Outcomes of 50 leukemia patients who received bone marrow transplants from unrelated donors]

In this study, we examined the ability of tumour necrosis factor-alpha (TNF) to stimulate the mitogen-activated protein (MAP) kinase homologues p42/44 MAP kinase, c-Jun NH2-terminal kinase (JNK) and p38 MAP kinase and its effect upon DNA synthesis in primary cultures of bovine aortic endothelial cells (BAECs). TNF strongly stimulated p38 MAP kinase and JNK activity in both a time- and concentration-dependent manner. By contrast, TNF was a very poor activator of p42/44 MAP kinase relative to the known activator of p42/44 MAP kinase in endothelial cells, adenosine triphosphate (ATP). TNF-stimulated activation of p38 MAP kinase, and MAPKAP kinase-2, a known downstream target of p38 MAP kinase, was strongly inhibited by pre-incubation with the p38 MAP kinase inhibitor SB203580, whereas the minor activation of p42/44 MAP kinase was abolished by pre-incubation of the cell with the novel MAP kinase kinase 1 inhibitor PD098059. Addition of TNF resulted in a 50-60% decrease in DNA synthesis in BAECs. Pre-incubation with PD098059 or co-incubation with ATP failed to modify the inhibitory effect of TNF upon DNA synthesis. SB203580 reduced basal DNA synthesis by approximately 50%; however, if failed to modify the inhibition mediated by TNF. These results indicate that TNF strongly activates both p38 MAP kinase, JNK and, to a minor extent, p42/p44 MAP kinase. It is likely that only one of these kinases, JNK, plays a role in the regulation of DNA synthesis in these cells.     

Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia

BACKGROUND: Chronic myeloid leukemia can be cured by marrow transplantation from an HLA-identical sibling donor. The use of transplants from unrelated donors is an option for the 70 percent of patients without an HLA-identical sibling, but the morbidity and mortality associated with such transplants have been cause for concern. We analyzed the safety and efficacy of transplants from unrelated donors for the treatment of chronic myeloid leukemia and identified variables that predict a favorable outcome. METHODS: Between May 1985 and December 1994, 196 patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase received marrow transplants from unrelated donors. RESULTS: The median follow-up was 5 years (range, 1.2 to 10.1). Graft failure occurred in 5 percent of patients who could be evaluated. Acute graft-versus-host disease of grade III or IV severity was observed in 35 percent of patients who received HLA-matched transplants, and the estimated cumulative incidence of relapse at five years was 10 percent. The Kaplan-Meier estimate of survival at five years was 57 percent. Survival was adversely affected by an interval from diagnosis to transplantation of one year or more, an HLA-DRB1 mismatch, a high body-weight index, and an age of more than 50 years. Survival was improved by the prophylactic use of fluconazole and ganciclovir. The Kaplan-Meier estimate of survival at five years was 74 percent (95 percent confidence interval, 62 to 86 percent) for patients who were 50 years of age or younger who received a transplant from an HLA-matched donor within one year after diagnosis. CONCLUSIONS: Transplantation of marrow from an HLA-matched, unrelated donor is safe and effective therapy for selected patients with chronic myeloid leukemia.     

Results of allogeneic bone transplants in spondylodesis of the spine

The use of allogeneic bone bank bone was evaluated in 67 patients, operated for disorders of the spine. In 26 patients with paralytic scoliosis a pseudarthrosis developed three times and there was one infection. In 28 patients with other causes of scoliosis there were also three cases with pseudarthrosis. In the group of posterolateral arthrodesis of the lumbar spine we saw four patients out of 13 with pseudarthrosis. The results are in accordance with the literature. The use of allogeneic bone in scoliosis surgery is justified in view of the acceptable pseudarthrosis rate and the low incidence of infection. In the lumbar spine group, however, the use of bone bank bone gives less satisfactory results. The use of autologous bone is recommended for this group. There were no signs of transmission of infectious diseases in the total group of patients.     

Early cyclosporine taper in high-risk sibling allogeneic bone marrow transplants

Graft-versus-tumour reactions as a form of adoptive immunotherapy may help prevent the recurrence of haematological malignancy following allogeneic BMT. We hypothesised that such reactions may be maximised by shortening the duration of post-transplant immunosuppression by a rapid taper of cyclosporine (CYA). CYA dose was tapered between days 30 and 60 in patients at high risk of relapse, provided there was no evidence of prior significant acute GVHD. Twenty-six of 58 high-risk patients eligible at the time of transplant were subsequently tapered. Seven (27%) developed grade III/IV acute GVHD after completion of the taper, which was fatal in one patient. Chronic GVHD was observed in most patients, although with minimal overall impact on performance status. The overall probability of survival at 2 years was 43%. This non-randomised experience indicates that a rapid taper of CYA is tolerable and may provide an alternative to immunotherapy with donor leukocyte infusion in the high-risk allograft setting.     

Donor helper T-cell frequencies as predictors of acute graft-versus-host disease in bone marrow transplantation between HLA-identical siblings

BACKGROUND: Despite the current level of sophistication of molecular typing for class I and class II alleles, a significant proportion (20-40%) of recipients of HLA-identical sibling marrow develop severe, acute graft-versus-host disease (GVHD) after bone marrow transplantation. It has been suggested that the frequency of patient-specific helper T lymphocyte precursors (HTLp) detected in the HLA-identical sibling donor correlates with the incidence and severity of acute GVHD after transplantation. METHODS: This study group consisted of 42 patients who all received bone marrow from HLA-identical sibling donors from January 1990 to December 1996. Using a limiting dilution analysis, donor HTLp frequencies were determined on samples collected before transplantation. The HTLp assay used the cytotoxic T-cell line, CTLL-2, which proliferates in the presence of interleukin-2. The reliability and reproducibility of this assay was established by using cryopreserved batches of CTLL-2 cells of known sensitivity. RESULTS: The recipient-directed HTLp frequencies detected in the donor before transplantation were correlated with the incidence and severity of acute GVHD experienced by the recipient after transplantation. Statistical analysis revealed an extremely significant correlation between donor precursor frequencies and the development of acute GVHD in the patient after transplantation (P<0.0001). CONCLUSIONS: This study suggests that together with molecular typing the HTLp frequency should be considered when selecting the most suitable sibling donor for bone marrow transplantation.     

Influence of protective isolation on outcome of allogeneic bone marrow transplantation for leukemia

Most of the previously published surgical series of suprasellar meningiomas have two disadvantages: (1) patients involved were treated within a relatively long time period, making analysis more difficult, (2) radiographic long term follow-up examinations with either CT- or MRI-scans were not performed. Both disadvantages were overcome in our retrospective clinical study, consisting of 50 consecutive patients with suprasellar meningiomas treated between 1982 and 1991. Radiological, ophthalmological, and neurological investigations were performed preoperatively, postoperatively and at long term follow-up (mean: 5.7 years). A radiologically confirmed radical tumour removal could be achieved in 84% of patients. Both, the peri-operative mortality (2%) and serious operative morbidity (6%) were low. However, 12% of patients developed late onset epilepsy. At long term follow-up, visual function was improved in 67%, unchanged in 9% and worsened in 24%. In more than 50% of patients the vision showed recovery over a longer time period than the first 10 days after operation. Radiographic control examinations revealed tumour recurrences in 2 patients (both asymptomatic) and progress of residual tumour in 5 patients (2 symptomatic, 3 asymptomatic). Since introduction of modern neurosurgery, a clear improvement in the surgical treatment of suprasellar meningiomas can be observed. However, the still long delay in diagnosing these tumours correctly prevents a further improvement of the ophthalmological results at long-term follow-up. Due to a relatively high rate of late onset epilepsy, anticonvulsive prophylaxis for 6 months seems to be justified. Regarding present preoperative diagnostic measures, ia-DSA seems only be indicated in patients with CT/MRI-scans, suspicious for tumourous narrowing or invasion of major cerebral arteries. In addition, we recommend radiographic control examinations at regular time intervals to confirm radical tumour removal and to detect the "ideal" point of time for renewed treatment.     

Multiple minor histocompatibility antigen disparities between a recipient and four HLA-identical potential sibling donors for bone marrow transplantation

A patient with acute leukemia and her family including four HLA-identical siblings were analyzed to select a donor who was not only HLA- but also minor histocompatibility (mH) antigen compatible for allogeneic bone marrow transplantation (BMT). The HLA-A2 restricted mH antigen-specific HA-1, -2, -4, and -5 cytotoxic T-lymphocyte (CTL) clones were used to type the family members for expression of these mH antigens. The patient and one HLA-identical sibling were compatible for these mH antigens. This sibling was selected as the bone marrow donor. The patient engrafted promptly but developed acute and chronic graft-versus-host disease. To study the presence of other mH antigen disparities between recipient and donor, host-versus-graft CTL lines and clones were generated by stimulation of recipient peripheral blood lymphocytes (PBLs) with donor bone marrow cells, and graft-versus-host CTL lines were generated after BMT by stimulation of PBLs of donor origin with recipient bone marrow cells. These CTL lines were cytotoxic to cells from the bone marrow donor and from the recipient, respectively, and to cells from several other family members. T-cell lines, generated from the patient after BMT by stimulation of recipient-derived PBLs with donor bone marrow cells, exhibited no specific cytotoxicity to donor or recipient cells. Chimerism studies after BMT revealed that the PBLs and T-cell lines generated after BMT were of donor origin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Early neurologic complications following allogeneic bone marrow transplant for leukemia: a prospective study

BACKGROUND: Bone marrow transplant (BMT) is used for both neoplastic and nonneoplastic diseases. Following BMT, particularly during the first 3 months, patients have a number of neurologic complications. We evaluated the early neurologic complications following BMT and their influence on survival. METHODS: We prospectively followed 115 consecutive patients having BMT for leukemia, for a median period of 90 days after transplantation. RESULTS: Sixty-four patients (56%) had neurologic complications. Sixteen developed more than one complication. Twenty-seven patients (25%) had major neurologic complications: metabolic encephalopathy (8), seizures (8), psychiatric symptoms (3), cerebral hemorrhage (1), cerebral abscess (1), leukemic meningitis (1), peripheral neuropathies (5), and myopathies (2). Forty patients (35%) had minor complications, including headache (16) and tremor (31). Major neurologic complications occurred after engraftment in most patients. Metabolic encephalopathy correlated with graft-versus-host disease (GVHD) (p < 0.03). Seven percent of patients had generalized seizures that occurred without signs of structural cerebral lesions. Probability of survival at day 90 was lower in patients with than in those without major central nervous system complications (63% versus 87.5%, p < 0.01). CONCLUSIONS: Neurologic complications are frequent during the first 3 months following BMT and affect patient survival. Drug neurotoxicity and acute GVHD are the main factors influencing their occurrence.     

Donor leukocyte transfusion as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation

We reviewed 4 cases of high-grade transitional-cell carcinoma (TCC) of the urinary tract with solitary pulmonary metastases that were studied by transthoracic needle aspiration biopsy cytology. There were two grade II and two grade III TCCs. The two grade II tumors yielded, in needle aspirates, syncytial tumor-cell clusters showing ill-defined, granular cytoplasm and slightly pleomorphic nuclei with inconspicuous nucleoli. In one case the tumor-cell cluster showed a focal acinar arrangement, mimicking cells of an adenocarcinoma. In both cases the electron microscopy (EM) study of aspirated tumor cells revealed epithelial cells with well-formed cell junctions, intracytoplasmic vesicles, apical short microvilli, and focal interdigitation of lateral cell membranes, suggesting a urothelial neoplasm. The two grade III TCCs yielded, in needle aspirates, pleomorphic malignant cells singly and in small clusters, showing well-defined, granular cytoplasm and pleomorphic nuclei containing prominent nucleoli, suggesting a poorly differentiated adenocarcinoma or an anaplastic large-cell carcinoma. By EM examination the aspirated tumor cells from one case revealed well-formed cell junctions, intracytoplasmic vesicles, poorly formed microvilli, and focal interdigitation of lateral cell membranes, suggesting a urothelial differentiation. In the other case the tumor cells were pleomorphic cells with occasional cell junctions and no ultrastructural features as seen in the other 3 cases of TCC. The tumor cells from the two grade II TCCs showed strong immunopositive reaction with keratin 7 antibody and weakly positive reaction with carcinoembryonic antigen antibody (CEAA), while those of the two grade III TCCs displayed only a weak and focal immunopositive staining with keratin 7 antibody and strong reaction with CEAA.     

Worldwide Web of bone marrow donors

The first successful Bone Marrow Transplant (BMT) was performed in the 1960s. Initially, patients had to have a sibling donor which limited BMT to approximately 30% of patients. The development of regional donor registries and subsequently the establishment of the National Marrow Donor Program (NMDP) in 1986 has expanded the availability of BMT so that the majority of patients in need of a BMT have access to a donor. Physicians need to be aware of the donor registry to encourage their patients to be donors and to know when to refer a patient for consideration for BMT.     

Possible transmission of sarcoidosis via allogeneic bone marrow transplantation

Allogeneic bone marrow transplantation (BMT) was performed in a 34-year-old man for non-Hodgkin's lymphoma. Two years before bone marrow harvest, pulmonary sarcoidosis was diagnosed in the donor. After steroid therapy, disease of the donor was in clinical remission with only minor radiological signs at the time of BMT. On day 90 after BMT, active sarcoidosis was diagnosed in the recipient. Besides radiologic signs and increased angiotensin converting enzyme levels, diagnosis was proved by characteristic histologic changes in lung and liver biopsies. Immunosuppressive therapy was changed from high dose cyclosporine to high dose methylprednisolone and symptoms promptly resolved within 10 weeks. This case indicates the possibility of transmission of sarcoidosis by marrow transplantation.