Strategy for improving the prognosis of patients with intrahepatic cholangiocarcinoma by surgical treatment†:†Considerations based on experience and a literature review.

The prognosis of patients with intrahepatic cholangiocarcinoma (ICC) is still poor, and the 5-year survival rate in patients undergoing radical surgery (R0) is less than one-third. Since the prognosis depends mainly on tumor factors, so early diagnosis is necessary. To extend the survival time of these patients with a poor prognosis, cases of long-term survival were examined based on the results of our experiences and the literature. It was found that the hepatitis virus was highly involved in the carcinogenesis of ICC, and patients who were infected with hepatitis virus had rather good survival. J. Med. Invest. 68 : 15-21, February, 2021.

Growth inhibition of experimental liver metastasis by portal embolization.

BACKGROUND/AIMS: The current available treatments for multiple liver cancer are not satisfactory. The aim of this study is to investigate the effects of portal embolization (PE) on the growth of experimental liver metastasis in rats. METHODOLOGY: One million of tumor cells (AH130 hepatoma cell originated from rat) were injected intraportally into Donryu rats to produce liver metastasis. The rats were divided into five groups as follows: Group A, laparotomy (as control); Group B, embolization of the left branch of portal vein; Group C, ligation of the left branch of the portal branch (PVL); Group D, ligation of the left branch of the hepatic artery (HAL); Group E, left hepatic resection (HR). Body weight, liver weight, weight ratio of the right lobes to the total liver, tumor occupation rates, liver tissue blood flow, liver dye-staining test, and immunohistochemical stainings were studied in each group. The survival duration of each group was also studied. RESULTS: Significantly hypertrophy of the right lobes and atrophy of the left lobes was observed in Group B and C, Body weight increased significantly in Group B and C compared with Group A, D, and E. The tumor occupation rates in the right lobes were significantly smaller in Group B and C than those in Group A, D, and E. Liver tissue blood flow of the left lobes changed from 31.9 +/- 6.5 ml/mn/100 g to 9.0 +/- 3.2 on clamping the main portal vein and to 18.2 +/- 4.2 on clamping the left portal branch, suggesting a compensatory increase of hepatic artery flow in the left lobes in Group B and C. PE resulted in marked hepatic hypertrophy and significant reduction of tumor growth in the non-embolized lobes. CONCLUSIONS: PE resulted in marked hepatic hypertrophy and significant reduction of tumor growth in the non-embolized lobes, probably owing to decrease in arterial flow in the non-embolized lobes. The attractive concept of PE may have utility in clinical setting in the event of multiple liver cancer.

Mechanism of liver regeneration after liver resection and portal vein embolization (ligation) is different?

Whether or not liver regeneration after portal branch embolization (PE) (ligation, PVL) in the non-embolized (ligated) lobe is by the same mechanism as regeneration in the remnant lobe after liver resection has been reviewed. Portal vein branch embolization and heat shock protein are then discussed. Tumor growth accelerated in the remnant liver after hepatectomy. In contrast, PE or PVL resulted in marked contralateral hepatic hypertrophy and significant reduction of tumor growth in the non-embolized (non-ligated) lobes. Follistatin administration significantly increased liver regeneration after hepatectomy in rats. In contrast, regeneration of non-ligated lobes after PVL was not accelerated by exogenous follistatin. Tumor growth also was not accelerated. The liver regeneration rate peaked at 48-72 h in the nonligated lobe after PVL, a delay of 24 h compared with the remnant liver after hepatectomy. In the postoperative early stage, the expression of activin betaA, betaC, and betaE mRNAs was stronger in PVL than in hepatectomy. At 72 h the expression of activin receptor type IIA mRNA reached a peak in hepatectomy, but was significantly lower in PVL. Thus, regulation of activin signaling through receptors is one of the factors determining liver regeneration after hepatectomy and PVL. These serial experimental results imply that the mechanism of liver regeneration after portal branch ligation (embolization) is different from that after hepatectomy. Heat shock protein was induced in the liver experimentally by intermittent ischemic preconditioning and could play some beneficial role in the recovery of liver function after hepatectomy, even in cirrhotic patients. When heat shock protein following right portal vein embolization in both the embolized and non-embolized hepatic lobes was investigated in clinical cases, a two to fourfold increase in HSP70 was induced in the non-embolized lobe compared with the embolized lobe. Oral administration of geranylgeranylacetone (a non-toxic HSP inducer) suppressed inflammatory responses and improved survival after 95% hepatectomy by induction of HSP70 in rats.

The protective effect of selenoprotein P on injury in rat liver transplantation.

BACKGROUND/AIMS: Selenoprotein P (SeP), a plasma protein, is considered to have a protective effect against various organ damages. We investigated whether addition of SeP to storage solution could attenuate cold ischemia/reperfusion injury (IRI) in rat liver transplantation. METHODOLOGY: After 24 hrs cold preservation in either University of Wisconsin (UW) solution with or without SeP (1 micromol/L or 10 micromol/L), the liver was flushed with warm lactated Ringer's solution. Alanine aminotransferase (ALT) level in the venous effluent was measured. Orthotopic liver transplantation (OLTx) was then performed after the same preservation as above. Blood biochemical features and tissue lipid peroxide levels were measured after OLTx, and morphometric changes analyzed by hematoxylin and eosin, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) staining. RESULTS: ALT levels in effluent in the SeP 10 group were significantly lower than those in other groups. Serum aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) were significantly decreased in the SeP 10 group. Histological examinations showed amelioration of sinusoidal damage in the SeP 10 group at 1 hr after OLTx. Percentages of necrotic areas and apoptotic sinusoidal endothelial cells were decreased in the SeP 10 group. CONCLUSIONS: The addition of SeP to UW solution attenuates injury in OLTx.

Effect of a new adjuvant systemic interferon alpha, 5-fluorouracil and cisplatin on advanced hepatocellular carcinoma with macroscopic portal invasion.

BACKGROUND/AIMS: Despite an adequate hepatic resection, theprognosis of the patients with hepatocellular carcinoma (HCC) that have macroscopic tumor thrombus in the portal vein has still been poor. The prognosis of those patients and was investigated the significance of postoperative adjuvant therapy was discussed in this study. METHODOLOGY: Twenty five patients who had Vp2 or more portal invasion were included in this study. Those patients were retrospectively divided into 2 groups: the systemic interferon alpha, 5-Fluorouracil (FU) and cisplatin group (n = 10, IFN+ chemo group); and the no adjuvant therapy group (n = 15, control group). RESULTS: The overall survival rate was significantly higher in the IFN+chemo group compared with the control group. There was no significant difference between the 2 groups in regard to the disease-free survival rate. However, a difference in the recurrence pattern was observed between the 2 groups. In the IFN+chemo group, 3 of 6 patients with a recurrence had a single tumor in the remnant liver. While in the control group, 10 of 11 recurrent patients had either distant metastasis or multiple recurrences in the residual liver. CONCLUSIONS: Our new adjuvant systemic therapy including interferon alpha, 5FU and cisplatin for advanced HCC with macroscopic portal invasion is promising.

Surgical strategy for advanced gallbladder carcinoma according to invasive depth of the tumor.

BACKGROUND/AIMS: The postoperative survival rate is dependent on the invasive depth of the gallbladder carcinoma. When this carcinoma has invaded beyond the subserosal layer, lymph node and adjacent organ involvement is found in a large number of patients, and long-term survival cannot be achieved. The aim of this study is to establish a surgical strategy for advanced gallbladder carcinoma according to the invasive depth. METHODOLOGY: A retrospective analysis was conducted of 44 patients with the gallblader carcinoma. The invasive depth was histologically defined by the Japanese Society of Biliary Surgery system as follows. (hinf0: within muscle layer, hinf1a: subserosal layer, hinf1b: hepatic infiltration within 5 mm, hinf2.3: hepatic infiltration more than 5 mm) RESULTS: Wedge resection of the gallbladder bed was performed in 5 cases, and in four of the five patients (80%), intrahepatic recurrence occurred within 6 months. S4a+S5 subsegmentectomy of the liver is performed in 11 cases (hinf0,1a/b:n=5, hinf2,3:n=6) and the postoperative survival rate was significantly better in cases of hinf0,1a/b (p<0.05). In cases of hinf2,3 an extended hepatic lobectomy (n=5) tended to obtain a better survival rate, compared with S4a+S5 subsegmentectomy (n=6)(p=0.13). CONCLUSIONS: S4a+S5 subsegmentectomy of the liver is a standard operation for GB carcinoma with subserosal invasion.

Role of geranylgeranylacetone as non-toxic HSP70 inducer in liver surgery: clinical application.

Heat shock proteins (HSPs) are rapidly synthesized into cells in response to various types of physical or chemical insults and induce potent resistance to the stressors. A stress-inducible HSP70 is not expressed in normal conditions, but once HSP70 is excessively induced under various environmental stresses, HSP70-expressing cells can survive even under lethal conditions. In this review, we focused on the potential role of HSPs particularly HSP70 in liver surgery. A non-toxic HSP70 inducer, geranylgeranylacetone (GGA), has been introduced to exert a potent cytoprotective action against liver injury after ischemia/reperfusion, massive hepatectomy and liver transplantation in animal experiments. We have tried to explain possible therapeutic benefits of GGA in liver surgery. However, any dependable clinical application has not been done. One of the reasons is that any randomized clinical trial has not being carried out in clinical cases. Therefore, we have advocated the national scale randomized clinical trial for dependable clinical application of GGA.

Effects of preactivation by portal vein ligation on liver regeneration following massive hepatectomy in rats.

BACKGROUND/AIMS: We performed a long-term assessment of liver regeneration with or without PVL after massive hepatectomy in similar sized remnant livers to evaluate effects of regenerating livers preactivated by PVL following massive hepatectomy. METHODOLOGY: Rats were randomly divided into two groups, PVL-88%Hx and sham 88%Hx. As the initial operation, PVL or sham operation was performed by ligation of the portal vein of the left and median lobes or a similar manipulation without ligation, respectively. Four days after PVL, the volume of the posterior caudate lobe (5%) increased approximately two-fold (12%) and was the same size as the whole caudate lobe (12%) in the sham animals. Subsequently, 88%Hx was performed in the two groups. RESULTS: Survival rates were not significantly different between the two groups. Relative liver weight in PVL-88%Hx group was significantly higher up to 24hr, but after 48hr no significant difference was evident between the two groups. PCNA LI in sham-89%Hx group was significantly higher than that in PVL-88%Hx group after 48hr. The mRNA expression levels of activin A and ActRIIA were significantly higher in PVL-88%Hx group than in sham-88% group at 72 hr. CONCLUSIONS: The regenerating liver preactivated by PVL is restricted late-phase liver regeneration after massive hepatectomy.

p53 and MIB-1 expression of esophageal carcinoma concominant with achalasia.

Achalasia, insufficient relaxation of the lower esophageal sphincter (LES) causes the retention and stasis of food and secretions, chronic hyperplastic esophagitis and eventual malignant transformation. p53 alternation has been suggested to play an important role in the malignant transformation. A 53-year-old man was endoscopically followed up for esophageal achalasia for seven years, and endoscopy revealed an ulcerative region in the upper thoracic esophagus, and histopathologically the biopsy specimens showed moderately differentiated squamous cell carcinoma. In resected specimens, p53 staining was strong and diffuse in the tumor and MIB-1 immunoreactivity was strong and patchy in the tumor and the basal layer of squamous mucosa of the esophagus. No staining for either immunostains was noted in normal esophageal mucosa. It is necessary for patients with esophageal achalasia to be followed-up with endoscopy, and that p53 and MIB-1 immunostaining of biopsy specimens should be performed to detect pre-cancerous lesions.

Prevention of lethal hepatic injury in Long-Evans Cinnamon (LEC) rats by D-galactosamine hydrochloride.

Repeated injections of D-galactosamine hydrochloride (GalN) increase the survival rate of Long-Evans Cinnamon (LEC) rats, an animal model of Wilson's disease. The aim of the present study was to investigate the mechanism of GalN for prevention of spontaneous lethal hepatic injury in LEC rats. Male LEC rats were given a single subcutaneous injection of 300 mg/kg of GalN or vehicle (0.9% NaCl) at 14 weeks, and killed at 28 weeks of age. Next, 6-week-old male LEC rats were given weekly subcutaneous injections of 300 mg/kg of GalN or vehicle for 3 or 12 weeks, and their hepatic 8-hydroxydeoxy-2'-guanosine (8-OHdG), glutathione peroxidase (GPX), and catalase activities were measured. None of GalN-treated rats died of hepatic injury (0/12), whereas the mortality rate of control rats given 0.9% NaCl was 17% (2/12). GalN administration for 12 weeks decreased the hepatic 8-OHdG, and GalN administration for either 3 or 12 weeks increased the glutathione peroxidase activity. GalN administration increased the serum level of alanine aminotransferase, and accelerated megalocytic degeneration of the hepatocytes. GalN treatment is effective in preventing lethal hepatitis in LEC rats and decrease of oxidative DNA damage by GalN plays an important role in increase of the survival rate.

Bioelectrical impedance analysis to assess changes in body water compartments after digestive surgery.

BACKGROUND/AIMS: Accurate monitoring of fluid balance in patients after surgery is a difficult task. Bioelectrical impedance analysis (BIA) is a safe and noninvasive method to measure extracellular water (ECW) and intracellular water (ICW) by passing a weak alternating current through the body. The purpose of the present study was to evaluate changes in body water compartments after gastroenterological surgery by BIA in relation to patient age, type of operation, postoperative complications and systemic inflammatory response syndrome (SIRS). METHODOLOGY: Ninety-four patients undergoing digestive surgery in our department [laparoscopic cholecystectomy (n=9), gastrectomy (n= 23), colectomy (n=26), hepatectomy (n=29), pancreatoduodenectomy (n=4) and esophagectomy (n=3)] were enrolled in the study. Body fluids were measured by bioelectrical impedance analysis before and after surgery (one hour after operation and on postoperative days 1, 3, 7 and 14). RESULTS: Total body water (TBW) and ICW in all groups were significantly lower than preoperative values on day 14. Day 14 ECW in patients less than 70 years or age without postoperative SIRS or complications was significantly lower than the preoperative value. In contrast, ECW was not significantly different from the preoperative value in patients older than age 70 with postoperative SIRS. Additionally, ECW on day 14 was significantly higher than the preoperative value in patients with postoperative complications. When types of surgery were taken into consideration, day 14 TBW was significantly lower than preoperative value only in patients with gastrectomy and hepatectomy. CONCLUSIONS: Development of postoperative SIRS and complications resulted in an increase of ECW above its preoperative value. BIA is useful for detecting small changes in body composition following gastroenterological surgery, and provides a means for monitoring perioperative water balance.

Perioperative hemodynamic study of patients undergoing abdominal surgery using pulse dye densitometry.

BACKGROUND/AIMS: Pulse dye densitometry (PDD) using indocyanine-green (ICG) is a newly developed technique for monitoring cardiac output (CO), cardiac index (CI), circulating blood volume (BV) and ICG elimination rate (K-ICG). We measured hemodynamic changes during the perioperative period in patients undergoing digestive surgery to analyze relationships between hemodynamic changes and surgical procedures, blood loss, water balance and SIRS. METHODOLOGY: Eighty-seven patients who underwent gastrectomy (n=46) and colectomy (n=41) without postoperative complications were enrolled in this study. The corresponding data from 15 patients who underwent laparoscopic cholecystectomy were used as controls. CO, CI, BV and K-ICG were measured by PDD before operation, on the first postoperative day (POD 1), POD 3, POD 7 and POD 14. RESULTS: In all patients, CO and CI increased significantly until POD 3 compared with preoperative levels. BV on POD 1 decreased significantly compared to the preoperative level. K-ICG increased significantly until POD 14. Laparoscopic cholecystectomy resulted in less surgical stress than gastrectomy or colectomy as measured by hemodynamic changes. There were minimal differences in hemodynamics between the gastrectomy and colectomy groups. There were significant negative correlations between intraoperative blood loss and the [POD 1: preoperative values] ratios for CO, CI, BV or K-ICG. There was no correlation between changes in water balance from operation to POD 1 and [POD 1: preoperative value] BV ratio. CONCLUSIONS: An increase in CO and decrease in BV were observed at the early operative stage, especially in patients with systemic inflammatory response syndrome (SIRS). Interestingly, hepatic artery flow volume (K-ICG) remained high until POD 14. It is important to minimize intraoperative blood loss, since it markedly affects postoperative hemodynamics.

Experimental Studies on Protective Effects of FK506 Against Hepatic Ischemia-Reperfusion Injury.

Purposes; FK506 (strong immunosuppressive agent) was investigated experimentally whether to protect the hepatic IRI. Methods; Warm ischemic experiment using pigs and rats were performed and examined whether FK506 is effective. Results; The results obtained are as follows. 1. Warm ischemia allowed time of the pigs without FK506 was 150 minutes, but as for that of FK506 group, the extension of 30 minutes was got in 180 minutes. 2. Biliary excretion rate of BSP after reperfusion were better in the group of 180 minutes ischemia with FK506 than in without FK506 group. 3. Chemiluminescence intensity in the peripheral neutrophils and adhered and infiltrated leukocytes in the liver were suppressed markedly by FK506. 4. The vascular endothelium with the scanning electron microscope was relatively preserved in the FK506 group comparing to the placebo group on 30 minutes after reperfusion. 5. Stress gastric ulcer was controlled and myeloperoxidase activity in the gastric mucosa was suppressed by FK506. Conclusion; Based on the results of theses experiments, it was suggested that FK506 has a protective effect on IRI by suppressing: the impairment of sinusoidal endothelial cells; the activation of KCs; the disturbance of micro-circulation; oxidative stress; inflammation; and the accumulation of leukocytes. J. Med. Invest. 63: 262-269, August, 2016.

Overexpression of a novel superoxide-producing enzyme, NADPH oxidase 1, in adenoma and well differentiated adenocarcinoma of the human colon.

A superoxide-producing enzyme, NADPH oxidase 1 (Nox1), dominantly expressed in the colon, is implicated in the pathogenesis of colon cancer. Immunohistochemistry showed that Nox1 was constitutively expressed in surface mucous cells. Adenomas and well differentiated adenocarcinomas up-regulated Nox1 expression. Ki-67-negative, well differentiated tumor cells contained abundant Nox1, whereas Ki-67-positive, proliferating cells did not express it. This differentiation-dependent expression in normal as well as tumor tissues suggests distinct roles of Nox1 besides mitogenic function. Nuclear factor (NF)-kappaB was predominantly activated in adenoma and adenocarcinoma cells expressing abundant Nox1, suggesting that Nox1 may stimulate NF-kappaB-dependent antiapoptotic pathways in colon tumors.

Balloon occluded retrograde transvenous obliteration and percutaneous transhepatic obliteration for ruptured duodenal varices after operation for rectal cancer with multiple liver metastasis: report of a case.

We report a patient with duodenal varices oozing blood who had undergone low anterior resection of the rectum and resection of the liver tumor because of multiple liver metastasis from rectal cancer 80 months previously. Although endoscopic variceal ligation (EVL) was carried out for the ruptured duodenal varices, their bleeding persisted and hepatic encephalopathy also appeared. Finally, balloon occluded retrograde transvenous obliteration (BRTO) with percutaneous transhepatic obliteration (PTO) was carried out for the duodenal varices. Percutaneous transhepatic portography revealed detailed hemodynamics. Following PTO, the duodenal varices were stagnated by BRTO, and no complications were recognized. No re-bleeding episode has been observed since the treatment. In addition, the hepatic encephalopathy was also improved.

Multiple hepatic angiomyolipomas with a solitary omental angiomyolipoma.

Angiomyolipoma (AML) is a rare benign tumor that occurs most commonly in the kidney. Lesions in the liver are usually solitary and multiple AMLs of the liver are extremelyrare. Furthermore, extra renal or hepatic AML are rarely found. We report an unusual case of a 34-year-old man with a solitary omental AML and multiple hepatic AMLs. At the age of 23, the patient underwent right nephrectomy and enucleation of a left renal tumor because of bilateral AMLs. At the age of 34, more than 6 lesions in the liver and an enlarged solitary omental AML were discovered. The omental tumor, 50 x 40mm, 49g, was extirpated; it was well-defined and encapsulated a soft elastic mass. Histologically it was an epithelioid AML and positive for the melanogenesis-related marker HMB-45, the same as the earlier right renal tumor. We describe the first case of a solitary omental AML, which had metastasized, and with more than 6 hepatic AMLs.

Effect of follistatin on rat liver regeneration and tumor growth after portal occlusion.

BACKGROUND/AIMS: Although follistatin is known to be a positive regulator in liver regeneration after hepatectomy, the effects of follistatin on regeneration following portal occlusion and on tumor growth are not known. METHODOLOGY: In experiment 1, rats were injected with follistatin immediately following 70% hepatic resection (HR), ligation of the left portal vein (PVL), or ligation of the left hepatic artery (HAL). Hepatic regenerative activity then was determined. In experiment 2, rats were injected intraportally with AH130 tumor cells. At 7 days after injection, the same procedures were carried out as in experiment 1. In a third experiment, in vitro, AH130 cells were cultured with various concentrations of activin A or follistatin, and cell proliferation was assessed. RESULTS: In experiment 1, follistatin did not accelerate liver regeneration after PVL. In experiment 2, follistatin significantly increased liver weight after HR, but did not accelerate tumor growth in any group. In vitro, neither follistatin nor activin affected proliferation of tumor cells. CONCLUSIONS: The mechanism of liver regeneration after PVL appears to differ from that after HR. Follistatin acts as a growth promoter for hepatocytes, but not for cancer cells.

Possible endocrine control by follistatin 315 during liver regeneration based on changes in the activin receptor after a partial hepatectomy in rats.

BACKGROUND/AIMS: Activin A is an autocrine inhibitor of cell growth in the liver. The biological activity of activin A is mediated by a heteromeric receptor complex. Follistatin (FS) binds to activin and inhibits its biological effects, and acts as a negative regulator of muscle cells. The role of activin receptors during liver regeneration following a hepatectomy has not been fully assessed. This study investigates the mechanism underlying how activin receptors regulate hepatocyte growth, and the effects of intravenous administration of FS during liver regeneration. METHODOLOGY: The expression of both activins and activin receptors in the liver after a 70% partial hepatectomy (HT) was assessed by RT-PCR and immunohistochemistry. FS 315 or 288 was infused for different periods of time based on changes in hepatocyte activin receptor expression after HT. RESULTS: Activin receptor expression peaked between 48 and 72 hours after HT. 72 hours after HT, an injection of FS 315 resulted in a more potent stimulation of DNA synthesis and produced a greater increase in body weight compared with the control rats. CONCLUSIONS: The expression of activin receptors after peak DNA synthesis might be a key component in the downregulation of DNA synthesis. Intravenous administration of FS 315 might promote liver regeneration and have anabolic actions.

Case report of chylous ascites with strangulated ileus and review of the literature.

We describe a case of chylous ascites with strangulated ileus, and review all 22 cases (including our case) of chylous ascites with strangulated ileus reported in the English and Japanese literature. The patient we describe was a 51-year-old woman with medical history of radiotherapy for cervical cancer of the uterus 15 months prior to being admitted to our hospital with abdominal pain after consuming a meal. A computed tomography (CT) scan revealed ascites, expansion of the small intestine, and whirl sign. Laparotomy revealed chylous ascites with an incarcerated internal hernia of the small intestine, which was released without intestinal resection. In our case the postoperative phase was uneventful, and as in the other 21 literature cases reviewed, treatment by either detorsion, release of the incarcerated internal hernia, or incision of the adhesion band without intestinal resection resulted in rapid improvement in the color of the intestine. It is considered that minimally invasive laparoscopic laparotomy should be selected as the treatment of first choice, because the degree of strangulation is slight in cases where chylous ascites is associated with strangulated ileus.

No-touch pylorus-resecting pancreatoduodenectomy can reduce postoperative complications even in low volume center.

PURPOSES: Pancreatoduodenectomy (PD) was performed for 6 periampullary cancer patients by using methods verified by quality randomized controlled trials (RCT) in a low-volume center (LVC). The purpose of this study was to verify the clinical results. METHODS: No-touch pylorus-resecting pancreatoduodenectomy (PrPD), antecolic gastrojejunostomy, pancreatico-jejunostomy with a lost stent tube to the main pancreatic duct, and early removal of a prophylactic drain were performed. RESULTS: The drain could be removed 4 days after operation, and no pancreatic fistula was observed in all cases. Solid food could be started on POD4 after removing the drain. Furthermore, postoperative systemic chemotherapy could be started earlier. CONCLUSION: Although we have only a few PD cases a year in our institution, PD can be conducted safely without complications by using the methods verified by quality RCTs.