Adjuvant heparanase inhibitor PI-88 therapy for hepatocellular carcinoma recurrence

AIM: To demonstrate that administering heparanase inhibitor PI-88 at 160 mg/d is safe and promising in reducing hepatocellular carcinoma(HCC) recurrence for up to 3 year following curative resection. METHODS: A total of 143 patients(83.1% of the 172 participants in the phase Ⅱ study) participated in the follow-up study. Of these patients, 50 had received no treatment, 48 had received 160 mg/d PI-88, and 45 had received 250 mg/d PI-88 during the phase Ⅱ trial. Safety parameters and the following efficacy endpoints were investigated:(1) time to recurrence;(2) diseasefree survival; and(3) overall survival. RESULTS: PI-88 at 160 mg/d delayed the onset and frequency of HCC recurrence, and provided a clinically significant survival advantage for up to 3 years after treatment compared with those of the control group:(1) the recurrence-free rate increased from 50% to 63%, and(2) time to recurrence at the 36 th percentile was postponed by 78%. The efficacy of administering PI-88 at 250 mg/d was confounded by a high dropout rate(11 out of 54 patients). Additionally, subgroup analyses of patients with(1) multiple tumors or a single tumor ≥ 2 cm; and(2) hepatitis B or C revealed that administering PI-88 at 160 mg/d conferred the most significant survival advantage(56.8% improvement in disease-free survival, P = 0.045) for patients with both risk factors for recurrence. CONCLUSION: Administering PI-88 at 160 mg/d is a safe and well-tolerated dosage that may confer significant clinical benefits for patients with HCC.

Prognostic analysis of patients with pancreatic head adenocarcinoma less than 2cm undergoing resection

AIM:To investigate the differences in clinicopathological features between patients with pancreatic cancer greater or less than 2 cm situated over the pancreatic head and the prognostic factors for survival of patients with pancreatic cancer<2 cm over the pancreatic head. METHODS:From 1983 to 2006,159 patients with histologically proven pancreatic adenocarcinoma(PAC) at the pancreatic head undergoing curative resection at the Department of Surgery,Chang Gung Memorial Hospital,Taipei,Taiwan were reviewed,comprising 123 cases of large(L)-PAC(tumor>2 cm)and 36 cases of small(S)-PAC(tumor≤2 cm).We compared the clinicopathological characteristics and prognosis of L-PAC and S-PAC patients.The clinicopathological characteristics of S-PAC were investigated to clarify the prognosis predictive factors of S-PAC. RESULTS:One hundred and fifty-nine PAC patients, aged 16-93 years(median,59.0 years)with a tumor at the pancreatic head undergoing intentional curative resection were investigated.The S-PAC and L-PAC patients had similar demographic data,clinical features,and tumor markers(a similar positive rate of carcinoembryonic antigen and carbohy- drate antigen 19-9).There were also similar rates of lymph node metastasis,portal vein invasion,stage distribution,tumor differentiation,positive resection margin,surgical morbidity and mortality observedbetween the two groups.During a follow-up period ranging from 1.0 to 122.7 mo(median,10.9 mo), S-PAC and L-PAC patients had a similar prognosis after resection(P=0.4805).Among the S-PAC patients group,patients with higher albumin level(>3.5 g/dL) had more favorable survival than those with lower albumin levels,which was the only favorable predictive prognostic factor.Meanwhile,early-staged(stageⅠ,Ⅱ) S-PAC patients tended to have a more favorable outcome than late-stage(stageⅢ,Ⅳ)S-PAC patients, but this was not statistically significant. CONCLUSION:S-PAC patients should not be regarded as early PAC.Only higher albumin level(>3.5 g/dL) and early stage disease(stageⅠ,Ⅱ)were the favorable prognosis factors for S-PAC patients.

Efficacy of surgical resection in management of isolated extrahepatic metastases of hepatocellular carcinoma

AIM:To clarify the benefit of surgical excision for patients with extrahepatic metastases of hepatocellular carcinoma(HCC). METHODS:We retrospectively reviewed the medical records of 140 patients with pathologically proven extrahepatic metastases of HCC and evaluated the outcomes of those who had undergone surgical resection(SR)for extrahepatic metastatic lesions.Prognoses made on the basis of extrahepatic metastatic sites were also examined. RESULTS:The survival rates of patients who underwent SR of extrahepatic metastases were significantly better than those of patients who did not receive SR. For the SR group,1-and 3-year survival rates were 24%and 7%,respectively,while for the non-resection group,the survival rates were 8%and 0%,respec- tively(P<0.0001).Survival rates related to metastatic sites were also significantly superior after SR of extrahepatic metastases:median survivals were 32 mo with lung metastasis,10 mo with bone metastasis,6.1 mo with brain metastasis. CONCLUSION:SR can provide survival benefits forpatients with 1 or 2 isolated extrahepatic metastases and who concurrently exhibit good hepatic functional reserve and general performance status as well as successful treatment of intrahepatic HCC.

Hepatic resection for hepatocellular carcinoma in end-stage renal disease patients: Two decades of experience at Chang Gung Memorial Hospital

AIM: Hepatocellular carcinoma (HCC) is a common disease in Taiwan. The prevalence of viral hepatitis infection and the subsequent development of HCC are well known to be higher in patients with end-stage renal disease (ESRD) requiring hemodialysis (HD) or peritoneal dialysis (PD) than among the general population. However, information on hepatic resection for ESRD-HCC patients is limited. METHODS: The clinical features of 26 ESRD-HCC patients who underwent hepatic resection from 1982 to 2001 were retrospectively reviewed. Meanwhile, the clinicopathological features and the outcome of 1 198 HCC patients without ESRD undergoing hepatic resection were used for comparison. RESULTS: Of 1 224 surgically resected HCC patients, 26 (4.2%) were ESRD-HCC. Univariate analysis revealed more associated disease, more physical signs of anemia and postoperative complications, lower hemoglobin, platelet, α-fetoprotein, elevated blood urea nitrogen (BUN) and creatinine levels, smaller tumors, lower HBsAg positivity, higher HCV positivity, and longer hospital stays in the ESRDHCC group compared with the HCC group. Furthermore, multivariate stepwise logistic regression analysis revealed that elevated BUN and creatinine levels were the only two independently significant factors in the patients in the ESRD-HCC group. Overall and disease-free survival rates were similar between the ESRD-HCC and HCC groups.CONCLUSION: Elevated BUN and creatinine were the only two main independent factors differentiating ESRD-HCC from HCC patients. ESRD should not be a contraindication of hepatic resection in HCC patients; however, careful operative techniques and perioperative care are crucial to achieving lower morbidity and mortality. Comparable overall survival and disease-free survival can be achieved in selected ESRD-HCC patients undergoing hepatic resection when compared with conventional HCC patients.

Liver resection for hepatocellular carcinoma larger than 10 cm: A multi-institution long-term observational study

BACKGROUND The treatment of hepatocellular carcinoma(HCC)≥10 cm remains a challenge.AIM To consolidate the role of surgical resection for HCC larger than 10 cm.METHODS Eligible HCC patients were identified from the Chang Gung Research Database,the largest multi-institution database,which collected medical records of all patients from Chang Gung Memorial Foundation.The surgical outcome of HCC≥10 cm(L-HCC)was compared to that of HCC<10 cm(S-HCC)(model 1).The survival of L-HCC after either liver resection or transarterial chemoembolization(TACE)was also analyzed(model 2).The long-term risks of all-cause mortality and recurrence were assessed to consolidate the role of surgery for L-HCC.RESULTS From January 2004 to July 2015,a total of 32403 HCC patients were identified from the Chang Gung Research Database.Among 3985 patients who received liver resection,3559(89.3%)had S-HCC,and 426 had L-HCC.The L-HCC patients had a worse disease-free survival(0.27 for L-HCC vs 0.40 for S-HCC)and overall survival(0.18 for L-HCC vs 0.45 for S-HCC)than the S-HCC after liver resection(both P<0.001).However,the surgical and long-term outcome of resected L-HCC had improved dramatically in the recent decades.After adjusting for covariates,surgery could provide a better outcome for L-HCC than TACE(adjusted hazard ratio of all-cause mortality:0.46,95%confidence interval:0.38-0.56 for surgery).Subgroup analysis stratified by different stages showed similar trend of survival benefit among L-HCC patients receiving surgery.CONCLUSION Our study demonstrated an improving surgical outcome for HCC larger than 10 cm.Under selected conditions,surgery is better than TACE in terms of disease control and survival and should be performed.Due to inferior survival,a subclassification within T1 stage should be considered.Future studies are mandatory to confirm our findings.

Outcomes associated with the intention of loco-regional therapy prior to living donor liver transplantation for hepatocellular carcinoma

transplantation(LT)appears to be a logical approach to reduce the risk of tumor progression and dropout in the waitlist.Living donor LT(LDLT)offers a flexible timing for transplantation providing timeframe for well preparation of transplantation.AIM To investigate outcomes in relation to the intention of pre-transplantation locoregional therapy in LDLT for HCC patients.METHODS A total of 308 consecutive patients undergoing LDLTs for HCC between August 2004 and December 2018 were retrospectively analyzed.Patients were grouped according to the intention of loco-regional therapy prior to LT,and outcomes of patients were analyzed and compared between groups.RESULTS Overall,38 patients(12.3%)were detected with HCC recurrence during the follow-up period after LDLT.Patients who were radiologically beyond the University of California at San Francisco criteria and received loco-regional therapy as down-staging therapy had significant inferior outcomes to other groups for both recurrence-free survival(RFS,P<0.0005)and overall survival(P=0.046).Moreover,patients with defined profound tumor necrosis(TN)by locoregional therapy had a superior RFS(5-year of 93.8%)as compared with others(P=0.010).CONCLUSION LDLT features a flexible timely transplantation for patient with HCC.However,the loco-regional therapy prior to LDLT does not seem to provide benefit unless a certain effect in terms of profound TN is noted.

Modified preoperative score to predict disease-free survival for hepatocellular carcinoma patients with surgical resections

BACKGROUND No prognostic models specific to hepatocellular carcinoma patients receiving surgical resection have been considered strong and convincing enough for survival prediction thus far,and there are no models including only preoperative predictors.We derived a nomogram to predict disease-free survival in a previous study.AIM To simplify our score and compare research outcomes among other scoring systems.METHODS We retrospectively reviewed data from 1106 patients with hepatocellular carcinoma who underwent liver resection at the Linkou Chang Gung Memorial Hospital between April 2003 and December 2012.Multivariate analyses were conducted to identify the significant survival predictors.Homogeneity,Harrell’s C-index,and Akaike information criterion were compared between our score,AJCC 8^(th)edition,Tokyo score,and Taipei Integrated Scoring System(TTV-CTPAFP model).RESULTS Among the 1106 patients,731(66.1%)had tumor recurrence at a median followup of 83.9 mo.Five risk factors were identified:platelet count,albumin level,indocyanine green retention rate,multiplicity,and radiologic total tumor volume.Patients were divided into three risk groups,and the 5-year survival rates were 61.7%,39%,and 25.7%,respectively.The C-index was 0.617,which was higher than the Tokyo score(0.613)and the Taipei Integrated Scoring System(0.562)and equal to the value of the AJCC 8th edition(0.617).CONCLUSION The modified score provides an easier method to predict survival.Appropriate treatment can be planned preoperatively by dividing patients into risk groups.

Living donor liver transplantation for Barcelona clinic liver cancer (BCLC) intermediate-stage hepatocellular carcinoma

Background:Barcelona clinic liver cancer(BCLC)stage B(intermediate stage)hepatocellular carcinoma(HCC)is highly heterogeneous;thus,identifying the most effective treatment for individual patients represents a significant clinical challenge.However,transarterial chemoembolization(TACE)is the only recommended treatment option.Therefore,we aimed to investigate the patient characteristics and outcomes of living donor liver transplantation(LDLT)for BCLC stage B HCC.Methods:A total of 516 patients with BCLC stage B HCC who underwent LDLT(n=104)or did not undergo LDLT(non-LDLT;n=412)between 2004 to 2018 were analyzed by propensity score matching(PSM;1:4)analysis.Factors influencing overall survival(OS)and recurrence were analyzed using Cox’s proportional hazards models.Results:Patients treated with LDLT achieved better OS than the non-LDLT group,including liver-and non-liver related survival(all P<0.001).Multivariate Cox regression analysis showed age>60 years(P=0.006),a neutrophil-lymphocyte ratio(NLR)>4(P=0.016)and>3 locoregional therapies(LRT)before LDLT(P<0.001)were independent risk factors for HCC recurrence.In addition,age>60 years(P<0.001)and>3 LRT before LDLT(P=0.001)were independent risk factors for OS.Using a combination of age,NLR,and LRT before liver transplantation(LT),the patients can be divided into low-risk(none of risk),intermediate-risk(one of risk),and high risk(more than two of risk)groups.There were significant differences in the cumulative HCC recurrence(P<0.001)and mortality(P<0.001)rates among the three groups.Conclusions:LDLT may represent a valuable therapeutic option for selected patients with BCLC stage B HCC.

Health-related quality of life of living liver donors 1 year after donation

Background:Improving the health-related quality of life(HRQOL)of living liver donors post-donation is an important aspect of care quality.Analyzing the HRQOL of living liver donors prospectively could help improve our understanding of the recovery of HRQOL and help improve the quality of donor care.In this study,we examined the HRQOL of living liver donors at pre-donation and at 1-year post-donation and analyzed the effect of pre-and post-donation factors on the donors'physical and mental HRQOL.Methods:This was a prospective study.During the enrollment period(August 2013 to December 2015),68 living liver donors completed the study questionnaires 5 times:at pre-donation and at 1,3,6,and 12 months post-donation.The Medical Outcomes Study Questionnaire Short Form-36,which yields both physical(PCS)and mental(MCS)component summary scores,was used to measure the HRQOL.The pre-and post-donation factors included donation ambivalence,recipients'physical condition,post-donation complications,and recipients'survival status.Results:Participants'mean PCS scores were 43.59 and 56.50 at 1 and 12 months after donation,respectively,whereas their mean MCS scores were 46.89 and 46.28,respectively.The mean PCS score was worse at 1 month after donation but improved significantly over time(P<0.05);conversely,the MCS was quite stable over time(P>0.05).A good PCS score was associated with no surgical complications of donation(coefficient=2.87,P=0.02),whereas a poor MCS score was associated with an education of less than a bachelor's degree(coefficient=?3.60,P=0.004),a higher Model for End-Stage Liver Disease(MELD)score in the recipient(coefficient=?0.13,P=0.03),and recipient death(coefficient=?3.48,P=0.03).Pre-donation ambivalence and sense of coherence were not significant predictors of the PCS or MCS scores.Conclusions:The impact of living liver donation on HRQOL was strongest in the early stages of the post-surgery period for the physical domain.Health-care professionals should carefully manage and monitor the progress of surgical outcomes,particularly in high-risk groups such as donors with a low education level or donors whose recipients have severe illness or end up dying after the surgery.Doing so may allow for suitable intervention opportunities to improve the HRQOL of living liver donors.

Cell-mediated immunotherapy for hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is the most common primary liver cancer.Most of the time,these tumors are diagnosed at late stages.Because no effective treatments exist for patients with advanced stage HCC,there is an urgent need for novel,effective treatments.Cancer cells originate as a consequence of abnormal expression of oncogenes or loss of tumor suppressor genes.Often,neoplastic transformation results in a hyper-mutated cellular genome,which in turn produces neo-antigens from mutated genes.These tumor-specific or tumor-associated antigens can be recognized by antigen-presenting cells and trigger T-lymphocytes to elicit anticancer immunity.Immune responses to cancers are often rendered ineffective by tumor immune-editing and immune-suppressive mechanisms.Yet,therapeutic strategies to stimulate anti-cancer immunity have had remarkable success in several solid and hematological malignancies.Among the various strategies for cancer immunotherapy,cell-mediated immunotherapy holds considerable promise to overcome anergy and systemic immune suppression.This brief review will focus on cell-mediated immunotherapy for HCC.