Language：English   Publishing type：Research paper (scientific journal)  

A 72-year-old man with intractable left shoulder pain due to bone metastasis from cholangiocellular carcinoma was admitted to our hospital. Computed tomography showed an osteoblastic metastatic lesion of the left scapula. Since the pain persisted even after the administration of opioids and external irradiation, microspheres were injected through a catheter; the catheter tip was placed at the arteries feeding the metastatic lesion. After the intervention, the shoulder pain was alleviated without any procedure-related complications, leading to a reduction in the opioid dose. This case suggests the efficacy of transcatheter arterial embolization using microspheres for palliating pain from bone metastasis.

DOI： 10.2169/internalmedicine.5351-20

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A 70-year-old man was admitted to our hospital with gait disturbance due to marked edema of the lower limbs for more than 6 months. He had been receiving systemic chemotherapy over two years for multiple recurrence after sigmoid colon cancer resection. Contrast-enhanced computed tomography demonstrated severe inferior vena cava (IVC) stenosis due to compression by lymph node metastases, i.e. IVC syndrome. As increased doses of diuretic agents failed to improve the edema, IVC stent placement was performed. This led to significant improvement of the edema and complete gait normalization. This case demonstrates the efficacy of IVC stent placement for IVC syndrome.

DOI： 10.2169/internalmedicine.5033-20

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A 69-year-old man was referred to our hospital because of appetite loss. Imaging showed a nodular tumor in the perihilar bile duct and a second flat lesion in the distal bile duct. Right hepatopancreaticoduodenectomy was performed, and the histopathological findings demonstrated that the perihilar and distal lesions were moderately and poorly differentiated adenocarcinoma, respectively, and anatomically separated. Furthermore, the resected specimens showed no pancreaticobiliary maljunction. Histological and TP53 gene analyses in a rare case of synchronous double bile duct cancers suggest that there are various genetic pathways through which bile duct cancer develops, highlighting the complexity of its pathogenesis.

DOI： 10.2169/internalmedicine.4613-20

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A 70-year-old man with insulinoma-associated antigen-2 autoantibodies developed diabetes mellitus (DM) without ketoacidosis after starting nivolumab to treat advanced gastric cancer. He subsequently exhibited preserved insulin-secretion capacity for over one year. Immune checkpoint inhibitors (ICIs) infrequently cause type 1 DM associated with the rapid loss of insulin secretion and ketoacidosis as an immune-related adverse event. ICIs may also cause non-insulin-dependent DM by inducing insulin resistance if there is islet autoantibody-related latent beta-cell dysfunction. The present case highlights the importance of testing blood glucose levels regularly to diagnose DM in patients treated with ICIs, even if they do not have diabetic ketoacidosis.

DOI： 10.2169/internalmedicine.3208-19

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BACKGROUND: Immunosuppression is effective in treating a number of diseases, but adverse effects such as bone marrow suppression, infection, and oncogenesis are of concern. Methotrexate is a key immunosuppressant used to treat rheumatoid arthritis. Although it is effective for many patients, various side effects have been reported, one of the most serious being methotrexate-related lymphoproliferative disorder. While this may occur in various organs, liver involvement is rare. Information on these liver lesions, including clinical characteristics, course, and imaging studies, has not been summarized to date. CASE SUMMARY: We present a case of 70-year-old woman presented with a 2-wk history of fever and abdominal pain. She had had rheumatoid arthritis for 5 years and was being treated with medication including methotrexate. Contrast-enhanced computed tomography revealed multiple low density tumors in the liver and the histological analyses showed significant proliferation of lymphocytes in masses that were positive on immunohistochemical staining for CD3, CD4, CD8, and CD79a but negative for CD20 and CD56. Staining for Epstein-Barr virus-encoded RNA was negative. And based on these findings, the liver tumors were diagnosed as Methotrexate-related lymphoproliferative disorders. A time-dependent disappearance of the liver tumors after stopping methotrexate supported the diagnoses. CONCLUSION: The information obtained from our case and a review of 9 additional cases reported thus far assist physicians who may face the challenge of diagnosing and managing this disorder.

DOI： 10.12998/wjcc.v7.i21.3553

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DOI： 10.1111/den.13349

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BACKGROUND: Shear wave speed has been widely applied to quantify a degree of liver fibrosis. However, there is no standardized procedure, which makes it difficult to utilize the speed universally. AIM: To provide procedural standardization of shear wave speed measurement. METHODS: Point shear wave elastography (pSWE) was measured in 781 patients, and two-dimensional shear wave elastography (2dSWE) was measured on the same day in 18 cases. Regions-of-interest were placed at 12 sites, and the median and robust coefficient-of-variation (CVR) were calculated. A residual sum-of-square (Σdi2) was computed for bootstrap values of 1000 iterations in 18 cases with each assumption of 1 to 12 measurements. The proportion of the Σdi2 (%Σdi2) was calculated as the ratio of Σdi2 to pSWE after converting it based on the correlation between pSWE and 2dSWE. RESULTS: The CVR showed a significantly broader distribution in the left lobe (P < 0.0001), and the smallest CVR in the right anterior segment that covered 95% cases was 40.4%. pSWE was significantly higher in the left lobe than in the right lobe (1.63 ± 0.78 m/s vs 1.61 ± 0.78 m/s, P = 0.0004), and the difference between the lobes became further discrete when the subjects were limited to the cases with a CVR less than 40.4% in any segment (1.76 ± 0.80 m/s vs 1.70 ± 0.82 m/s, P < 0.0001). The highest values of the CVR in every 0.1 m/s interval were plotted in convex upward along pSWE and peaked at 1.93 m/s. pSWE and 2dSWE were significantly correlated (P < 0.0001, r = 0.95). In 216000 resamples from 18 cases, the %Σdi2 of 12 sites was 8.0% and gradually increased as the acquisition sites decreased to reach a significant difference with a %Σdi2 of 7 sites (P = 0.027). CONCLUSION: These data suggest that shear wave speed should be measured at 8 or more sites of spreading in both lobes.

DOI： 10.3748/wjg.v25.i20.2503

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We encountered a small cell lung cancer (SCLC) patient with intertrabecular vertebral metastasis (IVM). A 59-year-old man was admitted to our hospital with weight loss. 18F-fluorodeoxyglucose positron emission tomography (FDG PET)-CT demonstrated the uptake of fluorodeoxyglucose in the hilum of the left lung and whole-body bones. Despite intensive support, the patient died within a month. Subsequent autopsy revealed a small lesion consisting of small round cells in the left lung. The cancer cells were found to have spread through the replacement of the bone marrow cells while sparing the trabecular bone. This case demonstrated the potential of 18F-FDG PET for detecting IVM in SCLC patients.

DOI： 10.2169/internalmedicine.1394-18

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

Hepatic progenitor cell (HPC) marker-positive hepatocellular carcinomas (HCCs) have recently been extensively analyzed, and their prognosis has been reported as poor compared to HPC marker-negative HCCs. However, previous studies have analyzed the existence of HPC marker-positive cancer cells only in primary lesions, as well as the recurrence rate and prognosis of such tumors. Here, we are the first to report the behavior of HPC marker-positive cancer cells during vascular invasion and metastasis of an HCC. We concurrently analyzed EpCAM- and/or NCAM-expressing cancer cells in the primary, vascular invasion, and metastatic lesions of an HCC. An HCC which includes EpCAM- and/or NCAM-expressing cancer cells has not been previously reported. EpCAM- and/or NCAM-positive cancer cells invaded the vessels and formed heterogeneous populations of these HPC marker-positive cancer cells with HPC marker-negative cancer cells. The frequency of HPC marker-positive cancer colonies and cells in vessels was higher than that in the primary HCC. In the metastatic lesions, EpCAM-positive cancer cells were more frequently detected than NCAM-positive cancer cells, indicating that EpCAM may be more important than NCAM for cancer cell settlement in the metastatic lesions. Furthermore, bigger metastatic tumors tended to include HPC marker-positive cancer cells, suggesting that HPC marker-positive cancer cells have a growth advantage in the metastatic lesions. These results showed that HPC marker-positive cancer cells would be important for vascular invasion and metastasis and suggested that HPC marker-positive cancer cells are an important target in HCC treatment. (C) 2019 The Author(s) Published by S. Karger AG, Basel.

DOI： 10.1159/000498913

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To distinguish and characterize nonalcoholic steatohepatitis (NASH) candidates from among medical checkup visitor diagnosed with nonalcoholic fatty liver diseases (mcNAFLDs).A cut-off value has not been established to differentiate NASH at the earliest stage in NAFLD.Shear wave speed (SWS) was measured in the livers of 480 mcNAFLDs. NASH candidates were screened out by adopting a statistically defined cut-off value of SWS and were characterized in terms of food preference.SWS ranged between 1.11 and 2.18 m/s and fit a Gaussian distribution (r = 0.98) with an average and SD of 1.324 and 0.0847 m/s, respectively, in 320/160 males/females 64.4 (interquartile range 57.3-69.4) years old. The average plus SD (1.41 m/s) screened out 82 (17.1%) NASH candidates, who were significantly older (66.8 vs. 64.1 years old, P = 0.001) and had higher fibrosis 4 index values (1.58 vs. 1.33, P < 0.0001) than the remaining mcNAFLDs. The number of patients with a BMI greater than 25 kg/m was 118 (29.6%) mcNAFLDs and 34 (41.5%) NASH candidates, with a significantly higher frequency in NASH candidates (P = 0.05). Obese patients preferentially ate fatty acids in general, while NASH candidates preferred to consume several long-chain unsaturated fatty acids irrespective of their BMI.These results suggest that NASH candidates who have a longer disease duration and pathological progression can be distinguished from mcNAFLDs by a statistically defined cut-off value of SWS. The defined value indicates that there are different food habitats associated with obesity and NAFLD progression.

DOI： 10.1097/MD.0000000000013958

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BioMed Central Ltd.  

Background: An intra-abdominal abscess can sometimes become serious and difficult to treat. The current standard treatment strategy for intra-abdominal abscess is percutaneous imaging-guided drainage. However, in cases of subphrenic abscess, it is important to avoid passing the drainage route through the thoracic cavity, as this can lead to respiratory complications. The spread of intervention techniques involving endoscopic ultrasonography (EUS) has made it possible to perform drainage via the transmural route. Case presentation: We describe two cases of subphrenic abscess that occurred after intra-abdominal surgery. Both were treated successfully by EUS-guided transmural drainage (EUS-TD) without severe complications. Our experience of these cases and a review of the literature suggest that the drainage catheters should be placed both internally and externally together into the abscess cavity. In previous cases there were no adverse events except for one case of mediastinitis and pneumothorax resulting from transesophageal drainage. Therefore, we consider that the transesophageal route should be avoided if possible. Conclusions: Although further studies are necessary, our present two cases and a literature review suggest that EUS-TD is feasible and effective for subphrenic abscess, and not inferior to other treatments. We anticipate that this report will be of help to physicians when considering the drainage procedure for this condition. As there have been no comparative studies to date, a prospective study involving a large number of patients will be necessary to determine the therapeutic options for such cases.

DOI： 10.1186/s12876-018-0782-2

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Our case highlights the need for caution during vascular endothelial growth factor pathway inhibitor (VPI) therapy and for the occurrence of aortic dissection. If Stanford classification type A aortic dissection occurs during VPI therapy, surgical intervention should be considered to prevent cardiac tamponade if the patient's clinical condition permits it.

DOI： 10.1002/ccr3.1674

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Background: Sorafenib (SOR) is a molecular medicine that prolongs the survival of patients with hepatocellular carcinoma (HCC). Therefore, the management of side effects is essential for the longer period of continuous medication. Among the various side effects, hand-foot syndrome (HFS) is the most common, occurring in 30%-50% of patients, and often results in discontinuation of the SOR medication. However, its mechanism has not been clarified, and no effective prevention method has been reported for the symptoms. Therefore, this study aimed to analyze its mechanism and to develop an effective prevention regimen for the symptoms. Materials and methods: To assess the mechanism of SOR-induced HFS, the peripheral blood flow in the hand and foot was carefully monitored by Doppler ultrasound, thermography, and laser speckle flowgraphy in the cases treated with SOR and its contribution was assessed. Then, the effect of dried-bonito broth (DBB), which was reported to improve peripheral blood flow, on the prevention of the symptom was examined by monitoring its occurrence and the peripheral blood flow. Results: A total of 25 patients were enrolled in this study. In all, eight patients developed HFS, and all cases showed a significant decrease in the peripheral blood flow. DBB contributed to an increase in the flow (p = 0.009) and significantly decreased occurrence of HFS (p = 0.005) than control. Multivariable analysis showed that the ingestion of DBB is a significant independent contributor to HFS-free survival period (p = 0.035). Conclusion: The mechanism of SOR-induced HFS involves a decrease in the peripheral blood flow, and the ingestion of DBB effectively prevents the development of the syndrome by maintaining the flow.

DOI： 10.2147/CMAR.S159370

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：GEORG THIEME VERLAG KG  

DOI： 10.1055/s-0043-109428

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BAISHIDENG PUBLISHING GROUP INC  

Hepatocellular carcinoma (HCC) is one of the most common cancers and the third highest cause of cancerassociated mortality worldwide. The treatment of HCC is complicated by its variable biological behavior and the frequent coexistence of chronic liver disease, particularly cirrhosis. To date, multiple treatment modalities have been developed according to the stage of the tumor and the hepatic functional reserve, including transarterial treatments such as transarterial chemoembolization, transarterial oily chemoembolization (TOCE), and hepatic arterial infusion chemotherapy (HAIC). We conducted a phase I and II study of the combination therapy with double platinum agents, miriplatin and cisplatin, and confirmed its safety and efficacy. Here, we describe two cases of unresectable HCC who were successfully treated by miriplatin-TOCE/cisplatin-HAIC combination therapy, resulting in complete responses with no significant adverse events. This report will provide that the combination therapy can be the therapeutic option for HCC patients in the advanced stage.

DOI： 10.12998/wjcc.v5.i6.238

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Language：Japanese   Publisher：(NPO)日本食道学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: Based on promising results from a Phase I study of hepatic arterial infusion chemotherapy using a combination of miriplatin and cisplatin powder (DDP-H) for unresectable hepatocellular carcinoma (UMIN-CTR000003541), a multicenter, open-label, randomized phase II study was conducted to evaluate the efficacy and safety of the combination therapy versus miriplatin monotherapy.
Methods: Nineteen patients, five and fourteen Barcelona-Clinic Liver Cancer staging classification A and B cases, respectively, were randomly assigned to receive either miriplatin monotherapy (n = 9) or miriplatin/DDP-H combination therapy (n = 10). DDP-H and/or miriplatin were administered through the hepatic arteries supplying the lobes of the liver containing tumors, and progression free survival was analyzed as a primary end point in addition to other secondary endpoints. The corresponding therapy was repeated unless disease progression or severe adverse events were recorded.
Results: The monotherapy or combination therapy was performed for 15 or 36 sessions in total, respectively. Although there were no significant differences between the two groups for treatment intervals (p = 0.96) or the dose of miriplatin used in each session (p = 0.99), the progression free survival and overall disease control rate were significantly better in the combination therapy group (91 vs 423 days, p = 0.025; 40.0 vs 77.8%, p = 0.0025, respectively). Consistent with these observations, a trend of a significantly slower increase in des-gamma-carboxyprothrombin was observed, and the number of treatment sessions was nearly significantly larger in the combination therapy group (p &lt; 0.0001, p = 0.057, respectively). Conversely, the median survival time did not show a significant difference (706 days, monotherapy vs 733 days, combination therapy; p = 0.40). A significant decrease in cholinesterase was observed during the course of treatment only in patients receiving combination therapy (r = -0.86, p &lt; 0.0001). A few cases in both arms showed hematological and/or non-hematological toxicities that were categorized as grade 1 (NCI-CTCAE).
Conclusions: The higher disease control effects with the combination of miriplatin and DDP-H indicate that it is a promising alternative treatment for cases with multiple HCCs, especially for those that can tolerate the treatment without experiencing a reduction in hepatic reserve.

DOI： 10.1186/s12885-017-3320-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：GEORG THIEME VERLAG KG  

DOI： 10.1055/s-0042-118704

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Objective Radiofrequency ablation has been used widely for the local ablation of hepatocellular carcinoma, particularly in its early stages. The study aim was to identify significant prognostic factors and develop a predictive nomogram for patients with hepatocellular carcinoma who have undergone radiofrequency ablation. We also developed the formula to predict the probability of 3- and 5-year overall survival based on clinical variables.
Methods We retrospectively studied 96 consecutive patients with hepatocellular carcinoma who had undergone radiofrequency ablation as a first-line treatment. Independent and significant factors affecting the overall survival were selected using a Cox proportional hazards model, and a prognostic nomogram was developed based on these factors. The predictive accuracy of the nomogram was determined by Harrell's concordance index and compared with the Cancer of the Liver Italian Program score and Japan Integrated Staging score.
Results A multivariate analysis revealed that age, indocyanine green plasma disappearance rate, and log (des-gamma-carboxy prothrombin) level were independent and significant factors influencing the overall survival. The nomogram was based on these three factors. The mean concordance index of the nomogram was 0.74 +/- 0.08, which was significantly better than that of conventional staging systems using the Cancer of the Liver Italian Program score (0.54 +/- 0.03) and Japan Integrated Staging score (0.59 +/- 0.07).
Conclusion This study suggested that the indocyanine green plasma disappearance rate and age at radiofrequency ablation (RFA) and des-gamma-carboxy-prothrombin (DCP) are good predictors of the prognosis in hepatocellular carcinoma patients after radiofrequency ablation. We successfully developed a nomogram using obtainable variables before treatment.

DOI： 10.2169/internalmedicine.56.7278

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Language：English   Publisher：WILEY-BLACKWELL  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BAISHIDENG PUBLISHING GROUP INC  

One of the major research focuses in the field of gene therapy is the development of clinically applicable, safe, and effective gene-delivery methods. Since the first case of human gene therapy was performed in 1990, a number of gene-delivery methods have been developed, evaluated for efficacy and safety, and modified for human application. To date, viral-vector-mediated deliveries have shown effective therapeutic results. However, the risk of lethal immune response and carcinogenesis have been reported, and it is still controversial to be applied as a standard therapeutic option. On the other hand, delivery methods for non-viral vector systems have been developed, extensively studied, and utilized in in vivo gene-transfer studies. Compared to viral-vector mediated gene transfer, nonviral systems have less risk of biological reactions. However, the lower gene-transfer efficiency was a critical hurdle for applying them to human gene therapy. Among a number of nonviral vector systems, our studies focus on hydrodynamic gene delivery to utilize physical force to deliver naked DNA into the cells in the living animals. This method achieves a high gene-transfer level by DNA solution injections into the tail vein of rodents, especially in the liver. With the development of genome editing methods, in vivo gene-transfer therapy using this method is currently the focus in this research field. This review explains the method principle, efficiency, safety, and procedural modifications to achieve a high level of reproducibility in large-animal models.

DOI： 10.3748/wjg.v22.i40.8862

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Language：English   Publisher：WILEY  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CELL PRESS  

Hydrodynamic gene delivery is a common method for gene transfer to the liver of small animals, and its clinical applicability in large animals has been demonstrated. Previous studies focused on functional analyses of therapeutic genes in animals with normal livers and little, however, is known regarding its effectiveness and safety in animals with liver fibrosis. Therefore, this study aimed to examine the effects of liver fibrosis on hydrodynamic gene delivery efficiency using a rat liver fibrosis model. We demonstrated for the first time, using pCMV-Luc plasmid, that this procedure is safe and that the amount of fibrotic tissue in the liver decreases gene delivery efficiency, resulting in decrease in luciferase activity depending on the volume of fibrotic tissue in the liver and the number of hepatocytes that are immunohistochemically stained positive for transgene product. We further demonstrate that antifibrotic gene therapy with matrix metalloproteinase-13 gene reduces liver fibrosis and improves efficiency of hydrodynamic gene delivery. These results demonstrate the negative effects of fibrotic tissue on hydrodynamic gene delivery and its recovery by appropriate antifibrotic therapy.

DOI： 10.1038/mtna.2016.63

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Language：Japanese   Publishing type：Research paper (scientific journal)  

To examine whether the consumption of dried bonito both is effective for the prevention of hand-foot syndrome(HFS), concentrated bonito broth was administered to 10 patients with HCC who were treated with sorafenib. Among the 10 patients, seven showed an increase in peripheral blood flow, as observed on Doppler ultrasonography. Only one patient showed Grade 1 HFS on day 14 after the initiation of sorafenib (10%); this incidence rate of HFS was significantly lower than that obtained in our previous studies and reported data. These results suggest that consumption of dried bonito broth contributes to the prevention of HFS by maintaining peripheral blood flow.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Background It remains unknown whether Kupffer-phase images in Sonazoid-enhanced ultrasonography (US) can be used to predict hypervascularization of borderline lesions. Therefore, we aimed to clarify whether Kupffer-phase images in Sonazoid-enhanced ultrasonography can predict subsequent hypervascularization in hypovascular borderline lesions detected on hepatobiliary-phase gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (GdEOB-DTPA)-enhanced magnetic resonance imaging.
Methods From January 2008 to March 2012, 616 low-intensity hypovascular nodules were detected in hepatobiliary-phase images of Gd-EOB-DTPA-enhanced MRI at nine institutions. Among these, 167 nodules, which were confirmed as hypovascular by Gd-EOB-DTPA-enhanced MRI and Sonazoid-enhanced US, were evaluated in this study. Potential hypervascularization factors were selected based on their clinical significance and the results of previous reports. The Kaplan-Meier model and log-rank test were used for univariate analysis and the Cox regression model was used for multivariate analysis.
Results The cumulative incidence of hypervascularization of borderline lesions was 18, 37, and 43 % at 1, 2, and 3 years, respectively. Univariate analyses showed that tumor size (p = 0.0012) and hypoperfusion on Kupffer-phase images in Sonazoid-enhanced US (p = 0.004) were associated with hypervascularization of the tumor. Multivariate analysis showed that tumor size [HR: 1.086, 95 % confidence interval = 1.027-1.148, p = 0.004] and hypo perfusion on Kupffer-phase images [HR: 3.684, 95 % confidence interval = 1.798-7.546, p = 0.0004] were significantly different.
Conclusions Kupffer-phase images in Sonazoid-enhanced US and tumor diameter can predict hypervascularization of hypointense borderline lesions detected on hepatobiliary-phase Gd-EOB-DTPA-enhanced MRI.

DOI： 10.1007/s00535-015-1094-8

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Language：English   Publishing type：Part of collection (book)   Publisher：Springer Japan  

Various metabolic and monogenic diseases have genetic defects in the liver and are often caused by lack or overproduction of a critical gene product in its cells. Conventional therapeutic methods are often insuffi cient or unavailable to manage genetic diseases in the liver
therefore, more effi cient strategies are urgently needed. Gene therapy emerged as novel method of treatment relying on liverdirected transfer of a gene-coding sequence to produce the missing gene products or a nucleic acid sequence to inhibit the production of the gene product in excess. Practically, the success of the nucleic acid-based approaches is dependent on the availability of a method capable of delivering the gene or nucleic acid therapeutics to liver cells. Various methods of gene delivery have been developed, including viral methods and nonviral methods comprising synthetic vectors and physical methods. Hydrodynamic gene delivery is among the most effi cient and the most commonly used method for liver-directed gene delivery. Here we will briefl y summarize the principles and the progress that have been made in hydrodynamic gene delivery toward clinical applications.

DOI： 10.1007/978-4-431-55666-4_8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Liver fibrosis is the final stage of liver diseases that lead to liver failure and cancer. While various diagnostic methods, including the use of serum marker, have been established, no standard therapy has been developed. The objective of this study was to assess the approach of overexpressing matrix metalloproteinase-13 gene (MMP13) in rat liver to prevent liver fibrosis progression. A rat liver fibrosis model was established by ligating the bile duct, followed by liver-targeted hydrodynamic gene delivery of a MMP13 expression vector, containing a CAG promoter-MMP13-IRES-tdTomato-polyA cassette. After 14 days, the serum level of MMP13 peaked at 71.7 pg/ml in MMP13-treated group, whereas the nontreated group only showed a level of similar to 5 pg/ml (P &lt; 0.001). These levels were sustained for the next 60 days. The statistically lower level of the hyaluronic acids in treated group versus the nontreated group (P &lt; 0.05) reveals the therapeutic effect of MMP13 overexpression. Quantitative analysis of tissue stained with sirius red showed a statistically larger volume of fibrotic tissue in the nontreated group compared to that of MMP13-treated rats (P &lt; 0.05). These results suggest that the liver-targeted hydrodynamic delivery of MMP13 gene could be effective in the prevention of liver fibrosis.

DOI： 10.1038/mtna.2015.49

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Gastroenterology  

DOI： 10.11405/nisshoshi.113.235

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Other Link： http://search.jamas.or.jp/link/ui/2016186705

Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

DOI： 10.2169/internalmedicine.55.6036

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DOI： 10.2169/internalmedicine.55.5729

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：HINDAWI PUBLISHING CORP  

To establish a versatile means for screening and management of nonalcoholic steatohepatitis (NASH), shear wave velocity was measured in 20 normal controls and 138 consecutive nonalcoholic fatty liver disease (NAFLD) cases. Referencing biochemical properties in 679 healthy volunteers, a formula to distinguish NASH suspects was established and validated in another cohort of 138 histologically proven NAFLD cases. NASH and simple steatosis (SS) suspects were selected based on a plot of shear wave velocity against age. A formula consisting of five factors (gamma-glutamyl transpeptidase, alkaline phosphatase, platelet counts, body mass index, and presence/absence of type 2 diabetes mellitus) distinguished NASH suspects from SS suspects with area under the receiver operating characteristic curve values of 86% and 84% in the development and validation cohorts. Among 25 NAFLD cases in which shear wave velocity was repeatedly measured, 8 and 9 cases revealed an increase or decrease, respectively, of shear wave velocity in the entire liver, and the corresponding change in shear wave velocity was primarily observed in the right lobe or the left lateral segment, respectively. These results suggest that the new formula and sequential shear wave velocity measurements at each segment enable high throughput screening of NASH suspects and noninvasive assessment of pathophysiological alleviation/aggravation in cases of NASH.

DOI： 10.1155/2016/6343656

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

A hemodynamic study of hydrodynamic gene delivery (HGD) from the tail vein in rodents has inspired a mechanism and an approach to further improve the efficacy of this procedure. However, there is no report on the hemodynamics of a regional HGD, which is an inevitable approach in large animals. Here, we report the hemodynamics of a regional hydrodynamic injection in detail based on 3D volume data and the dynamism of tissue intensity over time by using computed tomography (CT) both during and after a regional hydrodynamic injection that targeted the liver of a pig weighing 15.6 kg. Contrast medium (CM) was injected at a steady speed of 20 mL/s for 7.5 s under the temporal balloon occlusion of the hepatic vein (HV). A retrograde flow formed a wedge-shaped strong enhancement area downstream of the corresponding HV within 2.5 s, which was followed by drainage into another HV beginning from the target area and the portal vein (PV) toward a non-target area of the liver. After the injection, the CM was readily eliminated from the PV outside the target area. These data suggest that an interventional radiology approach is effective in limiting the hydrodynamic impacts in large animals at a target area and that the burden overflowing into the PV is limited. A further investigation that simultaneously evaluates gene delivery efficiency and hemodynamics using CT is needed to establish feasible parameters for a regional HGD in large animals.

DOI： 10.3390/pharmaceutics7030334

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DOI： 10.1016/S1525-0016(16)34197-1

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DOI： 10.1016/S1525-0016(16)33964-8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BAISHIDENG PUBLISHING GROUP INC  

AIM: To establish a prognostic formula that distinguishes non-hypervascular hepatic nodules (NHNs) with higher aggressiveness from less hazardous one.
METHODS: Seventy-three NHNs were detected in gadolinium ethoxybenzyl diethylene-triamine-pentaacetic-acid magnetic resonance imaging (Gd-EOB-DTPA-MRI) study and confirmed to change 2 mm or more in size and/or to gain hypervascularity. All images were interpreted independently by an experienced, board-certified abdominal radiologist and hepatologist; both knew that the patients were at risk for hepatocellular carcinoma development but were blinded to the clinical information. A formula predicting NHN destiny was developed using a generalized estimating equation model with thirteen explanatory variables: age, gender, background liver diseases, Child-Pugh class, NHN diameter, T1-weighted imaging/T2-weighted imaging detectability, fat deposition, lower signal intensity in arterial phase, lower signal intensity in equilibrium phase, alpha-fetoprotein, des-gamma-carboxy prothrombin, alpha-fetoprotein-L3, and coexistence of classical hepatocellular carcinoma. The accuracy of the formula was validated in bootstrap samples that were created by resampling of 1000 iterations.
RESULTS: During a median follow-up period of 504 d, 73 NHNs with a median diameter of 9 mm (interquartile range: 8-12 mm) grew or shrank by 68.5% (fifty nodules) or 20.5% (fifteen nodules), respectively, whereas hypervascularity developed in 38.4% (twenty eight nodules). In the fifteen shrank nodules, twelve nodules disappeared, while 11.0% (eight nodules) were stable in size but acquired vascularity. A generalized estimating equation analysis selected five explanatories from the thirteen variables as significant factors to predict NHN progression. The estimated regression coefficients were 0.36 for age, 6.51 for lower signal intensity in arterial phase, 8.70 or 6.03 for positivity of hepatitis B virus or hepatitis C virus, 9.37 for des-gamma- carboxy prothrombin, and -4.05 for fat deposition. A formula incorporating the five coefficients revealed sensitivity, specificity, and accuracy of 88.0%, 86.7%, and 87.7% in the formulating cohort, whereas these of 87.2% +/- 5.7%, 83.8% +/- 13.6%, and 87.3% +/- 4.5% in the bootstrap samples.
CONCLUSION: These data suggest that the formula helps Gd-EOB-DTPA-MRI detect a trend toward hepatocyte transformation by predicting NHN destiny.

DOI： 10.3748/wjg.v21.i15.4583

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We herein report the case of a leukemia patient who developed hepatitis E seven months after undergoing a transfusion with contaminated blood products. The latency period in this case was significantly longer than that of typical hepatitis E. Recently, chronic infection with hepatitis E virus (HEV) genotype 3 has been reported in immunocompromised patients. There is a possibility that our patient was unable to eliminate the virus due to immunosuppression following chemotherapy and the administration of steroids. The prevalence of HEV in healthy Japanese individuals is relatively high and constitutes a critical source of infection via transfusion. Hepatitis E is an important post-transfusion infection, and immunocompromised patients may exhibit a long latency period before developing the disease.

DOI： 10.2169/internalmedicine.54.2332

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AimIncreased serum -fetoprotein (AFP) has been associated with a good prognosis following acute liver failure (ALF), but the levels of the fucosylated fraction of AFP (Lens culinaris agglutinin-reactive fraction of AFP [AFP-L3]) following acute liver injury remain unknown. The aim of the present study was to investigate the clinical significance of AFP and AFP-L3 in patients with acute liver injury.
MethodsWe investigated the serum levels of AFP and highly sensitive AFP-L3% in 27 patients with acute-onset autoimmune hepatitis (AIH), 28 patients with acute hepatitis (AH) and 22 patients with ALF at the onset using a highly sensitive immunoassay (micro-total analysis system).
ResultsThe serum AFP levels were increased in patients with AIH, AH and ALF, but the levels did not significantly differ among them. However, the mean AFP-L3% level was significantly higher in patients with AIH than in patients with AH (P=0.0039). Moreover, significantly more patients with AIH demonstrated AFP-L3 positivity (10%) when compared with patients with AH (P=0.014). Although the percentage of AFP-L3 positivity increased with AFP levels, at low serum AFP levels (&lt;10ng/mL), significantly more patients with AIH demonstrated AFP-L3 positivity than did patients with AH (P=0.024) or ALF (P=0.038).
ConclusionWe demonstrated for the first time that highly sensitive AFP-L3% levels were increased at the onset of AIH. The mechanism underlying the increase in AFP-L3 remains to be elucidated, but this finding may reflect an alteration of the glycosylation such as hyperfucosylation, which can influence the modifications of self-antigens in hepatocytes.

DOI： 10.1111/hepr.12318

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Evidence in support of safety of a gene delivery procedure is essential toward gene therapy. Previous studies using the hydrodynamics-based procedure primarily focus on gene delivery efficiency or gene function analysis in mice. The current study focuses on an assessment of the safety of computer-controlled and liver-targeted hydrodynamic gene delivery in dogs as the first step toward hydrodynamic gene therapy in clinic. We demonstrate that the impacts of the hydrodynamic procedure were limited in the injected region and the influences were transient. Histological examination and the hepatic microcirculation measurement using reflectance spectrophotometry reveal that the liver-specific impact of the procedure involves a transient expansion of the liver sinusoids. No systemic damage or toxicity was observed. Physiological parameters, including electrocardiogram, heart rate, blood pressure, oxygen saturation, and body temperature, remained in normal ranges during and after hydrodynamic injection. Body weight was also examined to assess the long-term effects of the procedure in animals who underwent 3 hydrodynamic injections in 6 weeks with 2-week time interval in between. Serum biochemistry analysis showed a transient increase in liver enzymes and a few cytokines upon injection. These results demonstrate that image-guided, liver-specific hydrodynamic gene delivery is safe.

DOI： 10.1371/journal.pone.0107203

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Language：English   Publisher：NATURE PUBLISHING GROUP  

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To evaluate the value of measuring shear wave velocity evoked by acoustic radiation force impulse (VTTQ) for the risk assessment of hepatocellular carcinoma (HCC) development in patients with nonalcoholic fatty liver disease (NAFLD).
VTTQ was measured three times in each of the four liver segments in 163 NAFLD patients, including 14 HCC cases; the results were statistically evaluated.
The VTTQ was 3.04 +/- A 0.17 m/s (median +/- A median absolute deviation) and 1.27 +/- A 0.25 m/s in patients with and without HCC, respectively, and was significantly higher in HCC cases (p &lt; 0.001). When the patients were classified as F0-F4 based on VTTQ cutoff values, VTTQ was significantly higher in the left lobe than in the right lobe for F0 (p &lt; 0.0001) and for F1 and F2 combined (p &lt; 0.0001), but not significantly higher for F3 and F4 combined (p = 0.070). The robust coefficient of variation was significantly higher in the left than in the right (p = 0.018) and significantly increased as VTTQ increased (p = 0.0002). Multivariate analysis showed that total bilirubin concentration {p = 0.014, 38.9 (2.08-727) [odds ratio (95 % confidence interval)]} and VTTQ [p = 0.006, 113 (3.91-3245)] were the only independent explanatory factors for HCC presence among the seven variables identified by univariate analysis. The area under the receiver-operating characteristic curve in the differentiation of HCC from non-HCC was 0.943 for VTTQ and was comparable to that for other noninvasive markers such as Fib-4 (0.964) or higher than that in BARD (0.838).
These results suggest that fibrosis occurs heterogeneously throughout the liver and that VTTQ measurements are useful in HCC risk evaluation in a NAFLD cohort.

DOI： 10.1007/s12072-014-9517-9

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Severe alcoholic hepatitis has a high mortality rate due to limited therapeutic methods. Although corticosteroids have been used to control the inflammatory response, the outcomes vary and no standardized therapy has been established. Novel therapeutic approaches, such as anti-TNF-alpha, pentoxifilline, and others have been tested clinically on the basis of their cytokinemic pathophysiology with limited success. However, treatment of leukocytosis that causes cytokinemia and hepatic inflammation in patients via granulocytapheresis and leukocytapheresis showed promising results in a number of reports. Here, we report two cases of severe alcoholic hepatitis treated with granulocytapheresis. The liver function and inflammation recovered after the therapy. A review of 35 cases treated with granulocytapheresis and leukocytapheresis demonstrated their efficacy in treating alcoholic hepatitis by controlling leukocytosis as well as cytokines such as IL-8. Multidisciplinary treatment for severe alcoholic hepatitis should be considered case by case on the basis of the complexity and severity of the condition.

DOI： 10.1007/s10620-013-2871-y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CELL PRESS  

The hemodynamics during a hydrodynamic injection were evaluated using cone beam computed tomography (CBCT) and fluoroscopic imaging. The impacts of hydrodynamic (5 seconds) and slow (60 seconds) injections into the tail veins of mice were compared using 9% body weight of a phase-contrast medium. Hydrodynamically injected solution traveled to the heart and drew back to the hepatic veins (HV), which led to liver expansion and a trace amount of spillover into the portal vein (PV). The liver volumes peaked at 165.6 +/- 13.3% and 165.5 +/- 11.9% of the original liver volumes in the hydrodynamic and slow injections, respectively. Judging by the intensity of the CBCT images at the PV, HV, right atrium, liver parenchyma (LP), and the inferior vena cava (IVC) distal to the HV conjunction, the slow injection resulted in the higher intensity at PV than at LP. In contrast, a significantly higher intensity was observed in LP after hydrodynamic injection in comparison with that of PV, suggesting that the liver took up the iodine from the blood flow. These results suggest that the enlargement speed of the liver, rather than the expanded volume, primarily determines the efficiency of hydrodynamic delivery to the liver.

DOI： 10.1038/mtm.2014.29

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We herein report three cases of alcoholic cirrhosis complicated by deep bleeding. In two of the three cases, intramuscular or retroperitoneal hematomas developed spontaneously. In contrast, in the remaining case, an intramuscular hematoma developed after trauma. In the former two patients, the intramuscular hematomas recurred at other sites during hospitalization. All three patients received conservative therapy, and one patient with a retroperitoneal hematoma underwent transcatheter arterial embolization. All of the patients eventually died of liver failure. The occurrence of severe alcoholic liver disease with deep bleeding has recently been reported with increasing frequency, and clinicians should bear this condition in mind as a life-threatening complication of alcoholic liver disease.

DOI： 10.2169/internalmedicine.53.2123

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Development of a safe and effective method for gene delivery to hepatocytes is a critical step toward gene therapy for liver diseases. Here, we assessed the parameters for gene delivery to the livers of large animals (pigs, 40-65 kg) using an image-guided hydrodynamics-based procedure that involves image-guided catheter insertion into the lobular hepatic vein and hydrodynamic injection of reporter plasmids using a computer-controlled injector. We demonstrated that injection parameters (relative position of the catheter in the hepatic vasculature, intravascular pressure upon injection, and injection volume) are directly related to the safety and efficiency of the procedure. By optimizing these parameters, we explored for the first time, the advantage of the procedure for sequential injections to multiple lobes in human-sized pigs. The optimized procedure resulted in sustained expression of the human alpha-1 antitrypsin gene in livers for more than 2 months after gene delivery. In addition, repeated hydrodynamic gene delivery was safely conducted and no adverse events were seen in the entire period of the study. Our results support the clinical applicability of the image-guided hydrodynamic gene delivery method for the treatment of liver diseases.

DOI： 10.1038/mtna.2013.52

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The development of a safe and reproducible gene delivery system is an essential step toward the clinical application of the hydrodynamic gene delivery (HGD) method. For this purpose, we have developed a novel electric power-driven injection system called the HydroJector-EM, which can replicate various time-pressure curves preloaded into the computer program before injection. The assessment of the reproducibility and safety of gene delivery system in vitro and in vivo demonstrated the precise replication of intravascular time-pressure curves and the reproducibility of gene delivery efficiency. The highest level of luciferase expression (272 pg luciferase per mg of proteins) was achieved safely using the time-pressure curve, which reaches 30 mm Hg in 10 s among various curves tested. Using this curve, the sustained expression of a therapeutic level of human factor IX protein (&gt
500 ng ml-1) was maintained for 2 months after the HGD of the pBS-HCRHP-FIXIA plasmid. Other than a transient increase in liver enzymes that recovered in a few days, no adverse events were seen in rats. These results confirm the effectiveness of the HydroJector-EM for reproducible gene delivery and demonstrate that long-term therapeutic gene expression can be achieved by automatic computer-controlled hydrodynamic injection that can be performed by anyone. © 2013 Macmillan Publishers Limited.

DOI： 10.1038/gt.2013.2

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The fucosylated fraction of alpha-fetoprotein (AFP-L3) has been used as a diagnostic marker for hepatocellular carcinoma (HCC). Recently, a highly sensitive immunoassay using an on-chip electrokinetic reaction and separation by affinity electrophoresis (micro-total analysis system; mu TAS) has been developed.
The aim of this study was to investigate the relationship between changes in the serum AFP-L3 level measured by mu TAS assay and recurrence of HCC after curative treatment.
A total of 414 HCC patients who met the Milan criteria and underwent hepatectomy or radiofrequency ablation were investigated prospectively for the relationship between HCC recurrence and values of tumor markers.
There were significant differences in recurrence-free survival between groups with and without AFP-L3 elevation measured before and after treatment (p = 0.024 and p = 0.001 for before and after treatment, respectively). Multivariate analysis revealed that AFP-L3 status (p = 0.002) measured 1 month after treatment was a significant independent predictor of HCC recurrence after curative treatment.
Elevation of the serum AFP-L3 level before treatment is a predictor of HCC recurrence, and sustained elevation of the AFP-L3 level after treatment is an indicator of HCC recurrence. Repeated measurement of mu TAS AFP-L3 should be performed for surveillance of HCC recurrence after curative treatment.

DOI： 10.1007/s10620-013-2661-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: This study aimed to clarify whether dietary deviation is associated with pathological manifestations in hepatocellular carcinoma (HCC) patients.
Methods: Dietary intake was estimated in 35 HCC cases before and after hospitalization by referencing digital camera images of each meal. Pathological conditions were evaluated in nitrogen balance, non-protein respiratory quotient (npRQ), neuropsychiatric testing and recovery speed from HCC treatment.
Results: On admission, nitrogen balance and npRQ were negative and less than 0.85, respectively. Five patients were judged to have suffered from minimal hepatic encephalopathy that tended to be associated with a lowered value of npRQ (p = 0.082). The energy from fat intake showed a tendency of positive correlation with npRQ (p = 0.11), and the patients with minimal hepatic encephalopathy took significantly fewer energy from fat (p = 0.024). The energy difference from fat between diets at home versus those in the hospital showed a significant positive correlation with npRQ change after admission (p = 0.014). The recovery speed from invasive treatments for HCC showed a significant negative correlation with npRQ alteration after admission (p = 0.0002, r = -0.73).
Conclusions: These results suggest the lower fat intake leads to deterioration of energy state in HCC patients, which associates with poor recovery from invasive treatments and various pathological manifestations.

DOI： 10.1186/1475-2891-12-79

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BAISHIDENG PUBL GRP CO LTD  

AIM: To determine whether an active intervention is beneficial for the survival of elderly patients with hepatocellular carcinoma (HCC).
METHODS: The survival of 740 patients who received various treatments for HCC between 1983 and 2011 was compared among different age groups using Cox regression analysis. Therapeutic options were principally selected according to the clinical practice guidelines for HCC from the Japanese Society of Hepatology. The treatment most likely to achieve regional control capability was chosen, as far as possible, in the following order: resection, radiofrequency ablation, percutaneous ethanol injection, transcatheter arterial chemoembolization, transarterial oily chemoembolization, hepatic arterial infusion chemotherapy, systemic chemotherapy including molecular targeting, or best supportive care. with a clinical goal of striking the best balance between functional hepatic reserve and the volume of the targeted area, irrespective of their age. The percent survival to life expectancy was calculated based on a Japanese national population survey.
RESULTS: The median ages of the subjects during each 5-year period from 1986 were 61, 64, 67, 68 and 71 years and increased significantly with time (P &lt; 0.0001). The Child-Pugh score was comparable among younger (59 years of age or younger), middle-aged (60-79 years of age), and older (80 years of age or older) groups (P = 0.34), whereas the tumor-node- metastasis stage tended to be more advanced in the younger group (P = 0.060). Advanced disease was significantly more frequent in the younger group compared with the middle-aged group (P = 0.010), whereas there was no difference between the middleaged and elderly groups (P = 0.75). The median survival times were 2593, 2011, 1643, 1278 and 1195 d for 49 years of age or younger, 50-59 years of age, 60-69 years of age, 70-79 years of age, or 80 years of age or older age groups, respectively, whereas the median percent survival to life expectancy were 13.9%, 21.9%, 24.7%, 25.7% and 37.6% for each group, respectively. The impact of age on actual survival time was significant (P = 0.020) with a hazard ratio of 1.021, suggesting that a 10-year-older patient has a 1.23-fold higher risk for death, and the overall survival was the worst in the oldest group. On the other hand, when the survival benefit was evaluated on the basis of percent survival to life expectancy, age was again found to be a significant explanatory factor (P = 0.022); however, the oldest group showed the best survival among the five different age groups. The youngest group revealed the worst outcomes in this analysis, and the hazard ratio of the oldest against the youngest was 0.35 for death. The survival trends did not differ substantially between the survival time and percent survival to life expectancy, when survival was compared overall or among various therapeutic interventions.
CONCLUSION: These results suggest that a therapeutic approach for HCC should not be restricted due to patient age. (C) 2013 Baishideng. All rights reserved.

DOI： 10.3748/wjg.v19.i24.3831

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Patent ductus venosus (PDV) is a rare condition of a congenital portosystemic shunt from the umbilical vein to the inferior vena cava. This report presents the case of an adult patient with PDV, who was successfully treated with laparoscopic shunt division. A 69-year-old male was referred with hepatic encephalopathy. Contrast-enhanced CT revealed a large connection between the left portal vein and the inferior vena cava, which was diagnosed as PDV. The safety of a shunt disconnection was confirmed using a temporary balloon occlusion test for the shunt, and the shunt division was performed laparoscopically. The shunt was carefully separated from the liver parenchyma with relative ease, and then divided using a vascular stapler. Portal flow was markedly increased after the operation, and the liver function of the patient improved over the 3-month period after surgery. Although careful interventional evaluation for portal flow is absolutely imperative prior to surgery, a minimally invasive laparoscopic approach can be safely used for treating PDV.

DOI： 10.1007/s00595-012-0316-4

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Language：Japanese  

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Cisplatin (CDDP) is an anticancer agent that is commonly used in hepatic arterial infusion (HAI) chemotherapy for hepatocellular carcinoma (HCC). This study aimed to clarify the safe and effective dose of CDDP in HAI for HCC. The hypervascular area was measured in 42 HCCs before and after HAI with CDDP. Serum platinum concentration was quantified in the peripheral and/or middle hepatic veins by atomic absorption spectrometry. The relation between the HCC response and CDDP dose was statistically analyzed. The multiple HCC nodules in an individual case generally demonstrated the same response to CDDP. The free-platinum concentration stayed relatively constant in the hepatic vein during HAI followed by a rapid decline, while total-platinum gradually increased then slowly disappeared over several days. After CDDP-HAI, 15 HCCs shrunk and 27 HCCs grew. The reduction rate in the shrunken nodules was tended to be correlated with CDDP dose after standardization with the target liver volume. On the other hand, the growth rate of the enlarged HCCs was significantly correlated with CDDP dose after normalization with creatinine clearance. These data support a recommendation of CDDP-HAI infusion where the amount of CDDP (mg) administered is less than patient creatinine clearance (mL/min/1.73 m(2)) upon an assumption of HCC doubling time of 90 days, and the targeted liver is smaller than 200 times the CDDP dose (mg). A further analysis is required to define appropriate injection speeds.

DOI： 10.1002/cam4.55

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：S. Karger AG  

Objective: We aimed to investigate the natural outcome of nonhypervascular lesions detected in the hepatobiliary phase of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI by performing a longitudinal study retrospectively enrolled in a nationwide manner. Methods: Between February 2008 and March 2011, 224 patients with 504 nodules that were diagnosed as nonhypervascular by imaging were recruited from institutions that participated in the present study. We examined the natural outcome of nonhypervascular lesions and evaluated the risk factors. Results: Of the 504 nodules, 173 (34.3%) showed hypervascular transformation. The overall cumulative incidence of hypervascular transformation was 14.9% at 12 months and 45.8% at 24 months. Multivariate analysis using the Cox regression model revealed previous treatment history for hepatocellular carcinoma (HCC
relative risk = 1.498
p = 0.036, 95% CI 1.03-2.19) and hyperintensity on T2-weighted images (relative risk = 1.724
p = 0.015, 95% CI 1.11-2.67) were identified as independent factors for hypervascular transformation. Conclusions: Patients who have a previous treatment history for HCC and with hypointense nodules showing hyperintensity on T2-weighted images need careful follow-up because of the high incidence of hypervascular transformation.

DOI： 10.1159/000355248

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Background: There is no standard therapeutic procedure for the hepatocellular carcinoma (HCC) in patients with poor hepatic reserve function. With the approval of newly developed chemotherapeutic agent of miriplatin, we have firstly conducted the phase I study of CDDP powder (DDP-H) and miriplatin combination therapy and reported its safety and efficacy for treating unresectable HCC in such cases. To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) for the combination of transarterial oily chemoembolization (TOCE) and transarterial chemotherapy (TAC) using miriplatin and DDP-H for treating unresectable hepatocellular carcinoma (HCC).
Methods: Transarterial chemotherapy using DDP-H was performed through the proper hepatic artery targeting the HCC nodules by increasing the dose of DDP-H (35-65 mg/m(2)) followed by targeting the HCC nodules by transarterial oily chemoembolization with miriplatin.
Results: A total of nine patients were enrolled in this study and no DLT was observed with any dose of DDP-H in all cases in whom 80 mg (median, 18-120) miriplatin was administered. An anti-tumour efficacy rating for partial response was obtained in one patient, while a total of four patients (among eight evaluated) showed stable disease response, leading to 62.5% of disease control rate. The pharmacokinetic results showed no further increase in plasma platinum concentration following miriplatin administration.
Conclusion: Our results suggest that a combination of DDP-H and miriplatin can be safely administered up to their respective MTD for treating HCC.

DOI： 10.1186/1471-230X-12-127

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Purpose: To establish a formula to guide appropriate embolization volume for postprocedural platelet gain following partial splenic arterial embolization (PSE) for hypersplenism.
Materials and Methods: The hepatic volume (Vh) and splenic volume (Vsp) were measured by using 2-mm-thick computed tomography images before and after PSE in 20 patients with various chronic liver diseases. A formula was derived from the relationship between the platelet count increase ratio (dPlt%) and the organ volumes, which was then evaluated in another cohort.
Results: After an embolization of a median of 72.1% of the spleen (interquartile range, 38.2%-93.8%), the dPlt% was 67.7% +/- 40.0 and significantly correlated with the increasing ratio of Vh to Vsp (P = .019, rho = 0.52). Because the difference in Vh/Vsp ratio after PSE was significantly correlated with the spleen embolization ratio (eVsp%; P = .0003, rho = 0.72), the estimated dPlt% could be derived from the Vh/Vsp ratio before PSE and the eVsp%. The estimated dPlt% was significantly correlated with the actual dPlt% (P = .0003, rho = 0.72). When the formula was evaluated in another cohort of 14 cases, another strict correlation was observed (P &lt; .0001, rho = 0.92).
Conclusions: These data suggest that platelet count after PSE can be predicted before the procedure by using the Vh/Vsp ratio and the anticipated spleen embolization volume. The use of such a prediction can prevent too much or too little embolization, thereby leading to an improvement in the risk/return trade-off in PSE.

DOI： 10.1016/j.jvir.2012.03.008

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

肝性脳症に対しバルーン下逆行性経静脈的塞栓術(B-RTO)を施行した14例(男9例、女5例、平均64.5歳)の成績を報告した。門脈大循環シャントの部位は胃腎7例、脾腎5例、mesocaval 3例、奇静脈1例、傍臍静脈1例であった。10例でB-RTO施行による門脈圧上昇緩和目的で部分脾動脈塞栓術を施行した。シャント血管の完全な塞栓が得られなかったのは2例で、1例は翌日バルーン破損を認め、他の1例は排血路が多彩でコイル塞栓が中心であった。残り12例は完全な塞栓が得られ、血中アンモニア値正常化と脳症症状改善が認められた。術後合併症は症候性胸腹水4例、特発性細菌性腹膜炎或いは敗血症2例、門脈血栓症1例、麻痺性イレウス1例が認められた。術後2ヵ月以上経過した13例において、血中アンモニア値は正常値維持4例、時折軽度上昇5例、再上昇し高値持続2例、低下なし2例であった。顕性脳症は3例に認め、うち2例は肝病変進展によるものであった。

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Purpose: To evaluate the efficacy and safety of simultaneous combined balloon-occluded retrograde transvenous obliteration (B-RTO) and partial splenic embolization (PSE) for gastric varices and/or hepatic encephalopathy.
Materials and Methods: B-RTO was performed in 19 consecutive patients with gastric varices and/or hepatic encephalopathy, of whom 10 received simultaneous combined B-RTO and PSE (group 1) and nine received B-RTO monotherapy (group 2). To evaluate the safety of these techniques, we analyzed 20 patients who received PSE monotherapy during the same period as a control group (group 3). Outcomes were retrospectively assessed.
Results: No significant differences were observed in baseline characteristics among the three groups except for significantly lower platelet counts and larger spleen volumes in group 3. In all cases in groups 1 and 2, gastric varices disappeared and hepatic encephalopathy improved after treatment. Procedure times were not significantly different between groups 1 and 2 (P = .7435). In group 1, the volume of sclerosing agent required for B-RTO was significantly lower (P = .0355) and exacerbation of esophageal varices was significantly less frequent (P = .0146) than in group 2. Few serious complications occurred in patients who received combined therapy.
Conclusions: This study indicates that concomitant PSE may help diminish the increase in portal venous pressure after B-RTO for portosystemic shunts, and may allow a reduction in the volume of hazardous sclerosing agent used. It is worth evaluating the efficacy of simultaneous B-RTO and PSE in a prospective study.

DOI： 10.1016/j.jvir.2012.01.065

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We report the case of a 73-year-old woman having diffuse large B-cell primary gastric lymphoma with a cirrhotic liver caused by hepatitis C virus infection. She visited our hospital with symptoms of nausea and vomiting, which appeared to be caused by stenosis due to the tumor. Metastatic tumors were seen in the gastric and jugular lymph nodes. The clinical stage was IVB with a high risk of poor prognosis according to the international index. Because of poor hepatic reserve function, standard chemotherapy could not be administered. To maintain her quality of life, palliative involved-field radiotherapy was performed. The symptoms and tumor markers significantly improved, and computed tomography and endoscopy indicated the disappearance of the primary gastric tumor. Two months after radiotherapy and her return home, she died of pneumonia. Autopsy showed neither lymphoma cells nor stenosis of gastric lesion. The significant antitumor effect on primary tumor in our case suggests that the involved-field radiotherapy, although palliative, can be a therapeutic option for primary gastric lymphoma patients with various complications. © Springer 2012.

DOI： 10.1007/s12328-012-0292-7

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Acoustic Radiation Force Impulse (ARFI) imaging is a novel ultrasound-based elastography method that is integrated in a conventional ultrasound machine enabling the exact localization of measurement site. It might present an alternative method to transient elastography for the noninvasive assessment of liver fibrosis. At present, studies with small patient population have shown promising results. A systematic review and meta-analysis of pooled patient data were performed to evaluate the overall performance of ARFI for the staging of liver fibrosis. Literature databases were searched up to 10/2010. The authors of the original publication were contacted, and the original patient data were requested. A meta-analysis was performed using a random effect meta-analytic method for diagnostic tests. In addition, available data comparing ARFI with FibroScan with the DeLong test were evaluated. Literature search yielded nine full-paper publications evaluating ARFI while using liver biopsy as reference method. Original patient data were available from eight studies including 518 patients. The mean diagnostic accuracy of ARFI expressed as areas under ROC curves (AUROC) was 0.87 for the diagnosis of significant fibrosis (F = 2), 0.91 for the diagnosis of severe fibrosis (F = 3), and 0.93 for the diagnosis of cirrhosis. ARFI can be performed with good diagnostic accuracy for the noninvasive staging of liver fibrosis.

DOI： 10.1111/j.1365-2893.2011.01537.x

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Aim : To investigate the impact of hepatitis B virus (HBV) infection on cellular gene expression, by conducting both in vitro and in vivo studies. Methods: Knockdown of HBV was targeted by stable expression of short hairpin RNA (shRNA) in huH-1 cells. Cellular gene expression was compared using a human 30K cDNA microarray in the cells and quantified by real-time reverse transcription-polymerase chain reaction (RT-PCR) (qRT-PCR) in the cells, hepatocellular carcinoma (HCC) and surrounding non-cancerous liver tissues (SL). Results: The expressions of HBsAg and HBx protein were markedly suppressed in the cells and in HBx transgenic mouse liver, respectively, after introduction of shRNA. Of the 30K genes studied, 135 and 103 genes were identified as being down- and up-regulated, respectively, by at least twofold in the knockdown cells. Functional annotation revealed that 85 and 62 genes were classified into four up-regulated and five downregulated functional categories, respectively. When gene expression levels were compared between HCC and SL, eight candidate genes that were confirmed to be up- or down-regulated in the knockdown cells by both microarray and qRT-PCR analyses were not expressed as expected from HBV reduction in HCC, but had similar expression patterns in HBV- and hepatitis C virus-associated cases. In contrast, among the eight genes, only APM2 was constantly repressed in HBV non-associated tissues irrespective of HCC or SL. Conclusion: The signature of cellular gene expression should provide new information regarding the pathophysiological mechanisms of persistent hepatitis and hepatocarcinogenesis that are associated with HBV infection. ©2012 Baishideng.

DOI： 10.4254/wjh.v4.i4.139

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Language：Japanese  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

We analyzed hepatocellular carcinoma (HCC) with progenitor cell features using hepatic stem/progenitor cell marker neural cell adhesion molecule (NCAM). Approximately 8.3% of the operated HCC cases expressed NCAM, and 22.3% of the HCC patients had soluble NCAM levels &gt;1000 ng/ml (the "highly soluble" NCAM group). Soluble NCAM status was a significant independent factor predictive of long-term survival in patients with HCC, and high levels of soluble NCAM were significantly related to intrahepatic metastasis. The 140-kDa NCAM isoform was specifically detected in the "highly soluble" NCAM group of HCC patients and its related signals are potential drug targets for NCAM+ HCC. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.canlet.2011.05.021

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Publisher：5  

DOI： 10.2165/11594020-000000000-00000

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

See article in J. Gastroenterol. Hepatol. 2011; 26: 739-744.

DOI： 10.1111/j.1440-1746.2011.06671.x

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Alpha-fetoprotein (AFP)-producing adenocarcinoma is known for its rapid progression and poor prognosis, and chemotherapy regimens are yet to be standardized. Here we describe the first report of AFP-producing adenocarcinoma with calcification. The metastatic route was visualized from the calcification, and combination chemotherapy was performed. A 77-year-old Japanese man was transferred to our hospital for treatment of liver tumors. Computed tomography (CT) revealed multiple liver tumors with portal vein tumor thrombosis. The tumors were highly attenuated before enhancement, suggesting various degrees of calcification. Serum levels of carcinoembryonic antigen (CEA), AFP, and the proportion of fucosylated AFP were considerably elevated. Gastroduodenoscopy revealed an elevated tumor occupying the duodenal bulb with an ulcerative lesion in the vicinity of the gastroduodenal junction, and biopsy specimens from the duodenum and liver revealed medullary adenocarcinoma with calcification. Three-dimensional reconstruction of CT images clearly showed that the calcified lesions had spread from the gastroduodenal junction to the liver via a route comprising the corresponding local vein, the superior mesenteric vein, and portal vein. The patient was accordingly diagnosed with calcified AFP-producing adenocarcinoma with multiple liver metastases. Combination chemotherapy using TS-1 and cisplatin (CDDP) resulted in a striking response for the initial 4 months in terms of tumor markers and CT findings. This is the first report of AFP-producing adenocarcinoma with calcification. A metastatic route from the primary tumor to the liver was clearly visualized by tracing the calcified lesions. Combination chemotherapy based on 5-fluorouracil and CDDP may have the potential to prolong survival. © 2011 Springer.

DOI： 10.1007/s12328-011-0209-x

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Language：Japanese   Publisher：(一社)日本内科学会  

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Aim: To reveal the manner of hepatocellular carcinoma (HCC) development in patients with nonalcoholic steatohepatitis (NASH) focusing on multicentric occurrence (MO) of HCC. Methods: We compared clinicopathological characteristics between patients with and without MO of HCC arising from NASH background. The clinical features were implicated with reference to the literature available. Results: MO of HCC was identified with histological proof in 4 out of 12 patients with NASH-related HCC (2 males and 2 females). One patient had synchronous MO
an advanced HCC, two well-differentiated HCCs and a dysplastic nodule, followed by the development of metachronous MO of HCC. The other three patients had multiple advanced HCCs accompanied by a well-differentiated HCC or a dysplastic nodule. Of these three patients, one had synchronous MO, one had metachronous MO and the other had both synchronous and metachronous MO. There were no obvious differences between the patients with or without MO in terms of liver function tests, tumor markers and anatomical extent of HCC. On the other hand, all four patients with MO of HCC were older than 70 years old and had the comorbidities of obesity, type 2 diabetes mellitus (T2DM), hypertension and cirrhosis. Although these conditions were not limited to MO of HCC, all the conditions were met in only one of eight patients without MO of HCC. Thus, concurrence of these conditions may be a predisposing situation to synchronous MO of HCC. In particular, old age, T2DM and cirrhosis were suggested to be prerequisite for MO because these factors were depicted in common among two other cases with MO of HCC under NASH in the literature. Conclusion: The putative predisposing factors and necessary preconditions for synchronous MO of HCC in NASH were suggested in this study. Further investigations are required to clarify the accurate prevalence and predictors of MO to establish better strategies for treatment and prevention leading to the prognostic improvement in NASH. © 2011 Baishideng.

DOI： 10.4254/wjh.v3.i1.15

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Language：Japanese  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Alpha-fetoprotein (AFP) has been widely used as a diagnostic master for hepatocellular carcinoma (HCC), and the fucosylated fraction of AFP (AFP-L3) has been reported to be a specific marker for HCC. However, AFP-L3 has not always been reliable in cases with low serum AFP concentrations. Recently, a novel automated immunoassay for AFP-L3, the micro-total analysis system (mu-TAS), has been developed.
The aim of this study is to evaluate the clinical usefulness of mu-TAS AFP-L3.
Serum AFP-L3 was measured in 295 patients with HCC and in 350 with benign liver diseases. The diagnostic accuracy of mu-TAS AFP-L3 was compared with that of the conventional assay (liquid-phase binding assay; LiBASys). The relationship between mu-TAS AFP-L3 and clinical features was investigated.
When the cutoff value was set at 7%, the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of mu-TAS AFP-L3 were 60.0%, 90.3%, 76.4%, 83.9%, and 72.8%, respectively. Its sensitivity was particularly good (41.1%) in HCC subgroups with lower AFP concentrations (&lt; 20 ng/ml). The positivity rates for mu-TAS AFP-L3 were higher at each tumor stage than those of LiBASys AFP-L3 (mu-TAS/LiBASys: stage I, 44.2%/16.3%; stage II, 52.9%/37.5%; stage III, 66.4%/44.5%; stage IV, 82.8%/65.5%).
mu-TAS AFP-L3 is more sensitive for discriminating HCC than the conventional LiBASys AFP-L3, particularly in subgroups with lower AFP concentrations and early-stage HCC.

DOI： 10.1007/s10620-010-1222-5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

The aim of this study was to evaluate the clinical usefulness of measuring the Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) for prognostic predictor in patients with hepatocellular carcinoma (HCC).
A total of 477 HCC patients who underwent percutaneous ablative therapy or hepatectomy were enrolled. Overall survival and recurrence-free survival were respectively evaluated retrospectively and prospectively. Multivariate analyses of clinical prognostic factors were performed by Cox&apos;s stepwise proportional hazard model.
AFP-L3 status was a statistically significant independent prognostic factor of long-term survival (P = 0.013) and recurrence-free survival (P = 0.006) in patients who underwent percutaneous ablative therapy. In contrast, AFP-L3 did not affect prognosis in patients who underwent hepatectomy.
AFP-L3 had different impacts on prognosis in patients with HCC who underwent percutaneous ablative therapy and hepatectomy. Our results suggest that AFP-L3 positivity (a parts per thousand yen15%) might be a promising indicator for choosing therapeutic modalities in HCC patients.

DOI： 10.1007/s10620-009-0954-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W J G PRESS  

AIM: To investigate whether a noninvasive measurement of tissue strain has a potential usefulness for management of nonalcoholic steatohepatitis (NASH).
METHODS: In total 26 patients, 23 NASHs and 3 normal controls were enrolled in this study. NASH was staged based on Brunt criterion. At a region of interest (ROT), a shear wave was evoked by implementing an acoustic radiation force impulse (ARFI), and the propagation velocity was quantified.
RESULTS: Shear wave velocity (SWV) could be reproducibly quantified at all ROIs in all subjects except for 4 NASH cases, in which a reliable SWV value was not calculated at several ROIs. An average SWV of 1.34 +/- 0.26 m/s in fibrous stage 0-1 was significantly slower than 2.20 +/- 0.74 m/s and 2.90 +/- 1.01 m/s in stages 3 and 4, respectively, but was not significantly different from 1.79 +/- 0.78 m/s in stage 2. When a cutoff value was set at 1.47 m/s, receiver operating characteristic analysis showed significance to dissociate stages 3 and 4 from stage 0-1 (P = 0.0092) with sensitivity, specificity and area under curve of 100%, 75% and 94.2%, respectively. In addition, the correlation between SWV and hyaluronic acid was significant (P &lt; 0.0001), while a tendency toward negative correlation was observed with serum albumin (P = 0.053).
CONCLUSION: The clinical implementation of ARFI provides noninvasive repeated evaluations of liver stiffness at an arbitrary position, which has the potential to shed new light on NASH management. (C) 2010 Baishideng. All rights reserved.

DOI： 10.3748/wjg.v16.i23.2918

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The association between serum alpha-fetoprotein (AFP) levels during and after interferon (IFN) therapy and the development of hepatocellular carcinoma (HCC) was evaluated in patients with chronic hepatitis C (CHC). A total of 263 patients treated by IFN with or without ribavirin were enrolled in the study. Serum AFP levels during and after IFN therapy were investigated retrospectively, and statistical analysis was performed to identify the factors associated with HCC development. During IFN therapy, serum AFP levels significantly decreased, regardless of virologic response to treatment. Increased serum AFP levels (a parts per thousand yen10 ng/ml) at the end of IFN therapy (EOT) was a close-to-significant variable affecting the development of HCC (P = 0.057), and a significantly higher cumulative incidence of HCC was seen in patients with increased serum AFP levels at EOT (P = 0.021). Serum AFP level at EOT is a possible predictor of HCC in CHC patients after IFN therapy.

DOI： 10.1007/s10620-008-0642-y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Image-guided, lobe-specific hydrodynamic gene delivery to liver was assessed in pigs. The procedure involved image-guided insertion of a balloon catheter to the hepatic vein of the selected lobe from the jugular vein and hydrodynamic injection of plasmid DNA using a newly developed computer-controlled injection device. We demonstrated that the impact of the procedure was regional with minimal effects on neighboring lobes. Level of gene expression resulted from the procedure was 10(7) relative light units (RLU)/mg in the targeted lobes and 10(2)-10(5) RLU/mg in the nontargeted lobes 4 hours after hydrodynamic injection of pCMV-Luc plasmids. Occlusion of blood flow in the inferior vena cava (IVC) or IVC plus portal vein (PV) was effective in elevating hydrodynamic pressure in the targeted vasculature but did not enhance gene delivery efficiency. Physiological examination on pigs with IVC occlusion revealed transient decreases of blood pressure and respiration rate. Removal of occlusion from IVC resulted in a rapid and transient increase in heart rate. Occlusion of the PV and hepatic vein showed no effect on physiological and cardiac activities. No major changes in serum composition were observed. These results suggest that (i) image-guided, lobe-specific hydrodynamic procedure is effective for regional gene delivery to liver, (ii) blockade in IVC should be avoided for hydrodynamic gene delivery to the liver, and (iii) clinical application of hydrodynamic gene delivery to liver is feasible.

DOI： 10.1038/mt.2008.294

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

The recently developed hydrodynamic delivery method makes it possible to deliver DNA and RNA into parenchyma cells by intravascular injection of nucleic acid containing solution. While this procedure is effective in rodents, it is difficult to perform in large animals, because manual control while delivering the injection cannot be sufficiently reliable for achieving a just-right hydrodynamic pressure in targeted tissue. In order to overcome this problem, we have developed a computer-controlled injection device that uses real-time intravascular pressure as a regulator. Using the new injection device, and mouse liver as the model organ, we demonstrated continuous injection at a single pressure and different pressures, and also serial ( repeated) injections at intervals of 250 ms, by programming the computer according to the need. When assessed by reporter plasmids, the computer-controlled injection device exhibits gene delivery efficiency similar to that of conventional hydrodynamic injection. The device is also effective in gene delivery to kidney and muscle cells in rats, with plasmids or adenoviral vectors as gene carriers. Successful gene delivery to liver and kidney was also demonstrated in pigs, with the computer-controlled injection being combined with image-guided catheterization. These results represent a significant advance in in vivo gene delivery research, with potential for use in gene therapy in humans.

DOI： 10.1038/mt.2008.66

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Language：Japanese   Publisher：The Japan Society of Hepatology  

A 54-year-old man was admitted to our hospital with jaundice and abdominal distension. He was pointed out the multiple liver tumors five years ago. During the follow-up period, tumor size showed no remarkable changes, but jaundice and ascites were observed after five years. Further examinations including the peritoneoscopy and biopsy from disseminated lesion in the skin revealed hepatic epithelioid hemangioendothelioma. According to the autopsy, the tumors infiltrated to the hepatic arteries, veins and bile ducts which induced severe deformity of right lobe of the liver and disseminated to ...

DOI： 10.2957/kanzo.49.14

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Niigata University  

Several integrated scoring systems for hepatocellular carcinoma (HCC) have recently been proposed, but there is still no consensus regarding their validity. The present study developed a new scoring system to obtain a better model for predicting the survival of patients with HCC. Data obtained from 1,070 patients with HCC diagnosed at 31 hospitals affiliated with the Niigata Liver Disease Study Group from January 1993 through December 2003 were retrospectively analyzed. The significant factors, which affected the survival of the patients were analyzed, and the best fitting model for the patients' survival was constructed. Fourteen factors were identified based on a univariate analysis, and those factors were used in a multivariate analysis as the candidate prognostic factors. The first Cox's analysis revealed that the Cancer of the Liver Italian Program (CLIP) score, tumor diameter, metastasis (N factor and/or M factor) based on the Liver Cancer Study Group of Japan (LCSGJ), and Japan Integrated Staging (JIS) score were all significant factors. Since the results suggested that both the CLIP and JIS scores were insufficient for the prediction of survival, the Japan Integrated Triform system (JITs) score was designed by removing tumor morphology and portal vein thrombosis from the CLIP score and by adding T factor and metastasis of the LCSGJ. An evaluation by the Akaike information criteria (AIC) showed the JITs score to be a good-fitting model in the present study population. JITs score may hopefully be useful for physicians in determining the appropriate management options.

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Other Link： http://search.jamas.or.jp/link/ui/2009186907

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Niigata University  

Limitations to physical activity lead to impairments of insulin sensitivity and deterioration of health related quality of life (HRQOL) in patients with chronic liver diseases (CLD). The effects of regular exercise on physical and psychosocial factors were prospectively evaluated in CLD. Five patients with various etiologies and stages were enrolled. Daily aerobic and resistance trainings were conducted for a course of five months with an oral intake of branched-chain amino acids (BCAA) starting one month prior to the exercise. Various biochemical, physical parameters, and profile of mood states (POMS) were measured before and after the course. Statistical significance was evaluated using a resampling method. No event was marked during the course to require additional treatments. A significant improvement in insulin sensitivity was observed as reductions of fasting blood glucose and serum insulin levels. Physical capability was significantly improved in both strength and endurance as increments of grasping and knee extension powers, and ventilatory threshold. The fatigue score was significantly reduced in accordance with a decreasing tendency of all other negative aspects in POMS. While significant decreases in serum concentrations of cholinesterase and prealbumin, platelet count, and bone mass were observed, serum concentrations of transferrin and BCAA as well as prothrombin activity showed increasing tendency. Regular exercise could be a promising alternative to improve insulin sensitivity and HRQOL in CLD, though medications and close evaluation should be conducted for possibilities of osteoporosis and hemorrhagic events.

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Other Link： http://search.jamas.or.jp/link/ui/2008231310

Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING  

Background: The aim of the present study was to establish L3 fraction before initial treatment as a useful prognostic factor in a prospective fashion in hepatocellular carcinoma (HCC) where the alpha-fetoprotein (AFP) was very low.
Methods: From 1990 to 2004, 298 HCC patients in whom L3 could be measured were examined in the present study. Enrolled patients with HCC underwent operation, transcatheter arterial chemoembolization and percutaneous ablation therapy. The current patient status was confirmed as of the end of March 2005. L3 was determined by crossed immuno-affinoelectrophoresis when AFP was &gt;= 30 ng/mL. It was carried out by liquid-phase binding assay system on cases where AFP &lt; 30 ng/mL. The tentative discriminating line of L3 was set at 15%.
Results: The HCC group included four subgroups: 110 patients with AFP concentrations &lt;= 100 ng/mL, 70 with AFP &lt;= 50 ng/mL, 38 with AFP &lt;= 30 ng/mL and 29 with AFP &lt;= 25 ng/mL. The mean survival rate in the HCC group, whose L3 was &gt; 15% (high L3), was significantly lower than that in the HCC group whose L3 was &lt;= 15% (low L3). There were also statistically significant differences in survival rates between high and low L3 in the four HCC subgroups. The statistically significant differences were more distinct in the subgroups with low AFP concentrations.
Conclusion: The present study indicates that the L3 fraction before treatment serves as a useful prognostic indicator when the serum concentrations of AFP were very low.

DOI： 10.1111/j.1872-034X.2007.00147.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

The impact of hydrodynamic injection on liver structure was evaluated in mice using various microscopic techniques. Upon hydrodynamic injection of approximately 9% of body weight by volume, the liver rapidly expanded, reaching maximal size at the end of the injection and returned to its original size in 30 min. Histological analysis revealed a swollen appearance in the peri-central region of the liver where delivery of genes and fluorescence-labeled markers was observed. Scanning and transmission electron microscopy showed enlargement and rupture of endothelium that in about 24 - 48 h regains its morphology and normal function as a barrier against infection by adenovirus viral particles. At the cellular level in hydrodynamically treated animals, four types of hepatocytes were seen: cells with normal appearance; cells with enriched vesicles in the cytoplasm; cells with lightly stained cytosol; and cells with significant dilution of the cytoplasm. In addition, red blood cells and platelets were observed in the space of Disse and even inside hepatocytes. Vesicle formation is triggered by hydrodynamic injection and resembles the process of macropinocytosis. These results, whereas confirming the physical nature of hydrodynamic delivery, are important for a better understanding of this efficient method for intrahepatic gene and small interfering RNA delivery.

DOI： 10.1038/sj.gt.3302865

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：MEDICAL IMAGING AND INFORMATION SCIENCES  

Chronic liver disease causes health problem such as hepatic failure or hepatocellular carcinoma. As the disease progresses, some fibroses become apparent, and, as such, influence a vascular structure. We have proposed, previously, a method to extract various vascular features from CTAP images. In this paper we suggested that the method improved in this paper should be applicable to CTAP images of 9 patients. It reveals that the vascular-structure analysis can be useful for estimating liver fibrosis level.

DOI： 10.11318/mii.23.130

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Other Link： http://search.jamas.or.jp/link/ui/2008047878

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Objective. In this study we compared the potential roles of preoperative human-telomerase reverse transcriptase (h-TERT) mRNA versus a-fetoprotein (AFP) mRNA expression in the peripheral blood as a tool to predict prognosis and tumor recurrence after living donor liver transplantation (LDLT) in hepatocellular carcinoma (HCC) patients.
Patients and Methods. We examined 14 patients with unresectable HCC who underwent LDLT. Six patients displayed stage IVA HCC that deviated from the Milan criteria, while the rest of the patients fell within the limitations of the Milan criteria. We analyzed the relationship between preoperative h-TERT mRNA or AFP mRNA expression in the peripheral blood and survival without recurrence.
Results. There was no significant difference between the survival curves without recurrence of those patients who did versus did not meet the Milan criteria. There was also no significant difference between the survival curves without recurrence among patients with positive versus negative AFP mRNA expression. However, there was a significant difference (P = .005) between the survival curves without recurrence of those patients with positive preoperative h-TERT mRNA expression versus those who either had an initially negative preoperative h-TERT mRNA or who converted from positive to negative after neoadjuvant immunochemotherapy.
Conclusions. h-TERT mRNA seemed to prove more valuable than AFP mRNA not only to assess preoperative treatment modalities and postoperative patient surveillance, but also to evaluate prospective LDLT patients with HCC. Moreover, use of h-TERT mRNA could potentially expand the indications for transplantation to patients outside the Milan criteria.

DOI： 10.1016/j.transproceed.2006.10.172

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W J G PRESS  

AIM: To determine which treatment modality hepatectomy or percutaneous ablation - is more beneficial for patients with small hepatocellular carcinoma (HCC) (&lt;= 4 cm) in terms of long-term outcomes.
METHODS: A retrospective analysis of 149 patients with HCC &lt;= 4 cm was conducted. Eighty-five patients underwent partial hepatectomy (anatomic in 47 and non-anatomic in 38) and 64 underwent percutaneous ablation (percutaneous ethanol injection in 37, radiofrequency ablation in 21, and microwave coagulation in 6). The median follow-up period was 69 mo.
RESULTS: Hepatectomy was associated with larger tumor size (P&lt;0.001), whereas percutaneous ablation was significantly associated with impaired hepatic functional reserve. Local recurrence was less frequent following hepatectomy (P&lt;0.0001). Survival was better following hepatectomy (median survival time: 122 mo) than following percutaneous ablation (median survival time: 66 mo; P = 0.0123). When tumor size was divided into &lt;= 2 cm vs &gt; 2 cm, the favorable effects of hepatectomy on long-term survival was seen only in patients with tumors &gt;2 cm (P=0.0001). The Cox proportional hazards regression model revealed that hepatectomy (P=0.006) and tumors &lt;= 2 cm (P=0.017) were independently associated with better survival.
CONCLUSION: Hepatectomy provides both better local control and better long-term survival for patients with HCC &lt;= 4 cm compared with percutaneous ablation. Of the patients with HCC &lt;= 4 cm, those with tumors &gt; 2 cm are good candidates for hepatectomy, provided that the hepatic functional reserve of the patient permits resection. (C) 2006 The WJG Press. All rights reserved.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: In this study we evaluated the potential role of preoperative h-TERT mRNA expression in peripheral blood as a tool for predicting prognosis and tumor recurrence after living-related liver donor transplantation (LRLDT).
Methodology: The study included patients with unresectable HCC who underwent LRLDT from July 1999 to May 2003.
Results: There was no significant difference between the survival curves of those patients who met the Milan criteria and those who did not. However, there was a statistically significant difference (p=0.032) between the survival curves of those patients with positive preoperative h-TERT mRNA expression, and those who either had an initially negative preoperative h-TERT mRNA or who converted from positive to negative after neoadjuvant immunochemotherapy.
Conclusions: In conclusion, the presence or absence of h-TERT mRNA in the peripheral blood may be a useful criterion in evaluating HCC patients for transplantation, as well as a valuable method of assessing anti-tumor therapy and tumor relapse.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI IRELAND LTD  

Here, we report a case of 70-year-old female with metastatic choroidal melanoma in the liver, which was detected 30 years after enucleation of the left eyeball. At first, two hypovascular tumors (4 cm and 1 cm in diameter) were detected in the liver as high-density areas on plain computed tomography (CT). They were demonstrated as hyper- and hypo-intensity lesions on T1- and T2-weighted image of magnetic resonance imaging (MRI), respectively, with superparamagnetic iron oxide uptake. During about 2-years follow-up, the larger tumor did not change significantly in size and in the character. However, the smaller one grew up in size and changed its nature to hypervascular and hyperintensity on T2-weighted image of MRI. These hypervascular tumors increased in number and in size rapidly. The specimens obtained with tumor biopsy revealed epithelioid tumor cells positive for HMB45 immunohistochemical stain with and without brown pigment, and the tumors were diagnosed as melanoma. The patient underwent transcatheter arterial chemoembolization with cisplatin and epirubicin hydrochloride, and subsequent transcatheter arterial infusion chemotherapy with cisplatin, nimustine and dacarbazine. Unfortunately, however, the tumor rapidly progressed and she died. We discuss the imaging of the melanoma metastasized to the liver with the estimation of doubling time (DT) of the tumors. (C) 2004 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.hepres.2004.10.007

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KLUWER ACADEMIC/PLENUM PUBL  

Human telomerase RNA component (hTR) expression, which increases in the majority of cancer cells with an acquisition of telomerase activity, was concomitantly evaluated with methylation status and human telomerase reverse transcriptase ( hTERT) expression in colorectal cancers and precursor lesions. hTR and hTERT expressions were detected by in situ hybridization and reverse transcription following polymerase chain reaction, respectively, in 15 colonic adenomas, 19 sporadic colonic cancers at various histological stages, and 3 normal colonic mucosa samples. The methylationstatus of hTR was evaluated by methylation-specific polymerase chain reaction following restriction endonuclease digestion and direct sequencing. hTERT expression was detected in 16 of 19 cancers. hTR expression was detected in all cancers including two cases of intramucosal carcinoma. No hTR signals were detected in the normal epithelium or in the adenomas with severe atypism. CpG dinucleotides in the 5'-untranslated region of hTR were completely unmethylated from - 204 to - 3 and mosaically methylated from - 290 to - 272, irrespective of the atypism. These results suggest that hTR expression is increased at the adenoma-to-carcinoma transition stage but is not always associated with hTERT expression. Hypomethylation of the hTR promoter region is not likely to be the main mechanism regulating hTR expression.

DOI： 10.1023/B:DDAS.0000042256.89282.c4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI IRELAND LTD  

Our previous results showed that the fucosylation index (FI) was considered to be a useful prognostic factor in patients with hepatocellular carcinoma (HCC). On the other hand, serum concentrations of alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) were regarded as prognostic indicators. However, the relationship among FI, AFP, and DCP as prognostic factors remained unknown. The aim of this study was to elucidate the correlation among these three prognostic factors. One hundred and seventy-six patients with HCC from 1990 to 1998, who showed increment of serum AFP concentrations more than 30 ng/ml before treatment, were examined in the present study. FI was determined in these patients by crossed immumoaffino-electrophoresis in the presence of Lens culinaris agglutinin. FI of AFP was defined as the percentage of the L. culinaris agglutinin (LCA)-reactive species in total AFP (same as U fraction). Serum concentrations of DCP were also measured. Enrolled patients with HCC underwent transcatheter arterial embolization, chemoembolization, percutaneous ethanol injection, and/or percutaneous microwave coagulation therapy. The current patients status was the one which was confirmed at the end of March 2001. Analysis by the Cox's proportional hazards model showed that FI, AFP, and DCP were significant prognostic factors. When the tentative demarcation levels of FI, AFP, and DCP were set at 18%, 200 ng/ml, and 0.06 arbitrary units (AU)/ml, respectively, the following results for the prognostication of patients with HCC were obtained. First, the survival rates in the groups with one out of the three optional markers over the demarcation level were significantly lower than the survival rates of other groups, whose optional one marker was equal to or less than the demarcation level, respectively. Next, the survival rates in the groups in which two out of three optional markers were over the demarcation levels were lower than the survival rates of other groups, whose optional two markers were equal to or less than the demarcation levels, with high significance. On the contrary, there was absence or attenuation of statistically significant differences in the survival rates between the groups in which two of the three optional markers showed no accordant results (high FI and low AFP versus low FI and high AFP, low FI and high DCP versus high FI and low DCP, high DCP and low AFP versus low DCP and high AFP). Finally, we compared the survival rates between the HCC groups, whose optional one marker was over the demarcation level and whose remainders were equal to or less than the demarcation levels and another HCC group whose optional one marker was equal to or less than the demarcation level and whose remainders were over the demarcation levels to reconfirm the weight of each prognostic factor. These comparisons together with Cox's analysis showed that the weight of each prognostic factor in the survival rates is consecutively ordered as DCP, FI, and AFP. The present study indicates that measurements of FI, AFP, and DCP from the sera before the initial treatment improve prognostic estimates and appraisal of the therapeutic outcome in patients with HCC. (C) 2003 Elsevier B.V. All rights reserved.

DOI： 10.1016/S1386-6346(03)00266-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC CANCER RESEARCH  

Purpose: The purpose of this study was to evaluate whether IFN therapy for chronic hepatitis C could overcome telomere reduction in the liver, a possible risk factor for hepatocellular carcinoma (HCC) development.
Experimental Design: Relative telomeric repeat content (RTC) in the liver was measured before and after IFN therapy in 21 chronic hepatitis C cases. Liver samples were obtained at average intervals of 12, 75, and 32 months in eight complete responders (CRs) and one biochemical responder (BR), four CRs in whom HCC developed after an eradication of hepatitis C virus, and eight nonresponders, respectively. Telomeric repeat binding factor 1(TRF1) was immunostained in specimens from CRs and a BR.
Results: Although the average RTC of 0.96+/-0.14 (mean+/-SD) significantly decreased to 0.85+/-0.12 after IFN therapy in nonresponders (P = 0.023), the value of 0.91+/-0.14 before IFN therapy in CRs and a BR increased significantly to 1.0+/-0.085 (P = 0.031). TRF1 expression was barely detectable and attenuated after IFN therapy, except in CRs developing HCC, in which frequent staining appeared, and the RTC evidently decreased from 0.97+/-0.11 to 0.63+/-0.0092 in corresponding noncancerous liver tissues.
Conclusions: It is strongly suggested that successful IFN therapy blocks telomere erosion, except in rare cases in which telomere reduction continues with overexpression of TRF1. Successive RTC evaluation in the liver may distinguish a risky case from a clinically cured one.

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Purpose: We evaluated whether detection of human telomerase reverse transcriptase (hTERT) mRNA after immunomagnetic separation is useful to detect circulating cancer (CC) cells.
Experimental Design: Two ml of peripheral blood were collected from 55 cases with hepatocellular carcinoma (HCC), 20 cases with chronic liver diseases devoid of cancer, and 20 healthy volunteers. Then 1500 and 500 mul were subjected to immunomagnetic separations using Ber-EP4 and anti-CD45 antibodies, harvested and supernatant cells were collected as epithelial and nonleukocyte fractions, respectively. Samples of each fraction were subjected' to reverse transcription-PCR detecting beta-actin, intekeukin-2 receptor (IL-2r), alpha-fetoprotein, and hTERT mRNAs. The cases were judged to be positive, equivocal, or negative for CC cells when hTERT positivity with IL-2r negativity, hTERT positivity with IL-2r positivity, or hTERT negativity was seen in epithelial and/or nonleukocyte fractions, respectively.
Results: The dilution experiments revealed that our system could detect 10(0-1) HeLa cells involved in 2 ml of blood. The Ber-EP4-harvested cells from cases with distant metastasis were positive for immunostaining using Hep Par 1 monoclonal antibody. CC cells were judged to be positive in 29 of 55 (53%) HCC cases. On the contrary, no cases without HCC were determined to be positive. The frequency of positivity was significantly correlated with disease extent of HCC.
Conclusions: These results strongly suggest that detection of hTERT mRNA after immunomagnetic separation is a specific and sensitive tool to detect CC cells and that it would provide useful source for further investigation of cancer metastasis.

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BACKGROUND. Despite the recent discovery of interchromosomal telomere length variation, a role for heterogeneity in telomere maintenance has yet to be established. This study investigated the significance of telomere length variation between chromosomes with respect to the association of cancer progression and telomere length regulation.
METHODS. Terminal restriction fragment (TRF) was evaluated in 20 surgically resected hepatocellular carcinoma specimens (HCC), corresponding noncancerous liver tissue specimens (NCL), and in 10 liver tissue specimens with chronic liver diseases devoid of cancer (DOC). Average TRF length (TRF-A) was defined as the point of maximum intensity. Shorter and longer TRF lengths (TRF-S and TRF-L) were defined as the length above which 90% of TRF distribution was involved. A ratio, (TRF-L-TRF-S)/TRF-A, was defined as telomere length dispersion.
RESULTS. The dispersion was significantly larger in HCC than in NCL specimens (P = 0.012) and in NCL than in DOC (P = 0.048). TRF-A and TRF-S were significantly shorter in HCC than in NCL (P = 0.0026, P = 0.0010). In seven patients in whom HCC recurred within 1 year, TRF-A and TRF-S were significantly shorter than in 10 patients in whom recurrence occurred after 1 year (P = 0.018, P = 0.0097). Telomeric repeat binding factor 1 was up-regulated in HCC with elongated TRF-L, whereas expression of human telomerase reverse transcriptase was greater in HCC with a shorter TRIF-S.
CONCLUSIONS. These results suggest that telomere length varied through chronic liver diseases by preferentially increasing shorter telomeres, whose length is a good indicator for malignant potential of HCC. Telomere length variation may be a crucial code in telomere maintenance through hepatocarcinogenesis. Cancer 2003;98:110-8. (C) 2003 American Cancer Society.

DOI： 10.1002/cncr.11428

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DOI： 10.1023/A:1019608509402

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Aim of this study was to establish fucosylation index (H) of alpha-fetoprotein (AFP) before and after initial treatment as a useful prognostic factor in patients with hepatocellular carcinoma (HCC). One hundred ninety-seven patients with HCC from 1990 to 2000, in whom an increment of serum AFP concentrations more than 30 ng/ml was observed before treatment, were examined in the present study. Enrolled patients with HCC underwent transcatheter arterial embolization, chemoembolization, percutaneous ethanol injection and/or percutaneous microwave coagulation therapy. The current patients status was confirmed as of the end of March 2001. FI was determined by crossed immunoaffinoelectrophoresis in the presence of Lens culinaris agglutinin (LCA). F1 of AFP was defined as the percentage of the LCA-reactive species in total AFP (same as L3 fraction). When the tentative discriminating line of 171 was set at 18%, the mean survival rate in the HCC group, whose FI-1 (before treatment) was higher than 18% (high FI), was significantly lower than that in another HCC group, whose FI-1 was equal to or less than 18% (low FI) by the generalized Wilcoxon test and the log rank test (P&lt;0.0001). There were statistical significant differences of survival rate when FI-2 (2 months after treatment) and FI-3 (at the time of HCC recurrence or 2 years after treatment in the case of no recurrence) were introduced in the same analysis. Additionally, statistical significant differences of survival rates were obtained between HCC groups with high and low FI-1 when the patient stage was limited to II, III, IVA or IVB. The HCC group, FI-1, FI-2 and FI-3 of which were persistently equal to or less than 18%, showed considerably better prognosis than the group, whose FI-1, FI-2 and FI-3 were persistently higher than 18%. The univariate analysis in the prognostic factor by the Cox's proportional hazards model showed that FI-1, FI-2 and FI-3 were independent prognostic factors. The present study indicates that measuring FI from the sera before and after the treatment serves as a new prognostic indicator and may improve prognostic estimates and appraisal of therapeutic outcome in patients with HCC. (C) 2002 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S1386-6346(01)00184-X

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DOI： 10.1023/A:1016452813815

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Background: Idiopathic portal hypertension is an uncommon condition characterized by presinusoidal portal perfusion disturbance without known causes. Methods: In the present study, portal and arterial perfusion dynamics were evaluated in two cases with idiopathic portal hypertension using computed tomography during arterial portography and hepatic arteriography. Ten cases with liver cirrhosis were also studied as a reference. Results: In cases with idiopathic portal hypertension, portal perfusion was conspicuously heterogeneous and decreased especially at the periphery of the liver where arterial perfusion was reciprocally increased. When the spatial heterogeneity of an enhancement of the liver was quantified using a densitometric analysis of computed tomography during hepatic arteriography images, the densities at the periphery were higher and varied more than those of the inner areas in cases with idiopathic portal hypertension. In contrast, the densities did not vary between the periphery and the inner areas at the cases with liver cirrhosis. Conclusions: The heterogeneous increase of arterial perfusion in periphery of the liver may be an important feature of idiopathic portal hypertension.

DOI： 10.1046/j.0106-9543.2002.01663.x

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Despite the recent discovery of interchromosomal telomere length variation, a role for heterogeneity in telomere maintenance has yet to be established. This study aimed to clarify relative telomere length differences between chromosomes. Combined chromosomal sorting and telomeric repeat content analysis in GM130B cells, the relative telomeric repeat content in each chromosome, were calculated. Each chromosome could be isolated except for chromosomes 1 and 2 and chromosomes 9 to 12, which were isolated in a group. Telomere length was correlated with the size of the corresponding chromosome. Concomitant relative telomeric repeat content analysis in each chromosome and terminal restriction fragment analysis using the whole genome revealed that the terminal restriction fragments of each chromosome were heterogenously distributed through the smear of the fragments. This is the first description of an association between telomere length and chromosome size. (C) 2002 Elsevier Science (USA).

DOI： 10.1006/bbrc.2002.6425

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Background: A close relationship has been shown to exist between the metastatic potential and beta1-6 branched oligosaccharides in human and rodent cells. N-acetylglucosaminyltransferase V (GnT-V) catalyzes this process. Although this phenomenon has been reported, little is known about the clinical usefulness of the determination of GnT-V in the evaluations of tumor invasiveness in hepatocellular carcinoma (HCC). In this study, we measured the GnT-V activity in serum of patients with HCC, together with its activity and gene expression in HCC tissues, and elucidated the clinical usefulness of the GnT-V level in evaluating tumor invasiveness.
Methods: Seventy-three serum samples from 38 patients with HCC, 11 with chronic hepatitis, eight with hepatic cirrhosis and 16 healthy controls were used. Twenty-one liver tissues were obtained by surgical resection from 17 patients with HCC, three with colorectal cancers and one with gallbladder cancer metastatic to the liver. The GnT-V activity was determined by using high performance liquid chromatography. The GnT-V mRNA was quantified by using competitive RT-PCR.
Results: There were statistically significant correlations between GnT-V activity in sera of HCC, and GnT-V activity and GnT-V mRNA expression in tumor tissue. The mean GnT-V activity in the sera of patients with HCC increased in accordance with the degree of tumor invasion. The HCC group with intrahepatic and extrahepatic metastases showed the highest serum GnT-V-value.
Conclusions: The present study demonstrated that there was a close association between tumor invasiveness and GnT-V activity in sera, and that the measurement of GnT-V may improve prognostic estimates and therapeutic outcomes for patients with HCC. (C) 2001 Blackwell Science Asia Pty Ltd.

DOI： 10.1046/j.1440-1746.2001.02612.x

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Purpose: We evaluated the diagnostic efficacy of detection of human telomerase reverse transcriptase (hTERT) message, a catalytic domain of human telomerase, in endoscopic retrograde pancreatography (ERP)-derived pancreatic juice.
Experimental Design: Both hTERT and CD25 expression were detected by reverse transcription-PCR (RT-PCR) in 17 patients with pancreatic adenocarcinoma (PC), 12 patients with chronic pancreatitis (CP), and 7 patients with no ERP abnormality (N). In the same patients, beta -actin message was semiquantified by competitive RT-PCR, K-ras codon 12 mutations were concomitantly analyzed by enriched PCR-SSCP in 11 and 7 PC and CP cases, respectively.
Results: Expression of hTERT was detected in 88% of PC cases and 17% of CP cases but not in the normal control (N). Alterations in K-ras were detected in 73% of PC cases and 57% of CP cases, respectively, beta -Actin mRNA was expressed in &gt;3.0 x 10(1) copies/mul in all but two PC cases in which hTERT mRNA was not detected. CD25-positive and -negative peripheral lymphocytes were isolated from a normal volunteer using a fluorescent activating cell sorter. The hTERT message was detected in CD25-positive peripheral lymphocytes and in 18, 25, and 0% of the pancreatic juice samples from PC, CP, and N cases, respectively. All CP cases expressing hTERT message were also CD25 positive.
Conclusions: These results suggest that detection of hTERT mRNA in pancreatic juice is a powerful tool to discriminate PC from CP, particularly when the samples are qualified against beta -actin mRNA levels and contaminating CD25-positive lymphocytes.

DOI： 10.1177/153331750101600512

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Background and Aims: Budd-Chiari syndrome (BCS) comprises hepatic vein thrombosis and inferior vena cava (NC) obstruction known as membranous obstruction of the IVC (MOVC). The latter is frequently complicated by hepatocellular carcinoma (HCC). The etiology of MOVC-associated HCC in relation to hepatitis viral infection is not known. In this study, we investigated the clinical features and etiology of HCC in MOVC.
Methods: Membranous obstruction of NC and HCC were diagnosed and studied by using imaging techniques. Sera from patients with MOVC, complicated by HCC, were examined for hepatitis viral antigens and antibodies (hepatitis B surface antigen (HBsAg), antibody to HBsAg (anti-HBs), antibody to hepatitis B core antigen (anti-HBc) and third generation antibody to hepatitis C virus (anti-HCV)) and for hepatitis viral nucleic acids (hepatitis B virus (HBV)-DNA, hepatitis C virus (HCV)-RNA, hepatitis G virus (HGV)-RNA and TT virus DNA).
Results: We studied 12 patients with BCS who were seen between April 1968 and February 1999. All of them had MOVC. Hepatocellular carcinoma developed in three (25%) of them. There were no obvious differences in the clinical features and imaging findings concerning MOVC between patients with and without HCC. Hepatocellular carcinoma in these three patients showed no clear trend in clinical features and imaging findings. Of the hepatitis viral markers examined, HBsAg, anti-HBc and HBV-DNA were positive in only one of three patients with HCC and all of the viral markers were negative in the other two patients.
Conclusions: Chronic congestion in the liver, caused by an outflow block of hepatic veins and subsequent histopathologic change, must have led to HCC in two patients without any hepatitis viral markers. Patients with MOVC should be followed closely as a high-risk group for HCC. (C) 2000 Blackwell Science Asia Pty Ltd.

DOI： 10.1046/j.1440-1746.2000.02303.x

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Background/Aims: Our previous results showed that the percentage of fucosylated species of alpha-fetoprotein (AFP) in total AFP, fucosylation index, was a very useful diagnostic tool to distinguish AFP due to hepatocellular carcinoma from AFP due to non-neoplastic liver diseases. On the other hand, alpha 1-6 fucosyltransferase (alpha FT) catalyzes the addition of fucose from GDP-fucose through an alpha 1-6 linkage to the reducing end of N-acetylglucosamine residue of N-linked oligosaccharides of glycoproteins. However, the biological and clinical significance of alpha FT in patients with hepatocellular carcinoma is not fully understood. In the present study, we measured alpha FT activity to elucidate the enzymatic background of fucosylated species of AFP in hepatocellular carcinoma.
Methods: Plasma samples from 84 cases of hepatocellular carcinoma, 40 of liver cirrhosis, 40 of chronic hepatitis and 30 of normal controls, and 25 paired samples of hepatocellular carcinoma and surrounding noncancerous tissues were enrolled in the present study. alpha FT activity was measured by high performance liquid chromatography with a synthesized fluorescence-labeled glycopeptide with an asialoagalactobiantennary sugar chain as a substrate in the presence of GDP-fucose.
Results: Plasma alpha FT activities (mean+/-SD, pmol/ml/h) in patients with hepatocellular carcinoma, liver cirrhosis, chronic hepatitis and normal controls were 435+/-271, 490+/-290, 590+/-209 and 380+/-133, respectively. alpha FT levels in hepatocellular carcinoma and chronic liver diseases were increased compared with that in normal controls. A statistically significant positive correlation was observed between plasma alpha FT activity and fucosylation index of AFP (r=0.34, p= 0.0032) in 60 patients with hepatocellular carcinoma, in which increments of serum AFP were observed. When the tentative cutoff value of fucosylation index was set at 18%, which corresponded to the cutoff value to discriminate between hepatocellular carcinoma and non-neoplastic liver diseases in our previous study the plasma alpha FT activity in hepatocellular carcinoma patients whose fucosylation index was more than 18% (n=32, 523+/-324 pmol/ml/h) was higher than that in hepatocellular carcinoma patients whose fucosylation index was equal to or less than 18% (n=28, 383+/-229) (p=0.055). An increment of the plasma levels of alpha FT occurred in accordance with an advancement of hepatocellular carcinoma stages. Tissue alpha FT activity in hepatocellular carcinoma (175+/-178 pmol/mg/h) was higher than those in surrounding noncancerous liver (144+/-134) and in normal liver (79+/-19). The mean alpha FT activities in well-, moderately- and poorly-differentiated hepatocellular carcinoma were 38+/-0.7, 177+/-182 and 219+/-189, respectively, and they tended to increase with dedifferentiation in hepatocellular carcinoma tissues.
Conclusions: The present study indicates that alpha FT is responsible for the formation of the fucosylated species of AFP in hepatocellular carcinoma and suggests that the measurement of alpha FT provides a possible aid in the evaluation of the degree of advancement in patients with hepatocellular carcinoma.

DOI： 10.1016/S0168-8278(00)80099-9

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Both loss of heterozygosity (LOH) and replication error (RER) are considered to be phenotypes of genomic instability To unveil the role of the genomic instability in hepatocarcinogenesis, frequencies of LOH and RER were simultaneously determined in 15 hepatocellular carcinomas (HCCs), surrounding nontumorous liver tissues (SL), and 13 liver tissues with chronic viral hepatitis void of cancer (NC) by referencing peripheral blood leukocytes (PBLs) from the corresponding donor using 18 microsatellite markers spread throughout the genome. LOH was significantly frequent in HCC compared with that in SL or NC (P = .005, P = .0003, respectively) and observed preferentially at particular microsatellite loci, D1S204, D2S123, D8S1106, D9S266, D16S748, and D19S601. Although the higher prevalence of RER was also significant in HCC compared with that in NC (P = .03), in most cases the errors were detected at very low frequencies and random loci. Both LOH and RER tended to appear more prevalently in SL than in NC. The occurrence rate of LOH was higher in the tissues associated with hepatitis B virus (HBV) than with hepatitis C virus (HCV) infection especially in HCC (P = .03). When referencing SL instead of PBLs, the prevalence of LOH and RER in HCC significantly decreased (P = .02 and P = .03, respectively). These results suggest that: LOH is closely associated with multistep hepatocarcinogenesis especially under HBV infection, but RER is imperceptibly associated. The quantitative evaluation of the frequency of LOH by referencing PBLs may be a useful predictor for HCC development in chronic liver diseases.

DOI： 10.1053/jhep.2000.7298

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Background: The Trefoil factor family 1 (TFF1), one of the trefoil peptides, has been considered to play protective and reparative roles of experimentally induced ulcers in the stomach. However, the alteration of the TFF1 mRNA in the non-ulcerated areas of living human gastric mucosa in gastric ulcer is not well known. We examined TFF1 gene expression at non-ulcerated sites during the healing of a gastric ulcer by semiquantitative determination of the TFF1 mRNA.
Methods: Gastric mucosal biopsy specimens were taken before and after the healing of the gastric ulcer from seven consecutive patients and from seven patients diagnosed with non-ulcer dyspepsia (NUD). The relative value of TFF1 mRNA (R-TFF1) was calculated by the single tube method of polymerase chain reaction (ST-PCR) and Southern hybridization. Immunohistochemistry using monoclonal antibodies was performed to confirm the presence of the TFF1 peptide. The status of Helicobacter pylori and the severity of gastritis were investigated simultaneously.
Results: The mean relative values of TFF1 mRNA at both the gastric angle (RTFF1AS) and the gastric body (RTFF1BS) of patients with gastric ulcers at the healed stage were significantly higher than those at the open stage (P &lt; 0.05). The mean RTFF1AS at both the open and healed stages were lower than those of RTFF1BS at the open and healed stages, respectively. The mean R-TFF1B at the open stage was lower than that in NUD (not significant), but the mean of R-TFF1B at the healed stage was significantly higher than that in NUD. The RTFF1AS and RTFF1BS of all patients did not correlate with H. pylori status nor with the severity of gastritis. The induction of TFF1 mRNA at the non-ulcerated background sites seemed not to be related to the status of H. pylori or to the severity of gastritis.
Conclusions: These results suggest that the increased levels TFF1 mRNA during the healing of gastric ulcers might be closely related to the protection and the cell differentiation at the non-ulcerated areas of living human gastric mucosa. (C) 2000 Blackwell Science Asia Pty Ltd.

DOI： 10.1046/j.1440-1746.2000.02209.x

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DOI： 10.1023/A:1005427223036

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Chronic idiopathic intestinal pseudo-obstruction is one of the disorders that is most refractory to medical and surgical treatment. Even when patients are given nutritional support, including total parenteral nutrition, obstructive symptoms seldom disappear. We report a case of chronic idiopathic intestinal pseudo-obstruction, due to myopathy, in which hyperbaric oxygenation therapy was strikingly effective. The presence of myopathy was histologically confirmed on the surgically resected jejunal specimen. Hyperbaric oxygenation resulted not only in relief of the patient's obstructive symptoms but also in a rapid decrease of abnormally accumulated intestinal gas. At last, he could resume oral intake without any critical adverse effects. These observations strongly suggest that hyperbaric oxygenation can be an effective therapy in the management of chronic idiopathic intestinal pseudo-obstruction. (Am J Gastroenterol 2000;95: 285-288. (C) 2000 by Am. Coll. of Gastroenterology).

DOI： 10.1016/S0002-9270(99)00769-8

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Hepatocellular carcinoma (HCC) mainly arises from the liver with chronic inflammation. Because telomere reduction reflects replicative history in somatic cells, we analyzed the possibility that liver tissues surrounding HCC consist of the cells carrying substantial reduction of telomere. We studied 20 HCC and surrounding noncancerous liver tissues (SL) obtained by surgical resection, and 10 laparoscopically obtained needle biopsy specimens of the liver with chronic inflammation including no overt HCC (CI). Five liver tissues without chronic liver diseases (ND) were also examined. Extracted genomic DNAs were blotted on a nylon membrane, and probed at first with radio-labeled d(TTAGGG)(3) and reprobed with radio-labeled d(CCT)(7). The intensity caused by d(TTAGGG)(3) was divided by that of d(CCT)(7). The ratio was defined as telomeric repeats content (TC). Dilution experiments reproducibly revealed almost the same TC, The reduction rate of telomere length through aging estimated by regression analysis of TC was 0.62% per year, Concomitant analyses of TC and average telomere length revealed that both values were significantly correlated (r =.45; P =.009). To compare TC in the liver with respect to chronic inflammation, the value was divided by TC in peripheral blood leukocytes (PBL) from the same donor, The ratio was defined as relative TC (RTC). There was a statistically significant decrease of RTC in CZ compared with that in ND (P =.03), Furthermore, RTC in SL was significantly lower than that in CI (P =.0001). These observations suggest that RTC value in liver tissues may digitally indicate a replicative history of hepatocytes under chronic inflammation, and a risk of HCC development.

DOI： 10.1002/hep.510300211

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We report here a case of a 21-year-old Japanese woman suffering from severe acute liver injury due to hepatitis C virus (HCV) infection in the third trimester of her first pregnancy. When a second-generation antibody reactivity to HCV had not yet appeared, HCV RNA was detected in her serum using a polymerase chain reaction. Subsequent natural interferon-alpha therapy played a key role in the recovery from severe hepatic injury, and the disappearance of HCV RNA in her serum. Consequently, HCV RNA has not been detected for over 17 months after the cessation of interferon administration. On the other hand HCV RNA was not detected in her cord or the baby serum. Therefore, maternal transmission of HCV was not evidenced. This is a rare case in which a severe form of acute hepatitis C was successfully treated with natural interferon-alpha, and no indication of a maternal transmission of HCV in acute hepatitis C could be demonstrated with polymerase chain reaction analysis.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

BACKGROUND. The aim of this study was to elucidate the usefulness of measuring the fucosylation index (FI) of or-fetoprotein (AFP) before the initiation of therapy as a new prognostic indicator for patients with hepatocellular carcinoma (HCC).
METHODS. One hundred twelve patients with HCC who underwent transcatheter arterial embolization, chemoembolization, and/or percutaneous ethanol injection were examined in the current study. FI was determined by crossed immunoaffino-electrophoresis in the presence of Lens culinaris agglutinin.
RESULTS. When the tentative discriminating value of FI was set at 18%, the mean survival rate for the group whose FI was higher than 18% was significantly lower than that for the group whose pi was equal to or less than 18%, according to the generalized Wilcoxon test (P = 0.0117) and the log rank test (P = 0.0183). The survival rate for HCC patients with AFP concentrations of more than 200 ng/mL was also significantly lower than that for patients with AFP in the range of 21-200 ng/mL, according to the generalized Wilcoxon test (P = 0.0017) and the log rank test (P = 0.0018). When FI was combined with AFP concentration, a highly significant difference was observed between the group with FI &gt; 18% and AFP &gt; 200 ng/mL and another group with FI less than or equal to 18% and AFP less than or equal to 200 ng/mL, as determined by the generalized Wilcoxon test (P &lt; 0.0001) and the log rank test (P = 0.0003). An analysis of multiple covariates in the prognostic factors with the Cox proportional hazards model showed that FI was one of the independent prognostic factors.
CONCLUSIONS. The current study indicates that measuring FI from sera before the initiation of treatment serves as a new prognostic factor and may improve prognostic estimates and appraisal of therapeutic outcomes for patients with HCC. Cancer 1998;83:2076-82. (C) 1998 American Cancer Society.

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BACKGROUND. Measurements of serum concentrations of des-gamma-carboxy prothrombin (DCP) are widely used for diagnosing hepatocellular carcinoma (HCC). However, the DCP is not always sensitive enough to detect small HCCs. In the current study, the authors investigated the usefulness of DCP in the early diagnosis of HCC, using a more sensitive enzyme immunoassay than is conventionally employed.
METHODS. The authors examined 148 serum samples with DCP concentrations from a conventional assay of less than 100 mAU (arbitrary unit)/mL from 91 patients with HCC and 57 with cirrhosis. DCP concentrations were determined by a more sensitive enzyme immunoassay (ED-036 kit, Eisai Laboratory, Tokyo, Japan) with a minimal detection level of 10 mAU/mL. Ninety-one HCC patients had 43 solitary small HCCs (with a greatest dimension of less than 2 cm). Of these 43 HCCs, 12 were well differentiated.
RESULTS. The mean serum concentration of DCP in HCC (48.3 +/- 24.3, mean +/- standard deviation [SD]) was higher than in cirrhosis (20.3 +/- 10.3); this difference was statistically significant. When the tentative cutoff level of 40 mAU/mL (almost corresponding to the mean value + 2SD in patients with cirrhosis) was used as the level of discriminating HCC from cirrhosis, 62% of patients (56 of 91) with HCC had DCP values above this level (sensitivity). However, only three patients with cirrhosis had higher DCP levels. Thus, the specificity of this test was 95% (54 of 57 patients). The total accuracy was 74% (56 + 54/91 + 57). Twenty-three of 43 solitary small HCCs (53%) had DCP values above the cutoff level. Furthermore, 7 of 12 (58%) small, well-differentiated HCCs less than 2 cm in greatest dimension had higher DCP values.
CONCLUSIONS. The results of this study indicate that DCP determination by sensitive enzyme immunoassay is useful in the early diagnosis of HCC because a high specificity is maintained. (C) 1998 American Cancer Society.

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Because telomerase activity is necessary for cell immortality and probably associated with tumor progression, we have evaluated a possible aid for quantitation of the activity to predict intrahepatic recurrences after surgery in patients with hepatocellular carcinoma (HCC). HCC tissues obtained by surgical resection from 20 patients were studied. Telomerase activity was expressed as peaks with a periodicity through a fluorescence-based telomeric repeat amplification protocol using an autosequencer, and the quantity of activity was calculated from peak areas. A ratio of fluorescence intensity depending on telomerase to that of an internal standard was used as a value of relative telomerase activity (RTA). RTA ia serially diluted S100 extracts from HepG2 cells was well correlated with the amount of the extracts. The mean RTA value of 36.4 +/- 27.8 (mean +/- SD, 3.21 to 105) in 9 patients suffering from early recurrences after surgery was significantly higher than that (9.84 +/- 7.65; mean +/- SD, 3.00 to 29.0) in 11 patients without intrahepatic recurrences during the early period (P = .004). These results indicate that RTA value can be a useful predictor for intrahepatic recurrences during the early period after surgical resection of HCC.

DOI： 10.1002/hep.510270213

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Tumor cells with metastatic potential may have a high telomerase activity that augments telomeric DNA repeats, allowing the cells to escape from the inhibition of cell proliferation due to shortened telomeres. We examined the expression level of telomerase activity using the telomeric repeat amplification protocol among a series of cell lines obtained by repeated transplantation of a mouse fibrosarcoma. The lines could be grouped into three; one has no metastatic potential, and the other two show metastatic abilities after intravenous or subcutaneous injection. Comparison of their telomerase activity indicated that more malignant Lines had higher activity. A similar relation was seen in metastatic nodules formed through clonal expansion from the heterogeneous population of inoculated cells; clonality was monitored in terms of variable patterns of subtelomeric repeats. The results suggest that a high level of telomerase activity may not be requisite for metastasis, but may confer a propensity to dominate in a tumor tissue.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

The high mobility group protein (HMG)-box is a DNA-binding domain found in many proteins that bind preferentially to DNA of irregular structures in a sequence-independent manner and can bend the DNA, We show here that GST-fusion proteins of HMG domains from HMG1 and HMG2 promote a triple-stranded complex formation between DNA containing the (GGA/TCC)(11) repeat and oligonucleotides of d(GGA)(11) probably due to G:G base pairing, The activity is to reduce association time and requirements of Mg2+ and oligonucleotide concentrations, The HMG box of SRY, the protein determining male-sex differentiation, also has the activity, suggesting that it is not restricted to the HMG-box domains derived from HMG1/2 but is common to those from other members of the HMG-box family of proteins, Interestingly, the box-AB and box-B of HMG1 bend DNA containing the repeat, but SRY fails to bend in a circularization assay, The difference suggests that the two activities of association-promotion and DNA bending are distinct, These results suggest that the HMG-box domain has a novel activity of promoting the association between GGA repeats which might be involved in higher-order architecture of chromatin.

DOI： 10.1093/nar/24.23.4733

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

N-acetylglucosaminyltransferase (GnT) III catalyzes the addition of N-acetylglucosamine through a beta 1-4 linkage to the mannose of the trimannosyl core, resulting in conversion of the concanavalin-A-(ConA)-reactive glycan into the ConA-nonreactive one. In this study, we measured GnT III levels in serum, tumor, and surrounding normal tissues together with a glucosaminylation index of alpha-fetoprotein (AFP), which is defined as the percentage of the ConA-nonreactive species in total AFP, in a case of AFP-producing renal cell carcinoma. The glucosaminylation index was determined by affinoelectrophoresis in the presence of ConA. GnT III was measured by using a pyridylaminated asialoagalactobiantennary sugar chain as a substrate by high-performance liquid chromatography. The glucosaminylation index of serum AFP, the concentration of which was 68 ng/ml, was 60%. This value is much higher than observed in hepatocellular carcinomas. The tumor tissue level of GnT III was 55.34 pmol/mg/h which was about six fold higher (9.50 pmol/mg/h) than in normal surrounding tissues. The serum level of this enzyme before surgery was 27.65 pmol/ml/h and decreased to 5.38 pmol/ml/h thereafter in association with a depression of serum Am from 68 to 5.4 ng/ml. Thus, an increased level of GnT III in tumor tissues could account for the elevated conversion of a biantennary complex type sugar chain of AFP into a bisecting glucosaminylated biantennary one resulting from the addition of an N-acetylglucosamine residue at the trimannosyl core. This is, to our knowledge, the first report explaining the change in the carbohydrate structure of AFP with different affinity to ConA on the enzymatic basis in a renal cell carcinoma.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

BACKGROUND. Measurements of serum alpha-fetoprotein (AFP) concentration and plasma concentration of des-gamma-carboxy prothrombin (DCP) have been widely used for the early diagnosis of hepatocellular carcinoma (HCC). The two markers generally run parallel to each other. However, in our study, they sometimes fluctuated independently in response to tumor regression or recurrence.
METHODS. A longitudinal series of concentrations of serum AFP and plasma DCP were determined simultaneously for 245 patients with HCC from the time of diagnosis to tumor recurrence after treatment.
RESULTS. Positive reactions for AFP were noted in 168 patients (69%) and for DCP in 126 patients (51%). One hundred and ten of 245 patients with HCC (45%) were positive for both AFP and DCP. In 35 patients (14%), these 2 tumor markers fluctuated independently in response to tumor regression and recurrence. These patients were categorized into four groups as follows: Group 1 had elevated AFP only at diagnosis; it then decreased after treatment, but DCP was elevated at the time of tumor recurrence without AFP elevation (3 patients); Group 2 had elevated DCP at diagnosis and elevated AFP at tumor recurrence (4 patients); Group 3 had elevated AFP and DCP at diagnosis, but only AFP (8 patients) or DCP (7 patients) was elevated at tumor recurrence; Group 4 had only elevated AFP (2 patients) or DCP (11 patients) at diagnosis, but both AFP and DCP were elevated at tumor recurrence.
CONCLUSIONS. The results of this study indicate that simultaneous determinations of AFP and DCP are useful for monitoring recurrence in patients with HCC after treatment, and that the decrease to normal levels of a single marker does not always indicate the absence of tumor recurrence. (C) 1996 American Cancer Society.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE  

Heterogeneous reactivity of human serum transferrin (Tf) with lectins was analysed using patient sera to determine whether it can be used to distinguish patients with hepatocellular carcinoma (HCC) from those with liver cirrhosis (LC). Microheterogeneity of Tf was analysed by crossed immunoaffinity electrophoresis (CIAE) with concanavalin A (Con A) and Lens cullinaris agglutinin (LCA). Sample sera from 58 patients with HCC, 43 patients with LC and 10 normal controls were used in this study and the results were e-valuated statistically The increments of Con A-non-reactive (C1) and -weakly reactive (C2) species of Tf were observed in HCC compared with those of LC and Norm. Significant increase in the combined percentage of Con A- C1 + C2 species was also revealed in HCC (35.5 +/- 8.5%, mean +/- s.d.) compared with those of LC (29.1 +/- 6.8%; P &lt; 0.001) and normal controls (17.1 +/- 2.3%; P &lt; 0.001). The elevation of LCA-reactive (L2) species of Tf was recognized in HCC (8.2 +/- 3.8%) in comparison with those of LC (4.8 +/- 3.1%; P &lt; 0.001) and normal controls (1.3 +/- 1.7%; P &lt; 0.001). The increment of C1 + C2 species and for L2 species of Tf was observed in 78% (sensitivity) of patients with HCC. The specificity, the positive predictive value and the overall accuracy were 81, 88 and 72%, respectively. Positive ratio of C1 + C2 and/or L2 species was 77 and 70% in alpha-fetoprorein low and -high producing HCC patients, respectively, These results indicate that the microheterogeneity analysis of human serum Tf is useful for distinguishing patients with HCC from those with LC and normal controls.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN BIOCHEMICAL SOC  

Incubation of the 162-bp duplex containing d(GGA:TCC)(11) repeats with d(GGA)(11) and d(GGT)(11) oligonucleotides, but not with d(TCC)(11), gave a mobility-shifted band in polyacrylamide gel electrophoresis, suggestive of the tripler formation. The two conformers, however, showed difference in binding affinity and structure. The complex formed with d(GGT)(11) exhibited patterns protected from DNase I digestion and from modifications with osmium tetroxide and dimethyl sulfate. The patterns were conformed to a proposed tripler model. In contrast, the complex with d(GGA)(11) was sensitive to DNase I and to osmium tetroxide, which is reactive to pyrimidine bases of single-stranded DNA. These results suggest that the d(GGA:TCC)11 and d(GGA)(11) triple-stranded complex forms a D-loop-like structure. By considering the ability of d(GGA)(11) oligonucleotides to form a parallel homoduplex, the structure may be one in which the GGA-strand of the duplex pairs with d(GGA)(11) in parallel, with the TCC-strand being looped out.

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DOI： 10.1093/nar/23.18.3771

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI IRELAND LTD  

The reactivity of transferrin (Tf) with concanavalin A (Con A) was examined by crossed immune-affinity electrophoresis (CIAE) of the sera from patients with hepatocellular carcinoma (HCC). Serum Tf was separated into three species - C1 (Con A-nonreactive), C2 (-weakly reactive) and C3 (-reactive) - designated consecutively from the anode by CIAE. Nineteen pairs of serum samples were evaluated before and 1 month after therapies for HCC by transcatheter arterial embolization and/or percutaneous ethanol injection, and surgical resection. The significant decrease in the mean percentage of Tf-Cl species was observed after the above therapies, although there was no statistical difference between the serum Tf concentration before and after therapies. Thus, the present study suggests that the measurement of these species would be useful as an index of several therapeutic effects on HCC, especially in the case of alpha-fetoprotein (AFP)- and des-gamma-carboxy prothrombin (DCP)-non-producing HCC.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS UNITED KINGDOM  

The GGA9-H molecules consisting of a double helical stretch followed by a single-stranded 3'-terminal overhang of nine GGA sequence repeats exhibited a gel mobility-shifted band in a concentration-dependent manner, suggestive of the intermolecular complex formation. The position of the shifted band in a gel was almost identical to that of the Y-shaped dimer marker of the same molecular weight that had the two double-helices at one side, This suggests that GGA9-H dimerizes in a parallel orientation without the formation of four-stranded hairpin structure, Since the GGA9-H homoduplex was stably formed at pH 4, 7 and 9, the formation does not require protonation or deprotonation of the N1 position of adenines, Neither does it require the N7 group of guanines responsible for Hoogsteen base pairing from the methylation interference and modification studies, Modification of the N7 group of guanines with dimethyl sulfate (DMS) did not inhibit the association and also the N7 group in the homoduplex was not protected from DMS, On the other hand, the GAA9-H having the G to A base substitution did not show such an association with either GGA9-H or GAA9-H. These results suggest that the homoduplex formation may be due to G G base pairing through non-Hoogsteen hydrogen bonds.

DOI： 10.1093/nar/23.18.3771

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE  

A 69 year old female with a duodenal bulb obstruction due to direct invasion of common bile duct cancer who received total enteral nutrition through the route of percutaneous transhepatic internal drainage (PTID) was presented. The tip of PTID tube was placed over the duodeno-jejunal flexure. Jejunal infusion of all nutrients and the bile juice through this route kept her in good nutritional condition until the terminal stage of primary disease. This procedure did not cause the infection of the biliary system. Major problems, tube obstruction and diarrhoea, were easily resolved with the selection of an appropriate infusion schedule and nutrient concentration. We conclude that nutritional support through the PTID route is a beneficial means for compromised patients without laparotomy or hospitalization.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI IRELAND LTD  

We have examined whether or not mutations exist in the proximal promoter region of the human alpha-fetoprotein (AFP) gene in the hepatocellular carcinoma (HCC) tissue. Genomic DNA was extracted from four patients: one HCC tissue, one HCC and its corresponding non-cancerous (cirrhosis) tissues, one liver cirrhosis (LC) tissue without HCC and one matching HCC tissue and peripheral blood leukocytes. Serum concentrations of AFP in the patients ranged from less than 5 to 10138 ng/ml. Nucleotide sequence was determined by direct sequencing using a single-stranded DNA template that was produced first through the polymerase chain reaction (PCR) amplification and then asymmetric PCR. In one HCC tissue taken from the patient with a high concentration of serum AFP, nucleotides different from published ones were detected at -120 and -113. These changes, however, probably reflect a DNA polymorphism, because peripheral blood leukocytes of the same patient had the same changes. Including this patient, no mutations in the region from -160 to -10 were detected in the HCC specimens we have examined. These results suggest that the extremely proximal promoter region of the AFP gene where glucocorticoid-responsive element and HNF-1 binding sites exist is not responsible for the re-expression of AFP in HCC.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Universal Academy Press Inc.  

Sixty-nine sequences containing microsatellites were determined by analysis of clones from a pUC118 library of total genomic mouse DNA. These sequences were examined for size variation using polymerase chain reaction and gel electrophoresis. Fifty-one of them showed allelic variations between C57BL/6 and MSM, the two strains used for genetic mapping. Hence, their chromosomal location was determined using a panel consisting of 131 backcross mice that had been typed with 85 anchor loci. The microsatellites were distributed to most chromosomes except for chromosomes 16 and 19. These novel markers with defined locations are useful in linkage and genome mapping studies.

DOI： 10.1093/dnares/1.4.169

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

Background. We have recently reported that simultaneous determination of the fucosylation and glucosaminylation of alpha-fetoprotein (AFP) was useful in the differential diagnosis of various liver diseases. Here, we measured these indices in germ cell tumor and compared them with those in various diseases to reveal the characteristic feature of the carbohydrate moiety of AFP in this tumor.
Methods. Fucosylation and glucosaminylation indices of AFP were determined for 743 serum samples from 10 patients with germ cell tumor, 437 with hepatocellular carcinoma (HCC), 241 with benign liver diseases (24 patients with acute viral hepatitis, 99 with chronic hepatitis, and 118 with hepatic cirrhosis), and 55 with carcinoma metastatic to the liver from digestive organs (41 from stomach, 10 from gallbladder, 2 from pancreas, and 2 from colon) by crossed immunoaffinoelectrophesis in the presence of concanavalin A and Lens culinaris agglutinin.
Results. The fucosylation index of AFP in germ cell tumors (99% +/- 2%, mean +/- SD) was higher than those in HCC (39% +/- 31%), carcinoma metastatic to the liver (76% +/- 27%), and benign liver diseases (4% +/- 7%); the differences were statistically significant (P &lt; 0.001). The glucosaminylation index of AFP in germ cell tumor (45% +/- 20%) also was significantly higher than those in HCC (4% +/- 4%) and in benign liver diseases (1% +/- 4%) (P &lt; 0.001). The difference in mean percentage of the glucosaminylation index, however, was not significant between germ cell tumors (45% +/- 20%) and carcinoma metastatic to the liver (39% +/- 23%).
Conclusions. The current study indicates that the most characteristic feature of glycosylation of AFP in germ cell tumors is fucosylation rather than glucosaminylation.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Chemical structures of the sugar chains of various human alpha-fetoprotein (AFP) species with different affinity for Concanavalin A (Con A) and Lens culinaris agglutinin (LCA) were examined by pyridylamination of their oligosaccharides and stepwise exoglycosidase digestion. Using reversed-phase and size-fractionation high performance liquid chromatography systems we identified six pyridylamino-sugar chains. The Con A-reactive and LCA-nonreactive species of AFP from patients with hepatocellular carcinoma contained a biantennary sugar chain, and the Con A-reactive and LCA-reactive species had a biantennary one with a fucose residue at the innermost N-acetylglucosamine residue. The Con A-nonreactive and LCA-reactive species contained a biantennary sugar chain both with a bisecting-N-acetylglucosamine residue at the trimannosyl core and with a focuse residue at the innermost N-acetylglucosamine residue. The Con A-nonreactive and LCA-nonreactive species contained a fucosylated triantennary sugar chain as a major component, and two minor components: a triantennary sugar chain and a biantennary sugar chain with a bisecting-N-acetylglucosamine residue at the trimannosyl core. Thus, the fucosylated and non-fucosylated triantennary sugar chains were newly identified in human AFP. Essentially identical results were obtained for AFP from the patient with gallbladder carcinoma which metastasises to the liver. These results indicate that the increment in fucosylation and branching to form new antennae is a characteristic feature of the carbohydrate chains of AFP from patients with neoplastic diseases of the liver.

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Chemical structures of the sugar chains of alpha1-antitrypsin (AAT) from patients with hepatocellular carcinoma (HCC) with different affinity for Lens culinaris agglutinin (LCA) were examined by pyridylamination of their oligosaccharides and stepwise exoglycosidase digestion. By using reversed-phase and size-fractionation high-performance liquid chromatography systems we confirmed that the LCA-reactive species of AAT from patients with HCC contained a biantennary sugar chain with a fucose residue at the innermost N-acetylglucosamine residue, Galbeta1-4GlcNAcbeta1-2Manalpha1-6(Galbeta1-4GlcNAcbeta1-2Manalpha1-3)Manbeta1-4GlcNAcbeta1-4(Fucalpha1-6)GlcNAc, as a major component, and a biantennary sugar chain without a fucose residue, Galbeta1-4GlcNAcbeta1-2Manalpha1-6(Galbeta1-4GlcNAcbeta1-2Manalpha1-3)Manbeta1-4GlcNAcbeta1-4GlcNAc, as a minor component. Thus, present results indicate that a characteristic feature of the carbohydrate chains of AAT from patients with HCC is an increment in fucosylation.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO  

We report here on three patients with cirrhosis for whom an early recognition of hepatocellular carcinoma was made possible by the measurement of the degree of fucosylation (fucosylation index) of alpha-fetoprotein. Increased levels of this index associated with a moderate increment of serum concentration of alpha-fetoprotein were observed in three patients with cirrhosis who showed no indication of hepatocellular carcinoma by several imaging modalities. Four years after the onset of an increase in the fucosylation index, small hepatocellular carcinoma with a tumor diameter less than 2 cm was revealed in case 1. In cases 2 and 3, small hepatocellular carcinomas were detected 24 mo and 9 mo, respectively, after the first sign of the increase in the index. However, the development to hepatocellular carcinoma was not detected in five patients with cirrhosis in whom continuous increments of serum concentration of alpha-fetoprotein with low levels of fucosylation index were observed during the prospective follow-up from 3 to 9 yr. These findings indicated that the fucosylation index of alpha-fetoprotein can be used as an aid in an early recognition of hepatocellular carcinoma, especially in patients with cirrhosis during the follow-up process in which the moderate increment of serum concentration of alpha-fetoprotein is noted.

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Language：Japanese   Publisher：(株)癌と化学療法社  

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症例は認知症のある80歳代、女性。黄疸を主訴に当院を受診した。腹部CT検査で胆管、十二指腸浸潤を伴う膵頭部癌を疑われ、腫瘍部の細胞診を目的とした超音波内視鏡検査を施行した際に十二指腸球部の穿孔を来した。全身麻酔下の開腹手術を回避すべく、Over-The-Scope Clip(OTSC)を用いて内視鏡的に創部を縫縮した。術後より禁食管理、抗生剤投与を行った。症状の悪化なく、2日後の消化管造影検査では穿孔部からの造影剤漏出を認めず、食事を再開した。その後も腹膜炎の発症なく良好な経過を得た。胆膵内視鏡検査・治療時に伴う重篤な合併症の一つに消化管穿孔がある。穿孔に対する治療の第一選択は外科手術であるが、穿孔に伴う死亡率は依然高い。OTSCは腸管の全層縫合を可能とする画期的な内視鏡治療器具であり、腸管穿孔や術後縫合不全、難治性出血の止血などに汎用されている。外科的な創閉鎖に伴うリスクが憂慮される症例に対しても高い治療効果が報告されており、手術治療の代替手段として活用されることが期待される。(著者抄録)

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：日本臨床寄生虫学会  

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Language：Japanese   Publisher：(株)癌と化学療法社  

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Language：Japanese   Publisher：(一社)日本インターベンショナルラジオロジー学会  

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Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY-BLACKWELL  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY-BLACKWELL  

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Language：Japanese   Publisher：(一社)日本内科学会  

DOI： 10.2169/naika.105.2263

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Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

70歳女性。膵胆管合流異常にて肝外胆管切除、胆管空腸吻合術施行。1年後に急性胆管炎を発症し経皮経肝胆道ドレナージを施行した。その後に内瘻化を企図したが高度の吻合部狭窄にて通過困難であった。経皮経路より気管支内視鏡を用いた観察にて吻合部にpin hole状の瘢痕狭窄を認め、同部をガイドワイヤーで通過し内外瘻チューブを留置しえた。その後、狭窄部にフルカバー金属ステントを留置した。拡張は良好であり、留置4ヵ月後に抜去した。造影検査でも吻合部は良好に開存しており外瘻チューブも抜去した。フルカバー金属ステントは持続的に狭窄部を拡張し抜去も可能である。本法は良性胆道狭窄に対し有効で実行可能な治療法と考える。(著者抄録)

DOI： 10.11280/gee.58.2279

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Language：Japanese   Publisher：(株)癌と化学療法社  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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鰹だしの末梢血流増加作用を利用した手足症候群(HFS)の予防効果について検討した。ソラフェニブ(SFN)内服開始のために入院した肝細胞癌症例10例を対象とした。濃厚鰹だしを飲用せず、SFNを内服した対照群3例では、足底血管のtime averaged mean blood flow velocity(TAMEAN)の平均値はSFN内服開始1週後に前値に比較して低下を認め、2例にGrade 1、2のHFSを認めた。濃厚鰹だしを飲用した10例中7例でTAMEAN値が内服開始前後(1週)で上昇を認め、2例では33.5%の低下を認め、1例では著変を認めなかった。各症例における濃厚鰹だし飲用前後の血流変化は、飲用群で対照群に比較して有意に血流増加を認めた。血流増加を認めた症例ではサーモグラフィを施行すると手足末梢温が維持、改善していた。血流低下を認めたうちの1例のみでGrade 1のHFSを内服開始14日目に発症した(発症率10%)。経過中、濃厚鰹だしによる副作用を認めなかった。

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Language：Japanese   Publisher：新潟医学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J00990&link_issn=&doc_id=20160215140052&doc_link_id=%2Fdg3nigta%2F2015%2Fs12910%2F046%2F0628-0628%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg3nigta%2F2015%2Fs12910%2F046%2F0628-0628%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(株)東京医学社  

生検を極めるには、スコープ操作や採取手技だけでなく、実際の内視鏡所見を踏まえて、どの場所から生検を採取すると、どのような組織像が得られるのかを予測しながら検査を行うトレーニングが必要である。内視鏡観察を疎かにして、診断を安易に生検に頼っていては、内視鏡検査をいくら行っても実力は身につかない。内視鏡診断力の向上のためには、生検を含めた病理組織診断に関する知識や理解も必要となる。生検後に動脈性出血をきたした経験もあり、緊急止血を含めた偶発症対策も欠かすことはできない。これらは、内視鏡を用いた各種治療手技を目指すための第一歩でもあり確実に習得したい。(著者抄録)

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：NATURE PUBLISHING GROUP  

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Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：ELSEVIER ACADEMIC PRESS INC  

Hydrodynamic delivery (HD) is a broadly used procedure for DNA and RNA delivery in rodents, serving as a powerful tool for gene/protein drug discovery, gene function analysis, target validation, and identification of elements in regulating gene expression in vivo. HD involves a pressurized injection of a large volume of solution into a vasculature. New procedures are being developed to satisfy the need for a safe and efficient gene delivery in clinic. Here, we summarize the fundamentals of HD, its applications, and future perspectives for clinical use.

DOI： 10.1016/bs.adgen.2014.10.002

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：NATURE PUBLISHING GROUP  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：NATURE PUBLISHING GROUP  

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Other Link： http://search.jamas.or.jp/link/ui/2015113677

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Other Link： http://search.jamas.or.jp/link/ui/2014161054

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J-GLOBAL

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Language：Japanese   Publisher：The Japan Society of Mechanical Engineers  

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Other Link： http://search.jamas.or.jp/link/ui/2013193690

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Language：English   Publisher：日本癌学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：NATURE PUBLISHING GROUP  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：(株)東京医学社  

腫瘍出血は、緊急内視鏡が必要な上部消化管出血の約5%を占め、進行胃癌の頻度が高い。腫瘍出血の多くは慢性的な少量出血であるが、腫瘍表面の潰瘍形成に伴う大量出血に対しては、緊急内視鏡が必要である。検査前には腫瘍の存在が確認できていないことも多く、出血源同定と止血処置を優先しつつ、消化性潰瘍との鑑別を行う。緊急内視鏡における止血の手順や止血法の選択は、消化性潰瘍に対する場合と大きく異なるものではないが、一般に腫瘍出血では観察や治療の条件が不良であり、より簡便で確実な止血法が望まれる。近年、ESDや消化性潰瘍出血で頻用されている止血鉗子を用いた高周波凝固法は、腫瘍出血に対しても有用であり、露出血管を正確に把時するか、出血ポイントに、鉗子を閉じた状態で軽く押し当て、soft凝固で処置する。止血困難な場合や出血を繰り返す症例では、内視鏡治療に固執せずIVRや手術による止血を考慮する。(著者抄録)

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Language：Japanese   Publisher：新潟医学会  

【目的】非アルコール怪脂肪性肝疾患 (nonalcoholic fatty liver disease, 以下NAFLD) における肝細胞癌に対する外科治療成績を明らかにする. 【対象・方法】肝細胞癌に対して肝切除を施行した225例を対象とし, HBs抗原単独陽性群 (以下, B群) 61例, HCV抗体単独陽性群 (以下, C群) 147例, NAFLD群17例の3群に分類した. 3群間における臨床病理学的背景因子, 術後遠隔成績を比較検討した. 【結果】NAFLD群はB群, C群と比較して有意に高齢であり (P &lt;0.001), body mass index は高く (P &lt;0.001), 腫瘍径が大きかった (P =0.002). NAFLD群17例中8例は組織学的に非アルコール性脂肪肝炎 (nonalcoholic steatohepatitis, 以下NASH) と診断された. 術後合併症発生率, 在院死亡率は, B群 (各々28%, 8%), C群 (各々31%, 1.4%) と比較してNAFLD群 (各々59%, 12%) で有意に高かった (各々P =0.043, P =0.030). NAFLD群での在院死亡は2例であり, NASHに関連した肝硬変に合併した肝細胞癌に対して肝右葉切除が施行されていた. 術後累積5年無再発生存率は, B群39%, C群29%, NAFLD群66%であった. 術後累積無再発生存率はNAFLD群が単変量解析 (P =0.048), 多変量解析 (P =0.020) の両者で有意に良好な成績であった. 【結論】NAFLD関連肝細胞癌に対する外科治療は予後を改善する. NASH関連肝硬変患者に対して肝葉切除を行う際には細心の注意が必要である.

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Language：English   Publishing type：Book review, literature introduction, etc.   Publisher：WILEY  

The liver is involved in the synthesis of serum proteins, regulation of metabolism and maintenance of homeostasis and provides a variety of opportunities for gene therapy. The enriched vasculature and blood circulation, fenestrated endothelium, abundant receptors on the plasma membranes of the liver cells, and effective transcription and translation machineries in the hepatocytes are some unique features that have been explored for delivery, and functional analysis, of genetic sequences in the liver. Both viral and non-viral methods have been developed for effective gene delivery and liver-based gene therapy. This review describes the fundamentals of gene delivery, and the preclinical and clinical progress that has been made toward gene therapy using the liver as a target.

DOI： 10.1111/j.1872-034X.2008.00479.x

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Language：English   Publishing type：Book review, literature introduction, etc.   Publisher：NATURE PUBLISHING GROUP  

Efficient and safe methods for delivering genetic materials into cells must be developed before the clinical potential of gene therapy can be fully realized. Recently, hydrodynamic gene delivery using a rapid injection of a relatively large volume of DNA solution has opened up a new avenue for gene therapy studies in vivo. This method is superior to the existing delivery systems because of its simplicity, efficiency, and versatility. Wide success in applying hydrodynamic principles to delivery of DNA, RNA, proteins, and synthetic compounds, into the cells in various tissues of small animals, has inspired the recent attempts at establishing a hydrodynamic procedure for clinical use. In this review, we provide an overview of the theory and practice of hydrodynamic gene delivery so as to aid researchers for the use of this method in their pre-clinical and translational gene therapy studies.

DOI： 10.1038/sj.mt.6300314

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Other Link： http://search.jamas.or.jp/link/ui/2006217992

Language：Japanese   Publisher：Niigata University  

Hepatocellular carcinoma has occupied a third place of cancer death in Japan, and its incidence is still increasing. Because most of hepatocarcinogenensis takes place accompanying chronic hep-atitis virus infection and because reduction of hepatitis activity decreases the risk of hepatocellular carcinoma, prefecture-wide screening has been conducting for hepatitis B and C viruses to the general population in Niigata prefecuture. Recent technological advances in imaging and thera-peutic modalities increase the possibility to control the disease progression. Furthermore, molecu-lar and epidemiological studies indicate that conventional therapies preventing liver cell damage reduce the risk of hepatocarcinogenensis. Therefore fine organization of existing strategies beyond each hospital must improve prognosis of hepatocellular carcinoma, and be most important step toward the destruction of hepatocellular carcinoma.

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Other Link： http://hdl.handle.net/10191/3411

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DOI： 10.11318/mii.22.210

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Other Link： http://search.jamas.or.jp/link/ui/2004292797

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Other Link： http://hdl.handle.net/10191/2841

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Language：Japanese   Presentation type：Symposium, workshop panel (public)  

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