Oncolytic virus-based hepatocellular carcinoma treatment:Current status,intravenous delivery strategies,and emerging combination therapeutic solutions

Current treatments for advanced hepatocellular carcinoma(HCC)have limited success in improving patients’quality of life and prolonging life expectancy.The clinical need for more efficient and safe therapies has contributed to the exploration of emerging strategies.Recently,there has been increased interest in oncolytic viruses(OVs)as a therapeutic modality for HCC.OVs undergo selective replication in cancerous tissues and kill tumor cells.Strikingly,pexastimogene devacirepvec(Pexa-Vec)was granted an orphan drug status in HCC by the U.S.Food and Drug Administration(FDA)in 2013.Meanwhile,dozens of OVs are being tested in HCC-directed clinical and preclinical trials.In this review,the pathogenesis and current therapies of HCC are outlined.Next,we summarize multiple OVs as single therapeutic agents for the treatment of HCC,which have demonstrated certain efficacy and lowtoxicity.Emerging carrier cell-,bioengineered cell mimetic-or nonbiological vehicle-mediated OV intravenous delivery systems in HCC therapy are described.In addition,we highlight the combination treatments between oncolytic virotherapy and other modalities.Finally,the clinical challenges and prospects of OV-based biotherapy are discussed,with the aim of continuing to develop a fascinating approach in HCC patients.

Recent advances in the surgical treatment of hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is the most common primary liver malignancy. The treatment of HCC is complex and complicated by the severity of associated chronic liver disease, the stage of HCC, and the clinical condition of the patient. Liver resection(LR) is one of the most efficient treatments for patients with HCC, with an expected 5-year survival of 38%-61% depending on the stage of the disease. Improved liver function assessment, increased understanding of segmental liver anatomy from advanced imaging studies, and surgical technical progress are important factors that have led to reduced mortality in patients with HCC. The indication for LR may be expanded due to emerging evidences from laparoscopic hepatectomies and combined treatments with newly developed chemotherapies. Liver transplantation(LT) is considered as an ideal treatment for removal of existing tumors and the injured/preneoplastic underlying liver tissue with impaired liver function and the risk of multicentric carcinogenesis that results from chronically injured liver. However, LT is restricted to patients with minimal risk of tumor recurrence under immunosuppression. The expansion of criteria for LT in HCC patients is still under trial and discussion. Limited availability of grafts, as well as the risk and the cost of transplantation have led to considerable interest in expansion of the donor pool, living donor-related transplantation, and combined treatment involving LR and LT. This highlight presents evidence concerning recent studies evaluating LR and LT in HCC patients. In addition, alternative therapies for the treatment of early stage tumors and the management of patients on transplant waiting lists are discussed.

Application of cystoscope in surgical treatment of hepatocellular carcinoma with portal vein tumor thrombus

Development of portal vein tumor thrombus deteriorates the prognosis of hepatocellular carcinoma, while surgical treatment can offer a promising prognosis for selected patients. However, the possibility of residual lesions in portal vein after conventional thrombectomy is a main risk factor leading to postoperative recurrence. Therefore, ensuring the complete removal of tumor thrombus during operation is critical to improve prognosis. For the first time, we report here one case of hepatocellular carcinoma with portal vein tumor thrombus in which cystoscope was successfully applied as a substitute of intravascular endoscope to visualize the cavity of the portal vein. The patient was a 61-year-old man with a 7-cm tumor in the right lobe of the liver, with tumor thrombus invading the right branch and adjacent to the conjunction of the portal vein. After removal of the tumor, the Olympus CYF-VA2 cystoscope was used to check the portal vein from the opening stump of the right branch of the portal vein. In this case, residual thrombus tissue was found near the opening stump and the conjunction of the portal vein. The residual lesion was carefully retrieved from the stump after retraction of the cystoscope. The procedure was repeated until no residual lesion was found. The whole duration time of thrombectomy was 22.5(15 + 7.5) min. The patient was free from recurrence at 8 months after the procedure. Our work indicated that the cystoscope is a suitable substitute, with a proper size and function to check the portal vein system and ensure the curability of thrombectomy. Although welldesigned clinic trails are still needed, this procedure may further improve the postoperative prognosis of hepatocellular carcinoma with portal vein tumor thrombus.

Treatment Strategy for Post-Hepatectomy Recurrent Hepatocellular Carcinoma: A Single Center Experience with 556 Consecutive Cases in China

Background: Treatment strategy for recurrent hepatocellular carcinoma (HCC) remains scantily defined. This study was aimed to establish a treatment strategy to manage post-hepatectomy recurrent HCC and report the clinical outcomes. Methods: From January 2006 to December 2016, 556 consecutive patients who developed post-hepatectomy HCC recurrence were enrolled in the study. The patients were clinically stratified and treated according to a strategy established by a multi-disciplinary team. Clinical data and survival times were collected prospectively and analyzed retrospectively. Results: According to the strategy, there were 298 (53.6%), 214 (38.5%), 32 (5.7%) and 12 (2.2%) patients stratified into Early, Intermediate, Advanced and Terminal stages, respectively. In Early stage patients, 164 (55.0%) received curative treatment in the form of repeat resection or local ablation, 134 (45.0%) received transarterial chemoembolization (TACE), and the 1-, 3-, and 5-year overall survival (OS) rates were 82.0%, 46.8% and 37.3%, respectively. In Intermediate stage patients, 207 (96.7%) received TACE, 7 (3.3%) radiotherapy, and the 1-, 3-, and 5-year OS rates were 73.2%, 31.8% and 15.9%, respectively. In Advanced stage patients, 22 patients received sorafenib, 10 radiotherapy, and the mean survival time (MST) was 25.1 ± 3.1 months. All the 12 patients in Terminal stage received the best supportive treatment, and the MST was 6.5 ± 3.4 months. Clinical stages and duration of disease-free interval were independent factors relating to overall survival. Conclusions: A treatment strategy derived from the Barcelona Clinic Liver Cancer staging system, with some modifications, has been successfully established to manage post-hepatectomy recurrent HCC, and the clinical outcomes were commendable.

Surgical Treatment of Recurrent Hepatocellular Carcinoma (A report of 112 cases)

Objective The aim of this study was to evaluate the long term results of treatment and prognositic factors in patients with recurrent hepatocellular carcinoma after curative resection of hepatocellular carcinoma. Methods 112 patients of recurrent hepatocellular carcinoma who underwent surgical treatment were studied. Survival results after recurrence and from first hepatectomy were analyzed, and prognostic factors were determined by analyzing the clinicopathological variables.Results The mean survival of 112 patients was 26 months (4 to 76 months). 30 patients with tumor free state were still living. 1 year, 3 year and 5 year survival rates were 81.0%, 43.3% and 32 0%, respectively, and the 58 patients with hepatic resection were 87%, 59% and 38%, respectively. Among the 9 patients with secondary re resection, 6 had lived for over 3 years, and two for over 5 years. There were no operative death in this series, and few complications were found.Conclusion Early detection of recurrence depends on AFP measurements and ultrasonography follow up monitoring after resection. Re resection for recurrent hepatocellular carcinoma has been proved to be the most effective treatment modality. Aggressive treatment with a multimodality strategy is an option to improve long term survival in some patients with unresectable recurrent hepatocellular carcinoma.\;

Appropriate treatment strategies improve survival of hepatocellular carcinoma patients with portal vein tumor thrombus

AIM: To evaluate the survival benefits of different treatment strategies for hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT) and to determine the prognosis factors.

Hepatocellular carcinoma:Surgical perspectives beyond the barcelona clinic liver cancer recommendations

The barcelona clinic liver cancer(BCLC)staging system has been approved as guidance for hepatocellular carcinoma(HCC)treatment guidelines by the main Western clinical liver associations.According to the BCLC classification,only patients with a small single HCC nodule without signs of portal hypertension or hyperbilirubinemia should undergo liver resection.In contrast,patients with intermediate-advanced HCC should be scheduled for palliative therapies,even if the lesion is resectable.Recent studies report good short-term and long-term outcomes in patients with intermediate-advanced HCC treated by liver resection.Therefore,this classification has been criticised because it excludes many patients who could benefit from curative resection.The aim of this review was to evaluate the role of surgery beyond the BCLC recommendations.Safe liver resection can be performed in patients with portal hypertension and well-compensated liver function with a 5-year survival rate of 50%.Surgery also offers good long-term result in selected patients with multiple or large HCCs with a reported 5-year survival rate of over 50%and 40%,respectively.Although macrovascular invasion is associated with a poor prognosis,liver resection provides better long-term results than palliative therapies or best supportive care.Recently,researchers have identified several genes whose altered expression influences the prognosis of patients with HCC.These genes may be useful for classifying the biological behaviour of different tumours.A revision of the BCLC classification should be introduced to provide the best treatment strategy and to ensure the best prognosis in patients with HCC.

Preoperative predictors of short-term survival after hepatectomy for multinodular hepatocellular carcinoma

AIM： To investigate preoperative factors associated with poor shore-term outcome after resection for multi- nodular hepatocellular carcinoma （HCC） and to assess the contraindication of patients for surgery, METHODS： We retrospectively analyzed 162 multi- nodular HCC patients with Child-Pugh A liver function who underwent surgical resection. The prognostic significance of preoperative factors was investigated by univariate analysis using the log-rank test and by multivariate analysis using the Cox proportional hazards model. Each independent risk factor was then assigned points to construct a scoring model to evaluate the in- dication for surgical intervention. A receiver operating characteristics （ROC） curve was constructed to assess the predictive ability of this system.RESULTS： The median overall survival was 38.3 mo （range： 3-80 too）, while the median disease-free sur- vival was 18.6 mo （range： 1-79 too）. The 1-year mor- tality was 14%. Independent prognostic risk factors of 1-year death included prealburnin 〈 170 rng/L [hazard ratio （HR）： 5.531, P 〈 0.001], alkaline phosphatase 〉 129 U/L （HR： 3.252, P = 0.005）, α fetoprotein 〉 20 μg/L （HR： 7.477, P = 0.011）, total tumor size 〉 8 cm （HR： 10.543; P 〈 0.001）, platelet count 〈 100×109/L （HR： 9.937, P 〈 0.001）, and y-glutamyl transpeptidase 〉 64 U/L （HR： 3.791, P 〈 0.001）. The scoring model had a strong ability to predict 1-year survival （area under ROC： 0.925, P 〈 0.001）. Patients with a score ≥5 had significantly poorer short-term outcome than those with a score 〈 5 （1-year mortality： 62% vs 5%, P 〈 0.001; 1-year recurrence rate： 86% vs 33%, P 〈 0.001）. Patients with score ≥5 had greater possibility of microvascular invasion （P 〈 0.001）, poor tumor dif- ferentiation （P = 0.003）, liver cirrhosis with small nod- ules （P 〈 0.001）, and intraoperative blood transfusion （P = 0.010）. CONCLUSION： A composite preoperative scoring model can be used as an indication of prognosis of HCC patients after surgical resection. Resection should be considered with caution in patients with a score ≥5, which indicates a contraindication for surgery.

Hepatectomy for hepatocellular carcinoma with portal vein tumor thrombus

Despite surgical removal of tumors with portal vein tumor thrombus(PVTT) in hepatocellular carcinoma(HCC) patients, early recurrence tends to occur, and overall survival(OS) periods remain extremely short. The role that hepatectomy may play in long-term survival for HCC with PVTT has not been established. The operative mortality of hepatectomy for HCC with PVTT has also not been reviewed. Hence, we reviewed recent literature to assess these parameters. The OS of patients who received hepatectomy in conjunction with multidisciplinary treatment tended to be superior to that of patients who did not. Multidisciplinary treatments included the following: preoperative radiotherapy on PVTT; preoperative transarterial chemoembolization(TACE); subcutaneous administration of interferon-alpha(IFN-α) and intra-arterial infusion of 5-fluorouracil(5-FU) with infusion chemotherapy in the affected hepatic artery; cisplatin, doxorubicin and 5-FU locally administered in the portal vein; and subcutaneous injection of IFN-α, adjuvant chemotherapy(5-FU + Adriamycin) administration via the portal vein with postoperative TACE, percutaneous isolated hepatic perfusion and hepatic artery infusion and/or portal vein chemotherapy. The highest reported rate of operative mortality was 9.3%. In conclusion, hepatectomy for patients affected by HCC with PVTT is safe, has low mortality and might prolong survival in conjunction with multidisciplinary treatment.

Concurrent and subsequent radiofrequency ablation combined with hepatectomy for hepatocellular carcinomas

Partial hepatectomy has long been the standard treatment modality for patients with hepatocellular carcinoma(HCC),although the majority of patients with HCCs are not candidates for curative resection.Radiofrequency ablation(RFA) has been widely used as the preferred locoregional therapy.RFA and hepatectomy can be complementary to each other for the treatment of multifocal HCCs.Combining hepatectomy with RFA permits the removal of larger tumors while simultaneously ablating any smaller residual tumors.By using this combination treatment,more patients might become candidates for curative resection.For treating recurrent tumors involving the liver after hepatectomy,RFA has been performed recently instead of transcatheter arterial chemoembolization or ethanol ablation.Many retrospective studies on the combination of RFA and hepatectomy demonstrate favorable results of effectiveness and safety.However,further investigation of prospective design will be needed to confirm these encouraging results.

Innovative surgical approaches for hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is the sixth most common cancer worldwide,with an increasing diffusion in Europe and the United States.The management of such a cancer is continuously progressing and the objective of this paper is to evaluate innovation in the surgical treatment of HCC.In this review,we will analyze the modern concept of preoperative management,the role of laparoscopic and robotic surgery,the intraoperative use of three dimensional models and augmented reality,as well as the potential application of fluorescence.

Combined cavo-atrial thrombectomy and hepatectomy in hepatocellular carcinoma

To the Editor： Hepatocellular carcinoma （HCC） remains one of the commonest cancers worldwide especially in hepatitis B endemic regions. Its aggressive behavior is characterised by the natural history of increasing size, a tendency for vascular invasion into the hepatic veins and portal veins. Further growth into the inferior vena cava （IVC） and right atrium （RA） is an infrequent finding but signifies a pre-terminal event with a dismal prognosis.

Role of hepatectomy for recurrent or initially unresectable hepatocellular carcinoma

As a result of donor shortage and high postoperative morbidity and mortality after liver transplantation,hepatectomy is the most widely applicable and reliable option for curative treatment of hepatocellular carcinoma(HCC).Because intrahepatic tumor recurrence is frequent after loco-regional therapy,repeated treatments are advocated provided background liver function is maintained.Among treatments including local ablation and transarterial chemoembolization,hepatectomy provides the best long-term outcomes,but studies comparing hepatectomy with other nonsurgical treatments require careful review for selection bias.In patients with initially unresectable HCC,transarterial chemo-or radio-embolization,and/or systemic chemotherapy can down-stage the tumor and conversion to resectable HCC is achieved in approximately 20%of patients.However,complete response is rare,and salvage hepatectomy is essential to help prolong patients’survival.To counter the short recurrence-free survival,excellent overall survival is obtained by combining and repeating different treatments.It is important to recognize hepatectomy as a complement,rather than a contraindication,to other nonsurgical treatments in a mul-tidisciplinary approach for patients with HCC,including recurrent or unresectable tumors.

Surgical resection of a solitary para-aortic lymph node metastasis from hepatocellular carcinoma

Lymph node (LN) metastases from hepatocellular carcinoma (HCC) are considered uncommon. We describe the surgical resection of a solitary para-aortic LN metastasis from HCC. A 65-year-old Japanese man with B-type liver cirrhosis was admitted for the evaluation of a liver tumor. He had already undergone radiofrequency ablation, transcatheter arterial chemoembolization, and percutaneous ethanol injection therapy for HCC. Despite treatment, viable regions remained in segments 4 and 8. We performed a right paramedian sectionectomy with partial resection of the left paramedian section of the liver. Six months later, serum concentrations of alpha-fetoprotein (189 ng/mL) and PIVKA-2 (507 mAU/mL) increased. Enhanced com- puted tomography of the abdomen revealed a tumor (20 mm in diameter) on the right side of the abdominal aorta. Fluorine-18 fluorodeoxyglucose positron emission tomography revealed an increased standard uptake value. There was no evidence of recurrence in other regions. Esophagogastroduodenoscopy and colonoscopy revealed no malignant tumor in the gastrointestinal tract. Para-aortic LN metastasis from HCC was thus diagnosed. We performed lymphadenectomy. Histopathological examination revealed that the tumor was largely necrotic, with poorly differentiated HCC on its surface, which confirmed the suspected diagnosis. After 6 mo tumor marker levels were normal, with no evidence of recurrence. Our experience suggests that a solitary para-aortic LN metastasis from HCC can be treated surgically.

The current role of radiofrequency ablation in the treatment of hepatocellular carcinoma

Local ablative therapy is used in treating liver tumors by either injection of cytotoxic agents（chemicals,radioactive isotopes,hyperthermic agents or chemotherapeutic agents）or application of an energy source to achieve thermal ablation,cryoablation or conformal external beam radiation（Table 1）.

Application value of mixed reality in hepatectomy for hepatocellular carcinoma

BACKGROUND As a new digital holographic imaging technology,mixed reality(MR)technology has unique advantages in determining the liver anatomy and location of tumor lesions.With the popularization of 5 G communication technology,MR shows great potential in preoperative planning and intraoperative navigation,making hepatectomy more accurate and safer.AIM To evaluate the application value of MR technology in hepatectomy for hepatocellular carcinoma(HCC).METHODS The clinical data of 95 patients who underwent open hepatectomy surgery for HCC between June 2018 and October 2020 at our hospital were analyzed retrospectively.We selected 95 patients with HCC according to the inclusion criteria and exclusion criteria.In 38 patients,hepatectomy was assisted by MR(Group A),and an additional 57 patients underwent traditional hepatectomy without MR(Group B).The perioperative outcomes of the two groups were collected and compared to evaluate the application value of MR in hepatectomy for patients with HCC.RESULTS We summarized the technical process of MR-assisted hepatectomy in the treatment of HCC.Compared to traditional hepatectomy in Group B,MR-assisted hepatectomy in Group A yielded a shorter operation time(202.86±46.02 min vs 229.52±57.13 min,P=0.003),less volume of bleeding(329.29±97.31 mL vs 398.23±159.61 mL,P=0.028),and shorter obstructive time of the portal vein(17.71±4.16 min vs 21.58±5.24 min,P=0.019).Group A had lower alanine aminotransferas and higher albumin values on the third day after the operation(119.74±29.08 U/L vs 135.53±36.68 U/L,P=0.029 and 33.60±3.21 g/L vs 31.80±3.51 g/L,P=0.014,respectively).The total postoperative complications and hospitalization days in Group A were significantly less than those in Group B[14(37.84%)vs 35(60.34%),P=0.032 and 12.05±4.04 d vs 13.78±4.13 d,P=0.049,respectively].CONCLUSION MR has some application value in three-dimensional visualization of the liver,surgical planning,and intraoperative navigation during hepatectomy,and it significantly improves the perioperative outcomes of hepatectomy for HCC.

CONVERSION OF SURGICALLY VERIFIED UNRESECTABLE TO RESECTABLE HEPATOCELLULAR CARCINOMA(A REPORT OF 26 PATIENTS WITH SUBSEQUENT RESECTION)

During the period 1978-1987, 255 patients with pathologically proven hepatocellular carcinoma (HCC) were determined by laparotomy to be un-resectable, 155 (60.8%) out of them had their tumor mainly confined in right or left lobe and considered to be potentially resectable if remarkable tumor shrinkage appears after treatment. Second look operation was performed in 26 (16.8%) out of the 155 patients after marked reduction of tumor size, resection was done in all of these 26 patients. Triple or quadruple combination treatment with hepatic artery ligation (HAL), hepatic artery infusion (HAI) with chemotherapy, radiotherapy using linear accelerator, and radioimmunotherapy using 131-I antihu-man HCC ferritin antibody yielded the highest conversion rate (29.8%, 14/47) as compared to double combination treatment with HAL+HAI, or cryosur-gery+HAL (16.9%, 12/71) and single treatment with HAL or HAI or HAE (embolization) (0%, 0/37). The median tumor size of these 26 patients was reduced from 9.5 cm to 5.0 cm after combination treatment. The median interval between the first laparotomy and the subsequent resection was 5.0 (2-16) months. The survival rates calculated by life table method were: 1-year 86.5%, 2-year 74.3% and 3-year 74.3%. Nine cases have survival more than 3 years. Thus, multimodality combination treatment with subsequent resection might prolong survival significantly for some patients with unresectable HCC particularly confined in right lobe of a cirrhotic liver.

Prospective comparative study of cool-tip radiofrequency ablation and surgical resection for hepatocellular carcinoma

Objective: The aim of this study was to compare the therapeutic efficacy of radiofrequency ablation (RFA) and surgical resection for the patients with hepatocellular carcinoma (HCC). Methods: From January 2002 to June 2009, 87 HCC patients with 3 or fewer nodules, no more than 3 cm in diameter, and liver function of Child-Pugh class A or B were enrolled. Forty-seven underwent RFA while 40 underwent surgical resection. Follow-up ranged from 6 to 69 months. We compared the overall and disease-free survival rate, recurrence patterns, and the complications between the two groups. Survival prob-abilities were estimated using the Kaplan-Meier method. Results: At the end of the study, 67 patients were alive. The 1-, 2- and 3-year overall cumulative survival rates after RFA and surgical resection were 91.0%, 76.7%, 69.7% and 90.0%, 82.9%, 75.4%, respectively. The difference between the two survival curves was not statistically significant (χ2 = 0.99, P = 0.32). Forty-three patients suffered intrahepatic recurrence, including 25 cases after RFA and 18 cases after surgical resection. The 1-, 2-, and 3-year disease-free survival rates after radiofrequency ablation and surgical resection were 57.3% vs 71.1%, 40.3% vs 45.7%, and 35.3% vs 30.9%. The difference between the two groups was not statistically significant (χ2 = 0.06, P = 0.80). Cox hazard model indicated tumor size and Child-Pugh scoring were significant risk factors for local tumor progression, while tumor numbers was risk factor for intrahepatic distant recurrence. Conclusion: RFA is as effective as surgical resection for the treatment of patients with HCC (≤ 5 cm), especially for those who are not suitable for curative resection.

Current management strategy of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) still remains a considerable challenge for surgeons.Surgery,including liver transplantation,is the most important therapeutic approach for patients with this disease.HCC is frequently diagnosed at advanced stages and has a poor prognosis with a high mortality rate even when surgical resection has been considered potentially curative.This brief report summarizes the current status of the management of this malignancy and includes a short description of new pharmacological approaches in HCC treatment.

Management of centrally located hepatocellular carcinoma:Update 2016

Centrally located hepatocellular carcinoma(HCC)is sited in the central part of the liver and adjacent to main hepatic vascular structures.This special location is associated with an increase in the difficulty of surgery,aggregation of the recurrence disease,and greater challenge in disease management.This review summarizes the evolution of our understanding for centrally located HCC and discusses the development of treatment strategies,surgical approaches and recurrence prevention methods.To improve patient survival,a multi-disciplinary modality is greatly needed throughout the whole treatment period.