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Bone Marrow Transplantation↗
Biomedical subjects
J Goldman
Publications and source records attributed to J Goldman.
European survey of bone marrow transplantation in acute promyelocytic leukemia (M3). Working Party on Acute Leukemia of the European Cooperative Group for Bone Marrow Transplantation (EMBT).
Acute promyelocytic leukemia (M3) is a distinct subtype of AML considered to have better response to chemotherapy and a higher cure rate than other subtypes. We analyzed the outcome for 362 M3 patients transplanted in Europe from November 1979 to December 1992 and reported to the acute leukemia registry of the European Cooperative Group for Bone Marrow Transplantation (EMBT). Of these 362 patients, 187 received an autograft, 129 in first remission (CR1) and 58 in second remission (CR2), and 175 an allograft, 142 in CR1 and 33 in CR2. Patients autografted in CR1 had at 7 years a leukemia-free survival (LFS) of 48 +/- 5%, a relapse rate (RR) of 41 +/- 5% and a probability of transplant-related mortality (TRM) of 18 +/- 6%. Patients allografted in CR1 had a LFS of 42 +/- 6%, a RR of 28 +/- 5% and a TRM probability of 42 +/- 8%. For patients transplanted in CR2, the respective figures after auto and allotransplantation were: LFS: 31 +/- 7% and 22 +/- 8%, RR: 54 +/- 8% and 64 +/- 11%, TRM: 23 +/- 9% and 40 +/- 9%. These data, which do not permit comparison between autologous and allogeneic BMT, indicate that roughly 45% of M3 patients achieving CR1 may be cured by a marrow transplant. Since the recent use of transretinoic acid-containing induction regimens has increased early control for patients with AML M3, it will be important to find out how these results affect outcome following allogeneic or autologous BMT.
Adolescent↗
Autologous stem cell transplantation in chronic myelogenous leukemia: a retrospective analysis of the European Group for Bone Marrow Transplantation. Chronic Leukemia Working Party of the EBMT.
Over a 3 year period (1989-1991), 49 patients who underwent autologous stem cell transplantation (ASCT) for chronic myelogenous leukemia (CML) in chronic phase were reported to the European Bone Marrow Transplant Registry. Most patients had bad prognostic factors. The results were analyzed by 1 September 1993. Hematological recovery was observed in 45 cases and was significantly quicker after blood stem cell transplantation (n = 30) than after BMT (n = 19). Five patients died early and five other patients did not achieve a complete hematological response (CHR) following ASCT. Of the 39 patients who achieved CHR, 34 are still alive 17 to 52 months after ABSCT. Fifteen of the 34 patients who had cytogenetic evaluation exhibited a major response (> or = 65%, Ph-negative metaphases). The actuarial risk of transformation for the 44 evaluable patients was 28.1 +/- 15% (95% CI) and the actuarial survival at three years was 81.5 +/- 15% (95% CI). No factors were found to significantly influence the response rate or the patients' survival. These encouraging results suggest that ASCT by itself could play a role in prolonging survival in CML patients.
Adolescent↗
Lack of reciprocal translocation in BCR-ABL positive Ph-negative chronic myeloid leukaemia.
We used fluorescence in situ hybridization (FISH) to metaphase chromosomes with BCR and ABL cosmid probes in conjunction with the polymerase chain reaction (PCR) to study the mechanism by which the ABL proto-oncogene is inserted into a morphologically normal chromosome 22 in patients with Ph-negative chronic myeloid leukaemia characterized by the BCR-ABL chimeric gene. In control patients with Ph-positive CML the ABL probe localized to 22q- and the 3' BCR probe localized to 9q+. In nine Ph-negative CML patients the ABL probe localized to one normal chromosome 9 and to one 'normal' chromosome 22. Both 5' and 3' BCR probes localized exclusively to the chromosomes 22. By PCR all had evidence of BCR-ABL transcripts, but none had evidence of the reciprocal ABL-BCR gene product that is seen in 70% of the Ph-positive CML patients. These data confirm the view that Ph-negative CML results from insertion of ABL-containing DNA sequences into a normal-appearing chromosome 22 without reciprocal translocation of sequences from chromosome 22 to chromosome 9.
Adult↗
Are patients with acute leukaemia, alive and well 2 years post bone marrow transplantation cured? A European survey. Acute Leukaemia Working Party of the European Group for Bone Marrow Transplantation (EBMT).
We investigated the occurrence of late events (beyond 2 years) in patients with acute leukaemia who received an allogeneic (BMT) (n = 1059), or an autologous bone marrow transplantation (ABMT) (n = 656) in Europe during the period from January 1979 to December 1990. Patients with no recurrence of leukaemia at 2 years had overall 82% chance of being alive in complete remission at 9 years following transplantation regardless of the nature of the leukaemia, the status at transplant, and the type of transplant. The incidence of late relapses continuously decreased with time. The latest relapses in acute myelogenous leukaemia (AML) were observed following BMT at 6.6 years in a patient transplanted in first remission (CR1) and at 3.7 years in a patient transplanted in second remission (CR2), and following ABMT at 6 years and 5.1 years respectively. The latest relapses in acute lymphoblastic leukaemia (ALL) were observed following BMT at 4 years in a patient transplanted in first remission (CR1) and at 6.8 years in a patient transplanted in second remission (CR2), and following ABMT at 5.3 years and 4.5 years respectively. Several factors predictive for late relapse or death were identified. Patients allografted experienced a lower frequency of late relapse than patients autografted. Of the numerous other prognostic factors studied, female sex in AML, the use of total body irradiation (TBI) in ALL and status in CR1, rather than CR2-3, for both ALL and AML allografted were correlated with a lower relapse incidence. The use of TBI in ALL was also associated with a better LFS and survival. The absence of acute graft-versus-host disease (GVHD) in allografted AML correlated with better LFS and better survival, but had no influence on the relapse incidence. This study indicates that patients alive and well at 2 years post transplant have a very high probability of being cured, but the possibility of late relapse still remains.
Adolescent↗
X-inactivation pattern in an Ullrich-Turner syndrome patient with a small ring X and normal intelligence.
In a description of 8 girls who had Ullrich-Turner syndrome (UTS) with a small r(X), mental retardation, and other unusual findings, it was hypothesized that the distinctive phenotype was associated with the loss of the X inactivation center from the r(X) and lack of genetic inactivation of the ring [Van Dyke et al., 1992]. Here, we present a 17-year-old young woman with 45,X/46,X,r(X)(?p11q13) mosaicism, Ullrich-Turner syndrome, and normal intelligence. In situ hybridization with the X-centromere DNA probe DXZ1 (Oncor, Inc., Gaithersburg, MD) was performed on previously G-banded slides, and the probe hybridized to the centromere regions of the normal X and the ring. The r(X) appears to be inactivated since a buccal smear demonstrated 5% Barr bodies. Furthermore, DAPI stain and FISH analysis with the X-centromere DNA probe DXZ1 was employed to distinguish the inactive X from the active X, and verified the presence of a sex chromatin mass in fibroblasts. These observations are consistent with the active-ring-X-and-mental-retardation hypothesis since the ring in this patient, although very small, appears to be normally inactivated and she has normal intelligence.
Adolescent↗
Brief report: myeloma-associated paraprotein directed against the HIV-1 p24 antigen in an HIV-1-seropositive patient.
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Adult↗
Unique pancreatic carcinoma cDNA found via subtracted libraries with limited normal tissue and tumor from the same patient.
We have approached the problem of isolating clones unique to specific malignancies such as T-cell acute lymphoblastic leukemia (ALL) and pancreatic adenocarcinoma by using subtractive hybridization techniques. Our initial studies involved using normal donor tissue (i.e., normal blood donors for ALL and cadaver renal transplant donors for normal pancreatic tissue) and cultured malignant cell lines. It occurred to us that normal pancreatic tissue from the same patient source as that of the malignant tissue might subtract out normal sequences more readily and enrich clones unique to pancreatic adenocarcinoma because of patient/donor identity. Using such a method meant that the amounts of tissue for overcoming this obstacle. We constructed independent UNI-ZAP-XR cDNA libraries (normal and malignant) and used them to amplify either the normal or malignant cDNA prior to subtractive hybridization. We then obtained rescued single stranded cDNA from the malignant ZAP library. The RNA which was not hybridized was isolated. The process was repeated and a double subtraction was effected. The residual non-hybridized RNA was used as a template for first and second strand synthesis. After the EcoRI adaptors were ligated to the double stranded cDNA it was cloned into Lambda ZAP II arms to form a double subtracted malignant cDNA library. A subtracted probe was prepared from the double subtracted cDNA library. Single stranded cDNA was rescued, double stranded plasmid was made, the plasmid DNA was digested with EcoRI, the digested DNA was run on a 1% SeaPlaque gel, and the insert cDNA was recovered using Ultra-Free MC and Ultra-Free Probind filters. The subtracted malignant cDNA library was probed with the subtracted probe and with normal cDNA (obtained from the normal ZAP library) and those plaques which were positive per the subtracted probe and negative per the normal cDNA were isolated; their cDNA inserts are being further characterized.
Actins↗
A study of plasma sodium levels in elderly people taking amiloride or triamterene in combination with hydrochlorothiazide.
This study was performed to compare the effect of one month's treatment with hydrochlorothiazide (25 mg) in combination with either amiloride (2.5 mg) or triamterene (50 mg) on plasma sodium levels in elderly people in institutional care. Fifty residents of NHS nursing or social service residential care established on diuretics for congestive cardiac failure and aged 64 years or over were recruited. Forty-one patients were included in the final data analysis. Patients on hydrochlorothiazide/amiloride had a significantly lower plasma sodium (137 vs 139 mmol/l, 95% confidence interval for difference between medians 0-2 mmol/l) than those on hydrochlorthiazide/triamterene (P = 0.01). In equivalent potassium-retaining doses, amiloride is associated with significantly lower plasma sodium levels than triamterene, when given in combination with hydrochlorothiazide in elderly patients with congestive cardiac failure. This finding adds weight to uncontrolled observations implicating thiazide/amiloride diuretic combinations in causing serious hyponatraemia. This danger, although uncommon, should perhaps influence prescribing habits in an at-risk population.
Aged↗
Late relapse after allogeneic bone marrow transplantation for Philadelphia-positive acute lymphoblastic leukaemia.
Late relapse of leukaemia is rare in patients with chronic myeloid leukaemia (CML) subjected to allogeneic bone marrow transplantation in chronic phase. Herein, we report a patient who presented with acute lymphoblastic leukaemia who after chemotherapy developed a picture consistent with CML in chronic phase. He then received an allograft from an HLA-identical sister and remained in complete remission for 4 years, before he eventually relapsed with features of myeloid transformation of CML. We speculate that the same population of already transformed leukaemic progenitor cells may have given rise to the original lymphoid blast cells and the myeloid blast cells that characterized the terminal relapse.
Adult↗
Potential mechanisms of action of interferon-alpha in CML.
Treatment with interferon-alpha (IFN-alpha) adequately controls the leukemic cell mass in the majority of newly diagnosed patients with chronic myeloid leukemia (CML). However, the degree of response ranges from no 'hematologic' response to complete suppression of the leukemic clone. The mechanism(s) by which IFN-alpha elicits these responses is unknown, but in vitro studies have indicated that IFN-alpha might function by (1) selective toxicity against the leukemic clone, (2) enhancement of 'immune' regulation, and (3) modulation of bone marrow microenvironmental regulation of hematopoiesis. Using in vitro clonogenic assays we were unable to demonstrate that IFN-alpha selectively inhibited the proliferation of CML progenitor cells. We also found no difference in the expression of LFA-3 on normal or CML CD34+ cells. However, by panning and co-culturing hematopoietic cells on monolayers of bone marrow stromal cells, grown with and without IFN-alpha, we found that IFN-alpha enhanced the adhesion of CML progenitors to stromal cells, whereas adhesion by normal progenitor cells was essentially unaffected. This enhanced adhesion by CML progenitor cells was associated with a reduction in neuraminic acid levels in the extracellular matrix overlying stromal cells. Therefore, it is possible that one of the mechanisms by which IFN-alpha exerts its regulatory effect on the leukemic clone is through enhancement of hematopoietic cell-microenvironmental cell interactions.
Antigens, CD↗
Peripheral blood stem cell autografts in CML.
The treatment of patients with CML in chronic phase by high dose chemotherapy followed by transfusion of autologous haemopoietic stem cells collected and cryopreserved previously may theoretically prolong survival. This benefit could result from reducing the number of leukaemia stem cells at risk for transformation or by partial re-establishment of Ph-negative haematopoiesis. In practice some patients achieve partial Ph-negative haematopoiesis after autografting but most patients have entirely Ph-positive haematopoiesis by one year after autografting. Results may be improved if methods to favour reconstitution with Ph-negative haematopoiesis can be perfected.
Antigens, CD↗
Arsenic and Ayurveda.
Manufacture of an Ayurvedic arsenic-containing compound is described, which is currently in use in India to control blood counts of patients with haematological malignancies. The efficacy and side effects of this compound are evaluated in the light of the fact that arsenic was recognised to be of use in the control of blood counts from patients with chronic myeloid leukaemia as long as 100 years ago, in the West.
Antineoplastic Agents↗
Neuroblastoma in the first year of life: clinical and biologic factors influencing outcome.
The survival for infants less than 1 year of age with neuroblastoma is twice that of older children. This report describes 70 babies with neuroblastoma who experienced an 84% survival. Survival was 100% for stages I, II, and III, 81% for stage IV-S, and 50% for stage IV. Most survivors had favorable biologic characteristics including spontaneous regression, favorable Shimada histology, normal first chromosome, aneuploid tumors, absent or low N-myc oncogene expression, and normal serum ferritin levels.
Biomarkers, Tumor↗
A friend in need or a counsellor?
Should workplace counselling be an in-house responsibility or does an external service provide greater benefits? JOHN GOLDMAN weighs up the arguments.
Accreditation↗
Variable region gene analysis of an isotype-switched (IgA) variant of chronic lymphocytic leukemia.
Chronic lymphocytic leukemia of B-cell origin (B-CLL) is generally thought to arise by neoplastic transformation of B lymphocytes, which express CD5 and have features of an early stage of B-cell differentiation. To study isotype-switched B-CLL as a potentially more differentiated variant, we performed genetic and functional immunoglobulin (Ig) gene analysis in two cases of CD5+ B-CLL in which the peripheral blood mononuclear cells (PBMC) secreted predominantly IgA (CLL-249) or IgG (CLL-412) when stimulated with pokeweed mitogen in vitro. By cDNA sequencing and by studies of CLL-heterohybridomas, CLL-249 expresses the heavy chain constant region C alpha as anticipated, while CLL-412 expresses C mu, not C gamma. In CLL-249, the expressed VH gene is 98% homologous to VH26, a germline VH3 gene that occurs frequently in the fetal repertoire, and which has been associated with anti-DNA specificity. The VL gene of CLL-249 is a lambda VL gene for which the germline sequence is not known. In CLL-412, the VH gene is 100% homologous to the VH1 gene of a published anti-DNA antibody (21/28), and is probably a germline gene sequence; the VL gene is 100% homologous to 15AVKI, also a germline gene. The supernatant antibody of the CLL-412 heterohybridoma is an IgM-kappa, which reacts with ssDNA and cardiolipin. The CLL-249 heterohybridoma secreted IgA-lambda, which bound none of the antigens tested, a finding that may be related to amino acid differences from the probable germline V genes. The demonstration of an in vivo isotype-switched variant, such as CLL-249, suggests that B-CLL may be a heterogeneous group of clonal disorders, of which less common variants may have features of more differentiated B-cell stages, such as isotype switching.
Amino Acid Sequence↗
Spectrum bias in the evaluation of diagnostic tests: lessons from the rapid dipstick test for urinary tract infection.
OBJECTIVE: To determine if the leukocyte esterase and bacterial nitrite rapid dipstick test for urinary tract infection (UTI) is susceptible to spectrum bias (when a diagnostic test has different sensitivities or specificities in patients with different clinical manifestations of the disease for which the test is intended). DESIGN: Cross-sectional study. PATIENTS: A total of 366 consecutive adult patients in whom clinicians performed urinalysis to diagnose or exclude UTI. SETTING: An urban emergency department and walk-in clinic. MEASUREMENTS: After the patient encounter, but before dipstick test or culture was done, clinicians recorded the signs and symptoms that were the basis for suspecting UTI and for performing a urinalysis and an estimate of the probability of UTI based on the clinical evaluation. For all patients who received urinalysis, dipstick tests and culture were done in the clinical microbiology laboratory by medical technologists blinded to clinical evaluation. Sensitivity for the dipstick was calculated using a positive result in either leukocyte esterase or bacterial nitrite, or both, as the criterion for a positive dipstick, and greater than 10(5) CFU/mL for a positive culture. RESULTS: In the 107 patients with a high (greater than 50%) prior probability of UTI, who had many characteristic UTI symptoms, the sensitivity of the test was excellent (0.92; 95% CI, 0.82 to 0.98). In the 259 patients with a low (less than or equal to 50%) prior probability of UTI, the sensitivity of the test was poor (0.56; CI, 0.03 to 0.79). CONCLUSIONS: The leukocyte esterase and bacterial nitrite dipstick test for UTI is susceptible to spectrum bias, which may be responsible for differences in the test's sensitivity reported in previous studies. As a more general principle, diagnostic tests may have different sensitivities or specificities in different parts of the clinical spectrum of the disease they purport to identify or exclude, but studies evaluating such tests rarely report sensitivity and specificity in subgroups defined by clinical symptoms. When diagnostic tests are evaluated, information about symptoms in the patients recruited for study should be included, and analyses should be done within appropriate clinical subgroups so that clinicians may decide if reported sensitivities and specificities are applicable to their patients.
Adolescent↗
A rapid limiting dilution assay for measuring frequencies of alloreactive, interleukin-2-producing T cells in humans.
A limiting dilution analysis (LDA) has been established which measures the total numbers of alloreactive interleukin-2 (IL-2)-secreting T cells in human peripheral blood mononuclear cells (PBMC). A significant advantage over most previous LDA is that the assay may be completed in approximately 48 h since an IL-2-dependent 'indicator' cell line is used to reduce assay time. Results are reproducible and correlate with the degree of HLA class II antigenic disparity between responder and stimulator cells. Use of both PBMC and Epstein-Barr virus-transformed B lymphoblastoid cell lines (B-LCL) as stimulator cells permits estimation of the frequency of Epstein-Barr virus-specific T cells in different responder individuals. A modification of the assay may also be used to measure the frequencies of 'primed' alloreactive cells, i.e., those alloreactive cells which have previously encountered their specific stimulating alloantigen. Use of the assay in the clinical context of bone marrow and renal transplantation is discussed.
Animals↗