Significance of functional hepatic resection rate calculated using 3D CT/^(99m)Tc-galactosyl human serum albumin singlephoton emission computed tomography fusion imaging

AIM: To evaluate the usefulness of the functional hepatic resection rate(FHRR) calculated using 3D computed tomography(CT)/^(99m)Tc-galactosyl-human serum albumin(GSA) single-photon emission computed tomography(SPECT) fusion imaging for surgical decision making. METHODS: We enrolled 57 patients who underwent bi- or trisectionectomy at our institution between October 2013 and March 2015. Of these, 26 patients presented with hepatocellular carcinoma, 12 with hilar cholangiocarcinoma, six with intrahepatic cholangiocarcinoma, four with liver metastasis, and nine with other diseases. All patients preoperatively underwent three-phase dynamic multidetector CT and ^(99m)Tc-GSA scintigraphy. We compared the parenchymal hepatic resection rate(PHRR) with the FHRR, which was defined as the resection volume counts per total liver volume counts on 3D CT/^(99m)Tc-GSA SPECT fusion images.RESULTS: In total, 50 patients underwent bisectionectomy and seven underwent trisectionectomy.Biliary reconstruction was performed in 15 patients, including hepatopancreatoduodenectomy in two. FHRR and PHRR were 38.6 ± 19.9 and 44.5 ± 16.0, respectively; FHRR was strongly correlated with PHRR. The regression coefficient for FHRR on PHRR was 1.16(P < 0.0001). The ratio of FHRR to PHRR for patients with preoperative therapies(transcatheter arterial chemoembolization, radiation, radiofrequency ablation, etc.), large tumors with a volume of > 1000 m L, and/or macroscopic vascular invasion was significantly smaller than that for patients without these factors(0.73 ± 0.19 vs 0.82 ± 0.18, P < 0.05). Postoperative hyperbilirubinemia was observed in six patients. Major morbidities(Clavien-Dindo grade ≥ 3) occurred in 17 patients(29.8%). There was no case of surgeryrelated death.CONCLUSION: Our results suggest that FHRR is an important deciding factor for major hepatectomy, because FHRR and PHRR may be discrepant owing to insufficient hepatic inflow and congestion in patients with preoperative therapies, macroscopic vascular invasion, and/or a tumor volume of > 1000 m L.

Hepatectomy for hepatocellular carcinoma with portal vein tumor thrombus

Despite surgical removal of tumors with portal vein tumor thrombus(PVTT) in hepatocellular carcinoma(HCC) patients, early recurrence tends to occur, and overall survival(OS) periods remain extremely short. The role that hepatectomy may play in long-term survival for HCC with PVTT has not been established. The operative mortality of hepatectomy for HCC with PVTT has also not been reviewed. Hence, we reviewed recent literature to assess these parameters. The OS of patients who received hepatectomy in conjunction with multidisciplinary treatment tended to be superior to that of patients who did not. Multidisciplinary treatments included the following: preoperative radiotherapy on PVTT; preoperative transarterial chemoembolization(TACE); subcutaneous administration of interferon-alpha(IFN-α) and intra-arterial infusion of 5-fluorouracil(5-FU) with infusion chemotherapy in the affected hepatic artery; cisplatin, doxorubicin and 5-FU locally administered in the portal vein; and subcutaneous injection of IFN-α, adjuvant chemotherapy(5-FU + Adriamycin) administration via the portal vein with postoperative TACE, percutaneous isolated hepatic perfusion and hepatic artery infusion and/or portal vein chemotherapy. The highest reported rate of operative mortality was 9.3%. In conclusion, hepatectomy for patients affected by HCC with PVTT is safe, has low mortality and might prolong survival in conjunction with multidisciplinary treatment.

Endoscopic naso-pancreatic drainage for the treatment of pancreatic fistula occurring after LDLT

Pancreatic fistula is a quite rare complication in patients who undergo living donor liver transplantation(LDLT).However,in the cases that show pancreatic fistula,the limited volume of the graft and the resultant inadequate liver function may complicate the management of the fistula.As a result,the pancreatic fistula may result in the death of the patient.We present 2 cases in whichendoscopic treatment was effective against pancreatic fistulas that developed after LDLT.In case 1,a 61-yearold woman underwent LDLT for primary biliary cirrhosis.Because of a portal venous thrombus caused by a splenorenal shunt,the patient underwent portal vein reconstruction,and a splenorenal shunt was ligated on postoperative day(POD)7.The main pancreatic duct was injured during the manipulation to achieve hemostasis,thereby necessitating open drainage.However,discharge of pancreatic fluid continued even after POD 300.Endoscopic naso-pancreatic drainage(ENPD)was performed,and this procedure resulted in a remarkable decrease in drain output.The refractory pancreatic fistula healed on day 40 after ENPD.In case 2,a 58-year-old man underwent LDLT for cirrhosis caused by the hepatitis C virus.When the portal vein was exposed during thrombectomy,the pancreatic head was injured,which led to the formation of a pancreatic fistula.Conservative therapy was ineffective;therefore,ENPD was performed.The pancreatic fistula healed on day 38 after ENPD.The findings in these 2 cases show that endoscopic drainage of the main pancreatic duct is a less invasive and effective treatment for pancreatic fistulas that develop after LDLT.

Clinical impacts of mesothelin expression in gastrointestinal carcinomas

Mesothelin,C-ERC/mesothelin is a 40-kD a cell surface glycoprotein that is normally present on normal mesothelial cells lining the pleura,peritoneum,and pericardium.Moreover,mesothelin has been shown to be overexpressed in several human cancers,including virtually all mesothelioma and pancreatic cancer approximately 70% of ovarian cancer and extra bile duc cancer,and 50% of lung adenocarcinomas and gastric cancer.The full-length human mesothelin gene encodes the primary product,a 71-k Da precursor protein.The71-kD a mesothelin precursor is cleaved into two products40-k Da C-terminal fragment that remains membranebound via glycosylphosphatidylinositol anchor,and a31-kD a N-terminal fragment,megakaryocyte potentiating factor,which is secreted into the blood.The biologica functions of mesothelin remain largely unknown However,results of recent studies have suggested tha the mesothelin may play a role of cell proliferation and migration.In pancreatic cancer,mesothelin expression was immunohistochemically observed in all cases,bu absent in normal pancreas and in chronic pancreatitis Furthermore,the expression of mesothelin was correlated with an poorer patient outcome in severa human cancers.The limited mesothelin expression in normal tissues and high expression in many cancers makes it an attractive candidate for cancer therapy.The present review discusses the expression and function o mesothelin in cancer cells and the utility of mesothelin as a target of cancer therapy.

α-fetoprotein,vascular endothelial growth factor receptor-1 and early recurrence of hepatoma

AIM:To investigate whether α-fetoprotein (AFP) and vascular endothelial growth factor receptor (VEGFR)-1 correlate with early recurrence of hepatoma/hepatocel-lular carcinoma (HCC).METHODS:From 2000 to 2005,114 consecutive pa-tients with HCC underwent primary curative hepatecto-my.The mean age was 60.7 (8.7) years and 94 patients were male.The median follow-up period was 71.2 mo (range:43-100 mo).Immediately prior to commencing laparotomy,5 mL bone marrow was aspirated from thesternum and collected in citrate-coated test tubes.The initial 2 mL of bone marrow aspirate was discarded in each case.AFP mRNA and VEGFR-1 mRNA in the bone marrow and peripheral blood (BM-and PH-AFP mRNA and BM-and PH-VEGFR-1 mRNA,respectively) were measured by real-time quantitative reverse transcription polymerase chain reaction.As normal controls,VEGFR-1 mRNA in the bone marrow and peripheral blood was also measured in 11 living liver donors.These data were evaluated for any correlation with early recurrence,comparing clinical and pathological outcomes.RESULTS:The cut-off value of the BM-AFP mRNA and PH-AFP mRNA level in patients with HCC was set at 1.92 × 10-7 and zero,respectively,based on data from the controls.A total of 34 (29.8%) and six (5.4%) patients were positive for BM-AFP mRNA and PH-AFP mRNA,respectively.The BM-VEGFR-1 mRNA levels in all HCC patients were higher than those in the normal con-trols,and this was the case also for PH-VEGFR-1mRNA.The 25-percentile values for the BM-and PH-VEGFR-1 mRNA in HCC patients were used as the cut-off values for assigning the patients into two groups based on these transcript levels.The High group for BM-VEG-FR-1 mRNA contained 81 (71.1%) HCC cases and the Low group was assigned 33 (28.9%) patients.These numbers for PH-VEGFR-1mRNA were 78 (75.0%) and 26 (25.0%),respectively.HCC recurred in 80 patients;in the remnant liver in 48 cases,in the remnant liver and remote tissue in 20,and in the remote tissue alone in 12.BM-AFP mRNA-positive cases showed a signifi-cantly higher rate of early recurrence (within 1 year of surgical treatment) compared with BM-AFP mRNA-negative patients (P=0.0091).Patients were classified into four groups according to the level/status of their BM-VEGFR-1 and BM-AFP mRNA as follows:group A (n=23),BM-VEGFR-1/BM-AFP mRNA=low/negative;group B (n=57) high/negative;group C (n=10) low/positive;group D (n=24),high/positive.This classifi-cation was found to correlate with a recurrence of thisdisease within 1 year (P=0.0228).The disease-free survival curve of group A was significantly better than that of groups B,C or D (P=0.0437,P=0.0325,P=0.0225).No other classification (i.e.,PH-VEGF-R1/BM-AFP,BM-VEGF-R1/PH-AFP,and PH-VEGF-R1/PH-AFP mRNA) showed such a correlation.CONCLUSION:The evaluation of BM-AFP and BM-VEG-FR-1 mRNA in patients with HCC may be a valuable pre-dictor of disease recurrence following curative resection.

Portal vein stenosis after pancreatectomy following neoadjuvant chemoradiation therapy for pancreatic cancer

Extrahepatic portal vein (PV) stenosis has various causes, such as tumor encasement, pancreatitis and as a postsurgical complication. With regard to post-pancreaticoduodenectomy, intraoperative radiation therapy with/ without PV resection is reported to be associated with PV stenosis. However, there has been no report of PV stenosis after pancreatectomy following neoadjuvant chemoradiation therapy (NACRT). Here we report the cases of three patients with PV stenosis after pancreatectomy and PV resection following gemcitabine-based NACRT for pancreatic cancer and their successful treatment with stent placement. We have performed NACRT in 18 patients with borderline resectable pancreatic cancer since 2005. Of the 15 patients who completed NACRT, nine had undergone pancreatectomy. Combined portal resection was performed in eight of the nine patients. We report here three patients with PV stenosis, and thus the ratio of post-operative PV stenosis in patients with PV resection following NACRT is 37.5% in this series. We encountered no case of PV stenosis among 22 patients operated with PV resection for pancreatobiliary cancer without NACRT during the same period. A relationship between PV stenosis and NACRT is suspected, but further investigation is required to determine whether NACRT has relevance to PV stenosis.

Functional transition:Inconsistently parallel to the increase in future liver remnant volume after preoperative portal vein embolization

BACKGROUND Preoperative portal vein embolization(PVE)is a widely used strategy to enable major hepatectomy in patients with insufficient liver remnant.PVE induces hypertrophy of the future liver remnant(FLR)and a shift of the functional reserve to the FLR.However,whether the increase of the FLR volume(FLRV)corresponds to the functional transition after PVE remains unclear.AIM To investigate the sequential relationship between the increase in FLRV and functional transition after preoperative PVE using 3-dimensional(3D)computed tomography(CT)and 99mTc-galactosyl-human serum albumin(99mTc-GSA)singlephoton emission computed tomography(SPECT)fusion images.METHODS Thirty-three patients who underwent major hepatectomy following PVE at the Department of Gastroenterological Surgery I,Hokkaido University Hospital between October 2013 and March 2018 were enrolled.Three-phase dynamic multidetector CT and 99mTc-GSA SPECT scintigraphy were performed at pre-PVE,and at 1 and 2 wk after PVE;3D 99mTc-GSA SPECT CT-fused images were constructed from the Digital Imaging and Communications in Medicine data using 3D image analysis system.Functional FLRV(FFLRV)was defined as the total liver volume×(FLR volume counts/total liver volume counts)on the 3D 99m Tc-GSA SPECT CT-fused images.The calculated FFLRV was compared with FLRV.RESULTS FFLRV increased by a significantly larger extent than FLRV at 1 and 2 wk after PVE(P<0.01).The increase in FFLRV and FLRV was 55.1%±41.6%and 26.7%±17.8%(P<0.001),respectively,at 1 wk after PVE,and 64.2%±33.3%and 36.8%±18.9%(P<0.001),respectively,at 2 wk after PVE.In 3 of the 33 patients,FFLRV levels decreased below FLRV at 2 wk.One of the three patients showed rapidly progressive fatty changes in FLR.The biopsy at 4 wk after PVE showed macroand micro-vesicular steatosis of more than 40%,which improved to 10%.Radical resection was performed at 13 wk after PVE.The patient recovered uneventfully without any symptoms of pos-toperative liver failure.CONCLUSION The functional transition lagged behind the increase in FLRV after PVE in some cases.Evaluating both volume and function is needed to determine the optimal timing of hepatectomy after PVE.

Outcomes of reduction hepatectomy combined with postoperative multidisciplinary therapy for advanced hepatocellular carcinoma

BACKGROUND The prognosis of advanced hepatocellular carcinoma(HCC)that is not indicated for curative hepatectomy remains poor,despite advances in the treatment of HCC,including the development of tyrosine kinase inhibitors(TKIs).The outcomes of reduction hepatectomy and multidisciplinary postoperative treatment for advanced HCC that is not indicated for curative hepatectomy,including those of recently treated cases,should be investigated.AIM To examine the outcomes of combination treatment with reduction hepatectomy and multidisciplinary postoperative treatment for advanced HCC that is not indicated for curative hepatectomy.METHODS Thirty cases of advanced HCC that were not indicated for curative hepatectomy,in which reduction hepatectomy was performed between 2000 and 2018 at the Department of Gastroenterological Surgery I,Hokkaido University Graduate School of Medicine,were divided into postoperative complete remission(POCR)(+)and POCR(-)groups,depending on whether POCR of all evaluable lesions was achieved through postoperative treatment.The cases in the POCR(-)group were subdivided into POCR(-)TKI(+)and POCR(-)TKI(-)groups,depending on whether TKIs were administered postoperatively.RESULTS The 5-year overall survival rate and mean survival time(MST)after reduction hepatectomy were 15.7%and 28.40 mo,respectively,for all cases;37.5%and 56.55 mo,respectively,in the POCR(+)group;and 6.3%and 14.84 mo,respectively,in the POCR(-)group(P=0.0041).Tumor size,major vascular invasion,and the number of tumors in the remnant liver after the reduction hepatectomy were also found to be related to survival outcomes.The number of tumors in the remnant liver was the only factor that differed significantly between the POCR(+)and POCR(-)groups,and POCR was achieved significantly more frequently when≤3 tumors remained in the remnant liver(P=0.0025).The MST was 33.52 mo in the POCR(-)TKI(+)group,which was superior to the MST of 10.74 mo seen in the POCR(-)TKI(-)group(P=0.0473).CONCLUSION Reduction hepatectomy combined with multidisciplinary postoperative treatment for unresectable advanced HCC that was not indicated for curative hepatectomy was effective when POCR was achieved via multidisciplinary postoperative therapy.To achieve POCR,reduction hepatectomy should aim to ensure that≤3 tumors remain in the remnant liver.Even in cases in which POCR is not achieved,combined treatment with reduction hepatectomy and multidisciplinary therapy can improve survival outcomes when TKIs are administered.

Impact of comorbid renal dysfunction in patients with hepatocellular carcinoma on long-term outcomes after curative resection

BACKGROUND Hepatocellular carcinoma(HCC)is one of the most common malignancies worldwide.However,the number of patients with chronic kidney disease(CKD)is on the rise because of the increase in lifestyle-related diseases.AIM To establish a tailored management strategy for HCC patients,we evaluated the impact of comorbid renal dysfunction(RD),as stratified by using the estimated glomerular filtration rate(EGFR),and assessed the oncologic validity of hepatectomy for HCC patients with RD.METHODS We enrolled 800 HCC patients who underwent hepatectomy between 1997 and 2015 at our university hospital.We categorized patients into two(RD,EGFR<60 mL/min/1.73 m^(2);non-RD,EGFR≥60 mL/min/1.73 m^(2))and three groups(severe CKD,EGFR<30 mL/min/1.73 m^(2);mild CKD,30≤EGFR<60 mL/min/1.73 m2;control,EGFR≥60 mL/min/1.73 m^(2))according to renal function as defined by the EGFR.Overall survival(OS)and recurrence-free survival(RFS)were compared among these groups with the log-rank test,and we also analyzed survival by using a propensity score matching(PSM)model to exclude the influence of patient characteristics.The mean postoperative observation period was 64.7±53.0 mo.RESULTS The RD patients were significantly older and had lower serum total bilirubin,aspartate aminotransferase,and aspartate aminotransferase levels than the non-RD patients(P<0.0001,P<0.001,P<0.05,and P<0.01,respectively).No patient received maintenance hemodialysis after surgery.Although the overall postoperative complication rates were similar between the RD and non-RD patients,the proportions of postoperative bleeding and surgical site infection were significantly higher in the RD patients(5.5%vs 1.8%;P<0.05,3.9%vs 1.8%;P<0.05,respectively),and postoperative bleeding was the highest in the severe CKD group(P<0.05).Regardless of the degree of comorbid RD,OS and RFS were comparable,even after PSM between the RD and non-RD groups to exclude the influence of patient characteristics,liver function,and other causes of death.CONCLUSION Comorbid mild RD had a negligible impact on the prognosis of HCC patients who underwent curative hepatectomy with appropriate perioperative management,and close attention to severe CKD is necessary to prevent postoperative bleeding and surgical site infection.

High HbA1c is a risk factor for complications after hepatectomy and influences for hepatocellular carcinoma without HBV and HCV infection

Background:Currently,the population with type 2 diabetes mellitus(DM)is increasing worldwide.However,the influence of DM or hyperglycemia on the outcome of resected hepatocellular carcinoma(HCC)is unclear.Methods:We analyzed 756 patients with HCC who underwent hepatectomy.These patients were assigned to an HbA1c≥7.0%(H-A1c;n=100)or HbA1c<7.0%(L-A1c;n=656)group depending on their HbA1c level at admission.We investigated prognoses,clinicopathological characteristics and surgical outcomes including morbidities of HCC patients with high HbA1c,prognoses according to the treatment for DM were also investigated.Results:Among all patients and those with hepatitis B virus(HBV)and hepatitis C virus(HCV)infection,overall survival(OS)and relapse-free survival(RFS)did not differ significantly between the H-A1c and L-A1c groups.In contrast,the 5-year OS rate of the H-A1c group was 55%and that of the L-A1c group 71%among patients without HBV and HCV(NBNC patients)(P=0.03).Among NBNC patients,the median RFS of the H-A1c group was 13 months,and that of the L-A1c group was 26 months(P=0.02).In addition,metformin use was an independent favorable factor for both OS and RFS.The H-A1c group had significantly higher rates of hyperbilirubinemia,wound infection,and pneumonia.Conclusions:HCC patients with high HbA1c might have poor prognoses for both survival and recurrence in NBNC-HCC.High HbA1c may also be a risk factor for morbidities after hepatectomy.Metformin use may constitute a good option for NBNC patients with HCC.