT) and extrahepatic metastases who underwent SBRT. Conclusions: SBRT results in promising local control, raises overall survival, and improves the quality of life in HCC patients with various stages.

A mechanistic study of radiotherapy on intratumoral NK cell infiltration augmentation by regulating the EZH2/CXCL10 pathway in hepatocellular carcinoma cells

Objective: To investigate the effect and associated mechanism of tumor tissue-infiltrating NK cells after receiving radiotherapy for hepatocellular carcinoma (HCC). Methods: A HCC tumor-bearing mouse model was constructed using human hepatocellular carcinoma cell line (SK-Hep-1) and divided into four groups: control, radiotherapy, NK cell clearance, and NK clearance combined with radiotherapy. Tumor growth condition was simultaneously recorded. The NK cell ratio in peripheral blood and the NK cell intratumoral infiltration condition were detected by flow cytometry and immunohistochemistry. Lentiviral-constructed SK-Hep-1 cells was used to detect the effect of radiotherapy on the regulation of CXCL10 and NK cell chemotaxis following EZH2 overexpression. SK-Hep-1 cells were irradiated in vitro and in vivo. The expression levels of EZH2 and CXCL10 mRNA and protein in the two groups of cell lines and mouse tumor tissues were detected by reverse transcription polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), western blotting (WB), and immunohistochemistry. The chemotaxis and blocking experiments were used to validate the chemotaxis effect of CXCL10 on NK cells. The independent sample t-test was used to compare the groups. P<0.05 was considered statistically significant. Results: The HCC tumor-bearing mouse model experiment showed that HCC tumor growth was most remarkable in the NK clearance combined with the radiotherapy group compared to the radiotherapy group (P<0.05). Compared with the control group, the number of NK cells in the peripheral blood of nude mice in the radiotherapy group was significantly reduced, while the NK cell intratumoral infiltration was significantly increased (P<0.05). Flow cytometry and immunohistochemistry showed in vitro and in vivo expressional alterations. The average expression levels of EZH2 mRNA and protein in hepatocellular carcinoma cell lines and tumor tissues were decreased in the radiotherapy group than the control group and mouse tumor tissues (P<0.05), while the mRNA and protein expression levels of CXCL10 increased (P<0.05). The cell supernatant following radiotherapy enhanced NK cell chemotaxis but inhibited CXCL10 neutralization. EZH2 overexpression validated that radiotherapy up-regulated CXCL10 mRNA and down-regulated protein expression levels in in vitro and in vivo experiments (P<0.05). The chemotactic effect on NK cells was significantly weakened with EZH2 overexpression following radiotherapy. Conclusion: NK cells, as immune effector cells, are directly involved in radiotherapy- activated anti-HCC immunity. Importantly, radiotherapy inhibits EZH2 expression in hepatocellular carcinoma, thereby upregulating CXCL10 expression and enhancing intratumoral NK cell invasion.

Liver injury and recovery following radiation therapy for hepatocellular carcinoma: insights from functional liver imaging

Aim: A critical need for hepatocellular carcinoma (HCC) management is understanding how the liver recovers following radiotherapy (RT). We hypothesized that functional liver imaging with 99mTc-sulfur colloid (SC) SPECT/CT provides additional information on liver injury and recovery after RT compared to conventional imaging. Methods: The liver function of patients with HCC was assessed using 99mTc-SC SPECT/CT imaging before and after definitive RT. The anatomical liver volume (ALV) was segmented on CT imaging. Liver function was measured as the total liver function (TLF) encompassing 30% of maximum SC uptake. Changes in ALV and TLF were compared to clinical characteristics. Results: Of 31 patients with evaluable post-RT SC SPECT/CT scans (total of 32), 23 had pre-treatment Child-Pugh (CP)-A and 9 had CP-B/C scores. The median follow-up post-RT was 57 days. The median change in ALV was -1.7% with no significant difference between CP-A and CP-B/C patients (P = 0.26) or between short- (32-99 days) and long-term (271-1120 days) follow-up imaging groups (P = 0.28). The median change in TLF post-RT was -24% and was significantly different between short- and long-term groups (-39% vs. 2%, P = 0.001) and between CP-A and CP-B/C patients (-19% vs. -57%, P = 0.002). TLF significantly decreased following treatment at all radiation dose levels, with the decline correlating with the dose (P &lt; 0.001). Conclusion: Functional imaging provides additional information regarding liver injury and recovery following RT that conventional imaging cannot reveal. Patients with CP-A liver status showed less decline following RT and most had liver function near or above pre-treatment levels.

Oncologic outcomes and rates of hepatotoxicity following stereotactic body radiotherapy for hepatocellular carcinoma

Aim: Hepatocellular carcinoma (HCC) localized to the liver has various treatment options, including external beam radiotherapy (EBRT). Despite many prospective and retrospective reports showing excellent local control (LC) and favorable toxicity, EBRT has not been widely adopted in the first-line setting and this may be due to a perceived lack of evidence. This study aims to share a decade of experience with Stereotactic Body Radiotherapy (SBRT) for HCC, leveraging a homogenous treatment technique. Methods: This retrospective study at a single institution included patients with HCC treated with SBRT, with a standardized treatment protocol. Freedom from local progression (FFLP), overall survival (OS), and rates of hepatotoxicity post-treatment using child-pugh (CP) and albumin-bilirubin (ALBI) scores were analyzed. A mixed-effects multivariable analysis (MVA) was also performed to assess various factors’ impact on outcomes. Results: A total of 138 lesions in 106 patients were treated between 2009 and 2020. FFLP was 91% at one year and 86% at three years. OS was 80% and 46% at 1 and 3 years, respectively. Baseline liver function was a significant predictor of FFLP and OS on MVA. CP scores and ALBI grades were stable 3 months after treatment in ≥ 70% of patients. Conclusion: SBRT provides excellent LC and low toxicity for HCC patients. While long-term survival remains challenging, treatment decisions should consider overall clinical status. Multidisciplinary review and forthcoming prospective trial results will further clarify radiotherapy’s role in HCC management.

Prognostic nomogram of overall survival for radiation therapy in hepatocellular carcinoma: a population study based on the SEER database and an external cohort.

Radiotherapy (RT) plays an important role in the treatment of hepatocellular carcinoma (HCC). To screen patients who benefit most from RT, a nomogram for survival prediction of RT based on a large sample of patients with HCC was created and validated. A total of 2,252 cases collected from the Surveillance, Epidemiology, and End Results (SEER) database were separated into a training or an internal validation cohort in a 7:3 ratio (n = 1,565:650). An external validation cohort of cases from our institute was obtained (n = 403). LASSO regression and Cox analyses were adopted to develop a nomogram for survival prediction. The decision curve analysis (DCA), calibration curve, and time-dependent receiver operating characteristic curves (TROCs) demonstrated the reliability of the predictive model. For patients with HCC who received RT, the analyses revealed that the independent survival prediction factors were T stage {T2 vs. T1, hazard ratio (HR) =1.452 [95% CI, 1.195-1.765], p < 0.001; T3 vs. T1, HR = 1.469 [95% CI, 1.168-1.846], p < 0.001; T4 vs. T1, HR = 1.291 [95% CI, 0.951-1.754], p = 0.101}, N stage (HR = 1.555 [95% CI, 1.338-1.805], p < 0.001), M stage (HR = 3.007 [95% CI, 2.645-3.418], p < 0.001), max tumor size (>2 and ≤5 vs. ≤2 cm, HR = 1.273 [95% CI, 0.992-1.633], p = 0.057; >5 and ≤10 vs. ≤2 cm, HR = 1.625 [95% CI, 1.246-2.118], p < 0.001; >10 vs. ≤2 cm, HR = 1.784 [95% CI, 1.335-2.385], p < 0.001), major vascular invasion (MVI) (HR = 1.454 [95% CI, 1.028-2.057], p = 0.034), alpha fetoprotein (AFP) (HR = 1.573 [95% CI, 1.315-1.882], p < 0.001), and chemotherapy (HR = 0.511 [95% CI, 0.454-0.576], p < 0.001). A nomogram constructed with these prognostic factors demonstrated outstanding predictive accuracy. The area under the curve (AUC) in the training cohort for predicting overall survival (OS) at 6, 12, 18, and 24 months was 0.824 (95% CI, 0.803-0.846), 0.824 (95% CI, 0.802-0.845), 0.816 (95% CI, 0.792-0.840), and 0.820 (95% CI, 0.794-0.846), respectively. The AUCs were similar in the other two cohorts. The DCA and calibration curve demonstrated the reliability of the predictive model. For patients who have been treated with RT, a nomogram constructed with T stage, N stage, M stage, tumor size, MVI, AFP, and chemotherapy has good survival prediction ability.

Radiation-induced liver disease mimicking liver metastasis after low-dose hepatic irradiation during radiotherapy for gastric mucosa-assisted lymphoid tissue lymphoma: A case report.

Radiation-induced liver disease (RILD) is an established complication of hepatic irradiation that is typically reported in patients receiving high-dose radiotherapy for hepatocellular carcinoma or liver metastases. However, RILD can also occur after unintentional low-dose liver exposure during radiotherapy for other gastrointestinal malignancies when careful precautions are not taken. We report the case of a 44-year-old woman with gastric mucosa-associated lymphoid tissue lymphoma who underwent salvage radiotherapy administered to the entire stomach. One month after completing this radiotherapy, computed tomography and magnetic resonance imaging of the patient's abdomen revealed a 4 cm lesion in the left lateral liver segment, suggestive of metastasis. An ultrasound-guided biopsy was performed, and the histopathological findings were consistent with those of RILD. Conservative management was pursued with close monitoring of liver function tests. The patient's imaging findings and liver enzyme levels normalized approximately 3 months after the initial diagnosis. This case highlights the importance of considering RILD in the differential diagnosis of new hepatic lesions detected after radiotherapy, even in patients with low-dose liver exposure within generally acceptable limits. Careful correlation with the radiotherapy plan is crucial to avoid misdiagnosing RILD as metastatic disease and to guide appropriate management.

Multidisciplinary assessment of tumor response after internal and external radiation therapy for hepatocellular carcinoma

Multidisciplinary assessment of tumor response after internal and external radiation therapy for hepatocellular carcinoma

Radiomic feature robustness in CT scans affected by fiducial marker induced streak artifacts for patients with hepatocellular carcinoma.

Stereotactic body radiation therapy for hepatocellular carcinoma necessitates the implantation of gold fiducial markers in the liver, resulting in artifacts on computed tomography (CT) scans, which affect radiomic feature values. This report aims to assess the effect of these artifacts on radiomic features and how removing CT slices affects radiomic features extracted from 3D regions of interest (ROI). First, the range variation in 38 tumor contours unaffected by artifacts was assessed after sequentially and randomly removing 25%, 50%, 75% of slices. Subsequently, the agreement of feature values before and after removing ROI slices containing artifacts from 186 patients' CT scans was assessed with Lin's concordance correlation coefficient (CCC) and a Wilcoxon signed-rank test. In artifact-free tumor volumes, at least 71% of features remain robust with up to 50% of slices removed, while 56% remains robust with up to 75% of slices removed. When comparing contours before and after removing slices containing artifacts, around a third of features in the tumor contour and surrounding area remain robust (CCC>0.9), compared to 44% in the healthy liver. Concerning the tumor, 13% (Gray Level Size Zone Matrix) to 61% (first order) of the features remain robust (CCC>0.9). Over 90% of features differ significantly as assessed by Wilcoxon signed-rank test, however. This study demonstrates that removing slices containing artifacts is a feasible solution for the CT fiducial problem in this patient population and provides insight into which features are affected.

The cumulative antitumor effects of regorafenib and radiotherapy in hepatocellular carcinoma.

Regorafenib is a second-line standard treatment for hepatocellular carcinoma (HCC). However, the efficacy of regorafenib is often limited due to drug resistance, individual differences among patients, and irrational drug use. Radiotherapy (RT) is an important method of localized HCC treatment, and combining RT with other therapies may exert a synergetic antitumor effect. Platelet-derived growth factor receptor-like (PDGFRL) is a tumor suppressor in various solid tumors. However, the function of PDGFRL in HCC is still unknown. In this study, we explored whether regorafenib and RT exert a synergetic effect on the treatment of HCC.The antitumor effect and mechanisms of the combination of regorafenib and RT were verified in a xenograft mouse model in vivo and in HCC cells in vitro.The combination treatment significantly inhibited cell proliferation and promoted apoptosis both in vitro and in vivo.PDGFRL, a potential target of regorafenib, was increased after cumulative treatment in HCC cells, and PDGFRL suppressed HCC cell proliferation and promoted apoptosis by inhibiting STAT3 pathway activation. Furthermore, the cumulative antitumor effect was dependent on the upregulated expression of PDGFRL and inhibition of STAT3 signaling pathway activation in HCC cells.This study increased the understanding of the molecular mechanism underlying the effect of regorafenib plus RT on HCC and provided a theoretical basis for the clinical practice of HCC.

Microinvasion in hepatocellular carcinoma: predictive factor and application for definition of clinical target volume for radiotherapy

BackgroundTo investigate the correlation between microinvasion and various features of hepatocellular carcinoma (HCC), and to clarify the microinvasion distance from visible HCC lesions to subclinical lesions, so as to provide clinical basis for the expandable boundary of clinical target volume (CTV) from gross tumor volume (GTV) in the radiotherapy of HCC.MethodsHCC patients underwent hepatectomy of liver cancer in our hospital between July 2019 and November 2021 were enrolled. Data on various features and tumor microinvasion distance were collected. The distribution characteristics of microinvasion distance were analyzed to investigate its potential correlation with various features. Tumor size compared between radiographic and pathologic samples was analyzed to clarify the application of pathologic microinvasion to identify subclinical lesions of radiographic imaging.ResultsThe average microinvasion distance was 0.6 mm, with 95% patients exhibiting microinvasion distance less than 3.0 mm, and the maximum microinvasion distance was 4.0 mm. A significant correlation was found between microinvasion and liver cirrhosis (P = 0.036), serum albumin level (P = 0.049). Multivariate logistic regression analysis revealed that HCC patients with cirrhosis had a significantly lower risk of microinvasion (OR = 0.09, 95%CI = 0.02 ~ 0.50, P = 0.006). Tumor size was overestimated by 1.6 mm (95%CI=-12.8 ~ 16.0 mm) on radiographic size compared to pathologic size, with a mean %Δsize of 2.96% (95%CI=-0.57%~6.50%). The %Δsize ranged from − 29.03% to 34.78%.ConclusionsCTV expanding by 5.4 mm from radiographic GTV could include all pathologic microinvasive lesions in the radiotherapy of HCC. Liver cirrhosis was correlated with microinvasion and were independent predictive factor of microinvasion in HCC.

Radiotherapy in Hepatocellular Carcinoma - A Review of Literature

Radiotherapy in Hepatocellular Carcinoma - A Review of Literature

TLR3 activation enhances abscopal effect of radiotherapy in HCC by promoting tumor ferroptosis

Radiotherapy (RT) has been reported to induce abscopal effect in advanced hepatocellular carcinoma (HCC), but such phenomenon was only observed in sporadic cases. Here, we demonstrated that subcutaneous administration of Toll-like receptor 3 (TLR3) agonist poly(I:C) could strengthen the abscopal effect during RT through activating tumor cell ferroptosis signals in bilateral HCC subcutaneous tumor mouse models, which could be significantly abolished by TLR3 knock-out or ferroptosis inhibitor ferrostatin-1. Moreover, poly(I:C) could promote the presentation of tumor neoantigens by dendritic cells to enhance the recruitment of activated CD8+ T cells into distant tumor tissues for inducing tumor cell ferroptosis during RT treatment. Finally, the safety and feasibility of combining poly(I:C) with RT for treating advanced HCC patients were further verified in a prospective clinical trial. Thus, enhancing TLR3 signaling activation during RT could provide a novel strategy for strengthening abscopal effect to improve the clinical benefits of advanced HCC patients.

Prognostic analysis of radiation-induced liver damage following carbon-ion radiotherapy for hepatocellular carcinoma

BackgroundRadiation-induced liver damage (RILD) occasionally occurs following carbon-ion radiotherapy (CIRT) for liver tumors, such as hepatocellular carcinoma (HCC), in patients with impaired liver function disease. However, the associated risk factors remain unknown. The present study aimed to determine the risk factors of RILD after CIRT.MethodsWe retrospectively analyzed 108 patients with HCC treated with CIRT at the Osaka Heavy Ion Therapy Center between December 2018 and December 2022. RILD was defined as a worsening of two or more points in the Child–Pugh score within 12 months following CIRT. The median age of the patients was 76 years (range 47–95 years), and the median tumor diameter was 41 mm (range 5–160 mm). Based on the pretreatment liver function, 98 and 10 patients were categorized as Child–Pugh class A and B, respectively. We analyzed patients who received a radiation dose of 60 Gy (relative biological effectiveness [RBE]) in four fractions. The median follow-up period was 9.7 months (range 2.3–41.1 months), and RILD was observed in 11 patients (10.1%).ResultsMultivariate analysis showed that pretreatment Child–Pugh score B (p = 0.003, hazard ratio [HR] = 6.90) and normal liver volume spared from < 30 Gy RBE (VS30 < 739 cm3) (p = 0.009, HR = 5.22) were significant risk factors for RILD. The one-year cumulative incidences of RILD stratified by Child–Pugh class A or B and VS30 < 739 cm3 or ≥ 739 cm3 were 10.3% or 51.8% and 39.6% or 9.2%, respectively.ConclusionIn conclusion, the pretreatment Child–Pugh score and VS30 of the liver are significant risk factors for RILD following CIRT for HCC.