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Biomedical subjects

A Fefer

Publications and source records attributed to A Fefer.

At least 91 records · Page 5Linked to original sources
PubMed1982

Nonbacterial nonfungal pneumonia following marrow transplantation in 100 identical twins.

Pneumonia attributable to causes other than bacterial or fungal infection is a major complication of allogeneic marrow transplantation. In this study, the incidence, mortality, and possible risk factors for the development of nonbacterial, nonfungal pneumonia after 100 syngeneic marrow transplants for hematological malignancy are reviewed and compared with the results found in 351 allogeneic marrow transplants performed during the same time period. Both the incidence and mortality of pneumonia were far lower among syngeneic patients, especially for pneumonia associated with cytomegalovirus. Idiopathic pneumonia, however, occurred with about equal frequency in the two populations. Among twins, an increased incidence of pneumonia was seen in older patients and in those who received chemotherapy in addition to cyclophosphamide and total body irradiation as part of the preparative regimen for transplantation.

Adolescent↗
PubMed1982

Analysis of late infections after human bone marrow transplantation: role of genotypic nonidentity between marrow donor and recipient and of nonspecific suppressor cells in patients with chronic graft-versus-host disease.

Infections occurring 6 mo or later after bone marrow transplantation for severe aplastic anemia or hematologic malignancy were analyzed in 98 long-term survivors. Varicella-zoster (VZ) infections were analyzed separately from all other infections. The factor predisposing most strongly to late VZ infection was genotypic nonidentity for HLA between marrow donor and recipient. There was a suggestion that chronic graft-versus-host disease (GVHD) associated with the presence of nonspecific suppressor cells also predisposed to late VZ infection, while age less than 10 yr was protective against such infections. Chronic GVHD predisposed to late non-VZ infections, but this was not increased by the presence of nonspecific suppressor cells. HLA nonidentify between patient and marrow donor further increased the risk of late non-VZ infections over and above that due to the presence of chronic GVHD. Receipt of a syngeneic transplant appeared protective for late non-VZ infections. These findings suggest that full genotypic identity for HLA between donor and recipient may be required for optimal immune reconstitution after marrow transplantation and may denote a possible biologic role for nonspecific suppressor T cells in humans.

Acute Disease↗
PubMed1982

Treatment of refractory acute nonlymphocytic leukemia with a combination of pyrazofurin and cytarabine.

Six patients with refractory acute nonlymphocytic leukemia were treated with pyrazofurin (15 mg/m2) followed by cytarabine (100 mg/m2) every 12 hours for 6--21 days. All patients cleared their peripheral blood of blast cells but no complete remissions were achieved. Excessive toxicity to skin and mucous membranes was observed. In the doses used, this combination is too toxic for further use. Alternate treatment schedules should be explored.

Acute Disease↗
PubMed1981

Bone marrow transplantation for acute myelosclerosis.

Four patients with acute myelosclerosis were treated with chemoradiotherapy and bone marrow transplantation. Three of the four had prompt engraftment with greater than 0.10 X 10(9) granulocytes/liter three weeks after transplantation. One patient continues in complete remission one year after transplantation. One patient experienced a partial remission and two patients died early in the post-transplantation period. Marrow fibrosis disappeared in three of the four patients. The patient with residual marrow fibrosis died 22 days after transplantation. It is apparent that marrow fibrosis is reversible. In view of the absence of other effective therapy, intensive therapy with marrow transplantation should be considered as primary therapy for patients with acute myelosclerosis who have a suitable marrow donor.

Acute Disease↗
PubMed1981

High-dose combination chemotherapy for acute nonlymphoblastic leukemia in adults.

One hundred thirty-nine consecutive unselected adults with acute nonlymphoblastic leukemia were treated with a high-dose chemotherapeutic remission-induction regimen consisting of daunomycin (70 mg/m2 IV on days 1, 2, 3), cytosine arabinoside (100 mg/m2 IV every 12 hours), 6-thioguanine (100 mg/m2 orally every 12 hours), prednisone (40 mg/m2 daily), all given on days 1 through 7, and vincristine (1 mg/m2 IV on days 1 and 7). Supportive care consisted of broad spectrum antibiotics for fever in the presence of granulocytopenia and prophylactic platelet transfusions. The complete remission (CR) rate was 60%. The median number of days to CR was 30. Fifty-eight of 77 (75%) patients under age 50 and 26 of 62 (42%) patients over age 50 attained CR. Despite the use of a relatively large dose of daunomycin and monthly maintenance chemotherapy, the median remission duration was only 39 weeks and the medial survival 64 weeks. Most patients who failed to achieve CR died early-77% of deaths occurred within the first six weeks. Infections accounted for the increase mortality in patients over age 50. Thirty-seven percent of patients over age 50 died of infections whereas only 10% under age 50 did so (P less than 0.001). Seven percent of the patients died of fungal infection during attempted remission induction. The incidence of resistance of the leukemia to the remission-induction regimen was low (8%).

Acute Disease↗
PubMed1981

Eradication of disseminated murine leukemia by chemoimmunotherapy with cyclophosphamide and adoptively transferred immune syngeneic Lyt-1+2- lymphocytes.

The phenotype of T cells therapeutically effective in immunotherapy of advanced Friend virus-induced (FBL) leukemia in vivo and cytotoxic to FBL in vitro was determined. Mice bearing disseminated FBL leukemia were successfully treated by a combination of cyclophosphamide and adoptive transfer of syngeneic immune lymphocytes. Therapeutic efficacy was largely dependent on the presence of Lyt-1+2- T cells in the transferred cells, whereas cells cytotoxic to FBL tumor in vitro were derived from the Lyt-1+2+ and Lyt-1-2+ subsets. Thus, the predominate cell required to eradicate tumor in adoptive chemoimmunotherapy was not cytolytic to tumor in vitro. Potentially, the Lyt-1+2- cell may operate in vivo as an amplifier cell rather than by a direct anti-tumor effect. Elimination of the Lyt-1+ population with alpha-Lyt-1 and complement prevented the generation of significant cytotoxic responses during both primary in vitro sensitization to alloantigens and in vitro sensitization of tumour-primed cells. The capacity of Lyt-1+ cell-depleted population to generate cytotoxic responses was partially reconstituted by addition, at the initiation of culture, of interluekin 2, a T cell growth factor derived from Lyt-1+2- cells, which contain the CTL and CTL precursors, were nearly as effective in vitro as unseparated immune cells. If the remaining effector cells (i.e., Lyt-1+2- T cells) function in vivo predominantly as amplifier cells, than the tumour-bearing host must be capable of making a positive contribution to the outcome of therapy.

Animals↗
PubMed1981

Studies of the response in mixed leukocyte culture of cells from patients with aplastic anemia to cells from HLA-identical siblings.

We have studied the mixed leukocyte culture (MLC) reactions of 64 patients with severe aplastic anemia. Their peripheral blood mononuclear cells showed an increased relative response (RR) to cells from HLA-identical siblings as compared to cells from normal HLA-identical siblings, confirming the results reported in an earlier series of 34 patients. Elevated RRs were associated with patient antidonor lymphocyte antibodies as detected by the antibody-dependent cell-mediated cytotoxicity assay, but were not associated with antidonor complement-dependent cytotoxic antibodies or with antidonor cytotoxic T lymphocytes. Among 98 patients receiving marrow grafts from HLA-identical sibling donors, those with elevated RRs before transplantation were more apt to reject the transplant than those without (P less than 0.0001). There was no elevation of the RR in 10 untransfused patients, although positive RRs were noted in 2 patients within 12 to 24 hr of their first transfusions. Five patients with identical twins were also tested, and elevated RRs were noted in three. Although blood transfusion appears to be responsible for the increased RRs observed in some aplastic patients, genetic differences between donor and recipient were not always necessary for eliciting an increased MLC response, suggesting that mechanisms other than alloimmunization are involved.

Adolescent↗
PubMed1981

Definition of alien H-2 determinants on a Friend leukaemia by analysis of alloreactivity of CTL from primary MLC.

A Friend virus-induced tumour of BALB/c (H-2d) origin, HFL/d, was examined for the expression of alien H-2 antigens. The alloantigens on HFL/d were typed by generating CTL in primary MLC with HFL/d as stimulator and measuring reactivity to targets with known H-2 antigens, and confirmed by assessing recognition of HFL/d targets by CTL generated in primary MLC with stimulators expressing known H-2 antigens. Potential cross-reactivities between alloantigens were analysed by cold-target inhibition experiments. BALB/c cells stimulated with HFL/d lysed H-2b targets, and BALB/c anti-H-2b CTL lysed HFL/d; analysis with recombinant haplotypes demonstrated both H-2Kb and H-2Db alien antigens antigens on HFL/d. C57BL/6 (H-2b) cells stimulated with HFL/D recognized H-2Kd, H-2Dd, and an additional determinant unique to HFL/d. (BALB/c x B6)F1 cells also recognised a unique HFL/d determinant not of H-2b or H-2d origin. These unique determinants, which induced a strong cytotoxic response in primary MLC, were not shared by BALB/c or B6 tumours induced by cross-reactive FMR viruses. Thus, HFL/d expressed the K and D antigens of its strain of origin, two typed alien H-2 antigens, and at lest one other untyped antigen which may represent an additional H-2 determinant. These studies further demonstrate the utility of examining the reactivity of CTL generated in primary MLC to probe for the presence of alien H-2 antigens.

Animals↗
PubMed1981

Distinct phenotypic expression of immunogenicity and immunosensitivity in sublines of a tumor.

Continuous in vitro or in vivo passage of a BALB/c leukemia has resulted in generation of 2 immunologically distinct sublines. The subline maintained by in vitro passage failed to stimulate an allogeneic response but was susceptible to lysis by alloreactive cytotoxic cells. Conversely, the subline maintained by in vivo passage induced an allogeneic response but was resistant to lysis by cytotoxic T lymphocytes (CTL) reactive to H-2d antigens. Resistance to lysis occurred despite expression of H-2d antigens in a form recognizable by differentiated alloreactive CTL, as determined by cold-target inhibition experiments. Moreover, resistance was immunologically specific, in that the subline was susceptible to immune lysis mediated through recognition of other determinants. The results imply that the display and/or orientation of antigen in the cell membrane of these sublines that is required for a lytic event is distinct from the antigen expression necessary for immunologic recognition.

Animals↗
PubMed1981

Chemoimmunotherapy of a Friend leukemia with cells secondarily sensitized in vitro: effect of culture duration on therapeutic efficacy.

Although in vivo-primed cells are known to be rendered more effective in adoptive tumor therapy by secondary sensitization in vitro, they were tested only at the time of maximum in vitro cytolytic reactivity. Since the requirements for in vitro cytotoxicity and tumor therapy differ, the present study was designed to evaluate and compare the influence of culture duration on these two effector functions. Spleen cells from inbred C57BL/6 mice primed in vivo with the Friend virus-induced leukemia FBL-3 were secondarily sensitized in vitro by culture with tumor and tested for cytotoxicity in vitro in a 4-hour 51Cr release assay and for therapeutic efficacy in vivo against established tumor. In vivo-primed cells tested directly without prior culture were effective in therapy but were not cytotoxic in vitro. Culture of primed cells for 3 days rendered them cytotoxic as measured in vitro. This cytotoxicity increased through day 5, then it plateaued. Cultured duration modified the in vivo efficacy of primed cells differently. Cells cultured for 3 days with secondary sensitization by tumor became more effective in tumor therapy than noncultured primed cells. Increasing the duration of in vitro sensitization from 3 to 5 days did not enhance in vivo therapeutic efficacy, despite a concurrent increase in in vitro cytotoxicity. However, further lengthening of the culture duration to 7 days rendered cells more effective in vivo. These discrepancies presumably reflect different effector cell requirements and/or regulation operative for tumor lysis during a short-term in vitro assay and for tumor eradication following adoptive transfer of immune cells in vivo.

Animals↗
PubMed1981

Bone marrow transplantation for refractory acute leukemia in 34 patients with identical twins.

Thirty-four patients aged 4-67 yr (median 17) with acute lymphocytic leukemia (ALL) (18 patients) or acute nonlymphocytic leukemia (ANL) (16 patients) who failed to enter complete remission (CR) or relapsed on conventional chemotherapy were treated with cyclophosphamide (CY), 60 mg/kg/day for 2 days, 1000 rad total body irradiation, and a marrow transplant from a genotypically identical normal twin. Sixteen of the patients received additional chemotherapy within the week before CY. After the transplant, 23 patients received immunotherapy consisting of killed autologous leukemic cells and/or normal twin peripheral blood lymphocytes, 16 as part of a prospectively randomized study. One moribund patient died before engraftment. Nine patients (6 ALL, 3 ANL) continued to have detectable leukemic cells. Twenty-four patients (70%) achieved CR. One of them died of viral hepatitis at 1 mo and another of viral interstitial pneumonitis at 4 mo in CR. Fourteen patients (7 ALL, 7 ANL) relapsed 2-16 mo (median 4) after transplantation. However, 8 patients (24%) (3 ALL, 5 ANL) remain in CR without any maintenance chemotherapy at 29-103 mo (median 80) after the transplant. The end results were not signficantly influenced by the type of leukemia, the immediated pre-CY chemotherapy, or the immunotherapy. The results show that this approach, even when applied to endstage patients with acute leukemia in relapse, causes tolerable morbidity, rare nonleukemic deaths, and frequent remissions, some of which represent cures.

Acute Disease↗
PubMed1981

Adoptive therapy of established syngeneic leukemia by cells primarily sensitized in vitro.

The aim of the current studies was to determine whether cells primarily sensitized in vitro are effective in adoptive therapy of established tumors. Spleen cells from normal BALB/c mice were cultured for 5 days at variable responder:stimulator ratios with an X-irradiated syngeneic Moloney virus-induced leukemia (LSTRA), denoted as BALB/c.(LSTRA)x, or with X-irradiated normal BALB/c spleen cells, denoted as BALB/c. (BALB/C)x, and tested for ability to eradicate an established lethal inoculum of LSTRA in adaptive chemoimmunotherapy. BALB/c mice inoculated with 2 X 10(3) LSTRA i.p. on Day 0 were treated on Day 5 with cyclophosphamide (180 mg/kg) plus 1 X 10(7) cultured cells. Treatment with cyclophosphamide alone cured only 3% of mice. As an adjunct to cyclophosphamide, therapy with BALB/c.(BALB/c)x cultured at responder:stimulator ratios of 8:1, 32:1, and 128:1 cured 29%, 37%, and 33% of mice, respectively; and BALB/c.(LSTRA)x cultured at the same responder:stimulator ratios cured 54, 83, and 29% of mice, respectively. Furthermore, the therapeutic efficacy of BALB/c.(LSTRA)x was abrogated by treatment with anti-Thy 1.2 + complement. Thus, culture of normal lymphoid cells with tumor at optimal responder:stimulator ratios substantially enhanced their ability to eradicate established tumor, and the enhanced therapeutic efficacy was mediated by a T-cell generated during culture. The specificity of primary in vitro sensitization in generating cells effective in the therapy of established tumors was confirmed by treating BALB/CH-2d X C57BL/6H-2b F1 (hereafter called B6F1) mice bearing either LSTRAH-2d or an antigenically distinct chemically induced leukemia, EL-4(G-)H-2b, with CB6F1 spleen cells sensitized in vitro to either of the parental tumors.

Animals↗
PubMed1981

Treatment of non-Hodgkin's lymphoma with marrow transplantation in identical twins.

Eight patients with disseminated non-Hodgkin's lymphoma who failed conventional combination chemotherapy were treated with high-dose chemotherapy, a supralethal dose of total-body irradiation, and a bone marrow transplant from a normal identical twin. Seven patients experienced complete remission. Four of the seven patients (two with diffuse poorly differentiated lymphocytic lymphoma, one with composite lymphoma, and one with diffuse moderately well differentiated lymphocytic lymphoma) remain in complete unmaintained remission 12-126 mo from transplantation. One patient relapsed after 10 mo but was retreated and is alive in unmaintained complete remission 73 mo from transplantation. One patient died of Pseudomonas pneumonia while in complete remission and one patient relapsed and died of progressive lymphoma. These results demonstrate that intensive chemoradiotherapy and twin marrow transplantation can induce frequent and enduring remissions in patients with disseminated non-Hodgkin's lymphoma who have failed conventional therapy.

Adolescent↗