Anti-CD20 antibody (rituximab) administration in patients with late occurring lymphomas after solid organ transplant.

BACKGROUND AND OBJECTIVES: Aggressive diffuse large cell non-Hodgkin's lymphoma (DLCL) occurring late after a solid organ transplant fails to regress after discontinuation of immunosuppression. Moreover, chemotherapy treatment is associated with a high mortality rate due to severe toxicity. Since the majority of post-transplant lymphoproliferative disorders derive from B-lineage lymphocytes, the administration of anti-B monoclonal antibodies represents a rational therapeutic option. DESIGN AND METHODS: Five patients who developed CD20-positive DLCL more than two years after heart or liver transplantation were treated with a weekly chemotherapy program (2 patients), radiotherapy (2 patients) and surgery (1 patient) followed by a minimum of 4 intravenous doses of rituximab (375 mg/m(2)). RESULTS: A favorable clinical outcome was observed in three patients in whom surgery or radiotherapy had produced significant tumor debulking. Only a partial clinical effect was documented in the two patients with advanced clinical stage disease. INTERPRETATION AND CONCLUSIONS: Rituximab can be safely administered to patients with aggressive CD20-positive DLCL occurring late after a solid organ transplant. However, a positive clinical outcome may be expected only in patients in whom surgery or radiotherapy has achieved significant regression of tumor burden.

Continuous retrograde warm blood reperfusion reduces cardiac troponin I release after heart transplantation: a prospective randomized study.

During heart surgery, cardiac troponin I (cTn-I) measurement provides a tool to evaluate different cardioprotective techniques. To investigate myocardial protection during heart transplantation (HTx), cTn-I and creatine kinase (CK)-MB release was measured in 42 patients randomized to receving either continuous retrograde warm blood reperfusion or no reperfusion after cold cardioplegia. A significant linear correlation was found between donor heart ischemic time and peaks and the area under the curve of cTn-I and CK-MB release. In patients with an ischemic time longer than 90 min, cTn-I release was significantly lower in those receiving continuous retrograde warm cardioplegia than in controls. No significant difference was observed for CK-MB, tCK, and myoglobin. Our data suggest that the measurement of postoperative cTn-I release may provide a method to evaluate ischemic cardiac damage after HTx. When the ischemic time is longer than 90 min, warm retrograde blood cardioplegia provides better myocardial protection than no reperfusion.

High levels of Epstein-Barr virus DNA in blood of solid-organ transplant recipients and their value in predicting posttransplant lymphoproliferative disorders.

Epstein-Barr virus (EBV) DNA was quantitated in peripheral blood mononuclear cells (PBMC) from 25 healthy subjects, 105 asymptomatic solid-organ transplant (SOT) recipients, and 15 SOT recipients with symptomatic EBV infections by using a newly developed quantitative-PCR technique. Patients with symptomatic EBV infections had significantly higher (P < 0.001) median EBV DNA levels than asymptomatic SOT recipients and immunocompetent individuals. In SOT recipients, the positive predictive value of EBV DNA levels of >1, 000 genome equivalents (GE)/0.5 microg of total PBMC DNA was 64.7% for symptomatic EBV infection, while the negative predictive value was 96.1%. In 19 of 32 (59.3%) asymptomatic SOT recipients, EBV DNA levels were consistently below 1,000 GE for as long as 18 months, while 10 of 32 (31.2%) patients had 1,000 to 5,000 EBV GE at least once during follow-up. In a minority of patients (3 of 32; 9.3%), >/=5,000 GE could be detected at least once during follow-up. Reduction of immunosuppressive treatment decreased EBV DNA levels by >/=1 log(10) unit in patients with symptomatic EBV infections. Quantification of EBV DNA is valuable for the diagnosis and monitoring of symptomatic EBV infections in SOT recipients.

Epstein-Barr virus-negative lymphoproliferate disorders in long-term survivors after heart, kidney, and liver transplant.

BACKGROUND: Solid organ transplant patients undergoing long-term immunosuppression have high risk of developing lymphomas. The pathogenesis of the late-occurring posttransplantation lymphoproliferative disorders (PTLD) have not yet been extensively investigated. METHODS: We studied 15 patients who developed PTLD after a median of 79 months (range 22-156 months) after organ transplant. Clonality, presence of Epstein-Barr virus (EBV) genome, and genetic lesions were evaluated by Southern blot analysis or polymerase chain reaction. RESULTS: All monomorphic PTLD and two of three polymorphic PTLD showed a monoclonal pattern. Overall, 44% of samples demonstrated the presence of the EBV genome. Within monomorphic PTLD, the EBV-positive lymphomas were even lower (31%). A c-myc gene rearrangement was found in two cases (13%), whereas none of the 15 samples so far investigated showed bcl-1, bcl-2, or bcl-6 rearrangement. The modulation of immunosuppression was ineffective in all patients with monomorphic PTLD independent of the presence of the EBV genome. The clinical outcome after chemotherapy was poor because of infectious complications and resistant disease. With a median follow-up of 4 months, the median survival time of these patients was 7 months. CONCLUSIONS: Late occurring lymphomas could be considered an entity distinct from PTLD, occurring within 1 year of transplant, because they show a histological and clinical presentation similar to lymphomas of immunocompetent subjects, are frequently negative for the EBV genome, are invariably clonal, and may rearrange the c-myc oncogene. New therapeutic strategies are required to reduce the mortality rate, and new modalities of long-lasting immunosuppression are called for.

Primary effusion lymphoma after heart transplantation: a new entity associated with human herpesvirus-8.

Deep immunosuppression and Epstein-Barr virus (EBV) infection promote the emergence of lymphoproliferative disorders in patients undergoing solid organ transplantation. In the last few years a new herpesvirus, named human herpesvirus-8 (HHV-8), has been identified in Kaposi's sarcoma and primary effusion lymphoma (PEL) developing in AIDS patients. Subsequently, the same viral DNA sequences have been identified in almost all cases of Kaposi's sarcoma emerged outside HIV infection, thus suggesting their possible pathogenetic role in this tumor. Similarly, the association between HHV-8 and PEL also emerged in cases without HIV infection, even though the total number of these patients is still limited. Here, we focus on the emergence of this unusual lymphoma in patients undergoing solid organ transplant and underline once again its association with the HHV-8. Moreover, despite the characteristic local growth of this peculiar type of lymphoma, we demonstrate at the molecular level, an early neoplastic spread to the bone marrow suggesting the need to investigate in more detail the origin of the disease, as well as the molecular mechanisms controlling its systemic dissemination.

The risk of coronary artery disease after heart transplantation is increased in patients receiving low-dose cyclosporine, regardless of blood cyclosporine levels.

BACKGROUND: Coronary artery disease (CAD) of allografted hearts is the main cause of late mortality after cardiac transplant, but its etiology is still undetermined. HYPOTHESIS: This study was undertaken to evaluate the relevance of several risk factors, including cyclosporine (CsA) dose and blood CsA levels, to the incidence of CAD. METHODS: In 163 heart transplants performed between November 1985 and August 1994 at our Institution, CAD was diagnosed by coronary angiography or at postmortem examination. Patients in whom postmortem examination or coronary angiography was not performed, as well as those < 15 years of age and those who died within 1 month of surgery, were excluded from the study. The following risk factors were analyzed: recipient age, gender, pretransplant diagnosis, donor age, number of human leukocyte antigen (HLA)-AB mismatches, cytomegalovirus serology, mear serum cholesterol and triglyceride levels, the number of treated acute rejections, mean weighted CsA dose (CsA dosew and weighted blood CsA levels (blood CsA levelw). RESULTS: Coronary artery disease was diagnosed in 32 patients (19.6%). A low mean CsA dosew was the only significant predictor for CAD at multivariate analysis (p < 0.01): there was no correlation with blood CsA levelw. In the patients receiving a CsA dosew > 4 mg/kg/day, the 8.9 year probability of their remaining CAD free was 69% [confidence interval (CI) 50-87%] in comparison with 31% (CI 0-65%) in patients receiving a CsA dosew < 4 mg/kg/day. CONCLUSION: In our experience, a low CsA maintenance dose is the main risk factor for CAD, irrespective of blood CsA levels.

Heart rate variability in the human transplanted heart: nonlinear dynamics and QT vs RR-QT alterations during exercise suggest a return of neurocardiac regulation in long-term recovery.

RATIONALE: Functional reinnervation of the transplanted human heart by the autonomic nervous system has not been demonstrated. A lack of autonomic control of the transplanted allograft is reflected by an increased resting heart rate, a sluggish heart rate response to dynamical exercise and a reduced heart rate variability. Recent evidence suggests that a measure of deterministic chaos in the heartbeat interval series (point correlation dimension, PD2i) is superior to the conventional power spectrum or other stochastic measures in detecting changes in the mechanism underlying heartbeat generation. METHODS: The PD2i is based on the presumption that the variability is determined and patterned, whereas the stochastic measures all assume that the variability is around a stationary mean and is noise. The PD2i reconstructs the degrees of freedom (number of independent variables) in the system that generates the time series examined, and does this irrespective of whether the system is stochastic or deterministic and is stationary in time. RESULTS: PD2i was determined for heartbeat intervals (RR, ECG digitized at 1200 Hz; supine posture) of 23 heart transplant recipients (HTR: 9 adults, 14 children; 0.04-7.7 years after transplantation) and 21 healthy control subjects (CTL; 13 adults, 8 children). The PD2i (+/-SD) averaged 5.4 +/- 0.7 for the CTL adults and 5.4 +/- 0.6 for the CTL children. Mean PD2i was reduced after transplantation to 1.1 +/- 0.1 in 6 HTRs recorded within 1 year after surgery; in one HTR recorded 2 weeks after surgery the mean PD2i was 3.7. Between 1 to 2 years PD2i was found increased in 2 of 3 subjects and between 2 to 8 years it was increased in 13 of 13, but not to control levels. In normal hearts the QT subinterval of each heartbeat cycle is associated with inotropy and the RR-QT remainder with chronotropy (i.e., the dyastolic interval during which RR is primarily regulated). To examine more closely the residual and returning heartbeat dynamics of the HTR subjects, these subinterval series were examined during mild exercise (40 to 90 Watts) and its recovery. In recent HTRs, resting QT and RR-QT were moderately reduced and modulated by exercise and recovery, but with an approximate 100 beat latency. In long-term (7-8 years) HTR subjects there was a rapid and larger response to exercise/recovery, but compared to normal the range was smaller and the complexity of the subinterval trajectories in time was simpler. CONCLUSIONS: Recurrence of low-dimensional deterministic dynamics after transplantation suggests recovery of neurocardiac control attributable to 1) reorganization of the viable intrinsic cardiac nervous system, 2) reinnervation by the extrinsic autonomic nervous system, or 3) both.

Possible pathogenic role for Sporothrix cyanescens isolated from a lung lesion in a heart transplant patient.

Sporothrix cyanescens is a fungus rarely isolated from human specimens. Its pathogenic role has never been demonstrated but has been postulated on the basis of its occurrence in normally sterile body sites, its isolation from debilitated individuals and its thermotolerance. A first case of nodular pulmonary lesions developing in an immunosuppressed, heart transplant patient is reported. Sporothrix cyanescens was isolated from a fine needle lung biopsy. The patient failed to respond to itraconazole therapy, whereas he was successfully treated with amphotericin B.

Reduction of haemorrhagic complications during mechanically assisted circulation with the use of a multi-system anticoagulation protocol.

Two different anticoagulation protocols were used in 49 consecutive patients mechanically supported either for bridge to transplantation (11) or for recovery of myocardial function after cardiac surgery (35). In 46 patients a Biomedicus centrifugal pump was used and in 3 patients a Pierce-Donachy ventricles. Mechanical support was provided to the left ventricle in 14 patients, to the right ventricle in 6 and to both ventricles in 12 patients; an extra-corporeal membrane oxygenator (ECMO) support was used in 17 patients. Thirty-seven males and 12 females, aged 0.2 to 58 years, were supported for an average time of 6.3 days (range 1-43). Anticoagulation was either based on a continuous infusion of heparin in the first 27 patients (group A) or on a multi-system therapy ("La Pitié" protocol) in the other 22 patients (group B). Overall survival rate was 47%. Patients in group A had a 30% (8/27) survival rate, whereas in group B a 68% (15/22) survival rate was observed (p = 0.006). Transplantation and ventricular assist device (VAD) removal was successfully obtained in 59% (16/27) and 91% (20/22) of patients in group A and group B respectively (p = 0.05). Significant bleeding occurred in 21 patients (81%) in group A and in 2 (9%) of group B (p = 0.001). In these patients bleeding averaged 230 +/- 231 ml/kg in group A versus 55 +/- 18 ml/kg in group B (p = 0.001). Surgical revision was necessary for cardiac tamponade or persistent bleeding in 12 patients of group A (25 procedures: mean 0.9/patient) and in 3 patients of group B (one each patient: mean 0.1/patient) (p = 0.01). Infection, thrombo-embolism and brain hemorrhage were also less frequent in group A than in group B. Our data suggest that the "La Pitié" protocol provides a better control of bleeding than the conventional heparin infusion in patients receiving assist device. this reduction in thrombo-hemorrhagic complications might improve the results of mechanical circulatory support.

A new frontier for cardiac therapy. Principles and practice of aerobic cardiac surgery.

As recently reported in the literature, aerobic cardiac surgery (normothermic total body perfusion + continuous normothermic blood cardioplegia) might achieve optimal heart protection by virtually eliminating myocardial ischemia during aortic cross-clamping. Two-hundred and fifty consecutive patients underwent cardiac surgery by this technique. Mean cross-clamp time was 72.6 +/- 30.7 minutes. Ten patients (4%) died, 20 (8%) needed major inotropic support and 8 (3.2%) required circulatory assistance. Two-hundred and twenty-three patients (89.2%) returned spontaneously to normal sinus rhythm and 8 (3.2%) had evidence of perioperative myocardial infarction. Nineteen patients (7.6%) had a cross-clamp time longer than 120 minutes and no significant difference in mortality was observed with those undergoing a shorter cross-clamping. When comparing 154 patients receiving retrograde continuous normothermic blood cardioplegia induction with 46 receiving antegrade induction, no difference was found in perioperative parameters, mortality and morbidity. By univariate analysis, impaired preoperative LV performance was identified as the only risk factor for operative mortality. In our experience aerobic cardiac surgery appears most suitable for emergency and redo operations, extensive coronary revascularization, complex mitral reconstruction, aortic valve replacement (particularly with unstented biological prostheses), cardiac transplants and whenever two or more valvular and/or coronary procedures are associated. Retrograde induction is as effective as antegrade and simplifies the technique, facilitating unmodified continuous normothermic blood cardioplegia in different anatomical and clinical situations.

Pediatric heart transplantation without chronic maintenance steroids.

From 1986 to February 1993, 40 children aged 2 months to 18 years (average age 10.4 +/- 5.8 years) underwent heart transplantation. Indications for transplantation were idiopathic cardiomyopathy (52%), congenital heart disease (35%) with and without prior repair (71% and 29%, respectively), hypertrophic cardiomyopathy (5%), valvular heart disease (3%), and doxorubicin cardiomyopathy (5%). Patients were managed with cyclosporine and azathioprine. No prophylaxis with antilymphocyte globulin was used. Steroids were given to 39% of patients for refractory rejection, but weaning was always attempted and generally successful (64%). Five patients (14%) received maintenance steroids. Four patients died in the perioperative period and one died 4 months later. There have been no deaths related to rejection or infection. Average follow-up was 36 +/- 19 months (range 1 to 65 months). Cumulative survival is 88% at 5 years. In patients less than 7 years of age, rejection was monitored noninvasively. In the first postoperative month, 89% of patients were treated for rejection. Freedom from serious infections was 83% at 1 month and 65% at 1 year. Cytomegalovirus infections were treated successfully with ganciclovir in 11 patients. No impairment of growth was observed in children who underwent transplantation compared with a control population. Twenty-one patients (60%) have undergone annual catheterizations and no sign of graft atherosclerosis has been observed. Seizures occurred in five patients (14%) and hypertension was treated in 10 patients (28%). No patient was disabled and no lymphoproliferative disorder was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of the Ilizarov apparatus in one case of severe congenital dysmetria of the leg with agenesis of the foot.

The authors present one case of severe congenital dysmetria of the leg with agenesis of the foot which was treated by the Ilizarov method. After a clinical and radiographic description of the case, the type of surgery used to create a new foot and the results obtained are discussed.

Assisted circulation for myocardial recovery after repair of congenital heart disease.

Between January 1987 and May 1990, six children underwent ventricular assisted circulation for recovery of myocardial function after cardiac surgery. Their ages ranged from 9 months to 12 years. Three patients had tetralogy of Fallot and one had atrioventricular discordance with ventriculoarterial concordance, ventricular septal defect, and under-over ventricles. Double outlet left ventricle and a large ventricular septal defect with pulmonary hypertension was present in the remaining two. The duration of circulatory support averaged 126 +/- 57 h. An extracorporeal membrane oxygenator (ECMO) was used in four patients, biventricular assistance with centrifugal pumps in one, and left ventricular assistance followed by ECMO in the last patient. Circulatory support was begun in the operating room in two patients who could not be weaned from cardiopulmonary bypass. Both these patients are long-term survivors. Assisted circulation was implanted in four patients in the intensive care unit because of low cardiac output refractory to any pharmacological treatment. Only one of these patients could be weaned from circulatory support but he died 20 days later because of multiorgan failure due to persistent poor myocardial function. The causes of death in the remaining three patients were intracranial hemorrhage, untreatable bleeding, and failure of myocardial recovery, respectively. We believe that early postoperative use of circulatory support can be a major determinant for recovery of myocardial function in patients who have severe low cardiac output following repair of congenital cardiac lesions. Our initial experience with the use of biventricular assistance in small children is encouraging. Nevertheless, further observations are clearly necessary to establish the role of postoperative circulatory support in children with congenital cardiac lesions.

[Non-invasive diagnosis of acute rejection in heart transplant]. / Diagnosi non invasiva del rigetto acuto nel trapianto cardiaco.

The purpose of this study was to evaluate the sensibility of some clinical and non-invasive parameters in the early diagnosis of cardiac rejection in heart transplant patients. Eighteen patients (15 males and 3 females) aged 13-57 years (mean 44 +/- 14), with orthotopic heart transplant were followed clinically for a mean period of 15 +/- 8.7 months (range 3-27). They were all treated with cyclosporin, associated with azathioprine or prednisone, or both. During the same day of the endomyocardial biopsy, the patients were submitted to a clinical examination, 12 leads ECG and 2-dimensional and Doppler-echocardiography. The following parameters were evaluated: systolic and diastolic blood pressure, heart rate, body weight, summated QRS voltage in the 12 leads ECG, interventricular septum and left ventricular posterior wall end-diastolic thickness, left ventricular myocardial mass and fractional shortening, isovolumic relaxation time. Biopsy specimens were graded according to the Billingham criteria. Totally, 251 biopsies were performed: 130 were negative, 98 positive for mild or moderate rejection, 23 had a resolving rejection pattern; in 61 cases the patients were treated for acute rejection. Compared to negative biopsies, during acute rejection the QRS voltage and the isovolumic relaxation time significantly decreased, while left ventricular wall thickness and body weight increased. To evaluate the effects of the acute immunosuppressive therapy, the same parameters before and after treatment were compared. The QRS voltage, the wall thickness and the isovolumic relaxation time were significantly modified, returning to the pre-rejection values. In conclusion, both clinical and non-invasive information, may be useful to suspect an episode of acute rejection in heart transplant patients and to program myocardial biopsy.

Experience with itraconazole in cryptococcosis and aspergillosis.

Cryptococcosis and aspergillosis in immunocompromised patients are extremely difficult clinical conditions to manage and treatment with available antifungal drugs often fails. Itraconazole, R-51211, Janssen Pharmaceutica, a new orally absorbed triazole, is a possible alternative drug which is potentially effective and nontoxic. Preliminary experience with 28 patients, eight with cryptococcosis and 20 with aspergillosis, is reported. Of these patients, 16 were immunocompromised (seven with the acquired immune-deficiency syndrome (AIDS), five heart transplant recipients and four with leukaemia or lymphoma). Overall, results of treatment were good (18 in remission, four markedly improved, four moderately improved and two failed). Prevention of relapses of cryptococcosis was obtained in all patients with AIDS on long-term itraconazole monotherapy (3 mg/kg). Treatment of invasive aspergillosis required a higher dosage (about 5 mg/kg) and prolonged administration. Besides its efficacy this antifungal agent allowed outpatient management.

Cationic concentrations and transmembrane fluxes in erythrocytes of humans during exercise.

The effect of exercise on the intraerythrocyte cationic concentrations and transmembrane fluxes such as the Na+-K+-adenosinetriphosphatase (ATPase) pump, the Na+-K+ cotransport, and the Na+-Li+ countertransport system was studied in 11 normal male volunteers. All subjects performed an uninterrupted incremental exercise test on a bicycle ergometer, starting at an initial work load of 20% of the subjects' maximal exercise capacity, as determined in a pretest. The work rate was increased with an additional 20% each 6 min up to a final work load of 80%. Blood samples were taken at rest, at 60 and 80% of maximal exercise capacity, and 1, 2, 3, 4, 5, and 30 min after cessation of exercise. At moderate exercise (60% of maximal exercise capacity) the intraerythrocyte potassium concentration was not changed, but at severe exercise (80% of maximal exercise capacity) it was decreased. After exercise the intraerythrocyte potassium concentration returned to base line within 2 min. Exercise did not affect the intraerythrocyte concentrations of sodium and magnesium. The activity of the Na+-K+-ATPase pump and the Na+-K+ cotransport in the erythrocytes during and after exercise was no different from the resting level. The activity of the Na+-Li+ countertransport system on the contrary tended to decrease during exercise. It is concluded that exercise is accompanied by a leakage of potassium out of the erythrocytes without major alterations in the active red cell cationic fluxes.

Erythrocyte cations and Na+,K+-ATPase pump activity in athletes and sedentary subjects.

The chronic effect of training on intraerythrocyte cationic concentrations and on red cell Na+,K+-ATPase pump activity was studied by comparing well-trained athletes with sedentary subjects at rest. Also the acute effect of a 50-min cross-country run on these erythrocyte measurements was studied in the athletes. At rest the intraerythrocyte potassium concentration was increased (P less than 0.01) in the athletes compared to that of the control subjects. The intraerythrocyte concentrations of sodium and magnesium and red cell Na+,K+-ATPase pump activity were, however, similar in the trained and the untrained subjects. As compared with the resting condition, the intraerythrocyte potassium concentration was decreased (P less than 0.05) after exercise in the athletes, and this was accompanied by a minor increase in the intraerythrocyte sodium concentration. Red cell Na+,K+-ATPase pump activity was slightly increased (P less than 0.05) after exercise.

Effects of ketanserin on the intracellular concentration and transmembrane fluxes of sodium and potassium in erythrocytes of normal male subjects.

The effect of acute and short-term administration of ketanserin on the intracellular concentrations and transmembrane fluxes of sodium and potassium was studied in erythrocytes of 12 sodium-replete normal male subjects. The subjects received 40 mg ketanserin three times a day for 1 week. Blood samples were drawn before and 1.5 h after the first dose, 12 h after the evening dose of the 6th day, and 1.5 h after the morning dose of the 7th day. The intraerythrocyte sodium concentration was not changed after the first dose of ketanserin, but was decreased during short-term treatment with ketanserin. The ouabain-sensitive 86Rb-uptake, an estimate of the Na+,K+-adenosine triphosphatase pump activity, was decreased after acute ketanserin administration, but not during short-term treatment. This change in intraerythrocyte sodium concentration was related to the change in ouabain-sensitive 86Rb-uptake. The red cell Na+,K+-cotransport and Na+,Li+-countertransport transport activity were not changed during acute and short-term administration of ketanserin. These results indicate that short-term ketanserin administration decreases the intraerythrocyte sodium concentration, but the flux measurements can not explain this observation.

Complications and technical errors in endo- and arthroprostheses of the wrist and hand. A critical reappraisal of 89 operations.

The authors analyse eighty-nine operations performed between 1969 and 1975 for the insertion of endo- and arthroprostheses is the wrist and hand, with special reference to the complications and errors of technique of this type of surgery. They have paid particular attention to possible errors of diagnosis, faulty indications, and technical operative errors. They confirm that this type of surgery, which is still in the developmental stages, should be restricted to carefully selected cases and performed only in specialist centres.