2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection.

The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.

Should HLA mismatch acceptability for sensitized transplant candidates be determined at the high-resolution rather than the antigen level?

Defining HLA mismatch acceptability of organ transplant donors for sensitized recipients has traditionally been based on serologically defined HLA antigens. Now, however, it is well accepted that HLA antibodies specifically recognize a wide range of epitopes present on HLA antigens and that molecularly defined high resolution alleles corresponding to the same low resolution antigen can possess different epitope repertoires. Hence, determination of HLA compatibility at the allele level represents a more accurate approach to identify suitable donors for sensitized patients. This approach would offer opportunities for increased transplant rates and improved long term graft survivals.

Assessment of five-year experience with abdominal organ cluster transplantation.

BACKGROUND: Upper abdominal exenteration (resection of the liver, stomach, spleen, pancreaticoduodenal complex, and part of the colon) for the treatment of otherwise unresectable tumors is one of the more radical operations in oncology. This study was done to analyze retrospectively a five-year experience with exenteration in 57 patients treated with variations of resectional and transplant reconstructive techniques. STUDY DESIGN: Sixty-one transplantations were performed upon 57 patients. Three different organ replacement techniques were used: liver-pancreas-duodenum en bloc (original procedure), liver only (modified procedure), and liver plus pancreatic islets. The diagnoses were cholangiocarcinoma (20 patients), hepatocellular carcinoma (12 patients), endocrine neoplasms (14 patients), sarcoma (six patients), and adenocarcinoma of the pancreas (two patients), colon (two patients), or gallbladder (one patient). Analyses of survival and tumor recurrence were stratified by procedure variations, type and extent of tumor, and immunosuppressive regimen. RESULTS: The three month and one, two, three, and five year actuarial patient survival rates were 82, 56, 38, 33, and 30 percent, respectively. Eighteen (31.5 percent) of the 57 patients are alive after 425 15 (standard deviation) months (range of 17 to 61 months) and 12 patients are tumor free. The actuarial survival rates stratified by transplantation procedure, immunosuppression, and tumor diagnosis and extent showed no statistically significant differences beyond the three different transplantation groups. Endocrine tumors had a better three-year survival rate (64 percent) than sarcoma (44 percent), hepatocellular carcinoma (25 percent), cholangiocarcinoma (20 percent), and the other adenocarcinomas (20 percent). Twenty-three patients (40 percent) died as a result of tumor recurrence. Patients with combined factors of no lymph node involvement, absence of vascular invasion, and metastases to the liver only (11 patients) had the lowest incidence of recurrence (27 compared to 73.5 percent, p = 0.006). CONCLUSIONS: Patients with unresectable endocrine neoplasms, fibrolamellar hepatocellular carcinoma, and selected cholangiocarcinoma confined to the liver can benefit from this radical operative approach. Patients with sarcoma can achieve long survival periods but have a high recurrence rate.

Early clinical and histologic viability of human liver-small intestinal allografts after implantation.

Our procedure for donor harvesting and preserving intestinal grafts has matured. In 27 consecutive cases, a protocol was established whose essentials consist of (a) selecting hemodynamically stable donors, (b) antibiotic pretreatment of the donor, and (c) short warm ischemic times (< 40 minutes). Assessment of graft quality can be achieved by daily inspection of stomas, inspection for diarrhea > 2.5 1/day in adults or > 300 ml in children, and weekly protocol or clinically directed endoscopic biopsies. Edema and microscopic separation of the mucosal surface and sloughing are routinely found during the first few post-engraftment days, but the crypt cells remain and regenerate a normal mucosa within a week. Recovery of a normal mucosal surface took place in all cases.

The latest advances in liver transplantation at the pittsburgh transplantation institute: evolution of FK506, liver-intestinal transplantation, clinical xenotransplantation, and the induction of graft acceptance.

During the past 30 years orthotopic liver transplantation (OLTx) has become a highly successful form of therapy, and as of this writing it is being performed at more than 100 institutions in the U.S., and a similar number in Europe. This is testimony to the great advances achieved in this field since the 1960s and 1970s, when there were essentially only two places actively engaged in liver transplantation. Essential to its success have been the technical refinements introduced during the last three decades, which have allowed many surgeons around the world to be able to do the procedure safely. Liver transplantation is still considered as one of the most complex operations, and therefore the margin of error is small and attention to technical detail is crucial to a satisfactory outcome. This is magnified in importance since OLTx, unlike kidney, heart, pancreas and intestinal transplantation, lacks a back-up system, such as dialysis, ventricular assist device, insulin or total parenteral nutrition. Thus, the smallest mistake in the surgical management of the patient may prove fatal.

FK 506 reverses acute graft-versus-host disease after allogeneic bone marrow transplantation in rats.

Severe graft-versus-host disease was induced by transplantation of ACI rat bone marrow and spleen cells into irradiated Lewis rat recipients. Treatment with FK 506 or cyclosporine A (CsA) was started after clinical and histologic evidence of acute GVHD was present. A 14-day course of FK 506 at 1.0 mg/kg/day could rescue 100% of the animals suffering from GVHD. In contrast only one half of the animals treated with CsA at a high dose of 25 mg/kg/day recovered. After cessation of immunosuppressive therapy, FK 506-treated animals displayed a marked prolonged disease-free interval as compared to CsA-treated bone marrow recipients. Recurrence of the disease in these animals could be prevented when FK 506 treatment was continued after the induction period with a low maintenance dose of 0.1 mg/kg/day every other day.

One hundred ten consecutive primary orthotopic liver transplants under FK 506 in adults.

An account is given of the 6- to 12-month survival, and causes of failure in 110 consecutive patients who underwent primary liver transplantation under treatment from the outset with FK 506 and steroids. The patient survival is 92.7%, and the first graft survival is 87.3%. At a very high frequency, the patients achieved good graft function, and they had a relatively low morbidity that was partially ascribable to minimal use and early discontinuance (in 60% of cases) of steroids. Renal dysfunction and other adverse findings were largely confined to patients with poor initial graft function and consequent apparent alteration of the kinetics of FK 506 elimination, causing functional overdosage. Results compare very favorably with our past record using conventional immunosuppression, and support the belief that FK 506 is a superior immunosuppressive agent which is suitable for chronic administration.

Selected topics on FK 506, with special references to rescue of extrahepatic whole organ grafts, transplantation of "forbidden organs," side effects, mechanisms, and practical pharmacokinetics.

FK 506 is a superior immunosuppressive agent that should improve the grafting of organs that already are part of our every day transplant practices, as well as those which are presently impractical. Immune intervention for serious autoimmune diseases also should be a more attractive option with this drug. Lessons are still being learned about dosage and what determines safe dose schedules. At a basic level, the study of FK 506 and its comparison to CyA may have shed light on mechanisms and characteristics of the whole class of so-called macrolide immunosuppresants and their cytosolic binding sites.

Rejection of multivisceral allografts in rats: a sequential analysis with comparison to isolated orthotopic small-bowel and liver grafts.

Multivisceral isografts and allografts were transplanted to Lewis rats, and the histopathologic changes were studied in the liver, intestine, and other constituent organs. Rats receiving isografts had indefinite survival with maintenance of weight. With multivisceral allografts (from Brown-Norway donors), the intestinal component was rejected more severely than the companion liver and with about the same severity as when intestinal transplantation was performed alone. Intestinal rejection in either circumstance was a lethal event, causing death in 10 to 12 days. The earliest (by day 4) and most intense cellular rejection was in the Peyer's patches and mesenteric lymph nodes. This was associated with or followed by cryptitis, epithelial cell necrosis, focal abscess formation, mural necrosis, and eventual perforation. Liver allografts transplanted alone or as part of multivisceral grafts also had histopathologic evidence of rejection, but this was self-limiting and spontaneously reversible when the liver was transplanted alone. Thus the Achille's heel of multivisceral grafts is the intestinal component that is not protected by the presence of the liver in the organ complex. Better immunosuppression should permit successful experimental and clinical transplantation of such grafts.