Trends and outcomes of pancreaticoduodenectomy for periampullary tumors: A 25-year single-center study of 1000 consecutive cases

AIM To evaluate the evolution, trends in surgical approaches a n d r e c o n s t r u c t i o n t e c h n i q u e s, a n d i m p o r t a n t lessons learned from performing 1000 consecutive pancreaticoduodenectomies(PDs) for periampullary tumors.METHODS This is a retrospective review of the data of all patients who underwent PD for periampullary tumor during the period from January 1993 to April 2017. The data were categorized into three periods, including early period(1993-2002), middle period(2003-2012), and late period(2013-2017).RESULTS The frequency showed PD was increasingly performed after the year 2000. With time, elderly, cirrhotic and obese patients, as well as patients with uncinate process carcinoma and borderline tumor were increasingly selected for PD. The median operative time and postoperative hospital stay decreased significantly over the periods. Hospital mortality declined significantly, from 6.6% to 3.1%. Postoperative complications significantly decreased, from 40% to 27.9%. There was significant decrease in postoperative pancreatic fistula in the second 10 years, from 15% to 12.7%. There was a significant improvement in median survival and overall survival among the periods.CONCLUSION Surgical results of PD significantly improved, with mortality rate nearly reaching 3%. Pancreatic reconstruction following PD is still debatable. The survival rate was also improved but the rate of recurrence is still high, at 36.9%.

Clinicopathological features and surgical outcome of patients with fibrolamellar hepatocellular carcinoma(experience with 22 patients over a 15-year period)

AIM To evaluate the clinicopathological features and the surgical outcomes of patients with fibrolamellar hepato-cellular carcinoma(FL-HCC)over a 15-year period. METHODS This is a retrospective study including 22 patients with a pathologic diagnosis of FL-HCC who underwent hepatectomy over a 15-year period. Tumor characteristics,survival and recurrence were evaluated. RESULTS There were 11 male and 11 female with a median age of 29 years(range from 21 to 58 years). Two(9%)patients had hepatitis C viral infection and only 2(9%)patients had alpha-fetoprotein level > 200 ng/m L. The median size of the tumors was 12 cm(range from 5-20 cm). Vascular invasion was detected in 5(23%)patients. Four(18%)patients had lymph node metastases. The median follow up period was 42 mo and the 5-year survival was 65%. Five(23%)patients had a recurrent disease,4 of them had a second surgery with 36 mo median time interval. Vascular invasion is the only significant negative prognostic factor CONCLUSION FL-HCC has a favorable prognosis than common HCC and should be suspected in young patients with non cirrhotic liver. Aggressive surgical resection should be done for all patients. Repeated hepatectomy should be considered for these patients as it has a relatively indolent course.

Impact of cirrhosis on surgical outcome after pancreaticoduodenectomy

AIM:To elucidate surgical outcomes of pancreaticoduodenectomy(PD)in patients with liver cirrhosis.METHODS:We studied retrospectively all patients who underwent PD in our centre between January 2002and December 2011.Group A comprised patients with cirrhotic livers,and Group B comprised patients with non-cirrhotic livers.The cirrhotic patients had ChildPugh classes A and B(patient’s score less than 8).Preoperative demographic data,intra-operative data and postoperative details were collected.The primary outcome measure was hospital mortality rate.Secondary outcomes analysed included duration of the operation,postoperative hospital stay,postoperative morbidity and survival rate.RESULTS:Only 67/442 patients(15.2%)had cirrhotic livers.Intraoperative blood loss and blood transfusion were significantly higher in group A(P=0.0001).The mean surgical time in group A was significantly longer than that in group B(P=0.0001).Wound complications(P=0.02),internal haemorrhage(P=0.05),pancreatic fistula(P=0.02)and hospital mortality(P=0.0001)were significantly higher in the cirrhotic patients.Postoperative stay was significantly longer in group A(P=0.03).The median survival was 19 mo in group A and 24 mo in group B.Portal hypertension(PHT)was present in 16/67 cases of cirrhosis(23.9%).The intraoperative blood loss and blood transfusion were significantly higher in patients with PHT(P=0.001).Postoperative morbidity(0.07)and hospital mortality(P=0.007)were higher in cirrhotic patients with PHT.CONCLUSION:Patients with periampullary tumours and well-compensated chronic liver disease should be routinely considered for PD at high volume centres with available expertise to manage liver cirrhosis.PD is associated with an increased risk of postoperative morbidity in patients with liver cirrhosis;therefore,it is only recommended in patients with Child A cirrhosis without portal hypertension.

Tailored pancreatic reconstruction after pancreaticoduodenectomy: a single-center experience of 892 cases

BACKGROUND: Pancreatic reconstruction following pancreaticoduodenectomy(PD) is still debatable even for pancreatic surgeons. Ideally, pancreatic reconstruction after PD should reduce the risk of postoperative pancreatic fistula(POPF) and its severity if developed with preservation of both exocrine and endocrine pancreatic functions. It must be tailored to control the morbidity linked to the type of reconstruction.This study was to show the best type of pancreatic reconstruction according to the characters of pancreatic stump. METHODS: We studied all patients who underwent PD in our center from January 1993 to December 2015. Patients were categorized into three groups depending on the presence of risk factors of postoperative complications: low-risk group(absent risk factor), moderate-risk group(presence of one risk factor) and high-risk group(presence of two or more risk factors). RESULTS: A total of 892 patients underwent PD for resection of periampullary tumor. BMI >25 kg/m~2, cirrhotic liver, soft pancreas, pancreatic duct diameter <3 mm, and pancreatic duct location from posterior edge <3 mm are risk variables for development of postoperative complications. POPF developed in 128(14.3%) patients. Delayed gastric emptying occurred in 164(18.4%) patients, biliary leakage developed in 65(7.3%) and pancreatitis presented in 20(2.2%). POPF in low-, moderate-and high-risk groups were 26(8.3%), 65(15.7%) and 37(22.7%) patients, respectively. Postoperative morbidity and mortality were significantly lower with pancreaticogastrostomy(PG) in high-risk group, while pancreaticojejunostomy(PJ) decreases incidence of postoperative steatorrhea in all groups. CONCLUSIONS: Selection of proper pancreatic reconstruction according to the risk factors of patients may reduce POPF and postoperative complications and mortality. PG is superior to PJ as regards short-term outcomes in high-risk group but PJ provides better pancreatic function in all groups and therefore, PJ is superior in low-and moderate-risk groups.

How does epidemiological and clinicopathological features affect survival after gastrectomy for gastric cancer patientssingle Egyptian center experience

AIM:To investigate the clinicopathological features and the significance of different prognostic factors which predict surgical overall survival in patients with gastric carcinoma.METHODS:This retrospective study includes 80 patients diagnosed and treated at gastroenterology surgical center,Mansoura University,Egypt between February 2009 to February 2013.Prognostic factors were assessed by cox proportional hazard model.RESULTS:There were 57 male and 23 female.The median age was 57 years(24-83).One,3 and 5 years survival rates were 71%,69% and 46% respectively.The median survival was 69.96 mo.During the follow-up period,13 patients died(16%).Hospital morbidity was reported in 10 patients(12.5%).The median number of lymph nodes removed was 22(4-41).Lymph node(LN) involvement was found in 91% of cases.After R0 resection,depth of wall invasion,LN involvement and the number(> 15) of retrieved LN,LN ratio and tumor differentiation predict survival.In multivariable analysis,tumor differentiation,curability of resection and a number of resected LN superior to 15 were found to beindependent prognostic factors.CONCLUSION:Surgery remains the cornerstone of treatment.Tumor differentiation,curability of resection and a number of resected LN superior to 15 were found to be independent prognostic factors.Extended LN dissection does not increase the morbidity or mortality rate but markedly improves long term survival.

Place of upper endoscopy before and after bariatric surgery: A multicenter experience with 3219 patients

AIM: To study the preoperative and postoperative role of upper esophagogastroduodenoscopy(EGD) in morbidly obese patients. METHODS: This is a multicenter retrospective study by reviewing the database of patients who underwent bariatric surgery(laparoscopic sleeve gastrectomy, laparoscopic Roux en Y gastric bypass, or laparoscopic minigastric bypass) in the period between 2001 June and 2015 August(Jahra Hospital-Kuwait, Hafr Elbatin Hospital and King Saud Medical City-KSA, and Mansoura University Hospital- Egypt). Patients with age 18-65 years, body mass index(BMI) > 40, or > 35 with comorbidities after failure of many dietetic regimen and acceptable levels of surgical risk were included in the study after having an informed signed consent. We retrospectively reviewed the medical charts of all morbidly obese patients. The patients' preoperative data included clinical history including upper digestive symptoms and preoperative full workup including EGD. Only patients whose charts revealed weather they were symptomatic or not were studied. We categorized patients accordingly into two groups; with(group A) or without(group B) upper digestive symptoms. The endoscopic findings were categorized into 4 groups based on predetermined criteria. The medical record of patients who developed stricture, leak or bleeding after bariatric surgery was reviewed. Logestic regression analysis was used to identify preoperative predictors that might be associated with abnormal endoscopic findings. RESULTS: Three thousand, two hundred and nineteen patients in the study period underwent bariatric surgery(75% LSG, 10% LRYDB, and 15% MGB). Mean BMI was 43 ± 13, mean age 37 ± 9 years, 79% were female. Twenty eight percent had presented with upper digestive symptoms(group A). EGD was considered normal in 2414(75%) patients(9% group A vs 66% group B, P = 0.001). The abnormal endoscopic findings were found high in those patients with upper digestive symptoms. Abnormal findings(one or more) were found in 805(25%) patients(19% group A vs 6% group B, P = 0.001). Seven patients had critical events during conscious sedation due to severe hypoxemia(< 60%). Rate of stricture in our study was 2.6%. Success rate of endoscopic dilation was 100%. One point nine percent patients with gastric leak were identified with 75% success rate of endoscopic therapy. Three point seven percent patients developed acute upper bleeding. Seventy-eight point two percent patients were treated by conservative therapy and EGD was performed in 21.8% with 100% success and 0% complications.CONCLUSION: Our results support the performance of EGD only in patients with upper gastrointestinal symptoms. Endoscopy also offers safe effective tool for anastomotic complications after bariatric surgery.

Single-session minimally invasive management of common bile duct stones

Up to 18% of patients submitted to cholecystectomy had concomitant common bile duct stones.To avoid serious complications,these stones should be removed.There is no consensus about the ideal management strategy for such patients.Traditionally,open surgery was offered but with the advent of endoscopic retrograde cholangiopancreatography(ERCP) and laparoscopic cholecystectomy(LC) minimally invasive approach had nearly replaced laparotomy because of its well-known advantages.Minimally invasive approach could be done in either twosession(preoperative ERCP followed by LC or LC followed by postoperative ERCP) or single-session(laparoscopic common bile duct exploration or LC with intraoperative ERCP).Most recent studies have found that both options are equivalent regarding safety and efficacy but the singlesession approach is associated with shorter hospital stay,fewer procedures per patient,and less cost.Consequently,single-session option should be offered to patients with cholecysto-choledocholithiaisis provided that local resources and expertise do exist.However,the management strategy should be tailored according to many variables,such as available resources,experience,patient characteristics,clinical presentations,and surgical pathology.

Predictors of long term survival after hepatic resection for hilar cholangiocarcinoma:A retrospective study of 5-year survivors

AIM:To determine predictors of long term survival after resection of hilar cholangiocarcinoma(HC) by comparing patients surviving > 5 years with those who survived < 5 years.METHODS:This is a retrospective study of patients with pathologically proven HC who underwent surgical resection at the Gastroenterology Surgical Center,Mansoura University,Egypt between January 2002 and April 2013.All data of the patients were collected from the medical records.patients were divided into two groups according to their survival:patients surviving less than 5 years and those who survived > 5 years.RESULTS:There were 34(14%) long term survivors(5 year survivors) among the 243 patients.Fiveyear survivors were younger at diagnosis than those surviving less than 5 years(mean age,50.47 ± 4.45 vs 54.59 ± 4.98,p = 0.001).Gender,clinical presentation,preoperative drainage,preoperative serum bilirubin,albumin and serum glutamic-pyruvic transaminase were similar between the two groups.The level of CA 19-9 was significantly higher in patients surviving < 5 years(395.71 ± 31.43 vs 254.06 ± 42.19,p = 0.0001).Univariate analysis demonstrated nine variables to be significantly associated with survival > 5 year,includingyoung age(p = 0.001),serum CA19-9(p = 0.0001),non-cirrhotic liver(p = 0.02),major hepatic resection(p = 0.001),caudate lobe resection(p = 0.006),well differentiated tumour(p = 0.03),lymph node status(0.008),R0 resection margin(p = 0.0001) and early postoperative liver cell failure(p = 0.02).CONCLUSION:Liver status,resection of caudate lobe,lymph node status,R0 resection and CA19-9 were demonstrated to be independent risk factors for long term survival.

Predictors of long-term survival after pancreaticoduodenectomy for peri-ampullary adenocarcinoma: A retrospective study of 5-year survivors

Background: Pancreaticoduodenectomy(PD) is the standard curative treatment for periampullary tumors. The aim of this study is to report the incidence and predictors of long-term survival( ≥ 5 years) after PD. Methods: This study included patients who underwent PD for pathologically proven periampullary adenocarcinomas. Patients were divided into 2 groups: group(I) patients who survived less than 5 years and group(II) patients who survived ≥ 5 years. Results: There were 47(20.6%) long-term survivors( ≥ 5 years) among 228 patients underwent PD for periampullary adenocarcinoma. Patients with ampullary adenocarcinoma represented 31(66.0%) of the long-term survivors. Primary analysis showed that favourable factors for long-term survival include age < 60 years old, serum CEA < 5 ng/mL, serum CA 19-9 < 37 U/mL, non-cirrhotic liver, tumor size < 2 cm, site of primary tumor, postoperative pancreatic fistula, R0 resection, postoperative chemotherapy, and no recurrence. Multivariate analysis demonstrated that CA 19-9 < 37 U/mL [OR(95% CI) = 1.712(1.24 8–2.34 8), P = 0.001], smaller tumor size [OR(95% CI) = 1.335(1.032–1.726), P = 0.028] and R0 resection [OR(95% CI) = 3.098(2.095–4.582), P < 0.001] were independent factors for survival ≥ 5 years. The prognosis was best for ampullary adenocarcinoma, for which the median survival was 54 months and 5-year survival rate was 39.0%, and the poorest was pancreatic head adenocarcinoma, for which the median survival was 27 months and 5-year survival rate was 7%. Conclusions: The majority of long-term survivors after PD for periampullary adenocarcinoma are patients with ampullary tumor. CA 19-9 < 37 U/mL, smaller tumor size, and R0 resection were found to be independent factors for long-term survival ≥ 5 years.

Biliary leakage following pancreaticoduodenectomy:Prevalence,risk factors and management

Background: Few studies investigated biliary leakage after pancreaticoduodenectomy(PD) especially when compared to postoperative pancreatic fistula(POPF). This study was to determine the incidence of biliary leakage after PD, predisposing factors of biliary leakage, and its management. Methods: We retrospectively studied all patients who underwent PD from January 2008 to December 2017 at Gastrointestinal Surgery Center, Mansoura University, Egypt. According to occurrence of postoperative biliary leakage, patients were divided into two groups. Group(1) included patients who developed biliary leakage and group(2) included patients without identified biliary leakage. The preoperative data, operative details, and postoperative morbidity and mortality were analyzed. Results: The study included 555 patients. Forty-four patients(7.9%) developed biliary leakage. Ten patients(1.8%) had concomitant POPF. Multivariate analysis identified obesity and time needed for hepaticojejunostomy reconstruction as independent risk factors of biliary leakage, and no history of preoperative endoscopic retrograde cholangiopancreatiography(ERCP) as protective factor. Biliary leakage from hepaticojejunostomy after PD leads to a significant increase in development of delayed gastric emptying, and wound infection. The median hospital stay and time to resume oral intake were significantly greater in the biliary leakage group. Non-surgical management was needed in 40 patients(90.9%). Only 4 patients(9.1%) required re-exploration due to biliary peritonitis and associated POPF. The mortality rate in the biliary leakage group was significantly higher than that of the non-biliary leakage group(6.8% vs 3.9%, P = 0.05). Conclusions: Obesity and time needed for hepaticojejunostomy reconstruction are independent risk factors of biliary leakage, and no history of preoperative ERCP is protective factor. Biliary leakage increases the risk of morbidity and mortality especially if concomitant with POPF. However, biliary leakage can be conservatively managed in majority of cases.

Intraoperative endoscopic retrograde cholangiopancreatography: A useful tool in the hands of the hepatobiliary surgeon

AIM: To evaluate the efficacy of intraoperative endoscopic retrograde cholangio-pancreatography(ERCP) combined with laparoscopic cholecystectomy(LC) forpatients with gall bladder stones(GS) and common bile duct stones(CBDS).METHODS: Patients treated for GS with CBDS were included. LC and intraoperative transcystic cholangiogram(TCC) were performed in most of the cases. Intraoperative ERCP was done for cases with proven CBDS.RESULTS: Eighty patients who had GS with CBDS were included. LC was successful in all cases. Intraoperative TCC revealed passed CBD stones in 4 cases so intraoperative ERCP was performed only in 76 patients. Intraoperative ERCP showed dilated CBD with stones in 64 cases(84.2%) where removal of stones were successful; passed stones in 6 cases(7.9%); short lower end stricture with small stones present in two cases(2.6%) which were treated by removal of stones with stent insertion; long stricture lower 1/3 CBD in one case(1.3%) which was treated by open hepaticojejunostomy; and one case(1.3%) was proved to be ampullary carcinoma and whipple's operation was scheduled. CONCLUSION: The hepatobiliary surgeon should be trained on ERCP as the third hand to expand his field of therapeutic options.

Efficacy of octreotide in the prevention of complications after pancreaticoduodenectomy in patients with soft pancreas and non-dilated pancreatic duct: A prospective randomized trial

Background: The efficacy of octreotide to prevent postoperative pancreatic fistula(POPF) of pancreaticoduodenectomy(PD) is still controversial. This study aimed to evaluate the effect of postoperative use of octreotide on the outcomes after PD.Methods: This is a prospective randomized controlled trial for postoperative use of octreotide in patients undergoing PD. Patients with soft pancreas and pancreatic duct < 3 mm were randomized to 2 groups.Group I did not receive postoperative octreotide. Group II received postoperative octreotide. The primary end of the study is to compare the rate of POPF.Results: A total of 104 patients were included in the study and were divided into two randomized groups.There were no significant difference in overall complications and its severity. POPF occurred in 11 patients(21.2%) in group I and 10(19.2%) in group II, without statistical significance(P = 0.807). Also, there was no significant differences between both groups regarding the incidence of biliary leakage(P = 0.083), delayed gastric emptying(P = 0.472), and early postoperative mortality(P = 0.727).Conclusions: Octreotide did not reduce postoperative morbidities, reoperation and mortality rate. Also, it did not affect the incidence of POPF and its clinically relevant variants.

Post-endoscopic retrograde cholangiopancreatography pancreatitis: Risk factors and predictors of severity

AIMTo detect risk factors for post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) and investigate the predictors of its severity. METHODSThis is a prospective cohort study of all patients who underwent ERCP. Pre-ERCP data, intraoperative data, and post-ERCP data were collected. RESULTSThe study population consisted of 996 patients. Their mean age at presentation was 58.42 (&plusmn; 14.72) years, and there were 454 male and 442 female patients. Overall, PEP occurred in 102 (10.2%) patients of the study population; eighty (78.4%) cases were of mild to moderate degree, while severe pancreatitis occurred in 22 (21.6%) patients. No hospital mortality was reported for any of PEP patients during the study duration. Age less than 35 years (P = 0.001, OR = 0.035), narrower common bile duct (CBD) diameter (P = 0.0001) and increased number of pancreatic cannulations (P = 0.0001) were independent risk factors for the occurrence of PEP. CONCLUSIONPEP is the most frequent and devastating complication after ERCP. Age less than 35 years, narrower median CBD diameter and increased number of pancreatic cannulations are independent risk factors for the occurrence of PEP. Patients with these risk factors are candidates for prophylactic and preventive measures against PEP.

Outcomes of pancreaticoduodenectomy in elderly patients

BACKGROUND： Although the mortality and morbidity of pancreaticoduodenectomy（PD） have improved significantly over the past years, the concerns for elderly patients undergoing PD are still present. Furthermore, the frequency of PD is increasing because of the increasing proportion of elderly patients and the increasing incidence of periampullary tumors. This study aimed to analyze the outcomes of PD in elderly patients.METHODS： We studied all patients who had undergone PD in our center between January 1995 and February 2015. The patients were divided into three groups based on age： group I（patients aged 〈60 years）, group II（those aged 60 to 69 years） and group III（those aged ≥70 years）. The primary outcome was the rate of total postoperative complications. Secondary endpoint included total operative time, hospital mortality, length of postoperative hospital stay, delayed gastric emptying, re-exploration, and survival rate.RESULTS： A total of 828 patients who had undergone PD for resection of periampullary tumor were included in this study. There were 579（69.9%） patients in group I, 201（24.3%） in group II, and 48（5.8%） in group III. The overall incidence of complications was higher in elderly patients（25.9% in group I, 36.8% in group II, and 37.5% in group III; P=0.006）. There were more patients complicated with delayed gastric emptying in group II compared with the other two groups. There was no significant difference in the incidence of postoperative pancreatic fistula, biliary leakage, pancreatitis, pulmonary complications and hospital mortality.CONCLUSIONS： PD can be performed safely in selected elderly patients. Advanced age alone should not be a contraindication for PD. The outcome of elderly patients who have undergone PD is similar to that of younger patients, and the increased rate of complications is due to the presence of associated comorbidities.

Associations between CD133,CK19 and G2/M in cirrhotic HCV(genotype-4)patients with or without accompanying tumor

Hepatitis C virus(HCV)-cirrhotic patients have the highest threat of developing hepatocellular carcinoma(HCC)and may be at risk of extra hepatic cancer.The present study was designed to investigate CD133 and CK19 in HCV(genotype-4)-cirrhotic patients with/without HCC or extra hepatic cancer,to assess the degree of their correlation with cell cycle abnormalities and finally to assess the role of their combination as diagnostic tool for discrimination of cirrhotic patients with HCC from those with extra hepatic cancer.The study included 77 HCV-cirrhotic patients and 20 healthy non-disease control group.Patients were categorized histo-pathologically into:24 have only liver cirrhosis,26 with HCC,and 27 patients with extra hepatic cancer.Cell cycle abnormalities,CD133 and CK19 were determined by flow cytometry technique.CD133 and CK19 showed marked elevation in HCC and extra hepatic cancer compared with liver cirrhosis and control subjects(p<0.0001).Positive associations were noted between CK19,CD133 and G2/M.They were gradually increased with progression from liver cirrhosis to HCC.Combination of the three showed the best AUC(0.978)and accuracy(92.5%)for discrimination of HCC from extra hepatic cancer.Combined CD133 with G2/M and CK19 comprises an excellent diagnostic panel for discrimination of HCV-cirrhotic patients with HCC from those with extra hepatic cancer.

The Author Reply

We thank the authors for their commentary on our paper. Pancreaticoduodenectomy can be performed safely in selected elderly patients. Advanced age alone should not be a contraindication to do pancreaticoduodenectomy. Careful patient selection is the cornerstone to improve the outcome of pancreaticoduodenectomy in elderly.

Synergistic impacts of rifampicin and doxorubicin against thioacetamide-induced hepatocellular carcinoma in rats

Background and aims:Combination therapy is a promising new strategy that has been proposed to increase the efficacy of cancer treatment.We aimed to investigate the anti-cancer activity of rifampicin monotherapy and its combination with doxorubicin against hepatocellular carcinoma(HCC).Materials and methods:The in vitro half maximal inhibitory concentration(IC50)and selectivity index(SI)of the drugs under investigation against HepG2 and human lung fibroblast(WI38)cell lines were determined.For the in vivo experiment,male Sprague-Dawley albino rats were injected with thioacetamide at 200 mg/kg twice a week for 90 days;HCC development was confirmed histopathologically.Following HCC induction,the rats were treated with intraperitoneal doxorubicin,rifampicin,or their combination for 45 or 90 days.After sacrifice,the livers were examined histopathologically.The levels of aminotransferases,albumin,bilirubin,malondialdehyde,superoxide dismutase(SOD),catalase(CAT),total antioxidant capacity(TAC),and nitric oxide were measured by spectrophotometry.Alphafetoprotein,cancer antigen 19-9,tumor necrosis factor-alpha,interleukin-6,Bcl-2-associated X protein,caspase 3,caspase 8,and p53 were estimated using ELISA.Results:In vitro,the combination of doxorubicin and rifampicin showed the highest SI of 3.43.In vivo,among the measured markers,the levels of TAC,CAT,SOD,and p53 decreased(P<0.001)and the rest of the measured marker levels increased(P<0.001)in the HCC-bearing rats;after treatment in all groups,all these changes improved toward normal in a time-dependent manner.The combination of doxorubicin and rifampicin optimized the effects of the two individual drugs and exerted the best antioxidant effects.Conclusions:In general,compared with rifampicin or doxorubicin alone,combination therapy has favorable outcomes.Based on our results,the combination of rifampicin and doxorubicin might be applicable for HCC chemotherapy.