Norman Briffa

Combined immunosuppression with cyclosporine (neoral) and SDZ RAD in non-human primate lung transplantation: systematic pharmacokinetic-based trials to improve efficacy and tolerability.

BACKGROUND We studied the efficacy and tolerability of combined immunosuppressive therapy with cyclosporine A microemulsion (Neoral) plus the macrolide SDZ RAD 40-0 (2-hydroxyethyl) rapamycin (RAD) in a stringent cynomolgus monkey lung graft model in comparison with cyclosporine or SDZ RAD monotherapy. METHODS Thirty-nine cynomolgus monkeys received mixed lymphocyte reaction (MLR) mismatched unilateral lung transplants. Immunosuppressants were administered orally as single daily doses. The observation period was 28 days and follow-up included serial trough blood drug concentrations measured by high performance liquid chromatography/mass spectrometry, blood analyses, chest radiographs, open lung biopsies, as well as tissue drug concentrations and graft histology at necropsy. RESULTS Graft biopsies in monkeys treated with vehicle (n=4), Neoral (day 1-7: 150 mg/kg/day; day 8-28: 100 mg/kg/day; n=6; mean +/- SE trough level (MTL): 292+/-17 ng/ml) or SDZ RAD monotherapy (1.5 mg/kg/day; n=6; MTL: 15+/-1 ng/ml) showed severe rejection. Coadministration in two transplant monkeys of Neoral (150/100 mg/kg/day) and SDZ RAD (1.5 mg/kg/day) caused their early death. In both animals, SDZ RAD blood levels were more than 5-fold higher than under monotherapy (MTL: 82+/-18 ng/ml). Simultaneous administration (n=6) of Neoral (150/100 mg/kg/day; MTL: 217+/-16 ng/ml) and SDZ RAD (0.3 mg/kg/day; MTL: 24+/-2 ng/ml) improved graft outcome (mild rejection). Side effects included renal failure (n=2) and seizures (n=1). Three monkeys survived to day 28. In this group the MTL for cyclosporin was 143+/-13 and for RAD 38+/-3. Staggered treatment completely prevented rejection in four of six grafts. However, five of six monkeys had moderate to severe diarrhea. In a concentration-controlled trial of simultaneously administered Neoral and SDZ RAD in transplant monkeys (target SDZ RAD MTL: 20-40 ng/ml; cyclosporine MTL: 100-200 ng/ml) all six monkeys survived with improved drug tolerability and an average biopsy score of mild rejection. CONCLUSION Combination of orally administered SDZ RAD and Neoral showed excellent immunosuppressive efficacy in a stringent lung transplant model. The drug interaction and the narrow therapeutic index of this drug combination required careful dose adjustments to optimize tolerability and efficacy.

New immunosuppressive regimens in lung transplantation

Survival after lung transplantation is less than 50% after 5 yrs and is limited by infection and obliterative bronchiolitis. There is, therefore, a need for new immunosuppressive regimens if we are to attempt to improve long-term survival. Several trials in lung transplantation of new immunosuppressive agents are in the planning stages. In this article, we review the experience with a new monoclonal agent (interleukin 2 (IL2) receptor antagonist) in kidney transplantation, together with the pharmacokinetic (PK) and pharmacodynamic properties and experience in transplantation in general, of the more promising of the new xenobiotic compounds (cyclosporine microemulsion, mycophenolate mofetil, tacrolimus and sirolimus). Recent novel approaches to the vexing problem of resistant lung rejection and obliterative bronchiolitis, such as the use of aerosolized cyclosporine, methotrexate, total lymphoid irradiation and phototherapy, are discussed. Finally an immunosuppressive regimen, using these new drugs in lung transplantation is suggested.

Off pump coronary artery bypass: a passing fad or ready for prime time?

Off pump coronary artery bypass (OPCAB) allows multivessel coronary disease to be bypassed surgically without the need for cardiopulmonary bypass, myocardial ischaemia, and in many cases ascending aortic manipulation. Many randomized controlled studies of OPCAB vs. on pump CABG (coronary artery bypass grafting) have been completed and published. Although non-inferior, OPCAB does not, in these trials, offer any clear benefits. As a consequence, surgeons and industry are losing interest in this undeniably harder technique. As the risk profile of patients being referred for coronary surgery is increasing, is it time for OPCAB to prove itself? A large, appropriately powered randomized controlled trial of OPCAB vs. on pump CABG in high-risk patients will determine whether it is now or never for OPCAB.

Atrial Myxomas: A Single Unit's Experience in the Modern Era

Background: Although an atrial myxoma is the commonest cardiac tumor, it is still relatively rare, with an annual incidence of approximately 0.5 per million. In our unit, which performs 1000 major cardiac procedures per year, this equates to approximately 3 patients annually. We therefore sought to evaluate our experience of managing this type of tumor over the last 5 years. Methods: A retrospective review was performed of prospectively collected data from the departmental database. We analyzed consecutive patients who were operated upon between 2002 and 2007. Three patients with a papillary fibroelastoma on histological examination were excluded from this study. Results: We have performed excision of atrial myxoma in 18 patients. Twelve patients (66%) were female; the median age was 64 years (range, 35-80 years), and the median logistic euroSCORE was 5.22% (range, 1.51-27.82%). Fifteen patients (83%) were deemed urgent, 2 elective, and 1 emergency. Sixteen tumors (89%) were left sided. Symptoms attributable to the tumor were found in 16 of the 18 patients (embolic, n = 9; chest pain, n = 3; palpitations, n = 2; incidental finding, n = 2, others n = 4), and the mean time from diagnosis to operation was 3 days (range, 0-22 months). The median cardiopulmonary bypass time was 87 minutes (range, 28-228 minutes), with the median aortic cross clamp time being 61 minutes (16-175 minutes). The approaches used were transeptal via right atriotomy (n = 8), biatrial/Dubost (n = 4), left atrial (n = 4), and right atrial (n = 2); the interatrial septum was involved in 14 patients. The resultant defect was closed using a pericardial (n = 8) or prosthetic patch (n = 5) or directly sutured (n = 5). Concomitant procedures were performed in 8 patients (coronary artery bypass graft [CABG], n = 4; mitral valve replacement [MVR], n = 2; valve + grafts, n = 2). All tumors were completely excised. Postoperatively there were no deaths within 30 days of the procedure. Indeed, only 2 patients have died at 4 and 25 months postoperatively, respectively, both of unrelated causes. Median intensive therapy unit (ITU) stay was 2 days (range, 1-9 days), and median hospital stay was 10 days (range, 5-20 days). A permanent pacemaker was required in only 1 patient, and median blood loss was 340 mL (range, 140-1760 mL). Atrial fibrillation was the commonest complication affecting 6/18 patients (33%). Conclusions: Excision of atrial myxoma can be performed using a variety of intraoperative approaches and closure techniques, all with acceptable postoperative morbidity and low mortality rates. To date, no recurrences have been found at median 2-year follow-up.

Histological and immunological characteristics of, and the effect of immunosuppressive treatment on, xenograft vasculopathy.

Abstract:  Like allografts, vascularized xenografts are susceptible to a process of chronic rejection. We have used the hamster‐to‐rat aortic transplant model to study characteristics of this phenomenon and to determine whether it could be controlled or prevented by immunosuppressive therapy. Golden Syrian hamster aortas were transplanted into untreated Lewis rats, athymic rats, and Lewis rats receiving cyclosporin (10 mg/kg), leflunomide (5, 10 or 15 mg/kg), or 10 mg/kg of both drugs. Grafts were harvested on days 2, 7, 14, 28 and 56. Grafts and recipient spleens were analysed using computerized morphometry, immunohistochemistry and immunofluorescence. Blood was taken on various days for the measurement of anti‐hamster antibodies (flow cytometry) and of the leflunomide metabolite A77 127. In untreated rats, by day 56, transplanted aortas developed a cell‐free media with a mature neointimal lesion consisting of actin‐positive cells, CD4 T cells, and macrophages. There were large increases in anti‐hamster immunoglobulin M (IgM) and IgG, collections of proliferating cell nuclear antigen (PCNA)‐positive cells in splenic germinal centres, and IgM, C3 and C5a deposition in aortas. In athymic recipients, the media architecture was preserved, and the changes in the neointima and in anti‐hamster IgM and IgG were markedly abrogated, but not prevented. In Lewis rats receiving leflunomide, absence of circulating or deposited IgM did not prevent neointimal formation by day 14. Combination treatment was the most effective at preventing neointimal formation and humoral changes. Leflunomide monotherapy was the least effective. There were no changes in peak concentrations of the main metabolite of leflunomide over 8 weeks. The hamster‐to‐rat aortic transplant model is suitable for the study of xenograft vasculopathy, the histological and serological changes of which are predominantly T‐cell dependant. Combination treatment with 10 mg/kg of cyclosporin and 10 mg/kg of leflunomide was most effective in preventing xenograft vasculopathy.

Multidimensional assessment of graft vascular disease (GVD) in aortic grafts by serial intravascular ultrasound in rhesus monkeys.

BACKGROUND Graft vascular disease (GVD) is an incompletely understood process and the primary cause of late allograft failure. A nonhuman primate model was established to study the progression of GVD by using serial intravascular ultrasound (IVUS). METHODS Aortic allografts were transplanted below the inferior mesenteric arteries (IMA) into 6 rhesus monkeys. Removed and re-implanted aortic segments between renal arteries, and the inferior mesenteric arteries served as autografts. IVUS was performed at days 0, 24, 52, 80, and 98 after transplantation. Vessel area (VA) and lumen area (LA) were measured from each cross-section at 0.5 mm intervals. Intimal index (II=100x (VA-LA/VA)) and corresponding vessel volumes were calculated for the whole grafts. Histologic features were assessed from autopsy samples using computerized morphometric method and a score from 0 to 3 for GVD (0=none, 3=severe). RESULTS In allografts, vessel volume and luminal volume decreased significantly (P<0.05 for both) and the intimal index increased from 12% to 59% by day 98. These parameters remained unchanged in autografts. Histologic analysis of allografts showed concentric intimal hyperplasia and scattered mononuclear cell accumulations, whereas the autografts had only occasional eccentric intimal changes. The GVD-scores were significantly higher in allografts than in autografts (median 3 vs. 1, P=0.042). CONCLUSIONS We introduce a nonhuman primate model of GVD that enables serial IVUS assessments of multiple parameters of GVD. Concentric intimal proliferation and decrease of vessel dimensions was observed in allografts as a consequence of alloimmunity. This is a potential new model for studying new therapies to prevent GVD or halt its progression.

The histology of subcutaneously implanted donor bronchial rings correlates with rejection scores of lung allografts in a primate lung transplant model.

BACKGROUND The diagnosis of acute rejection in lung transplantation generally relies on transbronchial biopsies. This invasive procedure may be associated with bronchial bleeding or pneumothorax and may not be feasible in patients with severely compromised lung function. The hypothesis of the current study was that histopathological findings of donor bronchial segments implanted into the subcutaneous tissue of lung allograft recipients would predict lung tissue rejection scores, thus providing the clinician with an alternate source of information. METHODS Unilateral left lung transplantation was performed in 34 cynomolgus monkeys as part of a drug efficacy study. After completion of the transplant procedure, 4 bronchial ring segments of the explanted recipient left lung and 4 bronchial ring segments of the non-transplanted right donor lung were implanted subcutaneously in the abdominal region. Lung allograft rejection was evaluated by open lung biopsies of the allograft performed on postoperative (PO) Day 14 and during sacrifice on PO Day 28. At the time of each biopsy, 2 donor and 2 recipient subcutaneous bronchial rings were explanted. Histologic evaluation of the lung tissue samples was performed according to the working formulation of the International Society for Heart and Lung Transplantation. Bronchial rings were independently evaluated by assessing the degree of airway narrowing; percentage of intact epithelial coverage as well as its specific histology (respiratory ciliated, flattened cuboidal, squamous); presence of lymphocytes, macrophages or spindle cells; and presence of peribronchial inflammation, luminal fibrosis, lymphocytic bronchitis or luminal mucous. Statistical analysis was performed by logistic regression. RESULTS In the recipient bronchial rings, there was no evidence of airway narrowing. There was 98% epithelial coverage, 71% that were respiratory ciliated cells, and there was no inflammation. Donor bronchial rings showed no airway narrowing for monkeys with grade A0 to A2 rejection in tissue biopsies and a maximum narrowing (41.2%) with A4 rejection. Epithelial cell coverage was approximately 100% with grade A0-A2 and 44+/-11% with A4 rejection. Lymphocytic bronchitis was most severe in A4 rejection and minimal in A0 to A2 rejection. By logistic regression analysis, independent predictors of a likelihood of rejection were the degree of airway obliteration, the percentage of epithelial cell coverage, the degree of lymphocytic bronchitis and the product of respiratory and flattened cuboidal cell coverage. CONCLUSIONS The current data show that histologic alterations of subcutaneously implanted donor bronchial rings correlate with lung tissue biopsy scores based on the ISHLT working formulation. Because subcutaneous bronchial rings can be explanted under local anesthesia, they may provide useful information for the diagnosis of acute allograft rejection in patients with impaired lung function, patients that obtaining lung tissue samples may not be feasible.

IMMUNOSUPPRESSIVE DRUGS AFTER LUNG TRANSPLANTATION

Survival figures after lung transplantation for the period up to 1996 were reported at a recent annual meeting of the International Society of Heart and Lung Transplantation in London. Although quality of life for patients is greatly improved for some years after transplantation, five year survival after heart-lung, single lung, or double lung transplantation is still less than 50%.1 Mortality in the first 30 days has improved because of advances in surgical technique and in methods of lung preservation,1 but after 30 days the survival curves in 1988-91 and in 1992-5 are parallel. The main cause of death between 30 days and a year after transplantation is infection. After a year the main cause is bronchiolitis obliterans syndrome. This fibroproliferative disorder affects the small airways of at least half of patients who survive for three months after transplantation.2 Its pathogenesis is unclear but it represents a fibrotic repair process occurring after chronic airway injury, and retrospective series have shown that …

Surgery for degenerative mitral valve disease

Rates of repair are improving, but there is still wide variation

Routine preoperative insertion of IABP in high-risk off-pump coronary artery bypass grafting.

The beneficial effects of intraaortic balloon pump (IABP) in coronary artery bypass graft surgery with cardiopulmonary bypass have been reported. However, whether preoperative insertion of IABP in high-risk off-pump coronary artery bypass grafting (OPCAB) has any beneficial effects remains to be established. We report our experience of preoperative insertion of IABP in OPCAB.