Targeted systemic chemotherapy using magnetic liposomes with incorporated adriamycin for osteosarcoma in hamsters.

To control the growth of primary tumors effectively with systemic chemotherapy, we recently developed intravenously administered small-sized magnetic liposomes as an anticancer drug carrier. We previously reported that intravenously administered magnetic liposomes with incorporated adriamycin (magnetic ADR liposomes) effectively delivered ADR to the target site where a permanent magnet was implanted. In the present study, the therapeutic efficacy of this novel treatment approach, which involves a combination of magnet implantation at the target site and intravenous administration of magnetic liposomes, was further evaluated by comparing tumor growth rates among different administration modalities and by histological examination of treated tumors. Small-sized magnetic ADR liposomes with a mean diameter of 146 nm were prepared by the reverse-phase evaporation method. Syrian male hamsters inoculated with osteosarcoma, Os515, in the right hind limb were studied 7 days after inoculation. One day prior to the animal study, either a permanent magnet (with magnetic force) or non-magnetic alloy (without magnetic force) was implanted in the center of the tumors. Treatment with magnetic ADR liposomes under magnetic force showed significantly greater antitumor activity than intravenous administration of ADR solution or that of magnetic ADR liposomes without magnetic force. ADR administered as magnetic liposomes eliminated weight loss of hamsters, one of the side effects produced by ADR. Interestingly, magnetic liposomes (without incorporated ADR) given under magnetic force also suppressed the tumor growth. The selective accumulation of magnetite particles in the tumor blood vessels was observed by histological examination. These results suggest that this systemic chemotherapy can effectively control the primary tumor without significant side effects, due to the targeting of magnetic ADR liposomes.

Targeted delivery of anticancer drugs with intravenously administered magnetic liposomes in osteosarcoma-bearing hamsters.

Although active targeting of anticancer drugs using magnetically responsive carriers is a very attractive treatment approach for solid tumors, successful results are limited. In particular, the therapeutic utility of intravenously administered magnetically responsive carriers has to date not been clearly established. The present study investigates magnetic liposomes designed to act as anticancer drug carriers, which can be effectively delivered to solid tumors via intravenous administration. Magnetic liposomes with incorporated adriamycin (magnetic ADR liposomes) were prepared by the reverse-phase evaporation method, and an in vivo study was carried out to assess the magnetic targeting of these liposomes to hamster osteosarcoma. The average diameter of liposomes thus prepared was 146 nm. Syrian male hamsters inoculated with osteosarcoma, Os515, in the right hind limb were studied 7 days after inoculation. After the hamsters had received an intravenous administration of either magnetic ADR liposomes or ADR solution (corresponding to 5 mg ADR/kg), the ADR concentrations in plasma, tumor, liver, lung, heart, and kidney were determined at designated time intervals. Administration of magnetic ADR liposomes under magnetic force using a permanent magnet (0.4 tesla) implanted in solid tumor produced an approximately 4-fold higher maximum ADR concentration in the tumor than did administration of ADR solution. The former administration modality induced an increase in ADR concentration in the liver and lung and a decrease in the heart compared with concentrations produced by the latter. The present results indicated that intravenously administered magnetic ADR liposomes can be used to effectively deliver ADR to osteosarcoma implanted with a magnet, as well as to the lung, a common site of metastases for osteosarcoma. Our results also suggest that this new treatment approach, which involves a combination of magnet implantation at the target site and intravenous administration of magnetic liposomes, can improve the clinical chemotherapy of solid tumors.

Effect of thermosensitive liposomal doxorubicin with hyperthermia on primary tumor and lung metastases in hamster osteosarcoma.

We evaluated the effect of intravenous thermosensitive liposomal doxorubicin (TL-DOX) together with local hyperthermia on primary tumors in highly metastatic hamster osteosarcoma. This combination resulted in higher DOX concentrations in plasma, primary tumors and lungs than standard DOX under the same conditions. Tumor growth and lung metastasis were also inhibited more by TL-DOX and hyperthermia than by hyperthermia alone, DOX with or without hyperthermia, and TL-DOX without hyperthermia. In addition, gains in hamster body weight were not suppressed. These results suggest that the combination of TL-DOX and hyperthermia can control primary tumors and suppress lung metastasis in hamsters.

Inhibitory effect of liposomal MDP-Lys on lung metastasis of transplantable osteosarcoma in hamster.

MDP-Lys (N2-[(N-acetylmuramyl)-L-alanyl-D-isoglutaminyl]-N6-stearoyl-L-lysine), a macrophage activator, is a lipophilic derivative of muramyl dipeptide (MDP). Multilamellar liposome incorporated MDP-Lys was prepared using phosphatidylcholine and phosphatidylserine by conventional film method, and its inhibitory effect on lung metastasis was compared with MDP-Lys as a solution in hamster's osteosarcoma. The lung metastatic rates after transplantation of the tumor to a lower extremity, in which the extremity was amputated 3 weeks later, were 50% and 100% 3 and 7 weeks, respectively, after transplantation. The rates after amputation were reduced by the treatment with MDP-Lys proportionally to the logarithmic MDP-Lys dose, and the rates 7 weeks after transplantation were 55% and 60%, respectively, in the MDP-Lys solution (50 microg/day) and liposomal MDP-Lys (20 microg twice/week) groups. Fifty percent of hamsters treated with liposomal MDP-Lys survived for more than 6 months. Considering that hamsters had a lung metastasis rate of 50% before MDP-Lys treatment, liposomal MDP-Lys given at a dose of 20 microg twice/week was effective for inhibiting lung metastasis at a far lower dose of MDP-Lys than that given as a solution (40 microg vs. 350 microg per week). No significant side effect of liposomal MDP-Lys, as evaluated by the comparison of body weight changes among differently treated hamsters, was detected. This greater inhibitory effect of liposomal MDP-Lys can be considered to be due to the longer retention of the liposomal form in the lung.

Double-toe transplantation following temporary insertion of a block of silicone for reconstruction of a traumatic metacarpal defect.

The treatment of the mutilated hand with more than one digit missing and a metacarpal defect is challenging. We used double-toe transfer after temporary insertion of a block of silicone to fill the bony defect.

Prolonged artificial liver support in a child with fulminant hepatic failure.

In Japan, liver transplantation from brain dead donors has not yet started. The authors present the first report of a clinical experience with a child with fulminant hepatic failure in whom the combined treatment of plasma exchange and continuous hemodiafiltration using a high-performance polymethylmethacrylate membrane was used successfully to sustain life for a period of as long as 54 days before liver transplantation from a living donor could be performed. The combination of plasma exchange and continuous hemodiafiltration appeared to maintain blood coagulation and level of consciousness effectively. Although the combined use of plasma exchange and continuous hemodiafiltration is still unsatisfactory as an artificial liver support, the authors suggest that this technique may be useful to support the life of a child who awaits liver transplantation.

Postoperative results of looped nylon suture used in injuries of the digital flexor tendons.

Primary or delayed suture was performed on 174 patients involving 234 digits with flexor tendon injury on the day of injury to a maximum of 486 days after injury during the past eight years from 1974. In the treatment a 4-0 or 5-0 looped nylon suture was used. Follow-up study was made on 121 patients involving 164 digits in whom at least six months had elapsed since the operation. The evaluation showed the results in 53.0% excellent, 15.3% good, 18.9% fair and 12.8% poor. Discussion is made of a number of factors which have effects upon the results of treatment of flexor tendon injury of the hand.

An absorbable pinned-ring device for microvascular anastomosis of vein grafts: experimental studies.

In the rabbit, posterior facial vein segments were grafted to the femoral arteries using either conventional suture technique or a mechanical absorbable pinned-ring device. The purpose of this study was to compare patency rates and anastomotic times for the two different methods. The anastomoses were evaluated macroscopically and using light and scanning electron microscopy. The grafts anastomosed with the absorbable rings exhibited 100% patency, while only 83% of the sutured grafts were patent. The mean anastomotic time using the mechanical pinned-ring device was 18.1 min (range 9.8-30 min). The conventionally sutured anastomoses were completed in a mean time of 60 min (range 50-75 min). The experiment has confirmed that the absorbable pinned-ring device provides a safe and fast way to perform microvascular anastomosis.

Superior nerve anastomosis using a low-output CO2 laser on fibrin membrane.

BACKGROUND AND OBJECTIVE: To date, no procedure of laser-aided nerve anastomosis has yet proved to be consistently superior to suture nerve repair. This study examines a new method for nerve repair using a low output CO2 laser and fibrin membrane to ascertain the efficacy of this method for nerve regeneration in comparison with the suture method. STUDY DESIGN/MATERIALS AND METHODS: Both sciatic nerves of 42 Wister rats were used. The left sciatic nerves were cut and reconnected using 70 mW of irradiation on fibrin membrane bridging the nerve stumps, whereas the right sciatic nerves were repaired with two stitches of epineuro-fascicular sutures. RESULTS: No deleterious effect of the irradiation on nerve regeneration was demonstrated at any time after surgery. The number of myelinated axons larger than 5 microns in diameter and the mean diameter of mylinated axons 8 weeks after surgery were significantly larger in the laser group than those in the suture group (P < 0.05). CONCLUSION: The results suggest this new method may be useful and effective for clinical nerve repair.

Resin corrosion cast in experimental evaluation of femoral microanastomosis.

In order to obtain more information about the site of microvascular anastomosis, the authors used the methylmethacrylate resin corrosion casts. 80 microvascular anastomoses were performed in Wistar albino rats and divided into two groups: in the Group 1 (40 anastomoses), the resin was injected into the vessel whereas in Group 2, the tissues were prepared without injecting resin. Both groups were compared under the scanning electron microscope (SEM). The SEM preparation was easier in the Group 1 and the artefacts were significantly reduced. The anastomotic site was better appreciated in Group 1 in three-dimensional views. The resin corrosion cast is a promising technique for the evaluation of the microvascular anastomosis.

Influence of distal nerve segment volume on nerve regeneration in silicone tubes.

The influence of a volume of a distal nerve segment upon nerve regeneration in an 8-mm gap created within a silicone tube was examined. The rats were randomly divided into four groups. Each group had 5 mm, 1 mm, or a half volume of 1-mm nerve segment (a nerve piece of 1 mm transected longitudinally) inserted into the distal end of a silicone tube of 11 mm. The empty group without a nerve segment was used as control. Diameters of regenerated cylindrical structure between the nerve ends in the silicone tube were measured under an operation microscope and myelinated axon diameter, myelinated axon density, myelin sheath width, and ratio of myelinated axon area to total cross sectional area were measured using the transverse sections at the midpoint of the silicone tube at 6 weeks after surgery. Although there was a significant difference in all of those parameters between the control group and any of the remaining three groups, no significant difference was found between any pair of these three groups. The results of this study indicated that the degree of nerve regeneration does not correlate with the volume of a distal nerve segment and even a very small piece can play an important role in supporting regenerating nerve beyond a definitive gap.

Resin corrosion cast (Mercox) in experimental evaluation of small vessel anastomosis.

This study focuses on obtaining more information about the site of anastomosis, with three-dimensional examination using methylmethacrylate resin (Mercox) corrosion casts. Seventy microvascular anastomoses were performed in Wistar albino rats, divided into two groups before sacrifice. In Group 1 (35), Mercox was injected into the vessels, whereas in Group 2 (35), the tissues were prepared without injecting Mercox. Both groups were compared under the scanning electron microscope (SEM). The SEM preparation in Group 1 was simple, easy, and artifacts were significantly minimized. The anastomotic site could be well appreciated in three-dimensional views. Clear negative imprints of the endothelial surface were achieved without any breakage in the Mercox corrosion cast, and it can be reliably used in the evaluation of small vessel anastomosis.

Release and skin distribution of silicone-related compound(s) from a silicone gel sheet in vitro.

The efficacy of topical silicone gel sheeting in prevention and/or reduction of keloids and hypertrophic scars is well recognized. In the present study, we reexamined the possible release of silicone-related compound(s) from a commercially available silicone gel sheet (Cica-Care, Smith and Nephew, Hull, England) in aqueous media in vitro. The silicone gel sheet was also applied on the excised skin surface to examine the possible distribution of silicone-related compounds into the skin in vitro. Silicone-related compounds were measured as silicon by an inductively coupled plasma-atomic emission spectrophotometer. When a piece of silicone gel sheet was placed in phosphate buffer solution (pH 3-9) at 37 degrees C for 7 days, the concentration of silicon in the medium increased with time, depending on the pH of the medium. This indicates that the released silicone-related compounds are water-soluble. When Cica-Care was applied on the surface of excised rat skin, human axilla skin and hypertrophic scars under hydrated conditions in vitro, silicon was detected in all skin samples. Greater distribution was observed in rat skin than in human axilla skin and hypertrophic scars. The release of silicone-related compounds from a silicone gel sheet (Cica-Care) and their distribution into the skin were demonstrated in vitro. Silicone-related compounds distributed into the skin may have pharmacological effects on the skin. Further investigation will be necessary to investigate in detail the action of silicone-related compounds on the proliferation of fibroblasts and excessive production of collagen.