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1.  Development of IgG4-related disease in a patient diagnosed with idiopathic membranous nephropathy 
Clinical Kidney Journal  2013;6(5):486-490.
We report a case of IgG4-related disease (IgG4-RD) diagnosed after 3 years of follow-up for idiopathic membranous nephropathy (MN). MN has been considered as glomerular lesion of IgG4-related kidney diseases in recent years and was diagnosed simultaneously with or after a diagnosis of IgG4-RD in previously reported cases. In the present case, IgG4-RD developed 3 years after the diagnosis of idiopathic MN, indicating a possible relationship between idiopathic MN and IgG4-RD through common underlying mechanisms of development.
PMCID: PMC3779618  PMID: 24058729
idiopathic membranous nephropathy; IgG4-related disease; membranous nephropathy associated with IgG4-RD
2.  Safety Assessment of Liver-Targeted Hydrodynamic Gene Delivery in Dogs 
PLoS ONE  2014;9(9):e107203.
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.
PMCID: PMC4175463  PMID: 25251246
3.  Successful management of severe intrahepatic cholestasis of pregnancy: report of a first Japanese case 
BMC Gastroenterology  2014;14(1):160.
Intrahepatic cholestasis of pregnancy (ICP) is a cholestasis condition caused by elevated levels of serum bile acids that mainly occurs in the third trimester of pregnancy. Maternal symptoms include pruritus; elevation of transaminases, biliary enzymes, and bilirubin levels; and abnormal liver function tests. Fetal symptoms include spontaneous preterm labor, fetal distress, and intrauterine death. It is more prevalent in the Caucasians and is rarely found in Asian countries, including Japan. The etiology of ICP has been reported as involving various factors such as, environmental factors, hormone balance, and genetic components. The genetic factors include single-nucleotide polymorphisms (SNPs) in the genes of canalicular transporters, including ABCB4 and ABCB11. It has also been reported that the combination of these SNPs induces severe cholestasis and liver dysfunction.
Case presentation
Here, we report for the first time a 24-year Japanese case of severe ICP diagnosed by typical symptoms, serum biochemical analysis, and treated with the administration of ursodeoxycholic acid which improved cholestasis and liver injury and prevented fetal death. The sequence analysis showed SNPs reported their association with ICP in the ABCB11 (rs2287622, V444A) and ABCB4 (rs1202283, N168N) loci.
The risk of ICP has been reported to be population-specific, and it is rare in the Japanese population. Our case was successfully treated with ursodeoxycholic acid and the genetic sequence analysis has supported the diagnosis. Because genetic variation in ABCB4 and ABCB11 has also been reported in the Japanese population, we need to be aware of potential ICP cases in pregnant Japanese women although further studies are necessary.
PMCID: PMC4175624  PMID: 25218883
Intrahepatic cholestasis of pregnancy; Bile acid; Ursodeoxycholic acid; Single-nucleotide polymorphism; ABCB11; ABCB4
4.  Parameters Affecting Image-guided, Hydrodynamic Gene Delivery to Swine Liver 
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 α-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.
PMCID: PMC4027427  PMID: 24129227
gene therapy; human α-1 antitrypsin; hydrodynamic gene delivery; image-guided gene delivery; non-viral vector
5.  Active treatments are a rational approach for hepatocellular carcinoma in elderly patients 
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. Each treatment was used alone, or in combination, 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 < 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 middle-aged 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.
PMCID: PMC3699049  PMID: 23840122
Hepatocellular carcinoma; Population aging; Survival; Life expectancy; Active intervention
6.  Immunohistochemical Character of Hepatic Angiomyolipoma: For Its Management 
Case Reports in Medicine  2013;2013:298143.
Hepatic angiomyolipoma (AML) is notoriously difficult to diagnose without an invasive surgery even with the recent development of the various imaging modalities. Additionally, recent reports showed its malignant behavior after the surgery; it is important to diagnose the character of each tumor including the possible malignant potential and determine the postoperative management for each case. For this purpose, we have reviewed reports and focused on the immunohistochemical staining with p53 and ki67 of the tumors showing the representative case of 60-year-old female. The imaging study of her tumor showed the character similar to the hepatocellular carcinoma, and she underwent the hepatectomy. The resected tumor stained positive for HMB-45 that is a marker of the AML, and 30–50% of the tumor cells were positively stained with Ki67 that is a mitotic marker. Also, the atypical epithelioid cells displayed p53 immunoreactivity. These results suggest the malignant potential of our tumor based on the previous reports; therefore the careful followup for this case is necessary for a long period whether it shows metastasis, sizing up, and so forth.
PMCID: PMC3705845  PMID: 23864864
7.  A safe and effective dose of cisplatin in hepatic arterial infusion chemotherapy for hepatocellular carcinoma 
Cancer Medicine  2013;2(1):86-98.
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 m2) 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.
PMCID: PMC3797567  PMID: 24133631
Cisplatin; dose recommendation; hepatic arterial infusion chemotherapy; hepatocellular carcinoma
8.  Hepatic Angiomyolipoma: Diagnostic Findings and Management 
Angiomyolipoma (AML) is a benign mesenchymal tumor that is frequently found in the kidney and, rarely, in the liver. The natural history of hepatic AML has not been clarified, and, because of the similar patterns in imaging studies, such as ultrasonography, computed tomography, and magnetic resonance imaging, some of these tumors have been overdiagnosed as hepatocellular carcinoma in the past. With an increase in the number of case reports showing detailed imaging studies and immunohistochemical staining of the tumor with human melanoma black-45, the diagnostic accuracy is also increasing. In this paper, we focused on the role of noninvasive imaging studies and histological diagnosis showing distinctive characteristics of this tumor. In addition, because several reports have described tumor progression in terms of size, recurrence after surgical resection, metastasis to other organs, and portal thrombosis, we summarized these cases for the management and discussed the indications for the surgical treatment of this tumor.
PMCID: PMC3540709  PMID: 23320180
9.  Phase I study of miriplatin combined with transarterial chemotherapy using CDDP powder in patients with hepatocellular carcinoma 
BMC Gastroenterology  2012;12:127.
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).
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/m2) followed by targeting the HCC nodules by transarterial oily chemoembolization with miriplatin.
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.
Our results suggest that a combination of DDP-H and miriplatin can be safely administered up to their respective MTD for treating HCC.
Trial registration
This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR000003541).
PMCID: PMC3482551  PMID: 22994941
Miriplatin; Hepatocellular carcinoma; Cisplatin powder; Phase I clinical trial
10.  Advances in Gene Delivery Systems 
Pharmaceutical medicine  2011;25(5):293-306.
The transfer of genes into cells, both in vitro and in vivo, is critical for studying gene function and conducting gene therapy. Methods that utilize viral and nonviral vectors, as well as physical approaches, have been explored. Viral vector-mediated gene transfer employs replication-deficient viruses such as retro-virus, adenovirus, adeno-associated virus and herpes simplex virus. A major advantage of viral vectors is their high gene delivery efficiency. The nonviral vectors developed so far include cationic liposomes, cationic polymers, synthetic peptides and naturally occurring compounds. These nonviral vectors appear to be highly effective in gene delivery to cultured cells in vitro but are significantly less effective in vivo. Physical methods utilize mechanical pressure, electric shock or hydrodynamic force to transiently permeate the cell membrane to transfer DNA into target cells. They are simpler than viral- and nonviral-based systems and highly effective for localized gene delivery. The past decade has seen significant efforts to establish the most desirable method for safe, effective and target-specific gene delivery, and good progress has been made. The objectives of this review are to (i) explain the rationale for the design of viral, nonviral and physical methods for gene delivery; (ii) provide a summary on recent advances in gene transfer technology; (iii) discuss advantages and disadvantages of each of the most commonly used gene delivery methods; and (iv) provide future perspectives.
PMCID: PMC3245684  PMID: 22200988
11.  Intracellular Gene Transfer in Rats by Tail Vein Injection of Plasmid DNA 
The AAPS Journal  2010;12(4):692-698.
In this study, we examined the effect of various factors on gene delivery efficiency of tail vein injection of plasmid DNA into rats. We measured the level of reporter gene expression in the internal organs including the lung, heart, spleen, kidney, and liver as function of injection volume, injection time, and DNA dose. Persistency of reporter gene expression in transfected animals was also examined. We demonstrated that plasmid delivery to rats by the tail vein is effective as long as the volume of injected DNA solution is adjusted to 7–8% of body weight with an injection time of less than 10 s. With the exception of a short-term increase in serum concentration of alanine aminotransferase and transient irregularity in cardiac function during and soon after the injection, the procedure is well tolerated. Lac Z staining of the liver from transfected animals showed approximately 5–10% positive cells. Persistency test for transgene expression in animals using plasmid carrying cDNA of human alpha 1 antitrypsin gene driven by chicken beta actin gene promoter with CMV enhancers showed peak level of transgene product 1 day after the injection followed by a gradual decline with time. Peak level was regained by a second injection performed on day 38 after the first injection. These results show that tail vein injection is an effective means for introducing plasmid DNA into liver cells in rats. We believe that this procedure will be extremely useful for gene function studies in the context of whole animal in rats.
PMCID: PMC2976992  PMID: 20859713
gene delivery; gene therapy; hydrodynamic gene delivery; nonviral vectors; siRNA delivery
12.  Multicentric occurrence of hepatocellular carcinoma with nonalcoholic steatohepatitis 
World Journal of Hepatology  2011;3(1):15-23.
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.
PMCID: PMC3035698  PMID: 21307983
Nonalcoholic steatohepatitis; Hepatocellular carcinoma; Multicentric occurrence
13.  Image-guided, Intravascular Hydrodynamic Gene Delivery to Skeletal Muscle in Pigs 
Development of an effective, safe and convenient method for gene delivery to muscle is a critical step toward gene therapy for muscle-associated diseases. Toward this end, we have explored the possibility of combining the image-guided catheter insertion technique with the principle of hydrodynamic delivery to achieve muscle specific gene transfer in pigs. We demonstrate that gene transfer efficiency of the procedure is directly related to flow rate, injection pressure and injection volume. The optimal gene delivery was achieved at a flow rate of 15 ml/sec with injection pressure of 300 psi and injection volume equal to 1.5% of body weight. Under such a condition, hydrodynamic injection of saline containing pCMV-Luc (100 µg/ml) resulted in luciferase activity of 106 –107 relative light units (RLU)/mg of proteins extracted from the targeted muscle 5 days after hydrodynamic gene delivery. Result from immunohistochemical analysis revealed 70–90% transfection efficiency of muscle groups in the hind limb and persistent reporter gene expression for 2 months in transfected cells. With an exception of transient edema and elevation of creatine phosphokinase, no permanent tissue damage was observed. These results suggest that the image-guided, intravenous hydrodynamic delivery is an effective and safe method for gene delivery to skeletal muscle.
PMCID: PMC2805042  PMID: 19738603
Hydrodynamic gene delivery; gene therapy; gene delivery; nonviral vectors; skeletal muscle
14.  Image-Guided, Lobe-Specific Hydrodynamic Gene Delivery to Swine Liver 
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 107 RLU/mg in the targeted lobes and 102−105 RLU/mg in the non-targeted lobes 4 hr after hydrodynamic injection of pCMV-Luc plasmids. Occlusion of blood flow in the inferior vena cava or inferior vena cava plus portal vein was effective in elevating hydrodynamic pressure in the targeted vasculature but did not enhance gene delivery efficiency. Physiological examination on pigs with inferior vena cava occlusion revealed transient decreases of blood pressure and respiration rate. Removal of occlusion from inferior vena cava resulted in a rapid and transient increase in heart rate. Occlusion of the portal vein and hepatic vein showed no effect on physiological and cardiac activities. No major changes in serum composition were observed. These results suggest that: (1) image-guided, lobe-specific hydrodynamic procedure is safe and effective for regional gene delivery to liver; (2) blockade in inferior vena cava should be avoided for hydrodynamic gene delivery to the liver; and (3) clinic application of hydrodynamic gene delivery to liver is feasible.
PMCID: PMC2680706  PMID: 19156134
Hydrodynamic gene delivery; gene therapy; gene delivery; nonviral vectors; hydrojector
15.  Physical Approaches for Nucleic Acid Delivery to Liver 
The AAPS Journal  2008;10(4):589-595.
The liver is a key organ for numerous metabolic pathways and involves many inherited diseases that, although being different in their pathology, are often caused by lack or overproduction of a critical gene product in the diseased cells. In principle, a straightforward method to fix such problem is to introduce into these cells with a gene-coding sequence to provide the missing gene product or with the nucleic acid sequence to inhibit production of the excessive gene product. Practically, however, success of nucleic acid-based pharmaceutics is dependent on the availability of a method capable of delivering nucleic acid sequence in the form of DNA or RNA to liver cells. In this review, we will summarize the progress toward the development of physical methods for nucleic acid delivery to the liver. Emphasis is placed on the mechanism of action, pros, and cons of each method developed so far. We hope the information provided will encourage new endeavor to improve the current methodologies or develop new strategies that will lead to safe and effective delivery of nucleic acids to the liver.
PMCID: PMC2628207  PMID: 19083101
gene delivery; liver; nonviral vectors; physical method; transfection
16.  Physical Approaches for Nucleic Acid Delivery to Liver 
The AAPS journal  2008;10(4):589-595.
Liver is a key organ for numerous metabolic pathways and involves many inherited diseases that, although being different in their pathology, are often caused by lack or overproduction of a critical gene product in the diseased cells. In principle, a straightforward method to fix such problem is to introduce into these cells with a gene-coding sequence to provide the missing gene product, or with the nucleic acid sequence to inhibit production of the excessive gene product. Practically, however, success of nucleic acid-based pharmaceutics is dependent on availability of a method capable of delivering nucleic acid sequence in the form of DNA or RNA to liver cells. In this review, we will summarize the progress toward development of physical methods for nucleic acid delivery to liver. Emphasis is placed on the mechanism of action, pros and cons of each method developed so far. We hope the information provided will encourage new endeavor to improve the current methodologies or develop new strategies that will lead to safe and effective delivery of nucleic acids to liver.
PMCID: PMC2628207  PMID: 19083101
Gene delivery; non-viral vectors; physical method; liver; transfection

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