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Biomedical subjects

C M Rubin

Publications and source records attributed to C M Rubin.

At least 37 records · Page 2Linked to original sources
PubMed1993

Basophilic differentiation in acute promyelocytic leukemia.

A rare variant of acute promyelocytic leukemia (APL) is associated with basophilic differentiation. Such a patient presented with basophilia, headaches, and diffuse engorgement of superficial blood vessels, attributable to hyperhistaminemia. Karyotype analysis showed a clonal rearrangement of chromosome 12p13 in addition to the t(15;17). During treatment with all-trans-retinoic acid (TRA), the absolute basophil count rose steadily during the first week, then declined. By one month, the basophilia resolved, an abrupt rise occurred in both the platelet and absolute neutrophil count, and the bone core biopsy showed complete maturation of all cell lines. Abnormalities of chromosome 12p13 in acute myelogenous leukemia have been associated with basophilia. Since every cell in our patient with t(12p13;?) also had the t(15;17), we speculate that the basophilia was due to clonal evolution with acquisition of the t(12p13;?). In two out of five other reported cases, abnormalities of chromosomes known to be associated with basophilia were present in addition to t(15;17). It is possible that the basophilia in this variant is reactive; however, since TRA induces differentiation of leukemic promyelocytes into mature neutrophils, we speculate that the leukemic promyelocytes in our patient differentiated into basophils. Future studies employing either fluorescent in situ hybridization or polymerase chain reaction using a probe to the breakpoint on t(15;17) may establish whether or not the basophils derive from the leukemic clone.

Adult↗
PubMed1992

Formation of a hyperdiploid karyotype in childhood acute lymphoblastic leukemia.

Hyperdiploidy with greater than or equal to 50 chromosomes is a frequent and distinct karyotypic pattern in the malignant cells of children with acute lymphoblastic leukemia. To understand better the mechanism of formation of the hyperdiploid karyotype, we studied 15 patients using 20 DNA probes that detect restriction fragment length polymorphisms. We first examined disomic chromosomes for loss of heterozygosity. Two patients had widespread loss of heterozygosity on all informative disomic chromosomes, and represent cases of near-haploid leukemia in which the chromosomes doubled. One other patient had loss of heterozygosity limited to chromosome 3; in this patient all of seven other informative disomic chromosomes retained heterozygosity. Loss of heterozygosity was not detected in the remaining 12 patients on a total of 87 informative disomic chromosomes. We then examined tetrasomic chromosomes for parental dosage. Of the 13 patients in whom widespread loss of heterozygosity was not present, 11 patients had tetrasomy 21; 10 of 11 (91%) had an equal dose of maternal and paternal alleles on chromosome 21 and only 1 of 11 (9%) had an unequal dose of parental alleles in a 3:1 ratio. These results suggest that the hyperdiploid karyotype usually arises by simultaneous gain of chromosomes from a diploid karyotype during a single abnormal cell division, and occasionally by doubling of chromosomes from a near-haploid karyotype. The hyperdiploidy in cases without widespread loss of heterozygosity is not caused by stepwise or sequential gains from a diploid karyotype or by losses from a tetraploid karyotype; the former should result in a 3:1 parental dosage for 67% of tetrasomic chromosomes (9% observed) and the latter should result in loss of heterozygosity for 33% of disomic chromosomes (1% observed). Additional studies of the molecular basis for this leukemia subtype are warranted.

Adolescent↗
PubMed1992

Technical advances in the cytogenetic analysis of malignant tissues.

Successful cytogenetic analysis of malignant tissues using conventional techniques depends upon the presence of viable, dividing malignant cells in the sample, and the ability to obtain metaphase cells with good-quality chromosome banding. Even when these necessary conditions are met, many tumors have complex karyotypes that may be difficult to define completely or have subtle chromosomal abnormalities that are difficult to detect. Overall, determination of the karyotype of a malignant tissue is a time-consuming and labor-intensive process, and for some tumors, is associated with a significant technical failure rate. A number of new methods, which are reviewed in this article, have been developed recently that potentially will improve the speed, accuracy, and success rate of cytogenetic analysis of malignant tissues.

Cell Cycle↗
PubMed1992

Chromosomal loss and deletion are the most common mechanisms for loss of heterozygosity from chromosomes 5 and 7 in malignant myeloid disorders.

We have examined a population of patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) for loss of heterozygosity of polymorphic markers on chromosomes 5 and 7. The rationale for this study was the observation that the majority of patients with therapy-related leukemia (t-AML or t-MDS), resulting from cytotoxic treatment for prior malignancies, have loss of chromosome 5 and/or 7 or deletions involving the long arms of one or both of these chromosomes. This cytogenetic finding suggested that tumor-suppressor genes, important in the development of AML, may be located in these chromosomal regions. We analyzed a total of 60 patients, 43 with primary MDS/AML de novo and 17 with t-MDS/t-AML. Leukemia cells were evaluated for restriction fragment length polymorphisms (RFLPs). Leukemia cell genotypes were compared with lymphoblastoid cell genotypes from the same patients. Two cases of loss of heterozygosity were identified from chromosomes lacking visible deletions: one involving chromosome 5 in a patient with AML de novo who had a visible deletion of 5q at a later stage of the disease, and one involving chromosome 7 in a patient with t-AML. We conclude that allele loss from loci on chromosomes 5 and 7 in MDS/AML, when it occurs, usually results from major deletion or simple chromosome loss, rather than from mitotic recombination or chromosome loss with duplication of the remaining homologue.

Base Sequence↗
PubMed1992

Chromosomal abnormalities in skin following total body or total lymphoid irradiation.

Patients undergoing bone marrow transplantation often receive total body or total lymphoid irradiation as part of the conditioning regimen prior to marrow infusion. The cytogenetic effects of this therapy on skin fibroblasts were studied. Fibroblast cultures from eight skin biopsies were harvested in early passages for G-banded chromosome analysis. Four biopsies were from three patients who had high-dose cyclophosphamide and total body radiotherapy; one was from within and one was from outside the radiation field of a patient who had high-dose cyclophosphamide and lymphoid radiotherapy, one was from a patient who had combination chemotherapy alone, and one was from a normal control. No abnormal mitoses were found in the control or the patient who had chemotherapy alone, and only two of 30 mitoses from skin outside the lymphoid radiotherapy field were abnormal. However, most cells (49-88%) from five biopsies within radiotherapy fields were abnormal. Typically, abnormal karyotypes were pseudodiploid and contained multiple balanced rearrangements, of which reciprocal translocations were most common. The data indicate that the radiotherapy used for bone marrow transplantation induces extensive, sustained chromosome abnormalities in vivo in skin fibroblasts.

Adolescent↗
PubMed1992

Hyperdiploidy arising from near-haploidy in childhood acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) of childhood is frequently characterized by a hyperdiploid karyotype. Typically, most of the affected chromosomes in the abnormal clone are present in three copies. We have studied two patients with hyperdiploid ALL whose leukemic cells were atypical in that all or most of the chromosomes were present in either two or four copies, raising a suspicion that the observed karyotype arose through duplication of chromosomes in a precursor cell with a near-haploid chromosome number. Analysis of restriction fragment length polymorphisms confirmed that both cases arose from a near-haploid cell; all informative disomic chromosomes tested had loss of heterozygosity. Furthermore, the hyperdiploid karyotypes did not arise via a perfect haploid cell with exactly 23 chromosomes, because tetrasomic chromosomes remained heterozygous. These two patients probably are classified best as near-haploid cases, which often are observed to have a co-existing hyperdiploid clone with a duplicated chromosome set. The distinction between typical hyperdiploidy and hyperdiploidy arising via a near-haploid cell may be clinically important, because the prognosis for patients with a hyperdiploid karyotype is favorable in comparison to that of patients with a near-haploid karyotype.

Adolescent↗
PubMed1992

Ultrasonic attenuation in fibroadenoma of the breast.

Fifteen patients are described who attended out Breast Screening Programme, and were found to have sclerosed fibroadenomas, the imaging of which raised the possibility of carcinoma. In six of these a reflective zone between a mass lesion and distal acoustic shadowing might have been used to infer the benign diagnosis.

Adenofibroma↗
PubMed1992

Allogeneic marrow transplantation in the treatment of infants with cancer.

Marrow transplantation in infants with cancer present special challenges particularly because of the need to use conditioning regimens containing cytotoxic agents during a period of rapid somatic growth. An up-date of the largest study in children under 2 years of age treated by marrow transplantation for acute myeloblastic leukaemia, and a review of late effects experienced by older children, demonstrate the necessity to develop conditioning regimens which avoid total body radiation. Efforts to achieve this aim in the treatment of leukaemia are summarised.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Therapy-related myelodysplastic syndrome and acute myeloid leukemia in children: correlation between chromosomal abnormalities and prior therapy.

We have studied 20 children with therapy-related myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) who were 3 months to 16 years old at diagnosis of their primary neoplasm and 1 to 24 years old at diagnosis of their secondary neoplasm. The median interval from initial treatment for the first malignancy to diagnosis of therapy-related MDS or AML was 46 months (range, 12 to 116 months). Twelve patients had chromosomal abnormalities resulting in loss of material from the long arm of chromosomes 5 and/or 7, three patients had abnormalities of chromosome 11 band q23, one patient had both classes of abnormalities, three patients had other abnormalities, and one patient had a normal karyotype. Ten of 12 patients with chromosome 5 and/or 7 abnormalities had been exposed to an alkylating agent, and two of three patients with 11q23 abnormalities had been exposed to an epipodophyllotoxin. The patient with both classes of abnormalities had been exposed to both types of therapy. We conclude that abnormalities of chromosomes 5 and/or 7 are common in children with therapy-related MDS or AML. The proposed relationships between exposure to alkylating agents and abnormalities of chromosomes 5 and/or 7 and between exposure to epipodophyllotoxins and abnormalities of 11q23 are supported in this pediatric series.

Adolescent↗
PubMed1991

Direct correlation of cytogenetic findings with cell morphology using in situ hybridization: an analysis of suspicious cells in bone marrow specimens of two patients completing therapy for acute lymphoblastic leukemia.

Bone marrow cells from two pediatric patients completing therapy for acute lymphoblastic leukemia were studied using in situ hybridization with an alpha-satellite DNA probe specific for chromosome 17. Morphologic analysis of the end-therapy specimens from each patient had shown small numbers (7.5%, 8.5%) of cells that were suspicious for residual or recurrent disease. These cells could not be morphologically or immunophenotypically distinguished with certainty from immature lymphoid cells (hematogones), which may be present normally, sometimes in increased numbers, in the bone marrow specimens of children. In situ hybridization with a probe to chromosome 17 was used because the leukemic cells from each patient had originally been shown to have an extra copy of this chromosome. In one patient, in situ studies showed a population of cells (106 of 1,000 cells) with three hybridization signals indicating trisomy 17, and thus residual/recurrent leukemia. In the other patient trisomy 17 could not be detected. Additional hybridizations to previously stained bone marrow aspirate smears permitted a direct correlation of the cytogenetic findings with the suspicious cells on a cell-to-cell basis. The questionable cells were identified, photographed, and then re-examined after hybridization. In one patient, 13 of 18 (72%) of the suspicious cells were found to have trisomy 17, whereas in the other patient 0 of 24 (0%) demonstrated an extra copy of this chromosome. These cases illustrate a clinical application of interphase cytogenetic analysis and demonstrate how this technology can be used for direct correlation of cytogenetic findings with cell morphology. This technique should prove useful for the detection of minimal residual disease and for lineage studies in leukemia and myelodysplasia.

Antigens, CD↗
PubMed1991

Technique and results of localization biopsy in a breast screening programme.

The techniques of ultrasonographic and hookwire localization biopsy of impalpable breast lesions detected by a large breast screening unit during its first year of operation are described. Hookwire localization (HL) was performed using mammography. Ultrasonographic localization (UL) was used for lesions readily detectable by ultrasonography by marking the skin directly over the lesion and calculating its depth below the surface. UL is not appropriate when microcalcification is the sole mammographic abnormality. Localization was required for 150 of the 191 (78.5 per cent) screen-detected lesions. HL was used for 94 (62.7 per cent) and UL for 56 (37.3 per cent). Four lesions were missed by HL, none by UL; 35 per cent of lesions removed by HL and 39 per cent by UL were malignant, giving benign: malignant biopsy ratios of 1.8:1 and 1.5:1 respectively. Only 22 percent of the patients required overnight hospital stay. Localization biopsy plays a major role in the surgery for screen-detected lesions and, where applicable, UL is the technique of choice.

Biopsy↗
PubMed1991

Immunoglobulin gene rearrangements in acute lymphoblastic leukemia with the 9;11 translocation.

The recurring chromosomal 9;11 translocation [t(9;11) (p22;q23)] typically is associated with acute monoblastic leukemia, but a number of patients with acute lymphoblastic leukemia also have been reported to have the t(9;11). To investigate the cell lineage in the latter cases, we analyzed DNA from the leukemic cells of an 8-year-old girl with acute lymphoblastic leukemia and a t(9;11) for rearrangements of the immunoglobulin and T-cell receptor genes. Rearrangements of both immunoglobulin heavy-chain loci and of one lambda light-chain gene were detected, as well as deletions affecting both alleles of the kappa light-chain genes; T-cell receptor genes were in germline configuration. These results provide further evidence that the 9;11 translocation is not limited to myeloid lineage leukemia and may be observed in acute lymphoblastic leukemia.

Child↗
PubMed1991

Bladder capacity in infants.

Bladder capacity was measured at micturating cystourethrography and normal ranges were established for children up to 1 year of age. Bladder capacity was compared with patient weight and distance from first lumbar to third lumbar vertebrae (L1 to L3). The simplified formula--Capacity (mL) = 7 x weight (kg)--was shown to give a reliable estimate of the expected bladder capacity in infants independent of age; this is useful in those infants whose weight lies outside the normal range for their age. Similarly, a formula was deduced relating expected bladder capacity to the measured L1 to L3 distance on an anteroposterior radiograph, which is of potential use to radiologists.

Body Weight↗
PubMed1991

Cytogenetic abnormalities in childhood acute lymphoblastic leukemia.

A number of recurring chromosomal abnormalities have been identified in childhood acute lymphoblastic leukemia. Many of these correlate closely with clinical, morphologic, and immunophenotypic features present at diagnosis and are useful in predicting outcome. Furthermore, these abnormalities point the way toward understanding the biologic basis for this disease. Challenges for the future include improvement in the quality and rapidity of cytogenetic analysis, the use of molecular probes to detect specific chromosomal abnormalities accurately and efficiently, and the incorporation of cytogenetic information into planning therapy.

Child↗
PubMed1991

Impact of chromosomal translocations on prognosis in childhood acute lymphoblastic leukemia.

The presence of a chromosomal translocation in the leukemic cells at diagnosis of acute lymphoblastic leukemia (ALL) in children is associated with a high risk for treatment failure. We have reexamined the relationship between translocations and prognosis in 146 children with ALL who received risk-based therapy such that high-risk patients were treated with intensive drug schedules. In univariate analysis, multiple factors were associated with a relatively poor event-free survival (EFS) including age less than 2 years or greater than 10 years (combined group), WBC count greater than 10 x 10(9)/L, French-American-British (FAB) morphologic classification L2, absence of common ALL antigen (CALLA, CD10) expression, absence of hyperdiploidy with a chromosome number of 50 to 60, and presence of the specific translocations t(4; 11)(q21;q23) or t(9;22)(q34;q11) (combined group). However, there was no disadvantage with respect to EFS in patients with translocations compared with those who lacked translocations (73% at 4 years in both groups). Furthermore, when patients with specific cytogenetic abnormalities for which the prognostic significance has been well established (hyperdiploid 50 to 60, t(4;11), and t(9;22] were removed from the analysis, the remaining group with other translocations had a better EFS than the remaining group lacking translocations, although this was not statistically significant (81% v 65% at 4 years, P = .24). In a multivariate analysis, a model including WBC count and FAB classification was the strongest predictor of EFS. The presence or absence of translocations was not an independent predictor of EFS and did not contribute to the ability of any model to predict EFS. In conclusion, when effective intensive therapy is used to treat childhood ALL with high-risk clinical features, categorization of patients on the basis of chromosomal translocations without attention to the specific abnormality is not useful as a prognostic factor.

Adolescent↗
PubMed1990

t(3;21)(q26;q22): a recurring chromosomal abnormality in therapy-related myelodysplastic syndrome and acute myeloid leukemia.

We have identified an identical reciprocal translocation between the long arms of chromosomes 3 and 21 with breakpoints at bands 3q26 and 21q22, [t(3;21)(q26;q22)], in the malignant cells from five adult patients with therapy-related myelodysplastic syndrome (t-MDS) or acute myeloid leukemia (t-AML). Primary diagnoses were Hodgkin's disease in two patients and ovarian carcinoma, breast cancer, and polycythemia vera in one patient each. Patients had been treated with chemotherapy including an alkylating agent for their primary disease 1 to 18 years before the development of t-MDS or t-AML. We have not observed the t(3;21) in over 1,500 patients with a myelodysplastic syndrome or acute myeloid leukemia arising de novo or in over 1,000 patients with lymphoid malignancies. We have previously reported that the t(3;21) occurs in Philadelphia chromosome-positive chronic myelogenous leukemia (CML). Thus, the t(3;21) appears to be limited to t-MDS/t-AML and CML, both of which represent malignant disorders of an early hematopoietic precursor cell. These results provide a new focus for the study of therapy-related leukemia at the molecular level.

Acute Disease↗
PubMed1990

Deletions of interferon genes in acute lymphoblastic leukemia.

Structural rearrangements involving the short arm of chromosome 9, including bands 9p21 and 22, are found in the leukemia cells of 7 to 13 percent of patients with acute lymphoblastic leukemia. The interferon-alpha gene cluster and the interferon-beta 1 gene have been localized to this chromosomal region. We have previously demonstrated deletions of these genes in several cell lines established in vitro from patients with lymphoblastic leukemia. We report here homozygous or hemizygous deletions of the interferon-alpha and interferon-beta 1 genes in samples of leukemia cells from patients with lymphoblastic leukemia. Of 62 patients examined, 18 (29 percent) had such deletions. Four patients (7 percent) had homozygous deletions of the interferon-alpha gene cluster; of these, one also had a homozygous deletion and three had hemizygous deletions of the interferon-beta 1 gene. Fourteen patients (23 percent) had hemizygous deletions of both the interferon-alpha gene cluster and the interferon-beta 1 gene. In 8 of the 18 patients with deletions, the deletions of interferon genes were submicroscopic; in the 11 other patients, chromosomal rearrangements of 9p, including translocations or deletions, were visible on light microscopy. These chromosomal and molecular deletions are likely to be related to the loss of a tumor-suppressor gene (or genes) located on 9p, which may be an interferon gene or an unrelated but closely linked gene.

Adolescent↗