Clinical and microbiologic investigation of an expedited peri-implantitis dog model: an animal study.

BACKGROUND: Animal studies are pivotal in allowing experimentation to identify efficacious treatment protocols for resolution of peri-implantitis. The purpose of this investigation was to characterize an expedited dog peri-implantitis model clinically, radiographically, and microbiologically. METHODS: Eight hound dogs underwent extractions (week 0) and implant (3.3 × 8.5 mm) placement with simultaneous surgical defect creation and ligature placement for induction of peri-implantitis (week 10). Ligatures were replaced at 6 weeks (week 16) and removed after 9 weeks (week 19) when supporting bone loss involved approximately 50% of the peri-implant bone. Microbial samples from the defects and healthy control implant sites collected at week 19 were analyzed utilizing a microarray. Clinical measures of inflammation were obtained and radiographic bone loss was measured from periapical radiographs. Radiographic depth and width measurements of bony defect were repeated at weeks 10 (baseline), 16, and 19. Canonical analysis of principal coordinates was used to visualize overall differences in microbial abundance between peri-implantitis and healthy implants. RESULTS: This accelerated disease protocol led to intrabony defect creation with a mean depth and width of 4.3 mm and 3.5 mm, respectively after 9 weeks of ligature placement. Microbial identification revealed 59 total bacteria in peri-implant sites, 21 of which were only present in peri-implant sites as compared to healthy controls. Overall microbial beta diversity (microbial between-sample compositional diversity) differed between peri-implantitis and healthy implants (p = 0.009). CONCLUSIONS: Within the limitations of this study, this protocol led to expedited generation of peri-implant defects with a microbial profile indicative of a shift to disease and defect patterns conducive to regenerative treatment. However, the possibility of potential spontaneous resolution of lesions due to the lack of a chronicity interval as compared to chronic disease models need to be further clarified and considered during preclinical peri-implantitis model selection.

Comparison of push-in versus pull-out tests on bone-implant interfaces of rabbit tibia dental implant healing model.

PURPOSE: This study aimed to investigate whether push-in and pull-out tests measure mechanical properties of the bone-implant interface differently, and which test is more sensitive to changes over the healing period. MATERIALS AND METHODS: Two identical self-threading dental implants (3.3×8.5mm) were placed in medial surface of the proximal condyles of left and right tibias of 20 rabbits (40 implants total). Five rabbits each were sacrificed after 1, 4, 8, and 12 weeks of healing. Push-in test was performed on one side's tibia implant and pull-out on the other side's implant, at a rate of 6mm/min. Primary and secondary implant stabilities and tibia weight were measured on all implants. RESULTS: The push-in test generated significantly higher failure load (p=.0001; 530N vs 279N), lower displacement at failure (p=.0003; 0.436mm vs 0.680mm), and higher interface stiffness (p<.0001; 1,641N/mm vs 619N/mm) than pull-out test. Failure load, stiffness, and secondary implant stability were significantly higher for longer compared with shorter healing periods, while displacement, tibia weight, and primary stability were not. Failure load and stiffness differed significantly for four healing times for the push-in but not for the pull-out test. Failure load was significantly correlated with secondary implant stability for both push-in (r=0.66) and pull-out (r=0.48) tests, but stiffness was significantly correlated with secondary stability only for the push-in test (r=0.72; pull-out test r=0.40). CONCLUSION: The push-in test appeared more sensitive than pull-out to changes in mechanical properties at bone-implant interfaces during healing in rabbit tibia model.

FDG positron emission tomography/computed tomography for the detection of extrahepatic metastases from hepatocellular carcinoma.

AIMS: To compare the efficacy of positron emission tomography (PET) computed tomography (CT), multi-detector helical computed tomography (MDCT) and bone scintigraphy for the detection of extrahepatic metastases in patients with hepatocellular carcinoma (HCC). METHODS: Thirty-four patients diagnosed with metastatic HCC were enrolled in this study. The lesions included lung (n = 18), bone (n = 12) and lymph node (n = 16) metastases. For receiver operating characteristic (ROC) analysis, lesions were diagnosed as metastatic HCC by two experienced abdominal radiologists. Another three physicians independently reviewed both positive and negative images. Each physician read three sets of images of MDCT, PET-CT and bone scintigraphy for bone metastasis. RESULTS: The mean sensitivity and specificity for diagnosis of lung metastasis were 85.2 and 88.9% for MDCT, and 59.2 and 92.6% for PET-CT, respectively. For lymph node metastasis, these values were 62.5 and 79.2% for MDCT, and 66.7 and 91.7% for PET-CT, respectively; and for bone metastasis 41.6 and 94.5% for MDCT, 83.3 and 86.1% for PET-CT, and 52.7 and 83.3% for bone scintigraphy, respectively. The mean Az values were 0.95 and 0.77 for MDCT and PET-CT in lung metastasis, respectively, 0.75 and 0.80 for MDCT and PET-CT for lymph node metastasis, respectively, and 0.59, 0.88 and 0.62 for MDCT, PET-CT and bone scintigraphy for bone metastasis, respectively. CONCLUSION: PET-CT has high sensitivity and is more suitable for the detection of bone metastases from primary HCC, relative to MDCT and bone scintigraphy.

Dose comparison study of pegylated interferon-alpha-2b plus ribavirin in naïve Japanese patients with hepatitis C virus genotype 2: a randomized clinical trial.

BACKGROUND AND AIM: To compare the efficacy and safety of pegylated interferon (PEG-I) at 1 and 1.5 microg/kg, and in combination with ribavirin (RBV) for 24 weeks in naïve Japanese patients infected with hepatitis C virus genotype 2. METHODS: The present study was an open-label, randomized trial of 55 patients receiving PEG-I (1 or 1.5 microg/kg body weight [BW], subcutaneously, once a week) and RBV for 24 weeks. The patients were followed up for 24 weeks without treatment. RESULTS: The intention-to-treat analyses showed that the proportion of patients with a sustained virological response (SVR) in the 1-microg/kg PEG-I-RBV group (38.5%, 10/26) was lower than that of the 1.5-microg/kg PEG-I-RBV group (74.1%, 20/27; P = 0.013). The PEG-I dose was reduced in two of the 26 patients of the 1-microg/kg PEG-I-RBV group (one because of thrombocytopenia at 2 weeks, and one because of generalized fatigue at 20 weeks), and four of the 27 patients of the 1.5-microg/kg PEG-I-RBV group (one because of neutropenia at 20 weeks, and three because of generalized fatigue at 1, 5, and 8 weeks). The multivariate analysis identified age (< 60 years) and dose of PEG-I (1.5 microg/kg) as significant determinants of SVR. CONCLUSION: The dose of PEG-I to be used at the start of therapy should be 1.5-microg/kg BW in naïve Japanese patients infected with hepatitis C virus genotype 2.

Beneficial effects of living-donor liver transplantation on esophageal varices.

BACKGROUND: Liver transplantation (LT) is known to improve bleeding esophageal varices (EVs) and portal hypertension. However, many issues related to EVs after LT remain unresolved, such as whether LT reduces blood supply to EVs, improves the diameter of unruptured EVs, or improves or worsens EVs. The aim of this retrospective study was to determine the effects of living-donor liver transplantation (LDLT) in patients with hepatic failure on EVs and inflow vessels to EVs and the factors associated with deterioration of EVs after LDLT. METHODS: The study subjects were 35 patients with cirrhosis who underwent LDLT. Endoscopy and multidetector helical computed tomography (MDCT) were performed before and after LDLT. The diameter of the inflow vessel of EVs was measured by MDCT before and after LDLT, together with the LDLT-related reduction rate of the diameter of the gastric vein (RRGV). RESULTS: Endoscopic examination showed improvement of EVs in 30 of 35 (86%) patients. RRGV improved in 17/35 (49%) patients, did not change in 13/35 (37%), and deteriorated in 5/35 (14%). The cause of RRGV deterioration seemed to be either the complication of portal vein or graft failure. In patients examined endoscopically at >1 year after LDLT, improvement of EVs was associated with significant changes in the rate of reduction of the major inflow vessel diameter and Child-Pugh score, compared with those who showed no improvement. CONCLUSIONS: LDLT results in improvement of EVs. EVs improved in 86% of the patients. Measurement of RRGV with MDCT is a good tool for prediction of EV improvement after LDLT.

Combination therapy of oral fluoropyrimidine anticancer drug S-1 and interferon alpha for HCC patients with extrahepatic metastases.

PURPOSE: There is no standard treatment for hepatocellular carcinoma (HCC) patients with extrahepatic metastases. We assessed the efficiency and safety of the oral fluoropyrimidine anticancer drug S-1 combined with interferon alpha (IFN-alpha) for HCC patients with extrahepatic metastases. METHODS: Twenty-nine HCC patients with extrahepatic metastases received S-1/IFN. One cycle of combination therapy represented 2 weeks followed by 2-4 weeks of rest. In each cycle, S-1 was administrated orally at 80-120 mg (depending on body surface area) every day and IFN-alpha intramuscularly at 5 million units thrice weekly. RESULTS: The overall response of 29 patients was complete response (CR) in 4 (14%), partial response (PR) in 1, stable disease in 4, progressive disease in 12, and dropout in 8 patients. Objective response (CR + PR) was 17%. The time to progression and survival rate were significantly higher in patients with lung metastases (n = 19) than in those with painful bone metastases (n = 7; p = 0.0058 and 0.0015). With regard to NCI-CTC grade 3 adverse reactions, 3 (10%), 3 (10%) and 2 (7%) patients developed anorexia, leukopenia, and neutropenia, respectively. No grade 4 adverse reaction or toxicity-related death occurred. CONCLUSION: S-1/IFN is a potentially safe and suitable combination therapy for HCC patients with extrahepatic metastases, especially those with lung metastases.

Etiology and outcome of acute liver failure: retrospective analysis of 50 patients treated at a single center.

BACKGROUND AND AIM: Acute liver failure (ALF) remains a devastating disease carrying considerable mortality. Since deceased donor liver transplantation is rarely performed in Japan, the artificial liver support system (ALS) and living donor liver transplantation (LDLT) are the main modalities used for treatment of ALF. The aim of this study was to analyze the outcome of ALF patients and to evaluate therapies for ALF according to etiology. METHODS: Fifty consecutive patients with ALF were treated between January 1990 and December 2006. Prior to 1997, patients received ALS only. After 1997, ALS and/or LDLT were applied. LDLT was performed in 10 patients. RESULTS: Four of 15 (27%) pre-1997 ALF patients survived, and 16 of 35 (46%) post-1997 ALF patients survived, including eight who underwent LDLT. The causes of ALF were acute hepatitis B virus (HBV) infection in 18%, severe acute exacerbation (SAE) of chronic HBV infection in 18%, autoimmune hepatitis (AIH) in 8%, and cryptogenic hepatitis in 44%. In total, 67% of the patients with ALF caused by acute HBV infection and AIH were cured without LDLT; only 11% of patients with ALF caused by SAE of HBV and 24% of cryptogenic hepatitis were successfully treated without LDLT. Notably, 80% of patients with cryptogenic hepatitis who underwent LDLT survived. CONCLUSION: Since 1997, the survival rate of ALF patients has increased, mainly due to the introduction of LDLT. Liver transplantation should be performed especially in patients with ALF caused by SAE of HBV and cryptogenic hepatitis.

Clinicopathological features of elderly patients with hepatitis C virus-related hepatocellular carcinoma.

BACKGROUND: It is well known that the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) correlates with progression of liver fibrosis. However, there is little information on the impact of aging on hepatocarcinogenesis. The aim of this study was to elucidate the clinicopathological features of elderly patients with HCV-related HCC. METHODS: The study subjects were 693 consecutive patients newly diagnosed with HCC with anti-HCV. First, we divided them into a younger group (<70 years) and an elderly group (> or =70 years) and compared clinicopathological features between the two groups. Next, we selected pure HCV-related HCC patients by excluding the patients with other probable factors for hepatocarcinogenesis (anti-HBc, interferon therapy, and alcohol) and compared the two groups again. RESULTS: Higher platelet count, lower male/female ratio, lower rate of habitual alcohol consumption, and better Child-Pugh class were recognized in the elderly group thant the younger group, statistically. In 133 cases of hepatic resection, fibrosis stage was lower in the elderly than the younger group. After selection of pure HCV-related HCC patients, in a stepwise multi variate analysis, male sex and platelet count <10 x 10(4)/mm3 were significant variables associated with age <70. Regarding the latency period to HCC development, the patients who received a blood transfusion at an older age developed HCC sooner despite their lower grade of fibrosis. CONCLUSIONS: The elderly patients developed HCC more often, despite their lower grade of fibrosis, compared with the younger patients. In addition to fibrosis, aging could be a factor affecting HCV-related hepatocarcinogenesis.

Pretreatment predictor of response, time to progression, and survival to intraarterial 5-fluorouracil/interferon combination therapy in patients with advanced hepatocellular carcinoma.

BACKGROUND: Several studies have reported survival benefits of combination therapy with intraarterial 5-fluorouracil (5-FU) and subcutaneous interferon (IFN) alpha for advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). We investigated the pretreatment predictive factors of early response, time to progression (TTP), and survival in response to intraarterial 5-FU/IFN combination therapy. METHODS: Patients with nonresectable HCC and variable PVTT grades (without PVTT to PVTT in the trunk) received intraarterial 5-FU/IFN combination therapy (n = 55). RESULTS: After two courses of the combination therapy, 1 (2%), 15 (27%), 16 (29%), 12 (22%), and 11 (20%) of 55 patients showed complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), or had dropped out (DO), respectively, when their early response to treatment was assessed. Univariate analysis identified only hepatitis C virus (HCV) antibody positivity as having significantly influenced the early response (P = 0.028) and TTP (P = 0.021). Multivariate analysis identified performance status (P = 0.003) and HCV antibody positivity (P = 0.007) as significant and independent determinants of survival. PVTT grade did not influence early response, TTP, or survival. The survival rate was significantly higher in patients who achieved CR or PR than in those that assessed as SD or PD, or DO (P < 0.0001, each). CONCLUSIONS: HCV antibody positivity may be a significant pretreatment predictor of early response, TTP, and survival of patients with advanced HCC treated with 5-FU/IFN. CR or PR as the early response to the combination therapy might indicate a more favorable prognosis in patients with advanced HCC. PVTT grade did not seem to influence the efficacy of combination therapy.

Similar effects of recombinant interferon-alpha-2b and natural interferon-alpha when combined with intra-arterial 5-fluorouracil for the treatment of advanced hepatocellular carcinoma.

AIM: Intra-arterial 5-fluorouracil (5-FU) plus interferon (IFN) combination therapy is effective against advanced hepatocellular carcinoma (HCC) with portal vein tumour thrombosis. In this study, we compared the efficiency and safety of recombinant IFN-alpha-2b with natural IFN-alpha as components of the combination therapy. METHODS: Consecutive HCC patients (n=31) with portal vein tumour thrombosis were enrolled in this prospective study. They received combination therapy of 5-FU and either recombinant IFN-alpha-2b (R group, n=15) or natural IFN-alpha (N group, n=16). We compared the two groups for the early response rate, adverse reactions, time to progression (TTP) and survival rates. In addition, we assessed the cost-effectiveness of each protocol. RESULTS: The early response rate (R: 26.7%, N: 31.2%), median TTP (R: 5.8 months, N: 5.6 months) and median survival time (R: 7.5 months, N: 6.5 months) were not significantly different between the R and N groups. There were no differences in adverse reactions between the two groups. The estimated cost-effectiveness ratio of recombinant IFN-alpha-2b was better than natural IFN-alpha. CONCLUSIONS: In our protocol of combination therapy, there were no significant differences between recombinant IFN-alpha-2b and natural IFN-alpha with regard to early response to therapy, adverse effects, TTP and survival rates. 5-FU could be combined with either recombinant IFN-alpha-2b or natural IFN-alpha, although the cost-effectiveness of the former warrants its use clinically.

Effects of a 24-week course of interferon-alpha therapy after curative treatment of hepatitis C virus-associated hepatocellular carcinoma.

AIM: To assess whether a 24-wk course of interferon (IFN) could prevent hepatocellular carcinoma (HCC) recurrence and worsening of liver function in patients with hepatitis C virus (HCV)-infected patients after receiving curative treatment for primary HCC. METHODS: Outcomes in 42 patients with HCV infection treated with IFN-alpha, after curative treatment for primary HCC (IFN group), were compared with 42 matched curatively treated historical controls not given IFN (non-IFN group). RESULTS: Although the rate of initial recurrence did not differ significantly between IFN group and non-IFN group (0%, 44%, 61%, and 67% vs 4.8%, 53%, 81%, and 87% at 1, 3, 5, and 7 years, P = 0.153, respectively), IFN group showed a lower rate than the non-IFN group for second recurrence (0%, 10.4%, 28%, and 35% vs 0%, 30%, 59%, and 66% at 1, 3, 5 and 7 years, P = 0.022, respectively). Among the IFN group, patients with sustained virologic response (SVR) were less likely to have a second HCC recurrence than IFN patients without an SVR, or non-IFN patients. Multivariate analysis identified the lack of SVR as the only independent risk factor for a second recurrence, while SVR and Child-Pugh class A independently favored overall survival. CONCLUSION: Most intrahepatic recurrences of HCV-related HCC occurred during persistent viral infection. Eradication of HCV is essential for the prevention of HCC recurrence and improvement of survival.

Effect of extracts from safflower seeds on osteoblast differentiation and intracellular calcium ion concentration in MC3T3-E1 cells.

Although safflower seeds have long been used in Korea as herbal medicines, very little research has been published on the effects of safflower seed on bone formation or bone density. The study reported here therefore examined bone nodule formation, calcium uptake, alkaline phosphatase activity, and intracellular concentration of calcium ion [Ca(2+)](i) in murine osteoblastic cells of the MC3T3-E1 line that were cultured on modified Eagle's minimal essential medium alone (controls) or with addition of 0.1% crude extract of safflower seed (experimental group I) or 0.1% aqueous fraction of safflower seed (experimental group II). Fluorescence spectrometry measurement of ([Ca(2+)](i)) showed significantly accelerated rates of osteoblast differentiation in experimental group I (3 microL of crude extract in 8 x 10(4) cells) and experimental group II (2 microL of aqueous fraction in 8 x 10(4) cells) compared to the control group.

Clinical features and prognosis of patients with extrahepatic metastases from hepatocellular carcinoma.

AIM: To assess the clinical features and prognosis of 151 patients with extrahepatic metastases from primary hepatocellular carcinoma (HCC), and describe the treatment strategy for such patients. METHODS: After the diagnosis of HCC, all 995 consecutive HCC patients were followed up at regular intervals and 151 (15.2%) patients were found to have extrahepatic metastases at the initial diagnosis of primary HCC or developed such tumors during the follow-up period. We assessed their clinical features, prognosis, and treatment strategies. RESULTS: The most frequent site of extrahepatic metastases was the lungs (47%), followed by lymph nodes (45%), bones (37%), and adrenal glands (12%). The cumulative survival rates after the initial diagnosis of extrahepatic metastases at 6, 12, 24, and 36 mo were 44.1%, 21.7%, 14.2%, 7.1%, respectively. The median survival time was 4.9 mo (range, 0-37 mo). Fourteen patients (11%) died of extrahepatic HCC, others died of primary HCC or liver failure. CONCLUSION: The prognosis of HCC patients with extrahepatic metastases is poor. With regard to the cause of death, many patients would die of intrahepatic HCC and few of extrahepatic metastases. Although most of HCC patients with extrahepatic metastases should undergo treatment for the primary HCC mainly, treatment of extrahepatic metastases in selected HCC patients who have good hepatic reserve, intrahepatic tumor stage (T0-T2), and are free of portal venous invasion may improve survival.

Efficacy of percutaneous cementoplasty for bone metastasis from hepatocellular carcinoma.

OBJECTIVE: To assess the efficacy of percutaneous cementoplasty for painful bone metastasis from hepatocellular carcinoma (HCC). METHODS: Cementoplasty was performed for 22 metastatic bone tumors in 13 patients. All patients had intractable pain and were diagnosed as metastatic bone tumor from HCC. The ostyneedle was inserted in the center of the site of bone metastasis under CT guidance. VAS score, Tokuhashi score and Frankel score were used for assessment of the efficacy of cementoplasty. We also assessed the response to treatment, adverse events and prognosis. RESULTS: Only the VAS score, but not Tokuhashi and Frankel scores, improved after cementoplasty. Cementoplasty for painful bone metastasis provided relief of severe pain but did not improve prognosis, neurological function or survival. Eleven of 13 (85%) patients showed CR or PR and the mean pain-free period was 5 months, including a 10-month pain-free period in one case. No major complications were encountered. CONCLUSIONS: Percutaneous cementoplasty can provide pain relief and improvement of quality of life, though without survival benefits, for HCC patients with painful bone metastasis.

Effects of chlorpromazine HCl on the structural parameters of bovine brain membranes.

Fluorescence probes located in different membrane regions were used to evaluate the effects of chlorpromazine .HCl on structural parameters (transbilayer lateral mobility, annular lipid fluidity, protein distribution, and lipid bilayer thickness) of synaptosomal plasma membrane vesicles (SPMVs) isolated from bovine cerebral cortex. The experimental procedure was based on the selective quenching of 1,3-di(1-pyrenyl)propane (Py-3-Py) by trinitrophenyl groups, radiationless energy transfer from the tryptophan of membrane proteins to Py-3-Py, and energy transfer from Py-3-Py monomers to 1-anilinonaphthalene-8-sulfonic acid (ANS). In this study, chlorpromazine .HCl decreased the lateral mobility of Py-3-Py in a concentration dependent-manner, showed a greater ordering effect on the inner monolayer than on the outer monolayer, decreased annular lipid fluidity in a dose dependent-manner, and contracted the membrane lipid bilayer. Furthermore, the drug was found to have a clustering effect on membrane proteins.