Segmental Allografts Research Articles

骨移植により再建を行った膝周辺悪性骨腫ようの長期成績

Eight patients with malignant bone tumor arising in knee region treated bymeans of bone graft were followed up for 25 months to 5 years. All of these patients are aliveand well. Most of the reconstructive procedures included a segmental bone allograft with knee fusion. They also had intensive adjuvant chemotherapy for a year. The drugs used were Adriamycin and high dose methotrexate. A local recurrence and a infection required amputations. Then 6 cases were followed up. There were three allograft resorptions which were successfully treated by additional autologous bone grafts. Other complications were a aseptic fistula formation and a fracture of a Kuntcher's nail due to nonunion. Bone healing of the grafts was evaluated on X-ray. All of the primary segmental allograft after the wide resection of the tumor failed in bone healing. Additional autologous bone graft led to the healing in a year. Functional evaluation (by Enneking) showed good in five fused patients and excellent in a hemiresected patient. Reconstructive surgery with massive bone grafts represents a successful alternative to prosthetic implant in young adults with a long life expectancy.

Intercalary bone allografts: radiographic evaluation.

The authors retrospectively evaluated the clinical records and radiographs of 20 patients with a variety of neoplasms in the long bones treated with local resection and allograft replacement. All of the tumors were peridiaphyseal and required an interposed (intercalary) segmental allograft replacement. Postoperative complications developed in 40% of the patients. However, the eventual clinical outcome was good or excellent in 85% of all cases. Various factors appeared to be responsible for the development of complications or the eventual clinical outcome, including union of the graft with the host tissue, soft-tissue swelling, callus formation, and type of allograft (hemi or full). Knowledge of these factors and the relationship between complications and radiographic findings may lead to an early diagnosis and appropriate treatment.

Long-term duct-occluded segmental pancreatic autografts. Does fibrosis lead to graft loss?

In clinical pancreas transplantation, duct-occluded segmental allografts are often used. There is concern that fibrosis following duct-occlusion may lead to progressive graft failure. In this study, sequential histology and endocrine function in long-term (up to 5 years) canine autografts were assessed. Segmental pancreatic autografts with residual pancreatectomy were performed, and the pancreatic duct was occluded with cyanoacrylate glue. Serial i.v. glucose tolerance tests (IVGTT) and percutaneous needle-core biopsies of the grafts were performed as long as grafts functioned. Ten dogs were long-term (greater than 18 months) survivors: 8 dogs had functioning grafts for a median of 48 months (range 18-60) after transplantation, and 3 dogs had graft failure at 21, 27, and 60 months. The mean 40-min blood glucose concentration (BGL-40') after i.v. glucose injection did not increase with time up to 5 years after grafting. Graft biopsies showed a universal picture of aggregated islet cells and fibrous replacement of acinar tissue. The total amount of fibrosis did not change with time, but the existing fibrosis became less cellular and more dense. This long-term study showed that in autografted animals, adequate endocrine function was maintained in the majority of cases, and progressive replacement of islet tissue by fibrosis could not be demonstrated in serial biopsies taken between 18 months and 5 years after autotransplantation. We therefore conclude, that while duct-occlusion results in extensive fibrosis, the process is not progressive, and although fibrosis may contribute to late graft failure this is not inevitable.

Prolongation of segmental and pancreaticoduodenal allografts in the primate with total-lymphoid irradiation and cyclosporine.

The prolongation of segmental and pancreaticoduodenal allografts (PDA) by total lymphoid irradiation (TLI) and in combination with cyclosporine (CsA) was assessed in a well established total pancreatectomy, diabetic, primate transplantation model. Pancreatic transplantation was performed in 119 pancreatectomized baboons (Papio ursinus). Of a total of 109 allografts performed, 71 were segmental allografts (open duct drainage) and 38 PDA. Of 119 graft recipients, 10 received segmental pancreatic autografts. TLI and CsA administered separately to segmental allograft recipients resulted in modest allograft survival and indefinite graft survival was not observed. 8 of 17 (47%) segmental allograft recipients that received TLI and CsA had graft survival beyond 100 days, indicating highly significant pancreatic allograft survival. All long-term segmental allograft recipients were rendered normoglycemic (plasma glucose less than 8 mmol/L) by this immunosuppressive regimen. In contrast, poor results were observed in PDA recipients treated with TLI and CsA. Mean survival in 18 treated PDA recipients was 23.8 days, 8 survived longer than 20 days (44.4%), and 1 greater than 100 days (5.5%). Despite treatment, early rejection of the duodenum in PDA recipients frequently resulted in necrosis and perforation and contributed to a high morbidity and mortality. This study indicates that, in contrast to the significant prolongation of segmental allografts by TLI and CsA, poor immunosuppression was achieved by this regimen in PDA recipients and was associated with a high morbidity and mortality caused by early rejection of the duodenum.

Bone Allografts in Salvage of Difficult Hip Arthroplasties

Fourteen bone allograft transplantations were performed in 12 patients: five whole-hip osteoarticular allografts, eight acetabular wall, and one proximal femur with long-stem prosthesis. Average followup time was 19 months. Average patient age was 46 years. Acetabular grafts appeared healed. There was narrowing of joint space in all whole-hip allografts. However, joint narrowing did not correlate with functional results. Failures were attributed to collapse of the femoral head in one patient and nonunion at the host-allograft junction in two patients. However, even in primary failures, allografts provided bone stock to substitute for massive bone loss; this allowed for further reconstruction with endoprostheses. Intercalary segmental allografts combined with prosthetic devices gave the best results.

Bone Grafts

We developed an experimental model to compare the efficacy of free vascularized bone grafts, conventional segmental autografts, matchstick autografts, and fresh segmental allografts in terms of their ability to reconstruct a 7-cm segmental diaphyseal defect created in the canine femur. Forty-five adult mongrel dogs were studied and followed for 6 to 12 months prior to sacrifice. Evaluation included radiologic assessment of graft incorporation and hypertrophy, histology, and biomechanical testing. These studies indicated that microsurgically revascularized autografts were superior to all other groups in terms of early incorporation, hypertrophy, and the highest mechanical strength to failure. Union of the bone graft to the recipient femur was achieved by 6 months in 25 of 26 autografts, and no difference in union rate was seen within the autograft group. However, only two of five allografts achieved bony union during this time interval. Arteriography, microangiography, fluorochrome, and histologic studies all supported the concept that microsurgically revascularized grafts, when successful, maintain their viability. However, the premise that all osteocytes survive in a successfully revascularized bone graft is open to question. While decalcified sections showed that all microsurgically revascularized grafts maintained normal viability in the central marrow and cancellous portions compared with the other three groups, the viability of cortical bone in the vascularized autografts was less clear. Undecalcified fluorochrome sections suggested that circulation was not preserved in all portions of the cortex. Revascularization of the nonvascularized autografts was complete at 3 months, while, in the avascular allografts, the process was not complete at 6 months.

Segmental pancreatic allograft survival in primates treated with total-body or lymphoid irradiation and peroperative blood transfusions.

Segmental pancreatic allograft survival in primates treated with total-body or lymphoid irradiation and peroperative blood transfusions.

Studies on the survival of simultaneous canine renal and segmental pancreatic allografts.

Prolonged survival of the vascularized free-draining intraperitoneal pancreatic segmental allografts (FDPS) has been observed previously in immunosuppressed beagle littermates matched for low mixed lymphocyte culture (MLC) reactivity. When rejection (hyperglycemia) did occur, it was abrupt, unpredictable, and irreversible. This contrasts with renal allograft rejection in which elevations of serum creatinine are reversible with increased immunosuppression. In the present experiments, low MLC-reactive littermate pairs underwent simultaneous transplantation of kidney and FDPS allografts from the same donor. Increases in serum creatinine from 0.5 mg/dl to 1.5 mg/dl (renal rejection) occurred 4 to 5 days after transplantation (mean = 20.5 +/- 4.1) and preceded the onset of hyperglycemia by 6 to 22 days (mean = 1.06 +/- 4.6) in nonimmunosuppressed animals. At the onset of kidney rejection but before hyperglycemia developed, renal allograft biopsies revealed generalized mononuclear infiltration, while FDPS biopsies showed diffuse interstitial infiltration, but islets of Langerhans appeared to be spared. Treatment intervention with azathioprine and corticosteroids at the time of creatinine elevation prevented the onset of hyperglycemia from 46 to greater than 260 days in four of nine animals. Biopsies after 2 weeks of therapy showed resolution of the lymphoid infiltrates in the kidney and limitation of infiltrates to perivascular areas in the FDPS allografts. Immunological monitoring of peripheral blood lymphocyte function demonstrated the development of positive in vitro cell-mediated lymphocytoxicity shortly before the onset of hyperglycemia but only after creatinine elevation was well established and biopsies revealed evidence of rejection in both the renal and FDPS allografts.

PROLONGATION OF SEGMENTAL PANCREATIC ALLOGRAFTS IN DOGS RECEIVING CYCLOSPORIN A

This study showed that a heterotopic autotransplant of the tail of the pancreas was capable of maintaining adequate glucoregulatory function in pancreatectomized dogs, glucose tolerance test curves, and K values not differing from normal dogs 4 months after transplantation. Hyperinsulinemia in the fasting state was observed in the absence of hypoglycemia in autograft and allograft recipients. Intraductal Ethibloc injection produced total replacement of the exocrine gland at 4 months by fibrosis but with the preservation of islets. Cyclosporin A (Cy A, oral drinking solution) in a dose of 25 mg/kg/day given to recipients of heterotopic segmental allografts produced a slight but significant prolongation of graft survival, but a dose of 40 mg/kg/day resulted in indefinite graft survival (greater than 100 days) in five of eight allograft recipients. During intravenous glucose tolerance tests (IVGTTs), fasting hyperinsulinemia and significantly impaired glucose degradation (K values) was observed in long-term surviving allograft recipients 4 months after transplantation. In four long-term surviving pancreatic allograft recipients initially given 40 mg/kg/day, the dose of Cy A was gradually reduced after 4 months to a maintenance dose of 5 mg/kg/day by 6 months. On a dose of 5 mg/kg/day, three dogs rejected their grafts between 18 and 28 days after this schedule had commenced. Successful reversal of the hyperglycemia in two of three dogs that rejected their grafts was achieved by i.v. methylprednisolone and increased doses of Cy A. These results indicate that Cy A alone could significantly prolong the survival of canine pancreatic segmental allografts, but initially higher doses were required than that found to be effective in prolonging renal allograft survival in the dog.

A technique for transplanting pancreatic islets as a vascularized graft and prevention of rejection with cyclosporin A.

Transplants of isolated allogeneic pancreatic islets behave as if extremely immunogenic but vascularized segmental pancreatic allografts do not evoke such a rapid rejection of islet tissue. We have transplanted rat pancreatic islets as a vascularized graft by implanting isolated islets under the renal capsule of a syngeneic diabetic rat and, after successful reversal of diabetes, a composite graft of kidney and islets was transplanted into an allogeneic diabetic host. Cyclosporin A was used to suppress rejection of the allografts in doses that have previously been shown to completely suppress rejection of renal allografts and delay rejection of vascularized segmental pancreatic allografts. This strategy produced indefinite survival of the allogeneic isolated pancreatic islets.

Long-term study of vascularized free-draining intraperitoneal pancreatic segmental allografts in beagle dogs.

The purpose of the present study was to evaluate the significance of immunogenetic factors on the survival of pancreatic allografts in beagle dogs. Donors and recipients were leukocyte antigen (DLA)-typed and mixed lymphocyte culture (MLC)-tested. Recipients were made diabetic by total pancreatectomy and immediately implanted intraperitoneally with a vascularized, free-draining (duct unligated) pancreatic segmental (FDPS) allograft. Two groups of dogs were studied. In group I consisting of donor-recipient littermates, recipients were immunosuppressed with prednisone and azathioprine (n = 16 dogs), or not immunosuppressed (n = 4). In group II, recipients were made specifically unresponsive by total body radiation, autologous marrow implantation, and kidney transplantation from DLA-MLC identical donors, 1 yr before FDPS transplantation from the corresponding original kidney donors. Survival of the FDPS grafts in group I was inversely related to pretransplant MLC reactivity, irrespective of DLA genotyped match between donor and recipient. Thus, immunosuppressed high MLC reactors (n = 8) rejected FDPS grafts between 7 and 14 d, whereas immunosuppressed low MLC reactors (n = 8) accepted grafts for 25 to 260+ days, and nonimmunosuppressed low MLC reactors (n = 4) accepted grafts for 9-55 d. Rejection (hyperglycemia) of FDPS grafts was sudden, permanent, and unpredictable despite weekly intravenous glucose tolerance tests with measurements of glucose disappearance rates and serum insulin responses. Nevertheless, serial in vitro cell-mediated lymphocytotoxicity (CML) assays revealed increases in CML before graft rejection in low MLC reactors, and decreases in both CML and MLC responses before graft rejection in high MLC reactors. FDPS graft survival was indefinite (>6 mo) in group II dogs, despite low-grade MLC reactivity (2:4 dogs) and CML responses (4:4 dogs). Biopsies of FDPS grafts at 6 mo in normoglycemic dogs showed disappearance of exocrine tissue and coalescence of islets in both groups I and II, but with less fibrosis in group I (immunosuppressed). These results indicate that (a) pancreatic islets in vascularized grafts (FDPS) may survive indefinitely in the presence of a good tissue match best predicted by MLC testing, (b) tissue specific histocompatibility factors appear to be common enough between kidney and pancreas to allow for long-term survival of both organs transplanted from the same donor, at least in appropriate recipients (group II), and (c) immunosuppression is associated with less fibrosis in FDPS allografts.