Treatment of adrenoleukodystrophy with bone marrow transplantation

Three children with adrenoleukodystrophy (ALD) underwent allogeneic bone marrow transplantation (BMT) between 1992 and 1993. The first boy had attention deficits, marked neuropsychological deficits and widespread demyelination in the frontal lobes on MRI before transplantation. Four years later he has mentally deteriorated and the demyelination on MRI has progressed. The second boy had no symptoms but had white matter lesions on MRI when diagnosed. He was regularly followed with MRI and neuropsychological investigations until BMT 18 months later. A progress of the lesions was noted on the initial MRI investigations, and 4 months before BMT a worsening of deficits in attention and kinaesthetic praxis could be observed. He rapidly deteriorated after the transplantation and died 18 months later. Both PCR and in situ hybridization confirmed the presence of donor cells in the brain. The third boy had no symptoms but white matter lesions on MRI when diagnosed. The neuropsychological tests remained normal but a slight progress was observed on MRI just before transplantation. This boy is still healthy 3.5 years after BMT. BMT as treatment for ALD has to be considered very early, even if a child without symptoms but signs of demyelination on MRI, if a suitable donor is available.     

Bulky lymphadenopathy in acute myeloid leukemia

Two cases of acute myeloid leukemia (AML) presenting with bulky adenopathy are reported. Both patients were febrile at admission and showed massive and diffuse lymph node involvement, hepatomegaly, and splenomegaly. Erythematopapular leukemic skin lesions were present in one case at the onset and developed in the other at the time of relapse. Anemia, thrombocytopenia, and moderate leukocytosis were present in both. The presence of immature cells in peripheral blood and bone marrow allowed a rapid diagnosis of AML, FAB M1, in one patient. In the other case, owing to the paucity of immature cells in peripheral blood and bone marrow, lymph node biopsy with histology, imprint cytology, and immunocytochemistry were essential for the diagnosis (AML, FAB M2, with trilineage dysplasia and basophilic involvement). Both patients achieved complete remission (CR), followed by an early relapse 3 months later. They underwent allogeneic bone marrow transplantation (BMT) from HLA identical siblings. One patient is actually alive and in CR at 6 months after BMT; the other patient showed a leukemic regrowth after transplantation and died 4 months later.     

Neurological and neuroradiological findings in long-term survivors of allogeneic bone marrow transplantation

The aim of this study was to assess neurological, neuropsychological, and neuroradiological findings in long-term survivors of allogeneic bone marrow transplantation (BMT) who were recruited from a hematological outpatient clinic. In addition, risk factors for the development of late neurological complications were identified. In contrast to previous studies on autopsied patients, our study design provoked a bias away from increased neurological sequelae, because patients with early complications after BMT were excluded. Fifty-nine allogeneic patients and 7 autologous BMT patients underwent clinical examination, short neuropsychological testing, and cranial magnetic resonance imaging (MRI) 34 +/- 26 months after BMT. The pathological results of the neurological examination (abnormal 64%) and the MRI examination (white matter lesions, 54%; atrophy, 11%) were associated with the occurrence of chronic graft-versus-host disease (GvHD) evolving from acute GvHD, with corticosteroid therapy and with cyclosporine medication. Neuropsychological impairment (cognitive deficits, 37%) was associated with long-term cyclosporine medication and age. No influence of pre-BMT disease, BMT donor status, or the conditioning regimen was found. These results suggest that the frequent neurological abnormalities in long-term survivors of allogeneic BMT are associated with chronic GvHD and with the resulting immunosuppression as major risk factors.     

Analysis of proteins that interact with the IL-2 regulatory region in patients with rheumatic diseases

Bone marrow transplantation (BMT) involves conditioning with cyclophosphamide and, for leukemic patients, total body irradiation (TBI). Based on the concern that this may lead to later neuropsychologic impairment in children, a longitudinal study was conducted. Thirty pediatric bone marrow transplant recipients, treated for leukemia or severe aplastic anemia (SAA), and their sibling donors, were given a neuropsychological examination in 1986 and 1988. A third follow-up study of patients treated before 12 years of age was undertaken in 1990-91. We present longitudinal data on patients treated with BMT when 3-11 (n = 15) and 12-17 (n = 11) years old. No neuropsychological deficits were found in the older group, or among non-irradiated SAA patients. In the first follow-up, children treated with BMT, including TBI at 3-11 years of age, performed less well than donors on tasks involving perceptual and fine-motor speed. In the second follow-up, this group of patients also demonstrated a slight deficit in non-verbal problem solving. An additional relative decline in verbal reasoning was noted in the third follow-up, 5.5-10 years after treatment. Alertness to signs of developmental difficulties in children treated with BMT, including TBI, is recommended.     

Fulminant, CMV-associated, haemophagocytic syndrome following unrelated bone marrow transplantation

We report a case of haemophagocytic syndrome (HPS) occurring after allogeneic bone marrow transplantation (BMT) for acute promyelocytic leukaemia (APL) in a patient in fourth complete remission (CR). Anti-cytomegalovirus (CMV) antibody (Ab) was negative in this patient before BMT. BMT was performed from an HLA-identical unrelated donor who was positive for CMV Ab. After bone marrow engraftment and haematological recovery, severe acute graft-versus-host disease (GVHD) developed. This patient was treated with methylprednisolone in addition to cyclosporin A (CsA). Acute GVHD showed partial improvement, but CMV antigenaemia was observed. Despite administration of gancyclovir and immunoglobulin, CMV antigenaemia showed no improvement and HPS developed. As no other infections or malignancies were observed, we suspect that CMV infection was the trigger for development of HPS.     

Effects of prednisolone on bone turnover in patients with corticosteroid resistant asthma

Many galactosaemics appear to have neuropsychological and/or linguistic problems in spite of dietary treatment. Because the neonatal screening program in Norway does not include galactosaemia, we have re-examined Norwegian galactosaemics. Of 16 known patients, 8 patients participated in the study. They had been diagnosed between 2 and 11 weeks of age, and were between 9 months and 19 years old at the time of this study. All had very low or 0 activity of galactose-1-phosphate uridyl transferase. As part of the study all were examined neurologically, and had an age-appropriate developmental/IQ test, an ABR and an EEG, and a comprehensive psycholinguistic evaluation. The three youngest patients had normal developmental/IQ tests, while the five older patients had IQ scores in or below low range of normal. The majority had delayed language development and three patients were classified as having verbal dyspraxia. ABR and EEG showed mild pathology in the oldest patient only. Galactosaemia appears to be associated with significant risks of developmental and language delays in this unscreened population.     

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)     

Methylsulfonyl metabolites of PCBs and DDE in human tissues

More than 15 years passed since bone marrow transplantation (BMT) have first introduced to the field of treatment of pediatric cancer. During this period, technology and modality of BMT have been improved steadily and several kinds of hemopoietic stem cell transplantation, for instance, allogeneic BMT from related or unrelated donor, unpurged or purged autologous BMT by 4-hydroperoxycyclophosphamide (4-HC) or magnetic immuno-beads, allogeneic or autologous peripheral blood stem cell transplantation and cord blood stem cell transplantation became available. Now we can choose the most suitable transplantation method for each patient from our repertory according to the patient's condition. In this article, treatment result of allogeneic BMT and 4-HC purged autologous BMT for children with acute leukemia and several kinds of hematopoietic stem cell transplantation for children with solid tumors in my hospital were reported.     

Relation between urinary cytology abnormalities and cyclosporine A therapy in bone marrow transplant recipients

The aim of the study was to determine the relationship, if any, between abnormalities in urinary cytology and the administration of cyclosporine A in bone marrow transplant recipients. Specific attention was given to the presence of tubular cells with round inclusions (TCRI). Two bone marrow transplant recipient groups were studied: one with allogeneic bone marrow transplantation (BMT) (20 patients) who were treated with cyclosporine A, and the other with autologous BMT (12 patients) who did not receive cyclosporine A. Urinary cytology showed TCRI in 41.66% of the patients after autologous BMT and in 80% of the patients after allogeneic BMT. In the group of patients treated with allogeneic BMT, the occurrence of TCRI was associated with a high incidence of glycosuria and was followed by an increase in the blood level of cyclosporine A, an increase in the serum creatinine concentration and a decrease in the creatinine clearance. These results demonstrated that TCRI, although related to, were not found to be exclusively specific to the administration of cyclosporine A.     

New somatic mutation in the PIG-A gene emerges at relapse of paroxysmal nocturnal hemoglobinuria

We report a detailed longitudinal study of the first patient to be treated (in 1973) for paroxysmal nocturnal hemoglobinuria (PNH) with syngeneic bone marrow transplantation (BMT). The patient subsequently relapsed with PNH in 1983, and still has PNH to date. Analysis of the PIG-A gene in a recent blood sample showed in exon 6 an insertion-duplication causing a frameshift. Polymerase chain reaction (PCR) amplification of the PIG-A exon 6 from bone marrow (BM) slides obtained before BMT showed that the duplication was not present; instead, we found several single base pair substitutions in exons 2 and 6. Thus, relapse of PNH in this patient was not due to persistence of the original clones; rather, it was associated with the emergence of a new clone. These findings support the notion that the BM environment may create selective conditions favoring the expansion of PNH clones.     

Which is the reality of Chagas disease in Argentina and in America?

Selective neutropenia lasting over five months occurred in a 17-year-old adolescent male who received an allogeneic bone marrow transplantation (BMT) from an HLA-identical sibling for severe aplastic anemia. Bone marrow specimens showed maturation arrest of myeloid precursor cells despite sustained engraftment. Cytogenetic analyses revealed complete donor-type chimerism in hematopoietic cells and mixed lymphoid chimerism. The patient received a second BMT from the same donor following more intensive conditioning, including total body irradiation. Neutrophil recovery was rapid and complete donor-type hematopoietic and lymphoid chimerism was observed within three weeks of the second transplant. The present case suggests that prolonged selective neutropenia following BMT is due to residual host-derived immunity which is resistant to the standard immunosuppressive conditioning used prior to BMT for aplastic anemia.     

Left hemispheric neuronal heterotopia: a PET, MRI, EEG, and neuropsychological investigation of a university student

A 21-year-old left-handed medical student had a prominent unilateral cerebral cortical malformation due to an ontogenetic migration disorder. We performed neuropsychological studies, EEG, T1- and T2-weighted and proton-density MRI, and positron emission tomography (PET) (under both the resting condition and neuropsychological activation). Neuropsychological testing revealed normal intelligence and generally normal memory functioning but selective deficits in tests of verbal fluency and spatial-figural relationships. Proton-density and T2-weighted MRI revealed extensive left cortical heterotopia that included parts of the Wernicke area. PET under the resting condition revealed a small interhemispheric difference with slightly reduced glucose metabolism in the left temporoparietal cortical zone. An activation PET (with the patient performing a verbal fluency test) resulted in a normal overall increase in metabolism but marked deviations in cortical areas. The highest activity changes were in the Broca and Wernicke areas of the right hemisphere, and there was very little activation in those regions of the left hemisphere that were expected to respond well to the activation--the temporal, parietal, and temporo-occipital cortical zones. We conclude that there can be large compensations for unilateral heterotopia.     

Pilot neuropsychological findings from a treatment regimen consisting of intensive chemotherapy and bone marrow rescue for young children with newly diagnosed malignant brain tumors

Ten children (6 girls and 4 boys) who completed a protocol in which their localized brain tumors were successfully treated without cranial irradiation were referred for neuropsychological assessment. At the time of testing, they were disease free without any neuroaxis dissemination or leptomeningeal disease. Tumor types included pineoblastoma, glioblastoma, ependymoma, PNET and medulloblastoma. They had a mean age of 5 years and 8 months (SD = 1.86; range = 2.1-8.9 years) and were an average of 37.8 months post bone marrow transplant (SD = 16.42; range = 14-58 months). Neuropsychological data from this study reveal that the mean scores for this nonradiated group of children were within the average range for the following domains: academic achievement tests of reading, spelling and mathematics, verbal and visual memory, visual-motor integration, social-emotional and behavioral functioning. Furthermore, this group of children were performing within the low average range of overall Intelligence, as well as both verbal IQ/verbal reasoning and performance IQ/abstract visual reasoning. On tasks of fine motor dexterity, this group was within the low average range when using their dominant hand; however, they performed within the borderline range when using their non-dominant hand. Of note, this group of children demonstrated significant deficits within the borderline to impaired ranges on language tasks of expressive picture naming and receptive picture vocabulary.     

Primary Sj?gren's syndrome followed by chronic myelogenous leukemia: a case report with a ten year history

We describe a female patient with primary Sj?gren's syndrome who subsequently developed chronic myelogenous leukemia. The patient received a bone marrow transplant (BMT) from a genotypically HLA-identical brother after pre-transplant preparation with busulfan and cyclophosphamide. Eighteen weeks later, cutaneous and mucosal chronic graft-versus-host disease developed, followed by death 11 months after transplantation. Anti-Ro/SS-A antibodies disappeared within 6 months post-BMT, but antinuclear antibodies remained positive through the post-transplant course.     

Fatal eosinophilic disease following autologous bone marrow transplantation

A 15-year-old girl developed massive, fatal eosinophilic disease following autologous bone marrow transplantation (BMT) for Hodgkin's disease (HD). Prior to autologous BMT, the erythrocyte sedimentation rate (ESR) was elevated, with active HD, but eosinophilia was absent. Post-autologous BMT, ESR and peripheral eosinophilia were observed to correlate with respiratory symptoms. Initial evaluation revealed no recurrent tumor, infection or other identifiable etiology. A diagnosis of chronic eosinophilic pneumonia was made following lung biopsy. A complete response was initially achieved with steroid therapy; however, when steroid therapy was tapered, the eosinophilia and elevated ESR recurred with worsening respiratory symptoms. Terminally, severe pulmonary disease developed and recurrent HD was found in lung, lymph nodes and bone marrow. During episodes of eosinophilia, the patient's serum stimulated her bone marrow as well as control marrow to produce predominantly eosinophilic colonies. Eosinophilic colony production was not observed with patient's sera obtained prior to or during autologous BMT or with control sera. This patient died of eosinophilic inflammatory disease following autologous BMT. The etiology of this disease was not definitely identified but appeared to be due to an eosinophilic-stimulating factor which developed after autologous BMT.     

Immunoablation does not delay the neurologic progression of X-linked adrenoleukodystrophy

We report the results of a near total myeloablation in preparation for bone marrow transplantation in a boy with minimal symptoms of X-linked adrenoleukodystrophy. Severe cerebral X-linked adrenoleukodystrophy developed in the patient after failure of bone marrow transplantation. This experience suggests that immunotherapy alone is not responsible for the improvement observed in some patients with X-ALD after BMT.     

Minimal residual disease after allogeneic bone marrow transplantation for chronic myeloid leukaemia: a metaphase-FISH study

Metaphase-FISH was adopted for the detection of proliferating Philadelphia-positive (Ph+) residual leukaemic cells in 25 patients with chronic myeloid leukaemia treated with allogeneic bone marrow transplantation (BMT). Patients were followed up during their clinical remission for 4-50 months (median 17 months) after BMT. 80 bone marrow samples were studied. For most of the cases no fewer than 1000 metaphases were analysed. Six patients (24%) showed residual Ph+ cells during the first 6 months and two others by the end of the first year after BMT. Three patients relapsed during the study and in two of them residual Ph+ cells were detected during the first 6 months after BMT. In 17 patients no Ph+ cells were detected at any stage of follow-up and 16 (94.1%) of them continue in complete clinical and haematological remission. Our results indicate that metaphase-FISH is a reliable tool in the quantitation of proliferating residual leukaemic cells. We suggest that consecutive findings of equal amounts of residual leukaemic cells do not necessarily predict a relapse. However, their presence calls for follow-up at shorter intervals where an increasing number of these cells predicts an ensuing relapse.     

Outcomes of recipients of both bone marrow and solid organ transplants. A review

In this review we examine the clinical outcomes of patients who have received both bone marrow transplantation (BMT) and solid organ transplantation (SOT) and discuss the possible immunologic consequences of the dual transplants. We collected cases through a comprehensive literature search (MEDLINE database, English literature only) covering the years 1990 through 1997 and correspondence with the International Bone Marrow Transplant Registry. Our study selected case reports of patients who have undergone both bone marrow and solid organ transplants; cases in which bone marrow transplantation was undertaken as an adjunct ot induce or augment donor-specific tolerance in a recipient to the transplanted organ were excluded. Clinical characteristics included patient's demographic information, underlying disorders for each transplant, source of donor organ or tissue, time between transplants, and immunosuppressive regimens used to prevent graft-versus-host disease (GVHD) or graft rejection. Clinical outcomes included patient survival, complications of transplantation, and donor-specific tolerance that was experienced in many cases. Twenty-one cases of SOT after BMT and 7 cases of BMT after SOT were reviewed. Solid organ transplantations included lung, liver, cardiac, and kidney for a variety of BMT-related complications including GVHD, hepatic veno-occlusive disease, chronic renal failure, end-stage pulmonary disease, and severe cardiomyopathy. Bone marrow transplants were performed following SOT for aplastic anemia and hematologic malignancies. Clinical outcomes for patients who received both BMT and SOT were variable and depended on transplant indication and degree of histocompatibility. Prior bone marrow transplantation may tolerize for a subsequent organ transplant from the same donor. Conversely, severe GVHD may follow BMT from human leukocyte antigen (HLA)-matched donors following SOT. The favorable survival in this high-risk group of patients may represent a literature review bias (that is, an undetermined number of unsuccessful cases may not have been reported). Nonetheless, dual transplantation is clearly feasible in selected cases.     

Filgrastim for the treatment of leukemia relapse after bone marrow transplantation

The absence of an effective therapy for most patients with leukemia who relapse after allogeneic BMT has generated interest in new strategies. We present our experience on the use of filgrastim 5 micrograms/kg/day s.c., in four patients with leukemia (three with AML and one with CLL) who relapsed after allogeneic transplantation. One patient with AML achieved CR after 55 days of treatment. No response was observed in the remaining three. The patient who responded developed extensive chronic GVHD but relapsed 10 months later. In one of the unresponsive patients a dramatic increase in bone marrow infiltration and WBC count followed administration of filgrastim. We conclude that filgrastim can occasionally induce CR in leukemic patients who relapse after BMT.     

High-performance liquid chromatographic analysis of aminoglycoside antibiotics

The Category Test (CT) and the Wisconsin Card Sort Test (WCST) have long been the major instruments used for the assessment of "frontal lobe" brain damage. These tests have often been used interchangeably by clinicians. However, research to date has disagreed on the extent to which these tests can be interpreted in a similar manner. The current paper examined the interrelationships between the tests in 112 mixed brain injured clients. The results showed relatively small correlations between the tests in the range of .4 to .6 which were eliminated when age, education, premorbid IQ (Vocabulary) and spatial skills (Block Design) were used as covariates. Regression analyses showed clear differences in which WAIS-R tests predicted each test, while factor analysis revealed little overlap between the tests except for a small relationship between the number of WCST categories completed and CT errors. The CT appeared to reflect spatial and spatial analysis skills while the WCST reflected verbal analysis and sequential skills. The results clearly indicate that the tests are not interchangeable and do not reflect the same underlying cognitive skills nor can they be interpreted in the same manner for neuropsychological purposes.