Search PubMed⌕ Search

Biomedical subjects

C D Bloomfield

Publications and source records attributed to C D Bloomfield.

At least 91 records · Page 5Linked to original sources
PubMed1994

Prognostic importance of mutations in the ras proto-oncogenes in de novo acute myeloid leukemia.

Mutations of the N- and K-ras genes are the most frequent genetic aberrations in acute myeloid leukemia (AML) and their detection in preleukemic conditions such as the myelodysplastic syndrome (MDS) suggests a role in the earliest phases of leukemogenesis. Despite these observations, little is known about the clinical importance of ras mutations in AML. We studied the clinical impact of ras mutations in 99 patients with de novo AML. All patients were treated in two prospective multicenter trials. The polymerase chain reaction was used to amplify areas surrounding the codons 12, 13, and 61 of the three ras genes N-, K-, and H-ras from DNA from bone marrow cells, ras mutations were detected by an algorithm based on allele-specific oligonucleotide hybridization. Eighteen of 99 (18%) patients harbored mutations in either N- or K-ras. All of the observed mutations occurred in N-ras (N = 10) and K-ras (N = 5) or concurrently in both N- and K-ras (N = 3). There were no significant differences between ras-negative and ras-positive patients according to age, sex, blood counts, cytogenetic abnormalities, or French-American-British classification. However, univariate analysis suggested a longer survival in ras-positive patients (P = .11). When adjusted for age, which was the most important factor affecting outcome, the presence of a ras mutation emerged as a significant predictor for improved survival (P = .03) and along with lower bone marrow blast counts (P = .02) and better cytogenetic category (P = .01). However, the presence of an aberrant ras allele was strongly correlated with lower bone marrow blast counts (P = .007). Thus, whether a mutation in the N-ras or K-ras proto-oncogenes directly affects treatment outcome or indirectly through an association with lower leukemic burden remains to be determined. Nevertheless, these findings counter the prevailing bias that oncogene mutations lead to more aggressive behavior in human malignancies.

Adult↗
PubMed1994

Molecular rearrangement of the ALL-1 gene in acute myeloid leukemia without cytogenetic evidence of 11q23 chromosomal translocations.

Translocations which involve chromosome band 11q23 are frequently found in infants and adults with acute myeloid leukemia (AML) or acute lymphoblastic leukemia. We previously cloned a gene called ALL-1 which spans the 11q23 breakpoint and is rearranged in most cases of leukemia with 11q23 abnormalities. In the present report, we have investigated the occurrence of ALL-1 rearrangement in cases of AML without cytogenetic evidence of 11q23 abnormalities. We detected molecular rearrangements of the ALL-1 gene in 3 of 4 patients with de novo AML and trisomy 11 as a sole chromosomal abnormality. Furthermore, we found DNA rearrangements of ALL-1 in 2 of 19 patients with de novo AML and normal cytogenetics. We conclude that molecular rearrangement of ALL-1 often can be detected in de novo AML, despite the absence of cytogenetic abnormalities involving 11q23.

Acute Disease↗
PubMed1994

Prognostic factors for therapeutic outcome of diffuse small non-cleaved cell lymphoma in adults.

Most reports of prognosis and therapy in diffuse small non-cleaved cell lymphoma (DSNCL), an aggressive high-grade non-Hodgkin's lymphoma (NHL) which appears to be of two histopathologic subtypes, have included predominantly a pediatric population and very few adults. We studied 20 newly diagnosed, previously untreated adults with DSNCL. Three patients had Ann Arbor Stage I disease, five Stage II, and 12 Stage IV. Bone marrow involvement was present in seven of 20 (35%) patients; no patient had central nervous system involvement at diagnosis. Clonal chromosomal abnormalities were found on cytogenetic analysis of all 12 cases studied. Ten patients had specific recurring translocations, including t(8;14) (q23;q32) (five patients), t(14;18) (q32;q21) (four patients), and t(2;8) (p12;q24) (one patient). Induction chemotherapy with the COMP regimen (cyclophosphamide, vincristine, methotrexate, and prednisone) or a variant schedule of the same drugs resulted in complete remission for 13 patients (65%), and partial remission for 5 patients (25%). Clinical characteristics predictive of a favorable response to induction therapy included Stage I or II disease, a normal lactic dehydrogenase (LDH), and performance status (PS) of 0 or 1. Remission duration ranged from two to 125+ (median 37+) months. Survival ranged from one to 126+ (median 23) months; ten patients (50%) remain alive, nine with no active disease. Factors predictive of longer survival included achievement of a complete remission with induction therapy, a normal LDH, and PS 0 or 1. As in children with DSNCL, long-term disease-free survival may be achieved in adults with combination chemotherapy.

Adolescent↗
PubMed1994

Band 11q13 is nonrandomly rearranged in hibernomas.

Cytogenetic study of a short-term culture from a hibernoma, a very rare benign proliferation of the brown fat, demonstrated a four-break translocation t(5;7;11;17)(p14;q11.23;q13.1-13.3;p11.2) as the sole abnormality in all analyzed cells. Complex translocation involving band 11q13 have also been detected in the two other published cases of hibernoma. The consistent finding of 11q13 rearrangements appears to distinguish hibernoma from other benign adipose tissue tumors cytogenetically and suggests that 11q13 changes may play an important role in hibernoma pathogenesis.

Adipose Tissue, Brown↗
PubMed1994

Long-term survival in acute myelogenous leukemia: a second follow-up of the Fourth International Workshop on Chromosomes in Leukemia.

Patients with acute myeloid leukemia (AML, equivalent to acute non-lymphoblastic leukemia [ANLL]) who were studied at the Fourth and Sixth International Workshops on Chromosomes in Leukemia and who have long survival have been re-assessed to identify factors which may be associated with good prognosis in AML. In a long-term survivor (LTS) group, there were more cases than expected in each age decade below 50, more cases than expected with FAB type M3, and fewer cases than expected of secondary leukemia. Of the distribution of chromosome abnormalities, t(15;17), t(8;21), and inv/del(16) were over-represented, and -5, -7, and rearrangements of 11q were under-represented. Multivariate analysis of all patients showed that age group, cytogenetic classification, FAB type, and sex all had independent, significant effects on survival. A new observation from a very small subgroup of patients was that deletion of 7q without concurrent abnormality of chromosome 5 appeared to be associated with a good prognosis.

Adolescent↗
PubMed1993

Prolonged subcutaneous administration of recombinant alpha 2b interferon in patients with previously untreated Philadelphia chromosome-positive chronic-phase chronic myelogenous leukemia: effect on remission duration and survival: Cancer and Leukemia Group B study 8583.

We investigated whether recombinant alpha 2b interferon (r alpha 2bIFN) would reduce the proportion of bone marrow Philadelphia chromosome (Ph) cells in chronic-phase chronic myelogenous leukemia (CML) by treating 107 previously untreated patients daily with r alpha 2bIFN at 5 x 10(6)IU/m2 subcutaneously. Patients with complete remission, partial remission, or partial hematologic remission received treatment until progression; those with progressive disease were taken off study and observed for survival. Sixty-three (59%) of the patients achieved at least a partial hematologic remission (24 complete remissions and 39 partial remissions). The median time to response for the 63 responders was 3.4 months, with a median duration of remission of 52 months and with 81% of responders continuing in remission beyond 12 months. The median survival for the 107 patients was 66 months. Of 78 patients with cytogenetic follow-up data, 31 (40%) achieved a partial cytogenetic response (n = 17) or a complete cytogenetic response (n = 14). The percentage of cytogenetic responders among all patients was 29% (31 of 107 patients). The median time to first cytogenetic response was 9 months. A major dose reduction of r alpha 2bIFN (> or = 50%) was required at some time during treatment in 38% of patients, 26% required 10% to 49% dose reductions, and 36% had minor dose reductions of < or = 10%. No association was observed between dose received and the attainment of a cytogenetic response. None of the usual prognostic factors (sex, race, performance status, weight loss, time from diagnosis to treatment, hepatosplenomegaly, age, symptoms, hemoglobin, or platelet, blast, basophil, or white blood cell count) were significantly related to survival. These data provide confirmation that major cytogenetic responses to prolonged administration of subcutaneous r alpha 2bIFN occur in 20% to 38% (95% confidence interval) of chronic-phase Ph-positive patients. Although it is hypothesized that patients achieving major cytogenetic responses to r alpha 2bIFN should have prolonged remission duration and survival compared with nonresponders, analyses of the effect of cytogenetic responders by both "landmark" and time-dependent covariate techniques fail to provide statistically significant evidence for an effect of cytogenetic response on remission duration or survival. This may be due in part to an effect size insufficiently large to be detected with the number of patients treated in this study. Thus, confirmation of remission duration or survival benefit, if any, of r alpha 2bIFN therapy in Ph-positive chronic-phase CML must await the outcome of randomized trials comparing IFN with conventional agents.

Adolescent↗
PubMed1993

Chromosome 12 breakpoints are cytogenetically different in benign and malignant lipogenic tumors: localization of breakpoints in lipoma to 12q15 and in myxoid liposarcoma to 12q13.3.

Cytogenetic study of short-term cultures from 10 adipose tissue tumors (eight lipomas, one myxoid liposarcoma, and one mixed liposarcoma) have revealed clonal chromosome abnormalities in seven cases. In both malignant tumors, translocation (12;16) was the sole aberration, and in the mixed liposarcoma, the breakpoints could be sublocalized to bands 12q13.3 and 16p11.2, thus confirming findings of Eneroth et al., Cancer Genet. Cytogenet., 48: 101-107, 1990. Three lipomas displayed predominantly normal karyotypes; in a fourth case, the karyotype 44,XX,-6,der (7)t(6;7)(p21.3-22;p22)ins(7)(p22q11.2q22),-13 was found. Four remaining lipomas were characterized by structural rearrangements of chromosome 12. We were able to achieve high resolution banding patterns in two tumors with translocations (3;12)(q28;q15) and (1;2;12)(p36.;q13;q15). In both of these cases, the chromosome 12 breakpoint could be unequivocally assigned to band q15. Similarly, band 12q15 was also rearranged in two other lipomas with translocations (12;14)(q15;q32) and (12;20)(q15;q13.1). Our results support the hypothesis that the chromosome 12 breakpoint in lipomas is located more distally than the breakpoint in myxoid liposarcomas and some other soft-tissue malignant neoplasms and that it is cytogenetically identical with breakpoints detected in such benign tumors as uterine leiomyoma and pleomorphic adenoma of the salivary gland.

Adult↗
PubMed1993

Hodgkin disease in patients 60 years of age or older. Histologic and clinical features of advanced-stage disease. The Cancer and Leukemia Group B.

BACKGROUND: This article reviews the salient pathologic and clinical features of 171 patients with Stage III-IV disease who were 60 years of age or older who were treated on four Hodgkin disease (HD) protocols from 1969 to 1988. METHODS: Pretherapy sections were reviewed centrally for correlation of the histologic classification with anatomic sites of involvement and survival. RESULTS: The diagnosis of HD was confirmed in 114 (66.7%) patients. Non-Hodgkin lymphomas (NHL) and a miscellaneous non-HD group accounted for 52 (30.4%) and 5 (2.9%) of the cases. The overall median survival times of patients with Stage III-IV HD and NHL who were 60 years of age or older in the four protocols were not significantly different (1.5 versus 1.3 years, respectively; P = 0.28). There also was no significant correlation between the survival of these patients with HD and either the Rye classification, 19 specific histologic parameters, or the British National Lymphoma Investigation grading system for HDNS. In the last protocol, the 5-year survival rate of patients with HD who were 60 years of age or older was lower than that of patients 40-59 years of age or that of those younger than 40 years of age (31% versus 63% versus 79%, respectively, P < 0.0001). Patients with HD entered into the two most recent protocols showed lower incidences of involvement of cervical and iliac-inguinal-femoral lymph nodes and skin-subcutaneous tissues than the patients with NHL who were misdiagnosed as HD. Moreover, patients with Stage III-IV HD in the most recent protocol who were 60 years of age or older had lower rates of involvement of the cervical and mediastinal-hilar lymph nodes and a higher rate of involvement of the gastrointestinal tract than younger patients. CONCLUSIONS: Patients with Stage III-IV HD and NHL who are 60 years of age or older differ with respect to the rates of involvement of specific anatomic sites but not in survival when treated with HD protocols. In contrast, patients of different age groups with Stage III-IV HD disease differ with regard to the rates of involvement of anatomic sites and survival.

Age Factors↗
PubMed1993

Translocation t(12;22)(q13;q12.2-12.3) in a clear cell sarcoma of tendons and aponeuroses.

Cytogenetic analysis of a short-term culture from a clear cell sarcoma revealed a complex karyotype with the mainline of 49,XY,t(7;18)(p11.2;q21.3), +der(7)t(7;18)(p11.2;q21.3), +8, +der (8;17)(q10;q10),t(12;22)(q13;q12.2-12.3),add(13)(p13). An apparently identical translocation t(12;22) has been described recently in four clear cell sarcomas, indicating that this constitutes a primary cytogenetic change specific for this type of tumor. In our case, the breakpoint on chromosome 22 could be assigned to band 22q12.2 or 22q12.3. Together with the present case, trisomy or tetrasomy 8 has been found in six of nine clear cell sarcomas, suggesting that, as in Ewing's sarcoma and myxoid liposarcoma, trisomy/tetrasomy 8 represents a nonrandom secondary aberration. We conclude that the finding of the specific translocation t(12;22) may prove to be an important marker in the differential diagnosis of clear cell sarcoma from some other soft tissue sarcomas and malignant melanoma.

Adult↗
PubMed1993

High-dose cytarabine, idarubicin, and granulocyte colony-stimulating factor remission induction therapy for previously untreated de novo and secondary adult acute myeloid leukemia.

This report describes the preliminary results of the remission induction phase of a protocol for previously untreated de novo and secondary acute myeloid leukemia (AML) designed to deliver very intensive therapy over a brief period of time using hematopoietic growth factor support. Remission induction therapy consisted of cytarabine 3 g/m2 (1.5 g/m2 for age > 50 years) intravenously over 1 hour every 12 hours for 12 doses and idarubicin 12 mg/m2 over 30 minutes on days 2, 3, and 4 of cytarabine, followed by 10 micrograms/kg granulocyte colony-stimulating factor subcutaneously daily until the absolute neutrophil count increased to > or = 5.0 x 10(9)/L on 2 consecutive days. Twenty-seven patients received all the planned doses of chemotherapy. The complete remission (CR) rate to a single course of therapy was 65% in 20 patients with de novo AML (median age, 60.5 years; age range, 26 to 78 years); for those aged less than 60 and > or = 60 years, the CR rates were 90% and 40%, respectively. In contrast, only two of 10 patients with secondary AML (median age, 68 years; age range, 35 to 77 years) achieved a CR. The median time from initiation of chemotherapy to recovery of 0.5 x 10(9)/L neutrophils in de novo AML patients achieving CR was 20 days (range, 18 to 23 days). Median times to last platelet transfusion and to 100 x 10(9)/L platelet count were 23 days (range, 18 to 41 days) and 28 days (range, 24 to 97 days), respectively. The major nonhematologic toxicity was transient hyperbilirubinemia, which was observed in 64% of patients. Reversible cerebellar toxicity was seen in three patients. Thus, idarubicin at full dose (12 mg/m2 x 3 days) may be safely administered with high-dose cytarabine, even in elderly patients. The use of granulocyte colony-stimulating factor is associated with rapid neutrophil recovery without obvious toxicity. The CR rate for de novo AML patients treated with a single course of high-dose cytarabine, idarubicin, and granulocyte colony-stimulating factor is at least comparable to CR rates achieved with standard-dose cytarabine and anthracycline regimens. The response of secondary AML patients remains inferior.

Acute Disease↗
PubMed1992

Clinical significance of the BCR-ABL fusion gene in adult acute lymphoblastic leukemia: a Cancer and Leukemia Group B Study (8762).

The Philadelphia (Ph1) chromosome, or its molecular counterpart, the BCR-ABL fusion gene, is a rare but important prognostic indicator in childhood acute lymphoblastic leukemia (ALL), but its impact on adult ALL has not been well ascertained. A prospective study of the BCR-ABL fusion gene was begun on patients entered on clinical trials conducted by the Cancer and Leukemia Group B (CALGB). All patients received intensive, multiagent chemotherapy that included daunorubicin. Over 2 years, 56 patients were studied for molecular evidence of a BCR-ABL gene using Southern blot and pulsed-field gel hybridization analysis. Results were compared with cytogenetic detection of a Ph1 chromosome, and clinical features were compared for the BCR-ABL-positive and -negative groups. Molecular methods detected the BCR-ABL gene in 30% of cases compared with cytogenetic detection of the Ph1 chromosome in only 23%. The majority of cases (76%) showed the p190 gene subtype similar to pediatric ALL; the BCR-ABL-positive cases displayed a more homogeneous immunophenotype than the BCR-ABL-negative cases and were predominantly CALLA positive (86%) and B-cell surface antigen positive (82%). The rate of achieving complete remission was similar in the BCR-ABL-positive and -negative groups (71% and 77%, respectively, P = .72). There were more early relapses in the BCR-ABL-positive group, resulting in a shorter remission duration that was especially marked in the CALLA-positive and B-cell antigen-positive populations. These preliminary data suggest that the impact of the BCR-ABL gene on clinical outcome in ALL may be on maintenance of complete remission (CR) rather than achievement of CR when aggressive, multiagent chemotherapy is used. This study identifies the BCR-ABL gene as an important factor in adult ALL and demonstrates the utility of molecular methods for its accurate diagnosis.

Adolescent↗
PubMed1992

ras oncogene activation and occupational exposures in acute myeloid leukemia.

BACKGROUND: Epidemiologic studies of acute myeloid leukemias (AMLs) show small increases in risk of disease associated with certain occupations and chemical exposures. PURPOSE: This study was designed to determine whether the presence of mutationally activated ras oncogenes in AML are associated with occupational and chemical exposures. METHODS: We interviewed 62 patients with newly diagnosed AML (or their next-of-kin), all of whom were enrolled in a national multicenter clinical trial, and 630 healthy control subjects. DNA extracted from patients' pretreatment bone marrow samples was amplified by using the polymerase chain reaction and probed with allele-specific oligonucleotides for activating point mutations at the 12th, 13th, and 61st codons of three protooncogenes: H-ras (also known as HRAS), K-ras (also known as KRAS2), and N-ras (also known as NRAS). RESULTS: Patients with ras mutation-positive AML had a higher frequency (six of 10 patients) of working 5 or more years in an a priori high-risk occupation than did patients with ras mutation-negative AML (eight of 52; odds ratio [OR] = 6.8; 95% confidence interval [CI] = 1.3-36). Patients with ras mutation-positive AML were more likely than patients with ras mutation-negative AML to have breathed chemical vapor on the job (OR = 9.1; 95% CI = 1.3-64) or to have had skin contact with chemicals (OR = 6.9; 95% CI = 1.3-37). When ras-positive patients were compared with healthy control subjects, the ORs for occupation and occupational exposures remained elevated, while patients with ras mutation-negative AML showed no increased risk when compared with control subjects. CONCLUSION: Activation of ras proto-oncogenes may identify an etiologic subgroup of AML caused by occupation and chemical exposure. IMPLICATION: Disease etiology may be better understood if epidemiologic measures of exposure are integrated with molecular assays of the genetic defects responsible for cancer initiation and promotion.

Acute Disease↗
PubMed1992

Immunohistochemical identification of P-glycoprotein in previously untreated, diffuse large cell and immunoblastic lymphomas.

Expression of P-glycoprotein has been linked to multidrug resistance in cancer cell lines and human tumors. We investigated the frequency and clinical significance of P-glycoprotein immunoreactivity in 57 previously untreated diffuse large cell and immunoblastic lymphomas. Banked frozen tissue, which had been obtained prior to chemotherapy, was tested for reactivity with 2 monoclonal antibodies (MRK16 and C219) that recognize different domains of P-glycoprotein, using an immunoperoxidase technique. Thirteen of 57 lymphomas (23%) showed strong staining of greater than 50% of neoplastic cells; 15 of 57 (26%) showed labeling of a minority (11-50%) of neoplastic lymphocytes; 14 of 57 (25%) yielded equivocal results (reactivity in less than 10% of cells); and 15 of 57 (26%) were negative for P-glycoprotein. The 2 monoclonal antibodies were comparable in reactivity. Expression of MDR-1 mRNA was determined in 6 cases with sufficient available tissue, and did not correlate well with the percentages of cells reactive for P-glycoprotein by immunohistochemistry. Thirty-nine of our 57 patients completed multiagent chemotherapy. Contrary to our expectations, we found that P-glycoprotein immunoreactivity did not decrease the likelihood of response to induction chemotherapy. Median survival also was not adversely affected.

ABO Blood-Group System↗
PubMed1992

An altered 11-kilobase transcript in leukemic cell lines with the t(4;11)(q21;q23) chromosome translocation.

The 11q23 chromosome band is frequently associated with chromosomal aberrations in human leukemias. We have previously cloned a DNA fragment derived from chromosome 11 which could be used as a probe to detect rearrangements in DNAs from the leukemic cells of patients with the t(4;11), t(9;11), and t(11;19) translocations. In this study we now show that the same probe detects DNA rearrangements in malignant cells from patients with the t(1;11), t(6;11), t(10;11), and del (11q23) chromosomal abnormalities. A second probe obtained from a region located centrometric to the breakpoint cluster detects major and minor transcripts of 12.5 and 11.5 kilobases, respectively, in all cell lines examined. The same probe identifies an altered 11-kilobase RNA in all three independent cell lines with the t(4;11)(q21;q23) chromosome translocation.

Chromosomes, Human, Pair 11↗
PubMed1992

Recurring chromosome abnormalities in Hodgkin's disease.

Cytogenetic analysis was performed on lymph nodes or other tumor masses from 33 patients with Hodgkin's disease. Metaphase cells were obtained in 25 of the 33 cases. Analyzable abnormal clones were found in nine cases. Characteristic abnormalities included polyploidy and complex structural rearrangements nonrandomly involving certain chromosomal regions. Chromosomes most commonly gained were 2, 9, 11, 19, and 20, and those most often lost were 10, 13, 15, 16, 21, and Y. Translocation breakpoints clustered in bands 1p11-1p13, 1p36, 4q35, 14q11, and 15p11. In five patients, breakpoints were in bands to which T-cell receptor genes have been mapped. No specific, recurring translocation was identified. There was, however, recurring loss of chromosomal material from 1q, 4q, 6q, and 17p. Loss or deletions of chromosomes 4 and 6 were found in five and six patients, respectively. Deletions overlapped; the smallest overlapping segments included bands 4q25-4q27 and 6q21-6q23. The data suggest that loss of specific chromosomal regions may be important in the pathogenesis of Hodgkin's disease. With respect to tumor specificity, deletions of 4q are of particular interest because these have not been previously reported to occur nonrandomly in other human malignancies.

Adolescent↗
PubMed1992

The use of monoclonal antibodies against primary myeloid granules in normal and leukemic cells.

Three monoclonal antibodies, K101, D46, and H36/71 (CD15), reactive with membrane components of primary granules of human promyelocytes, were studied to assess their binding to normal and leukemic cells. Using the alkaline phosphatase antialkaline phosphatase technique, these antibodies were applied to sections of normal organs and to peripheral blood and bone marrow films from hematologically normal individuals and patients with hematologic malignancies. In control experiments, antibodies showed reactivity with cytoplasmic constituents of granulocytes from the promyelocytic to the neutrophilic stage. In acute myeloid leukemia, antibody K101 was positive (more than 20% of blasts) in 13 of 21 (62%) cases, while antibody D46 was positive in 11 of 17 (65%) cases. Antibody H36/71 was positive in only 4 of 24 (17%) cases of acute myeloid leukemia. At least one marker was present in 6 of 8 (75%) cases of acute lymphoblastic leukemia with myeloid antigen-positive blasts and was negative in 20 cases of acute lymphoblastic leukemia with myeloid antigen-negative blasts. These results support the view that abnormal granules (with defective expression of the D46, K101, and H36/71 antigens) form in blastic and leukemic cells of patients with acute myeloid leukemia. Data also suggest that membrane components of myeloid granules are made in the cytoplasm of cells from some acute lymphoblastic leukemia patients with myeloid antigen-positive blasts.

Antibodies, Monoclonal↗