Serum lnc34a is a potential prediction biomarker for bone metastasis in hepatocellular carcinoma patients.

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.

Stereotactic body radiation therapy vs. radiofrequency ablation in Asian patients with hepatocellular carcinoma.

BACKGROUND & AIMS: Few studies have been conducted to compare the efficacies of stereotactic body radiation therapy (SBRT) and radiofrequency ablation (RFA). Thus, in this multinational study, we compared the effectiveness of SBRT and RFA in patients with unresectable HCC. METHODS: The retrospective study cohort included 2,064 patients treated in 7 hospitals: 1,568 and 496 in the RFA and SBRT groups, respectively. More than half of the patients (56.5%) developed recurrent tumors, mainly after transarterial chemoembolization (44.8%). Propensity score matching was performed to adjust for clinical factors (n = 313 in each group). RESULTS: At baseline, the SBRT group had unfavorable clinical features compared to the RFA group, including BCLC stage (B-C 65% vs. 16%), tumor size (median 3.0 cm vs. 1.9 cm), and frequent history of liver-directed treatment (81% vs. 49%, all p <0.001). With a median follow-up of 27.7 months, the 3-year cumulative local recurrence rates in the SBRT and RFA groups were 21.2% and 27.9%, respectively (p <0.001). After adjusting for clinical factors, SBRT was related to a significantly lower risk of local recurrence than RFA in both the entire (hazard ratio [HR] 0.45, p <0.001) and matched (HR 0.36, p <0.001) cohorts. In subgroup analysis, SBRT was associated with superior local control in small tumors (≤3 cm) irrespective of location, large tumors located in the subphrenic region, and those that progressed after transarterial chemoembolization. Acute grade ≥3 toxicities occurred in 1.6% and 2.6% of the SBRT and RFA patients, respectively (p = 0.268). CONCLUSIONS: SBRT could be an effective alternative to RFA for unresectable HCC, particularly for larger tumors (>3 cm) in a subphrenic location and tumors that have progressed after transarterial chemoembolization. LAY SUMMARY: It is currently not known what the best treatment option is for patients with unresectable hepatocellular carcinoma. Here, we show that stereotactic body radiation therapy provides better local control than radiofrequency ablation, with comparable toxicities. Stereotactic body radiation therapy appears to be an effective alternative to radiofrequency ablation that should be considered when there is a higher risk of local recurrence or toxicity after radiofrequency ablation.

The molecular mechanism of LncRNA34a-mediated regulation of bone metastasis in hepatocellular carcinoma.

BACKGROUND: Bone metastasis (BM) has long been recognized as a major threat to the quality of life of hepatocellular cancer (HCC) patients. While LncRNA34a (Lnc34a) has been shown to regulate colon cancer stem cell asymmetric division, its effect on HCC BM remains unknown. METHODS: In situ hybridization and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect the expression of Lnc34a in HCC tissues and cell lines. Ventricle injection model was constructed to explore the effect of Lnc34a on BM in vivo. The methylation of miR-34a promoter and histones deacetylation were examined by using bisulfate-sequencing PCR and chromatin immunoprecipitation assays. RNA pull down and RNA immunoprecipitation were performed to investigated the interaction between Lnc34a and epigenetic regulators. Dual-luciferase reporter assay was conducted to find miR-34a target. The involvement of TGF-ß pathway in the BM from HCC was determined by qRT-PCR, western, and elisa assays. RESULTS: We found that Lnc34a was significantly overexpressed in HCC tissues and associated with BM. Both in vitro and in vivo experiments indicate that the restoration or knockdown of Lnc34a expression in HCC cells had a marked effect on cellular migration, invasion, and metastasis. Mechanistic analyses suggested that Lnc34a epigenetically suppresses miR-34a expression through recruiting DNMT3a via PHB2 to methylate miR-34a promoter and HDAC1 to promote histones deacetylation. On the other hand, miR-34a targets Smad4 via the TGF-ß pathway, followed by altering the transcription of the downstream genes (i.e., CTGF and IL-11) that are associated with BM. CONCLUSIONS: Our study is the first to document the pro-bone metastatic role of Lnc34a in BM of HCC and reveal a novel mechanism for the activation of the TGF-ß signaling pathway in HCC BM, providing evidence of a potential therapeutic strategy in HCC BM.

Does liver resection/transplantation affect respiratory induced liver motion in patients with hepatocellular carcinoma?

The purpose of this study was to evaluate the changes in magnitude of three-dimensional (3D) liver motion after liver resection/transplantation in patients with hepatocellular carcinoma (HCC) using four-dimensional (4D)-computed tomography (CT) images. From January 2012 to April 2016, 74 HCC patients underwent 4D-CT scans under a free-breathing state to assess respiratory liver motion. Of the 74 patients, 40 did not have a liver resection/transplantation (Group A), 34 with liver resection/transplantation. 15 underwent major or minor resection in the right liver lobe (Group B), 14 underwent major or minor resection in the left liver lobe (Group C), and five underwent liver transplantation (Group D). The 4D-CT images were sorted into 10 image series according to the respiratory phase from the end inspiration to the end expiration, and then transferred to treatment planning software. All liver contours were drawn by a single physician and confirmed by a second. Liver relative coordinates were automatically generated to calculate liver respiratory motion in different axial directions and compiled into a single composite image. Differences in respiratory liver motion were assessed using one-way ANOVA. The average liver respiratory motion in the cranial-caudal direction and 3D magnitude were 10.46 ± 2.78 mm (range, 5.60-18.80 mm) and 11.74 ± 2.65 mm (range, 7.45-20.79 mm) for patients without liver resection/transplantation, and 7.74 ± 2.79 mm (range, 2.20-12.90 mm) and 9.07 ± 2.38 mm (range, 4.79-14.08 mm) for posthepatectomy/post-transplant patients respectively. There were significant differences between Group A and B, Group A and C, Group A and D. However, there were no significant differences among Group B, C, and D. Liver resection/transplantation greatly affected respiratory-induced liver motion in patients with HCC. We, therefore, recommend discriminatory internal target volume (ITV) determination for patients with or without liver resection/transplantation undergoing external radiotherapy for hepatic tumors while respiratory motion management is unavailable.

High dose radiotherapy with image-guided hypo-IMRT for hepatocellular carcinoma with portal vein and/or inferior vena cava tumor thrombi is more feasible and efficacious than conventional 3D-CRT.

OBJECTIVE: To compare the efficacies of conventional three-dimensional conformal radiotherapy and image-guided hypofractionated intensity-modulated radiotherapy treatments in advanced hepatocellular carcinoma patients with portal vein and/or inferior vena cava tumor thrombi. METHODS: A total of 118 hepatocellular carcinoma patients with portal vein and/or inferior vena cava tumor thrombi who received external beam radiation therapy focused on tumor thrombi and intrahepatic tumors were retrospectively reviewed. During the three-dimensional conformal radiotherapy treatments, a median total dose of 54 Gy with a conventional fraction (1.8-2.0 Gy/fx) was delivered. During the image-guided hypofractionated intensity-modulated radiotherapy treatments, a median total dose of 60 Gy with fractions of 2.5-4.0 Gy/fx was delivered. RESULTS: The median follow-up time was 11.8 months (range, 1.7-43.7 months). Higher radiation doses were delivered by image-guided hypofractionated intensity-modulated radiotherapy than by three-dimensional conformal radiotherapy (average dose 57.86 ± 7.03 versus 50.88 ± 6.60 Gy, P ≤ 0.001; average biological effective dose 72.35 ± 9.62 versus 61.45 ± 6.64 Gy, P < 0.001). A longer median survival was found with image-guided hypofractionated intensity-modulated radiotherapy than with three-dimensional conformal radiotherapy (15.47 versus 10.46 months, P = 0.005). Multivariate analysis showed that image-guided hypofractionated intensity-modulated radiotherapy is a significant prognostic factor for overall survival. Toxicity was mild for both image-guided hypofractionated intensity-modulated radiotherapy and three-dimensional conformal radiotherapy. CONCLUSIONS: High dose radiotherapy delivered by image-guided hypofractionated intensity-modulated radiotherapy appears to be an effective treatment that provides a survival benefit without increasing severe toxicity in hepatocellular carcinoma patients with portal vein and/or inferior vena cava tumor thrombi.

TLR4-dependant immune response, but not hepatitis B virus reactivation, is important in radiation-induced liver disease of liver cancer radiotherapy.

Toll-like receptor 4 (TLR4) is an important trigger of the immune response against hepatitis B virus (HBV) infection and liver injuries. The roles of HBV reactivation versus TLR4-dependant immune response may be critical factors in preventing radiation-induced liver diseases (RILDs) after liver cancer radiotherapy. This study consists of three phases. In the primary phase, livers of mutant TLR4 (TLR4(-)) mice were irradiated with 30 Gy in either the absence or presence of HBV infection. The latter was done by introduction of plasmid pAAV/HBV 1.2. In the advanced phase, RILDs were compared in normal TLR4 (TLR4(+)) versus TLR4(-) mice. In the validation phase, 28 liver cancer patients who had undergone radiotherapy before hepatectomy were enrolled. Liver biopsies near tumors, irradiated with 35-48 Gy, were used to construct tissue microarrays. HBV reactivation, TLR4 expression, and severity of RILDs were studied in both mouse and human. More HBV reactivation, without significant RILD, was observed in irradiated versus unirradiated TLR4(-) mice. RILD scores of TLR4(+) mice were higher than TLR4(-) mice. In humans, serious RILDs tended to develop in patients with high TLR4 expression, but not in patients with low TLR4 or high HBV surface antigen expression. High TLR4 expression was seen in only 2 of 12 HBV-reactive patients, but in HBV-nonreactive patients, it was seen in 6 of 9 (P < 0.03). In summary, RILDs correlated with high TLR4 expression, but not with HBV reactivation, which is inhibited in liver with high TLR4 expression after liver cancer radiotherapy.

Radiotherapy treatment of adrenal gland metastases from hepatocellular carcinoma: clinical features and prognostic factors.

BACKGROUND: The optimal treatment for adrenal metastases from hepatocellular carcinoma (HCC) has not been established. This study analyzed the effects of radiation therapy (RT) for such metastases and identified clinical features and predictors of survival in these patients. METHODS: We retrospectively investigated 55 patients with adrenal metastasis from HCC who had been treated with RT. Radiation doses to the adrenal lesions ranged from 26 to 60 Gy, while the intrahepatic lesions were treated by surgical resection, transarterial chemoembolization (TACE), liver transplantation, and/or RT. RT was conducted to adrenal lesions after their intrahepatic lesions were controlled more than 2 months. The parameters studied included survival rates and tumor responses to RT. The Kaplan-Meier method was used to evaluate survival rate and the Cox regression model was used to identify potential predictors of outcome. RESULTS: The patients treated by RT had adrenal metastasis on the right side (41), the left (6), or on both sides (8). In all 55 patients, the median survival duration was 13.6 months and there was 100% pain relief after completion of RT. Adverse effects were mild to moderate. Unfavorable pretreatment predictors determined by univariate analysis were associated with multiple intrahepatic foci, metastases to additional organs, high γ-glutamyltransferase and alpha-fetoprotein levels, liver function of Child-Pugh classification B and uncontrolled primary HCC. By multivariate analysis, unfavorable predictors were multiple intrahepatic foci, metastases to additional organs and uncontrolled primary HCC. CONCLUSIONS: Radiotherapy as treatment for adrenal metastases in HCC is a good palliative therapy that is associated with reasonable safety. It appears reasonable that such patients should be considered to be treated with radiotherapy. Multiple intrahepatic foci, metastases to additional organs and uncontrolled primary HCC were unfavorable predictors.

Stereotactic body radiation therapy in patients with centrally located hepatocellular carcinoma: A retrospective, single-arm, multi-center study.

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.

Mechanism of immune activation mediated by genomic instability and its implication in radiotherapy combined with immune checkpoint inhibitors.

Various genetic and epigenetic changes associated with genomic instability (GI), including DNA damage repair defects, chromosomal instability, and mitochondrial GI, contribute to development and progression of cancer. These alterations not only result in DNA leakage into the cytoplasm, either directly or through micronuclei, but also trigger downstream inflammatory signals, such as the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. Apart from directly inducing DNA damage to eliminate cancer cells, radiotherapy (RT) exerts its antitumor effects through intracellular DNA damage sensing mechanisms, leading to the activation of downstream inflammatory signaling pathways. This not only enables local tumor control but also reshapes the immune microenvironment, triggering systemic immune responses. The combination of RT and immunotherapy has emerged as a promising approach to increase the probability of abscopal effects, where distant tumors respond to treatment due to the systemic immunomodulatory effects. This review emphasizes the importance of GI in cancer biology and elucidates the mechanisms by which RT induces GI remodeling of the immune microenvironment. By elucidating the mechanisms of GI and RT-induced immune responses, we aim to emphasize the crucial importance of this approach in modern oncology. Understanding the impact of GI on tumor biological behavior and therapeutic response, as well as the possibility of activating systemic anti-tumor immunity through RT, will pave the way for the development of new treatment strategies and improve prognosis for patients.

Is it time to adopt external beam radiotherapy in the NCCN guidelines as a therapeutic strategy for intermediate/advanced hepatocellular carcinoma?.

OBJECTIVE: External beam radiotherapy (EBRT) is recommended as a therapeutic strategy for stage III hepatocellular carcinoma (HCC) in national guidelines of the Chinese Society of Liver Disease and in Korea Liver Cancer Study Group practice guidelines, but has not been considered a therapeutic option for HCC in Western countries. In this study, we review evidence supporting EBRT as an option for HCC treatment. METHODS: Retrospective investigation was made of 775 patient records of intermediate/advanced HCC treated in our hospital during the last 10 years, including 98 patients with confined intrahepatic tumor, 181 with portal vein (PV) or inferior vena cava (IVC) tumor thrombi, 191 with lymph node metastases, 55 with adrenal gland metastases, 205 with bone metastases, 13 with lung metastases and 32 with brain metastases. RESULTS: Transcatheter arterial chemoembolization combined with radiotherapy was found to constitute an improved therapeutic strategy for unresectable but confined intrahepatic HCC with poor lipid accumulation. Survival of HCC patients with PV/IVC tumor thrombi was prolonged to 10.7 months by radiotherapy, and it was 8.0 months in patients with abdominal lymph node metastasis. Radiotherapy also shrinks adrenal and lung metastatic HCC lesions, resulting in median survival times of 13.6 and progression-free survival of 13.4 months, respectively. In bone metastatic HCC, radiotherapy significantly relieved symptoms, although median survival time was only 7.4 months. Radiotherapy is effective for treatment of intermediate/advanced stages of HCC. Although our finding is based only on retrospective analysis, no therapeutic option that provides better treatment than EBRT in this indication has thus far been identified. Because sorafenib has been recommended as a treatment strategy by the National Comprehensive Cancer Network (NCCN) for HCC, we compared the survival after EBRT with sorafenib treatment on the basis of published clinical data. From this comparison, we found that EBRT treatment was more effective than sorafenib for improving patient survival when tested on tumors of comparable metastatic size. CONCLUSION: Based on the evidence reviewed, we propose that EBRT be included in the NCCN guideline as a treatment strategy for intermediate/advanced HCC.

Early complete tumor response as a survival predictor in hepatocellular carcinoma patients receiving stereotactic body radiation therapy.

Background and Purpose: To 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 methods: Seventy-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. Results: The 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. Conclusions: Early 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.

Maternal embryonic leucine zipper kinase in tumor cells and tumor microenvironment: An emerging player and promising therapeutic opportunity.

Maternal embryonic leucine zipper kinase (MELK) is a member of the AMPK (AMP-activated protein kinase) protein family, which is widely and highly expressed in multiple cancer types. Through direct and indirect interactions with other targets, it mediates various cascades of signal transduction processes and plays an important role in regulating tumor cell survival, growth, invasion and migration and other biological functions. Interestingly, MELK also plays an important role in the regulation of the tumor microenvironment, which can not only predict the responsiveness of immunotherapy, but also affect the function of immune cells to regulate tumor progression. In addition, more and more small molecule inhibitors have been developed for the target of MELK, which exert important anti-tumor effects and have achieved excellent results in a number of clinical trials. In this review, we outline the structural features, molecular biological functions, potential regulatory mechanisms and important roles of MELK in tumors and tumor microenvironment, as well as substances targeting MELK. Although many molecular mechanisms of MELK in the process of tumor regulation are still unknown, it is worth affirming that MELK is a potential tumor molecular therapeutic target, and its unique superiority and important role provide clues and confidence for subsequent basic research and scientific transformation.

miR-146a-5p Alleviates Radiation-Induced Liver Fibrosis by Regulating PTPRA-SRC Signaling in Mice.

Patients with hepatobiliary tumors who accept radiotherapy are at risk for radiation-induced liver fibrosis. MicroRNAs (miRNAs) have been implicated in the pathogenesis of radiation-induced liver damage and possess potential as novel biomarkers and therapeutic targets. However, the role of miR-146a-5p in radiation-induced liver fibrosis is less well understood. The current study was designed to evaluate the role of miR-146a-5p in radiation-induced liver fibrosis in mice and to investigate the possible mechanisms involved in miR-146a-5p-mediated effects. The experiments were performed on Institute of Cancer Research (ICR) mice which received fractionated radiation (30 Gy in 5 fractions) to the liver. The results show radiation could induce histopathological changes, liver dysfunction and fibrosis accompanied with decreased miR-146a-5p expression. miR-146a-5p agomir treatment resulted in recovery of liver function and reduced the amount of alpha-smooth muscle actin (α-SMA), collagen 1, protein tyrosine phosphatase receptor type A (PTPRA) and phosphorylated SRC in the livers of irradiated mice. Therefore, our study reveals that miR-146a-5p inhibits the progression of hepatic fibrosis after radiation treatment. And the beneficial role of miR-146a-5p may be relevant to PTPRA-SRC signaling pathway.

Molecular mechanisms investigation for liver metastasis of colorectal cancer by combined bioinformatic gene expression profile analysis.

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers worldwide. As the molecular mechanism for liver metastasis of CRC has not yet been completely discovered, identification of hub genes and pathways of this disease is of importance for revealing potential molecular mechanism of colorectal cancer progression. This study aimed to identify potential biomarkers and survival analysis of hub genes for CRC treatment. METHODS: The differentially expressed genes (DEGs) between colorectal cancer liver metastasis and primary tumor were screened using microarray data from two datasets GSE179979, GSE144259 obtained from the Gene Expression Omnibus (GEO) database. Gene ontology (GO) and KEGG pathway enrichment analyses were performed for DEGs using DAVID database, the protein-protein interaction (PPI) network was constructed using the Cytoscape software, and module analysis was performed using MCODE. Then, overall survival (OS), progression free interval (PFI) and disease specific survival (DSS) analysis of hub genes was performed by using TCGA database. The correlations between hub genes and clinical values were validated through CRN and immunohistochemistry (IHC) stain. RESULTS: A total of 64 DEGs were obtained, KEGG pathway analysis showed that the significant pathways included PPAR signaling pathway, Complement and coagulation cascades. Four hub genes (ITIH2, ALB, CPB2, HGFAC) and two biomarkers (CPB2, HGFAC) with significantly prognostic values were verified by Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) cohort. CONCLUSIONS: CPB2 and HGFAC may serve as new biomarkers in diagnosing liver metastasis of CRC or potential drug target.

Stereotactic body radiotherapy combined with sintilimab in patients with recurrent or oligometastatic hepatocellular carcinoma: A phase II clinical trial.

BACKGROUND: Stereotactic body radiotherapy (SBRT) and programmed cell death 1 inhibitors have shown potential in treating hepatocellular carcinoma (HCC) in retrospective studies. AIM: To evaluate the efficacy of combining SBRT with sintilimab for patients with recurrent or oligometastatic HCC. METHODS: This trial involved patients with recurrent or oligometastatic HCC intravenously treated with SBRT plus sintilimab every 3 wk for 12 mo or until disease progression. The primary endpoint was progression-free survival (PFS). RESULTS: Twenty-five patients were enrolled from August 14, 2019, to August 23, 2021. The median treatment duration was 10.2 (range, 0.7-14.6) months. SBRT was delivered at a median dose of 54 (range, 48-60) Gy in 6 (range, 6-10) fractions. The median follow-up time was 21.9 (range, 10.3-39.7) mo, and 32 targeted lesions among 25 patients were evaluated for treatment response according to the Response Evaluation Criteria in Solid Tumors version 1.1. The median PFS was 19.7 mo [95% confidence interval (CI): 16.9-NA], with PFS rates of 68% (95%CI: 52-89) and 45.3% (95%CI: 28-73.4) at 12 and 24 mo, respectively. The median overall survival (OS) was not reached, with OS rates of 91.5% (95%CI: 80.8-100.0) and 83.2% (95%CI: 66.5-100.0) at 12 and 24 mo, respectively. The 1- and 2-year local control rate were 100% and 90.9% (95%CI: 75.4%-100.0%), respectively. The confirmed objective response rate and disease control rate was 96%, and 96%, respectively. Most adverse events were graded as 1 or 2, and grade 3 adverse events were observed in three patients. CONCLUSION: SBRT plus sintilimab is an effective, well-tolerated treatment regimen for patients with recurrent or oligometastatic HCC.

Expression of connective tissue growth factor and interleukin-11 in intratumoral tissue is associated with poor survival after curative resection of hepatocellular carcinoma.

In the present study, we evaluated the prognostic value of intratumoral and peritumoral expression of connective tissue growth factor (CTGF), transforming growth factor-beta 1 (TGF-ß1), and interleukin-11 (IL-11) in patients with hepatocellular carcinoma (HCC) after curative resection. Expression of CTGF, TGF-ß1, and IL-11 was assessed by immunohistochemical staining of tissue microarrays containing paired tumor and peritumoral liver tissue from 290 patients who had undergone hepatectomy for histologically proven HCC. The prognostic value of these and other clinicopathologic factors were evaluated. The median follow-up time was 54.3 months (range, 4.3-118.3 months). High intratumoral CTGF expression was associated with vascular invasion (P = 0.015), intratumoral IL-11 expression correlated with higher tumor node metastasis (TNM) stage (P = 0.009), and peritumoral CTGF overexpression correlated with lack of tumor encapsulation (P = 0.031). Correlation analysis of these proteins revealed that intratumoral CTGF and IL-11 correlated with high intratumoral TGF-ß1 expression (r = 0.325, P < 0.001; and r = 0.273, P < 0.001, respectively). TNM stage (P < 0.001), high intratumoral CTGF levels (P = 0.010), and intratumoral IL-11 expression (P = 0.015) were independent prognostic factors for progression-free survival (PFS). Vascular invasion (P = 0.032), TNM stage (P < 0.001), high intratumoral CTGF levels (P = 0.036), and intratumoral IL-11 expression (P = 0.013) were independent prognostic factors for overall survival (OS). High intratumoral CTGF and intratumoral IL-11 expression were associated with PFS and OS after hepatectomy, and the combination of intratumoral CTGF with IL-11 may be predictive of survival.

The expression of HIF-1α in primary hepatocellular carcinoma and its correlation with radiotherapy response and clinical outcome.

The purpose of this study was to evaluate the relationship between hypoxia-inducible factor-1α (HIF-1α) protein expression in hepatocellular carcinoma (HCC), and responses of abdominal metastatic lymph nodes (LNs) from HCC patients treated with external beam radiotherapy (EBRT). HIF-1α immunohistochemical staining was performed on tissue microarrays (TMAs) of primary HCC specimens from 69 HCC patients with abdominal LN metastases. All patients received abdominal metastatic LN EBRT at the Department of Radiation Oncology at Zhongshan Hospital. A receiver-operating characteristic (ROC)-based approach and logistical regression analysis were used to determine the predictive value of HIF-1α expression in primary tumors with HCC metastatic LN EBRT response. Kaplan-Meier curves and log-rank tests were used to analyze patient survival. Cox proportional hazards regression model was used to analyze independent prognostic factors. HIF-1α expression was correlated with blood hemoglobin (Hb: r = -0.280, P = 0.020), response of abdominal metastatic LNs to EBRT (r = 0.286, P = 0.017), locoregional recurrence (r = 0.278, P = 0.021), and cancer-specific deaths (r = 0.298, P = 0.013). HIF-1α expression was predictive of EBRT response of metastatic LNs [area under the curve (AUC): 0.646; 95% confidence interval (CI): 0.499-0.793; P = 0.047], locoregional recurrence (AUC: 0.657; 95% CI: 0.509-0.805; P = 0.049) and cancer-specific deaths (AUC: 0.671; 95% CI: 0.531-0.812; P = 0.035). Patients with tumors exhibiting high HIF-1α expression had significantly poorer overall survival (OS) than those with low tumor expression of HIF-1α (P = 0.016). Multivariate analysis showed that Hb (P = 0.035), vascular invasion (P = 0.026), Child-Pugh score (P < 0.001), intrahepatic tumor control (P < 0.001), and HIF-1α (P = 0.020) were independent prognosis factors for OS of HCC patients after receiving abdominal metastatic LN EBRT. HIF-1α expression in primary HCCs was associated with EBRT response of abdominal metastatic LNs and poor prognosis.

CircTUBD1 Regulates Radiation-induced Liver Fibrosis Response via a circTUBD1/micro-203a-3p/Smad3 Positive Feedback Loop.

Background and Aims: Radiation-induced liver fibrosis (RILF), delayed damage to the liver (post-irradiation) remains a major challenge for the radiotherapy of liver malignancies. This study investigated the potential function and mechanism of circTUBD1 in the development of RILF. Methods: By using a dual luciferase assay, RNA pull-down assays, RNA sequencing, chromatin immunoprecipitation (known as ChIP) assays, and a series of gain- or loss-of-function experiments, it was found that circTUBD1 regulated the activation and fibrosis response of LX-2 cells induced by irradiation via a circTUBD1/micro-203a-3p/Smad3 positive feedback loop in a 3D system. Results: Knockdown of circTUBD1 not only reduced the expression of α-SMA, as a marker of LX-2 cell activation, but also significantly decreased the levels of hepatic fibrosis molecules, collagen type I alpha 1 (COL1A1), collagen type III alpha 1 (COL3A1), and connective tissue growth factor (CTGF) in a three-dimensional (3D) culture system and RILF model in vivo. Notably, knockdown of circTUBD1 alleviated early liver fibrosis induced by irradiation in mice models. Conclusions: This study is the first to reveal the mechanism and role of circTUBD1 in RILF via a circTUBD1/micro-203a-3p/Smad3 feedback loop, which provides a novel therapeutic strategy for relieving the progression of RILF.

Does HCC Etiology Impact the Efficacy of Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma? An Asian Liver Radiation Therapy Group Study.

Background/Purpose: The Asian Liver Radiation Therapy Study Group has formed a large and detailed multinational database of outcomes following stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC). Here, we explored the potential impact of HCC etiology on SBRT efficacy. Tumor control probability (TCP) models were established to estimate the likelihood of local control (LC). Methods: Data from 415 patients who were treated with SBRT for HCC were reviewed. Cox proportional hazards models were used to identify key predictors of LC. TCP models accounting for biologic effective dose (BED) and tumor diameter were generated to quantify associations between etiology and LC. Results: Cox models demonstrated that hepatitis C virus (HCV) infection was associated with favorable LC following SBRT (HR=0.52, 95% CI 0.04-0.96, p=0.036). The 2-year LC rate for patients with HCV etiology was 88%, compared to 78% for other patients. Small tumor and high BED were also associated with favorable LC. TCP models demonstrated a 10-20% absolute increase in predicted LC across the range of SBRT doses and tumor sizes. Conclusion: We found a novel association between HCV status and LC after SBRT for HCC that warrants further exploration. If validated in other datasets, our findings could help clinicians tailor SBRT schedules.