Yoshimune Shiratori

Prevention of Second Primary Tumors by an Acyclic Retinoid, Polyprenoic Acid, in Patients with Hepatocellular Carcinoma

Background. In patients with hepatocellular carcinoma (hepatoma), the rate of recurrent and second primary hepatomas is high despite surgical resection and percutaneous ethanol-injection therapy. We developed an acyclic retinoid, polyprenoic acid, that inhibits hepatocarcinogenesis in the laboratory and induces differentiation and apoptosis in cell lines derived from human hepatoma. In a randomized, controlled study, we tested whether the compound reduced the incidence of recurrent and second primary hepatomas after curative treatment. Methods. We prospectively studied 89 patients who were free of disease after surgical resection of a primary hepatoma or the percutaneous injection of ethanol. We randomly assigned the patients to receive either polyprenoic acid (600 mg daily) or placebo for 12 months. We studied the remnant liver by ultrasonography every three months after randomization. The primary end point of the study was the appearance of a histologically confirmed recurrent or new hepatoma. Results. Treatment with polyprenoic acid significantly reduced the incidence of recurrent or new hepatomas. After a median follow-up of 38 months, 12 patients in the polyprenoic acid group (27 percent) had recurrent or new hepatomas as compared with 22 patients in the placebo group (49 percent, P = 0.04). The most striking difference was in the groups that had second primary hepatomas-7 in the group receiving polyprenoic acid as compared with 20 in the placebo group (P=0.04 by the log-rank test). Cox proportional-hazards analysis demonstrated that as an independent factor, polyprenoic acid reduced the occurrence of second primary hepatomas (adjusted relative risk, 0.31 ; 95 percent confidence interval, 0.12 to 0.78). Conclusions. Oral polyprenoic acid prevents second primary hepatomas after surgical resection of the original tumor or the percutaneous injection of ethanol.

Diffusion-weighted imaging of the liver: Optimizing b value for the detection and characterization of benign and malignant hepatic lesions

To determine the optimal b values required for diffusion‐weighted (DW) imaging of the liver in the detection and characterization of benign and malignant hepatic lesions.

Prevention of Second Primary Tumors by an Acyclic Retinoid in Patients with Hepatocellular Carcinoma

Oral administration with acyclic retinoid, a synthetic vitamin A analog, for a limited period of 12 months (48 weeks) prevented the development of second primary hepatocellular carcinoma (HCC) and also improved the survival of patients who underwent curative treatments of the initial tumor. Following that randomized controlled study reported in 1996 and 1999, we have continued to follow up the patients by medical imaging and blood chemical analyses, and found that the preventive effect of acyclic retinoid lasted up to 199 weeks after randomization (or 151 weeks after completion of retinoid administration). The retinoid’s effect was not mediated by reduction in hepatic necro-inflammation since no significant decrease in serum aminotransferase activity was seen in the retinoid group. Such observation seems quite distinct from the cancer-preventive mechanism of interferon, a potent immunopreventive agent for HCC. We have also shown here the reduction by the retinoid in serum levels of lectin-reactive α-fetoprotein (AFP-L3) and protein induced by vitamin K absence or antagonist-II (PIVKA-II), both of which indicate the presence of latent HCC cells. These results suggest that acyclic retinoid may delete such malignant clones before they expand to clinically detectable tumors and thereby inhibited second primary HCC. Once such latent clones are eradicated, it may well take at least several years for the next cancer clone to arise clinically. This may possibly explain a reason for the long-term effect of the retinoid even after the limited period of administration.

Evaluating local hepatocellular carcinoma recurrence post-transcatheter arterial chemoembolization: Is diffusion-weighted MRI reliable as an indicator?

To evaluate the detectability of local hepatocellular carcinoma (HCC) recurrence after transcatheter arterial chemoembolization (TACE) by diffusion‐weighted MR imaging in correlation with those of gadolinium‐enhanced MR imaging.

Role of tissue factor in disseminated intravascular coagulation

We examined plasma antigen levels of tissue factor (TF) in 95 cases of disseminated intravascular coagulation (DIC), to investigate the role of TF in DIC. A significant elevation of plasma antigen levels of TF was observed in cases of DIC associated with cancer. However, no such significant elevation was observed in cases of DIC associated with acute promyelocytic leukemia (APL), acute leukemia except APL, blastic crisis of chronic myelogenous leukemia, non-Hodgkin lymphoma (NHL), sepsis or fulminant hepatitis. No significant elevation of TF was observed in patients without DIC, except 4 cases of cancer who developed DIC thereafter. Plasma antigen levels of TF were higher in both cases of DIC with renal failure and chronic renal failure without DIC than its levels in those without renal failure. Therefore, plasma antigen levels of TF in DIC patients with renal failure were considered to be carefully estimated. The levels of TF were decreased with the clinical improvement in some cases of DIC but were further increased or remained at high levels in patients who showed no improvement of DIC. Thus, plasma antigen levels of TF is an important marker to predict the development and/or prognosis of DIC, especially in patients with cancer.

MDCT of the Pancreas: Optimizing Scanning Delay with a Bolus-Tracking Technique for Pancreatic, Peripancreatic Vascular, and Hepatic Contrast Enhancement

OBJECTIVE The purpose of this study was to determine the optimal MDCT scanning delay for peripancreatic arterial, pancreatic parenchymal, peripancreatic venous, and hepatic parenchymal contrast enhancement with a bolus-tracking technique. SUBJECTS AND METHODS Three-phase 8-MDCT of the pancreas was performed on 170 patients after administration of 2 mL/kg of 300 mg I/mL contrast medium injected at 4 mL/s to a total dose of 150 mL. Patients were prospectively randomized into three groups with different scanning delays for the three phases (arterial, pancreatic, and venous) after bolus tracking was triggered at 50 H of aortic contrast enhancement: group 1 (5, 20, 45 seconds); group 2 (10, 25, 50 seconds); and group 3 (15, 30, 55 seconds). Mean attenuation values of the abdominal aorta, superior mesenteric artery, pancreatic parenchyma, splenic vein, superior mesenteric vein, portal vein, and hepatic parenchyma were measured. Increases in attenuation values after contrast administration were assessed as change in attenuation value. Qualitative analysis also was performed. RESULTS Mean contrast enhancement in the aorta (change in attenuation, 321-327 H) and the superior mesenteric artery (change in attenuation, 304-307 H) approached peak enhancement 5-10 seconds after bolus tracking was triggered. Pancreatic parenchyma became most intensely enhanced (change in attenuation, 84-85 H) 15-20 seconds after triggering, and then the enhancement gradually decreased. Enhancement of the splenic vein and portal vein peaked 25 seconds and that of the superior mesenteric vein peaked 30 seconds after triggering. Liver parenchyma reached 52 H 30 seconds after triggering and reached a plateau (change in attenuation, 58-61 H) at a further scanning delay of 45-55 seconds. Qualitative results were in good agreement with quantitative results. CONCLUSION For the injection protocol used in this study, optimal scanning delay after triggering of bolus tracking at 50 H of aortic contrast enhancement was 5-10 seconds for the peripancreatic arterial phase, 15-20 seconds for the pancreatic parenchymal phase, and 45-55 seconds for the hepatic parenchymal phase.

Acyclic retinoid induces partial differentiation, down-regulates telomerase reverse transcriptase mRNA expression and telomerase activity, and induces apoptosis in human hepatoma-derived cell lines.

BACKGROUND/AIMS Acyclic retinoid (AR; all trans-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid) prevented hepatocarcinogenesis in animal models and in a randomized clinical trial by eradicating premalignant and latent malignant clones of transformed cells from the liver. We investigated the possible mechanism of this clonal deletion at the cellular level. METHODS Human hepatoma-derived cell lines, PLC/PRF/5, HuH-7, and JHH-7, were treated in vitro with AR. Secretion of albumin and that of lectin-reactive isoform of alpha-fetoprotein (AFP-L3) were measured as markers of differentiation and dedifferentiation of the cells, respectively. Telomerase reverse transcriptase (TERT) mRNA expression and telomerase activity were measured by reverse transcriptase polymerase chain reaction (RT-PCR) and stretch PCR assay, respectively. Caspase activities were measured by colorimetric protease assay. Mitochondrial membrane permeability transition was examined by Rhodamine staining. RESULTS Production of albumin was recovered while that of AFP-L3 was reduced after exposure of the cells to 10 microM AR for 2 days. This differentiation was maintained for another 2 days without retinoid. In parallel, both TERT mRNA expression and telomerase activity were down-regulated. The cells subsequently died due to apoptosis after 4-6 experimental days. Serial increases in mitochondrial membrane permeability and caspase-9 and -3 activities induced apoptosis. CONCLUSIONS AR first induces differentiation and reduces telomerase activity. Subsequent apoptosis may contribute to the eradication of the clone.

Hepatic hemangioma and metastasis: differentiation with gadoxetate disodium-enhanced 3-T MRI.

OBJECTIVE The purpose of this study was to evaluate the gadoxetate disodium-enhanced MRI findings of hepatic hemangioma and to investigate the diagnostic performance in differentiating hepatic hemangioma and metastasis. MATERIALS AND METHODS Images of 32 hepatic hemangiomas in 25 patients and of 29 hepatic metastatic lesions in 20 patients were retrospectively reviewed. Two independent readers interpreted hepatobiliary phase images alone, dynamic extracellular phase images alone, and combined hepatobiliary and dynamic extracellular phase images. MRI findings and performance with respect to the differential diagnosis of hemangioma and metastasis were assessed. RESULTS During the hepatic arterial phase, 11 of the 32 hemangiomas (34%) exhibited early total enhancement, and nine (28%) exhibited peripheral nodular enhancement. A bright dot sign or minimal peripheral enhancement during the late dynamic phase was observed for a small number of lesions (6% and 28%, respectively). Twenty-three of the 29 metastatic lesions (79%) exhibited ring enhancement during the hepatic arterial phase. Twenty-nine hemangiomas (91%) and all of the metastatic lesions exhibited homogeneous or heterogeneous hypointensity during the hepatobiliary phase. The sensitivity, specificity, and area under the receiver operating characteristic curve for the detection of hemangioma were 76%, 81%, and 0.87 for the hepatobiliary phase alone; 97%, 88%, and 0.97 for the dynamic extracellular phase alone; and 97%, 88%, and 0.98 for the combination. Five nodules smaller than 1 cm (four hemangiomas, one metastatic lesion) that exhibited no enhancement during the arterial phase and minimal enhancement during the late dynamic phase were not differentiated. CONCLUSION Gadoxetate disodium-enhanced MRI was found useful for differentiating hepatic hemangiomas and metastatic lesions, especially during the dynamic extracellular phase. Only a limited number of lesions smaller than 1 cm in diameter, which exhibited minimal enhancement on late dynamic phase images, were difficult to diagnose.

Body Size Indexes for Optimizing Iodine Dose for Aortic and Hepatic Enhancement at Multidetector CT: Comparison of Total Body Weight, Lean Body Weight, and Blood Volume

PURPOSE To evaluate and compare total body weight (TBW), lean body weight (LBW), and estimated blood volume (BV) for the adjustment of the iodine dose required for contrast material-enhanced multidetector computed tomography (CT) of the aorta and liver. MATERIALS AND METHODS Institutional review committee approval and written informed consent were obtained. One hundred twenty patients (54 men, 66 women; mean age, 64.1 years; range, 19-88 years) who underwent multidetector CT of the upper abdomen were randomized into three groups of 40 patients each: (a) TBW group (0.6 g of iodine per kilogram of TBW), (b) LBW group (0.821 g of iodine per kilogram of LBW), and (c) BV group (men, 8.6 g of iodine per liter of BV; women, 9.9 g of iodine per liter of BV). Change in CT number between unenhanced and contrast-enhanced images per gram of iodine and maximum hepatic enhancement (MHE) adjusted for iodine dose were examined for correlation with TBW, LBW, and BV by using linear regression analysis. RESULTS In the portal venous phase, correlation coefficients for the correlation of change in CT number per gram of iodine with TBW for the aorta and liver were -0.71 and -0.79, respectively, in the TBW group; -0.80 and -0.86, respectively, in the LBW group; and -0.68 and -0.66, respectively, in the BV group. In the liver, they were marginally higher in the LBW group than in the BV group (P = .03). Adjusted MHE remained constant at 77.9 HU +/- 10.2 (standard deviation) in the LBW group with respect to TBW, but it increased in the TBW (r = 0.80, P < .001) and BV (r = 0.70, P < .001) groups as TBW increased. CONCLUSION When LBW, rather than TBW or BV, is used, the iodine dose required to achieve consistent hepatic enhancement may be estimated more precisely and with reduced patient-to-patient variability.

Acid sphingomyelinase regulates glucose and lipid metabolism in hepatocytes through AKT activation and AMP-activated protein kinase suppression

Acid sphingomyelinase (ASM) regulates the homeostasis of sphingolipids, including ceramides and sphingosine‐1‐phosphate (S1P). Because sphingolipids regulate AKT activation, we investigated the role of ASM in hepatic glucose and lipid metabolism. Initially, we overexpressed ASM in the livers of wild‐type and diabetic db/db mice by adenovirus vector (Ad5ASM). In these mice, glucose tolerance was improved, and glycogen and lipid accumulation in the liver were increased. Using primary cultured hepatocytes, we confirmed that ASM increased glucose uptake, glycogen deposition, and lipid accumulation through activation of AKT and glycogen synthase kinase‐3β. In addition, ASM induced up‐regulation of glucose transporter 2 accompanied by suppression of AMP‐activated protein kinase (AMPK) phosphorylation. Loss of sphingosine kinase‐1 (SphK1) diminished ASM‐mediated AKT phosphorylation, but exogenous S1P induced AKT activation in hepatocytes. In contrast, SphK1 deficiency did not affect AMPK activation. These results suggest that the SphK/S1P pathway is required for ASM‐mediated AKT activation but not for AMPK inactivation. Finally, we found that treatment with high‐dose glucose increased glycogen deposition and lipid accumulation in wild‐type hepatocytes but not in ASM_/_ cells. This result is consistent with glucose intolerance in ASM_/_ mice. In conclusion, ASM modulates AKT activation and AMPK inactivation, thus regulating glucose and lipid metabolism in the liver.—Osawa, Y., Seki, E., Kodama, Y., Suetsugu, A., Miura, K., Adachi, M., Ito, H., Shiratori, Y., Banno, Y., Olefsky, J. M., Nagaki, M., Moriwaki, H., Brenner, D. A., Seishima, M. Acid sphingomyelinase regulates glucose and lipid metabolism in hepatocytes through AKT activation and AMP‐activated protein kinase suppression. FASEBJ. 25, 1133‐1144 (2011). www.fasebj.org