Stem cell therapy for diabetes.

Stem cell therapy holds immense promise for the treatment of patients with diabetes mellitus. Research on the ability of human embryonic stem cells to differentiate into islet cells has defined the developmental stages and transcription factors involved in this process. However, the clinical applications of human embryonic stem cells are limited by ethical concerns, as well as the potential for teratoma formation. As a consequence, alternative forms of stem cell therapies, such as induced pluripotent stem cells, umbilical cord stem cells and bone marrow-derived mesenchymal stem cells, have become an area of intense study. Recent advances in stem cell therapy may turn this into a realistic treatment for diabetes in the near future.

Early days of liver transplantation.

The early days of liver transplantation were exciting, demanding, subject to terrible disappointments and sadness but occasional elation, and a gradual understanding of the factors necessary to achieve a satisfactory operation. In addition, care of an extremely sick patient, the management of the disease, especially if it was infectious or malignant, and the support of the relatives and the transplant team, required a group of loyal, dedicated and above all optimistic members who could see through the repeated unhappy outcomes that eventually most of the problems would be solved. This in fact has come to pass.

Alemtuzumab (Campath-1H) and tacrolimus monotherapy after renal transplantation: results of a prospective randomized trial.

The lymphocyte-depleting antibody alemtuzumab was evaluated in a prospective randomized multicenter trial in deceased donor kidney transplantation. The 65 patients in the study group received induction with alemtuzumab followed by delayed tacrolimus monotherapy, while the 66 patients in the control group were started on tacrolimus in combination with mycophenolate mofetil and steroids. Tacrolimus levels of 8-12 ng/mL for the first 6 months and 5-8 ng/mL thereafter were aimed for in both groups. At 12 months the biopsy-proven rejection rate was 20% in the study group and 32% in the control group (p = 0.09). Patient survival at 1 year was 98% for both groups. Graft survival was 96% for the study group versus 90% for the control group (p = 0.18). Graft function was identical in both groups. Adverse events were similar in both groups apart for more CMV infections in the study group. At the end of the first year 82% of the patients in the study group were steroid-free and 71% continued on tacrolimus monotherapy. These results suggest that alemtuzumab induction together with tacrolimus monotherapy is at least as efficient in renal transplantation as is a tacrolimus-based triple-drug regimen with a similar safety profile but more CMV infections.

Life-threatening coagulopathy associated with use of Campath (alemtuzumab) in maintenance steroid-free renal transplant given before surgery.

We report a case in which an alarming coagulopathy occurred during the operation in a patient receiving a kidney from his spouse. Campath was used for induction of immunosuppression immediately before surgery. There was catastrophic intra-abdominal bleeding associated with severe hypotension, respiratory failure, prolonged partial thrombin time (PTT), normal prothrombin time (PT) and absence of signs of disseminated intravascular coagulation. Multiple tranfusions of blood and blood products were given. Repeated explorations were carried out to secure hemostasis and removal of intra-abdominal blood clots. The coagulopathy improved after 24 h, but recurred within 3 h after the second dose of Campath, given exactly 24 h after the first dose. The coagulopathy also resulted in graft dysfunction, bilateral basal pneumonia, pleural effusions and prolonged abdominal ileus. In spite of the above, the patient went into diuresis and was discharged well after 3 weeks. He was on Prograf (tacrolimus), the sole maintenance immunosuppressor. The pathogenesis of the Campath-related coagulopathy is unclear. We wish to alert the transplant community to this unusual, but catastrophic, complication. We also advocate administering intravenous Campath following the operation, when surgical wounds are more secure and the patient is in a more stable environment.

Prope tolerance--the future of organ transplantation from the laboratory to the clinic.

This is a short review of tolerance from the point of view of the clinician. Various examples of tolerance occurring in patients and animal models that relate to the clinical experience are described. It is suggested that there may be different mechanisms by which tolerance is achieved, but from the patient's point of view operational tolerance is the goal whereby, after a short induction procedure, the patient will maintain good function in the grafted organ indefinitely without maintenance immunosuppression. It is pointed out that such a goal may be difficult to achieve with any given protocol due to the enormous variation between donors and recipients of organ grafts of tissue matching, innate immune reactivity and susceptibility to disturbance of a tolerant state by infections or allergic reactions. Thus, the case is made for prope or almost tolerance in which graft acceptance is maintained by a low, non-toxic dosage of maintenance immunosuppression, which may not be required indefinitely.

Adult small intestinal transplantation in England and Wales.

BACKGROUND: In 1996 two transplantation centres in the UK were commissioned by the National Specialist Commissioning Advisory Group for England and Wales to assess small intestinal transplantation in adults. The joint experience of the two centres is presented. METHODS: Patients with irreversible small intestinal failure and complications of parenteral nutrition, and those with abdominal disease requiring extensive visceral resection, were assessed as candidates and where appropriate listed for surgery. RESULTS: Thirty-six patients were assessed for small intestinal transplantation and, of these, 14 underwent surgery. Twelve patients survived the transplantation procedure. Of these, seven patients were alive at 1 year, five at 3 years and three at 5 years. Three patients remain alive. Patient and graft survival improved with experience; the 1-year survival rate improved in the last 4 years of this experience from 43 to 57 per cent, and the 3-year survival rate from 29 to 43 per cent. CONCLUSION: Small intestinal transplantation is associated with a high mortality rate but may benefit carefully selected patients in whom conservative management is likely to carry a greater mortality rate.

Solitary splenic metastasis: case report and review of the literature.

Solitary splenic lesion is a rare presentation of a previous or current malignancy. We describe a case of an isolated splenic lesion caused by endometrial carcinoma and summarize all the published reports on solitary splenic metastasis.

The future of organ transplantation: from the laboratory to the clinic.

This is a short review of tolerance from the point of view of the clinician. Various examples of tolerance occurring in patients and animal models that relate to the clinical experience are described. It is suggested that there may be different mechanisms by which tolerance is achieved, but from the patient's point of view operational tolerance is the goal, whereby, after a short induction procedure, the patient will maintain good function in the grafted organ indefinitely without maintenance immunosuppression. It is pointed out that such a goal may be difficult to achieve with any given protocol due to the enormous variation between donors and recipients of organ grafts of tissue matching, innate immune reactivity and susceptibility to disturbance of a tolerant state by infections or allergic reactions. Thus the case is made for prope or almost tolerance in which graft acceptance is maintained by a low, non-toxic dosage of maintenance immunosuppression that may not be required indefinitely.

Prope tolerance: a step in the search for tolerance in the clinic.

Following the demonstration by Knechtle and colleagues that profound T cell depletion in rhesus monkeys treated with a CD3 diphtheria immunotoxin resulted in tolerance to renal allografting, we have used a similarly depleting protocol that, in addition, depletes B cells in recipients of a cadaveric renal transplant. The humanized antiCD52 monoclonal antibody had a rapid depleting effect when given intravenously, 20 mg on days 0 and 1 after-renal transplantation, to 31 patients. At 48 hours after the second dose of low dose monotherapy cyclosporine (Neoral) was given to maintain blood levels averaging 100 ng/ml. Initially no other immunosuppression was given. With an average follow-up of 24 months all but one of the patients are alive, 29 with intact functioning grafts. There have been five rejection episodes, which responded to pulsed steroid treatment. One patient had a recurrence of her original disease. Two patients developed opportunistic infections, which responded to therapy; and one patient with severe heart failure at the time of surgery died from this condition after 11 months. Currently 29 patients are still on the original low dose cyclosporine monotherapy. The outcome in this cohort of patients has been encouraging, with efficacy that compares favorably to our conventional triple therapy but in most cases allows the patients to be steroid-free on low dose immunosuppressive monotherapy. The maintenance treatment is inexpensive and should be beneficial in the context of tight budgetary constraints worldwide. The patients who avoided steroids are pleased with this aspect of the protocol. A randomized trial comparing this treatment with standard therapy is planned.

Historic landmarks in clinical transplantation: conclusions from the consensus conference at the University of California, Los Angeles.

The transplantation of organs, cells, and tissues has burgeoned during the last quarter century, with the development of multiple new specialty fields. However, the basic principles that made this possible were established over a three-decade period, beginning during World War II and ending in 1974. At the historical consensus conference held at UCLA in March 1999, 11 early workers in the basic science or clinical practice of transplantation (or both) reached agreement on the most significant contributions of this era that ultimately made transplantation the robust clinical discipline it is today. These discoveries and achievements are summarized here in six tables and annotated with references.

Thrombocytopenia following liver transplantation is associated with platelet consumption and thrombin generation.

Thrombocytopenia frequently occurs immediately after orthotopic liver transplantation. We have investigated the cause of this phenomenon in a cohort of 45 consecutive liver transplant recipients. The median preoperative platelet count (range) of 129 x 10(9)/l (14-719) fell to 56 x 10(9)/l (23-334) by the fourth postoperative day. The median preoperative reticulated platelet percentage (range) of 6.7% (2.2-23.9) increased to 16.4% (4.6-40.8) on day 7. There was a significant rise in prothrombin fragment F1.2 by the first postoperative day which was followed by rises in fibrinogen and fibrin degradation products. There was no increase in platelet-associated immunoglobulin or markers of endothelial activation. We conclude that there is an increased rate of platelet consumption associated with thrombin generation that reflects the magnitude of liver transplant surgery.

Successful use of size-mismatched liver allografts in children by delayed primary closure of the abdominal wall.

Children who are too ill to await a liver graft of suitable size may be transplanted with a relatively oversized graft by leaving the abdominal wound partially open, the defect reduced being bridged with polypropylene mesh and the mesh reduced in stages until it can be removed and the wound directly closed. This technique has been used in seven children who received nine grafts (five reduced and four full size). Their mean age was 7.3 (range 0.5-11) months and mean weight 5.8 (range 2.3-7.2) kg. Progressive reduction in the size of the transplanted liver made primary closure possible in survivors in up to four stages. Over a follow-up period of 3 to 58 months, five of the nine grafts and five of the seven patients survived. No significant complications attributable to the technique were encountered. The technique of delayed primary abdominal wall closure may be of benefit in children at risk of graft failure because of a size-mismatched graft.

Heart-lung-liver transplantation.

We report three patients with cystic fibrosis and one patient with primary biliary cirrhosis and plexogenic pulmonary hypertension who have undergone heart-lung-liver transplantation as a combined procedure. Liver transplantation was necessary in the three patients with cystic fibrosis because of portal hypertension secondary to either hepatic fibrosis or established cirrhosis in addition to their advanced lung disease. Three of the four patients were alive at 20, 50, and 100 months after transplantation (one patient with cystic fibrosis died on day 16 of pneumonia) with well-preserved pulmonary function (forced expiratory volume in 1 second 110%, 49%, and 100% predicted, respectively), normal hepatic function and New York Heart Association class 1 performance status. Heart-lung and concurrent liver transplantation is a feasible and successful procedure with a satisfactory long-term outcome in selected patients with advanced pulmonary and hepatic disease.

Donor arterial variations in liver transplantation: management and outcome of 527 consecutive grafts.

The impact of donor arterial variations and their management was investigated retrospectively in 527 consecutive allografts. Anomalous arteries were found in 161 grafts (30.6 per cent). There was no significant difference in the overall incidence of arterial complications between grafts with normal (3.6 per cent) and abnormal (5.6 per cent) anatomy. However, there was a higher incidence of arterial complications in transplants requiring multiple arterial anastomoses (P = 0.02), or anastomosis of donor vessels to recipient aorta with (P = 0.0003) or without (P = 0.04) an interposition graft for arterial reconstruction. The incidence of biliary complications was similar in grafts with a normal (18.8 per cent) or anomalous (18.0 per cent) arterial supply. Anomalies of hepatic arterial anatomy occur in one-third of all livers and do not compromise graft outcome unless multiple anastomoses or direct anastomosis to the recipient aorta are required for arterial reconstruction.

Effective administration of heparin and antibiotic prophylaxis.

A prospective audit was performed to determine whether new departmental procedures had improved the administration of heparin and antibiotic prophylaxis in patients undergoing major surgery who were at risk of deep vein thrombosis, pulmonary embolism and postoperative wound infection. The results are compared with a previous retrospective audit of the same 'at-risk' groups. A significant improvement in prophylaxis administration is demonstrated.