OBJECTIVE: Postpneumonectomy bronchial stump fistula (PBSF) is a serious complication with a reported incidence between 0 and 12%. The aim of this retrospective study was to investigate the effectiveness of different coverage techniques of the bronchial stump applied in a consecutive series of pneumonectomies in avoiding this particular problem. METHODS: Between 1/87 and 10/97, 129 patients (90 male, 39 female, mean age 57.8 years, range: 15-78 years) underwent pneumonectomy by one surgeon (W.K.). In 14 patients, additional resection procedures were performed (aorta n = 6, vena cava n = 5, thoracic wall n = 3). In all patients with malignancies (n = 123), mediastinal lymphadenectomy was routinely added to the procedure. Bronchial stump closure was performed by means of stapling devices in all patients. Coverage of the bronchial stump was performed with a generous pedicled pericardial flap and concomitant reconstruction of the pericardium with Vicryl mesh (n = 50), with a portion of the posterior pericardium (n = 16), with the azygos vein (n = 12), with surrounding mediastinal tissue (n = 25), with pleura (n = 16), or with intercostal muscle flap (n = 3); no coverage at all was performed in seven patients. In all patients with high risk for development of PBSF, i.e. patients who received any form of neoadjuvant therapy or had extended resections, the pericardial flap technique was used. RESULTS: Perioperative mortality was 5.4% (n = 7) and five patients (3.9%) experienced significant perioperative complications, with one of them directly related to the method of bronchial stump coverage (cardiac tamponade due to the use of a too small Vicryl mesh for reconstruction of the pericardium). Follow-up was 96.1% complete (five patients were lost to follow-up). Fourty-seven patients (36.4%) died late after operation (mean 19+/-13 months, median 17 months), mainly due to recurrence of their underlying malignant disease. PBSF occurred in one patient only (0.8%), 2 weeks after operation (coverage with pleura). No PBSF was seen in the long term follow-up period. CONCLUSION: Coverage of the bronchial stump contributes to a low incidence of PBSF. In view of the fact, that this serious complication was completely avoided in the pericardial flap group (used in patients with expected higher risk for PBSF), this particular technique seems to offer the best results.

Adolescent↗

PubMed1999

Noninvasive monitoring of peak filling rate with acoustic quantification echocardiography accurately detects acute cardiac allograft rejection.

BACKGROUND: Acute cardiac allograft rejection is associated with early diastolic dysfunction. The development of chronic rejection is dependent on the frequency and severity of acute rejection episodes. Therefore, early diagnosis and therapy influence long-term survival significantly. For the first time, acoustic quantification, a new echocardiographic technology for on-line measurement of cardiac volumes and their changes, facilitates quantitative assessment of systolic and diastolic function noninvasively. METHODS: Since May 1996, all consecutive patients after cardiac transplantation (n = 94) underwent 475 endomyocardial biopsies and the same number of echocardiographic studies within 6 hours after biopsy before the histological results were available. RESULTS: Nineteen patients showed 23 episodes of acute rejection (ISHLT > or = 2). There was a significant decrease in left ventricular peak filling rate [PFR: end-diastolic volume (EDV)/ second) as a parameter of diastolic function during rejection (2.9 +/- 0.4, n = 23) as compared to PFR measured under nonrejection status (4.5 +/- 0.8; n = 452; p < 0.0001). Most importantly we found that in these 19 patients showing rejection, the PFR was normal in the last examination before rejection, but was significantly reduced during rejection (2.9 +/- 0.4 vs 4.5 +/- 0.7; n = 23, p < 0.0001). After successful rejection therapy, PFR again normalized in all patients, with the exception of 1 patient with steroid-refractory humoral rejection. We calculated sensitivity and specificity for several cutpoints for the event "first rejection" in 15 patients and plotted them in a receiver operating characteristic curve, showing that a PFR > or = 4.0 EDV/second is never associated with treatable rejection. A decrease of PFR of more than 18% from its prevalue of the last biopsy with no rejection increases the accuracy for the diagnosis of rejection significantly. CONCLUSIONS: We conclude that diastolic dysfunction during acute cardiac allograft rejection can be accurately detected by noninvasive measurement of peak filling rate with acoustic quantification echocardiography. Monitoring of this parameter provides reliable discrimination between treatable and nontreatable rejection.

Acute Disease↗

PubMed1999

Comparison between mycophenolate mofetil- and azathioprine-based immunosuppressions in clinical lung transplantation.

BACKGROUND: The aim of the study was to assess the impact of mycophenolate mofetil (MMF) on the early phase after lung transplantation. PATIENTS AND METHODS: Thirty-eight consecutive patients between November 1994 and January 1997 were treated with cyclosporine, prednisolone, antithymocyte globuline induction therapy, and either MMF (n = 21) or azathioprine (Aza) (n = 17). Four patients from the MMF group and 2 patients from the Aza group were intubated and in the ICU prior to transplantation. Demographic data and primary diagnosis were comparable. MMF was administered at a dosage of 2 gm/day whereas Aza was initiated at 2 mg/kg/day and adapted by leukocyte count. Three-month survival and incidence of rejections and infections were compared. RESULTS: Six-month survival in the MMF group was 76% compared to 65% in the Aza group (n.s.). The mean number of acute rejection episodes in the MMF and Aza group were 0.29+/-0.10 and 1.53+/-0.29 (p<0.01) respectively. Transbronchial biopsy (TBB) results > or =grade 2 ISHLT were seen in 10% of MMF and in 43% of Aza-treated patients; completely free from rejection were 17 MMF and 3 Aza patients. The mean number of infections per patient in the MMF and Aza group were 1.57+/-0.29 and 2.29+/-0.40 respectively, bacterial (1.10 vs. 1.71), viral (0.35 vs. 0.33), and fungal (0.14 vs. 0.24) infections were the same in both groups. CONCLUSIONS: These data result suggest that mycophenolate mofetil therapy is more effective in preventing rejection episodes in patients early after lung transplantation than therapy with azathioprine. We therefore conclude that MMF is a safe and effective drug to optimize immunosuppressive therapy in the early phase after lung transplantation.

Adolescent↗

PubMed1999

The erythrocyte-perfused "working heart" model: hemodynamic and metabolic performance in comparison to crystalloid perfused hearts.

A brief period of ischemia was used to evaluate an erythrocyte-enriched Krebs-Henseleit (KH) buffer (n=8) compared to KH only (n=8) in an isolated working rabbit heart. Experimental protocol was as follows: preischemic baseline, 5 min of global ischemia followed by 45 min of reperfusion. Preischemic heart rate was identical, coronary flow was significantly lower (2.7 versus 5.6 mL/min/g wet wt, p<0.01), the other hemodynamic and biochemical values were significantly higher in erythrocyte-perfused hearts: aortic flow 23.5 versus 12.0, p<0.01; cardiac output 26.2 versus 17.6, p<0.01; all in mL/min/g wet wt; dp/dt max 1286 versus 997 mmHg/s, p<0.01; myocardial oxygen consumption 3.5 versus 2.3 micromol/min/g wet wt, p<0.05. During early reperfusion, in the erythrocyte-perfused hearts, coronary flow further increased (p<0.003), the other hemodynamic parameters returned to baseline values in both groups. High-energy phosphates showed significantly higher values (ATP 2.0+/-0.1 versus 1.3+/-0.1, p<0.05; CrP 2.0+/-0.2 versus 1.6+/-0.1, p<0.05 all in micromol/g wct wt), water content was significantly lower (81% versus 74%, p<0.05) in erythrocyte-perfused hearts. It can be concluded that the erythrocyte-perfused working heart model provides excellent oxygenation, leading to superior hemodynamic and metabolic performance. Additionally, in the erythrocyte-perfused hearts preservation of coronary flow reserve underlines the physiological competency of this preparation.

Adenine Nucleotides↗

PubMed1999

Post-transplant acute myeloid leukemia (PT-AML).

Acute myeloid leukemia following organ transplantation (PT-AML) is a rare event with only a few published cases in the literature. We present three patients who developed AML (FAB M1, M5, M4) after renal, double lung or liver transplantation. Molecular analysis detected a t(9;11) in one patient and documented the recipient origin of AML in a second patient. All patients were treated with chemotherapy. Immunosuppression was reduced to cyclosporin A (CsA) and prednisone in two patients and to prednisone alone in one patient. Two patients achieved a complete remission (CR), with a remission duration of 4.6 months in one patient, the other patient died from septicemia after 15.2 months in CR. One patient was refractory to chemotherapy and died from septicemia. This report together with the documented cases in the literature suggests that PT-AML (1) develops after a median interval of 5 years after transplantation with variable latency (range, <1-17 years); (2) is heterogeneous with respect to FAB classification; (3) shows chromosomal and molecular changes typical of therapy-related AML (t-AML: -7, +8, 11q23, inv16, t(15;17)); (4) standard chemotherapy is feasible after reduction of immunosuppression and produces a CR rate of 56% with a median remission duration of 4.6 months and an overall survival of 2.6 months; (5) the major complications are early death (25%), gram-negative septicemia, progressive disease or relapse. This review provides diagnostic and therapeutic experiences and guidelines for the management of this increasing group of post-transplant patients.

Acute Disease↗

PubMed1999

IgG subclass reactivity to human cardiac myosin in cardiomyopathy patients is indicative of a Th1-like autoimmune disease.

Studies performed in mice together with the demonstration of increased levels of heart-specific autoantibodies, cytokines and cytokine receptors in sera from cardiomyopathy (CMP) patients argued for a pathogenic role of autoimmune mechanisms in CMP. This study was designed to analyse the presence of IgG anti-heart antibodies in sera from patients suffering from hypertrophic and dilatative forms of CMP as well as from patients with ischaemic heart disease and healthy individuals. Patients' sera were analysed for IgG reactivity to Western-blotted extracts prepared from human epithelial and endothelial cells, heart and skeletal muscle specimens as well as from Streptococcus pyogenes. The IgG subclass (IgG1-4) reactivity to purified human cardiac myosin was analysed by ELISA. While sera from CMP patients and healthy individuals displayed comparable IgG reactivity to a variety of human proteins, cardiac myosin represented the prominent antigen detected strongly and preferentially by sera from CMP patients. Pronounced IgG anti-cardiac myosin reactivity was frequently found in sera from patients with dilatative CMP and reduced ventricular function. ELISA analyses revealed a prominent IgG2/IgG3 anti-cardiac myosin reactivity in CMP sera, indicating a preferential Th1-like immune response. Elevated anti-cytomegalovirus, anti-enterovirus IgG titres as well as IgG reactivity to nitrocellulose-blotted S. pyogenes proteins were also frequently observed in the group of CMP patients. If further work can support the hypothesis that autoreactivity to cardiac myosin represents a pathogenic factor in CMP, specific immunomodulation of this Th1- towards a Th2-like immune response may represent a promising therapeutic strategy for CMP.

Adolescent↗

PubMed1999

Long-term in vivo left ventricular assist device study for 284 days with Gyro PI pump.

A totally implantable centrifugal artificial heart has been developed. The plastic prototype, the Gyro PI 601, passed 2 day hemodynamic tests as a functional total artificial heart (TAH), 2 week screening tests for anti-thrombogenecity, and a 1 month system feasibility study. Based upon these results, a metallic prototype, the Gyro PI 700 series, was subjected to long-term in vivo left ventricular assist device (LVAD) studies of over 1 month. The Gyro PI 700 series has the same inner dimension and same characteristics of the Gyro PI 601 such as an eccentric inlet port, a double pivot bearing system, and a magnet coupling system. The PI metallic pump is also driven with the Vienna DC brushless motor actuator like the PI 601. The pump-actuator package was implanted in 3 calves in the preperitoneal space, bypassing from the left ventricular (LV) apex to the descending aorta. Case 1 achieved a 284 day survival. Case 2 was euthanized early at 72 postoperative days as a result of the functional obstruction of the inlet port due to the excessive growth of the calf. There was no blood clot inside the pumps of either case. Case 3 is on-going (22 days on July 24, 1998). During these periods, all cases showed no physiological abnormalities. In conclusion, the PI 700 series pump has excellent results as a long-term implantable LVAD.

Animals↗

PubMed1999

Valve-preserving treatment of Ebstein's anomaly: perioperative and follow-up results.

BACKGROUND: Ebstein's anomaly is a rare congenital cardiac defect of the tricuspid valve (TV) leading to severe tricuspid insufficiency (TI). METHODS: In ten patients, 6 adults (39-53 years) and 4 children (5-10 years), operated between 1989 and 1995 echocardiography was performed pre and post repair and at follow-up. Patients were assessed in our institution at two cut-off points, resulting in a mean first follow-up of 17 +/-15 months and a mean second follow-up of 53+/-23 months. All patients had additional congenital cardiac defects (ASD,VSD). In all patients the TV was repaired by techniques described by Carpentier et al. with some modifications. The goal of this reparative attempt is to mobilize restricted leaflet tissue and aid coaptation through implantation of a ring. RESULTS: Echocardiographically we were able to identify significant characteristics for the successful repair of Ebstein's anomaly. The severity of the disease is represented by the size and function of the right ventricle and the atrialized chamber, the most advanced cases exhibiting a dilated right ventricle with poor contractility. There was severe preoperative TI ( mean grade 3.2 +/- 0.3). Postoperatively TI was significantly reduced to a mean grade of 2+/-0.2. 60% of the patients demonstrated an improvement in the ratio of atrialized chamber to functional right ventricle. Right-ventricular function was improved, the mean score being 2.8+/-0.1. At follow-up I and II right-ventricular function and tricuspid insufficiency was improved in most patients and all patients benefited in quality of life. CONCLUSION: These results suggest that surgical correction should not be delayed until severe right heart failure develops as, particularly in children, good results are achieved, improving the quality of life.

Adult↗

PubMed1999

Prognostic role of cyclin D1 in lung cancer. Relationship to proliferating cell nuclear antigen.

We developed an immunohistochemical assay specific for cyclin D1 and suitable for formalin-fixed and paraffin-embedded sections, to evaluate cyclin D1 expression in a group of 135 surgically resected lung-cancer patients for the purpose of investigating the prognostic role of this protein in lung cancer. In addition, we compared cyclin D1 expression with the expression of proliferating cell nuclear antigen (PCNA), considered to be a reliable index of the proliferation rate. We found cyclin D1 expressed in more than 60% of the neoplastic cells in 26.5% of our specimens. A total of 24.5% of the specimens showed cyclin D1 expression in a percentage of cells ranging from 30 to 60%; 36.7% of the specimens expressed cyclin D1 in less than 30% of the cells; and 12.2% of the specimens expressed cyclin D1 in less than 1% of the evaluated cells. Western blot analyses confirmed the specificity of this assay by correlating statistically in a highly significant fashion with the immunohistochemical results (P = 0.0003). Furthermore, we found a direct relationship between cyclin D1 and PCNA immunodetection (P = 0.0004), which correlated cyclin D1 overexpression with a higher tumor proliferation rate. When we analyzed our data statistically, cyclin D1 expression was found to be a negative prognostic marker (P < 0.00005) whose expression correlates with a shorter patient survival time.

Adenocarcinoma↗

PubMed1999

Mycophenolic acid influences T helper 2 (Th2) cytokine induced expression of intercellular cell adhesion molecule-1 (ICAM-1) on human endothelial cells.

A possible synergistic effect of mycophenolic acid (MPA) and the immunosuppressive cytokines IL-4, IL-10 and IL-13 was investigated in human umbilical vein endothelial cells (HUVEC). These cytokines, which are produced by Th2-lymphocytes, were shown to induce the expression of vascular cell adhesion molecule-1 (VCAM-1) and production of IL-6 in endothelial cells. In this study we found IL-4 to induce both intercellular cell adhesion molecule-1 (ICAM-1) and VCAM-1 expression, whereas IL-13 induced VCAM-1 only. The surface expression of E-selectin was not influenced by any of the cytokines tested. MPA on its own led to statistically significant ICAM-1 expression on HUVEC. The combination of MPA with IL-4 led to a significant ICAM-1 expression in an additive manner compared to the cytokine alone. In contrast, MPA neither induced VCAM-1 nor did it influence the effects of IL-4 and IL-13 on VCAM-1 expression. A clinically relevant concentration of mycophenolic acid (10 micromol/l) decreased intracellular guanosine-5'-triphosphate (GTP) levels significantly. Since intracellular nucleotides are responsible for the glycosylation of proteins, a disturbance of the endothelial nucleotide balance could be responsible for the effects of MPA on ICAM-1. Guanine and guanosine prevented and partially reversed the actions of MPA, on both intracellular GTP and ICAM-1 expression, which strongly implies that MPA by interfering with nucleotide metabolism, affects the adhesive properties of endothelial cells, and by acting synergistically with IL-4 probably influences Th2 cytokine effects.

Cell Adhesion Molecules↗

PubMed1999

Alterations of endothelial nucleotide levels by mycophenolic acid result in changes of membrane glycosylation and E-selectin expression.

The effect of the inhibitor of inosine-5'-monophosphate dehydrogenase (IMPDH), mycophenolic acid, on intracellular nucleotides and the synthesis of cellular glycoproteins was evaluated in human umbilical vein endothelial cells. A clinically attainable concentration (10 micromol/l) of mycophenolic acid decreased guanosine-5'-triphosphate (GTP) levels significantly and led to a strong elevation of uridine-5'-triphosphate (UTP), whereas intracellular adenosine-5'-triphosphate (ATP) pools remained unaffected. The staining of the endothelial cell membranes with lectins specific for fucose and mannose (Ulex europaeus- and Galanthus nivalis agglutinin, respectively) was reduced, reflecting an inhibition of fucose and mannose incorporation into endothelial glycoproteins. The surface expression of E-selectin, an important determinant for leuko-endothelial interactions decreased significantly. Guanine and guanosine prevented the actions of mycophenolic acid and reversed the drug-induced decrease in GTP and its associated effects. The findings that mycophenolic acid produces alterations in the formation of glycoproteins and in the membrane architecture are indicative of metabolic lesions induced by an agent that depresses guanine nucleotide synthesis through inhibition of IMPDH. The pronounced reduction of E-selectin surface expression on endothelial cells accompanied by changes of endothelial cell fucosylation, a prerequisite for the contact with lymphocytic L-selectin, indicates an inhibitory effect of mycophenolic acid in the rolling phase of leukocyte recruitment and strongly implies a new and additional immunosuppressive mechanism of this agent.

Adenosine Triphosphate↗

PubMed1999

A simple HPLC method for monitoring mycophenolic acid and its glucuronidated metabolite in transplant recipients.

Mycophenolic acid (MPA) is nowadays in broad clinical use as a substitute for azathioprine. An immunoassay for MPA recently received approval for clinical applications. The high performance liquid chromatography (HPLC) assay for measuring MPA and its glucuronide conjugate (MPAG) we describe here is not only rapid and simple but also extremely sensitive at plasma levels obtained during standard immunosuppressive regimens. The determination of MPAG is possible without any change of the chromatographic conditions (detection wavelength of 214 nm, mobile phase: acetonitrile and 50 mmol/l o-phosphoric acid (50:50, V/V), run time: 15 min). The required equipment is a standard HPLC system including a simple UV-detector. Sample volume of 400 microl is required for both determinations. Detection limit is 0.25 micromol/l for MPA and 5 micromol/l for MPAG. Linearity is excellent for serial dilutions (0.5-25 micromol/l for MPA, 25-500 micromol/l for MPAG) and high accuracies favour the method described. More than 2000 plasma samples tested for MPA in patients after heart transplantation within one year and more than 500 samples for MPAG underline the clinical applicability of this assay.

Blood Chemical Analysis↗

PubMed1998

Combined heart and kidney transplantation using a single donor: a single center's experience with nine cases.

BACKGROUND: Simultaneous double-organ transplants comprising various organ combinations have become frequent. The purpose of this article is to report on a single center's experience of simultaneous heart and kidney transplantation (HNTX) with particular emphasis on selection criteria and patient outcome. METHODS: From September 1990 to January 1997, nine patients underwent HNTX, receiving both grafts from a single donor selected on ABO blood group compatibility and a negative lymphocytotoxic crossmatch, but without regard to HLA-antigen matching. RESULTS: One patient died of acute humoral rejection of the cardiac graft shortly after surgery. Eight patients are alive and well and have normal cardiac and renal function at a mean follow-up of 44+/-28 months. CONCLUSION: HNTX offers a compelling therapeutic solution in the treatment of advanced cardiac and renal failure in carefully selected patients. Because the heart and kidney rejection episodes were independent of each other, rejection surveillance should be carried out separately for each transplanted organ.

Adult↗