Familial amyloidotic polyneuropathy: long-term follow-up of abdominal fat tissue aspirate in patients with and without liver transplantation

To estimate the evolution of amyloid in tissue, we studied abdominal fat aspirates of cases with familial amyloidotic polyneuropathy (FAP) longitudinally at regular intervals between 1994 and 2006. In 22 cases (13 carriers and nine patients) not yet transplanted median follow-up was 3.3 years (range 0.4–11.3). We found a significant increase in the amyloid grade of fat tissue from 2+ to 4+ and from 0 to 4+ in two of three subjects with follow-ups of >7 years, after 7 and 11 years, respectively. All other subjects remained negative or did not show a significant change. In 11 liver transplant patients, follow-up with fat aspirate was available with a median duration of 3.1 years (range 1.0–10.1). A comparison was made with cardiac amyloid as judged by the cardiac septum diameter and the serum NT-ProBNP (N-terminal pro-B-type natriuretic peptide) level. No stable increase of amyloid in fat was seen in any patient. A stable decrease of amyloid grade was seen in one patient 5 years after transplantation. In contrast, the cardiac septum diameter increased ≥4 mm in six of the 11 transplant patients. Our study shows the diagnostic utility of a regularly repeated fat aspirate in carriers at risk for the development of ATTR amyloidosis. Evolution of amyloid deposition in fat tissue is very gradual. After liver transplantation, amyloid deposition in fat tissue seems to stabilize and may even decrease in the long term, whereas amyloid deposition in cardiac tissue appears to be progressive.     

Histological regression of amyloid in AL amyloidosis is exclusively seen after normalization of serum free light chain

Background

Histological regression of amyloid has not been studied systematically but is assessed by clinical parameters. We analyzed the change of amyloid deposition in fat tissue in patients with AL amyloidosis following chemotherapy and studied the relation with type of hematologic response.

Design and Methods

Between January 1994 and July 2007 all consecutive patients with AL amyloidosis were evaluated in whom fat tissue aspirate was obtained before and following chemotherapy. Patients were divided into three groups depending on response of serum free light chain: complete, partial or non-responders. Fat tissue was assessed using a validated semi-quantitative test (grading 0–4). A change of 2 grades of amyloid deposition in fat tissue was considered significant and used as event to construct Kaplan-Meier curves of the patients who were able to reflect such a change.

Results

One hundred and twenty consecutive patients were studied. Fifty-one patients fulfilled inclusion criteria. Thirty patients had a complete response of the amyloidogenic free light chain a median 0.5 year (range 0.3–2.9 years) following chemotherapy. Reduction of 2 grades of amyloid deposition in fat tissue was seen in 50% of these patients after 2.4 years and in 80% after 3.2 years. In contrast to complete responders, none of the patients with partial (n=9) and non-response (n=12) showed reduction of 2 grades (p=0.02) with median follow-up of fat tissue analysis of 1.3 and 0.8 years, respectively.

Conclusions

This study in a selected group of patients with AL amyloidosis shows significant histological regression of amyloid deposition in fat tissue exclusively after normalization of serum free light chain.     

Diagnostic value of abdominal wall fat pad biopsy in senile systemic amyloidosis

Senile systemic amyloidosis (SSA) is a main cause of intractable heart failure in elderly individuals. To demonstrate transthyretin (TTR)-derived amyloid deposition endomyocardial biopsy has been commonly carried out in the patients with SSA, but this invasive biopsy technique cannot always be performed in aged patients with severe cardiac dysfunction. During the past 3 years, 11 patients with SSA (6 males and 5 females; ages from 70 to 97 years) were examined. All underwent skin biopsy from the abdominal wall and 8 showed TTR-immunoreactive amyloid deposition (sensitivity: 73%): amyloid deposits were seen mainly in the deep layer of subcutaneous fat tissue and showed a patchy distribution. They were weakly Congophilic, but were strongly immunolabeled by an anti-TTR antibody. The severity and pattern of amyloid deposition in this biopsy of SSA patients were considerably different from those obtained from age-matched patients with TTR-related familial amyloid polyneuropathy. Surgical skin biopsy including the deep subcutaneous fat pad can be performed safely at the bedside and is useful for the histopathological diagnosis of SSA.     

Progression of cardiac amyloid deposition in hereditary transthyretin amyloidosis patients after liver transplantation.

It has been hypothesized that transthyretin (TTR) amyloidosis may progress after orthotopic liver transplantation (OLT) as a result of continued amyloid fibril synthesis and deposition from normal TTR. To test this hypothesis amyloid fibrils were isolated from cardiac tissues of three patients who died 1(1/2) to 5(1/2) years after OLT: two with Val30Met and one with Thr60Ala TTR. The ratio of variant to normal TTR in each case was determined and compared with the ratio of variant to normal in cardiac tissues from seven patients who died with TTR amyloidosis but who had not had liver transplantation. Tissues from patients with TTR amyloidosis without OLT included three with Val30Met, two with Thr60Ala, one with deltaVal122, and one with Val122Ile. All tissues from patients without OLT had greater amounts of variant TTR than normal TTR except for the Val122Ile in which the ratio was 50:50. The overall median variant to normal ratio was 60:40 with a range of 50-70% variant. In contrast, the mean percentage of variant TTR in the three tissues from patients after OLT was 25% (range 20-35). These data are consistent with the continued deposition of normal TTR in cardiac tissue after liver transplantation.     

Progression of cardiac amyloid deposition in hereditary transthyretin amyloidosis patients after liver transplantation

It has been hypothesized that transthyretin (TTR) amyloidosis may progress after orthotopic liver transplantation (OLT) as a result of continued amyloid fibril synthesis and deposition from normal TTR. To test this hypothesis amyloid fibrils were isolated from cardiac tissues of three patients who died 1½ to 5½ years after OLT: two with Val30Met and one with Thr60Ala TTR. The ratio of variant to normal TTR in each case was determined and compared with the ratio of variant to normal in cardiac tissues from seven patients who died with TTR amyloidosis but who had not had liver transplantation. Tissues from patients with TTR amyloidosis without OLT included three with Val30Met, two with Thr60Ala, one with ΔVal122, and one with Val122Ile. All tissues from patients without OLT had greater amounts of variant TTR than normal TTR except for the Val122Ile in which the ratio was 50:50. The overall median variant to normal ratio was 60:40 with a range of 50–70% variant. In contrast, the mean percentage of variant TTR in the three tissues from patients after OLT was 25% (range 20–35). These data are consistent with the continued deposition of normal TTR in cardiac tissue after liver transplantation.     

Immunoglobulin light chain amyloidosis: 2011 update on diagnosis, risk-stratification, and management

Immunoglobulin (Ig) light chain amyloidosis is a clonal but nonproliferative plasma cell disorder in which fragments of an Ig light chain are deposited in tissues. The clinical features depend on the organs involved but can include restrictive cardiomyopathy, nephrotic syndrome, hepatic failure, and peripheral/autonomic neuropathy. Tissue biopsy stained with Congo red demonstrating amyloid deposits with apple-green birefringence is required for diagnosis. Invasive organ biopsy is not required because amyloid deposits can be found in bone marrow biopsy or subcutaneous fat aspirate in 85% of patients. N-terminal pro-brain natriuretic peptide and serum troponin T values are used to classify patients into three groups of approximately equal size; median survivals are 26.4, 10.5, and 3.5 months, respectively. All patients with a visceral amyloid syndrome require therapy to prevent deposition of amyloid in other viscera and to prevent progressive organ failure of involved sites. Stem cell transplant (SCT) is a preferred technique, but only 20% of patients are eligible. Requirements for safe SCT include mild or no cardiac involvement, troponin T value <0.06 ng/mL, age younger than 70 years, <3 organs involved, and serum creatinine value ≤1.7 mg/dL. Nontransplant candidates can be offered melphalan-dexamethasone. Pomalidomide appears to have activity, as do other combinations of chemotherapy with agents such as cyclophosphamide-thalidomide-dexamethasone, bortezomib-dexamethasone, and melphalan-prednisone-lenalidomide. Late diagnosis remains a major obstacle to initiating effective therapy when organ dysfunction is still recoverable. Recognizing the presenting syndromes is necessary for improvement in survival.     

Sequential heart and autologous stem cell transplantation for systemic AL amyloidosis

Extensive cardiac amyloid deposition in systemic AL amyloidosis is associated with a grave prognosis. Heart transplantation is rarely performed because of the systemic and progressive nature of the disease. Patients with severe cardiac amyloid infiltration are ineligible for the preferred treatment of melphalan chemotherapy with stem cell transplantation (SCT) rescue because of the high risk for treatment-related mortality. Heart transplantation followed by SCT was performed in 5 patients with AL amyloidosis and predominant cardiomyopathy. Patients were followed up for a median of 95 months (range, 37-118 months) from diagnosis. At censor, 3 of 5 patients were well without evidence of intracardiac or extracardiac amyloid accumulation, and median overall survival by Kaplan-Meier estimate was not reached. Two patients died of progressive amyloidosis 33 and 90 months after heart transplantation after relapse of their underlying plasma cell dyscrasia. Heart transplantation followed by SCT is feasible in selected patients with cardiac AL amyloidosis and may confer substantial survival benefit.     

Pittsburgh B Compound Positron Emission Tomography in Patients With AL Cardiac Amyloidosis

BackgroundIt remains unknown whether the noninvasive evaluation of the degree of amyloid deposition in the myocardium can predict the prognosis of patients with light chain (AL) cardiac amyloidosis.ObjectivesThe purpose of this study was to demonstrate that ¹¹C-Pittsburgh B compound positron emission tomography (¹¹C-PiB PET) is useful for prognostication of AL cardiac amyloidosis by noninvasively imaging the myocardial AL amyloid deposition.MethodsThis study consecutively enrolled 41 chemotherapy-naïve AL cardiac amyloidosis patients. The amyloid deposit was quantitatively assessed with amyloid P immunohistochemistry in endomyocardial biopsy specimens and was compared with the degree of myocardial ¹¹C-PiB uptake on PET. The primary endpoint was a composite of all-cause death, heart transplantation, and acute decompensated heart failure.ResultsThe degree of myocardial ¹¹C-PiB PET uptake was significantly higher in the cardiac amyloidosis patients compared with normal subjects and correlated well with the degree of amyloid deposit on histology (R² = 0.343, p < 0.001). During follow-up (median: 423 days, interquartile range: 93 to 1,222 days), 24 patients experienced the primary endpoint. When the cardiac amyloidosis patients were divided into tertiles by the degree of myocardial ¹¹C-PiB PET uptake, patients with the highest PiB uptake experienced the worst clinical event-free survival (log-rank p = 0.014). The degree of myocardial PiB PET uptake was a significant predictor of clinical outcome on multivariate Cox regression analysis (adjusted hazard ratio: 1.185; 95% confidence interval: 1.054 to 1.332; p = 0.005).ConclusionsThese proof-of-concept results show that noninvasive evaluation of myocardial amyloid load by ¹¹C-PiB PET reflects the degree of amyloid deposit and is an independent predictor of clinical outcome in AL cardiac amyloidosis patients.     

A fludarabine-based dose-reduced conditioning regimen followed by allogeneic stem cell transplantation from related or unrelated donors in patients with myelodysplastic syndrome.

We investigated the feasibility and efficacy of a fludarabine-based dose-reduced conditioning regimen followed by stem cell transplantation from related (n = 5) or unrelated HLA-matched donors (n = 7) in 12 patients with high risk MDS, who were not eligible for a standard myeloablative conditioning regimen. The conditioning regimen consisted of fludarabine 30 mg/m(2) daily for 6 days, busulfan 4 mg/kg daily for 2 days and anti-thymocyte globulin (ATG, rabbit) 10 mg/kg daily for 4 days in 11 patients, while one patient received fludarabine, ATG, cyclophosphamide and thiotepa. Graft-versus-host disease prophylaxis consisted of cyclosporine and a short course of methotrexate. The median age of the patients was 53 years (range 37-59). The median percentage of blasts in bone marrow aspirate at transplantation was 15% (range <5% to 35%). Diagnosis at transplant was RA (n = 1), RAEB (n = 5), RAEB-T (n = 5) and sAML (n = 1). A complex karyotype including monosomy 7 was noted in five patients. The reasons for using a dose-reduced conditioning regimen were prior autologous/syngeneic BMT (n = 4), active fungal infection (n = 2) or age/reduced performance status (n = 6). Engraftment was observed in all patients with complete donor chimerism. The incidence of acute GVHD (grade II-IV) was 33%. Eight patients died during follow-up due to relapse (n = 4), liver toxicity (n = 2), aspergillus (n = 1) or aGVHD grade IV (n = 1). After a median follow-up of 19 months, the 2-year estimated disease-free survival is 12% (95% CI: 2-23%) and the overall survival is 26% (95% CI: 4-52%). Fludarabine dose-reduced conditioning prior to allogeneic stem cell transplantation in high risk MDS patients, who were not eligible for standard transplantation, resulted in stable engraftment with complete chimerism, but the toxicity and relapse rate were considerable.     

Cardiac Transplantation in Danon Disease

BackgroundDanon disease (DD) is a rare X-linked dominant cardioskeletal myopathy caused by mutations in the lysosome-associated membrane protein-2 (LAMP-2) gene that is usually lethal without cardiac transplantation. The purpose of this study was to characterize post-transplant outcomes in a large cohort of patients with DD who underwent cardiac transplantation.MethodsThe clinical phenotype and outcome data of patients with DD who underwent cardiac transplantation (n = 38; 19 males and 19 females) were obtained from 8 centers. Study outcomes included graft survival, defined as death or retransplantation, and episodes of acute cellular and antibody-mediated rejection and cardiac allograft vasculopathy at 1 year.ResultsMedian follow-up time after transplantation for the entire cohort was 4.4 years (IQR: 1.5–12.8 years). The median age at transplant for the cohort was 20.2 years (15.8–27.9 years), with no difference in age between sexes. Median pretransplant left-ventricular ejection fraction for the entire cohort was 30% (range 11%–84%). Males had higher pretransplant aspartate aminotransferase, alanine aminotransferase and creatine phosphokinase levels than females (P < 0.001). There were 2 deaths in the entire cohort and 2 retransplants. There was no difference in actuarial graft survival between males and females (P = 0.8965); the estimated graft survival was 87.1% (95%CI: 63.6%–95.9%) at 5 years. One episode (2.7%) of antibody-mediated rejection, grade 2, and 7 episodes (19%) of acute cellular rejection, grade 2 or 3, were reported in patients who survived to discharge (6 females and 1 male; P = 0.172).ConclusionsHeart transplantation outcomes are acceptable in DD with high probabilities of 5-year graft survival for males and females suggesting that cardiac transplantation is an effective treatment option for DD patients.     

Amyloid load in fat tissue reflects disease severity and predicts survival in amyloidosis

Objective

The severity of systemic amyloidosis is thought to be related to the extent of amyloid deposition. We studied whether amyloid load in fat tissue reflects disease severity and predicts survival.

Methods

We studied all consecutive patients with systemic amyloidosis seen between January 1994 and January 2007 in our tertiary referral center. Congo red–stained abdominal fat smears were graded by 2 observers using a validated semiquantitative scoring system. Disease severity was measured by the total number of major organs involved and the extravascular retention of the serum amyloid P component (EVR₂₄). The association of amyloid load in fat tissue with disease severity and overall survival was studied using multiple regression analysis.

Results

Two hundred twenty patients were included in the study (120 with AL amyloidosis, 66 with AA amyloidosis, and 34 with ATTR amyloidosis). Amyloid grade in fat tissue was associated with the number of major organs involved and EVR₂₄. Female sex turned out to be associated with a higher grade of amyloid in fat tissue than male sex. Amyloid grade in fat tissue was an independent predictor of decreased survival, as were heart involvement, the number of organs involved, AA or AL type of amyloid, and age.

Conclusion

The amount of amyloid in subcutaneous fat tissue in systemic amyloidosis reflects disease severity, as measured by the number of organs involved and EVR₂₄, and predicts decreased survival independent of other well‐known factors.     

Update on treatment of light chain amyloidosis

Light chain amyloidosis is the most common type of amyloidosis as a consequence of protein misfolding of aggregates composed of amyloid fibrils. The clinical features are dependent on the organs involved, typically cardiac, renal, hepatic, peripheral and autonomic neuropathy and soft tissue. A tissue biopsy or fat aspirate is needed to confirm the presence/type of amyloid and prognostic tools are important in a risk stratified approach to treatment. Autologous stem cell transplant eligibility should be assessed at baseline, weighing the reversible or non-reversible contraindications, toxicity of treatment and chemotherapy alternatives available. Chemotherapy options include melphalan, thalidomide, bortezomib, lenalidomide, bendamustine in combination with dexamethasone. Many studies have explored these treatment modalities, with ongoing debate about the optimal first line and sequential treatment thereafter. Attaining a very good partial response or better is the treatment goal coupled with early assessment central to optimizing treatment. One major challenge remains increasing the awareness of this disease, frequently diagnosed late as the presenting symptoms mimic many other medical conditions. This review focuses on the treatments for light chain amyloidosis, how these treatments have evolved over the years, improved patient risk stratification, toxicities encountered and future directions.     

Heart Transplantation and End-Stage Cardiac Amyloidosis: A Review and Approach to Evaluation and Management

Cardiac amyloidosis is one of the most common of the infiltrative cardiomyopathies and is associated with a poor prognosis. The extent of cardiac involvement with amyloid deposition is an important determinant of treatment options and is the major determinant of outcome in patients with amyloidosis. Several small case series with sequential orthotopic heart transplantation and autologous stem cell transplant have demonstrated an improvement in post-transplant outcome and have revived enthusiasm about heart transplantation for patients with end-stage heart failure due to AL amyloidosis. The purpose of this review is to summarize the evaluation and management of cardiac amyloidosis and to provide our single-center experience with end-stage heart failure due to AL amyloidosis treated with heart transplantation followed by an autologous stem cell transplant.     

Echocardiographic study of heart rhabdomyoma in tuberous sclerosis

In order to study the prevalence of cardiac rhabdomyoma in tuberous sclerosis using non invasive methods, 11 consecutive patients affected by tuberous sclerosis (age: 3 months-22 years, mean 6 years) were examined between January 1984 and April 1987. In each patient clinical examination, 12 lead electrocardiogram, M-mode and two-dimensional echocardiogram were performed: on 7 of them a 24-hour ambulatory electrocardiogram was also performed. Clinical examination revealed a systolic murmur (grade 3/6) in two cases. In one of them it was associated with cyanosis and cardiac failure. None of other patients showed signs or symptoms related to the heart during clinical examination. ECG was abnormal in 3 cases (ventricular pre-excitation in 2 cases and left ventricular strain in 1). Two-dimensional echocardiogram showed single or multiple intracardiac masses suggestive of cardiac rhabdomyoma in 8 cases; in 3 of them masses were isolated, intramural, and in the interventricular septum, from 5 to 16 mm in diameter; in the other 5 cases they were multiple, intramural and endoluminal, in the interventricular septum, in the right or left ventricle, from 7 to 20 mm in diameter. Ambulatory electrocardiogram revealed only isolated ectopic supraventricular and ventricular beats in 2/7 cases. Each patient was clinically controlled every six months using ECG standard and two-dimensional echocardiogram. The mean follow-up period was 32 months (range 9-53). This study confirms the usefulness of the two-dimensional echocardiography to visualize intramural or intracavitary masses due to cardiac rhabdomyoma in patients with tuberous sclerosis, especially when they appear clinically asymptomatic. Two-dimensional echocardiography is probably the ideal method to use in order to evaluate potential increase in cardiac rhabdomyoma, when prolonged follow-up studies are performed.     

Right ventricular volumes and hemodynamics after successful orthotopic heart transplantation. A comparison to coronary artery disease using thermodilution.

Only few data exist concerning right ventricular function in the chronic stage after cardiac transplantation. Therefore, we investigated hemodynamic and right ventricular volumetric data by a computerized thermodilution Swan-Ganz catheter in 17 patients (median age: 53, range: 18-63 yr) at a median of 24 (4 to 44) months after cardiac transplantation during rest and supine bicycle exercise. Myocardial biopsy showed grade one or less according to the classifications of Billingham. Sixteen patients with coronary artery disease, but without prior myocardial infarction, served for comparison. While angiographic left ventricular ejection fraction was nearly identical in transplant recipients [77 (60-92)%, median (range)] and in patients with coronary artery disease [78 (64-94)%], right ventricular ejection fraction was lower (p < 0.001) in patients after cardiac transplantation [37 (16-58)%] as compared to patients with coronary artery disease [56 (46-62)%]. In transplant recipients right atrial pressure was significantly higher both at rest [10 (2-18) mmHg] and exercise [18 (8-30) mmHg] than in patients with coronary artery disease [5 (1-11) and 8 (3-18) mmHg]. Pulmonary capillary wedge pressure behaved similar in both groups. To further evaluate reasons for right ventricular impairment, a correlation analysis was performed. This showed a negative correlation between right ventricular ejection fraction and the time interval after transplantation (p < 0.0002). However, there was no correlation between right ventricular ejection fraction and acute rejection or a rejection score. In conclusion, right ventricular function may be severely altered in transplant recipients, in contrast to an only slight impairment of left ventricular function.     

Screening for amyloid deposition by subcutaneous fat tissue aspiration technique in rheumatoid arthritic patients and investigating its clinical significance in Iran

Aim: This study examined the frequency of secondary amyloidosis in Iranian patients with rheumatoid arthritis (RA) in order to determine its clinical significance. Methods: A total of 220 RA patients (167 female, 53 male), with minimum disease duration of 5 years, were included in this prospective study over a period of about 2 years. Abdominal subcutaneous fat‐pad aspiration (ASFA) method was used in obtaining specimens from all subjects. All of the specimens were examined for apple‐green birefringence under polarized light microscope. Amyloid deposits were graded from 1+ to 3+. Clinical, radiological, and laboratory characteristics of the patients were assessed and recorded. Results: Amyloid deposition was detected in 11 (5%) of the fat smears stained with Congo red stain. All of the samples had minimal (1+) amyloid deposits. In this study, amyloid‐positive cases showed clinically significant symptoms; six of the patients (55%) presented with proteinuria, and seven other cases (64%) presented with severe constipation. Conclusion: Abdominal fat amyloid deposition was found to be uncommon in adult Iranian RA patients. In up to half of the patients the deposits were subclinical. A longer follow‐up and larger multicentric collaborative study is needed to determine the significance of subclinical amyloid deposits.     

Screening for amyloid in subcutaneous fat tissue of Egyptian patients with rheumatoid arthritis: clinical and laboratory characteristics

OBJECTIVE: To screen for amyloid and to assess associated clinical and laboratory characteristics in Egyptian patients with rheumatoid arthritis (RA). METHODS: Abdominal subcutaneous fat aspirates were consecutively collected from 112 patients (103 women, nine men) having RA for five years or more. To detect amyloid, fat smears were stained with Congo red and the concentration of amyloid A protein in fat tissue was measured. Clinical, radiological, and laboratory characteristics of the patients were assessed. RESULTS: Amyloid was detected in eight (7%) of the fat smears stained with Congo red. Compared with the Congo red stain, the sensitivity for detecting amyloid by measurement of amyloid A protein in fat tissue was 75% and the specificity was 100%. The amount of amyloid found was small for both methods. The median disease duration of the eight amyloid patients was significantly longer (17 years) than that of the non-amyloid patients (10 years). Bronchopulmonary disease and constipation were more common, whereas proteinuria and chronic renal insufficiency were not. The number of swollen joints and the number of red blood cells were significantly lower in the amyloid group. CONCLUSIONS: Quantification of amyloid A protein and staining with Congo red are strongly concordant methods of screening for amyloid in fat tissue. The prevalence of amyloid in Egyptian patients with RA is 7%. Proteinuria is not a discriminating feature, whereas long disease duration, constipation, bronchopulmonary symptoms, and a moderate to low number of red blood cells may help to identify the arthritic patients with amyloid.     

Transplantation of CD34+ selected peripheral blood to HLA-identical sibling patients with aplastic anaemia: results from a single institution

We evaluated the use of CD34+ selected allogeneic peripheral blood as a source of hematopoietic progenitors for allogeneic transplantation in 11 patients with aplastic anemia (AA). The median age was 17 years (range, 6--9), and the median time between diagnosis and transplant 1 month (range, 1--4). Conditioning consisted of cyclophosphamide (50 mg/kg per day) on days--7 to--4 and antithymocyte globulin (30 mg/kg per day) on days--4 to--2 in nine patients. Total lymphoid irradiation was added to the preparative regimen for two. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine A and prednisone. Median doses of CD34+ and CD3+ cells infused were 3.91 x 10(6) and 0.3 x 10(6)/kg, respectively. The median time taken to achieve a neutrophil count >0.5 x 10(9)/l was 12 days and to recover a platelet count >20 x 10(9)/l, 13 days. Two patients developed acute GVHD grade I--II and one developed limited chronic GVHD. There were two treatment-related deaths. At a median follow-up of 44 months (range, 4--3), nine patients were alive with sustained and complete engraftment. This is a promising procedure in patients with AA, resulting in a rapid hematopoietic recovery, a low transplant-related mortality, and a low incidence of GVHD.     

Second autologous transplantation after failure of a first autologous transplant in 18 patients with non-Hodgkin's lymphoma

High-dose chemotherapy and autologous marrow or peripheral stem cell support offers the best chance of cure in some subgroups of patients with non-Hodgkin's lymphoma (NHL). Less is known about the role of a second course of myeloablative chemotherapy in patients who relapse after a first autologous transplant. The aim of this retrospective study was to evaluate the disease outcome, morbidity and mortality associated with second autologous transplantation in patients with NHL. Between 1985 and 2001, 225 patients who had received autologous transplantation for NHL in two institutions in Lyon relapsed. Of these 225 patients 18 underwent a second autologous transplantation. The median age at second transplant was 41 years. There were six indolent lymphomas and 12 aggressive lymphomas. The median follow-up from the second transplant was 42 months. The OS rate at 2 and 5 years were 58 and 27%, respectively. The PFS rate at 2 and 5 years was 36%. Five patients are alive without disease 20 to 100 months after the second transplant. Seven patients died of disease recurrence. Four (22%) toxic deaths occurred: one of pulmonary fibrosis, one of fungal infection and cardiac failure and two of acute leukaemia. A minority of patients with NHL recurrence after a first transplant can be cured by a second course of myeloablative chemotherapy at the cost however of high-risk toxic death.     

Nitroglycerin-induced coronary vasodilation in cardiac transplant recipients. Evaluation with in vivo intracoronary ultrasound.

BACKGROUND. Coronary artery vasomotion is altered after cardiac transplantation. The impact of accelerated transplant coronary atherosclerosis and myocardial rejection on vasomotion is not well understood. Intravascular ultrasound is a new imaging method with the ability to study real-time changes in coronary artery dimensions. METHODS AND RESULTS. Epicardial coronary artery response to nitroglycerin was studied in 32 cardiac transplant recipients (age, 47 +/- 11 years) 3 weeks to 10 years after transplantation with intracoronary ultrasound. Cross-sectional luminal area and diameter were measured at a fixed position in the left anterior descending artery immediately before and every 30 seconds for 5 minutes after 0.4 mg of sublingual nitroglycerin. Cross-sectional area increased from a baseline of 13.1 +/- 3.9 mm2 to 15.8 +/- 3.9 mm2 at maximal vasodilation; luminal diameter increased from 4.0 +/- 0.6 mm to 4.5 +/- 0.6 mm. This increase reached statistical significance (p less than 0.001) at 1.5 minutes after administration of nitroglycerin; mean maximum increase occurred at 4.5 minutes (24% for cross-sectional area and 11% for luminal diameter). Patients with biopsy-proven mild or moderate concurrent rejection had a significantly blunted vasodilatory response versus the nonrejection group (9% versus 27% for cross-sectional area, p less than 0.04), although a vasodilatory effect was still present. Nitroglycerin response was well preserved in patients up to 10 years after transplantation; however, there was a trend toward a decreased response in patients studied immediately after transplantation (21% versus 29%, p = 0.37). Coronary intimal thickness, as measured by ultrasound, had no impact on the vasodilatory response (R = 0.23, p = 0.34). CONCLUSIONS. Vasodilatory response to nitroglycerin in cardiac transplant recipients is attenuated during episodes of cardiac rejection. This response is preserved in long-term survivors and is independent of the degree of intimal thickening. Intravascular ultrasound provides a new method to document real-time epicardial coronary vasomotion.