Biomedical subjects

C D Bloomfield

Publications and source records attributed to C D Bloomfield.

At least 127 records · Page 7Linked to original sources

PubMed1990

Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia.

The National Cancer Institute (NCI) sponsored a workshop to develop a set of standardized diagnostic and response criteria for acute myeloid leukemia (AML) clinical trials. The French-American-British (FAB) classification was retained for diagnosing AML, with the addition of patients with bone marrow morphologic features of a myelodysplastic syndrome and less than 30% bone marrow blasts, but with greater than or equal to 30% blasts in the peripheral blood. In this report, there are four important subgroups of AML not defined in the FAB classification that are discussed: undifferentiated acute leukemia, MO (AML lacking definitive myeloid differentiation by morphology or conventional cytochemistry but with ultrastructural or immunophenotypic evidence for AML), mixed lineage leukemia, and hypocellular AML. Definitions of response for clinical trials are presented to facilitate comparisons among different studies. Complete remission is considered the only response worth reporting in phase III trials, since lesser responses do not improve survival. Partial remissions may be of interest to identify active new agents in phase I and II studies. Monoclonal antibodies and cytogenetic studies are not part of the routine assessment of remission or reassessment at relapse, and their role in the evaluation of patients with AML is currently being evaluated in clinical trials. Although we recognize that some of the definitions in this report are arbitrary, generalized use of these guidelines will make results of clinical trials more comparable and interpretable.

Antibodies, Monoclonal↗

PubMed1990

Clinical significance of the cytogenetics of acute leukemias.

Numerous chromosome abnormalities are repeatedly found in the acute leukemias. These abnormalities have both diagnostic and prognostic utility. Some abnormalities, such as the t(4;11) (q21;q23) and t(9;22) (q34;q11) are found in both lymphoid and myeloid leukemias. In both disorders, these rearrangements are associated with a poor prognosis. Some abnormalities are found exclusively in myeloid malignancies, e.g., the t(8;21) (q22;q22) and rearrangements of chromosome 16q22, both of which carry a good prognosis. Other abnormalities are found only in lymphoid malignancies, like those of chromosome 14 at band q11 which involve T lymphoblasts. T-cell receptor (TRC) genes have been mapped to the 14q11 band. Recombinations involving the TCR alpha gene and the myc oncogene have been found in the t(8;14) (q24;q11). Similar involvement of immunoglobulin heavy chain genes and the myc oncogene has been well documented in molecular studies of B-cell lymphoma patients with a t(8;14) (q24;q32).

Acute Disease↗

PubMed1990

Cytogenetics of non-Hodgkin's lymphoma.

In the non-Hodgkin's lymphoma (NHL), recurring cytogenetic abnormalities have been identified, and significant correlations among them and morphology, immunophenotyping, and parameters of clinical outcome have been recognized. The structural involvement of the 14q32 band is substantially more frequent than are other common abnormalities, which include del(6q), i(17q), +3, +7, +12, +18, and +21. Twenty-two recurring translocations have been identified. Almost three-fourths of all breakpoints in NHL occur at sites to which lineage-determining, transformation-related genes, or fragile sites have been mapped. Besides the well-known association of the t(14;18) (q32;q21) with the follicular histologies and t(8;14)(q24;q32) with small non-cleaved cell lymphoma, several other associations between recurring cytogenetic abnormalities and morphologic subtypes have been found. Similarly, several associations between cytogenetic abnormalities and the B or T immunophenotype have been delineated. Trisomy 3 or duplications of 3p predict a favorable clinical outcome; trisomy 2 or duplication 2p and abnormalities of chromosome 17 predict a poor prognosis. Common sequential changes include a (second) 14q32 break and abnormalities of chromosomes 1 and 2. Continuing work in these areas will serve to identify more clearly those regions of the genome important to transformation, differentiation, clinical aggressiveness, and progression in NHL.

Chromosome Aberrations↗

PubMed1990

Chromosomal abnormalities in myelodysplastic syndromes and acute myeloid leukemia.

Clonal chromosome abnormalities are found in more than half the patients with hematologic malignancies. Karyotype is an independent prognostic factor in these patients. Cytogenetic findings correlate significantly with morphologic, immunologic, and clinical features as well as response to treatment, remission duration, and survival. The number of different cytogenetic abnormalities is enormous; however, many cytogenetic findings frequently occur in a given disease (e.g., abnormalities of 5 or 7 in 75% to 90% of patients with therapy-related AML). Some abnormalities are found only in myeloid malignancies, for example, the t(8;21)(q22;q22) and rearrangements of chromosome 16q22, both of which have a good prognosis. Other abnormalities usually are found in both myeloid and lymphoid malignancies, for example, the t(4;11)(q21;q23) and t(9;22)(q34;q11), both of which have a poor prognosis. The Human Gene Mapping Conferences have compiled much cytogenetic data and produced several interesting correlations in myeloid malignancies: rearrangements of 3q21-26 with myeloid proliferations associated with environmental exposure (similar to abnormalities of 5q, 7q, 12p, and 17q), aberrations of 12p, 11q13 and 11q23 with both myeloid and lymphoid disorders, and the lack of myeloid involvement and abnormalities of chromosomes 14 and 18. In conclusion, cytogenetic analysis of neoplastic cells at diagnosis for patients with MDS, AML, and SAML is required for appropriate diagnosis and treatment. The use of chromosome abnormalities to separate patients into high- and low-risk groups eventually may allow us to be more effective in selecting curative therapy.

Bone Marrow↗

PubMed1990

Interferon therapy of relapsed and refractory Hodgkin's disease: Cancer and Leukemia Group B Study 8652.

A phase II trial of alpha 2b-interferon in patients with relapsed or refractory Hodgkin's disease was conducted by the Cancer and Leukemia Group B. Nineteen patients were eligible for study. These patients had received at least two (median of four) previous chemotherapeutic programs and 79% had received prior radiation therapy. Three patients had undergone intensive chemotherapy and autologous bone marrow transplantation. The treatment regimen consisted of interferon-alpha 2b 10 X 10(6) IU/m2 subcutaneously three times per week. Only limited antineoplastic activity was seen in this heavily pretreated group of patients. There was one partial response and four patients had reduction in measurable disease not meeting the criteria for partial response. The drug was well tolerated. Toxicity was predominantly myelosuppression. Thrombocytopenia was particularly severe in patients with bone marrow involvement. The observed antineoplastic activity, albeit limited, in this heavily pretreated group of patients suggests a potential role for this agent in combination regimens in patients with earlier disease.

Adult↗

PubMed1989

Cytogenetic studies of 21 patients with acute lymphoblastic leukemia in relapse.

Karyotypes of 21 patients, originally entered into the Third International Workshop on Chromosomes in Leukemia (3IWCL), were investigated in first, second and/or subsequent relapses. Karyotypes at diagnosis were related to the relapses in the following ways: normal to normal (N-N) (five cases); abnormal to normal (A-N) (two cases); abnormal to abnormal with no change (A-A) (five cases); abnormal to abnormal with clonal evolution (A-A+) (eight cases); and normal to abnormal (N-A) (one case). The A-A group comprised two each of t(4;11) and t(9;22) cases and one pseudodiploid case; included in this group were the only two patients who did not receive intensive treatment. Both A-N cases had been pseudodiploid at diagnosis. Clonal evolution A-A+ occurred in patients who had had 47-49 chromosomes or pseudodiploidy at diagnosis and was mainly due to the addition of structural change. The additional abnormalities were different in each case. The only de novo appearance of a clone (N-A) was in host cells in relapse following bone marrow transplantation. Clonal evolution occurred in patients who had been intensively treated and who relapsed late; the median time from diagnosis to relapse studied for the A-A group was 6 months and for the A-A+ group was 24 months. Survival following relapse was shorter for patients who had had a clonal abnormality at any time (median 10 months) than for those with no abnormality at diagnosis or in relapse (median 26 months).

Adolescent↗

PubMed1989

Six-year follow-up of the clinical significance of karyotype in acute lymphoblastic leukemia.

To evaluate the importance of pretreatment karyotype in predicting long-term outcome in acute lymphoblastic leukemia (ALL), we performed a follow-up study of the 329 patients from the Third International Workshop on Chromosomes in Leukemia. Living patients have now been followed a minimum of 6 years. Patients were divided into ten groups according to pretreatment karyotype: no abnormalities, one of the following structural abnormalities [the Philadelphia chromosome, rearrangements involving 8q24, t(4;11), 14q+, 6q-] or, in the remaining cases, modal number (less than 46, 46, 47-50, greater than 50). As previously reported for achievement and duration of complete remission, and overall survival, disease-free survival differed significantly (p less than 0.001) among chromosome groups for both adults and children. Among children, karyotype was an independent prognostic factor for predicting disease-free survival. Because of the long follow-up, we now have been able to utilize statistical models to estimate the percentage of patients cured, according to karyotype alone and combined with other risk factors. Adults with the highest likelihood of cure (21-33%) were those patients with FAB-L1, a leukocyte count of 50,000/microliters or less, and one of the following chromosome groups: greater than 50, 47-50, 6q-, or normal. In children these same characteristics were associated with the highest percentage of cure (58-71% cured). In addition, we identified several groups of children with less than 15% chance of cure who clearly need to be treated as high-risk patients at diagnosis. Future studies of patients who have received risk-adapted therapy based on these chromosome data are needed to determine if more intensive treatment will improve the outlook of patients with cytogenetically unfavorable types of ALL.

Adult↗

PubMed1989

The clinical significance of karyotype in acute myelogenous leukemia.

To evaluate further the prognostic significance of karyotype at diagnosis of acute myelogenous leukemia (AML), we have made a follow-up study of 711 patients who were diagnosed between January 1, 1980, and March 31, 1982, and who were originally reported by the Fourth International Workshop on Chromosomes in Leukemia (4IWCL). Three different chromosomal classifications were evaluated, including presence of normal and abnormal metaphases (NN-AN-AA classification), a modification of the Chicago classification, and a complexity classification. All three chromosomal classifications were shown to correlate significantly with outcome in patients with de novo AML. Furthermore, the NN-AN-AA classification and the complexity classification had independent prognostic significance when age, sex, and FAB morphology were also considered in multivariate analyses of survival. These data provide further evidence that karyotype is an important factor in predicting the outcome of patients with AML.

Adolescent↗

PubMed1989

Expression of the three myeloid cell-associated immunoglobulin G Fc receptors defined by murine monoclonal antibodies on normal bone marrow and acute leukemia cells.

Monoclonal antibodies (MoAbs) have been prepared recently that recognize the three cell-surface receptors for the Fc portion of immunoglobulin (Ig), termed Fc gamma RI (MoAb 32.2), Fc gamma R II (MoAb IV-3), and Fc gamma R III (MoAb 3G8) that are expressed on selected subsets of non-T lymphocyte peripheral blood leukocytes. In the blood, Fc gamma R I is expressed exclusively on monocytes and macrophages, Fc gamma R II on granulocytes, mononuclear phagocytes, platelets, and B cells, and Fc gamma R III on granulocytes and natural killer (NK) cells. We have examined the expression of these molecules on normal bone marrow (BM) cells and on leukemia cells from the blood and/or BM in order to determine their normal ontogeny as well as their distribution on leukemic cells. BM was obtained from six normal volunteers and from 170 patients with newly diagnosed acute leukemia. Normal BM cells were found to express Fc gamma R I, II, and III with the following percentages: 40%, 58%, and 56%, respectively. Cell sorting revealed that both Fc gamma R I and Fc gamma R II were detectable on all subclasses of myeloid precursors as early as myeloblasts. Cell sorting experiments revealed that 66% of the granulocyte-monocyte colony-forming cells (CFU-GM) and 50% of erythroid burst-forming units (BFU-E) were Fc gamma R II positive with only 20% and 28%, respectively, of CFU-GM and BFU-E were Fc gamma R I positive. Acute myeloid leukemia (AML) cells expressed the three receptors with the following frequency (n = 146): Fc gamma R I, 58%; Fc gamma R II, 67%; and Fc gamma R III, 26% of patients. Despite the fact that Fc gamma R I is only expressed on monocytes among blood cells, AML cells without monocytoid differentiation (French-American-British [FAB]M1, M2, M3, M6) were sometimes positive for this receptor. However, Fc gamma R I was highly correlated with FAB M4 and M5 morphology (P less than .001). Fc gamma R II was also correlated with FAB M4 and M5 morphology (P = .003). Cells from 11 patients with acute lymphoblastic leukemia were negative for Fc gamma R I, but six cases were positive for Fc gamma R II and III (not the same patients). These studies demonstrate that Ig Fc gamma R are acquired during normal differentiation in the BM at or before the level of colony-forming units. In addition, we show that acute leukemia cells commonly express Fc gamma R.

Acute Disease↗

PubMed1989

Morphologic and cytochemical characteristics of acute promyelocytic leukemia.

The existence of two distinct subtypes of acute promyelocytic leukemia was confirmed and characterized based on morphologic features of leukemic cells in a series of 63 patients studied by the Cancer and Leukemia Group B (CALGB). Seventeen patients (27%) had microgranular leukemic cells (M3V), and 46 patients (73%) had hypergranular leukemic cells (M3). These patient cohorts were studied for other laboratory and clinical features. Leukemic cells from M3V patients stained less frequently than leukemic cells from M3 patients for myeloperoxidase (median, 93% vs. 99%; P = .006), periodic acid-Schiff (median, 57% vs. 92%; P = .0001), ASD-chloroacetate esterase (median, 45% vs. 87%; P less than .0001), and alpha-naphthyl acetate esterase (0% vs. 37%; P = .0003). Patients with M3V had a higher platelet count (median, 50 vs. 30 x 10(9)/L; P = .01) and tended to have a higher leukocyte count (median, 7.4 vs. 2.2 x 10(9)/L; P = .06) than M3 patients. The patients with M3V morphology were more likely to be nonwhite (29% vs. 7%; P = .03), female (71% vs. 37%; P = .02), and to be infected at the time of presentation (71% vs. 35%; P = .02). No differences in the frequency of the t(15;17) karyotype or the immunophenotypic expression of the leukemic cells were noted in the two morphologic subtypes of acute promyelocytic leukemia. Fewer patients with M3V tended to enter complete remission (65% vs. 80%; P = .20), but no significant differences were found in the duration of complete remission (P = .81; 1 year rate, 50% vs. 85%), or probability of survival (P = .67; 1 year rate, 49% vs. 68%).

Adolescent↗

PubMed1989

The role of heredity in cancer.

Heredity is generally felt to play a minor role in the development of cancer. This review critically examines this assumption. Topics discussed include evidence for heritable predisposition in animals and humans; the potential importance of genetic-environmental interactions; approaches that are being used to successfully locate genes responsible for heritable predisposition; comparability of genetic findings among heritable and corresponding sporadic malignancies; and future research directions. Breast, colon, and lung cancer are used to exemplify clinical and research activity in familial cancer; clinical phenotypes, segregation and linkage analyses, models for environmental interactions with inherited traits, and molecular mechanisms of tumor development are discussed. We conclude that the contribution of heredity to the cancer burden is greater than generally accepted, and that study of heritable predisposition will continue to reveal carcinogenic mechanisms important to the development of all cancers.

Animals↗

PubMed1989

Four new recurring translocations in non-Hodgkin lymphoma.

The identification of recurring chromosomal translocations has provided clues to the gene regions important in lymphoma development. Among 157 patients with non-Hodgkin lymphoma studied by cytogenetic analysis, four new recurring translocations have been identified--t(8;9) (q24;p13), t(11;18)(q21;q21), t(14,15)(q32;q15), and an unbalanced translocation giving rise to der(22)t(17;22) (q11;p11). Each translocation appeared twice. The t(11;18) was the only karyotypic abnormality in the two patients with it, and the t(14;15) was the sole karyotypic abnormality in one patient. All translocations were found in B-cell malignancies and were associated with both nodal and extranodal disease. Among the regions affected, only the immunoglobulin heavy-chain gene MYC, and BCL2, have thus far been associated with lymphoma. The breakpoint sites identified by these translocations warrant further investigation at the molecular level.

Aged↗

PubMed1989

Human bone marrow cytogenetics: growth factors stimulate metaphases for specific lineages.

Fresh and/or frozen bone marrow cells from five healthy individuals and seven patients with myeloid leukemia were studied using growth factors and a cytogenetic technique which allows simultaneous analysis of karotype and cell lineage. Cell lineages were identified using monoclonal antibodies in an alkaline phosphatase antialkaline phosphatase staining method. In general, cultures stimulated with a colony stimulating factor containing conditioned medium (CSF) and erythropoietin (EPO) had a higher (approximately 2-fold) mitotic index (MI) than cultures without these growth factors (maximum 7.0 vs. 3.8 after 4-day culture). The significantly higher MI in cultures with growth factors was shown to result from an increase in both erythrocytic and granulocytic-monocytic mitoses. Every culture with CSF and EPO had more erythrocytic metaphases than the identical culture without these growth factors (mean erythrocytic MI 3.1 vs. 0.3, p = 0.01 in healthy subjects; 6.9 vs. 0, p = 0.05 in leukemia). In each of the three patients showing an increased MI where lineage-specific MI was studied, the granulocytic-monocytic MI increased (mean 4.0 vs. 2.1, p = 0.05). These data suggest that growth factors increase the number of metaphases available for cytogenetic analysis from fresh or frozen marrow, and may be used to stimulate metaphases from specific lineages.

Adolescent↗

PubMed1989

Serum and urine glycosaminoglycans in myeloid leukemia and myelodysplasia.

Urinary glycosaminoglycan excretion is increased in a variety of human diseases, including malignancy. We have measured serum and urine glycosaminoglycan levels by the carbazole method of uronic acid determination in patients with myeloid leukemia or myelodysplasia. Eleven patients were studied during active disease as well as eight in complete remission. Serum levels in patients with active disease did not differ significantly from 11 healthy volunteers with no hematological disease. In contrast, the median urine level for the patients with active disease was 7.6 mg uronate/g Creatinine (Creat) compared to 2.6 for controls (p less than 0.002). Interestingly, the eight patients in complete remission also had a significant increase in uronate excretion with a median of 7.3 (p less than 0.002). These results suggest that elevated urinary glycosaminoglycan levels in leukemia are not due to impaired ability of the liver to clear circulating glycosaminoglycans or overproduction by leukemic cells. The observed increase in glycosaminoglycan excretion may be due to altered bone marrow matrix metabolism that is often not reversed by the achievement of hematologic remission.

Adolescent↗

PubMed1988

The Non-Hodgkin Lymphoma Pathologic Classification Project. Long-term follow-up of 1153 patients with non-Hodgkin lymphomas.

STUDY OBJECTIVE: To document the long-term prognosis of patients with non-Hodgkin lymphoma treated between 1971 and 1975 and to determine how the prognosis varies by histologic subtype and stage. SETTING: Three cancer referral centers in the United States and one center in Italy. PATIENTS: A consecutive sample of 1153 previously untreated patients with non-Hodgkin lymphoma. At the time of analysis, 71% of the patients had died and the median follow-up for patients still alive was 11.2 years. MEASUREMENTS AND MAIN RESULTS: The 10-year survival proportions were 45% (CI, 40% to 50%); 26% (CI, 22% to 30%); and 23% (CI, 18% to 30%) for patients with low-, intermediate-, and high-grade lymphomas, respectively. Patients with intermediate- and high-grade lymphomas were curable, but this was not apparent for patients with advanced stage low-grade lymphomas. For the low-grade follicular small cleaved and follicular mixed lymphomas, the Ann Arbor staging system distinguished the prognosis of patients with stage I disease from those with more extensive involvement. For the diffuse large cell and immunoblastic lymphomas, the Ann Arbor staging system distinguished long-term prognosis for patients with stage I disease from patients with stage II disease and those with more disseminated involvement. CONCLUSIONS: The probability of long-term survival for unselected patients with non-Hodgkin lymphoma can be substantial. Long-term prognosis depends on the histologic subtype of the tumor and the extent of dissemination. The Working Formulation for non-Hodgkin lymphomas is a simple and useful nomenclature for selecting treatment and reporting results. The Ann Arbor staging system is a useful but imperfect prognostic indicator.

Bone Marrow↗

PubMed1988

Clonal chromosomal abnormalities showing multiple-cell-lineage involvement in acute myeloid leukemia.

To determine whether one or more hematopoietic-cell lineages are involved in acute myeloid leukemia (AML), we designed a technique that simultaneously identifies a cell as malignant and determines its lineage. We used numerical clonal chromosomal abnormalities, which are readily detected, to indicate neoplasia, and monoclonal antibodies in an alkaline phosphatase-antialkaline phosphatase detection procedure to identify lineages as granulocytic-monocytic, erythrocytic, or megakaryocytic. Examination of bone marrow from 12 patients with AML showed metaphases of granulocytic-monocytic lineage with abnormal karyotypes in all patients. In seven patients, we also detected abnormal karyotypes in the erythrocytic or megakaryocytic lineage. In all four patients with monosomy 7, both granulocytic-monocytic and erythrocytic cells were affected. Two of four patients with trisomy 8 also had evidence of multiple-lineage involvement, but in two the erythrocytic lineage had normal karyotypes, suggesting an origin at a progenitor-cell stage committed to granulocytic-monocytic development. Multiple-lineage involvement was found in AML both arising de novo (four of five analyzable cases) and following another cancer (three of four analyzable cases). These data demonstrate multiple-lineage involvement in a high proportion of cases of AML and suggest that many cases originate from the multipotent hematopoietic cell or from an earlier progenitor cell.

Adult↗

PubMed1988

Chemotherapy with cyclophosphamide, vinblastine, procarbazine, and prednisone (CVPP) for Hodgkin disease: fourteen-year follow-up results.

Thirty-eight patients with advanced Hodgkin disease were treated with a combination of cyclophosphamide, vinblastine, procarbazine, and prednisone (CVPP) from 1970 to 1973 and followed prospectively. Long-term results after a median follow-up of 14 years are reported. Seventeen of the 28 complete responders (61%) survived more than 10 years from the initiation of chemotherapy. At the current time, 12 of the 28 patients (43%) are continuously disease-free 12.8 to 15.3 years after completing induction chemotherapy. Two additional patients are alive in third and fifth remissions. All relapses occurred within 5.5 years of completing induction chemotherapy. Late complications included sterility, aseptic osteonecrosis, severe pulmonary fibrosis, and chronic uveitis. Four of the complete responders (14%) developed second neoplasms, including acute myelogenous leukemia, non-Hodgkin lymphoma and small cell carcinoma of the lung. All second malignancies were fatal and developed 5-13 years after initiation of induction chemotherapy. Our data confirm that cure is possible with alternative regimens to MOPP (nitrogen mustard, vincristine, procarbazine, and prednisone).

Adolescent↗

PubMed1988

Treatment of refractory lymphoma with methotrexate, VM-26 (teniposide), procarbazine, and dexamethasone: Cancer and Leukemia Group B study 7902.

Seventy-eight individuals previously treated with chemotherapy for non-Hodgkin's lymphoma were enrolled in a phase II pilot study employing methotrexate 100 mg/M2 iv (day 1), calcium leucovorin 10 mg/M2 iv and/or po q6h (days 2-4), VM-26 (teniposide) 100 mg/M2 iv (days 2 and 9), procarbazine 100 mg/M2 po (days 2-15), and dexamethasone 15 mg/M2po (days 2-8) (MV26PD). Thirty percent of the 78 patients treated had a response to therapy (8% complete, 22% partial). Twenty-four percent of patients with diffuse histiocytic (large cell) lymphoma had a response (12% complete, 12% partial). The estimated failure-free survival was 41% at 3 months and the median survival (death from any cause) was 4.5 months for the entire cohort. Two individuals, including one individual with diffuse histiocytic lymphoma, remain in a complete response for over 900 days. Significant hematologic toxicity and infectious complications were seen in this heavily pretreated group of patients. MV26PD represents an active combination of agents for the treatment of non-Hodgkin's lymphoma. The optimal dosing for MV26PD remains to be determined.

Adult↗