Increased frequency of posttransplant lymphomas in patients treated with cyclosporine, azathioprine, and prednisone.

We have documented seven B cell lymphomas over a six-month period in 132 (5.3%) kidney and heart allograft recipients immunosuppressed with cyclosporine, azathioprine, and prednisone (triple therapy). This is a significant increase (P less than 0.0001) over the number of such tumors seen by us previously. Only 2 lymphomas had occurred in 669 cadaver and 29 living-related kidney allografts treated with azathioprine and prednisone alone (0.3%). In 160 cadaver kidney recipients treated with cyclosporine and prednisone there have been no lymphomas. Similarly in 14 living-related kidney recipients who were transplanted since the introduction of triple therapy for cadaver grafts, but continued to receive only azathioprine and prednisone, no lymphomas occurred. There seemed to be a clear relationship between this increase and the use of triple therapy. This led us to examine other possible contributing factors. A case control study has not shown any other factor that differs in patients in whom lymphomas developed. We have only been able to demonstrate Epstein Barr virus nuclear antigen in the cells of one tumor. Four of these 7 tumors were monoclonal, one polyclonal, and two indeterminate. All patients had their immunosuppression withdrawn and six received intravenous acyclovir. Three patients have shown some response but four patients died. Triple therapy is being used by many centers to reduce the level of cyclosporine toxicity. We wish to sound a note of caution that this may result in an increased incidence of posttransplant lymphomas.

Successful pulmonary thromboendarterectomy in a patient with Klippel-Trenaunay syndrome.

Klippel-Trenaunay syndrome (KTS) is a congenital disorder characterized by a triad of cutaneous vascular nevi, soft tissue or bony hypertrophy, and varicose veins or venous malformations involving one or more extremities. An incidence of venous thromboembolism of up to 22% has been reported in this disorder. Also reported is the development of chronic thromboembolic pulmonary hypertension (CTEPH) and subsequent death from right ventricular failure. We report the first patient with KTS to undergo a successful pulmonary thromboendarterectomy for CTEPH.

Cytokine and complement levels in patients undergoing cardiopulmonary bypass.

Patients undergoing cardiopulmonary bypass are known to develop whole body inflammation that often results in a characteristic syndrome early postoperatively. This phenomenon has been attributed to complement activation caused by exposure of blood to the foreign surfaces of the cardiopulmonary bypass circuit. It has been unknown if cytokines are involved. Plasma levels of complement activation products (C3a, C4a, C5a, and C5b-9), interleukins (IL-1 beta, IL-2, IL-4, and IL-6), and tumor necrosis factor-alpha were measured at multiple time points before, during, and after cardiopulmonary bypass in 29 patients. No significant increase over preinduction levels was seen in the cytokines except for IL-6, which was significantly increased during cardiopulmonary bypass (p < 0.001), reaching a maximum 3 hours after cardiopulmonary bypass. C3a, C4a, and C5b-9 levels were significantly elevated during cardiopulmonary bypass (p < 0.001), with maximum C5b-9 levels preceding the IL-6 elevation. Heparin coating of the cardiopulmonary bypass circuit was not demonstrated to have an effect on activation of complement or cytokine production. There was no statistically significant correlation among hemodynamic variables or pulmonary function and complement, interleukin, or tumor necrosis factor-alpha levels. These results confirm the presence of complement activation and demonstrate the production of IL-6 after the generation of C5b-9 in patients undergoing cardiopulmonary bypass. IL-6 may contribute to adverse systemic reactions associated with cardiopulmonary bypass.

Lung reperfusion injury is reduced by inhibiting a CD18-dependent mechanism.

CD18 designates a component of a leukocyte surface glycoprotein complex that mediates endothelial adherence. To determine whether interference with CD18-dependent leukocyte adhesion modifies reperfusion injury, we transplanted 16 canine left lungs after 4-hour preservation with modified Euro-Collins solution. Anti-canine CD18 monoclonal antibody (R15.7, 1 mg/kg, intravenously) was administered to eight lung recipients 5 minutes before reperfusion; eight control recipients were not treated. Ventilation was identical in donor-recipient pairs (tidal volume, 600 ml; fraction of inspired oxygen, 0.53; positive end-expiratory pressure, 5 cm H2O). Respiratory and inert gas exchange and hemodynamics were assessed in left lung donors one-half hour after right lung exclusion and in allograft recipients at 0.5, 1.5, 2.5, 3.5, and 6.0 hours after transplantation and right lung exclusion. Reperfusion injury was evident in both recipient groups at 6 hours after transplantation, but inert gas shunt was lower in monoclonal antibody-treated dogs (13% +/- 6%) than in controls (30% +/- 17%, p < 0.05); comparisons of arterial blood gases in monoclonal antibody recipients (PaO2, 209 +/- 83 mm Hg; PaCO2, 45 +/- 7 mm Hg) and controls (PaO2, 108 +/- 54, p < 0.05; PaCO2, 64 +/- 25, p < 0.05) at 6 hours indicated that monoclonal antibody administration distinctly improved respiratory gas transfer. Gravimetric lung water was less in monoclonal antibody recipients (5.78 +/- 1.01 ml/kg) than in controls (8.02 +/- 1.90 ml/kg, p < 0.05), but lung compliance at 6 hours was equally reduced in monoclonal antibody recipients (40 +/- 9 ml/cm H2O) and in controls (39 +/- 7 ml/cm H2O, p = not significant). Pulmonary vascular resistance doubled immediately after transplantation but was identical in monoclonal antibody-treated dogs (890 +/- 168 dynes.sec.cm-5) and in controls (874 +/- 162 dynes.sec.cm-5, p = not significant) at 6 hours. We conclude that inhibition of CD18-dependent leukocyte function attenuates the development of both shunt and abnormal respiratory gas exchange in lung reperfusion injury. Significant physiologic abnormalities occurred despite R15.7 treatment and may represent inadequate preservation or the effect of CD18-independent adhesion mechanisms.

Survival in lung reperfusion injury is improved by an antibody that binds and inhibits L- and E-selectin.

The selectins are a three-member family of leukocyte, platelet, and endothelial cell adhesion proteins that mediate leukocyte traffic into normal and inflamed tissues. P-selectin is expressed by endothelial cells and platelets, E-selectin by endothelial cells, and L-selectin by circulating leukocytes. To determine if selectin-mediated leukocyte adhesion influences the development of lung reperfusion injury, we studied hemodynamics and respiratory and inert gas exchange in sheep subjected to 3-hour in situ left lung ischemia followed by 6-hour left lung reperfusion with the right lung excluded. Ten minutes before reperfusion, eight animals received EL-246 (1 mg/kg intravenously), a novel antihuman selectin antibody that recognizes and blocks both L- and E-selectin and cross-reacts in sheep. Eight control animals with ischemia received no treatment, whereas three received an isotype-matched antihuman L-selectin antibody that does not cross-react in sheep (DREG-56, 1 mg/kg intravenously). Eight sham control sheep underwent an identical operative procedure but were never subjected to ischemia. Volume-cycled, pressure-limited (20 cm H2O) mechanical ventilation was consistent in all animals throughout the experiment. Six-hour survival in EL-246 recipients (100%) was significantly higher than in either ischemic control sheep (37.5%) or DREG-56 recipients (33.3%), but gravimetric lung water was equivalent in EL-246 recipients (5.9 +/- 1.7 ml/kg), ischemic control sheep (8.3 +/- 3.0 ml/kg), and DREG-56 recipients (9.1 +/- 2.6 ml/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Volume reduction surgery in the native lung after single lung transplantation for emphysema.

The natural history of emphysema suggests that progression of disease in the native lung may contribute to late deterioration in respiratory function after single lung transplantation. In this report, we describe our experience with unilateral volume reduction surgery in three single lung transplant recipients with emphysema. Each patient had had a late decline in lung function with a recurrence of symptoms. Chest radiographs demonstrated hyperinflation of the native lungs with encroachment on the grafts. Serial pulmonary function testing documented progressive reduction in expiratory flows with increases in residual volumes. Exercise testing confirmed severe intolerance to maximal exercise. Unilateral volume reduction surgery was undertaken at 36, 39, and 55 months after transplantation without incident. Radiographs obtained after the procedures demonstrated restoration of normal diaphragmatic contour, decreased aeration of the native lungs, and improved inflation of the allografts. Exercise testing at 3 months documented a mean improvement in maximal oxygen consumption of 35%. Expiratory flows improved by a mean of 60%. Quantitative ventilation and perfusion scans, however, were essentially unchanged. This experience suggests that unilateral volume reduction surgery may be considered as an alternative strategy in single lung transplant recipients with emphysema who exhibit clinically significant functional deterioration. Differentiation of the adverse effects of hyperinflation of the native lung from other potential causes of late deterioration might not be necessary but may be predictive of the degree of functional improvement after volume reduction. The relief of thoracic overdistention seems to play a primary role in the improvement pulmonary function.

Lung transplantation without the use of antilymphocyte antibody preparations.

Survival, infection, and rejection rates and functional data are reported in 35 lung recipients treated with triple-drug immunosuppression without antilymphocytic antibody therapy. Early mortality (less than 60 days) was 6%. Thirty recipients (86%) are alive, with a mean follow-up period of 16 months (range, 1 to 36 months). Actuarial survival was 91% at 1 year and 83% at 2 years. Thirty-seven infections occurred in 24 patients. Actuarial freedom from infection was 61% at 3 months and 27% at 1 year. Only one patient died of infection (aspergillosis). Thirty-six episodes of acute rejection were treated in 23 patients. Time to first rejection was 14 +/- 7.8 days. Actuarial freedom from acute rejection was 36% at 2 months. Significant functional improvement was evident in all operative survivors. Pulmonary function and exercise performance data in patients without bronchiolitis obliterans remain stable 1 year after transplantation. We conclude that the use of triple-drug immunosuppression without antilymphocytic antibody preparations in lung transplantation provides effective immunosuppression with a low risk of serious infectious complications.

Techniques for bronchial anastomosis.

BACKGROUND: Many techniques have been described to optimize the construction of the bronchial anastomosis in lung transplantation. Over the past 60 months we have performed 86 bronchial anastomoses in 70 patients receiving single lung or bilateral single lung transplants. METHODS: No anastomosis was wrapped and no attempt was made at revascularization of bronchial arteries. A continuous nonabsorbable suturing technique was used in all cases. Standard triple-drug immunotherapy with cyclosporine, azathioprine, and prednisone (starting at day 7) was used for each patient. RESULTS: There were no anastomotic leaks, and seven stenoses were identified in five patients (7%). All complications were managed conservatively with stenting, and there were no related deaths. Mean time to stent placement was 109 days. One patient had bilateral stents placed prophylactically during an episode of severe infection for questionable anastomotic viability but without evidence of airway necrosis or obstruction. This patient died of infection at 16 days. Another patient died with stents in place at 71 days. In the four remaining patients, all stents have been removed after a mean of 310 days. These patients were followed up with serial bronchoscopy and were without evidence of recurrent obstruction at 2, 34, 35, and 36 months. Six of seven stenoses occurred in patients with cystic fibrosis. In each patient where stenosis developed the anastomosis was telescoped. Since abandoning the telescoping technique in the remaining 50 anastomoses (14 in patients with cystic fibrosis), no dehiscence or stenosis was encountered. CONCLUSIONS: These data suggest that elaborate techniques aimed at construction of the bronchial anastomosis are not necessary. Moreover, attempts at telescoping may be detrimental. Patients with cystic fibrosis may be a population at higher risk for anastomotic complications. Airway complications can be managed conservatively with good results and little risk to the patient.

Primary pulmonary artery sarcoma: a report of six cases.

Pulmonary artery tumors are rare and a frequently overlooked cause of pulmonary artery occlusion. The presentation is one of progressive pulmonary dysfunction and right ventricular failure. The diagnosis seldom is made preoperatively. We report 6 cases of primary sarcoma of the pulmonary artery identified at operation, which were treated surgically. Resection with or without adjuvant therapy currently offers the only chance for survival. Emphasis must be placed on earlier identification of these tumors.

Pulmonary thromboendarterectomy combined with other cardiac operations: indications, surgical approach, and outcome.

BACKGROUND: Patients with pulmonary hypertension due to chronic thromboembolic disease benefit from pulmonary thromboendarterectomy. A subset of these patients present with concomitant coronary or valvular disease. METHODS: From July 1990 to July 2000, 90 patients (68 males, 22 females, mean age 68 years) with pulmonary vascular resistance (PVR) ranging from 297 to 2261 dynes x sec x cm(-5) underwent pulmonary thromboendarterectomy in conjunction with coronary bypass grafting (59 patients), coronary artery bypass grafting/foramen ovale closure (24 patients), tricuspid annuloplasty (3 patients), mitral valve repair (2 patients), and aortic valve replacement (2 patients). The perioperative and hemodynamic outcomes of these patients were compared with the cohort of 1,100 isolated pulmonary thromboendarterectomies performed at our institution during this time. RESULTS: Overall perioperative survival (93.3%; 84 of 90 patients) and mean diminution in PVR (521 dynes x sec x cm(-5)) for patients undergoing combined operations were similar to those undergoing pulmonary thromboendarterectomy alone (94.2% survival; 1034 of 1100 patients; 547 dynes x sec x cm(-5) mean PVR reduction). Although patients undergoing combined operations were older (mean age 68 vs 50 years, p < 0.0001), had longer hospital stays (median 14 vs 9 days), and had worse left ventricular function (mean preoperative cardiac output 3.1 vs 4.4, p < 0.0001), there was no difference in cross-clamp time, resolution of tricuspid regurgitation, or postoperative systolic function between these two groups. CONCLUSIONS: Pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension may be performed safely in conjunction with other cardiac operations. Older patients evaluated for pulmonary thromboendarterectomy should be screened for concomitant coronary and valvular disease.

Reoperative pulmonary thromboendarterectomy.

BACKGROUND: Recurrent symptomatic pulmonary hypertension is uncommon after primary pulmonary thromboendarterectomy (PTE). We reviewed our experience with patients undergoing repeat PTE to determine the risk factors for recurrent disease, and the selection criteria, relative risks, and functional outcomes of reoperative PTE. METHODS: Since 1990, 13 of 870 (1.5%) patients underwent reoperative PTE at our institution. These 7 men and 6 women (mean age 38.6 years) were contrasted with the most recent 225 patients (111 men, 114 women, mean age 52.7 years) who underwent primary PTE for whom complete hemodynamic data are available. The preoperative evaluation of all patients was similar. Pulmonary hemodynamic data and outcome measures were compared between groups. RESULTS: Of 13 reoperated patients: 69% (9/13) had their primary operation at another institution, 54% (7/13) initially underwent unilateral PTE, 38% (5/13) had identifiable coagulation disorders, 38% (5/13) had ineffective caval filtration, 31% (4/13) had suboptimal anticoagulation management, and 31% (4/13) had complete unilateral pulmonary artery obstruction. The mean interval to reoperation was 5.2 years (range 0.7 to 10.9 years). All control patients underwent bilateral PTE using hypothermic circulatory arrest. Operative mortality was 7.7% (1/13) with reoperation vs 8.4% (19/225) in controls. No difference (p = NS) was observed between groups in the preoperative pulmonary artery pressure (PAP) or pulmonary vascular resistance; however, the control group had a significantly (p < 0.05) greater reduction in the postoperative PAP (46/19, mean 28 mm Hg vs 59/23, mean 35 mm Hg) and PVR (271 +/- 172 vs 399 +/- 154 dynes/s/cm(-5)) compared with the redo group. No substantial difference in morbidity or functional outcomes was observed between groups. CONCLUSIONS: Reoperative PTE can be performed with a perioperative risk comparable with primary PTE, although the improvement in pulmonary hemodynamics is not as favorable. Bilateral primary operation, effective caval filtration, and vigilant anticoagulant management would prevent the need for most reoperative PTEs.

Characteristics of the primary lesion of malignant melanoma as a guide to prognosis and therapy.

The histologic materal from the original lesion of 113 patients suffering from Clinical Stage I and Clinical Stage II malignant melanomas were reviewed in an attempt to correlate depth of invasion with prognosis and to test whether or not current methods of microstaging were a valid guide to therapy. Both the microstaging methods of Clark and Breslow were eminently successful in indicating the prognosis of the patient, but were of no greater utility than other histologic parameters such as mitotic activity, perineural, vascular, or lymphatic invasion, or the presence of superficial ulceration. The value of elective node dissection for the treatment of primary malignant melanoma is uncertain. Deterents against empiric dissection are its low yield of occult metastases, its inability to prevent recurrence in a substantial portion of patients independent of the status of the nodes, and the difficulty in demonstrating an improved survival rate when this method of therapy is employed. Neither Clark's nor Breslow's methods or microstaging appeared to yield adequate criteria by which to choose node dissection. A simplified method of microstaging is proposed utilizing well defined anatomic levels, and yields statistically valid criteria for the performance of elective node dissection. Using this method, elective node dissection is advocated solely for those tumors that clearly invade the reticular dermis. Patients with tumors restricted to the papillary dermis do not appear to be benefited by empiric node dissection.

Ventriculographic features predictive of surgical outcome for left ventricular aneurysm.

Although clinical and hemodynamic stability predicted outcome very well when left ventricular aneurysm was electively resected in 25 patients (95% survival), more discriminate criteria were essential for 20 patients undergoing urgent operation for severe myocardial decompensation (50% survival). Three methods of ventriculographic analysis primarily sensitive to the function of the non-aneurysmal left ventricle were evaluated. These methods separated patients undergoing urgent operation into a population with high operative risk (less than 18% survival) and a population with low operative risk (greater than 82% survival). These criteria also separated 15 patients undergoing operation within three months of myocardial infarction into a group with excellent prognosis (greater than 85% survival) and a group with poor prognosis (less than 15% survival). The high operative risk in patients undergoing urgent operation or operation within three months of myocardial infarction, when non-aneurysmal ventricular function is poor, may be too high; it should be undertaken only under unusual circumstances.

Heparin and modified heparin inhibit complement activation in vivo.

Heparin regulates C activity in vitro, but has not been examined for this activity in vivo. The present study investigated the ability of commercial heparin and derivatized (N-desulfated, N-acetylated) heparin (Hep-NAc) with greatly diminished anticoagulant activity to inhibit C activation in guinea pigs. Catheters were placed in the right atrium of guinea pigs and kept patent with frequent saline flushes. The next day, heparin, Hep-NAc, or saline was given and 2.5 min later cobra venom factor or saline was given. Blood was drawn at intervals and assayed for total hemolytic C, C3 hemolytic activity, free hemoglobin, and activated partial thromboplastin time. Total hemolytic C and C3 activity decreased less rapidly in heparin- and Hep-NAc-pretreated animals than in non-pretreated animals, indicating that both heparins inhibited C activation. Heparin and Hep-NAc also inhibited cobra venom factor-induced hemolysis. This study demonstrates that commercial heparin and modified heparin inhibit C activation in vivo. This represents an important step in the development of an oligosaccharide drug to regulate C activation.

Use of autoperfusion for distant procurement of heart-lung allografts.

Heart-lung transplantation has been limited to on-site organ procurement because current methods of lung preservation are unreliable for periods in excess of one hour. A method of dynamic heart-lung preservation has been evaluated as a possible means for distant procurement for human transplantation. Canine and bovine heart-lung blocks were removed and preserved by autoperfusion for periods of two to nine hours. The key features of the method included normothermic coronary autoperfusion with donor blood by an autoregulating beating heart, and a stabilizing reservoir bag interposed between the donor aorta and the right atrium. The reservoir is positioned one meter above the aortic valve, and determines the pressure in the aorta. Flow from the bag to the right heart dictates venous return, pulmonary blood flow, and ventricular stroke volume. The lungs are ventilated with room air and 5% to 10% of CO2, at 4 liters/minute. Normothermia is ensured by immersion of the heart-lungs block in a temperature controlled crystalloid bath. Eleven canine and eight bovine heart-lung blocks were evaluated for two to nine hours. Lung function was excellent during this period, and cardiac output did not decline from pre-harvest levels. Five heart-lung allografts were transplanted after an average of four hours of autoperfusion and all functioned satisfactorily. All animals could be weaned from the extracorporeal circulation support. Two to three hours later, cardiac outputs and arterial pO2 were normal. The peak airway pressures averaged 29 cm H2O.(ABSTRACT TRUNCATED AT 250 WORDS)