Mixed allogeneic chimerism as a reliable model for composite tissue allograft tolerance induction across major and minor histocompatibility barriers.

BACKGROUND: Although prolonged composite tissue allograft (CTA) survival is achievable in animals using immunosuppressive drugs, long-term immunosuppression of CTAs in the clinical setting may be unacceptable for most patients. The purpose of this study was to develop a model for reliable CTA tolerance induction in the adult rat across a major MHC mismatch without the need for long-term immunosuppression. METHODS: Mixed allogeneic chimeras were prepared by using rat strains with strong MHC incompatibility [WF (RT1Au), ACI (RT1Aa)] WF + ACI-->WF, n=23. The bone marrow (BM) of recipient animals was pretreated with low-dose irradiation (500-700 cGy), followed by reconstitution with a mixture of T cell-depleted syngeneic (WF) and allogeneic (ACI) cells. Additionally, the recipient animals received a single dose of anti-lymphocyte serum (10 mg) 5 days before bone marrow transplantation (BMT) and tacrolimus (1 mg/kg/day) from the day before BMT to 10 days post-BMT. Hindlimb transplants were performed 12 months after BMT. Five animals received a limb allograft irradiated (1000 cGy) just before transplantation. Rat chimeras were characterized (percentage of donor cells present within the bloodstream) by flow cytometry at 3 and 12 months after BM reconstitution and after hindlimb transplantation. RESULTS: Peripheral blood lymphocyte chimerism (WF/ACI) remained stable >12 months after BM reconstitution in 18/23 animals. Multi-lineage chimerism of both lymphoid and myeloid lineages was present, suggesting that engraftment of the pluripotent rat stem cell had occurred. In animals with donor chimerism >60% (n=18) no sign of limb rejection was present for the duration of the study. All animals with chimerism <20% (n=5) developed moderate signs of rejection clinically and histologically. Gross motor and sensory reinnervation (weight bearing, toe spread) developed at >60 days in 14/21 rats. Postoperative flow cytometry studies demonstrated stable chimerism in all animals studied (n=10). Five out of five animals with irradiated limb transplants showed no sign of GVHD at >100 days. CONCLUSIONS: Stable mixed allogeneic chimerism can be achieved in a rat hindlimb model of composite tissue allotransplantation. Hindlimb allografts to mixed allogeneic chimeras exhibit prolonged, rejection-free survival. Partial functional return should be expected. The BM transplanted as part of the hindlimb allograft plays a role in the etiology of GVHD. Manipulating that BM before transplantation may influence the incidence of GVHD. This represents the first reliable rat hindlimb model demonstrating rejection-free CTA survival in an adult animal across a major MHC mismatch without the long-term need for immunosuppressive agents.

Giant congenital melanocytic nevi: the significance of neurocutaneous melanosis in neurologically asymptomatic children.

Patients with a giant congenital melanocytic nevus can develop melanotic tumors characterized by central nervous system involvement, termed leptomeningeal melanocytosis or neurocutaneous melanosis. Although symptomatic neurocutaneous melanosis is rare, we previously reported distinct magnetic resonance (MR) findings of T1 shortening, strongly suggestive of neurocutaneous melanosis, in 30 percent (6 of 20) of children with giant congenital melanocytic nevi who presented initially without neurological symptoms. The purpose of this study was to determine the incidence of neurocutaneous melanosis in high-risk patients and its long-term clinical significance. Magnetic resonance imaging was recommended for all 46 patients with "at-risk" giant congenital melanocytic nevi involving the skin overlying the dorsal spine or scalp. The clinical histories and follow-up of these patients were evaluated by retrospective chart review. Forty-two underwent MR imaging of the brain and 11 underwent additional MR scanning of the spinal cord. Abnormalities were identified in 14 of 43 MR studies, and 23 percent (n = 10) had T1 shortening indicative of melanotic rests within the brain or meninges. None had associated masses or leptomeningeal thickening. The most common areas of involvement in these 10 included the amygdala (n = 8), cerebellum (n = 5), and pons (n = 3). In the group of 11 patients with spinal MR scans, a tethered spinal cord was demonstrated in one. Additional abnormalities were detected by MR scanning, including a middle cranial fossa arachnoid cyst, a Chiari type I malformation, and a crescentic enhancement that subsequently resolved. Clinical follow-up averaging 5 years (range, 2 to 8 years) revealed that only one of the 46 patients evaluated developed neurological symptoms, manifested as developmental delay, hypotonia, and questionable seizures but no other signs of neurocutaneous melanosis. No patient has developed a cutaneous or central nervous system melanoma. Magnetic resonance findings of neurocutaneous melanosis are relatively common, even in asymptomatic children with giant congenital melanocytic nevi. Although these findings suggest an increased lifetime risk of central nervous system melanoma, they do not signify the eventual development of symptomatic neurocutaneous melanosis during childhood.

Complex abdominal wall reconstruction: a comparison of flap and mesh closure.

OBJECTIVE: To analyze a series of patients treated for recurrent or chronic abdominal wall hernias and determine a treatment protocol for defect reconstruction. SUMMARY BACKGROUND DATA: Complex or recurrent abdominal wall defects may be the result of a failed prior attempt at closure, trauma, infection, radiation necrosis, or tumor resection. The use of prosthetic mesh as a fascial substitute or reinforcement has been widely reported. In wounds with unstable soft tissue coverage, however, the use of prosthetic mesh poses an increased risk for extrusion or infection, and vascularized autogenous tissue may be required to achieve herniorrhaphy and stable coverage. METHODS: Patients undergoing abdominal wall reconstruction for 106 recurrent or complex defects (104 patients) were retrospectively analyzed. For each patient, hernia etiology, size and location, average time present, technique of reconstruction, and postoperative results, including recurrence and complication rates, were reviewed. Patients were divided into two groups based on defect components: Type I defects with intact or stable skin coverage over hernia defect, and Type II defects with unstable or absent skin coverage over hernia defect. The defects were also assigned to one of the following zones based on primary defect location to assist in the selection and evaluation of their treatment: Zone 1A, upper midline; Zone IB, lower midline; Zone 2, upper quadrant; Zone 3, lower quadrant. RESULTS: A majority of the defects (68%) were incisional hernias. Of 50 Type I defects, 10 (20%) were repaired directly, 28 (56%) were repaired with mesh only, and 12 (24%) required flap reconstruction. For the 56 Type II defects reconstructed, flaps were used in the majority of patients (n = 48; 80%). The overall complication and recurrence rates for the series were 29% and 8%, respectively. CONCLUSIONS: For Type I hernias with stable skin coverage, intraperitoneal placement of Prolene mesh is preferred, and has not been associated with visceral complications or failure of hernia repair. For Type II defects, the use of flaps is advisable, with tensor fascia lata representing the flap of choice, particularly in the lower abdomen. Rectus advancement procedures may be used for well-selected midline defects of either type. The concept of tissue expansion to increase both the fascial dimensions of the flap and zones safely reached by flap transposition is introduced. Overall failure is often is due to primary closure under tension, extraperitoneal placement of mesh, flap use for inappropriate zone, or technical error in flap use. With use of the proposed algorithm based on defect analysis and location, abdominal wall reconstruction has been achieved in 92% of patients with complex abdominal defects.

Endoscopic subcondylar fracture repair: functional, aesthetic, and radiographic outcomes.

An endoscopic method of mandibular subcondylar fracture repair has been described recently. To determine the effectiveness of this new technique, we longitudinally studied functional, aesthetic, and radiographic parameters following endoscopic repair of 22 subcondylar fractures in 20 patients. Restoration of mandibular function was achieved without postoperative maxillomandibular fixation. Premorbid occlusion was restored. Clinical jaw motion was found to progressively increase with a mean interincisal jaw opening of 43 mm achieved after the eighth postoperative week. Patients were pleased with the aesthetic restoration of their chin projection,jaw line, and the symmetric midline movement of the chin point onjaw opening. Anatomic fracture reduction with rigid plate fixation was confirmed on early postsurgical radiographs. Late radiographs showed fracture union without remodeling of the condylar head. Endoscopic subcondylar fracture repair was efficacious at functional, aesthetic, and radiographic restoration of the mandible.

The arterial supply of the face lift flap.

The cutaneous arterial circulation of the face lift flap was investigated using multiple anatomic techniques in fresh cadaver specimens. Perforation sites of the transverse facial and submental arteries were preserved or transected according to protocol during bilateral rhytidectomy prior to selective injections with ink or lead oxide. It was observed that the transverse facial perforating artery provides the major direct blood supply to the lateral cheek and preauricular area following rhytidectomy if preserved. This perforator occupies a constant anatomic location 3.1 cm lateral and 3.7 cm inferior to the lateral canthus with 95 percent tolerance limits of +/-1.1 cm. There is greater variability in localizing the submental perforating artery; however, this perforator also contributes significantly to lateral facial blood supply. Both perforator locations are within the area of "standard" undermining for rhytidectomy; however, they may be preserved during this procedure if desired. Transection of the lateral facial perforators leaves vascularization of these cutaneous areas dependent on collateral flow from the pedicle of the face lift flap. The ability to preserve optimal blood supply to the lateral face lift flap may be useful in the clinical setting of a vascularly compromised or smoking patient.

Flap selection as a determinant of success in pressure sore coverage.

OBJECTIVE: To establish a treatment algorithm for the long-term surgical management of pressure sores. DESIGN: Retrospective case series. SETTING: University-based teaching hospital. PATIENTS: From March 1979 to July 1995, 280 unselected pressure sore reconstructions (113 ischial, 94 sacral, and 73 trochanteric sores) were performed in 201 patients (130 men and 71 women; age range, 16-90 years; mean, 50 years). Of the patients, 90% had severe spinal cord injuries (paraplegia or quadriplegia). Forty-one percent of the wounds were chronic (present longer than 3 months). MAIN OUTCOME MEASURES: Length of stay, postoperative morbidity and mortality, and flap success (defined as a completely healed wound). RESULTS: Overall, 89% of the flaps healed primarily (ischium, 83% [94/113]; sacrum, 91% [86/94]; trochanter, 93% [68/73]). Three fourths of cases were treated in a single stage (debridement and reconstruction). The inferior gluteus maximus island flap (ischium) (94% [32/ 34]), the V-Y gluteus maximus advancement flap (sacrum) (97% [36/37]), and the tensor fascia lata flap (trochanter) (95% [42/44]) had the highest success rates. Flap success was not significantly affected by the size of the pressure sore or the number of previous flaps used. Postoperative hospital stays averaged 20 days. The overall complication rate was 28%, most commonly from a slight wound edge dehiscence. CONCLUSIONS: Flap selection and the appropriate short- and long-term sequence of flap use significantly improve success rates for pressure sore coverage. Reconstruction can be reliably performed in a single stage with a relatively short hospitalization.

Ischial pressure sore coverage: a rationale for flap selection.

The role of wound debridement and flap coverage in treating pressure sores is clearly established. However, criteria and supportive clinical data for specific flap selection and the sequence of flaps for coverage of the ischium remain ill-defined. From 1979-1995, 114 consecutive patients underwent flap coverage of 139 ischial pressure sores. Preoperative risk factors, prior flap history, defect size, flap success, complication rates, and the length of hospitalization were retrospectively evaluated and compared for 112 flaps in 87 patients. Flap success was defined as a completely healed wound. Average follow-up was 10 months (range: 1 month-9 years). Overall, 83% (93/112) of the flaps healed. In the majority of cases (75%, 84/112), wound debridement and flap reconstruction was achieved in a single stage. However, there were significant differences in the healing rates among the various flaps used. The inferior gluteus maximus island flap and the inferior gluteal thigh flap had the highest success rates, 94% (32/34) and 93% (25/27), respectively, while the V-Y hamstring flap and the tensor fascia lata flap had the poorest healing rates, 58% (7/12) and 50% (6/12), respectively. Flap success was not significantly affected by the age of the patient or the prior number of flaps used and preoperative risk factors were equally distributed across all types of flaps. The overall complication rate was 37% (41/112), most commonly from a slight wound edge dehiscence (n = 16) that healed with local wound care within one month postoperatively. Results of this study show that proper flap selection and the appropriate sequence of flap use significantly improve success rates for ischial pressure sore coverage in both the short- and long-term. Based upon flap reliability (successful healing rates), reusability, and the need to preserve as many future flap options as possible, a rationale for flap selection is presented which can be individualized to any patient.

Reconstruction of complex midfacial defects.

Modern treatment of complex midfacial defects has evolved over the past 5 years, primarily with the advent of reliable vascularized bone flaps and osseointegrated implants. To determine the effectiveness of these advances, 26 consecutive patients with complex midfacial defects treated from 1991 through 1995 with immediate muscle-flap coverage were evaluated. The etiology of the defect included neoplasm (n = 23) and trauma (n = 3). Seventy-eight percent of the patients received adjuvant radiation therapy. Follow-up ranged from 3 months to 4 years, with a mean of 18 months. Twenty-three patients (88 percent) were reconstructed with a single major procedure. All patients had free-flap reconstruction, and 100 percent of the flaps survived. Late tumor recurrence was seen in 5 of 23 patients (22 percent) and was detected promptly. Aesthetic and functional results were rated good or excellent in 77 and 88 percent of the patients, respectively, as determined by patient questionnaires and physical examinations. Fourteen of 18 patients (78 percent) undergoing partial or complete alveolar ridge resection received dental rehabilitation, 43 percent of whom received osseointegrated implants into either a bone flap or remaining native bone. Osseointegrated implants were inset during the initial reconstruction 50 percent of the time. A treatment algorithm for free-flap selection based on the size of the defect and the bony requirement for reconstruction is presented. Bony restoration is only required in those areas where osseointegrated implants need to be placed. In such cases, the fibula osteocutaneous free flap is the flap of choice. Otherwise, soft-tissue flaps are selected based on wound size. Immediate free-flap coverage provides effective, single-stage treatment, both aesthetically and functionally, for complex midfacial defects.

Radiation injury.

Despite advance radiotherapy techniques, long-term complications of radiation injury are still commonly seen. Acute effects are largely time dependent and can be controlled by alteration of therapy schedule. Chronic effects are dose dependent, and are associated with increased fibrosis and decreased vascularity which can lead to tissue necrosis, infection, and ulceration. The damaging effects of radiation therapy may not be clinically apparent for months or even years after treatment is given. The most commonly accepted theory explaining the effects of radiation injury on tissue healing has focused on decreased vascularity and hypoxia in affected tissues. More recently, impaired leukocyte function has been implicated as an additional factor in the pathophysiology of radiation injury. Reconstructive surgical plans may require alteration when operating in a radiated field, especially in the head and neck. Radiation wounds are best treated by standard, accepted techniques of thorough debridement and coverage with well-vascularized tissue. Hyperbaric oxygen may have a role in the management of early radiation injury or in prophylaxis against postoperative wound complications.

Microsurgical reconstruction of the midface.

OBJECTIVE: To establish a treatment algorithm for reconstructing complex midfacial defects. DESIGN: Retrospective case series. SETTING: University-based teaching hospital. PATIENTS: Thirty-one consecutive patients were treated from 1991 through 1995. The 18 males and 13 females were aged 15 to 90 years (mean age, 58 years). The cause of the defect included neoplasm (n = 27) and trauma (n = 4). Reconstruction consisted of 1 of 4 free flaps: rectus abdominis, radial forearm, fibula, or latissimus dorsi. Aesthetic and functional results were determined by patient questionnaires and physical examinations. MAIN OUTCOME MEASURES: Length of stay, postoperative morbidity and mortality, degree of aesthetic and functional restoration, and detection of tumor recurrence. RESULTS: Twenty-seven (87%) of the 31 patients underwent reconstruction with a single major procedure. All of the flaps survived. Postoperative hospital stays averaged 14 days. Late tumor recurrence occurred in 7 (23%) of the 31 patients and was promptly detected. Aesthetic and functional results were rated good or excellent in 77% (24/31) and 87% (27/31) of patients, respectively. Of the 20 patients who underwent alveolar ridge resection, 16 (80%) received dental rehabilitation, 44% of whom received osseointegrated implants into either a bone flap or remaining native bone. Osseointegrated implants were inset during the initial reconstruction 57% (4/7 patients) of the time. CONCLUSIONS: For complex midfacial defects, free-flap transfer can be performed with a high degree of success, restoring both appearance and function in most patients. The only instance in which bone is necessary to reconstruct the midface involves those areas in which osseointegrated implants are needed, ie, alveolar ridge (dental implant) and/or orbit (ocular prosthesis). In such cases, the fibula osteocutaneous free flap is the flap of choice. Otherwise, soft-tissue flaps are selected based on wound size.

Use of combination of low-dose cyclosporine and RS-61443 in a rat hindlimb model of composite tissue allotransplantation.

Despite technical feasibility, composite tissue allotransplantation has not been applied clinically because of immunosuppressive toxicity associated with these highly antigenic allografts. Combination immunosuppression therapy can help overcome this obstacle by allowing lower doses of individual drugs and minimizing toxicity. RS-61443 (mycophenolate mofetil), an effective immunosuppressant that inhibits lymphocyte proliferation, was tested at subtherapeutic doses in combination with cyclosporine (CsA) in a rat hindlimb allotransplantation model with a major antigenic mismatch at the MHC. Five groups were studied: untreated autograft controls (n=4), untreated allograft controls (n=6), allografts receiving low-dose CsA 1.5 mg/kg/day (n=11), allografts receiving low-dose RS-61443 15 mg/kg/day (n=17), and allografts receiving combination low-dose CsA 1.5 mg/kg/day + RS-61443 15 mg/kg/day (n=18). The autograft controls survived indefinitely, while untreated allograft control animals developed severe rejection within 12 days. Subtherapeutic CsA and RS-61443 monotherapy groups developed acute rejection in 64% and 100% of rats, respectively. In contrast, only 11% of rats receiving combination therapy with CsA + RS-61443 at these same subtherapeutic doses developed acute rejection (P < or = 0.0013). Bone marrow toxicity, manifested primarily by anemia and measured objectively by hematocrits, was reduced significantly (P=0.04) in animals receiving low-dose RS-61443 therapy when compared with high-dose controls. These results confirm that subtherapeutic RS-61443 + CsA combination therapy is efficacious in preventing rejection while minimizing toxicity.

The arterial anatomy of larynx transplantation: microsurgical revascularization of the larynx.

Advances in immunosuppression and selective reinnervation may soon make laryngeal transplantation a potential therapy for patients undergoing total laryngectomy. Successful transplantation requires a clear delineation of those vessels necessary to completely revascularize the larynx. Our hypothesis is that the arterial inflow provided by a single superior thyroid artery is sufficient to revascularize the entire larynx. To test this hypothesis, 8 cadavers were studied via either barium latex injection (n = 4) to assess contralateral tissue perfusion or India ink (n = 4), to determine the degree of mucosal perfusion. Following injection via a single superior thyroid artery, all larynges demonstrated either complete, bilateral tissue perfusion evidenced by x-ray visualization of the barium latex injected specimen or bilateral mucosal staining with India ink. We conclude that bilateral perfusion of the entire larynx transplant, including laryngeal and epiglottic mucosa, would occur after revascularization of a single superior thyroid artery. These findings suggest that reliable revascularization of a larynx transplant is technically possible using modern microsurgical techniques.

An experimental model to determine the effect of irradiated tissue on neutrophil function.

Complications of irradiated tissue include infections and impaired healing. Although fibrosis and hypovascularity contribute, a cellular mechanism has not been identified. This study examines the effect of radiation (10 to 30 Gy) on neutrophil function in a rabbit wound cylinder model. At 3 to 12 weeks after radiation, subcutaneous wound cylinders were implanted in both irradiated and control fields in 19 rabbits. Wound neutrophils were subsequently assayed for phagocytosis (3H-labeled Staphylococcus aureus assay), superoxide production (cytochrome c reduction assay), and surface Mac-1 expression (flow cytometric assay using MHM 23 monoclonal antibody). Phagocytosis of 3H-labeled S. aureus was significantly lower in neutrophils from irradiated fields compared with controls at 6 and 12 weeks after radiation (6.5 versus 18.9 bacteria per neutrophil at 12 weeks; p = 0.027). Stimulated neutrophils from irradiated tissue could not increase superoxide production or Mac-1 expression as much as controls, with differences increasing as postirradiation time increased. The diminished phagocytosis, superoxide production, and Mac-1 expression provide a cellular mechanism that may account for susceptibility to infection and poor healing in irradiated tissues.

The incidence of lethal graft-versus-host disease in rat limb allotransplantations

To study graft-versus-host disease (GVHD) in rat hindlimb allotransplantation, a model similar to intestinal transplantation was used. ACI and Lewis rats were crossed to produce F(1) generation rats (ACI-Lewis). These underwent limb transplantation receiving a donor limb from a Lewis rat. The animals were examined daily and skin biopsies were performed. Results showed that all limbs were viable at 34 weeks and no rats demonstrated any clinical evidence of GVHD and biopsies were grade 0.

Rat limb allotransplantation: efficacy of subtherapeutic dose combination immunotherapy with cyclosporine (CsA) and RS-61443

The synergic effect of subtherapeutic doses of cyclosporine and RS-61443 was demonstrated in a vascularized rat hindlimb allotransplantation across a strong histocompatibility barrier (Brown-Norway as donors and Fischer 344 as recipients). Low doses of agents in combination minimized the toxicity while increasing the therapeutic efficacy. All animals showed weight loss during the first 15 days posttransplantation and they regained protective sensation within 45 postoperative days. Only 15.38 per cent of the animals presented complications: thrombosis, enteritis, autophagia and disorders of unknown etiology.

Controle do processo de rejeiçäo em transplante alógeno microcirúrgico de membro tratado com ciclosporina e RS-61443, em ratos / Control of the rejection process treated with cyclosporine and RS-61443, in allogeneic microsurgery transplantation of a limb, in rats

Os transportes alógenos de tecido composto contribuiram sobremaneira para reparaçäo das deformidades congênitas, traumáticas e tumorais. OBJETIVO. Prevenir ou inibir o processo de rejeiçäo em transplante microcirúrgico alógeno de membro; diminuir a toxicidade das drogas imunossupressoras; verificar um melhor efeito imunossupressor através da possibilidade do efeito sinérgico da associaçäo de doses subterapêuticas de ciclosporina e RS-61443. MÉTODOS. Cinco grupos foram estudados, usando Brown-Norway, doadores e Fischer 244, receptores: grupo A, controle autógeno sem tratamento; grupo B, alógeno, sem tratamento; grupo C, alógeno + ciclosporina 1,5mg/Kg/d sc; grupo D; alógeno + RS-61443 15mg/Kg/d; e grupo E, alógeno + CsA + RS. RESULTADOS. De acordo com o processo de rejeiçäo, os resultados foram o seguinte: grupo A, nenhum animal apresentou rejeiçäo (0 por cento). Todas as biópsias resultaram em grau 0; grupo B, todos desenvolveram rejeiçäo entre o 10º e o 13º dia pós-operatório. As biópsias cutâneas confirmaram a necrose epidérmicas (grau 4); grupo C, 55 por cento desenvolveram rejeiçäo; grupo D, 94 por cento apresentaram rejeiçäo e em contraste; no grupo E, 94 por cento dos animais sobreviveram livres do processo de rejeiçäo, por mais de 172 dias de transplante. CONCLUSäO. A associaçäo de duas drogas imunossupressoras (ciclosporina + rs-61443), em doses subterapêuticas, foi eficiente em prevenir o processo de rejeiçäo e apresentou um melhor efeito imunossupressor pelo efeito sinérgico da associaçäo destas drogas

[Control of the rejection process treated with cyclosporine and RS-61443, in allogeneic microsurgery transplantation of a limb, in rats]. / Controle do processo de rejeição em transplante alógeno microcirúrgico de membro tratado com ciclosporina e RS-61443, em ratos.

Composite tissue allotransplantations would contribute to the reconstructions of the congenital, traumatic and tumors deformities. PURPOSE--The aim of this study is to prevent or inhibit the rejection in limb vascularized allotransplantation; decrease the toxicity of available immunosuppressive agents; determine whether combination subtherapeutic doses of CsA +RS-61443 will have an additive immunosuppressive effect. METHODS--Five groups were studied, using Brown-Norway limb donors and Fischer 344 recipient rats: group A Untreated autograft controls; group B Untreated allograft controls; group C Allografts: CsA 1.5 mg/kg/d SQ; group D Allograft: RS-61443 15 mg/kg/d; group E Allograft: combination CsA + RS-61443. RESULTS--The results were the following concerning the rejection: Group A animals displayed no rejection clinically (0%). All the skin biopsies obtained were devoid of rejection (grade 0). Group B animal developed rejection at 10-13 days post-transplantation. Skin biopsies confirmed the epidermal necrosis (grade 4). Group C animals developed rejection in 55%. Group D animals developed rejection in 94%. In contrast, Group E animals had 96% rejection-free survival up to POD 172 thus far. CONCLUSION--Combination subtherapeutic doses of CsA + RS-61443 was effective in preventing acute rejection of limb allografts and had an additive immunosuppressive effect because of the agents immunosuppressive synergistic effect.

Canine laryngeal transplantation: preliminary studies and a new heterotopic allotransplantation model.

While transplantation of the larynx may eventually be useful in post-laryngectomy reconstruction, three criteria must first be met before human transplants can be attempted: transplant viability must be high, immunosuppression must be safe and effective and functional recovery of the larynx must occur. To study these first two criteria, a total of 11 canine larynx transplants were performed: 3 autografts, 6 orthotopic allografts and 2 heterotopic allografts. The rationale and technical performance of these different transplant procedures are reviewed in detail. Orthotopic transplant recipients received cyclosporin A (CsA) while the heterotopic allograft recipients received RS-61443 and methylprednisolone in addition to CsA. Overall, 9 of 11 of the transplants remained viable. In contrast, all 3 autografted animals developed esophageal-cutaneous fistulas; 2 developed sepsis and were sacrificed on post-operative days (POD) 5 and 28, respectively. The third survived for 91 days and demonstrated a high degree of regeneration in the recurrent and superior laryngeal nerves of the transplant. Orthotopically transplanted dogs also had a high morbidity and perioperative mortality (5 of 6 animals). The single "long-term" survivor was treated with CsA alone, but developed complete transplant rejection on POD 33. The two heterotopic transplant recipients had no perioperative morbidity and the combination of CsA, RS-61443 and methylprednisolone given these latter animals was effective in the long-term prevention of rejection. One of these heterotopic recipients died of sepsis on POD 68 while the other remained alive and well on POD 168. Our present findings show that currently available microsurgical techniques allow experimental canine laryngeal transplantation to be done with significantly high transplant viability rates. (ABSTRACT TRUNCATED AT 250 WORDS)