Evaluation of adhesion barrier types in a rat hepatectomy-induced adhesion model.

BACKGROUND: Adhesion formation after hepatectomy creates problems for repeat hepatectomy. This study aimed to compare the effectiveness of a spray (AdSpray) and sheet adhesion barrier (Seprafilm) in a rat hepatectomy-induced adhesion model. METHODS: Thirty male Sprague-Dawley rats underwent partial resection of the left lateral liver lobe. They were randomly assigned to control (n = 10), AdSpray (n = 10), and Seprafilm groups. Seven days after surgery, the animals were sacrificed, and adhesions at the hepatic resection surface were blindly evaluated. RESULTS: In the control group, adhesions were formed in all 10 animals (100%), with a 69% adhesion extent (mean). In the AdSpray group, the incidence of adhesions (40%) and the adhesion extent (mean, 10%) were significantly lower than in the control group (incidence; p = 0.0147, adhesion extent; p = 0.0007). In the Seprafilm group, the incidence of adhesions was 70%. The adhesion extent of Seprafilm (mean, 30%) was significantly lower than in the control group (p = 0.0492). No significant differences were observed between the AdSpray and Seprafilm groups. As for histopathological examination, animals in the AdSpray group showed a similar healing profile to that of the control group without delayed healing and regeneration of mesothelial cells. In contrast, the Seprafilm group showed ongoing foreign body reaction to Seprafilm, and regeneration of mesothelial cells was immature at 7 days. CONCLUSIONS: Both the spray-type gel and sheet adhesion barriers significantly reduced adhesion formation after hepatectomy. The spray-type adhesion barrier caused no adverse events and induced favorable healing. These adhesion barriers may be effective in hepatectomy. Further animal studies and clinical trials are required to determine their benefits in clinical use.

Efficacy of Hyaluronic Acid/Carboxymethyl Cellulose-Based Bioresorbable Membranes in Reducing Perihepatic Adhesion Formation: A Prospective Cohort Study.

BACKGROUND: Perihepatic adhesions induced by hepatectomy make the subsequent repeat hepatectomy technically demanding. The aim of this study was to verify the effect of hyaluronic acid/carboxymethyl cellulose-based bioresorbable membrane (HA membrane) in preventing posthepatectomy adhesion formation by focusing on the ease of the adhesiolysis in subsequent hepatectomy for recurrent tumors. METHODS: A total of 201 patients who underwent hepatectomy using HA membrane were prospectively followed-up for 3 years. Thirty of the 201 patients underwent a repeat hepatectomy for recurrence. The operative data of 85 cases of repeat hepatectomy, the primary hepatectomy of which had been performed without the use of HA membrane, served as the historical control data. The primary endpoint was the time interval between the skin incision and the start of hepatic parenchymal transection (the preparation time) including adhesiolysis. Secondary endpoints were blood loss during the operation, incidence of postoperative complications, and the biochemical data. RESULTS: The median preparation time (183 vs. 228 min; p = 0.027) and total operation time (374 vs. 439 min; p = 0.041) were significantly shorter in the HA membrane group than in the control group. CONCLUSION: Use of HA membranes during hepatectomy enabled significant shortening of the adhesiolysis time during the sequential hepatectomy performed for recurrent tumors.

Retrospective comparative study of irinotecan and pegylated liposomal doxorubicin for platinum-resistant or -refractory epithelial ovarian and primary peritoneal carcinoma.

PURPOSE: This study was conducted to retrospectively compare the efficacy and safety of irinotecan (CPT-11) and pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant or -refractory recurrent epithelial ovarian and primary peritoneal carcinoma. METHODS: Nineteen patients who received CPT-11 and eleven patients who received PLD were enrolled. CPT-11 was intravenously administered at a starting dose of 60-100 mg/m(2) on day 1, 8, and 15 every 28 days, and PLD was administered at a starting dose of 40-50 mg/m(2) on day 1 every 28 days. Primary outcomes were overall response rate (complete response [CR] + partial response [PR]), disease control rate (CR + PR + stable disease), and progression-free survival (PFS) in each group. Clinical response was evaluated every two or three cycles using the Response Evaluation Criteria in Solid Tumors criteria; CA125 analysis was not performed. RESULTS: The overall response rate was 21.1 % (PR, four cases) and 0 % (p = 0.10) in the CPT-11 and PLD groups, respectively, and the disease control rate was 73.7 and 45.5 % (p = 0.12), respectively. Median PFS was 25.3 (range 5.4-69.9) weeks and 12.7 (range 4.0-43.1) weeks in the CPT-11 and PLD groups, respectively; however, this difference was not statistically significant (p = 0.064). Major adverse events in the CPT-11 group were neutropenia, nausea, and diarrhea, whereas those in the PLD group included thrombocytopenia, anemia, stomatitis, and hand-foot syndrome. CONCLUSIONS: This retrospective study demonstrated comparable efficacy outcomes for CPT-11 and PLD. The overall response rate, disease control rate, and median PFS were more favorable in the CPT-11 group compared to the PLD group, although the difference was not significant. The adverse event profiles were different between groups. These results suggest that CPT-11 might be a feasible choice as single-agent salvage chemotherapy for platinum-resistant or -refractory recurrent epithelial ovarian and primary peritoneal carcinoma beside established regimen like PLD.

Hepatocyte Growth Factor DNA Aptamer for Prevention of Postoperative Peritoneal Adhesion via Enhancement of Fibrinolysis and Inhibition of Mesothelial Mesenchymal Transition.

Postoperative peritoneal adhesion (PPA) is a prevalent complication of abdominal surgery, posing a significant hindrance to postsurgical recovery. Although several strategies have been developed to alleviate and prevent adhesions, their efficacy remains unsatisfactory. For the first time, we studied the therapeutic effect and mechanism of our recently developed thermally stable oligonucleotide-based mimetics of hepatocyte growth factor (HGF DNA aptamer) to prevent PPA. The HGF DNA aptamer effectively inhibited canonical TGF-ß1 signaling transduction, partially suppressing mesothelial mesenchymal transition. Additionally, the aptamer, respectively, upregulated and downregulated the expression of tissue plasminogen activator and plasminogen activator inhibitor 1, thereby enhancing fibrinolytic activity. As a pleiotropic factor, the HGF DNA aptamer also enhanced the migratory and proliferative capacities of mesothelial cells. Finally, the aptamer demonstrated a higher level of effectiveness in preventing PPAs than the commercially available antiperitoneal adhesion barrier, Seprafilm. Due to its therapeutic benefits, excellent stability, biosafety, cost-effectiveness, and versatility, the HGF DNA aptamer demonstrates promise for preventing PPA in future clinical settings.

In situ cross-linkable hydrogel of hyaluronan produced via copper-free click chemistry.

Injectable hydrogels are useful in biomedical applications. We have synthesized hyaluronic acids chemically modified with azide groups (HA-A) and cyclooctyne groups (HA-C), respectively. Aqueous HA-A and HA-C solutions were mixed using a double-barreled syringe to form a hydrogel via strain-promoted [3 + 2] cycloaddition without any catalyst at physiological conditions. The hydrogel slowly degraded in PBS over 2 weeks, which was accelerated to 9 days by hyaluronidase, while it rapidly degraded in a cell culture media with fetal bovine serum within 4 days. Both HA-A and HA-C showed good biocompatibility with fibroblast cells in vitro. They were administered using the double-barreled syringe into mice subcutaneously and intraperitoneally. Residue of the hydrogel was cleared 21 days after subcutaneous administration, while it was cleared 7 days after intraperitoneal administration. This injectable HA hydrogel is expected to be useful for tissue engineering and drug delivery systems utilizing its orthogonality.

Advancement of Biomaterial-Based Postoperative Adhesion Barriers.

Postoperative peritoneal adhesion (PPA) is a prevalent incidence that generally happens during the healing process of traumatized tissues. It causes multiple severe complications such as intestinal obstruction, chronic abdominal pain, and female infertility. To prevent PPA, several antiadhesion materials and drug delivery systems composed of biomaterials are used clinically, and clinical antiadhesive is one of the important applications nowadays. In addition to several commercially available materials, like film, spray, injectable hydrogel, powder, or solution type have been energetically studied based on natural and synthetic biomaterials such as alginate, hyaluronan, cellulose, starch, chondroitin sulfate, polyethylene glycol, polylactic acid, etc. Moreover, many kinds of animal adhesion models, such as cecum abrasion models and unitary horn models, are developed to evaluate new materials' efficacy. A new animal adhesion model based on hepatectomy and conventional animal adhesion models is recently developed and a new adhesion barrier by this new model is also developed. In summary, many kinds of materials and animal models are studied; thus, it is quite important to overview this field's current progress. Here, PPA is reviewed in terms of the species of biomaterials and animal models and several problems to be solved to develop better antiadhesion materials in the future are discussed.

Interleukin-2 receptor antagonist immunosuppression and consecutive viral management in living-donor liver transplantation for human immunodeficiency virus/hepatitis C-co-infected patients: a report of 2 cases.

Management of immunosuppression for human immunodeficiency virus/hepatitis C (HIV/HCV) in living-donor liver transplantation (LDLT) has not been established. We performed LDLT for two patients with HIV/HCV-co-infected end-stage liver disease. The immunosuppression protocol consisted of early calcineurin inhibitor-free and interleukin-2 receptor antagonist (IL2Ra) induction and methylprednisolone. Maintenance low-dose tacrolimus was started and anti-retroviral therapy for HIV was re-started 1 week after LDLT. Consecutively, pegylated interferon and ribavirin therapy were successfully added as pre-emptive therapy for HCV. HIV-RNA and HCV-RNA were undetectable on anti-retroviral therapy and HCV treatment at 17 and 8 months after LDLT, respectively, with normal liver function. This study is the first report of early calcineurin inhibitor-free and IL2Ra induction with methylprednisolone immunosuppression in LDLT for HIV/HCV-co-infected patients with a favorable outcome. Consecutive HIV/HCV treatment was well tolerated.

Use of simeprevir following pre-emptive pegylated interferon/ribavirin treatment for recurrent hepatitis C in living donor liver transplant recipients: a 12-week pilot study.

BACKGROUND: The management of recurrent hepatitis C following liver transplantation remains a challenge. METHODS: We prospectively investigated the efficacy and safety of simeprevir in combination with pegylated interferon and ribavirin in five patients undergoing living donor liver transplantation (LDLT) with recurrent hepatitis due to hepatitis C virus (HCV) genotype 1b. RESULTS: As the immunosuppressive regimen, four received cyclosporine A (CsA) and one received tacrolimus (FK); no dose adjustment was made prior to the introduction of simeprevir, but the dose was accordingly modified afterwards. All five patients completed the intended 12-week treatment course without significant adverse events greater than grade 2, and no episodes of rejection were detected during the study period. The trough levels of CsA and FK were stably maintained. At week 12, HCV-RNA was not detectable in three of the five patients, whereas the HCV titer of the other two patients, including one with Q80L and V170I mutations at the HCV NS3 position, was at the lower level of quantification (1.2 log10 IU/ml). CONCLUSIONS: Based on this pilot study, simeprevir-based triple therapy is safe and somewhat effective within the first 12 weeks in LDLT recipients with HCV recurrence. Further studies are warranted to obtain robust conclusions.

Development of carboxymethyl cellulose nonwoven sheet as a novel hemostatic agent.

Carboxymethyl cellulose (CMC) is a plant-derived material that has high biocompatibility and water solubility. We developed a CMC nonwoven sheet as a hemostatic agent by carboxymethylating a continuous filament cellulose nonwoven sheet. The CMC nonwoven sheet was able to absorb water and dissolve in it. The rates of absorption and dissolution depended on the degree of carboxymethylation. After dissolving in blood, CMC accelerated clot development (possibly owing to the incorporation of CMC into fibrin fibers) and increased the viscosity of the blood, both of which would contribute to the improved blood clotting of an injured surface. In vivo experiments using a rat tail cutting method showed that a CMC nonwoven sheet shortened the bleeding time of the tail when applied to the cut surface. The hemostatic effect of the CMC nonwoven sheet was almost at the same level as a commercial hemostatic bandage. These results suggest that a CMC nonwoven sheet could be used as a novel sheet-type hemostatic agent.

Telaprevir-based triple therapy for hepatitis C null responders among living donor liver transplant recipients.

Telaprevir (TVR), a direct -acting protease inhibitor, was recently reported to improve treatment efficacy when used in combination with peg-interferon (PEG-IFN) and ribavirin (RBV) as triple therapy for HCV in non-transplant patients. The aim of the present study was to investigate the feasibility of TVR-based triple therapy among Japanese living donor liver transplant (LDLT) recipients who had been resistant to dual treatment with PEG-IFN and RBV. Among 133 HCV-positive LDLT recipients, 8 null responders during or after dual treatment with PEG-IFN and RBV were finally indicated for TVR-based triple therapy after treatment. All 8 patients had been resistant to dual treatment with PEG-IFN and RBV. While the cyclosporine trough level was well controlled with an 80% dose reduction during TVR administration, the end - of - treatment response rate was only 25% (2/8), with 63% (5/8) of patients developing anemia that required a blood transfusion and 50% (4/8) of patients developing leukopenia that required filgrastim. Dose reduction or treatment discontinuation was required in all cases. Based on the poor efficacy and the unacceptable high rate of cytopenic events, TVR-based triple therapy is not indicated for those resistant to dual treatment with PEG-IFN and RBV.