Epstein-Barr virus, infectious mononucleosis, and posttransplant lymphoproliferative disorders.

PTLD may be considered as an "opportunistic cancer" in which the immunodeficiency state of the host plays a key role in fostering the environment necessary for abnormal lymphoproliferation. The following discussion reflects our own current thoughts regarding events which may result in PTLD and its sequelae. Many of the individual steps have not been rigorously proved or disproved at this point in time. Following transplantation and iatrogenic immunosuppression, the host:EBV equilibrium is shifted in favor of the virus. Most seronegative patients will become infected either via the graft or through natural means; seropositive patients will begin to shed higher levels of virus and may become secondarily superinfected via the graft. There is a "grace" period of approximately one month posttransplant before increased viral shedding begins. PTLD is almost never seen during this interval. In many cases infection continues to be silent whereas in rare individuals there is an overwhelming polyclonal proliferation of infected B lymphocytes. This is the parallel of infectious mononucleosis occurring in patients with a congenital defect in virus handling (X-linked lymphoproliferative disorder). It is possible that transplant patients with this presentation also suffer a defect in virus handling. In other cases excessive iatrogenic immunosuppression may paralyze their ability to respond to the infection. With CsA and FK506 regimens, individual tumors may occur within a matter of months following transplant. The short time of incubation suggests that these are less than fully developed malignancies. It may be that local events conspire to allow outgrowth of limited numbers of B-lymphocyte clones. A cytokine environment favoring B-lymphocyte growth may be one factor and differential inhibition by the immuno-suppressive drugs of calcium-dependent and -independent B-cell stimulation may be another. In addition, there is some evidence that CsA itself may inhibit apoptosis within B cells. Since most patients do not develop PTLDs, an additional signal(s) for B-cell stimulation may be required. Indeed, it is possible that the virus may simply serve to lower the threshold for B-cell activation and/or provide a survival advantage to these cells. The ability of individual cell clones to evade a weakened immune system may set into play a Darwinian type of competition in which the most rapidly proliferating cells with the least number of antigenic targets predominate. In this regard, differences in host HLA types may determine the repertoire of viral antigens which are subject to attack.(ABSTRACT TRUNCATED AT 400 WORDS

Treatment of fibrolamellar hepatoma with partial or total hepatectomy and transplantation of the liver

Fourteen patients with fibrolamellar hepatoma were treated with radical excision. In eight, a subtotal hepatic resection was performed from 16 months to more than 16 years ago. None of the patients have died and recurrences have been seen in only one patient. Six other patients had total hepatectomy and hepatic replacement. Two of these six patients have died of metastases and a third is living with recurrent tumor. This experience has justified the continuing use of quite aggressive extirpative procedures for the treatment of fibrolamellar hepatoma

Experience with posttransplant lymphoproliferative disorders in solid organ transplant recipients

Nearly 6000 solid organ transplants have been performed at the University of Pittsburgh since 1981. Posttransplant lymphoproliferative disorders (PTLD) have occurred in 131 patients, at a frequency of 2.2%. The majority of cases manifest within 6 months following allograft, but individual lesions may arise several years thereafter. From 1981 to 1989, cyclosporine-A (CsA) served as the primary immunosuppressant in this population. In March of 1989, FK506 was introduced for clinical trials. Since that time, 1421 patients have received FK506 either for primary immunosuppression or as rescue therapy. The frequency of PTLD in this subpopulation is 1.5%. PTLD arising under FK506-containing regimens have clinicopathologic features similar to those arising with CsA immunosuppression. The frequency of PTLD at this point in time is approximately 1%, in kidney allograft patients, 2.7% in liver, 3.3% in heart and 3.8%, in heart/lung or lung recipients. An understanding of the range of histologic appearance is important for the diagnosis of PTLD, especially when it involves the allograft itself. Immunoglobulin heavy chain gene analysis shows that lesions with no rearrangements or with a rearrangement in only a small proportion of cells are more likely to respond to reduced immunosuppression than are those with clonal rearrangement involving a high proportion of cells. However, this distinction is not absolute, and a trial of reduced immunosuppression appears to be indicated regardless of clonal status

Heterotopic heart transplantation in the rat receiving FK-506 alone or with cyclosporine.

In rats, FK significantly prolonged heterotopic heart graft survival over a wide dose range when given for 2 weeks starting on the day of the operation. Brief courses of FK for one to four days preoperatively, and especially beginning four days postoperatively, allowed long subsequent survival of heart grafts in otherwise untreated recipients. The seeming acceptance of the grafts with postoperative FK treatment was largely but not exclusively donor specific when tested eight days after the last FK dose by second grafts from the same donor v third-party donor grafts. FK in minimally therapeutic doses was synergistic with suboptimal doses of CyA

Pancreaticoduodenal transplantation in humans

Whole cadaveric pancreata were transplanted to the pelvic extraperitoneal location in four patients with diabetes who previously had undergone successful cadaveric renal transplantation. One graft was lost within a few hours from venous thrombosis but with patient survival. The other three are providing normal endocrine function after two and a half, 11 and 12 months. The exocrine pancreatic secretions were drained into the recipient jejunum through enteric anastomoses. Because mucosal slough of the graft and duodenum and jejunum in two patients caused a protein losing enteropathy and necessitated reoperations, we now do the pancreatic transplantation with only a blister of graft duodenum large enough for side-to-side enteroenterostomy. The spleen has been transplanted with the pancreas mainly for technical reasons, and this technique should have further trials in spite of the fact that delayed graft splenectomy became necessary in two recipients to treat graft induced hematologic complications