Dynamic changes of mitogen‐activated protein kinase signal transduction in rats with severe acute pancreatitis

OBJECTIVE: To investigate the dynamic changes of mitogen‐activated protein kinase (MAPK) signal transduction in rats with severe acute pancreatitis (SAP). METHODS: The SAP model was induced by infusing the bilio‐pancreatic duct of 56 Sprague‐Dawley rats with 5% sterile sodium taurocholate solution. The rats were randomly divided into seven groups: control group, 0.5 h postoperative group, 1 h group, 3 h group, 6 h group, 12 h group and 24 h group. Western blot analysis was used to determine the activities of p38 MAPK and c‐Jun N‐terminal kinase (JNK) in the pancreas and lungs. RESULTS: In the rats of the control group, basal p38MAPK activity could be detected but not that of JNK. After SAP was induced, the p38MAPK activity in the pancreas increased markedly and peaked at 3 h, but in the lung it peaked at 6 h. The p38MAPK activity in the pancreas and lungs was significantly higher than the basal activity at the 24 h time point. The activity of JNK was only increased at the 12 h point and was not detectable at 24 h. CONCLUSION: The MAPK signal transduction pathway, in particular p38MAPK, plays an important role in the pathogenesis of SAP.     

Clinicopathologic analysis of stage II-III hepatocellular carcinoma showing early massive recurrence after liver resection

BACKGROUND AND AIMS: Prognosis after hepatectomy for hepatocellular carcinoma (HCC) has been improved by progress in the evaluation of hepatic functional reserve, surgical techniques and perioperative management. However, even when curative resection is performed at a relatively early stage, a considerable number of patients develop early intrahepatic and/or extrahepatic recurrence postoperatively. This study analyzed the clinicopathologic features of HCC with early recurrence. METHODS: We reviewed records of 513 consecutive patients who had undergone liver resection for HCC. There were 48 deaths within a year after surgery from recurrence, including 21 patients with stage II or III HCC (group I). Clinicopathologic parameters of group I patients were compared with those of 188 patients (group II) who developed recurrence following resection of stage II or III HCC and died more than 1 year after surgery. RESULTS: On univariate analysis, age, tumor diameter (phi), alpha-fetoprotein (AFP):phi and protein induced by vitamin K absence or antagonist II (PIVKA-II):phi were significantly greater in group I than in group II. Macroscopic portal vein invasion, microscopic vascular invasion, intrahepatic metastasis, poor differentiation, pleomorphism, sarcomatous change, vascular lake, and angiographic condensed pooling were more frequently observed in group I than group II. Five independent determinants were selected by multivariate analysis: AFP:phi, histologic pleomorphism, sarcomatous change, vascular lake and angiographic condensed pooling. CONCLUSIONS: Highly malignant HCC with extremely poor prognosis exhibits peculiar clinicopathologic characteristics, particularly histologic immaturity, and can be predicted by preoperative indicators such as markedly elevated tumor marker concentrations and condensed pooling on angiography.     

Re-evaluation of lipiodolized transarterial chemoembolization therapy for intrahepatic recurrence of hepatocellular carcinoma after curative liver resection

Background/Purpose

While lipiodolized transarterial chemoembolization (lip-TACE) is effective for treating unresectable hepatocellular carcinoma (HCC), its effect for treating recurrent HCC after curative liver resection needs to be clarified.

Methods

Of 163 patients who had undergone curative liver resection between 1992 and December 2003, 65 patients (39.8%) had recurrent HCC in the liver without extrahepatic recurrence and were indicated for lip-TACE. The overall survival rate after lip-TACE was calculated, and its correlation with factors such as the histology of the primary HCC and background noncancerous tissue were analyzed.

Results

The overall survival rates after lip-TACE after the detection of the first recurrent HCC were 82.6%, 44.5%, and 24.8% at 1, 3, and 5 years, respectively. The factors affecting patient survival after lip-TACE were microscopic portal venous involvement of HCC at liver resection, grade of inflammation in the noncancerous liver parenchyma, and recurrence within 1 year after the initial liver resection. Multivariate analysis showed that the period between the resection and first recurrence had the highest hazard ratio.

Conclusions

Lip-TACE is a reasonable procedure for treating recurrent HCC in selected patients who are not eligible for hepatic re-resection. When HCC recurred within 1 year from the primary liver resection, the effect of lip-TACE on patient survival was limited.

     

Risk factors for early recurrence of small hepatocellular carcinoma after curative resection

BACKGROUND:Poorer prognosis is seen in patients with hepatocellular carcinoma (HCC) after curative hepatic resection with early recurrence (≤1 year) than in those with late recurrence (>1 year).This study aimed to identify risk factors for postoperative early recurrence of small HCC (≤3 cm in diameter).METHODS:The study population consisted of 158 patients who underwent curative resection for small HCC between January 2002 and July 2004.Risk factors for early recurrence were analyzed.RESULTS:Thirty-three (2...     

术前Fib-4指数对肝癌肝切除术后复发的预测价值

目的评价肝癌患者术前Fib-4指数对肝癌肝切除术后复发的预测价值。方法回顾性分析67例行肝部分切除肝癌患者的临床资料,根据患者术前Fib-4指数的大小分为低指数组（Fib-4指数〈3．25）和高指数组（Fib-4指数≥3．25）,术后应用门诊、电话方式随访,以Cox回归模型对术后复发情况进行相关因素分析。结果单因素分析提示,术前AFP≥400μg／L、肿瘤最大直径〉5cm、肿瘤数目〉3个、Fib-4指数I〉3．25、血管侵犯及切缘阳性、门静脉癌栓是影响肝癌肝切除术后无瘤生存的危险因素（P均〈0．05）,Cox回归分析显示术前Fib-4指数≥3．25、肿瘤数目〉3个及门静脉癌栓是肝癌术后复发的独立危险因素（P均〈0．05）。结论术前Fib-4指数≥3．25是影响肝癌患者术后复发的独立危险因素。     

ERS: A simple scoring system to predict early recurrence after surgical resection for hepatocellular carcinoma

Background

Surgical resection (SR) is a potentially curative treatment of hepatocellular carcinoma (HCC) hampered by high rates of recurrence. New drugs are tested in the adjuvant setting, but standardised risk stratification tools of HCC recurrence are lacking.

Objectives

To develop and validate a simple scoring system to predict 2-year recurrence after SR for HCC.

Methods

2359 treatment-naïve patients who underwent SR for HCC in 17 centres in Europe and Asia between 2004 and 2017 were divided into a development (DS; n = 1558) and validation set (VS; n = 801) by random sampling of participating centres. The Early Recurrence Score (ERS) was generated using variables associated with 2-year recurrence in the DS and validated in the VS.

Results

Variables associated with 2-year recurrence in the DS were (with associated points) alpha-fetoprotein (<10 ng/mL:0; 10–100: 2; >100: 3), size of largest nodule (≥40 mm: 1), multifocality (yes: 2), satellite nodules (yes: 2), vascular invasion (yes: 1) and surgical margin (positive R1: 2). The sum of points provided a score ranging from 0 to 11, allowing stratification into four levels of 2-year recurrence risk (Wolbers' C-indices 66.8% DS and 68.4% VS), with excellent calibration according to risk categories. Wolber's and Harrell's C-indices apparent values were systematically higher for ERS when compared to Early Recurrence After Surgery for Liver tumour post-operative model to predict time to early recurrence or recurrence-free survival.

Conclusions

ERS is a user-friendly staging system identifying four levels of early recurrence risk after SR and a robust tool to design personalised surveillance strategies and adjuvant therapy trials.     

Predictive factors of advanced recurrence after curative resection of small hepatocellular carcinoma

Background: The tumour recurrence rate after resection is still high even in patients with small hepatocellular carcinoma (HCC). The advanced patterns of recurrence occasionally occur after resection. In this study, we analysed the clinical and histological characteristics of small HCC and evaluated the predictive factors of advanced tumour recurrence. Methods: One hundred and sixty‐five patients underwent resection of small HCC measuring 3 cm or less in greatest dimension. Patterns of tumour recurrences were classified into advanced recurrence and minor recurrence based on size, number, vascular invasion and extrahepatic metastasis of recurrent tumour. We created a simple index to closely evaluate the malignant potential of small HCC, named α‐foetoprotein–size ratio index (ASRI). Results: Overall tumour recurrence was significantly associated with tumour multiplicity (P<0.001) and ASRI (P=0.001). Tumour multiplicity, ASRI and tumour differentiation were independent and significant predictive factors of advanced recurrences. The overall survival rates were lower in the advanced recurrence group than the minor recurrence or the no recurrence group. Conclusions: Patients with advanced recurrences have a poor prognosis, although they have undergone curative resection of small HCC. On the other hand, patients with minor recurrences have a relatively good prognosis. ASRI was a useful index to predict advanced recurrence after curative resection of small HCC. The therapeutic management to prevent advanced recurrences is needed.     

Persistent hepatitis B viral replication affects recurrence of hepatocellular carcinoma after curative resection

Background: Elevated serum hepatitis B virus (HBV) DNA increases the development of hepatocellular carcinoma (HCC). Rather than instantaneous DNA level, the duration of persistent HBV replication is more important in carcinogenesis. Nevertheless, most investigators evaluated the DNA level at study entry. We assessed the effects of persistently detectable serum HBV DNA on HCC recurrence. Patients and methods: We included 230 consecutive patients undergoing curative resection between 2000 and 2006. Patients who had antiviral therapy (at diagnosis or during follow‐up), fluctuating DNA (cut‐off value: 100 000 copies/ml) or recurrence within 12 months of resection were excluded. Ultimately, 157 were enrolled: 89 (non‐viraemia group) had consistently negative DNA (<100 000 copies/ml), while 68 (viraemia group) had consistently positive DNA (>100 000copies/ml). Serum DNA level, biochemical tests, α‐foetoprotein (AFP) and liver dynamic computed tomography were obtained every 3 months after surgery. Results: There were no significant differences in age, gender, liver function, histology, AFP, tumour stages or follow‐up duration between the two groups. During follow‐up (median: 35 months), patients in the non‐viraemia group had a lower 5‐year cumulative recurrence rate (54.7%) than those in the viraemia group (72.9%; P=0.043). In multivariate analysis, sustained viraemia (P=0.041) increased recurrence independently. Conclusions: Persistent viraemia increased recurrence independently after surgery. To prevent long‐term recurrences, antiviral therapy should be initiated in those with detectable serum HBV DNA.     

Prognostic factors after recurrence of resected hepatocellular carcinoma associated with hepatitis C virus

To clarify the variables related to survival after recurrence of resected hepatocellular carcinoma (HCC) associated with hepatitis C virus (HCV), we studied 17 clinicopathological factors in 99 patients with recurrence of HCC associated with HCV infection after hepatic resection. The 1-, 3-, and 5-year survival rates after first resection in these patients were 91%, 81%, and 49%, while after recurrence they were 81%, 51%, and 29%, respectively. Multivariate analysis showed that the following six variables were independent prognostic factors after recurrence: platelet count, albumin level, bilirubin level, number of hepatic lesions, distant metastasis, and any treatment at recurrence. A correlation between second hepatic resection (SHR) and liver function tests was seen in regard to albumin and total bilirubin values at recurrence. Indeed, hepatic function and progression of intrahepatic tumors at recurrence were significant prognostic factors after recurrence of HCC associated with HCV infection, while any treatment at recurrence was also a significant prognostic factor. Therefore, in order to improve prognosis after recurrence, we should actively treat the recurrent hepatic lesions whenever possible.     

Increased recurrence rates of hepatocellular carcinoma after DAA therapy in a hepatitis C‐infected Egyptian cohort: A comparative analysis

In Egypt, hepatocellular carcinoma (HCC) is the most common form of cancer and direct‐acting antivirals (DAA) are administered on a large scale to patients with chronic HCV infection to reduce the risk. In this unique setting, we aimed to determine the association of DAA exposure with early‐phase HCC recurrence in patients with a history of HCV‐related liver cancer. This was a prospective cohort study of an HCV‐infected population from one Egyptian specialized HCC management centre starting from the time of successful HCC intervention. The incidence rates of HCC recurrence between DAA‐exposed and nonexposed patients were compared, starting from date of HCC complete radiological response and censoring after 2 years. DAA exposure was treated as time varying. Two Poisson regressions models were used to control for potential differences in the exposed and nonexposed group; multivariable adjustment and balancing using inverse probability of treatment weighting (IPTW). We included 116 patients: 53 treated with DAAs and 63 not treated with DAAs. There was 37.7% and 25.4% recurrence in each group after a median of 16.0 and 23.0 months of follow‐up, respectively. Poisson regression using IPTW demonstrated an association between DAAs and HCC recurrence with an incidence rate ratio of 3.83 (95% CI: 2.02‐7.25), which was similar in the multivariable‐adjusted model and various sensitivity analyses. These results add important evidence towards the possible role of DAAs in HCC recurrence and stress the need for further mechanistic studies and clinical trials to accurately confirm this role and to identify patient characteristics that may be associated with this event.     

Pathologic response to preoperative transarte-rial chemoembolization for resectable hepato-cellular carcinoma may not predict recurrence after liver resection

BACKGROUND: Pathologic response(PR) predicts survival after preoperative chemotherapy and resection of a malignancy. Occasionally, transarterial chemoembolization(TACE)may be selected for preoperative management of resectable hepatocellular carcinoma(HCC). This study investigated whether PR to preoperative TACE can predict recurrence after resection for resectable HCC.METHODS: We conducted analysis of 106 HCC patients who underwent TACE followed by liver resection with a curative intent. The PR was evaluated as the mean percentage of nonviable tumor area within each tumor. We divided the patients into three groups according to response rate: complete PR(CPR), major response(MJR: PR≥50%) and minor response(MNR: PR50%). The primary endpoint was disease-free survival, and the secondary endpoints were predicting factors for tumor recurrence and MJR+CPR.RESULTS: Among the 121 TACE patients, PR could be measured in 106(87.6%). The mean interval between TACE and liver resection was 33.1 days. The 5-year disease-free survival rates by PR status were as follows: 40.6% CPR, 43.7% MJR, and 49.0% MNR(P=0.815). There were also no significant differences in overall survival between the three groups. Multivariate analyses revealed that microvascular invasion and capsular invasion(hazard ratio [HR]=11.224, P=0.002 and HR=2.220P=0.043) were independent predictors of disease-free survival.Multivariate analysis of the predictors of above 50% PR revealed that only hepatitis B was an independent factor.CONCLUSION: These data could reflect that the PR after TACE for resectable HCC may not be useful for predicting recurrence of HCC after resection.     

Perioperative change in white blood cell count predicts outcome of hepatic resection for hepatocellular carcinoma

Background

In spite of improvements in surgical management, hepatocellular carcinoma (HCC) still recurs after operation in 60–70% of patients. Therefore, we investigated the relation between perioperative change in white blood cell count (WBC) and tumor recurrence as well as survival in patients with HCC after hepatic resection.

Methods

Subjects were 53 patients who underwent elective hepatic resection for HCC. We retrospectively examined the relation between perioperative change in WBC and recurrence of HCC as well as overall survival.

Results

Advanced tumor stage and increasing of WBC on postoperative day (POD) 1 were positively associated with worse disease-free survival rate on both univariate and multivariate analysis (P < 0.05). Advanced tumor stage, increasing of WBC on POD 1, and blood transfusion were positively associated with worse overall survival rate on univariate analysis (P < 0.05), while change in WBC was the only independent factor on multivariate analysis (P < 0.05).

Conclusions

Perioperative change in WBC after elective hepatic resection for HCC is positively associated with recurrence and worse survival.     

Time‐dependent analysis of predisposing factors for the recurrence of hepatocellular carcinoma

Background/aim: There are many reports dealing with the risk factors for hepatocellular carcinoma (HCC) recurrence. However, in most of these reported studies, factors were analysed only at the initial treatment stage, and the predisposing factors for the recurrence during follow‐up have not been well studied. The aim of this study is to evaluate the predisposing factors after treatments. Methods: Two hundred and seventy‐one consecutive HCC patients curatively treated between January 1994 and March 2004 were followed up and analysed. The recurrence rate was estimated by the Kaplan– Meier method and the predisposing factors were evaluated by time‐fixed Cox regression analysis and by time‐dependent covariate analysis using multiple parameters. Results: The mean follow‐up period was 4.86 years and recurrence was observed in 169 patients (62.4%). The recurrence rates were 27.9, 65.1 and 84.3% at 1, 3 and 5 years respectively. Among the variables determined before treatment, predisposing factors for recurrence were low serum albumin [≤3.5 g/dl, hazard ratio (HR)=1.47, 95% confidence interval (CI)=1.07–2.01] and multiple tumour number (HR=2.04, 95% CI=1.46–2.84) by time‐fixed multivariate analysis. In the time‐dependent analysis, six variables with 12 013 plots were examined. The multivariate analysis revealed that high des‐ γ‐carboxy prothrombin (DCP≥40 mAU/ml, HR=2.33, 95% CI=1.61–3.39), high α‐fetoprotein (AFP≥100 ng/ml, HR=2.01, 95% CI=1.3–3.35) and high alanine aminotransferase (ALT≥40 IU/L, HR= 1.52, 95% CI=1.1–2.1) were significant predisposing factors for recurrence. Conclusion: Predisposing factors for the recurrence of HCC after treatment are different from those before treatments and special cautions are required when AFP, DCP or ALT is high during follow‐up.     

Portal venous invasion: the single most independent risk factor for immediate postoperative recurrence of hepatocellular carcinoma

Background and Aim: Despite improvements of treatment in hepatocellular carcinoma (HCC), the recurrence rate after curative hepatic resection still remains remarkably high. An immediate recurrence of HCC after surgery is frustrating. We tried to clarify risks of immediate postoperative recurrence of HCC; that is, within 4 months after curative hepatic resection. Methods: A total of 167 patients with HCC underwent hepatic resection; 60 had immediate postoperative recurrences (IPR group), and 107 had disease‐free survival for more than 5 years (DFS group). Variables were compared between the two groups. Results: Univariate analysis showed the following variables were significant risk factors for immediate postoperative recurrence of HCC: male sex, elevated serum aspartate aminotransferase level, greater amount of blood loss, longer operation time, worse tumor differentiation, higher tumor node metastasis stage, and presence of any of the following: intrahepatic metastasis, tumor‐rupture, portal venous invasion, or microvascular invasion. In multivariate analysis, only portal venous invasion was a significant risk factor (odds ratio = 3.2, P = 0.03, standard error = 0.5, Logistic regression analysis). Conclusions: Portal venous invasion may be the most significant risk factor for immediate postoperative recurrence of HCC. However, accurate assessment of this risk factor may require histological examination, limiting its utility as a preoperative predictor. Further research is necessary to definitively identify preoperative predictors.