Showing papers by "Fred Hutchinson Cancer Research Center published in 1979"

Antileukemic Effect of Graft-versus-Host Disease in Human Recipients of Allogeneic-Marrow Grafts

Abstract: To determine whether allogeneic bone-marrow transplantation is associated with a graft-versus-leukemia effect, we examined the relation between relapse of leukemia and graft-versus-host disease in 46 recipients of identical-twin (syngeneic) marrow, 117 recipients of HLA-identical-sibling (allogeneic) marrow with no or minimal graft-versus-host disease, and 79 recipients of allogeneic marrow with moderate to severe or chronic disease The relative relapse rate was 25 times less in allogeneic-marrow recipients with graft-versus-host disease than in recipients without it (P less than 001) This apparent antileukemic effect was more marked in patients with lymphoblastic than nonlymphoblastic leukemia, and in those who received transplants during relapse rather than during remission, and was most evident during the first 130 days after transplantation Survival of all patients was comparable since the lesser probability of recurrent leukemia in patients with graft-versus-host disease was offset by a greater probability of other causes of death

Marrow transplantation for acute nonlymphoblastic leukemia in first remission.

Abstract: MARROW transplantation provides the opportunity for aggressive antileukemic therapy without regard to marrow toxicity.1 We have reported the application of this approach combined with intensive che...

Cell surface antigens of human melanoma identified by monoclonal antibody

Abstract: Mouse NS-1 myeloma cells were fused with spleen cells from mice that had been immunized with cells from a human melanoma, M1804. Hybrid cells were grown in selective medium and tested for production of antibody to surface antigens of M1804 cells. Three hybrids that produced antibodies that bound to the melanoma cells but not to autologous skin fibroblasts were cloned. Antibodies produced by two of the clones were cytotoxic to M1804 cells in the presence of rabbit complement. Extensive specificity tests showed that the antibodies produced by the clones bound strongly only to M1804 cells; significant, although weaker, binding occurred with 2 of 11 allogeneic melanomas. Apart from weak binding of the antibody produced by one of the clones to a breast carcinoma, binding assays of five carcinomas, one sarcoma, and fibroblasts from 17 individuals were negative, as were cytotoxic tests of 10 lymphoblastoid cell lines and peripheral blood lymphocytes from 68 normal donors and 12 chronic lymphocytic leukemia patients. This suggests that we have identified one or more determinants of a melanoma-associated antigen(s), whose expression is limited to a small proportion of melanomas.

A qualitative discrepancy between censored data rank tests.

Abstract: Two popular censvred data rank tests were used to compare cancer incidence rates between dogs receiving bone marrow transplantation and control dogs. The logrank test gave a significance level of 0.01. In contrast, Gehan's generalized Wilcoxon test gave a significance level of 0. 76. The statistics are displayed in a manner that shows how such contrasting significance levels can arise. The Gehan statistic is shown to be subject to a serious criticism that does not apply to other Wilcoxon generalizations. Further insight into the data is obtained using a time-dependent logrank test and the proportional hazards regression model.

Hazard rate models with covariates.

Abstract: Many problems, particularly in medical research, concern the relationship between certain covariates and the time to occurrence of an event. The hazard or failure rate function provides a conceptually simple representation of time to occurrence data that readily adapts to include such generalizations as competing risks and covariates that vary with time. Two partially parametric models for the hazard function are considered. These are the proportional hazards model of Cox (1972) and the class of log-linear or accelerated failure time models. A synthesis of the literature on estimation from these models under prospective sampling indicates that, although important advances have occurred during the past decade, further effort is warranted on such topics as distribution theory, tests of fit, robustness, and the full utilization of a methodology that permits non-standard features. It is further argued that a good deal of fruitful research could be done on applying the same models under a variety of other sampling schemes. A discussion of estimation from case-control studies illustrates this point.

Intraventricular versus intralumbar methotrexate for central-nervous-system leukemia: prolonged remission with the Ommaya reservoir.

Abstract: Ten children had recurrence of central-nervous-system (CNS) leukemia despite monthly injections of methotrexate into their lumbar cerebrospinal fluid. Each child was then reinduced into remission and maintained with intraventricular methotrexate administered via an Ommaya reservoir and the length of this remission was compared with the duration of the child's previous intralumbar-treated remission. Of eight evaluable patients, seven had longer CNS remissions with intraventricular therapy than with intralumbar therapy (P less than 0.02). The median CNS remission duration in all patients was 475 days with intraventricular and 286 days with intralumbar therapy (P less than 0.05). The rate of CNS relapse was reduced from 2.94 relapses per thousand days at risk during intralumbar therapy to 0.93 relapse per thousand days of intraventricular therapy. We conclude that intraventricular chemotherapy is significantly more effective against CNS leukemia than the same therapy given by lumbar puncture.

Marrow transplantation from donors other than HLA-identical siblings.

Abstract: Twelve patients with acute leukemia and nine with aplastic anemia received marrow transplants from donors other than genotypically HLA-identical siblings. All donor-recipient pairs were genotypically identical for one HLA haplotype and shared antigens of the other. Of nine transplants between siblings, three were HLA-D incompatible and one HLA-A and B incompatible as a consequence of B-D recombination. One such recipient survives in good health at day 485. Three sibling pairs had parents homozygous for HLA-A and B and heterozygous for HLA-D. One rejected the transplant, one died of interstitial pneumonia, and one died of persistent leukemia. Two sibling pairs had parents homozygous for HLA-D but not for HLA-A and B. One recipient died of graft rejection on day 93, and one survives in good health at day 339. Three patients had parent donors identical for HLA-A, B, and D. One survives at day 742. Of two recipients whose parent donors were HLA-A and B compatible and D incompatible, one has minimal graft-versus-host disease (GVHD) at day 361, and one died of graft rejection at day 47. Six recipients had parent donors matched for HLA-D but not for HLA-A or B. One survives with recurrent leukemia in postchemotherapy remission at day 690, three died of graft rejection and two of GVHD. One recipient was HLA-D homozygous, received marrow from his HLA-A-mismatched, HLA-D heterozygous parent and died of graft rejection on day 47. The experience of GVHD was within the range encountered in transplants between genotypically HLA-identical siblings. The number of patients receiving transplants is much too small to permit any conclusions about the relative importance of various degrees and varieties of mismatching, but the results encourage further studies of well defined deviations from the HLA-identical sibling relationship in marrow transplantation. There is an increasing number of reports of marrow transplantation between identical twins or genotypically HLA-identical siblings as part of the therapy of aplastic anemia or hematological malignancy (1–5). We are extending our studies of marrow transplantation by performing allogeneic marrow transplants from donors other than HLA-matched siblings to evaluate the effects of precise histocompatibility differences. This paper reports our experience in this endeavor and presents the details of 21 such transplants.

Antihuman thymocyte globulin for prophylaxis of graft-versus-host disease. A randomized trial in patients with leukemia treated with HLA-identical sibling marrow grafts.

Abstract: SUMMARYPatients with hematological malignancies undergoing allogeneic marrow transplantation from HLA-identical siblings were entered into a randomized study to determine whether the prophylactic administration of horse anti-human thymocyte globulin (ATG) would decrease the incidence or severity of

Asbestos, dental X-rays, tobacco, and alcohol in the epidemiology of laryngeal cancer

Abstract: A case-control study of 47 laryngeal cancers in males of three counties of Washington State was conducted. Personal interview was used to obtain information on smoking, alcohol use, exposure to asbestos, and other substances, and x-rays of the head and neck area. Smoking and alcohol consumption were found to increase risk of laryngeal cancer independently, with a clear dose-response relationship. Neither asbestos exposure nor exposure to other substances was found to significantly increase the risk of laryngeal cancer, although the relative risk with asbestos exposure was 1.75. Lifetime history of exposure to dental x-rays on five or more occasions was associated with significantly increased risk of laryngeal cancer among heavy smokers but not among light smokers. The importance of tobacco and alcohol in the epidemiology of laryngeal cancer was re-affirmed, the importance of asbestos exposure was brought into question, and a possible relationship of laryngeal cancer with exposure to dental x-rays among heavy smokers was demonstrated.

The ultrastructure of the human epidermis in chronic graft-versus-host disease.

Abstract: The epidermal ultrastructure of 11 allogeneic bone marrow recipients with chronic graft-versus-host disease (GVHD) was compared with that of 4 recipients without chronic GVHD. This electron microscope study revealed three patterns of epidermal injury typical of chronic GVHD. The first type was a nonacantholytic (nondissecting) injury with a prominent cellular infiltrate consisting primarily of lymphocytes accompanied by a few macrophages. The second type was an acantholytic (dissecting) injury with a prominent infiltrate, while the third was a nondissecting injury with a sparse infiltrate. Broad-zone contact was observed between lymphocytes and all epidermal cell types as well as between other lymphocytes and macrophages. Point contact was only observed between lymphocytes and epidermal cells. Lymphocytes appeared to detach desmosomes from adjacent keratinocytes by isolating them with cytoplasmic projections, a phenomenon not previously described. Typical damage to the epidermal cells in the basal and spinous layers consisted of either swelling of the organelles or condensation of the cytoplasm and nucleus. In the keratinocyte, the condensation reaction resulted in the formation of colloid bodies, some of which were phagocytized by macrophages. Besides the cytolytic events, a concurrent stimulatory reaction occurred in the epidermal cells. The number of melanosomes in melanocytes and of Langerhans cell granules and dense bodies in the Langerhans cells all increased. Extensive areas of replication and disruption of the basal lamina were subjacent to areas of necrosis in the basal layer.

Efficiency of Smooth Goodness-of-Fit Tests

Abstract: The smooth goodness-of-fit test of Neyman (1937) was generalized to composite hypotheses by Javitz (1975) and Thomas and Pierce (1979). The test statistic is derived, as is its local asymptotic relative efficiency (LARE), which permits its comparison with other quadratic score statistic (QSS) tests, which include a Pearson-type χ2 test. For testing the negative exponential and normal distributions, the smooth test is seen to have greater LARE than the Pearson-type test and LARE comparable to certain other QSS tests for particular local alternatives.

Comparison of the structures of human fibronectin and plasma cold-insoluble globulin.

Abstract: Human amniotic fluid fibronectin and plasma fibronectin (cold-insoluble globulin) are indistinguishable both immunologically and by amino acid composition. Cyanogen bromide and tryptic peptides also suggest substantial structural homology. However, carbohydrate analysis has demonstrated additional saccharides in fibronectin and an overall increase in carbohydrate content relative to cold-insoluble globulin. Furthermore, limited proteolytic cleavage of the two proteins indicates differences in primary structure or in conformation. Using affinity-purified antibodies to cold-insoluble globulin, a glucosamine-labeled pronase-resistant component, probably proteoglycan, was found to coprecipitate with fibronectin, suggesting an association between these two macromolecules in the connective tissue matrix.

Tumor-enhancing suppressor activator T cells in spleens and thymuses of tumor immune mice

Abstract: Cells from the spleens and thymuses of BALB/c mice whose Moloney sarcoma virus (MSV)-induced, primary sarcomas have regressed 2-3 months earlier ("MSV regressors") or are in the process of regressing can, when adoptively transferred to syngeneic mice given MSV at the age of 20 days, prevent the natural regression of the MSV sarcomas in the recipient mice. The cells responsible for this tumor-enhancing effect express the Thy 1 marker. They are not demonstrable in the thymuses of normal untreated mice or in mice that have either been immunized against or are bearing methylcholanthrene-induced sarcomas. The tumor-enhancing cells are not destroyed after administration of 400 rads (1 rad = 1.00 x 10(-2) J/kg) of whole body radiation. However, the effect of the irradiated cells is seen only in the presence of a nonirradiated T-cell population, represented in the thymuses of normal control mice, with which we postulate that they interact. Studies on a transplantable, chemically induced, murine leukemia virus antigen-negative sarcoma, MCA-1460, further support the concept that relatively radioresistant thymus cells from immune mice can enhance tumor outgrowth by interacting with radiosensitive T cells that are present in nonimmune mice.

Successful treatment of juvenile chronic granulocytic leukemia with marrow transplantation.

Abstract: A 46-month-old boy with juvenile chronic granulocytic leukemia was treated intensively with hydroxyurea, dimethyl myleran, cyclophosphamide, and total body irradiation. He then received a marrow transplant from an HL-A matched brother. Thirty-two months after the transplantation, he is hematologically normal and remains disease free on no-maintenance therapy. The successful outcome of this case suggests that a bone marrow transplant for any patient with a suitable histocompatible donor should be considered in the treatment of this disease.

Combination chemotherapy for acute myelocytic leukemia during pregnancy: three case reports.

Abstract: The cases of three patients with acute myelocytic leukemia presenting during the second trimester of pregnancy are summarized. All three patients were treated with combination chemotherapy. One patient, while in remission, underwent elective abortion of an apparently normal fetus. This patient is alive and free of disease 2 years after bone marrow transplantation. Each of the other two patients was spontaneously delivered of a premature infant. Transient bone marrow suppression occurred in one of these infants. Both children were small for their gestational age. One patient died 9 days after her infant was delivered and the other survived for 13 months.

Selective localization of radiolabeled immune lymphocytes into syngeneic tumors.

Abstract: Newly formed long-lived small lymphocytes (LLSL) generated during the immunization of mice to tumor specific transplantation antigens (TSTA) of syngeneic MCA-induced sarcomas were labeled. We then studied the localization of these labeled cells into tumor implants. “Criss-cross” experiments were performed in which MCA sarcomas with individually distinct TSTA were studied in parallel. A selective localization of LLSL into tumors to which the lymphocytes were immune was found when small tumor pieces were implanted into immune mice whose LLSL had been labeled. Selective localization was also detected upon adoptive transfer of immune LLSL to tumor-bearing mice, but only when these mice had, before transfer, received a sublethal dose of whole body irradiation.