Indications of pro-inflammatory cytokines in laparoscopic and open liver resection for early-stage hepatocellular carcinoma

Background:Our clinical practice of laparoscopic liver resection(LLR)had achieved better short-term and long-term benefits for patients with hepatocellular carcinoma(HCC)over open liver resection(OLR),but the underlying mechanisms are not clear.This study was to find out whether systemic inflammation plays an important role.Methods:A total of 103 patients with early-stage HCC under liver resection were enrolled(LLR group,n=53;OLR group,n=50).The expression of 9 inflammatory cytokines in patients at preoperation,postoperative day 1(POD1)and POD7 was quantified by Luminex Multiplex assay.The relationships of the cytokines and the postoperative outcomes were compared between LLR and OLR.Results:Seven of the circulating cytokines were found to be significantly upregulated on POD1 after LLR or OLR compared to their preoperative levels.Compared to OLR,the POD1 levels of granulocytemacrophage colony-stimulating factor(GM-CSF),interleukin-6(IL-6),IL-8,and monocyte chemoattractant protein-1(MCP-1)in the LLR group were significantly lower.Higher POD1 levels of these cytokines were significantly correlated with longer operative time and higher volume of blood loss during operation.The levels of these cytokines were positively associated with postoperative liver injury,and the length of hospital stay.Importantly,a high level of IL-6 at POD1 was a risk factor for HCC recurrence and poor disease-free survival after liver resection.Conclusions:Significantly lower level of GM-CSF,IL-6,IL-8,and MCP-1 after liver resection represented a milder systemic inflammation which might be an important mechanism to offer better short-term and long-term outcomes in LLR over OLR.

Options and survival benefits of conversion therapy for unresectable hepatocellular carcinoma

In the study by Wu et al,patients with unresectable hepatocellular carcinoma were subjected to transarterial chemoembolization(TACE)as a conversion therapy in order to render their tumors suitable for resection.A nomogram was devised and shown to be effective in predicting the survival of these patients.Generalization of the results,however,is questionable since the study subjects consisted of patients who had resection after TACE while excluding patients with the same disease but not suitable for TACE.Immunotherapy can be considered to be an option for conversion therapy.However,markers for determining responses to a conversion therapy and for guiding the decision between TACE and sequential immunotherapy have been lacking.The question of whether effective conversion therapy can truly enhance overall survival remains unanswered.

Solitary extraovarian primary peritoneal carcinoma with direct invasion into the liver,diaphragm and lung without peritoneal dissemination or distant metastasis

To the Editor:Extraovarian primary peritoneal carcinoma(EOPPC)is an uncommon malignancy with many similarities to epithelial ovarian carcinoma in histological,clinical,and etiological aspects[1].This phenomenon is explained by their common embryonal origin,in which both develop from the coelomic epithelium in the early embryological stage.Despite their similarities,the incidence of EOPPC is significantly lower than that of epithelial ovarian carcinoma(6.78 cases per million vs.120.5 cases per million)[1].

Post-fontan circulation hepatocellular carcinoma:Open and laparoscopic hepatectomy

To the Editor:Fontan-associated liver disease shows increasing incidence as advances in pediatric cardiology have prolonged life expectancy in patients with single ventricle congenital heart defects[1].Their unique physiology and procedure-related sequelae present an increasingly relevant challenge in hepatic surgery.We hereby reported a series of patients suffering from hepatocellular carcinoma(HCC)who successfully underwent open and laparoscopic hepatectomy.

Strategies to increase the resectability of hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is best treated by liver transplantation, but the applicability of transplantation is greatly limited. Tumor resection in partial hepatectomy is hence resorted to. However, in most parts of the world, only 20%-30% of HCCs are resectable. The main reason for such a low resectability is a future liver remnant too small to be sufficient for the patient. To allow more HCC patients to undergo curative hepatectomy, a variety of ways have been developed to increase the resectability of HCC, mainly ways to increase the future liver remnants in patients through hypertrophy. They include portal vein embolization, sequential transarterial chemoembolization and portal vein embolization, staged hepatectomy, two-staged hepatectomy with portal vein ligation, and Associating Liver Partition and Portal Vein Ligation in Staged Hepatectomy. Herein we review, describe and evaluate these different ways, ways that can be life-saving.

Survival outcomes of liver transplantation for hepatocellular carcinoma in patients with normal, high and very high preoperative alpha-fetoprotein levels

AIM To investigate the impact of alpha-fetoprotein(AFP) on long-term recurrence rate and overall survival and we also aimed to define the level of AFP leading to a higher risk of disease recurrence and affecting patient survival.METHODS Data of adult patients who received liver transplant(LT) for hepatocellular carcinoma(HCC) at our hospital from January 2000 to December 2013 were reviewed. Reviewed data included demographic characteristics, preoperative AFP level, operative details, follow-up details, and survival outcomes. Patients were mostly listed for LT based on Milan or UCSF criteria. For the purpose of this study, normal AFP level was defined as AFP value < 10 ng/m L, high AFP level was defined as AFP value ≥ 10 to < 400 ng/m L, and very highAFP level was defined as AFP ≥ 400 ng/m L. The patients were divided into these 3 groups accordingly. Survival rates were plotted as Kaplan-Meier curves and compared by log-rank analysis. Continuous variables were expressed as median(interquartile range). Categorical variables were compared by Spearman's test. Discriminative analysis was used to define the lowest value of AFP that could affect the overall survival in study population. Statistical significance was defined by a P value of < 0.05.RESULTS Totally 250 adult patients underwent LT for HCC in the study period. Eight-four of them received deceaseddonor LT and 166 had living-donor LT. The patients were divided into 3 groups: Group A, AFP < 10 ng/m L(n = 83); Group B, AFP ≥ 10 to < 400 ng/m L(n = 131); Group C, AFP ≥ 400 ng/m L(n = 36). The commonest etiology was hepatitis-B-related cirrhosis. The Model for End-stage Liver Disease scores in these groups were similar(median, 13 vs 13 vs 12; P = 0.745). The time to operation in Group A was longer(median, 94 vs 31 vs 35 d; P = 0.001). The groups were similar in hospital mortality(P = 0.626) and postoperative complication(P = 0.702). Pathology of explants showed that the 3 groups had similar numbers of tumor nodules, but the tumors in Group C were larger(A: 2.5 cm, B: 3.0 cm, C: 4.0 cm; P = 0.003). Group C had a bigger proportion of patients who were beyond Milan criteria(P = 0.010). Poor differentiation and vascular permeation were also more common in this group(P = 0.017 and P = 0.003 respectively). It also had poorer 5-year survival(A: 85.5%, B: 82.4%, C: 66%; P = 0.029). The 5-year disease-free survival was 84.3% in Group A, 80.1% in Group B, and 61.1% in Group C. Receiver operating characteristic area under the curve for AFP in predicting tumor recurrence was 0.685. The selected cut-off value was 54 ng/m L for AFP(C-index 0.685; 95%CI: 0.592-0.779; sensitivity 0.595; specificity 0.687). On discriminative analysis, AFP value of 105 ng/m L was shown to affect the overall survival of the patients.CONCLUSION HCC patients with a high preoperative AFP level had inferior survival after LT. AFP level of 54 ng/m L was associated with disease recurrence, and AFP level of 105 ng/m L was found to be the cut-off value for overall survival difference.

Acute pancreatitis induced by transarterial chemoembolization:a single-center experience of over 1500 cases

BACKGROUND： Acute pancreatitis is a relatively rare but po- tentially lethal complication after transarterial chemotherapy. This study aimed to review the complications such as acute pancreatitis after transarterial chemotherapy with or without embolization for hepatocellular carcinoma. METHODS： A total of 1632 patients with hepatocellular car- cinoma who had undergone transarterial chemoembolization from ]anuary 2000 to February 2014 in a single-center were reviewed retrospectively. We investigated the potential com- plications of transarterial chemoembolization, such as acute pancreatitis and acute pancreatitis-related complications. RESULTS： Of the 1632 patients with hepatocellular carcinoma who had undergone 5434 transarterial chemoembolizations, 1328 were male and 304 female. The median age of these pa- tients was 61 years. Most （79.6%） of the patients suffered from HBV-related hepatoceUular carcinoma. The median tumor size was 5.2 cm. Of the 1632 patients, 145 patients underwent transarterial chemoembolization with doxorubicin elut- ing bead, making up a total of 538 episodes. The remaining patients underwent transarterial chemoembolization with cisplatin. Seven （0.4%） patients suffered from acute pancre- atitis post-chemoembolization. Six patients had chemoembo- lization with doxorubicin and one had chemoembolization with cisplatin. Patients who received doxornbicin eluting bead had a higher risk of acute pancreatitis [6/145 （4.1%） vs 1/1487 （0.1%）, P〈0.0001]. Two patients had anatomical arterial variations. Four patients developed acute pancreatitis- related complications including necrotizing pancreatitis （n=3） and pseudocyst formation （n=1）. All of the 4 patients resolved after the use of antibiotics and other conservative treatment. Three patients had further transarterial chemoembolization without any complication. CONCLUSIONS： Acute pancreatitis after transarterial chemo- embolization could result in serious complications, especially after treatment with doxorubicin eluting bead. Continuation of current treatment with transarterial chemoembolization after acute pancreatitis is feasible providing the initial attack is completely resolved.

Impact of small-for-size liver grafts on medium-term and long-term graft survival in living donor liver transplantation: A meta-analysis

BACKGROUND Small-for-size grafts (SFSGs) in living donor liver transplantation (LDLT) could optimize donor postoperative outcomes and also expand the potential donor pool. Evidence on whether SFSGs would affect medium-term and long-term recipient graft survival is lacking. AIM To evaluate the impact of small-for-size liver grafts on medium-term and longterm graft survival in adult to adult LDLT. METHODS A systematic review and meta-analysis were performed by searching eligible studies published before January 24, 2019 on PubMed, EMBASE, and Web of Science databases. The primary outcomes were 3-year and 5-year graft survival. Incidence of small-for-size syndrome and short term mortality were also extracted. RESULTS This meta-analysis is reported according to the guidelines of the PRISMA 2009 Statement. Seven retrospective observational studies with a total of 1821 LDLT recipients were included in the meta-analysis. SFSG is associated with significantly poorer medium-term graft survival. The pooled odds ratio for 3-year graft survival was 1.58 [95% confidence interval 1.10-2.29, P = 0.014]. On the other hand, pooled results of the studies showed that SFSG had no significant discriminatory effect on 5-year graft survival with an odds ratio of 1.31 (95% confidence interval 0.87-1.97, P = 0.199). Furthermore, incidence of small-for-size syndrome detected in recipients of SFSG ranged from 0-11.4% in the included studies. CONCLUSION SFSG is associated with inferior medium-term but not long-term graft survival. Comparable long-term graft survival based on liver graft size shows that smaller grafts could be accepted for LDLT with appropriate flow modulatory measures. Close follow-up for graft function is warranted within 3 years after liver transplantation.

Outcomes of right-lobe and left-lobe living-donor liver transplantations using small-for-size grafts

AIM To analyze the outcomes of living-donor liver transplantation(LDLT) using left-lobe(LL) or right-lobe(RL) small-for-size(SFS) grafts.METHODS Prospectively collected data of adult patients who underwent LDLT at our hospital in the period from January 2003 to December 2013 were reviewed. The patients were divided into the RL-LDLT group and the LL-LDLT group. The two groups were compared in terms of short-and long-term outcomes, including incidence of postoperative complication, graft function, graft survival, and patient survival. A SFS graft was defined as a graft with a ratio of graft weight(GW) to recipient standard liver volume(RSLV)(GW/RSLV) of < 50%. The Urata formula was used to estimate RSLV.RESULTS Totally 218 patients were included for analysis, with 199 patients in the RL-LDLT group and 19 patients in the LL-LDLT group. The two groups were similar in terms of age(median, 53 years in the RL-LDLT group and 52 years in the LL-LDLT group, P = 0.997) but had significantly different ratios of men to women(165:34 in the RL-LDLT group and 8:11 in the LL-LDLT group, P < 0.0001). The two groups were also significantly different in GW(P < 0.0001), GW/RSLV(P < 0.0001), and graft cold ischemic time(P = 0.007). When it comes to postoperative complication, the groups were comparable(P = 0.105). Five patients died in hospital,4(2%) in the RL-LDLT group and 1(5.3%) in the LLLDLT group(P = 0.918). There were 38 graft losses, 33(16.6%) in the RL-LDLT group and 5(26.3%) in the LL-LDLT group(P = 0.452). The 5-year graft survival rate was significantly better in the RL-LDLT group(95.2% vs 89.5%, P = 0.049). The two groups had similar 5-year patient survival rates(RL-LDLT: 86.8%, LL-LDLT: 89.5%, P = 0.476).CONCLUSION The use of SFS graft in LDLT requires careful tailormade surgical planning and meticulous operation. LLLDLT can be a good alternative to RL-LDLT with similar recipient outcomes but a lower donor risk. Further research into different patient conditions is needed in order to validate the use of LL graft.

Outcome analysis of management of liver trauma: A 10-year experience at a trauma center

AIM: To review the outcomes of liver trauma in patients with hepatic injuries only and in patients with associated injuries outside the liver.METHODS: Data of liver trauma patients presented to our center from January 2003 to October 2013 were reviewed. The patients were divided into two groups. Group 1 consisted of patients who had hepatic injuries only. Group 2 consisted of patients who also had associated injuries outside the liver.RESULTS: Seven(30.4%) patients in group 1 and 10(28.6%) patients in group 2 received non-operative management; the rest underwent operation. Blunt trauma occurred in 82.8%(48/58) of the patients and penetrative trauma in 17.2%(10/58). A higher injury severity score(ISS) was observed in group 2(median 45 vs 25, P < 0.0001). More patients in group 1 were hemodynamically stable(65.2% vs 37.1%, P = 0.036). Other parameters were comparable between groups. Group 1 had better 30-d survival(91.3% vs 71.4%, P = 0.045). On multivariate analysis using the logistic regression model, ISS was found to be associated with mortality(P = 0.004, hazard ratio = 1.035, 95%CI:CONCLUSION: Liver trauma patients with multiple injuries are relatively unstable on presentation. Despite a higher ISS in group 2, non-operative management was possible for selected patients. Associated injuries outside the liver usually account for morbidity and mortality.

Validated model for prediction of recurrent hepatocellular carcinoma after liver transplantation in Asian population

BACKGROUND Liver transplantation(LT) is regarded as the best treatment for both primary and recurrent hepatocellular carcinoma(HCC). Post-transplant HCC recurrence rate is relatively low but significant, ranging from 10%-30% according to different series. When recurrence happens, it is usually extrahepatic and associated with poor prognosis. A predictive model that allows patient stratification according to recurrence risk can help to individualize post-transplant surveillance protocol and guidance of the use of anti-tumor immunosuppressive agents.AIM To develop a scoring system to predict HCC recurrence after LT in an Asian population.METHODS Consecutive patients having LT for HCC from 1995 to 2016 at our hospital were recruited. They were randomized into the training set and the validation set in a60:40 ratio. Multivariable Cox regression model was used to identity factors associated with HCC recurrence. A risk score was assigned to each factor according to the odds ratio. Accuracy of the score was assessed by the area under the receiver operating characteristic curve.RESULTS In total, 330 patients were eligible for analysis(183 in training and 147 invalidation). Recurrent HCC developed in 14.2% of them. The median follow-up duration was 65.6 mo. The 5-year disease-free and overall survival rates were78% and 80%, respectively. On multivariate analysis, alpha-fetoprotein > 400 ng/mL [P = 0.012, hazard ratio(HR) 2.92], sum of maximum tumor size and number(P = 0.013, HR 1.15), and salvage LT(P = 0.033, HR 2.08) were found to be independent factors for disease-free survival. A risk score was calculated for each patient with good discriminatory power(c-stat 0.748 and 0.85, respectively,in the training and validation sets). With the derived scores, patients were classified into low-(0–9), moderate-(> 9–14), and high-risk groups(> 14), and the risk of HCC recurrence in the training and validation sets was 10%, 20%, 54%(cstat 0.67) and 4%, 22%, 62%(c-stat 0.811), accordingly. The risk stratification model was validated with chi-squared goodness-of-fit test(P = 0.425).CONCLUSION A validated predictive model featuring alpha-fetoprotein, salvage LT, and the sum of largest tumor diameter and total number of tumor nodule provides simple and reliable guidance for individualizing postoperative surveillance strategy.

Recurrent pyogenic cholangitis:An indication for liver transplantation

To the Editor:Recurrent pyogenic cholangitis(RPC),also known as Hong Kong disease[1],is an unique disease entity with a decreasing incidence.It is characterized by the formation of intrahepatic biliary pigmented stones,which results in stricturing of the biliary tree followed by obstruction and repeated attacks of cholangitis.

The ‘Unsigned highway’:An alternative route for portal vein anastomosis for non-malignant portal vein thrombosis during pediatric re-transplantation

To the Editor:Non-malignant portal vein thrombosis(PVT)remains an important issue in liver transplantation due to the technical challenges in re-establishing the portal flow to the liver graft.The prevalence of complex PVT(i.e.Yerdel grade 4)was reported to be around 2.0%[1].In the early history of liver transplantation,PVT was regarded as a contraindication.

The Hong Kong consensus recommendations on the diagnosis and management of pancreatic cystic lesions

Background:The finding of pancreatic cystic lesions(PCL)on incidental imaging is becoming increasingly common.International studies report a prevalence of 2.2-44.7%depending on the population,imaging modality and indication for imaging,and the prevalence increases with age.Patients with PCL are at risk of developing pancreatic cancer,a disease with a poor prognosis.This publication summarizes recommendations for the diagnosis and management of PCL and post-operative pancreatic exocrine insufficiency(PEI)from a group of local specialists.Methods:Clinical evidence was consolidated from narrative reviews and consensus statements formulated during two online meetings in March 2022.The expert panel included gastroenterologists,hepatobiliary surgeons,oncologists,radiologists,and endocrinologists.Results:Patients with PCL require careful investigation and follow-up due to the risk of malignant transformation of these lesions.They should undergo clinical investigation and pancreas-specific imaging to classify lesions and understand the risk profile of the patient.Where indicated,patients should undergo pancreatectomy to excise PCL.Following pancreatectomy,patients are at risk of PEI,leading to gastrointestinal dysfunction and malnutrition.Therefore,such patients should be monitored for symptoms of PEI,and promptly treated with pancreatic enzyme replacement therapy(PERT).Patients with poor response to PERT may require increases in dose,addition of a proton pump inhibitor,and/or further investigation,including tests for pancreatic function.Patients are also at risk of new-onset diabetes mellitus after pancreatectomy;they should be screened and treated with insulin if indicated.Conclusions:These statements are an accurate summary of our approach to the diagnosis and management of patients with PCL and will be of assistance to clinicians treating these patients in a similar clinical landscape.

A review on radiofrequency,microwave and high-intensity focused ultrasound ablations for hepatocellular carcinoma with cirrhosis

Importance:Hepatocellular carcinoma(HCC)is usually accompanied by liver cirrhosis,which makes treatment of this disease challenging.Liver transplantation theoretically provides an ultimate solution to the disease,but the maximal surgical stress and the scarcity of liver graft make this treatment option impossible for some patients.In an ideal situation,a treatment that is safe and effective should provide a better outcome for patients with the dilemma.Objective:This article aims to give a comprehensive review of various types of loco-ablative treatment for HCC.Evidence Review:Loco-ablative treatment bridges the gap between surgical resection and transarterial chemotherapy.Various types of ablative therapy have their unique ability,and evidence-based outcome analysis is the most important key to assisting clinicians to choose the most suitable treatment modality for their patients.Findings:Radiofrequency ablation(RFA)has a relatively longer history and more evidence to support its effectiveness.Microwave ablation(MWA)is gaining momentum because of its shorter ablation time and consistent ablation zone.High-intensity focused ultrasound(HIFU)ablation is a relatively new technology that provides non-invasive treatment for patients with HCC.It has been carried out at centers of excellence and it is a safe and effective treatment option for selected patients with HCC and liver cirrhosis.Conclusion and Relevance:Selective use of different loco-ablative therapies will enhance clinicians’treatment options for treatment of HCC.

Liver transplantation:would it be the best and last chance of cure for hepatocellular carcinoma with major venous invasion?

Background:Hepatocellular carcinoma(HCC)with portal vein tumour thrombus(PVTT)signifies advanced disease,whether LT confers any survival superiority over resection remains uncertain.Methods:A propensity score matched(PSM)analysis of liver transplantation(LT)and liver resection(LR)for HCC with PVTT was performed.Results:A consecutive series of 88 patients who received either LT(10 DDLTs and 3 LDLTs)or LR(n=75)respectively were recruited.Before PSM,the LT group has a higher MELD score(17.3 vs.7.8,P<0.001),lower serum AFP levels(96 vs.2,164 ng/mL,P=0.017)and smaller tumour size(4 vs.10 cm,P<0.001).The 5-year overall survival for LT and LR were 55.4%and 15.9%respectively(P=0.007).After matching for serum AFP levels and tumour size,1-,3-and 5-year overall survival for LT were 81 ng/mL,3.9 cm,80%,70%and 70%and the corresponding rates for LR were 1,417 ng/mL,5.3 cm,51.8%,19,6%and 9.8%(P value=0.12,0.27 and 0.009 respectively).Conclusions:LT is associated with significantly better oncological outcomes in HCC patients with PVTT involving the lobar or segmental level.A modest expansion of selection criteria to include small HCC with segmental PVTT should be considered.

Role of C11-FDG dual-tracer PET-CT scan in metastatic screening of hepatocellular carcinoma-a cost-effectiveness analysis

Background:We aimed to identify predictive factors for positron emission tomography(PET)-detected hepatocellular carcinoma(HCC)metastasis and a cost-effective approach to preoperative PET-computed tomography(CT)for detecting metastasis.Methods:Clinicopathological and survival data of HCC patients having PET-CT with 18F-fludeoxyglucose(FDG)and 11C-acetate(ACT)following contrast-enhanced CT/magnetic resonance imaging(MRI)for preoperative tumor staging were reviewed.Binary logistic regression was performed to identify predictive factors for PET-detected metastasis.A cost-benefit analysis model was built for the incurred costs and the impact of PET-CT findings on treatment strategy was studied.Results:Totally 152 patients were analyzed.Dual-tracer PET-CT detected metastasis in 17 patients(11%).By multivariate analysis,alpha-fetoprotein(AFP)≥400 ng/mL[relative risk(RR):4.30,95%confidence interval(CI):1.41-13.15,P=0.011]and bilobar disease(RR:3.94,95%CI:1.24-12.52,P=0.014)were independent predictive factors for PET-detected metastasis.PET-CT findings altered the treatment strategy for 12 patients(7.9%);three partial hepatectomies,eight episodes of transarterial chemoembolization(TACE)and one episode of ablation were avoided,with an estimated cost-saving of US$91,000,$150,000 and$10,600 respectively.Had the PET-CT been performed only for patients with AFP≥400 ng/mL or bilobar disease(n=74),metastasis would have been confirmed in 14 patients(18.9%),and the cost-saving per patient was estimated at US$1,070.Conclusions:Dual-tracer PET-CT is cost-effective and useful for preoperative HCC staging in patients with AFP≥400 ng/mL or bilobar disease.Its routine use in preoperative workup for all HCC patients is not recommended.Unilobar disease with AFP<400 ng/mL can achieve good negative predictive value for PET-detected metastasis.Screening patients with either factor can avoid unnecessary procedures and is thus cost-effective for preoperative HCC workup.

Erratum:Defining the role of laparoscopic liver resection in elderly HCC patients:a propensity score matched analysis

This is an Erratum of the publsihed paper:Defining the role of laparoscopic liver resection in elderly HCC patients:a propensity score matched analysis.The ethical approval and consent to participation information were missing in the DECLARATIONS section due to the production issue.The original article has been updated.