Assessment of safety and efficacy of transarterial chemoembolization combined with camrelizumab and donafenib in patients with hepatocellular carcinoma at BCLC stage C: A study of 20 cases.

Camrelizumab, donafenib, and transarterial chemoembolization (TACE) are recommended for advanced hepatocellular carcinoma (HCC), but their combined efficacy remains unclear. From July 2021 to January 2023, 20 Barcelona Clinic Liver Cancer stage C HCC patients were prospectively enrolled. Inclusion criteria were Eastern Cooperative Oncology Group performance status of 0 or 1, Child-Pugh Score ≤ 7, and Barcelona Clinic Liver Cancer B or C. Surgical candidates were excluded. The treatment included TACE, camrelizumab, and donafenib. Endpoints were median overall survival, progression-free survival, and adverse events (AEs) related to donafenib. Among 20 patients, 85% experienced AEs from targeted therapy and programmed cell death protein-1, with 40% having grade 3 AEs. No grade 4 or 5 AEs occurred. Median follow-up was 9 months, with 15% achieving complete response, 65% partial response, and 15% stable disease. Disease control rate was 90%. Median progression-free survival and overall survival were 9 and 14 months, respectively. TACE, camrelizumab, and donafenib combination therapy in Chinese advanced HCC patients show effectiveness in extending survival with low severe AEs incidence.

Optimal interventional treatment for liver cancer: HAIC, TACE or iTACE?

Primary liver cancer is a common and lethal malignancy in China. Transcatheter arterial chemoembolization (TACE) is globally recognized as the preferred treatment modality for the non-surgical resection of hepatocellular carcinoma (HCC), while transcatheter arterial infusion (TAI) is another effective interventional treatment for HCC. In recent years, hepatic arterial infusion chemotherapy (HAIC) has gained increasing attention as an application-regulated modality for TAI. Owing to the current debate in the medical community regarding the use of HAIC and TACE for the treatment of HCC, the application of both approaches should be considered at a higher level, with a broader perspective and a more normative aspect. Accordingly, we aimed to define the rational combination of liver cancer TAI/HAIC with TACE as infusion transcatheter chemoembolization (iTACE), which suggests that the two interventions are not superior but lead to a mutually beneficial situation. In this review, we sought to discuss the development, specification, application, challenge and innovation, debate, and union of TAI/HAIC and TACE, and the clinical application and latest research on iTACE. We aimed to introduce new concepts of iTACE and expect new breakthroughs in the treatment of liver cancer owing to the combined use of the two major interventional tools.

Portal vein embolization for closure of marked arterioportal shunt of hepatocellular carcinoma to enable radioembolization: A case report.

BACKGROUND: Marked arterioportal shunt (APS) can be a contraindication for transarterial radioembolization (TARE) because of the risk of radiation-induced liver toxicity or pneumonitis. To date, the best method to close marked APS to reduce intrahepatic shunt (IHS) and hepatopulmonary shunt (HPS) before TARE has not been elucidated. CASE SUMMARY: This case report describes a novel strategy of embolization of the portal venous outlet to reduce IHS and HPS caused by marked APS before TARE in a patient with advanced hepatocellular carcinoma (HCC). The patient had a significant intratumoral shunt from the tumor artery to the portal vein and had already been suspected based on pre-interventional magnetic resonance angiography, and digital subtraction angiography (DSA) confirmed the shunt. Selective right portal vein embolization (PVE) was performed to close the APS outlet and DSA confirmed complete closure. Technetium-99m macroaggregated albumin was administered and single photon emission computed tomography revealed a low HPS with 8.4%. Successful TARE was subsequently performed. No major procedure-related complication occurred. CONCLUSION: Closure of APS with PVE during mapping angiography of advanced-stage HCC to enable reduction of HPS and subsequent TARE is feasible.

Portal vein embolization in the treatment of portal vein bleeding after percutaneous transhepatic biliary drainage: A case report and literature review.

Percutaneous transhepatic biliary drainage (PTBD) is an effective treatment for benign and malignant obstructive jaundice. Major bleeding complications occur in approximately 2-3% of patients after PTBD, which can result in death. A case involving a 63-year-old male with malignant obstructive jaundice, who experienced severe bleeding after PTBD, is reported. Emergency digital subtraction angiography, celiac trunk artery and superior mesenteric artery angiography were performed; however, no signs of arterial bleeding were found. To identify etiology, portal venography was performed under ultrasound guidance and portal vein bleeding was diagnosed. Ultimately, selective portal vein embolization successfully stopped the bleeding.

Endovascular treatment for delayed post-pancreaticoduodenectomy hemorrhage of unusual origin (splenic artery branch).

Objective: The objective of this study was to investigate the method, efficacy, and safety of endovascular treatment (EVT) of delayed splenic artery branch (SAB) hemorrhage after pancreaticoduodenectomy. Methods: From March 2019 to January 2022, all patients underwent EVT of SAB for delayed post-pancreaticoduodenectomy hemorrhage were included. Demographic, laboratory, angiographic, and clinical follow-up data were collected and analyzed. Results: A total of eight patients were enrolled. In two patients, celiac axis angiography alone failed, but selective splenic artery (SA) angiography demonstrated the SAB bleeding; SAB erosions in four patients with recurrent bleeding were successfully detected by a second angiography; four patients underwent balloon catheter placement at the SA for temporary hemostasis and to further confirm the SAB bleeding before the subsequent EVT. Superselective embolization was performed in only one patient (12.5%; 1/8); covered stent implantation at the SA was performed in two patients (25%; 2/8); Embolization of the SA was performed in the remaining five patients (62.5%; 5/8). The technical success rate, clinical success rate, and in-hospital mortality were 100.0%, 87.5%, and 25%, respectively. No severe complications related to EVT occurred. Conclusions: EVT of SAB for delayed post-pancreaticoduodenectomy hemorrhage is effective and safe. An awareness of the SAB as a potential bleeding source, together with appropriate endovascular procedures including selective SA angiography, repeat angiography, balloon catheter placement at the SA, and applicable hemostasis protocol, could achieve a high success rate of managing SAB hemorrhage.

Conversion Therapy of Large Unresectable Hepatocellular Carcinoma With Ipsilateral Portal Vein Tumor Thrombus Using Portal Vein Embolization Plus Transcatheter Arterial Chemoembolization.

Background: The study aimed to assess the safety and efficacy of conversion therapy with portal vein embolization (PVE) and transcatheter arterial chemoembolization (TACE) in patients with large unresectable hepatocellular carcinoma (HCC) and ipsilateral portal vein tumor thrombus (PVTT). Methods: This retrospective study evaluated consecutive patients with initially large (≥5 cm) unresectable HCC with ipsilateral PVTT who underwent PVE + TACE at our center between June 2016 and September 2020 (Group A). Clinically equivalent patients from three centers who were receiving tyrosine kinase inhibitors (TKIs) + TACE (Group B) were included. The survival times were evaluated and compared between the two therapeutic groups. Results: In Group A (n = 33), the median tumor diameter was 14 cm (range, 5-18 cm) and 19 (57.6%) patients underwent radical resection 18-95 days after PVE. Radical liver resection was not performed because of inadequate hypertrophy (n = 11), pulmonary metastasis (n = 1), lack of consent for surgery (n = 1), and the rupture of the HCC (n = 1). There were no patients who underwent radical resection in Group B (n = 64) (P = 0.000). The mean and median overall survival (OS) were 736.5 days and 425.0 days in Group A and 424.5 days and 344.0 days in Group B, respectively. Compared with TKIs + TACE, treatment with PVE + TACE prolonged OS (P = 0.023). Conclusions: This study shows that conversion therapy was safe and effective in patients with initially large unresectable HCC with ipsilateral PVTT treated with PVE + TACE. Moreover, PVE + TACE conferred more favorable outcomes than treatment with TKIs + TACE.

Associating liver partition and portal vein ligation for staged hepatectomy versus sequential transarterial chemoembolization and portal vein embolization in staged hepatectomy for HBV-related hepatocellular carcinoma: a randomized comparative study.

Background: Both portal vein embolization (PVE) and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) have merits and demerits when used in patients with unresectable liver cancers due to insufficient volumes in future liver remnant (FLR). Methods: This study was a single-center, prospective randomized comparative study. Patients with the diagnosis of hepatitis B related hepatocellular carcinoma (HCC) were randomly assigned in a 1:1 ratio to the 2 groups. The primary endpoints were tumor resection and three-year overall survival (OS) rates. Results: Between November 2014 to June 2016, 76 patients with unresectable HBV-related HCC due to inadequate volume of FLR were randomly assigned to ALPPS groups (n=38) and TACE + PVE groups (n=38). Thirty-seven patients (97.4%) in the ALPPS group compared with 25 patients (65.8%) in the TACE + PVE group were able to undergo staged hepatectomy (risk ratio 1.48, 95% CI: 1.17-1.87, P<0.001). The three-year OS rate of the ALPPS group (65.8%) (95% CI: 50.7-80.9) was significantly better than the TACE + PVE group (42.1%) (95% CI: 26.4-57.8) (HR 0.50, 95% CI: 0.26-0.98, two-sided P=0.036). However, no significant difference in the OS rates between patients who underwent tumor resection in the 2 groups of patients was found (HR 0.80, 95% CI: 0.35-1.83, two-sided P=0.595). Major postoperative complications rates after the stage-2 hepatectomy were 54.1% in the ALPPS group and 20.0% in the TACE + PVE group (risk ratio 2.70, 95% CI: 1.17-6.25, P=0.007). Conclusions: ALPPS resulted in significantly better intermediate-term OS outcomes, at the expenses of a significantly higher perioperative morbidity rate compared with TACE + PVE in patients who had initially unresectable HBV-related HCC.

Feasibility and Safety of Delayed Catheter Removal Technique in Percutaneous Trans-Hepatic Portal Vein Embolization.

Background: This retrospective study aimed to evaluate the technical feasibility and safety of the delayed catheter removal technique in trans-hepatic portal vein embolization (PVE) and to explore a suitable technique. Methods: This was a retrospective study. In 278 consecutive patients, the puncture tract of the trans-hepatic PVE was treated using the delayed catheter removal technique after PVE. The existence of peripheral hepatic hematoma formation was assessed using ultrasound (US). Follow-up examinations such as magnetic resonance imaging (MRI), computed tomography (CT), and/or US were performed to evaluate perihepatic hematoma formation, hemoperitoneum, and other major complications. Results: Instant hemostasis was achieved in all patients after the procedure. PVE-associated complications were observed in 9 patients (3.24%). No perihepatic hematoma or hemoperitoneum was found in any of the patients. Conclusion: With the appropriate technique, the delayed catheter removal technique can be reliably utilized as a substitute for hemostasis as it is simple and free. This technique should be further evaluated and compared with other methods. Advances in knowledge: This study is the first to investigate the safety and feasibility of the delayed catheter removal technique for embolizing the puncture tract of the trans-hepatic PVE.

Endovascular therapy choices for different sites of delayed postoperative arterial hemorrhage after hepatobiliary pancreatic surgery: a retrospective study.

BACKGROUND: Angiography and subsequent endovascular therapy is an effective technique for delayed postoperative arterial hemorrhage (PAH) after hepatobiliary pancreatic surgery. In this research, we aimed to evaluate endovascular therapy choices for different sites of delayed PAH after hepatobiliary pancreatic surgery. METHODS: A total of 85 patients with delayed PAH who underwent endovascular therapy at the Department of Radioactive Intervention of Eastern Hepatobiliary Surgery Hospital were retrospectively enrolled. According to the hemorrhage site, participants were divided into 3 groups, all of whom then received embolization, covered stent placement, or a combination of both. Ongoing or recurrent hemorrhages, intervention times, complications associated with intervention, and mortality rate were documented. The chi-squared (χ2) test was used for statistical analysis. RESULTS: A total of 22 participants with arterial branch hemorrhage underwent superselective embolization. Overall, 81.8% (18/22) of patients underwent embolization once. The successful hemostasis rate was 77.3% (17/22), and the mortality rate was 13.6% (3/22). A total of 53 participants with arterial trunk hemorrhage underwent embolization or covered stent placement. The rate of multi-time intervention, failure to achieve hemostasis, complications associated with intervention, and mortality was lower in the stent group than in the embolization group, and there was a significant difference in complications between the 2 groups (χ2=4.93, P=0.026). Among a total of 10 patients with multisite hemorrhage who underwent embolization, covered stent placement, or a combination, the successful hemostasis rate was 20%; and the mortality rate was 70%. CONCLUSIONS: Superselective embolization is a safe treatment method for arterial branch hemorrhage, and covered stent placement may be a better choice for arterial trunk hemorrhage. Verification of these findings is required via additional large population studies.

Recurrent undifferentiated embryonal sarcoma of the liver in adult patient treated by pembrolizumab: A case report.

BACKGROUND: Undifferentiated embryonal sarcoma of the liver (UESL) is a neoplasm that rarely develops in adults. The main treatments for UESL are upfront gross total surgical resection and adjuvant multiagent chemotherapy. Here, we report a case of recurrent UESL in an adult treated with pembrolizumab and discuss a method to identify proper candidates for antibody of programmed cell death protein 1 (anti-PD-1) treatment. CASE SUMMARY: A 69-year-old woman was admitted for abdominal pain that developed for 1 wk. Computed tomography showed a 16 cm mass in the right lobe of the liver. Right hemihepatectomy and lymphadenectomy were performed, and histological diagnosis was UESL. Six months later, the patient suffered from painless obstructive jaundice, and positron emission tomography-computed tomography revealed multiple metastases. Then, percutaneous transhepatic cholangial drainage was applied to reduce jaundice, and radiofrequency ablation was used to control the lesion near the hepatic hilum. However, the patient suffered from a serious fever caused by the tumor. The patient received treatment with pembrolizumab, and the prescribed dosage was 2 mg/kg every 3 wk. After the seventh dose, positron emission tomography-computed tomography revealed that the multiple metastases had nearly disappeared. Radiologic exam was used to evaluate the disease state, and no new lesions were found. Next-generation sequencing and immunohistology were applied to determine the reason why the patient had such a favorable response to pembrolizumab. Tumor mutation burden, microsatellite instability, and programmed death ligand 1 expression can be combined to predict the effect of PD-1 antibodies. When every one of these biomarkers are detected in a tumor patient, the patient may be a proper candidate for PD-1 antibodies. CONCLUSION: Anti-PD-1 treatment for tumors needs further research to identify indications and proper biomarkers.

Adjuvant 131I-metuximab for hepatocellular carcinoma after liver resection: a randomised, controlled, multicentre, open-label, phase 2 trial.

BACKGROUND: Effective adjuvant treatment after hepatectomy for hepatocellular carcinoma (HCC) is an important area of research. Radioactive iodine (131I)-labelled metuximab is a radiolabelled monoclonal antibody against the CD147 (also known as basigin or HAb18G) antigen that is expressed in HCC. We aimed to examine the role of 131I-metuximab as an adjuvant therapy after HCC resection. METHODS: This randomised, controlled, multicentre, open-label, phase 2 trial was done at five medical centres in China. Patients aged 18-75 years who underwent curative-intent resection of histologically confirmed HCC expressing CD147 were randomly assigned (1:1) by a computer-generated random sequence, stratified by centre, to receive either adjuvant transarterial injection of one dose of 27·75 MBq/kg 131I-metuximab 4-6 weeks after the hepatectomy (treatment group) or no adjuvant treatment (control group). Patients and physicians were not masked to the study groups. The primary outcome was 5-year recurrence-free survival (RFS) in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT00819650. FINDINGS: Between April 1, 2009, and Nov 30, 2012, 485 patients were screened for eligibility. 329 (68%) of these patients were excluded and 156 (32%) were randomly assigned to receive either 131I-metuximab (n=78) or no adjuvant treatment (n=78). The median follow-up was 55·9 months (IQR 18·6-79·4). In the intention-to-treat population, the 5-year RFS was 43·4% (95% CI 33·6-55·9) in the 131I-metuximab group and 21·7% (14·2-33·1) in the control group (hazard ratio 0·49 [95% CI 0·34-0·72]; Z=2·96, p=0·0031). 131I-metuximab-associated adverse events occurred within the first 4 weeks in 34 (45%) of 76 patients, seven (21%) of whom had grade 3 or 4 adverse events. These adverse events were all resolved with appropriate treatment within 2 weeks of being identified. INTERPRETATION: Adjuvant 131I-metuximab treatment significantly improved the 5-year RFS of patients after hepatectomy for HCC tumours expressing CD147. This treatment was well tolerated by patients. FUNDING: State Key Project on Infectious Diseases of China.

Safety and efficacy of microwave ablation for periductal hepatocellular carcinoma with intraductal cooling of the central bile ducts through a percutaneous transhepatic cholangial drainage tube.

BACKGROUND AND AIMS: Biliary thermal injury caused by microwave ablation (MWA) for a hepatocellular carcinoma (HCC) close to the central bile ducts always results in severe complications and leads to mortality. Some studies have demonstrated that intraductal cooling of the biliary tract with chilled saline during thermal ablation can successfully prevent these complications. In this study, we present a novel bile duct cooling technique through a percutaneous transhepatic cholangial drainage (PTCD) tube for preventing biliary thermal injury caused by MWA, and compare the feasibility and safety of the intraductal cooling technique when performed with a PTCD tube and with an endoscopic nasobiliary drainage (ENBD) tube. METHODS: Participants were randomly assigned to undergo MWA of HCC with intraductal chilled saline perfusion through a PTCD tube or an ENBD tube. The main study outcomes were bile duct complications related to MWA and local tumor recurrence. p value < 0.05 was considered to indicate a statistically significant difference. RESULTS: A total of 23 patients with an HCC (23 nodules) close to a central bile duct were enrolled in this study. Of these patients, 12 had a PTCD tube and 11 had an ENBD tube placed into the hepatic duct close to the lesions. There were no PTCD- and ENBD-related mortality cases. There was no complication related to the PTCD procedure; however, 3 patients (27.27%) developed acute pancreatitis and 1 patient (9.09%) had hemorrhage in the ENBD group (p = 0.037). One patient (8.33%) in the PTCD group had bile leakage and 2 patients (18.18%) in the ENBD group developed a biloma. Within 5 years, 1 patient in the PTCD group and 2 patients in the ENBD group had local recurrence. There was no significant difference in local recurrence, nonlocal hepatic recurrence, mortality rate, or median cumulative overall survival between the 2 groups. CONCLUSIONS: The intraductal cooling technique using a PTCD tube is a feasible and effective method for preventing bile duct thermal injury caused by MWA for an HCC close to the central bile ducts. It does not increase local recurrence and may be safer than intraductal cooling through an ENBD tube.

Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China (2017 Edition).

BACKGROUND: Hepatocellular carcinoma (HCC) (about 85-90% of primary liver cancer) is particularly prevalent in China because of the high prevalence of chronic hepatitis B infection. HCC is the fourth most common malignancy and the third leading cause of tumor-related deaths in China. It poses a significant threat to the life and health of Chinese people. SUMMARY: This guideline presents official recommendations of the National Health and Family Planning Commission of the People's Republic of China on the surveillance, diagnosis, staging, and treatment of HCC occurring in China. The guideline was written by more than 50 experts in the field of HCC in China (including liver surgeons, medical oncologists, hepatologists, interventional radiologists, and diagnostic radiologists) on the basis of recent evidence and expert opinions, balance of benefits and harms, cost-benefit strategies, and other clinical considerations. KEY MESSAGES: The guideline presents the Chinese staging system, and recommendations regarding patients with HCC in China to ensure optimum patient outcomes.

I131 reinforces antitumor activity of metuximab by reversing epithelial-mesenchymal transition via VEGFR-2 signaling in hepatocellular carcinoma.

CD147 is highly expressed in hepatocellular carcinoma (HCC) and associated with the invasion and metastasis of HCC. The efficacy of I131 -metuximab (I131 -mab), a newly developed agent that targets CD147, as a radio-immunotherapy for local HCC, has been validated in clinical practice. However, the synergistic anticancer activity and molecular mechanism of different conjugated components within I131 -mab remain unclear. In this study, the cytological experiments proved that I131 -mab inhibited the proliferation and invasion of HCC cells. Mechanically, this inhibition effect was mainly mediated by the antibody component part of I131 -mab, which could reverse the epithelial-mesenchymal transition of HCC cells partially by suppressing the phosphorylation of VEGFR-2. The inhibitory effect of I131 on HCC cell proliferation and invasion is limited, whereas, when combined with metuximab, I131 significantly enhanced the sensitivity of HCC cells to CD147-mab and consequently reinforced the anticancer effects of CD147-mab, suggesting that the two components of I131 -mab exerted synergistic anti-HCC capability. Furthermore, the experiments using SMMC-7721 human HCC xenografts in athymic nude mice showed that I131 -mab and CD147-mab significantly inhibited the growth of xenograft tumors and that I131 -mab was more effective than CD147-mab. In conclusion, our results elucidated the mechanism underlying the anti-HCC effects of I131 -mab and provided a theoretical foundation for the clinical application of I131 -mab.

Small Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma in Cirrhotic Livers May Share Similar Enhancement Patterns at Multiphase Dynamic MR Imaging.

Purpose To assess the accuracy of magnetic resonance (MR) imaging-based differential diagnosis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) in a cohort of patients with focal liver lesions and cirrhosis. Materials and Methods This study was institutional review board approved, and the requirement for informed consent was waived. Between January 2009 and December 2014, a cohort of cirrhotic patients, including 71 with ICC and 612 with HCC, underwent unenhanced T1- and T2-weighted MR imaging, gadolinium-based contrast material-enhanced dynamic phase imaging, and partial hepatectomy. Results of pathologic examinations were obtained for all patients. Clinical, radiologic, and pathologic results in these patients were analyzed and compared comprehensively. Differences in signal intensity on baseline and contrast material-enhanced images and dynamic enhancement patterns were evaluated and compared by using the χ(2) test or the Fisher exact test. Results The preoperative diagnoses of 517 of 683 lesions were confirmed pathologically. Five ICCs and 481 HCCs displayed contrast material washout in delayed phases (P < .001). Thirty-six ICCs and 23 HCCs displayed a progressive enhancement pattern (P < .001). Twenty-six ICCs and 63 HCCs displayed a stable enhancement pattern (P < .001). ICCs displayed significantly different enhancement patterns according to size (P = .022). Conclusion The accurate discrimination of small ICCs from HCCs in the setting of cirrhosis at MR imaging is difficult, as substantial proportions of ICCs and HCCs have similar enhancement patterns. Absence of contrast material washout at MR imaging is not a factor that prevents the misdiagnosis of HCC. (©) RSNA, 2016 Online supplemental material is available for this article.

Multidisciplinary management of hepatocellular carcinoma with portal vein tumor thrombus - Eastern Hepatobiliary Surgical Hospital consensus statement.

Hepatocellular carcinoma (HCC) complicated by portal vein tumor thrombus (PVTT) is associated with poor prognosis, early recurrence of HCC, and limited treatment options. Current guidelines do not have standardized diagnostic and treatment modalities, thus creating a need for a multidisciplinary treatment model for standardization of the treatment. Eastern Hepatobiliary Surgical Hospital (China) convened two working parties of experts from all the departments, to consolidate the current evidence, prevailing vision for the future, and experience of the practicing clinicians engaged in HCC management, so as to develop a consensus for PVTT diagnosis and treatment according to the GRADE system. Based on the quality of the existing evidence and the strength of recommendations, the consensus statements were categorized into 3 evidence levels (A/B/C) and 5 classes (I/II/IIa/IIb/III).The panel discussed and provided clarity on the management and research options in the field of HCC with PVTT. In addition, the panel also assessed the quality of the cited studies and assigned grades to the recommendation statements. Among the group of experts, there was excellent agreement with regard to effective diagnosis and treatment of HCC with PVTT. The recommendations of this consensus will provide guidance to physicians and clinical researchers on the effective management of HCC with PVTT.

Evolving Role of Radiopharmaceuticals in Hepatocellular Carcinoma Treatment.

The global incidence of primary liver cancer has been increased during recent decades. Among the primary liver malignancies, hepatocellular carcinoma (HCC) is recognized as the most prevalent and aggressive. Although HCC has come to be regarded as a radioresponsive tumor during the last decade, it has also been noted that the ability to deliver destructive radioactive doses exclusively to HCC is limited with conventional external irradiation techniques. This review examines a number of radiotherapeutic techniques used to treat HCC, and the radiopharmaceuticals associated with those techniques. Selective internal radiotherapy (SIRT) is a powerful therapeutic technique developed during recent decades that is increasingly used in HCC treatment due to its superior ability to target and destroy cancer cells while sparing normal tissue. The radiopharmaceuticals used in SIRT are usually comprised of a simple ion and a complex or a carrier. Transarterial radioembolization (TARE) is a technique that is increasingly used in adjuvant or neoadjuvant therapy following the surgical treatment of HCC, as well as the treatment of unresectable or untransplantable HCC. The primary radiopharmaceuticals used in TARE include Iodine- 131-labeled Lipiodol and Yttrium-90 microspheres. Radioimmunotherapy (RAIT) is currently used as targeted procedure for adjuvant therapy and combination therapy of HCC. The primary radiopharmaceutical used in RAIT is 131I-metuximab. Interstitial brachytherapy has also been the subject of recent HCC treatment investigations. The primary radiopharmaceuticals used in interstitial brachytherapy are implanted iodine-125 seed strands. This review surveys the important milestones in the development and clinical implementation of the radiopharmaceuticals used in HCC therapy and critically examines new and emerging trends for the delivery of radiopharmaceuticals to HCC tissues.

High leukocyte mtDNA content contributes to poor prognosis through ROS-mediated immunosuppression in hepatocellular carcinoma patients.

Compelling epidemiological evidences indicate a significant association between leukocyte mitochondrial DNA (mtDNA) content and incidence risk of several malignancies, including hepatocellular carcinoma (HCC). However, whether leukocyte mtDNA content affect prognosis of HCC patients and underlying mechanism has never been explored. In our study, leukocyte mtDNA content was measured in 618 HCC patients and its prognostic value was analyzed. Moreover, we detected the immunophenotypes of peripheral blood mononuclear cells (PBMCs) and plasma concentrations of several cytokines in 40 HCC patients and assessed the modulating effects of mtDNA content on immunosuppression in cell models. Our results showed that HCC patients with high leukocyte mtDNA content exhibited a significantly worse recurrence-free survival (RFS) and overall survival (OS) than those with low leukocyte mtDNA content. Leukocyte mtDNA content and TNM stage exhibited a notable joint effect in prognosis prediction. Furthermore, we found that patients with high leukocyte mtDNA content exhibited a higher frequency of CD4+CD25+FOXP3+ regulatory T (Treg) cells and lower frequency of NK cells in PBMCs and had higher TGF-ß1 and lower TNF-α and IFN-γ plasma concentration when compared with those with low leukocyte mtDNA content, which suggests an immunosuppressive status. High leukocyte mtDNA content significantly enhanced the ROS-mediated secretion of TGF-ß1, which accounted for higher Treg and lower NK frequency in PBMCs. In a conclusion, our study for the first time demonstrates that leukocyte mtDNA content is an independent prognostic marker complementing TNM stage and associated with an ROS-mediated immunosuppressive phenotype in HCC patients.

pERK/pAkt phenotyping in circulating tumor cells as a biomarker for sorafenib efficacy in patients with advanced hepatocellular carcinoma.

Sorafenib is a multikinase inhibitor approved for the treatment of advanced hepatocellular carcinoma (HCC). However, therapeutic response to sorafenib was not equal among HCC patients. Here we present a novel system to provide quantitative information concerning sorafenib-related targets by simultaneous detection of phosphorylated ERK (pERK) and pAkt expressions in circulating tumor cells (CTCs) isolated from HCC patients. Our results showed that 90.0% of patients had a molecular classification of tissues concordant with that of CTCs. CTC counts showed a shaper decline in patients with pERK+/pAkt- CTCs after two weeks of sorafenib treatment (P < 0.01). Disease control rates were significantly different between patients with pERK+/pAkt- CTCs (11/15; 73.3%) and those without (13/44; 29.5%) (P < 0.05). Univariate and multivariate analysis indicated pERK+/pAkt- CTCs as an independent predictive factor of progression-free survival (PFS) (hazard ratio = 9.389; P < 0.01). PFS correlated with the proportion of pERK+/pAkt- CTCs (r = 0.968, P < 0.01), and was higher in patients with ≥ 40% pERK+/pAkt- CTCs compared to those with < 40% (8.4 vs. 1.3 mo; P < 0.05). In a validation set of twenty HCC patients, CTCs from patients with ≥ 40% pERK+/pAkt- CTCs had significantly higher inhibition rates of spheroid formation compared to those with < 40% (61.2 vs. 19.8%; P < 0.01). Our findings demonstrated that CTCs can be used in place of tumor tissue for characterization of pERK/pAkt expression. pERK+/pAkt- CTCs are most sensitive to sorafenib and an independent predictive factor of PFS in HCC patients treated with sorafenib.