Hepatobiliary Pancreat Dis Int

	2022 Vol. 21 No. 5
	Published: 2022-10-15


	Pages 307-408
	ORIGINAL ARTICLES/Liver ORIGINAL ARTICLES/Biliary LETTERS TO THE EDITOR GUIDELINES Special issue on modern technology in liver surgery and transplantation Special issue on cancer immunotherapy in hepatobiliary malignancies

Special issue on cancer immunotherapy in hepatobiliary malignancies

	409	Qin LX
		Immunotherapy for hepatobiliary malignancies: Progress and prospective
		Hepatobiliary malignancies include hepatocellular carcinoma (HCC) and biliary tract cancers (BTCs). They are characterized by high heterozygosity, rapid progression, and difficult to treat [1,2]. Recent rapid progress in targeted therapeutic agents has brought new hope for those with advanced HCC [3–5]. But there are problems such as lower response rate, or drug resistance (primary or acquired), as well as poor tolerance due to their side-effects, which make this treatment alone still face great challenges.
		Hepatobiliary Pancreat Dis Int. 2022; 21(5): 409-412 . [Abstract] ( 73 ) [HTML 1KB] [PDF 0KB] ( 74 )

	413	Lin ZF, Qin LX, Chen JH
		Biomarkers for response to immunotherapy in hepatobiliary malignancies ^Hot!
		Background: The advent of immune checkpoint inhibitors (ICIs) has revolutionized the therapeutic options of hepatobiliary malignancies. However, the clinical benefit provided by immunotherapy seems limited to a small subgroup of patients with hepatobiliary malignancies. The identification of reliable predictors of the response to immunotherapy is urgently needed. Data sources: Literature search was conducted in PubMed for relevant articles published up to May 2022. Information of clinical trials was obtained from https://clinicaltrials.gov/. Results: Biomarkers for ICI response of hepatobiliary malignancies remain in the exploration stage and lack compelling evidence. Tumor programmed death-ligand 1 (PD-L1) expression is the most widely studied biomarker in hepatocellular carcinoma (HCC) and biliary tract cancers (BTCs), but there are conflicting results on its predictive potential. Tumor mutational burden (TMB) is generally low both in HCC and BTCs, and the clinical trials of TMB are rare in hepatobiliary malignancies. Promisingly, mismatch repair deficiency (dMMR)/high microsatellite instability (MSI-H) may be a predictive biomarker of response to anti-PD-1 therapy in BTCs. Furthermore, some emerging biomarkers, such as gut microbiota, show predictive potential in the preliminary studies. Radiomics and liquid-biopsy biomarkers, including circulating tumor cells, circulating tumor DNA (ctDNA) and exosomal PD-L1 provide a quick and non-invasive approach for monitoring the ICI response, showing a new promising direction. Conclusions: Multiple potential biomarkers for predicting ICI response of hepatobiliary malignancies have been explored and tried to apply in clinic. Yet there is no robust evidence to prove their clinical value in predicting immunotherapeutic response for patients with hepatobiliary malignancies. The identification of predictors for response to ICIs is an urgent need and major challenge. Further studies are warranted to validate the role of emerging biomarkers in predicting immunotherapeutic responses.
		Hepatobiliary Pancreat Dis Int. 2022; 21(5): 413-419 . [Abstract] ( 93 ) [HTML 1KB] [PDF 0KB] ( 101 )

	420	Zhu Y, Qin LX
		Strategies for improving the efficacy of immunotherapy in hepatocellular carcinoma ^Hot!
		Primary liver cancer, mainly hepatocellular carcinoma (HCC), is the sixth most diagnosed cancer and third leading cause of cancer-related death globally. Recently, immunotherapies such as immune checkpoint inhibitors (ICIs) have made great progress in the systemic treatment of HCC. However, anti-PD-1 therapy with pembrolizumab or nivolumab as a single agent did not meet their predefined end points of overall survival in the KEYNOTE-240 and CheckMate 459 trials. It is urgent to understand the immunological rationale and explore novel ways to improve the efficacy of immunotherapy. The combination of ICIs with other therapies, such as tyrosine kinase inhibitors (TKIs), monoclonal antibodies, or local therapy, has been demonstrated to improve overall response rate and survival. In addition, modulating tumor microenvironment is a potential way to overcome the primary and secondary resistance to immunotherapies. In this review, we summarized the latest findings in the immune microenvironment, the mechanisms of their synergistic effects when combined with anti-VEGF agents or TKIs, as well as other kinds of immune treatment.
		Hepatobiliary Pancreat Dis Int. 2022; 21(5): 420-429 . [Abstract] ( 97 ) [HTML 1KB] [PDF 0KB] ( 78 )

	430	Xiong J, Wang QQ
		Mechanisms and strategies to overcome immunotherapy resistance in hepatobiliary malignancies ^Hot!
		Unprecedented advances have been achieved in hepatobiliary cancer treatment with immune checkpoint blockade (ICB). However, the efficacy of ICB in patients with hepatobiliary malignancies is still limited. Resistance to immunotherapies is often orchestrated by complicated tumor-host-microenvironment inter- actions but could also occur after initial efficacy, mostly when only partial responses are obtained. Clarifi- cation of cancer-resistance mechanisms will be beneficial to provide the rationale for the administration of personalized drugs. Here, we review the factors related to resistance to immune-targeted therapies in hepatobiliary malignancies and discuss the potential strategies for overcoming resistance and future directions of immunotherapy development.
		Hepatobiliary Pancreat Dis Int. 2022; 21(5): 430-439 . [Abstract] ( 88 ) [HTML 1KB] [PDF 0KB] ( 93 )

	440	Yuan ZG, Zeng TM, Tao CJ
		Current and emerging immunotherapeutic approaches for biliary tract cancers
		Background: Biliary tract cancers (BTCs) comprise a heterogeneous group of aggressive malignancies with unfavorable prognoses. The benefit of chemotherapy seems to have reached a bottleneck and, therefore, new effective therapeutic strategies for advanced BTCs are needed. Molecularly targeted therapies in selected patients are rapidly changing the situation. However, the low frequency of specific driver alterations in BTCs limits their wide application. Recently, immunotherapeutic approaches are also under active investigation in BTCs, but the role of immunotherapy in BTCs remains controversial. Data sources: PubMed, Web of Science, and meeting resources were searched for relevant articles published from January 2017 to May 2022. The search aimed to identify current and emerging immunotherapeutic approaches for BTCs. Information on clinical trials was obtained from https://clinicaltrials.gov/ and http://www.chictr.org.cn/ . Results: Immunotherapy in BTC patients is currently under investigation, and most of the investigations focused on the application of immune checkpoint inhibitors (ICIs). However, only a subgroup of BTCs with microsatellite-instability high (MSI-H)/DNA mismatch repair-deficient (dMMR) or tumor mutational burden-high (TMB-H) benefit from monotherapy of ICIs, and limited activity was observed in the second or subsequent settings. Nevertheless, promising results come from studies of ICIs in combination with other therapeutic approaches, including chemotherapy, in advanced BTCs, with a moderate toxicity profile. Recent studies demonstrated that compared to GEMCIS alone, durvalumab plus GEMCIS significantly improved patient survival (TOPAZ-1 trial) and that ICIs-combined chemoimmunotherapy is poised to become a new frontline therapy option, regardless of TMB and MMR/MSI status. Adoptive cell therapy and peptide- or dendritic-based cancer vaccines are other immunotherapeutic options that are being studied in BTCs. Numerous biomarkers have been investigated to define their predictive role in response to ICIs, but no predictive biomarker has been validated, except MSI-H/dMMR. Conclusions: The role of immunotherapy in BTCs is currently under investigation and the results of ongoing studies are eagerly anticipated. Several studies have demonstrated the safety and efficacy of ICIs in combination with chemotherapy in treatment-naive patients, such as the phase III TOPAZ-1 trial, which will change the standard care of first-line chemotherapy for advanced BTCs. However, further research is needed to understand the best combination with immunotherapy and to discover more predictive biomarkers to guide clinical practice.
		Hepatobiliary Pancreat Dis Int. 2022; 21(5): 440-449 . [Abstract] ( 70 ) [HTML 1KB] [PDF 0KB] ( 93 )

	450	Xue JN, Wang YY, Wang YC, Zhang N, Zhang LH, Lu ZH, Zhao LJ, Zhao HT
		Novel cellular therapies for hepatobiliary malignancies
		Background: The mortalities of hepatobiliary malignancies are high. With the failure of conventional chemotherapy and unsatisfactory outcome of molecular targeted drugs, immune-based therapy has become a new focus of research in hepatobiliary cancers treatment. Data sources: We performed a PubMed search with relevant articles published up to May 2022 and the following keywords: cellular immunotherapy, hepatobiliary cancer, antigen receptor T cell therapy, and receptor-engineered T cell. Information of clinical trials was obtained from https://clinicaltrials.gov/ . Results: Cell therapies for hepatobiliary malignancies are at early stage of development. The current review showed that cellular therapies are safe and feasible in patients. These findings provide an important platform for future lager scale clinical trials on immunotherapy in patients with hepatobiliary malignancies. Conclusions: With the continuous advances of cellular immunotherapy, the combination of cellular im- munotherapy with surgery, chemotherapy and radiotherapy will be new therapeutic strategies for patients with hepatobiliary cancer.
		Hepatobiliary Pancreat Dis Int. 2022; 21(5): 450-454 . [Abstract] ( 62 ) [HTML 1KB] [PDF 0KB] ( 82 )

Special issue on modern technology in liver surgery and transplantation

	455	Balci D, Kirimker EO, Raptis DA, Gao Y, Kow AWC
		Uses of a de dicate d 3D reconstruction software with augmented and mixed reality in planning and performing advanced liver surgery and living donor liver transplantation (with videos)?
		The development of digital intelligent diagnostic and treatment technology has opened countless new opportunities for liver surgery from the era of digital anatomy to a new era of digital diagnostics, virtual surgery simulation and using the created scenarios in real-time surgery using mixed reality. In this article, we described our experience on developing a dedicated 3 dimensional visualization and reconstruction software for surgeons to be used in advanced liver surgery and living donor liver transplantation. Furthermore, we shared the recent developments in the field by explaining the outreach of the software from virtual reality to augmented reality and mixed reality.
		Hepatobiliary Pancreat Dis Int. 2022; 21(5): 455-461 . [Abstract] ( 75 ) [HTML 1KB] [PDF 0KB] ( 78 )

GUIDELINES

	462	Xu M, Xie LT, Xiao YY, Liang P, Zhao QY, Wang ZM, Chai WL, Wei YT, Xu LF, Hu XK, Kuang M, Niu LZ, Yao CG, Kong HY, Tian G, Xie XY, Cui XW, Xu D, Zhao J, Jiang TA
		Chinese clinical practice guidelines for ultrasound-guided irreversible electroporation of liver cancer (version 2022)
		Liver cancer remains a global health challenge, and its incidence is increasing worldwide. It is estimated that by 2025, more than one million individuals will be affected by liver cancer annually [1,2]. In recent years, ablation has become a widely accepted treatment option for patients with primary and secondary liver malignancies [3]. The commonly used ablation method for liver cancer is thermal ablation, including radiofrequency ablation, microwave ablation, laser ablation and cryoablation. However, many tumors cannot be treated with thermal ablation owing to hazardous tumor location. Thermal ablation of tumors adjacent to large blood vessels is associated with a higher incidence of incomplete eradication (heat-sink effect). In addition, these modalities can cause thermal injury to important structures such as bile ducts or intestines in the vicinity of the ablated area and can therefore be contraindicated [4,5].
		Hepatobiliary Pancreat Dis Int. 2022; 21(5): 462-471 . [Abstract] ( 105 ) [HTML 1KB] [PDF 0KB] ( 92 )

ORIGINAL ARTICLES/Liver

	472	Xu XB, Hu C, Yang HJ, Zheng SS
		Isolated anti-HBc is an independent risk factor for tumor recurrence in intrahepatic cholangiocarcinoma after curative resection
		Background: Intrahepatic cholangiocarcinoma (ICC) is a poorly understood and aggressive malignancy with increasing incidence and mortality. Hepatitis B virus (HBV) infection is recognized as one of the important risk factors of ICC. There are few reports focusing on whether isolated antibody to hepatitis B core antigen (isolated anti-HBc, IAHBc) have prognostic role in ICC, while positive hepatitis B surface antigen (HBsAg) has been reported to be associated with the prognosis of ICC. The aim of this study was to investigate the prognostic value of IAHBc in ICC patients after curative resection, in order to identify those who have the high risk of ICC recurrence in the early stage. Methods: We divided 209 ICC patients who underwent curative resection into 4 groups: group I (n = 40), HBsAg (-)/antibody to hepatitis B surface antigen (anti-HBs) (-)/anti-HBc (+); group II (n = 70), HBsAg (+)/anti-HBc (-); group III (n = 55), HBsAg (-)/anti-HBs (+)/anti-HBc (+); and group IV (n = 44), HBsAg (-)/anti-HBc (-). We compared the recurrence-free survival (RFS) and overall survival (OS) among these four groups. Results: The median follow-up time was 16.93 months (range 1-34.6 months). The 1- and 2-year RFS and OS rates were 60% and 42%, and 78% and 63% respectively in all patients. Compared to the whole non-IAHBc patients (group II + group III + group IV), IAHBc patients (group I) showed significantly lower RFS at 1 year (39.8% vs. 64.4%, P = 0.001) and 2 years (20.7% vs. 46.7%, P = 0.001). When compared to other three individual groups, IAHBc patients (group I) also had the lowest RFS. We did not find significant difference in OS among the four groups. Further multivariate analysis revealed that IAHBc was an independent risk factor of RFS. Conclusions: IAHBc is an independent poor prognostic factor for tumor recurrence in ICC patients after curative resection.
		Hepatobiliary Pancreat Dis Int. 2022; 21(5): 472-478 . [Abstract] ( 74 ) [HTML 1KB] [PDF 0KB] ( 84 )

	479	Cheng DY, Zhao ZM, Wan G, Zheng HW, Huang JQ, Liu CH, Xing HC
		Impact of Fuzheng Huayu tablet on antiviral effect of entecavir in patients with hepatitis B cirrhosis
		Background: Fuzheng Huayu tablet is a traditional Chinese medicine (TCM) used for the treatment of liver fibrosis and cirrhosis. However, whether the combination with Fuzheng Huayu tablet could affect the antiviral efficacy of nucleos(t)ide remains a concern. The objective of this trial was to explore the impact of Fuzheng Huayu tablet on antiviral effect of entecavir in patients with hepatitis B cirrhosis. Methods: A prospective, randomized control trial was conducted. Patients with compensated hepatitis B cirrhosis were randomly divided into the treatment group (entecavir capsule plus Fuzheng Huayu tablet) and the control group (entecavir capsule plus simulant of Fuzheng Huayu), and followed up for 48 weeks. The dynamic changes of HBV DNA load, the rate of serological conversion of HBeAg, liver function, renal function and liver stiffness measurement (LSM) were monitored. The general clinical data and adverse events were also recorded. Results: There was no significant difference in the rate of virological response and cumulative virological response between the treatment group and the control group (P > 0.05). After 48 weeks of treatment, the HBeAg seroconversion rate, biochemical response rate and LSM value were 21.05% and 4.76% (P = 0.164), 86.96% and 65.96% (P = 0.017), 9.5 kpa and 10.6 kpa (P = 0.827) in the treatment group and the control group, respectively. No serious adverse events related to the study therapy occurred during the trial. Conclusions: The antiviral entecavir combined with Fuzheng Huayu tablet did not affect the antiviral efficacy of entecavir, but could improve the rate of biochemical response, and had a tendency to improve the rate of serological conversion of HBeAg and liver fibrosis in patients with hepatitis B cirrhosis. Fuzheng Huayu tablet is clinically safe for patients with hepatitis B cirrhosis.
		Hepatobiliary Pancreat Dis Int. 2022; 21(5): 479-484 . [Abstract] ( 90 ) [HTML 1KB] [PDF 0KB] ( 82 )

ORIGINAL ARTICLES/Biliary

	485	Fu J, McGrath NA, Lee J, Wang X, Brar G, Xie C
		Verteporfin synergizes the efficacy of anti-PD-1 in cholangiocarcinoma
		Background: Cholangiocarcinoma (CCA) is one of the primary hepatobiliary malignant neoplasms with only 10% of 5-year survival rate. Promising immunotherapy with the blockade of immune checkpoints has no clear benefit in CCA. The inhibition of YAP1 signaling by verteporfin has shown encouraging results by inhibiting cell proliferation and inducing apoptosis. This study aimed to evaluate the potential benefit of the combination of verteporfin and anti-programmed cell death 1 (PD-1) in CCA mouse model. Methods: We assessed the cytotoxicity of verteporfin in human CCA cell lines in vitro, including both intrahepatic CCA and extrahepatic CCA cells. We examined the in vitro effect of verteporfin on cell proliferation, apoptosis, and stemness. We evaluated the in vivo efficacy of verteporfin, anti-PD-1, and a combination of both in subcutaneous CCA mouse model. Results: Our study showed that verteporfin reduced tumor cell growth and enhanced apoptosis of human CCA tumor cells in vitro in a dose-dependent fashion. Nevertheless, verteporfin impaired stemness evidenced by reduced spheroid formation and colony formation, decreased numbers of cells with aldehyde dehydrogenase activity and positive cancer stem cell markers (all P < 0.05). The combination of verteporfin and anti-PD-1 reduced tumor burden in CCA subcutaneous SB1 tumor model compared to either agent alone. Conclusions: Verteporfin exhibits antitumor effects in both intrahepatic and extrahepatic CCA cell lines and the combination with anti-PD-1 inhibited tumor growth.
		Hepatobiliary Pancreat Dis Int. 2022; 21(5): 485-492 . [Abstract] ( 82 ) [HTML 1KB] [PDF 0KB] ( 104 )

	493	Choi JH, Lee KJ, Paik WH, Park N, Chun JW, Lee SH, Ryu JK, Kim YT
		Acetylsalicylic acid for metal stent in malignant distal common bile duct obstruction: A randomized controlled trial
		Background: Endoscopic biliary drainage is the treatment of choice for patients with malignant distal common bile duct obstruction. Self-expandable metal stents have clinical advantages including an increased duration of patency that may be prolonged by acetylsalicylic acid (ASA) use. The aim of this study was to investigate whether ASA had a positive effect on the patency of self-expandable metal stents compared with placebo. Methods: This prospective, multicenter, double-blinded, and randomized placebo-controlled trial was conducted from October 2017 to May 2020 in Korea. Patients who underwent palliative endoscopic biliary drainage with self-expandable metal stents for malignant distal bile duct obstruction were enrolled, and allocated to ASA treatment or placebo. The study outcomes were the rate of stent dysfunction at 6 months, duration of stent patency, risk factors for stent dysfunction, and any adverse events. Results: Interim analysis included 24 and 28 patients in the ASA and placebo groups, respectively. There was no significant difference between the ASA and placebo groups in stent dysfunction (25.0% vs. 20.7%, P = 0.761) or the duration of stent patency (150.97 ±10.55 vs. 158.07 ±8.70 days, P = 0.497). Six patients experienced suspected ASA-related adverse events, and there was one lethal case. Conclusions: ASA did not prolong stent patency. This study was terminated early because of the possibility of serious adverse events related to ASA treatment of these patients receiving palliative care.
		Hepatobiliary Pancreat Dis Int. 2022; 21(5): 493-499 . [Abstract] ( 72 ) [HTML 1KB] [PDF 0KB] ( 76 )

LETTERS TO THE EDITOR

	500	Inoue T, Kitano R, Yoneda M
		Troubleshooting of reinterventions after stent-by-stent placement for malignant hilar biliary obstruction (with videos)
		Biliary drainage is essential for controlling cholangitis and/or jaundice in patients with malignant hilar biliary obstruction, and endoscopy is the first choice of approach due to its less invasiveness. For unresectable cases, placement of self-expandable metal stents (SEMSs) has been recommended over that of plastic stents due to their longer patency, and bilateral placement is also recommended to achieve higher clinical success and patency rates [1]. However, approximately half of all cases develop recurrent biliary obstruction even after bilateral SEMS placement. Currently, physicians must manage biliary drainage in anticipation of recurrent biliary obstruction [1,2], but reintervention for recurrent biliary obstruction after bilateral SEMS placement is technically very challenging [3-7].
		Hepatobiliary Pancreat Dis Int. 2022; 21(5): 500-502 . [Abstract] ( 77 ) [HTML 1KB] [PDF 0KB] ( 78 )

	503	Huang JJ, Ma RW, Li DZ, Yin SY, Liu Z, Zhou L, Yan KP, Zheng SS
		Ultrasound-guided in vivo porcine liver ablation with nanosecond pulsed electric fields
		In recent decades, local ablative therapies have evolved considerably and played an increasingly important role in the treatment of inoperable tumors. Conventional modalities are mainly based on thermal ablation to destroy targeted lesions, such as radiofrequency ablation [1]. The clinical application of pulsed electric fields [2] is emerging as an innovative and promising technique for tumor ablation, which does not depend on heat energy and preserves surrounding tissues adjacent to tumors [3]. Highvoltage ultrashort electric pulses compromise the integrity of the plasma membrane and destroy intracellular homeostasis. Nanosecond pulsed electric fields (nsPEFs), with a strength of several tens of kV/cm and a nanosecond duration, have attracted much attention and been extensively studied in cancer ablation [4,5]. Furthermore, using nsPEFs to ablate tumors can elicit a systemic antitumor immune response against recurrence and metastasis [6]. In this study, a novel repetitive nsPEF generator was introduced and applied to planar cell treatment and porcine liver ablation. We aimed to investigate the feasibility and efficacy of tissue ablation with this device and the safety during the perioperative period.
		Hepatobiliary Pancreat Dis Int. 2022; 21(5): 503-507 . [Abstract] ( 79 ) [HTML 1KB] [PDF 0KB] ( 74 )

	508	Jegatheeswaran S, Finch LM, Siriwardena MC, Siriwardena AK
		The terminology of the 2012 Atlanta consensus conference on post-inflammatory collections after acute pancreatitis: An assessment of utilization in practice
		The report of the 1992 Atlanta consensus conference provided a framework for standardization of the terminology for description of acute pancreatitis and its complications [1]. Terms such as “pancreatic phlegmon” which had historically been subjected to differential interpretation were discontinued and modern terminology was introduced [1]. With subsequent clinical usage and with the accrual of new knowledge it became clear that further changes were necessary.
		Hepatobiliary Pancreat Dis Int. 2022; 21(5): 508-510 . [Abstract] ( 70 ) [HTML 1KB] [PDF 0KB] ( 102 )

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