Posttransplantation lymphoproliferative disorders treated with cyclophosphamide-doxorubicin-vincristine-prednisone chemotherapy.

BACKGROUND: Posttransplantation lymphoproliferative disorders after solid organ transplantation are a serious complication occurring in 1-10% of patients. Different therapies have been used, but the optimal treatment is unknown. There is relatively little information in the literature on the experience with cytotoxic chemotherapy. METHODS: The disease stage of patients with biopsy-documented posttransplantation lymphoproliferative was determined with standard methods to establish the extent of the disease. Patients in whom the disease failed to regress after initial management, which included reduction in immunosuppression, were treated with a combination chemotherapy regimen consisting of six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Response to therapy was determined by following previously defined sites of disease with appropriate tests. Patients were maintained on a reduced dose of immunosuppressants. RESULTS: In the four patients studied, lymphoproliferative disorders developed after heart (three cases) or lung (one case) transplantation, which did not regress after immunosuppression was reduced. All four experienced a complete remission with CHOP chemotherapy, which continued at 3, 13+, 20 and 30+ months after completion of treatment. One patient died of sepsis after completing therapy at a point when his leukocyte count was normal, and no evidence of posttransplantation lymphoproliferative disorder was found at autopsy. A second patient died of liver failure with no clinical evidence of lymphoproliferative disorder. CONCLUSION: Although this is a small series, it demonstrates that patients with posttransplantation lymphoproliferative disorders may respond to cytotoxic chemotherapy. The duration of response is undetermined.

Management of lymphoproliferative disorders after cardiac transplantation.

We conducted a retrospective study of 516 cardiac recipients who underwent transplantation between April 1983 and April 1992, 19 of whom had development of post-transplantation lymphoproliferative disorders (PTLDs). These 19 patients presented with involvement of lung (5), gastrointestinal tract (5), disseminated disease (6), and adenoids and lymph nodes (3). B-cell proliferations ranging from an atypical hyperplasia to malignant lymphoma developed in 18 patients, and mixed cellularity Hodgkin's disease developed in 1 patient. The 19 patients with PTLD displayed a predominance of both women and cardiomyopathy as the indication for transplantation when compared with two separate control populations. No correlation was found between demographic criteria analyzed and (1) early versus late diagnosis of PTLD after transplantation, (2) the site of PTLD involvement, or (3) the histopathologic category of the PTLD lesion. Patients with gastrointestinal tract and lung PTLD involvement enjoyed an improved survival after both transplantation and PTLD diagnosis when compared with patients with PTLD involvement of all other extranodal sites. We report a high incidence of PTLD involving the lung and gastrointestinal tract in our cohort study. These sites of involvement responded better to a reduction in immunosuppression than did the other extranodal sites of involvement.

Cytomegalovirus pneumonitis after cardiac transplantation.

To evaluate the incidence and clinical features of cytomegalovirus (CMV) pneumonitis after cardiac transplantation, we identified 27 (16%) of 171 consecutive recipients in whom CMV pneumonitis was confirmed by strict diagnostic criteria. Cytomegalovirus pneumonitis occurred in 6 (30%) of 20 patients treated with azathioprine and prednisone, and 8 (25%) of 32 patients treated with azathioprine, cyclosporine, and prednisone, but only 13 (11%) of 119 patients treated with cyclosporine and prednisone. The incidence of CMV pneumonitis was not related to recipient preoperative CMV titers or to postoperative cardiac rejection, but there was a trend toward increased CMV pneumonitis in patients who received organs from CMV-positive donors. Mean onset of CMV pneumonitis was 2.9 +/- 1.6 (SD) months after transplantation. In the azathioprine-prednisone group, CMV was always associated with at least one other respiratory pathogen (Aspergillus, n = 5; Pneumocystis carinii, n = 2). In the two cyclosporine groups, CMV was either the sole respiratory pathogen (n = 9), or associated with P carinii (n = 11). Roentgenographically, diffuse bilateral hazy pulmonary opacities were present in 19 (70%) of 27 patients, but focal subsegmental opacity (26%), small pleural effusion (26%), and lobar consolidation (7%) were also observed. When bronchoscopy was performed, bronchoalveolar lavage was the most sensitive technique for detecting CMV (72%), whereas transbronchial biopsy (39%) and combined washings and brushings (33%) were relatively insensitive techniques. Respiratory failure and death occurred in 52% and 44%, respectively, of patients with CMV pneumonitis. In this population of immunocompromised hosts: (1) CMV pneumonitis, alone or with other respiratory pathogens, was a major cause of morbidity and mortality; (2) localized roentgenographic opacity did not exclude CMV pneumonitis; (3) bronchoalveolar lavage was the most sensitive bronchoscopic technique for detecting CMV pneumonitis.

High-risk reparative surgery. A neglected alternative to heart transplantation.

The selection of patients for either high-risk reparative operations on the heart or for transplantation has become increasingly difficult as a result of improved results with both modalities. A retrospective review was done of patients referred for heart transplantation who were not considered candidates for conventional cardiac surgery, yet instead underwent reparative procedures rather than transplantation. Of 23 adult patients referred during a 7-year period, 18 had coronary artery disease, and five had valvular heart disease. All had New York Heart Association class IV symptoms. Preoperative left ventricular ejection fractions were in the range 0.08-0.63 (mean, 0.28). Ten of 18 patients with coronary artery disease required insertion of an intra-aortic balloon pump for hemodynamic support perioperatively. Seven patients had primary coronary artery bypass grafts, and 10 had reoperative coronary bypass procedures. One patient had a left ventricular aneurysmectomy, and one had endocardial stripping in addition to myocardial revascularization procedures. Of the patients with valvular disease, three had aortic valve replacement, of which two were reoperations, and two others had mitral valve replacements with tricuspid annuloplasties. With a mean follow-up of 25 months, 1-, 3-, 12-, and 24-month actuarial survival rates were 91%, 87%, 82%, and 76%, respectively. One patient who underwent aortic valve replacement in this study successfully received heart transplantation 19 months postoperatively. These results compare favorably with the current results for patients undergoing first-graft heart transplantation. All survivors enjoy New York Heart Association class I or II functional capacity.(ABSTRACT TRUNCATED AT 250 WORDS)

Cinevideodensitometric analysis of the effect of coronary angioplasty on coronary stenotic dimensions.

The accuracy and reproducibility of caliper and cinevideodensitometric measurements of coronary stenotic dimensions were compared in radiographic phantom models and in coronary arteriograms of 28 patients undergoing coronary angioplasty. Projected, single-plane coronary cine frames were analyzed by a computer-assisted videodensitometric method, which measures stenotic cross-sectional area without assumptions about lesion geometry. The accuracy (2.4%) and precision (+/- 1.9%) of cinevideodensitometry for measuring percent area stenosis in Plexiglas models of eccentric stenotic lesions was superior to the accuracy (24.7%) and precision (+/- 5.4%) of caliper measurements. Interobserver variability was significantly (p less than 0.05) better for cinevideodensitometric (r = 0.98; SEE = 6.4%) than for caliper measurements (r = 0.87; SEE = 13.1%). After angioplasty, percent diameter stenosis measured by calipers fell from 70 +/- 12% to 30 +/- 15%. Mean percent area reduction measured by cinevideodensitometry fell from 89.1 +/- 8% to 40.1 +/- 22% and stenotic area increased five-fold, from 0.59 +/- 0.5 to 3.47 +/- 1.6 mm2. Pre and post PTCA gradients did not correlate with lesion dimensions. Cinevideodensitometric measurements of absolute stenotic dimensions were more reproducible than relative measurements expressed as a percentage, due to the tapered caliber of normal arterial segments. Thus, cinevideodensitometric measurements were more accurate and reproducible than caliper measurements. The angiographic effects of coronary angioplasty are best measured by cinevideodensitometry, because residual lesions post PTCA are often eccentric, have indistinct margins, and are better characterized by changes in area than by changes in diameter.

Elevated pulmonary vascular resistance and cardiac transplantation.

Severe elevation of pulmonary vascular resistance has been considered a contraindication to cardiac transplantation. Most centers exclude patients with pulmonary vascular resistance greater than 6 Wood units. Wood units, however, do not correct for variations in body size and therefore may not be the best measure for use in comparison of patients. We performed a retrospective analysis of 82 cardiac transplant recipients and compared preoperative pulmonary vascular resistance (PVR) calculated in two ways to the incidence of right ventricular failure and death. Our data show that the PVR index unit (PVRI) identifies those patients that are at risk for right heart failure better than the Wood unit, which does not correct for body size. Four patients died of right heart failure with resistance less than 6 Wood units, but had PVRI greater than 6 units. High resistance is not an absolute contraindication to cardiac transplantation; 28 of 33 patients operated on with a PVRI greater than 6 survived. The degree of elevation of PVR did not correlate with survival. Ten of 12 patients with a PVRI greater than 9 survived. Testing with nitroprusside at cardiac catheterization was helpful in determining reversibility of pulmonary vascular obstruction. No patients with a PVRI less than 6 developed right heart failure.

Reversal of cardiac transplant rejection without massive immunosuppression.

Although cyclosporine has decreased the severity of acute cardiac transplant rejection, most centers have continued to use high-dose intravenous steroids to treat acute rejection. To minimize the morbidity of antirejection therapy, acute rejection episodes in 37 cardiac transplant recipients were treated prospectively with only a boost of oral prednisone. Cyclosporine was continued at the same maintenance dose while oral prednisone was increased to 100 mg/day for 3 days, then rapidly tapered over 1 week to the maintenance dose. Seventy-six of 85 acute rejection episodes (90%) showed histologic resolution of mycocyte necrosis on repeat biopsy. Three acute rejection episodes (3.5%) resolved only after "rescue therapy" with intravenous steroid, and an additional three episodes (3.5%) required the combination of intravenous steroid and rabbit antithymocyte globulin to effect resolution. In addition, three acute rejection episodes (3.5%) resulted in graft loss. This was fatal in two patients and one patient underwent successful retransplantation. Oral steroid therapy alone is adequate therapy for most acute rejection episodes in cyclosporine-treated heart transplant recipients, and low infectious morbidity and mortality has been associated with this antirejection protocol.

Release of norepinephrine from sympathetic nerve efferents by bilateral carotid occlusion.

To investigate the response of the efferent sympathetic nervous system to carotid sinus hypotension, norepinephrine and epinephrine were measured in the dog during control and following bilateral carotid occlusion in arterial, coronary sinus, renal vein, hepatic vein, femoral vein, and pulmonary artery plasma. Mean arterial pressure increased from 109 mmHg during control to 144 and 143 at 1 and 5 min after carotid occlusion, respectively (P less than 0.01). This was associated with an increase in arterial norepinephrine, which could be prevented by the ganglionic blocking agent mecamylamine. While the concentration of norepinephrine rose in all venous effluents, the venous minus arterial norepinephrine difference increased only in the coronary and renal circulations. The results indicate that bilateral carotid occlusion increases the arterial norepinephrine concentration and the overflow of this neurotransmitter from the heart and kidney. The data thus suggest that norepinephrine release from sympathetic axon terminals in the heart and kidney is increased by carotid sinus hypotension. The magnitude of the increase in sympathetic activity evoked by carotid occlusion may have little effect on renal hemodynamics but may have a significant influence on cardiac contractility and coronary blood flow.

Exercise-induced myocardial ischemia in patients with coronary artery disease: lack of evidence for platelet activation or fibrin formation in peripheral venous blood.

The hypothesis that exercise-induced myocardial ischemia is associated with abnormal platelet activation and fibrin formation or dissolution was tested in patients with coronary artery disease undergoing upright bicycle stress testing. In vivo platelet activation was assessed by radioimmunoassay of platelet factor 4, beta-thrombo-globulin and thromboxane B2. In vivo fibrin formation was assessed by radioimmunoassay of fibrinopeptide A, and fibrinolysis was assessed by radioimmunoassay of thrombin-increasable fibrinopeptide B which reflects plasmin cleavage of fibrin I. Peripheral venous concentrations of these substances were measured in 10 normal subjects and 13 patients with coronary artery disease at rest and during symptom-limited peak exercise. Platelet factor 4, beta-thromboglobulin and thromboxane B2 concentrations were correlated with rest and exercise catecholamine concentrations to determine if exercise-induced elevation of norepinephrine and epinephrine enhances platelet activation. Left ventricular end-diastolic and end-systolic volumes, ejection fraction and segmental wall motion were measured at rest and during peak exercise by first pass radionuclide angiography. All patients with coronary artery disease had documented exercise-induced myocardial ischemia manifested by angina pectoris, ischemic electrocardiographic changes, left ventricular segmental dyssynergy and a reduction in ejection fraction. Rest and peak exercise plasma concentrations were not significantly different for platelet factor 4, beta-thromboglobulin, thromboxane B2, fibrinopeptide A and thrombin-increasable fibrinopeptide B. Peripheral venous concentrations of norepinephrine and epinephrine increased significantly (p less than 0.001) in both groups of patients. The elevated catecholamine levels did not lead to detectable platelet activation. This study demonstrates that enhanced platelet activation, thromboxane release and fibrin formation or dissolution are not detectable in peripheral venous blood of patients with coronary disease during exercise-induced myocardial ischemia.

The effect of captopril on renal, coronary, and systemic hemodynamics in patients with severe congestive heart failure.

The effects of captopril (CPT), an oral angiotensin-converting enzyme (ACE) inhibitor, on systemic failure (CHF). In 15 patients, CPT decreased mean arterial pressure from 75 +/- 3 to 60 +/- 3 mm Hg associated with a 16% increase in cardiac output, a 24% reduction in systemic vascular resistance, and a 36% decrease in pulmonary capillary wedge pressure (all p less than 0.01). Despite the improved cardiac output, renal blood flow, creatinine clearance, and sodium excretion did not rise during the first 2 days of CPT therapy. In eight patients, coronary sinus blood flow diminished from 98 +/- 11 to 82 +/- 9 ml/min (p less than 0.01) following drug administration in association with a fall in arterial pressure and heart rate but no change in coronary sinus oxygen inhibitor failed to improve renal hemodynamics. In addition, initial CPT administration produced a decrease in coronary blood flow that was related to a decrease in myocardial oxygen requirements.