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Background: It is unclear to what extent cancer history affects posttransplantation mortality in solid organ transplant recipients., Methods: We identified a Swedish population-based cohort of solid organ transplant recipients in the National Patient Register 1970 to 2008 and linked it to the Cancer and Cause-of-Death Register. Overall and cause-specific mortality was estimated using Cox regression., Results: Of 10,448 eligible recipients, 416 (4%) had a prior malignancy unrelated to the indication for transplantation diagnosed 2 months or more before surgery (median, 5.7 years). Mortality among cancer history recipients was 30% increased after transplantation, compared with other recipients (adjusted hazard ratio [HR], 1.3; 95% confidence interval [CI], 1.1-1.5; P<0.001), driven by cancer-specific death with no increase in cardiovascular, infectious, or other noncancer mortality. An increased rate of death due to cancer history was primarily observed among nonkidney recipients (adjusted HR(nonkidney), 1.8; 95% CI, 1.3-2.5; HR(kidney), 1.2; 95% CI, 1.0-1.4). Rates were greatest for patients with waiting times of 5 years or less but persisted with waiting times more than 10 years among kidney and nonkidney recipients with prior aggressive cancer types (gastrointestinal, breast, kidney/urothelial, and hematologic malignancies)., Conclusion: We conclude that organ transplant recipients with cancer history are at a moderately increased rate of death after transplantation, driven primarily by death due to cancer recurrence.

Organ transplant recipients are at increased risk of a wide range of malignancies, especially cutaneous squamous cell carcinomas (SCC). Few previous population-based studies have quantified and compared cancer risks according to graft type and with long-term follow-up. Using nationwide Swedish registers, we identified 10,476 recipients transplanted from 1970 to 2008 and followed them for cancer occurrence. Relative risks of cancer in comparison with the general population were expressed as standardized incidence ratios (SIR) and within the transplanted cohort as incidence rate ratios (IRR). During a total follow-up of 93,432 person-years, patients were diagnosed with 1,175 cancers excluding SCC, and with 2,231 SCC, SIR(cancer excl SCC) 2.4 (95% CI, 2.2-2.5); SIR(SCC) 121 (95% CI, 116-127). Cancer risks were most increased among heart and/or lung recipients SIR(cancer excl SCC) 3.3 (95% CI, 2.8-4.0); SIR(SCC) 198 (95% CI, 174-224), followed by kidney SIR(cancer excl SCC) 2.3 (95% CI, 2.1-2.4); SIR(SCC) 121 (95% CI, 116-127) and liver recipients SIR(cancer excl SCC) 2.3 (95% CI, 1.9-2.8); SIR(SCC) 32 (95% CI, 24-42). During follow-up, risk of cancer excluding SCC remained stable while risk of SCC tripled over 20 years irrespective of graft type, partly due to a subgroup of patients developing new SCCs at a rapidly increasing rate. In summary, post-transplant cancer risk varied by transplanted organ and by cancer site, with the bulk of the excess risk driven by an exceptionally high and accelerating risk of SCC. These findings underscore the importance of regular skin screening in organ transplant recipients., (Copyright © 2012 UICC.)

Increased cancer risks are well documented in adult organ transplant recipients. However, the spectrum of malignancies and risk in the pediatric organ transplant population are less well described. We identified all solid organ transplanted patients aged <18 in Sweden between 1970-2007 (n = 536) in the National Patient Register and linked to the Cancer Register. Nationwide rates were used to calculate standardized incidence rate ratios and 95% CI estimating the association between transplant and cancer during maximum 36 years of follow-up. Nearly 7% of pediatric solid organ transplant recipients developed a premalignant or malignant tumor during follow-up. Transplantation was associated with an increased risk of any cancer (n = 24, SIR = 12.5, 95% CI: 8.0-18.6): non-Hodgkin lymphoma (NHL) (n = 13, SIR = 127, 95% CI: 68-217), renal cell (n = 3, SIR = 105, 95% CI: 22-307), vulva/vagina (n = 3, SIR = 665, 95% CI: 137-1934) and nonmelanoma skin cancers (n = 2, SIR = 64.7, 95% CI: 7.8-233.8). NHL typically appeared during childhood, while other tumors were diagnosed during adulthood. Apart from short-term attention toward the potential occurrence of NHL, our results suggest cancer surveillance into adulthood with special attention to skin, kidneys and the female genitalia., (©2010 The Authors Journal compilation©2010 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Two Six-month pilot studies were conducted in renal (n = 17) or liver (n = 15) transplant recipients to evaluate renal function after conversion from calcineurin inhibitor (CI)- to sirolimus (SRL)-based immunosuppression. After an SRL loading dose, doses were individualized to achieve whole blood trough levels of 10-22 ng/mL. Overall, serum creatinine did not change from baseline to six months post-conversion but an improvement from 219.9 to 201.4 micromol/L at three months was noted in renal transplant recipients (p < 0.05). Another finding was a numerical increase in the mean glomerular filtration rate (GFR) from 26.8 to 33.2 mL/min/1.73 m(2) at six months among liver transplant recipients (NS). All patients survived and all grafts were functioning at the end of the study. In conclusion, renal function remained stable, with a tendency towards improvement, after abrupt conversion from CI- to SRL-based therapy in renal or liver transplant recipients with moderate renal insufficiency.

Aims: The influence of the trimethoprim-sulphamethoxazole combination on the steady-state pharmacokinetics of sirolimus, a potent macrocyclic immunosuppressant, was studied in renal transplant recipients., Methods: Fifteen kidney transplant recipients were treated with sirolimus 8-23 mg m(-2) in combination with azathioprine and prednisolone from the day of transplantation. Whole blood sirolimus AUC and C(max) were determined on days 6 and 7 after transplantation. On day 7, sirolimus was coadministered with the first dose of trimethoprim (80 mg) and sulphamethoxazole (400 mg)., Results: On day 6, the mean (95% confidence interval) whole blood sirolimus AUC((0-24 h)) was 1040 (846, 1234) ng ml(-1) and mean C(max) was 109 (88, 129) ng ml(-1). Corresponding values on day 7 were AUC((0-24 h)) 1060 (826, 1293) ng ml(-1) and C(max) mean 107 (87, 127) ng ml(-1). The mean difference in the dose-corrected AUC((0-24 h)) was 0.40% (-9.4, +10)., Conclusions: A single dose of trimethoprim-sulphamethoxazole does not affect the pharmacokinetics of sirolimus in renal transplant patients.

Sirolimus is an interesting drug due to its original mechanism of action and because it seems to lack the nephrotoxicity associated with calcineurin inhibitors. During the past 10 years, sirolimus has undergone several clinical trials. Beginning with phase I studies, our first patient given sirolimus was enrolled in 1993, after which we participated in sirolimus phase II trials and finally conducted the large phase III study that led to registration of sirolimus in the European Union (EU) in 2001. Altogether, 111 patients have been treated with sirolimus in our department. Initially, we participated in clinical trials evaluating sirolimus in combination with cyclosporine, but later we focused on studies using sirolimus as base therapy. We found sirolimus to be an effective immunosuppressant lacking several of the disturbing side effects associated with calcineurin inhibitors. It has a high antirejection efficacy and yields excellent survival results, with better renal function than that achieved by calcineurin inhibitors. The main side effects, hyperlipidemia and leukothrombocytopenia, are usually easily manageable. Sirolimus presents an alternative to prophylactic immunosuppression with calcineurin inhibitors and, in the field of transplantation, it represents a welcome addition to the immunosuppressive armamentarium.

In 11 European centers, first cadaveric renal allograft recipients were randomized to CsA (n = 42) or sirolimus (n = 41). Dosing of these agents was concentration-controlled and open-labeled. All patients received corticosteroids and azathioprine. At 12 months, graft survival (98% sirolimus vs 93% CsA), patient survival (100% vs 98%), and incidence of biopsy-confirmed acute rejection (41% vs 38%) were similar. Serum creatinine was lower with sirolimus, significantly (P

Introduction: This study evaluated whether cyclosporine (CsA) could be eliminated from a sirolimus (Rapamune, rapamycin, SRL)-CsA-steroid (ST) regimen at 3 months., Methods: This was an open-label study conducted in Europe, Australia, and Canada. Upon enrollment, 525 primary (90%) or secondary (10%) renal allograft recipients with cadaveric (89%) or living (11%) donors received 2 mg of sirolimus (troughs>5 ng/ml), CsA, and steroids. At 3 months+/-2 weeks, eligible patients were randomized (1:1) to remain on SRL-CsA-ST or to have CsA withdrawn and therapy continued with SRL (troughs 20-30 ng/ml)-ST., Results: At 12 months, overall graft and patient survival were 89.1% and 94.9%, respectively. In the 430 (82%) randomized patients, there was no difference in graft survival (95.8% vs. 97.2%, SRL-CsA-ST vs. SRL-ST) or patient survival (97.2% vs. 98.1%, respectively). The incidence of biopsy-confirmed primary acute rejection was 13.1% during the prerandomization period. After randomization, the acute rejection rates were 4.2% and 9.8% for SRL-CsA-ST and SRL-ST, respectively (P=0.035). Renal function (calculated glomerular filtration rate, 57 vs. 63 ml/min, P<0.001) and blood pressure significantly improved when CsA was withdrawn. Hypertension, CsA nephrotoxicity, hyperuricemia, and Herpes zoster occurred statistically more frequently in patients remaining on CsA, whereas thrombocytopenia, abnormal liver function tests, and hypokalemia were reported more often for SRL-ST therapy., Conclusion: Sirolimus, CsA, and steroids for 3 months posttransplant, followed by elimination of CsA, is a safe and effective alternative to continuous therapy with sirolimus, CsA, and steroids that can result in better renal function and lower blood pressure.

Aim and Background: The pharmacokinetic interaction between sirolimus, a macrolide immunosuppressant metabolized by CYP3A4, and the calcium channel blocker diltiazem was studied in 18 healthy subjects. Several clinically important interactions have previously been reported for other immunosuppressive drugs that are metabolized by the same enzyme and for calcium antagonists., Methods: Healthy subjects who were 20 to 43 years old participated in an open, three-period, randomized, crossover study of the pharmacokinetics of a single 10-mg oral dose of sirolimus, a single oral 120-mg dose of diltiazem, and the two drugs given together. The three study periods were separated by a 21-day washout phase., Results: The geometric mean (90% confidence interval) whole blood sirolimus area under the plasma concentration time-curve increased 60% (35%-90%), from 736 to 1178 ng x h/mL, and maximum concentration increased 43% (14%-81%), from 67 to 96 ng/mL, with diltiazem coadministration, whereas the mean elimination half-life of sirolimus decreased slightly, from 79 to 67 hours. Apparent oral clearance and volume of distribution of sirolimus decreased with 38% and 45%, respectively, when sirolimus was given with diltiazem. The plasma maximum concentration and area under the plasma concentration-time curve of diltiazem, desacetyldiltiazem, and desmethyldiltiazem were unchanged after coadministration of sirolimus, and no potentiation of the effects of diltiazem on diastolic or systolic blood pressure or on the electrocardiographic parameters was seen., Conclusions: Single-dose diltiazem coadministration leads to higher sirolimus exposure, presumably by inhibition of the first-pass metabolism of sirolimus. Because of the pronounced intersubject variability in the extent of the sirolimus-diltiazem interaction, whole blood sirolimus concentrations should be monitored closely in patients treated with the two drugs.

A phase I study was conducted to determine the pharmacokinetics, safety, and tolerability of sirolimus, a new immunosuppressive drug, in 45 healthy men between 19 and 36 years of age. Nine subjects in each group were randomly assigned to receive single oral doses of either sirolimus (n = 6) or placebo (n = 3) in group I (0.3 mg/m2), group II (1 mg/m2), group III (3 mg/m2), group IV (5 mg/m2) and group V (8 mg/m2). No serious adverse events occurred during the study. Twenty-eight of the 45 volunteers (62%) reported an adverse event; 19 of 30 (63%) were in the sirolimus group and 9 of 15 (60%) were in the placebo group (ns). Asthenia was the most common adverse event, occurring in 7 of 30 (23%) in the sirolimus group compared with 6 of 15 (40%) in the placebo group (ns). Absorption occurred within 1 hour in all volunteers. Whole blood peak concentration and area under the concentration-time curve increased proportionally with dose. Mean (+/- SD) whole blood terminal disposition half-life (t1/2), apparent oral dose clearance (Cl/F), and volume of distribution (Vss/F) were 82 +/- 12 hours, 278 +/- 117 mL/h x kg and 23 +/- 10 L/kg, respectively. Distribution of sirolimus into formed blood elements was extensive, with a mean whole blood-to-plasma ratio of 36. Single oral doses of sirolimus (0.3 to 8 mg/m2) solution were well tolerated in healthy male volunteers.

Introduction: A previous trial in renal transplantation comparing sirolimus (rapamycin) to cyclosporine (CsA) in a triple-drug therapy regimen with azathioprine and corticosteroids found that the incidence of acute rejection was similar (approximately 40%) with a trend for better renal function with sirolimus., Methods: In 14 European centers, first cadaveric renal allograft recipients were randomized to receive sirolimus (n = 40) or CsA (n = 38) in an open-label design. All patients received corticosteroids and mycophenolate mofetil 2 g/day. Sirolimus and CsA were concentration controlled; trough levels of mycophenolic acid and prednisolone were also measured., Results: At 12 months, graft survival (92.5% sirolimus vs. 89.5% CsA), patient survival (97.5% sirolimus vs. 94.7% CsA), and the incidence of biopsy-proven acute rejection (27.5% sirolimus vs. 18.4% CsA) were not statistically different. The use of antibodies to treat suspected rejection episodes was also similar (7.5% sirolimus vs. 5.3% CsA). More sirolimus patients received bolus steroid therapy (20 vs. 11, P = 0.068). From month 2 onward, the calculated glomerular filtration rate was consistently higher in sirolimus-treated patients. The adverse events reported more frequently with sirolimus were thrombocytopenia (45% vs. 8%) and diarrhea (38% vs. 11%). In the CsA group, increased creatinine (18% vs. 39%), hyperuricemia (3% vs. 18%), cytomegalovirus infection (5% vs. 21%), and tremor (5% vs. 21%) were observed significantly more often., Discussion: Patient and graft survival and the incidence of biopsy-proven acute rejection at 12 months were comparable between sirolimus and CsA, whereas safety profiles were different. These data suggest that sirolimus may be used as primary therapy for the prevention of acute rejection.

Aims: To evaluate the relationship between tacrolimus whole blood concentrations and side-effects and rejections in 14 renal transplant recipients., Methods: Tacrolimus was measured by MEIA in whole blood in samples collected repeatedly during the first year after transplantation. Retrospectively, tacrolimus trough concentrations on the days with adverse events (n=172) or rejection (n=28) were related to the total distribution of the concentration values (n=656)., Results: Side-effects (one or more) were noted in connection with 76% of tacrolimus concentrations above 30 ng ml-1, with 41% of concentrations within the interval of 20-30 ng ml-1, with 26% of the concentrations within the interval of 10-20 ng ml-1 and with only 5.3% on the concentrations lower than 10 ng ml-1. No relation to the tacrolimus concentration was seen for rejection episodes., Conclusions: We conclude that therapeutic drug monitoring may be helpful in the management of tacrolimus therapy and that tacrolimus whole blood trough concentrations (MEIA) should preferably be kept below 20 ng ml-1 to avoid side-effects, such as nephro-and neurotoxicity and infections. The lower limit of the therapeutic range has yet to be defined.

A reversed-phase high-performance liquid chromatographic method for the simultaneous determination of mycophenolic acid and its metabolite, mycophenolic acid glucuronide, is presented herein. Sample purification is limited to protein precipitation with acetonitrile. The analytes were separated on a C18 column with a mobile phase containing 30% acetonitrile and a 40 mm phosphoric acid buffer at pH 2.1 and measured with UV-detection at 215 nm.

Background: Sirolimus (rapamycin) is a potent immunosuppressant with a mechanism of action different from cyclosporine (CsA) or tacrolimus., Methods: In 11 European centers, first cadaveric renal allograft recipients were randomized to CsA (n=42) or sirolimus (n=41). Dosing of these agents was concentration-controlled and open-labeled. All patients received corticosteroids and azathioprine., Results: At 12 months, graft survival (98% sirolimus vs. 90% CsA), patient survival (100% vs. 98%), and incidence of biopsy-confirmed acute rejection (41% vs. 38%) were similar. Serum creatinine was lower with sirolimus, significantly (P< or =0.05) so at 3 and 4 months, and serum uric acid and magnesium were normal. Laboratory abnormalities reported significantly more often with sirolimus included hypertriglyceridemia (51% vs. 12%), hypercholesterolemia (44% vs. 14%), thrombocytopenia (37% vs. 0%), leukopenia (39% vs. 14%), and, of lesser importance, increased liver enzymes and hypokalemia. These abnormalities improved 2 months after transplantation when the sirolimus target trough level was lowered from 30 to 15 ng/ml. Occurrence of cytomegalovirus was comparable (14% vs. 12%); incidences of herpes simplex (24% vs. 10%, P=0.08) and pneumonia (17% vs. 2%, P=0.03) were higher with sirolimus. No gingival hyperplasia was seen with sirolimus, tremor was rare, and hypertension was less frequent (17% vs. 33%). Two malignancies were observed with CsA and none with sirolimus., Conclusions: Results at 12 months suggest that sirolimus can be used as base therapy in the prophylaxis of acute renal transplant rejection, and has a safety profile that differs from CsA.

Background: The purpose of pancreatic transplantation in insulin-dependent diabetic patients is to restore normoglycemia and thereby prevent the secondary complications of diabetes. However, uncertainty remains as to whether the mortality rate in diabetic patients can be affected by this procedure., Method: We followed 14 patients with insulin-dependent diabetes mellitus (IDDM) and end-stage diabetic nephropathy for 10 years after successful combined kidney and pancreas transplantation. Fifteen diabetic patients subjected to kidney transplantation alone have served as controls. The glycemic control has been studied annually for 10 years and diabetic polyneuropathy has been assessed in both groups after 2, 4, and 8 years., Results: In recipients of pancreas-kidney grafts, metabolic control was maintained throughout the observation period, with values of glycated hemoglobin in the normal range. In contrast, glucose metabolism was impaired in the control group, with glycated hemoglobin values around 10%. Nerve conduction and parasympathetic autonomic dysfunction improved in both groups after 2 years; there was no difference between the groups. After 4 years, we found a significant difference between the study group and the control group, and after 8 years it had widened. At the 4-year evaluation, there was no difference in mortality between the groups. At 8 years, however, a significant difference was noted, which was further substantiated at 10 years with a 20% mortality rate in the pancreas-kidney group versus an 80% mortality in the kidney alone group., Conclusions: We found a substantial reduction in mortality in IDDM patients 10 years after successful combined pancreas and kidney transplantation. We speculate that the decrease in mortality was due to the beneficial effect of long-term normoglycemia on diabetic late complications and suggest therefore that combined pancreas and kidney transplantation, rather than kidney transplantation alone, should be offered to IDDM patients with end-stage diabetic nephropathy.

Background: Sirolimus is an interesting immunosuppressive drug that does not seem to cause nephrotoxicity, neurotoxicity, or diabetogenicity, as commonly seen in patients treated with cyclosporine or tacrolimus. In this report, we describe a possible association between sirolimus and observed hyperlipidemia., Methods: Serum levels of triglycerides and cholesterol were analyzed in 11 patients who participated in a pilot study evaluating the effect of oral sirolimus or placebo combined with cyclosporine and corticosteroids on the occurrence of acute renal transplant rejection., Results: In four of nine patients given sirolimus, significantly increased serum triglyceride levels were seen, with peak levels occurring 2-4 months after transplantation and ranging between 11.7 and 42.0 mmol/L (reference value <2.2 mmol/L). In two patients given placebo, the serum triglyceride levels remained below 5.0 mmol/L. After reduction or discontinuation of sirolimus, the serum triglyceride levels decreased within 1-2 months and after 1-8 months levels had returned to their pretransplant values. A significant increase in serum cholesterol levels was seen in one of nine patients given sirolimus., Conclusion: It seems that long-term treatment with sirolimus in combination with cyclosporine and corticosteroids may increase the risk of hypertriglyceridemia.

Sirolimus is a new immunosuppressive drug that has been evaluated in animal experiments. The current study was conducted on humans with reformulated sirolimus in doses from 3 mg/m2 to 15 mg/m2. Sixteen renal transplant recipients were included in this phase I study to determine the safety, tolerance, and preliminary pharmacokinetics of increasing single doses of orally administered sirolimus. All 16 patients had stable renal graft function after a renal transplant at least 6 months before the study. Basal immunosuppression consisted of cyclosporine and prednisolone (n = 10) or cyclosporine, azathioprine, and prednisolone (n = 6). Four groups (I, 3 mg/m2; II, 5 mg/m2; III, 10 mg/m2; IV, 15 mg/m2) of four patients were assigned randomly to receive sirolimus (n = 3) or placebo (n = 1). Among the 12 patients who received sirolimus, five had mild transient study events such as headache, nausea, mild dizziness, hypoglycemia, epistaxis, and decrease in platelets. No serious adverse events occurred and no nephrotoxic effects could be related to the single dose administration of sirolimus. The only study event that was judged as probably related to sirolimus was the single case of thrombocytopenia. The other events were evaluated as possibly related. Thrombocytopenia occurred at the highest dose level (15 mg/m2 sirolimus). In two of the patients in the placebo group, slight elevations of liver enzymes and serum amylase were seen. Blood and plasma sirolimus concentrations were analyzed by an electrospray-high performance liquid/mass spectrophotometric (ESP-HPLC/MS) method Sirolimus showed an extensive red blood cell distribution with a mean blood/ plasma ratio of 49.1. The elimination half-life ranged from 43.8 to 86.5 hours (mean 56.9 hours). The Cmax and the area under the concentration versus time curves (AUC) correlated reasonably with doses from 3 to 15 mg/m2. The oral dose clearance ranged from 42 to 339 ml/h.kg. No clinically significant differences were seen in the trough concentrations of cyclosporine or the AUCs before and after the administration of sirolimus. Administration of single oral doses of sirolimus from 3 to 15 mg/m2 was safe and well tolerated in stable renal transplant recipients. Thrombocytopenia may be the dose-limiting toxicity. Additional phase II and phase III clinical trials will define the immunosuppressive efficacy of sirolimus.

Sirolimus (rapamycin, RAPA) is a natural fermentation product (macrolide antibiotic) that has demonstrated potent immunosuppressive activity. A reverse-phase high-performance liquid chromatographic (HPLC) method is described for analysis of the drug in whole blood. The samples are purified by using liquid-liquid extraction with butyl chloride/diethyl ether combined with reversed-phase solid-phase extraction. RAPA and internal standard were traced by UV-detection at 278 nm. Linear calibration curves with correlation coefficients > 0.999 were obtained (range, 1-50 ng/ml). Minimum detectable concentration was approximately 0.4 ng/ml and recovery approximately 45% for both RAPA and internal standard. Coefficient of variation (day to day) was 9.8% at 5 ng/ml (n = 6) and 5.6% at 40 ng/ml (n = 6). The chromatography requires < 10 min per sample. The assay has proved to be free of interference peaks from cyclosporine or tacrolimus. The method has been used to determine the whole blood concentrations in samples from healthy volunteers and renal transplant recipients receiving single and multiple doses of oral rapamycin.

All renal allograft recipients (n = 32) in Sweden and Norway who were converted from cyclosporin (CyA)-based immunosuppression to FK 506 (tacrolimus) between October 1992 and June 1995 were analyzed retrospectively. The reasons for conversion were acute refractory rejection (n = 21), chronic rejection (n = 4), and suspected CyA toxicity (n = 6); one patient was converted for psychological reasons. The mean time from transplantation to conversion was 29 (range 1-243) weeks and there was a mean follow-up of 46 (2-143) weeks. Overall graft survival was 59%, with graft survival 52% in patients converted because of acute rejection, 50% in patients converted because of chronic rejection, and 83% in patients converted because of CyA toxicity. There was no significant correlation between preconversion serum creatinine and outcome. Seventy-two percent of the patients had significant side effects during FK 506 treatment, the most frequent ones being neurological and gastrointestinal symptoms. These improved after dose reduction. Two patients became overimmunosuppressed and developed lymphoma. One patient died of the primary kidney disease, hemolytic uraemic syndrome. We conclude that FK 506 therapy is able to salvage kidneys with acute refractory rejection and that it is an alternative in patients with CyA toxicity. However, the risk of overimmunosuppression must be considered.

A simplified technique for pancreaticoduodenal transplantation with enteric exocrine drainage is described. The whole-organ pancreaticoduodenal transplant is placed intraperitoneally with vascular anastomosis to the right common iliac artery and the caval vein, respectively. The graft duodenum is anastomosed side-to-side to the most proximal part of the donor jejunum. No Roux-en-Y loop or pancreatic duct catheter is used to protect the anastomosis with this technique. Nevertheless, excellent results have been obtained, with no graft losses occurring due to leakage or infection. With this technique, the 1-yr patient and graft survival rates in uremic recipients of simultaneous renal and pancreas transplants are 100% and 87%, respectively.

The finding that active cytomegalovirus (CMV) infection is associated with an increased mortality after organ transplantation and the introduction of successful antiviral treatment render more urgent the development of rapid and accurate diagnostic methods. Rapid immunodiagnosis of active CMV infection was investigated by means of immunofluorescence staining of leucocytes by monoclonal antibodies. Monoclonals directed against the matrix protein, pp65, and ClonabR monoclonal antibody, which has been claimed to be directed against immediate early antigens, were used. All monoclonal antibodies directed against the matrix protein reacted equally well in staining of polymorphonuclear cells. Monoclonals described by Gerna et al. [1991] and by Pereira et al. [1982] also reacted more clearly with mononuclear cells. One hundred fifty heparinized blood samples were collected monthly from 82 patients within 3 months after transplantation. In addition, 132 EDTA blood samples were tested in connection with suspected CMV infection. The latter approach gave a better agreement between antigen detection and virus isolation. There was a relationship between active CMV infection and the finding of antigen-positive leucocytes (P = 0.002, Fisher's exact test) found within 1 month of one another. When the number of antigen-positive cells was taken into account, a relationship to severe CMV disease was detected (P < 0.001, Fisher's exact test). The antigen test was positive at an early stage during the development of severe CMV disease. This rapid method is useful for following the disease process of CMV and in determining when to initiate antiviral treatment.

The early activation of T- and B-cell responses to cytomegalovirus was studied in immunosuppressed patients. Primary lymphocyte stimulation to cytomegalovirus (CMV) antigen, a measure of T-helper activity, and anti-CMV IgG subclass responses were analyzed. Ten patients suffering from primary CMV infection following renal transplantation were studied. Of the ten, nine became positive for CMV induced lymphocyte proliferation 5-40 weeks after transplantation. Nine showed an almost simultaneous appearance of anti-CMV IgG1 and three at 3-32 weeks after transplantation, while one patient synthesized only low levels of anti-CMV IgG1. The lymphocyte proliferation assays have limited diagnostic value for primary CMV infection in renal transplant patients. The humoral and cellular immune responses seemed to be independent of each other.

Cytomegalovirus (CMV) pancreatitis was diagnosed in eight out of 124 pancreatic transplant recipients. Five of the eight patients developed intrapancreatic abscesses and four of the grafts were lost, but one is still functioning. In the three additional cases of pancreatitis, antiviral treatment with foscarnet or ganciclovir was given as soon as signs of CMV pancreatitis were detected. No such grafts were lost during the acute phase. CMV infection was diagnosed in cells from pancreatic juice, by virus isolation, detection of CMV antigen in cells from pancreatic juice or by CMV serology. The signs and symptoms of CMV pancreatitis included fever, general malaise, abdominal pain, diarrhoea, localized peritonitis, hyperamylasaemia, leukopenia and hyperglycaemia. It is recommended that rapid diagnostic procedures for CMV should be carried out when early signs of pancreatitis develop in pancreatic graft recipients. Antiviral treatment should be given when CMV pancreatitis is suspected or diagnosed in order to prevent the development of intrapancreatic abscesses and graft loss.

The mean total serum amylase levels in patients was 3.2 +/- 0.5 mukat/l (+/-SE) before total body irradiation (TBI) prior to bone marrow transplantation of which 50% was due to pancreatic isoamylase and 50% salivary isoamylase. Total serum amylase increased to a maximum of 100.3 +/- 12.3 mukat/l on the first day after TBI and most of this increase was due to an increase in salivary isoamylase (90.0 +/- 12.1 mukat/l). In association with this, all patients had clinical symptoms of parotitis. An increase in pancreatic isoamylase was found in 27% of the patients; however, none of them had clinical symptoms of pancreatitis. Serum amylase levels returned to normal within 5 days after TBI but then decreased to subnormal values, remaining below the normal range for 3 weeks. Pancreatic isoamylase returned to pre-irradiation levels 1.5 months after TBI, while salivary isoamylase remained low for the rest of the observation time. TBI of 7.5 Gy at 26 cGy/min gave significantly lower salivary amylase at 2 days after TBI compared with 10 Gy at 4 cGy/min: 32 +/- 4 versus 76 +/- 13 mukat/l (P less than 0.05). At 2.5 and 6 months after TBI significantly higher total amylase levels were recorded for patients treated with 7.5 Gy of TBI compared with 10 Gy: 2.5 +/- 0.4 and 2.7 +/- 0.3 versus 2.0 +/- 0.5 and 0.8 +/- 0.3 mukat/l, respectively (P less than 0.01, P less than 0.05, respectively). Acute or chronic GVHD did not affect acinar cells in this investigation.

Human pancreatic elastase 1 (E1) is a novel pancreas-specific proteinase that has not yet been investigated after pancreatic transplantation (PTx). Using a recently developed E1 ELISA, we studied the E1 serum curves in 36 type I diabetic patients subjected to PTx with enteric exocrine diversion from the pretransplant value up to 8 years after transplantation (n = 731 samples). A characteristical pattern was observed: following PTx, E1 rose above the normal range to a peak within 6 days and then gradually fell to stabilize after 4-6 weeks at an elevated level (10 ng/ml) for approximately 1 year. Two to 8 years after PTx, E1 levels were still slightly elevated (1-6 ng/ml) in 14/20 patients. During 24 acute rejection episodes, E1 was found not be a sensitive rejection marker during the early postoperative period because of its slow decline from the peak level. However, increasing E1 levels in seven patients more than 2 months after PTx were associated with a variety of lesions to the pancreatic graft, thus suggesting a useful marker indicating exocrine graft damage late after PTx. The slightly elevated levels even years after PTx are most probably due to the non-portal venous drainage of the pancreatic graft.

Fibreoptic bronchoscopy with bronchoalveolar lavage (BAL), transbronchial lung biopsy (TBB) and brushing was performed, in 134 episodes of pulmonary disease in 118 compromised patients. Sixty eight of the patients were infected with immunodeficiency virus type 1 (HIV-1), 18 were renal and pancreas transplant recipients, 7 were liver and 15 were bone marrow transplant recipients, and 10 patients were undergoing immunosuppressive and/or cytotoxic drug therapy. Pneumocystis carinii (PC) was the predominant pathogen in HIV-1 infected patients. It was considered to be the aetiological cause of pneumonia in 54/82 (66%) episodes of lung complications noted in these patients. Cytomegalovirus (CMV) was the most common micro-organism in transplant recipients. CMV pneumonia was diagnosed in 22/42 episodes of pulmonary disease in these patients. CMV was detected by bronchoscopy procedures at a relatively high frequency of 36/82 (44%) episodes in HIV-1 infected patients. However, after analysis of clinical information, cultures from leucocytes and autopsy findings, CMV seemed to be involved in the pathogenicity of pneumonia in only two out of the 36 patients. Bacterial aetiology, including mycobacterial agents, was unusual, but was the major cause of pulmonary infections in 6/10 episodes in patients undergoing extensive immunosuppressive and/or cytotoxic drug therapy. Bronchoscopy was helpful in establishing correct aetiology in 98/134 (73%) episodes of pulmonary disease. Growth of Candida albicans and bacteria should always be viewed sceptically because of the possibility of contamination from colonization in the upper respiratory tract.

The penetration of pefloxacin (400 mg) into pancreatic juice, following a single oral dose, was investigated in five patients subjected to pancreatic transplantation as treatment for insulin-dependent diabetes mellitus. The pancreatic juice was temporarily diverted to the exterior by means of a pancreatic duct catheter. Studies on pure human pancreatic juice were thus made possible. Simultaneous blood and pure pancreatic juice samples were collected at regular intervals for up to 24 h after drug intake. The antibiotic concentrations were determined by bioassay. The average concentration of pefloxacin in pancreatic juice was 100% of that in serum. The mean peak concentration in pancreatic juice was 4.6 +/- 0.9 mg/l (+/- S.E.) and occurred at 2.5 h after drug intake. The decrease in concentration with time was parallel to the serum concentration curve. The concentrations of pefloxacin in pancreatic juice exceeded the MICs of many bacteria associated with pancreatic infections for several hours after administration of a single oral dose.