Judith A. Wade

Treatment of Kaposi's sarcoma after solid organ transplantation.

PURPOSE This retrospective review of all patients who developed Kaposis sarcoma (KS) after solid organ transplantation at a single institution was undertaken to define the clinical presentation of this malignancy in the setting of iatrogenic immunodeficiency, and to determine the most appropriate treatment for patients in this clinical setting. MATERIALS AND METHODS The records of 2,099 patients who underwent heart, lung, liver, or kidney transplantation at The Toronto Hospital between January 1, 1981 and June 30, 1995, were reviewed. Twelve patients were identified who developed biopsy-proven KS in the posttransplantation period. Five patients who had disseminated KS who had not responded to either reduction or withdrawal of immunosuppression or to local radiotherapy were treated with combination chemotherapy consisting of doxorubicin 20 to 30 mg/m2, bleomycin 10 mg/m2, and vincristine 2 mg (ABV) administered intravenously every 3 weeks. RESULTS Eight of 12 patients were male and nine were of Italian origin. KS was limited to a localized area of the skin for only six patients, all after kidney transplantation. Visceral KS was present in three patients. Four of five patients responded to ABV chemotherapy (two complete and two partial remissions). The fifth patient responded to second-line etoposide and cisplatin. The median duration of response was in excess of 13 months (range, 8+ to 45+ months). Toxicity was limited to grade 1 neurotoxicity and grade 1 skin toxicity. CONCLUSION KS is an uncommon but recognized complication of solid organ transplantation. Combination chemotherapy is a safe and effective treatment for patients with disseminated or visceral KS that fails to respond to changes in immunosuppression.

COLD PRESERVED NERVE ALLOGRAFTS: CHANGES IN BASEMENT MEMBRANE, VIABILITY, IMMUNOGENICITY, AND REGENERATION

Rat sciatic nerve graft segments were harvested and pretreated by either placement in the University of Wisconsin Cold Storage Solution at 5°C and storage from 1 to 26 weeks, or repeatedly freezing (−40°C) and thawing (20°C). Following pretreatment, grafts were transplanted as either syngeneic or allogeneic nerve grafts. Storage and freeze–thawing did not affect the Schwann cell basal lamina or laminin distribution of the peripheral nerve. Graft cell viability decreased with increasing time of storage, with some viable cells detectable even after 3 weeks of storage. Freeze–thawed grafts were not viable. Increasing time of storage led to decreasing immune response and graft rejection, but improved regeneration. Freeze–thawed and 26‐week stored allografts were nonimmunogenic and rejection was not seen, but regeneration was delayed compared to autografts. Graft storage may become a useful adjunct to clinical nerve allografting to permit elective scheduling of surgery, provide greater time for preoperative tissue testing, and possibly blunt the immune response.

Regeneration across cold preserved peripheral nerve allografts

The feasibility of peripheral nerve allograft pretreatment utilizing cold storage (5°C in the University of Wisconsin Cold Storage Solution) or freeze‐thawing to prevent rejection was investigated. Regeneration across cold‐stored (3 or 5 weeks) or freeze‐thawed (FT), 3.0‐cm sciatic nerve allografts were compared to fresh auto‐ and allografts in an inbred rat model. At 16‐week post‐engraftment, only FT allografts appeared similar to autografts on gross inspection; FT grafts were neither shrunken nor adherent to the surrounding tissue as seen in the other allograft groups. Qualitatively, the pattern of regeneration in the graft segments of the fresh allograft and to a lesser extent of pretreated allografts was inferior to that of autografts as evidenced by a disruption in the perineurium, more extrafascicular axons, smaller and fewer myelinated axons, increased intrafascicular collagen deposition, and the persistence of perineurial cell compartmentation and perivascular infiltrates. Distal to these grafts, the regeneration became more homogenous between groups, although areas of ongoing Wallerian degeneration, new regeneration as well as compartmentation, were more prevalent in fresh and pretreated allografts. Although the number of myelinated fibres was equivalent to autografts, the fibre diameters, the number of large diameter fibres, and the G‐ratio were significantly decreased in the allograft groups, which, in part, accounted for the significant decrease in conduction velocity in the 3‐week stored and fresh allograft, and the slight decrease in the 5‐week stored and FT allograft groups. There was a small return in the Sciatic Function Index towards normal, but no consistent differences between groups were found. Prolonged cold storage and freeze‐thawing of nerve allografts resulted in regeneration that was better than fresh allografts, but inferior to autografts. With the concomitant use of host immunosuppression or other immunotherapies, these storage techniques can provide a means of transporting nerve allografts between medical centres and for converting urgent into elective procedures.

Phenotypic analysis of migrant, efferent lymphocytes after implantation of cold preserved, peripheral nerve allografts

Cold-preservation of peripheral nerve allografts in vitro (3 weeks, 5 degrees C) was performed to determine its effect on local lymphocyte migration patterns in vivo. Lymphocyte migration was assessed by continuously monitoring the cell output in the regional lymph for nearly 1 month. Cold-preservation delayed or prevented the typical biphasic increase in efferent lymphocyte output observed after fresh allograft implantation. It also decreased the output of activated lymphocytes (CD 5 and MHC class II positive) compared with that seen in the fresh allograft response. These changes suggest that the host immune response to preserved nerve allografts is altered over a prolonged period in vivo (3 weeks). Cold-preservation may be a useful method of reducing allograft immunogenicity, thereby limiting systemic immunosuppression requirements for the successful clinical utilization of peripheral nerve allografts.

HLA-DRB1∗04 alleles in psoriatic arthritis: comparison with rheumatoid arthritis and healthy controls

Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis usually seronegative for rheumatoid factor. An increased frequency of HLA-DR4 has been noted in PsA, particularly among patients with a rheumatoid arthritis like (RA) arthritis. The aim of the current investigation was to compare HLA-DRB1*04 alleles in patients with PsA, patients with RA, and healthy controls. Sample size calculations based on the frequency of HLA-DR4 suggested that 90 individuals in each patient group would be sufficient to address our question. Therefore, 90 HLA-DRB1*04 positive patients from each patient group underwent high resolution molecular typing and were included in this study. Although HLA-DRB1*0401 was the most frequent allele in all groups, its frequency among the PsA patients was lower than that of RA patients and controls. HLA-DRB1*0402 was higher among patients with PsA. Patients with RA were more likely to have more than one shared epitope allele than either PsA or the healthy control group. HLA-DQB1 alleles did not contribute further information. We suggest that the differences in the class II HLA epitope(s) may also be related to interaction specificity with another molecule functioning in the immune response to a putative arthritogenic antigen and result in differences in disease expression.