Prophylactic donor lymphocyte infusions after moderately ablative chemotherapy and stem cell transplantation for hematological malignancies: high remission rate among poor prognosis patients at the expense of graft-versus-host disease.

We investigated the use of 'prophylactic' donor lymphocyte infusions (DLI) containing 1 x 107 CD3+ cells, given at 30, 60 and 90 days post-allogeneic blood and marrow transplantation (BMT), following conditioning with fludarabine 30 mg/m(2)/4 days and melphalan 70 mg/m(2)/2 days. GVHD prophylaxis consisted of cyclosporin A (CsA) 2 mg/kg daily with early tapering by day 60. Our goals were the rapid achievement of chimerism and disease control, providing an immunological platform for DLIs to treat refractory patients with hematological malignancies. Twelve heavily pre-treated patients with life expectancy less than 6 months were studied; none were in remission. Diagnoses were AML (n = 4), MDS (n = 1), ALL (n = 3), CML (n = 3) and multiple myeloma (n = 1). Response rate was 75%. Three patients are alive at a median of 450 days (range, 450-540). Two patients are in remission of CML in blast crisis and AML for more than 14 months. Median survival is 116 days (range, 25-648). Six patients received 12 DLIs; three patients developed acute GVHD after the first infusion and were excluded from further DLIs, but no GVHD occurred among patients receiving subsequent DLIs. One patient with CML in blast crisis went into CR after the first DLI. The overall incidence of acute GVHD was 70%. Primary causes of death were infections (n = 3), acute GVHD (n = 3), chronic GVHD (n = 1) and disease relapse (n = 2). We observed high response and chimerism rates at the expense of an excessive incidence of GVHD. DLI given at day +30 post BMT caused GVHD in 50% of the patients, and its role in this setting remains unclear.

Deficit of T-cell recovery after allogeneic bone marrow transplantation in chronic myeloid leukemia patients.

The immunological reconstitution that follows bone marrow transplantation (BMT) was studied in 40 leukaemia patients: 19 with chronic myeloid leukaemia (CML), 12 with acute myeloid leukaemia (AML) and the remaining 9 with acute lymphoblastic leukaemia (ALL). The recovery of the CML group was slower than that of the ALL and AML groups. This difference was produced by the T cell compartment, as NK cell activity and B cell numbers did not differ significantly. Factors such as conditioning treatment and graft versus host disease (GVHD) prophylaxis were analysed. Our experience suggests that all leukaemia patients should not be considered as one group when analysing their immunological reconstitution, as factors related to the original disease may affect their outcome.

Immunological recovery after bone marrow transplantation for severe aplastic anaemia: a Brazilian experience.

Twenty-nine patients with severe aplastic anaemia (SAA) were submitted to bone marrow transplantation (BMT) and their immunological recovery analysed. Total lymphocyte counts, estimation of B lymphocytes, T lymphocytes and their subsets, natural-killer (NK) activity were performed. Cells with the CD8+ phenotype and NK activity were the first signs of immunological recovery, whereas the CD4+ subset recovered later in patients who suffered from acute graft versus host disease (GvHD) and infections. Acute and chronic GvHD, cirrhosis, rejection and HIV viral infection contributed to the persistence of the profound immunodeficiency status observed after BMT. Our results did not differ greatly from the others and confirmed that BMT may be performed in underdeveloped countries despite the difficulties it might pose.

Improved in vitro models for assay of rheumatoid synoviocyte chemotaxis.

OBJECTIVES: (1) To define the optimal conditions for transwell assay of synoviocyte chemotaxis. (2) To develop a live cell imaging chemotaxis assay for synoviocytes. (3) To characterize the chemotaxis of rheumatoid synoviocytes (RAS). RESULTS: Optimal conditions for transwell assay of synoviocyte chemotaxis were 8 microns pore size filters coated with collagen I (C1), assayed for 24 hours. Without the C1 coating 2.9 x 10(3) RAS migrated to the lower chamber. This increased to 4.7 x 10(3) when 20 micrograms/ml fibronectin (Fn) was added. With the C1 coating 4.3 x 10(3) cells migrated through the filter without chemotactic stimulation compared to 12.8 x 10(3) with interleukin 1 beta (IL-1 beta) 5 ng/ml, 12.2 x 10(3) with granulocyte-macrophage colony stimulating factor (GM-CSF) 25 ng/ml, 11.7 x 10(3) with Fn 20 micrograms/ml, and 9.0 x 10(3) with transforming growth factor-beta 1 (TGF-beta 1) 20 ng/ml (all p < 0.01). In the imaging assay, 50.7% of the RAS migrated toward the C1 coating without bound chemoattract. The percentage of cells migrating toward each chemoattractant at its optimal concentration was 64.3% for IL-1 beta, 60.8% for IL-8, 64.7% for GM-CSF, 61.0% for Fn, 58.9% for IL-6, and 69.1% for TGF-beta 1 (all p < 0.01). All of these chemoattractants increased directed migration without changing the random migration. Indomethacin (100 ng/ml) and Dexamethasone (10 ng/ml) inhibited Fn-induced chemotaxis. CONCLUSION: We report two in vitro assays for synoviocyte chemotaxis adapted and optimized for the study of synoviocytes. The live cell imaging assay had the advantage that it could separate directed and random migration.

Late marrow allograft rejection following alpha-interferon therapy for hepatitis in a patient with paroxysmal nocturnal hemoglobinuria.

We describe a case of allograft rejection that occurred 23 months after successful bone marrow transplantation for severe aplastic anemia in a patient with paroxysmal nocturnal hemoglobinuria. The allograft rejection appears to have been induced by recombinant alpha-interferon (rINF-alpha) treatment for non-A, non-B hepatitis that developed 11 months after transplantation. During the 9 months of active hepatitis, the donor graft functioned normally; however, 3 months after rINF-alpha therapy was started, pancytopenia and a chimeric hematopoietic state developed. rINF-alpha was discontinued, cyclosporin A was reintroduced, and autologous bone marrow recovery followed. rINF-alpha treatment may be detrimental to some recipients of allogeneic bone marrow transplants.

Successful treatment of T-gamma lymphoproliferative disease with human-recombinant granulocyte colony stimulating factor.

A trial of recombinant human granulocyte colony-stimulating factor (rhG-CSF) was attempted in a male with agranulocytosis, infection, and T-gamma lymphoproliferative disease (T-gamma-LPD). During five days of rhG-CSF (960 micrograms/day), the absolute neutrophil count (ANC) increased from 0.0 to 4.5 K/microliters. There were no changes in eosinophil or lymphocyte counts. In addition, there was no toxicity. Bone marrow cytotoxic/suppressor cells (CD57+/CD8+) were elevated (21.9%) before and decreased to 10.6% (normal less than 12%) following rhG-CSF. By contrast, there was no change in activated T cells (CD3+DR+) or T cell gene rearrangements. These findings suggest rhG-CSF can improve granulopoiesis in T-gamma-LPD, possibly by altering T-cell mediated marrow suppression.

Study of lymphocyte populations and natural killer activity in severe aplastic anaemia.

Thirty-one patients (pts) with aplastic anaemia (AA) were studied whose probable etiology were: idiopathic (16 pts), nocturnal aroxysmal haemoglobinuria (NPH) (2 pts), benzene (4 pts), agrotoxics (5 pts), pharmaceutical drugs (2 pts) and insecticides (2 pts). A decrease in total lymphocyte counts was seen in 10 pts belonging mainly to the NPH and pharmaceutical drug groups, whereas, in the benzene group the opposite was found. B cell levels were low in 9 out of 20 pts. T cell levels varied, the majority of patients had normal levels, 13 presented low levels and 4 had increased numbers. CD4 levels were low in 14 pts and T cell numbers were compensated in some by an increase in CD8 cells. Our results show that there is a great heterogeneity among the patients and there might be differences in the immunological profile of aplastic anaemia depending on the causative agent of the disease.

Control of crystal-induced arthropathies.

Present approaches to the treatment to crystal-induced arthropathies and indications for their use are reviewed. Successes and limitations of such therapy are discussed and potential new approaches to treatment are discussed. Treatment of gout hyperuricemia is generally effective if appropriately applied and is likely to be improved principally by better application of presently available drugs. New approaches to treatment may improve care for those patients in whom present approaches to management remain unsatisfactory.

A multicenter study of outcome in systemic lupus erythematosus. II. Causes of death.

Causes of death were examined for 1,103 systemic lupus erythematosus patients who were followed from 1965 to 1978 at 9 centers that participated in the Lupus Survival Study Group. A total of 222 patients (20%) died. Lupus-related organ system involvement (mainly active nephritis) and infection were the most frequent primary causes of death. Causes of death were similar throughout the followup period. Hemodialysis had little impact on the length of survival for patients with nephritis. Active central nervous system disease and myocardial infarction were infrequent causes of death. There were no deaths from malignancy.

Retention in ambulatory detoxification.

The background characteristics and mean levels of neuroticism were compared for three groups of 20 male addicts, each, who (1) completed 21 d of ambulatory detoxification, (2) transferred to methadone maintenance before completing detoxification, and (3) dropped out of detoxification. The patients who completed treatment or dropped out were more likely to be Black and less neurotic than those who transferred to methadone maintenance. In addition, it was found that patients dropped out near the time of the first methadone dose reduction, whereas those who transferred to methadone maintenance did so near the final dose reduction in the 21-d detoxification schedule. The clinical implications for retaining patients until completion of ambulatory detoxification treatment are discussed.

Pulmonary function in scleroderma.

Pulmonary function tests were performed in 45 patients with scleroderma. Thirteen patients (29%) were found to have restrictive disease, 12 patients (27%) were found to have obstructive disease, and 19 patients (42%) had small airway disease (SAD). Smoking did not seem to be a factor underlying either obstructive or small airway disease in these patients. A low diffusing capacity was most common in patients with restrictive disease and rarely the only abnormality in pulmonary function. SAD was usually found in patients who had normal chest radiographs and no pulmonary symptoms and was often the only abnormality. SAD is therefore an early and sensitive indicator of pulmonary involvement in scleroderma.

Hyperuricosuria in the Fanconi syndrome.

A patient with asymptomatic adult Fanconi syndrome with glycosuria, amino-aciduria, hypophosphatemia, and renal tubular acidosis was found to have hypouricemia (serum uric acid, 1.5-1.8 mg/100 ml) secondary to increased renal clearance of urate (urate clearance/glomerular filtration rate, 32 per cent). Increased urate clearance in this patient with multiple reabsorptive defects probably represents diminished urate reabsorption. Consistent with this, the uricosuric response to probenecid was diminished. Reabsorption of filtered urate appeared to be intact. Inhibition of urate secretion with pyrazinamide completely suppressed the uricosuria in this patient, suggesting that increased urate clearance was due to either enhanced secretion or diminished reabsorption of secreted urate. There was no direct evidence for increased urate secretion. The response of urate excretion to pharmacologic inhibitors of tubular transport of urate differs in various clinical states associated with hyperuricosuria. The responses may reflect different mechanisms of hyperuricosuria.

Leiomyosarcoma of the inferior vena cava.

The thirty-second case of leiomyosarcoma of the inferior vena cava and the twelfth resectable patient in the series is presented. A review of the literature demonstrates a marked female preponderance (5 to 1). The most common presenting symptom is right abdominal pain and a palpable mass. The different surgical problems generated by the involved segment of the cava are discussed. Noteworthy is the high incidence of Budd-Chiari syndrome owing to hepatic vein obstruction with involvement of the upper third of the cava in the postmortem cases. An argument is developed for debulking the tumor for palliation when it is not completely removable.