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Biomedical subjects

W C Moloney

Publications and source records attributed to W C Moloney.

At least 19 recordsLinked to original sources
PubMed1995

Absence of parvovirus B19 infection in chronic fatigue syndrome.

OBJECTIVE: To evaluate the presence of infection with parvovirus B19 in patients with chronic fatigue syndrome (CFS) who also had rheumatologic symptoms and mild hematologic abnormalities. METHODS: Seven patients meeting the Centers for Disease Control and Prevention working case definition for CFS who also had mild leukopenia, thrombocytopenia, or anemia were studied. Bone marrow was aspirated from each patient, and examined for morphologic abnormalities, including features seen in marrow infections with parvovirus B19, as well as for parvoviral DNA, using polymerase chain reaction (PCR) amplification. Serum obtained at the time of marrow aspiration was also evaluated for parvoviral DNA, using the PCR method, and was examined for the presence of IgM and IgG antibodies to the virus. RESULTS: No evidence of marrow involvement with parvovirus B19 was found in any patient. One patient had antibody evidence of a transient parvoviral infection, during which time an underlying thrombocytopenia worsened. CONCLUSION: Despite examining a selected group of patients thought most likely to have parvoviral infection, based on clinical and hematologic measures, no evidence of clinically important parvoviral infection was noted. Thus, it seems unlikely that parvovirus B19 plays a role in CFS, even though it has been associated with fibromyalgia, a clinically similar syndrome.

Adult↗
PubMed1992

Risk of leukemia after chemotherapy and radiation treatment for breast cancer.

BACKGROUND: Few studies have evaluated the late effects of adjuvant chemotherapy for breast cancer. Moreover, the relation between the risk of leukemia and the amount of drug given and the interaction of chemotherapy with radiotherapy have not been described in detail. METHODS: We conducted a case-control study in a cohort of 82,700 women given a diagnosis of breast cancer from 1973 to 1985 in five areas of the United States. Detailed information about therapy was obtained for 90 patients with leukemia and 264 matched controls. The dose of radiation to the active marrow was estimated from individual radiotherapy records (mean dose, 7.5 Gy). RESULTS: The risk of acute nonlymphocytic leukemia was significantly increased after regional radiotherapy alone (relative risk, 2.4), alkylating agents alone (relative risk, 10.0), and combined radiation and drug therapy (relative risk, 17.4). Dose-dependent risks were observed after radiotherapy and treatment with melphalan and cyclophosphamide. Melphalan was 10 times more leukemogenic than cyclophosphamide (relative risk, 31.4 vs. 3.1). There was little increase in the risk associated with total cyclophosphamide doses of less than 20,000 mg. CONCLUSIONS: Although leukemia occurs in few patients with breast cancer, significantly elevated risks were linked to treatments with regional radiation and alkylating agents. Melphalan is a more potent leukemogen than cyclophosphamide or radiotherapy. Low risks were associated with the levels of cyclophosphamide in common use today. Systemic drug therapy combined with radiotherapy that delivers high doses to the marrow appears to enhance the risk of leukemia.

Aged↗
PubMed1990

Leukemia following chemotherapy for breast cancer.

Leukemia following chemotherapy for breast cancer was studied among patients diagnosed during 1973-1985 within the population-based tumor registries in the Surveillance, Epidemiology, and End Results Program. Among 13,734 women given initial chemotherapy, 24 developed acute nonlymphocytic leukemia (ANLL) compared to 2.1 expected based on general population rates (observed/expected = 11.5; 95% confidence interval = 7.4-17.1). Overall, 58 excess ANLL occurred per 100,000 women-years at risk for patients treated with chemotherapy. The cumulative incidence was 0.7% at 10 years. Risk remained high over all periods of observation up to 9 years after treatment. Among 7974 women treated only with surgery during 1973 and 1974, a period before the widespread use of adjuvant chemotherapy for breast cancer, ANLL was not significantly increased (observed = 7, expected = 5.1). A case-control study was then conducted in Connecticut to evaluate in more detail the risk associated with adjuvant chemotherapy in the general population. Among 20 cases (17 incident leukemias and 3 deaths due to preleukemia) and 60 matched controls, alkylating agents were linked to an 11.9-fold risk of ANLL and preleukemia (95% confidence interval = 2.6-55). Chemotherapy regimens including melphalan were related to a higher risk of leukemic conditions than those including cyclophosphamide. These data suggest that women in the general population treated with adjuvant chemotherapy for breast cancer are at an increased risk of leukemia, that the risk remains high among long-term survivors, and that risk differs by type of alkylating agent administered.

Age Factors↗
PubMed1990

Chronic myelomonocytic leukemia.

Thirty adult patients with CMML were evaluated to determine prognostic factors that might have an impact on conversion to acute leukemia and survival. Neither leukocyte count nor monocyte count correlated with survival. The median survival for all 30 cases was 41 months. Patients with less than 5% marrow blasts had a median survival of 60 months but those with 5-20% blasts had only a 9-month median survival.

Aged↗
PubMed1989

Leukemia risk following radiotherapy for breast cancer.

To evaluate further the relationship between high-dose radiotherapy and leukemia incidence, a nested case-control study was conducted in a cohort of 22,753 women who were 18-month survivors of invasive breast cancer diagnosed from 1935 to 1972. Women treated for breast cancer after 1973 were excluded to minimize the possible confounding influence of treatment with chemotherapeutic agents. The cases had histologically confirmed leukemia reported to the Connecticut Tumor Registry (CTR) between 1935 and 1984. A total of 48 cases of leukemia following breast cancer were included in the study. Two controls were individually matched to each leukemia case on the basis of age, calendar year when diagnosed with breast cancer, and survival time. Leukemia diagnoses were verified by one hematologist. Radiation dose to active bone marrow was estimated by medical physicists on the basis of the original radiotherapy records of study subjects. Local radiation doses to each of the 16 bone marrow components for each patient were reconstructed; the dose averaged over the entire body was 530 rad (5.3 Gy). Based on this dosage and assuming a linear relationship between dose and affect, a relative risk (RR) in excess of 10 would have been expected. However, there was little evidence that radiotherapy increased the overall risk of leukemia (RR = 1.16; 90% confidence interval [CI], 0.6 to 2.1). The risk of chronic lymphocytic leukemia, one of the few malignancies without evidence for an association with ionizing radiation, was not significantly increased (RR = 1.8; n = 10); nor was the risk for all other forms of leukemia (RR = 1.0; n = 38). There was no indication that risk varied over categories of radiation dose. These data exclude an association between leukemia and radiotherapy for breast cancer of 2.2-fold with 90% confidence, and provide further evidence that cell death predominates over cell transformation when high radiation doses are delivered to limited volumes of tissue.

Aged↗
PubMed1988

Radiation dose and second cancer risk in patients treated for cancer of the cervix.

The risk of cancer associated with a broad range of organ doses was estimated in an international study of women with cervical cancer. Among 150,000 patients reported to one of 19 population-based cancer registries or treated in any of 20 oncology clinics, 4188 women with second cancers and 6880 matched controls were selected for detailed study. Radiation doses for selected organs were reconstructed for each patient on the basis of her original radiotherapy records. Very high doses, on the order of several hundred gray, were found to increase the risk of cancers of the bladder [relative risk (RR) = 4.0], rectum (RR = 1.8), vagina (RR = 2.7), and possibly bone (RR = 1.3), uterine corpus (RR = 1.3), cecum (RR = 1.5), and non-Hodgkin's lymphoma (RR = 2.5). For all female genital cancers taken together, a sharp dose-response gradient was observed, reaching fivefold for doses more than 150 Gy. Several gray increased the risk of stomach cancer (RR = 2.1) and leukemia (RR = 2.0). Although cancer of the pancreas was elevated, there was no evidence of a dose-dependent risk. Cancer of the kidney was significantly increased among 15-year survivors. A nonsignificant twofold risk of radiogenic thyroid cancer was observed following an average dose of only 0.11 Gy. Breast cancer was not increased overall, despite an average dose of 0.31 Gy and 953 cases available for evaluation (RR = 0.9); there was, however, a weak suggestion of a dose response among women whose ovaries had been surgically removed. Doses greater than 6 Gy to the ovaries reduced breast cancer risk by 44%. A significant deficit of ovarian cancer was observed within 5 years of radiotherapy; in contrast, a dose response was suggested among 10-year survivors. Radiation was not found to increase the overall risk of cancers of the small intestine, colon, ovary, vulva, connective tissue, breast, Hodgkin's disease, multiple myeloma, or chronic lymphocytic leukemia. For most cancers associated with radiation, risks were highest among long-term survivors and appeared concentrated among women irradiated at relatively younger ages.

Female↗
PubMed1987

Splenic enlargement and hyperfunction as indications for splenectomy in chronic leukemia.

The chronic leukemias are associated with significant morbidity from splenic enlargement and hyperfunction. Although some patients with chronic leukemia benefit from splenectomy, the indications for operation are unclear. To identify those patients who benefit most from splenectomy, nine patients with chronic lymphocytic leukemia (CLL) and eight patients with chronic granulocytic leukemia (CGL) who had splenectomy to palliate the symptoms of massive splenic bulk or to improve the hematologic sequelae of splenic hyperfunction were studied. Splenectomy for bulk symptoms provided good palliation of symptoms, but the duration of the benefit was limited by the stage of the disease. Five of eight patients with CGL with bulk symptoms died within 6 months of operation. Splenectomy for hyperfunction was limited to a short-term hematologic response. In three of four patients with CLL who were Coombs positive, the presence of autoantibodies correlated with a recurrent transfusion requirement within 3 months of splenectomy. Thus, the benefit of splenectomy for bulk symptoms must be weighed against the risk of surgery and the patient's limited life expectancy. The benefit of splenectomy for treatment of splenic hyperfunction depends on the stimulus to hyperfunction and may not be beneficial for patients with refractory autoimmune anemias.

Adult↗
PubMed1987

Radiogenic leukemia revisited.

Radiation-induced leukemia is considered to be similar to the de novo disease. However, following an analysis of clinical and hematological findings in leukemia occurring in irradiated cervical cancer patients, adult Japanese atomic-bomb survivors, and spondylitics treated with x-ray, striking differences were noted. Acute leukemias in cervical cancer patients and Japanese survivors were similar in type to acute de novo leukemias in adults. Cell types among spondylitics were very dissimilar; rare forms, eg, acute erythromyelocytic leukemia (AEL) and acute megakaryocytic leukemia, were increased. Pancytopenia occurred in 25 of 35 cases and erythromyelodysplastic disorders were noted in seven of 35 acute cases. The leukemias and myelodysplastic disorders closely resembled those occurring in patients treated with alkylating agents. This similarity suggests a common pathogenesis involving marrow stem cell injury and extra-medullary mediators of hematopoiesis. Investigation of early acute leukemias and myelodysplastic disorders with newer techniques may provide valuable insights into the pathogenesis of leukemia in humans.

Adult↗
PubMed1987

Radiation dose and leukemia risk in patients treated for cancer of the cervix.

To quantify the risk of radiation-induced leukemia and provide further information on the nature of the relationship between dose and response, a case-control study was undertaken in a cohort of over 150,000 women with invasive cancer of the uterine cervix. The cases either were reported to one of 17 population-based cancer registries or were treated in any of 16 oncologic clinics in Canada, Europe, and the United States. Four controls were individually matched to each of 195 cases of leukemia on the basis of age and calendar year when diagnosed with cervical cancer and survival time. Leukemia diagnoses were verified by one hematologist. Radiation dose to active bone marrow was estimated by medical physicists on the basis of the original radiotherapy records of study subjects. The risk of chronic lymphocytic leukemia, one of the few malignancies without evidence for an association with ionizing radiation, was not increased [relative risk (RR) = 1.03; n = 52]. However, for all other forms of leukemia taken together (n = 143), a twofold risk was evident (RR = 2.0; 90% confidence interval = 1.0-4.2). Risk increased with increasing radiation dose until average doses of about 400 rad (4 Gy) were reached and then decreased at higher doses. This pattern is consistent with experimental data for which the down-turn in risk at high doses has been interpreted as due to killing of potentially leukemic cells. The dose-response information was modeled with various RR functions, accounting for the nonhomogeneous distribution of radiation dose during radiotherapy. The local radiation doses to each of 14 bone marrow compartments for each patient were incorporated in the models, and the corresponding risks were summed. A good fit to the observed data was obtained with a linear-exponential function, which included a positive linear induction term and a negative exponential term. The estimate of the excess RR per rad was 0.9%, and the estimated RR at 100 rad (1 Gy) was 1.7. The model proposed in this study of risk proportional to mass exposed and of risk to an individual given by the sum of incremental risks to anatomic sites appears to be applicable to a wide range of dose distributions. Furthermore, the pattern of leukemia incidence associated with different levels of radiation dose is consistent with a model postulating increasing risk with increasing exposure, modified at high doses by increased frequency of cell death, which reduces risk.

Adult↗
PubMed1987

Acute myeloid leukemia and other myelopathic disorders following treatment with alkylating agents.

Several large cohorts of patients treated with alkylating agents served as a means to review the clinical and pathologic features of 55 cases of myelopathic disorders that resulted. The incidence was 1.8% overall and consisted of five patients (9.9%) who developed bone marrow hypoplasia or aplasia, 15 (27.2%) who developed a myelodysplastic syndrome, and 35 cases of acute myeloid leukemia (62.9%). The median time to recognition of MPD was 14 months, following cessation of chemotherapy. The distribution of the treatment-related MDS cases was different than "de novo" MDS with a high percentage of RAEB-T, and with the treatment related AMLs, there were a higher percentage of patients with FAB M6 (erythroleukemia), and no cases of FAB M3 (hypergranular promyelocytic). The median survival of all patients was very brief.

Adolescent↗
PubMed1986

Melphalan may be a more potent leukemogen than cyclophosphamide.

We have evaluated the relation between alkylating agents and leukemic disorders in 3363 1-year survivors of ovarian cancer who were treated in five randomized clinical trials and at two large medical centers. Overall, 28 patients developed acute nonlymphocytic leukemia (expected, 1.2) and 7 developed preleukemia. A 93-fold increased risk for acute nonlymphocytic leukemia was seen in 1794 women treated with chemotherapy; the incidence of leukemic disorders was 7.7/1000 women per year. Risk was highest 5 to 6 years after the first treatment and appeared to decrease thereafter. The use of radiation therapy did not affect risk. The 10-year cumulative risk (mean +/- SE) of acquiring a leukemic disorder was 8.5% +/- 1.6% after treatment with any alkylating agent, 11.2% +/- 2.6% after treatment with melphalan, and 5.4% +/- 3.2% after cyclophosphamide treatment. A dose-response relationship was apparent in 605 women receiving melphalan and suggested in 333 women receiving cyclophosphamide. Women receiving melphalan were two to three times as likely to develop leukemic disorders than were women receiving cyclophosphamide. These data indicate that choice of chemotherapeutic agent and drug dosage may influence significantly the risk for long-term adverse effects of cancer therapy.

Acute Disease↗
PubMed1985

Long-term survivors of adult acute nonlymphocytic leukemia: fact or fiction?

From 1970 to 1982, remission rates from large series of patients with a median age of approximately 50 years continue to exceed 50% and in series of younger patients may be as high as 75%. These improved results have been due to the combination of cytosar and an anthracycline in RI programs. The current major question is whether or not "consolidation" therapy has improved long-term disease-free survival. Our current results, covering the decade 1970-1980 and using more and more intensive RC programs, do not demonstrate an increase in the percentage of long-term survivors. The results from 1980 to 1982 are encouraging, but must be tempered by the fact that late relapses of adult ANLL are becoming more frequent and 2-year follow-up is much too short an evaluation period. In addition, the prolonged survival in program D may be due to the more intensive RI program and not at all related to the RC. At the present time, our experience lends no support to the theory that more intensive RC programs meaningfully prolong long-term survival.

Acute Disease↗
PubMed1984

Biologic properties of factor-independent nonadherent hematopoietic and adherent preadipocyte cell lines derived from continuous bone marrow culture.

Cell lines dependent for growth upon an inducer T-cell synthesized glycoprotein factor interleukin-3 have been derived from continuous mouse bone marrow cultures. These factor-dependent (FD) lines have been shown to be multipotential (erythroid/basophil/neutrophil) or (eosinophil/basophil/neutrophil); or are unipotent basophil or neutrophil granulocyte cell lines. Both classes of cloned FD lines have maintained self-renewal in vitro for several years with absolute growth dependence on freshly added IL-3. In four instances, factor-independent (FI) variant cell lines were derived, one by subculture in medium containing hydrocortisone and 25% horse serum and three by evolution of variants from cloned FD lines. One class of (FI) lines demonstrated adherent fibroblast-like morphology with differentiation to differentiated adipocytes in medium containing 10(-5) hydrocortisone. A second class of cell lines evolved from cloned FD lines and each grew in suspension culture to a saturation density over 10-fold greater than that for the parent FD line (greater than 10(7)/ml) and each contained no detectable hematopoietic cellular differentiation markers by histochemistry or cell surface receptors. In contrast to IL-3 dependent cell lines, (FI) cell lines failed to differentiate to mature granulocyte morphology in diffusion chambers in vivo. The FI cell lines formed no detectable CFUs in vivo, did not reconstitute hematopoiesis in irradiated mice and did not form tumors in vivo. The failure of the (FI) lines to form tumors and lack of detectable hematopoietic differentiation capacity indicates that these lines may represent an intermediate state between normally regulated hematopoietic cellular self-renewal and malignant transformation.

Adipose Tissue↗
PubMed1984

Refractory dysmyelopoietic anemia and acute leukemia.

One hundred and seventeen consecutive patients with refractory dysmyelopoietic anemia (RDA) were followed and studied over 6 yr. All RDA cases had at least two marrow cell lines involved with dysplasia and usually all three. Morphologically, the series could be divided into 55 cases that had primarily "erythroid" hyperplasia and 62 cases with primarily "myeloid" dysplasia. There was a significantly higher number of acute leukemias in the myeloid group, 21/62 (33.9%), than in the erythroid group, 7/55 (12.7%). Of the 117 cases, 64 had marrow culture studies performed using implanted diffusion chambers (DC) in an irradiated rat host. There was a highly statistically significant correlation between the development of leukemia and abnormal growth in DC during the RDA stage.

Acute Disease↗
PubMed1983

Improved prognosis of diffuse histiocytic and undifferentiated lymphoma by use of high dose methotrexate alternating with standard agents (M-BACOD).

A new combination chemotherapy program (M-BACOD) was administered to 101 patients with advanced diffuse histiocytic and diffuse undifferentiated lymphoma (DHL and DUL). High dose methotrexate (M) 3 g/m2 with leucovorin factor rescue was given on day 14 between cycles of bleomycin (B), adriamycin (A), cyclophosphamide (C), oncovin (O), and dexamethasone (D) administered every 3 weeks for 10 cycles. The complete remission rate (CR) was 72% in all 101 patients or 77% in 95 evaluable patients. The median follow-up is 3 yr 2 mo with one-third of CR patients followed beyond 4 yr. Twenty-six percent of CR patients have relapsed with a projected 5-yr survival rate of 80% (5-yr disease-free rate 65%). The overall survival of all 101 study patients reaches a plateau at 59% projected out to 5 yr. Patients with prior therapy had a significantly lower CR rate than those without prior treatment (p = 0.001); however, no other unfavorable prognostic characteristics could be identified. Relapse in the central nervous system CNS occurred in only 5.4% of CR patients. M-BACOD results in prolonged survival and possible cure in a high proportion of all patients with DHL and DUL.

Actuarial Analysis↗
PubMed1982

Paradoxical effect of radiation on tumor incidence in the rat: implications for radiation therapy.

The high incidence of leukemia in the Fischer rat is reduced by radiation to an incidence below that seen spontaneously. Fractionating the radiation decreased this effect. In contrast, mammary tumors increased with dose until reaching a plateau at the highest doses. Fractionation had little effect. These results are consistent with a hypothesis suggesting that tumor incidence due to radiation is the result of competing processes of tumor induction and cell killing.

Animals↗