Therapists' and patients' experiences of using patients' self-reported data in ongoing psychotherapy processes-A systematic review and meta-analysis of qualitative studies.

OBJECTIVE: Using patient-generated quantitative data in psychotherapy (feedback) appears to enhance treatment outcome, but there is variability in its effect. Different ways and reasons to implement routine outcome measurement might explain such variability. The goal of this review is to address the insufficient knowledge on how these data are used by therapists and patients. METHODS: The present study is a systematic review and meta-analysis of qualitative reports of therapists' and patients' experiences using patient-generated quantitative data during ongoing psychotherapy. RESULTS: Four main categories of use were identified: (1) uses of patients' self-reported data as nomothetic/objective markers for assessment, process monitoring, and treatment planning; (2) intrapersonal uses that enhance self-awareness, initiate reflection, and influence patients' mood or responses; (3) uses that prompt interactional processes by facilitating communication, supporting exploration, creating ownership in patients, changing treatment focus, enhancing therapeutic alliance, or disturbing the psychotherapy process; and (4) patients responding for specific purposes due to uncertainty and interpersonal motives, or strategic responding to achieve a desired result. CONCLUSION: These results demonstrate that patient-reported data, when used in active psychotherapy, is very clearly not just an objective measurement of client functioning: the inclusion of patient-data has the potential to influence psychotherapy in numerous ways.

Effects of interleukin-3 on hematopoietic recovery after 5-fluorouracil or cyclophosphamide treatment of cynomolgus primates.

Interleukin-3 (IL-3) is a hematopoietic growth factor that supports the growth of early hematopoietic progenitors in vitro. In vivo administration of recombinant human interleukin-3 (rhIL-3) to normal primates results in a modest and delayed leukocytosis secondary to increases in neutrophils, basophils, and eosinophils. We postulated that the effects of rhIL-3 might be more pronounced in hematologically stressed primates, and therefore administered rhIL-3 to primates after intensive myelosuppressive therapy. Primates received either cyclophosphamide (CPM) at 60 mg/kg or 5-fluorouracil (5-FU) at 75 mg/kg i.v. on two consecutive days. Subsequently, rhIL-3 was administered intravenously or subcutaneously at 20 micrograms/kg per d for 14 d. Compared to controls, all rhIL-3 treated primates experienced higher absolute neutrophil count (ANC) nadirs and dramatic decreases in the period of severe neutropenia (ANC less than 500) after myelosuppressive therapy. RhIL-3 administration resulted in a significant basophilia and eosinophilia, which resolved after discontinuation of the drug. RhIL-3 did not enhance erythroid recovery. Platelet recovery was earlier in rhIL-3-treated animals. However, variations in the platelet recovery observed in control animals, precluded accurate estimation of this effect or its significance. Our results indicate that the administration of rhIL-3 following intensive myelosuppressive therapy dramatically enhances myeloid recovery and ablates the predicted period of prolonged severe neutropenia.

Clinical use of recombinant human hematopoietic growth factors.

Hematopoietic growth factors comprise a family of hematopoietic regulators with biologic specificities defined by their ability to support proliferation and differentiation of blood cells of different lineages. The biologic specificities of these factors are highly complex, dose dependent, and frequently overlapping. Recent advances in the cloning of hematopoietic growth factor genes and the availability of recombinant material have led investigators to conduct clinical trials with these agents. Some of these factors have been studied and used in chemotherapy-induced neutropenia, myelodysplastic syndromes, and bone marrow failure syndromes. In this paper, we review the experience with growth factors that have been tested and that currently are being introduced in clinical trials. In addition, we report some factors with possible future interest for clinicians and researchers.

Randomized trial of r-metHu granulocyte colony-stimulating factor in an intensive treatment for T-cell leukemia and advanced-stage lymphoblastic lymphoma of childhood: a Pediatric Oncology Group pilot study.

PURPOSE: Contemporary chemotherapy has significantly improved the event-free survival (EFS) among patients with T-cell disease. However, myelosuppression has been a significant adverse effect of this approach. In this study, we assessed the impact of r-metHu granulocyte colony-stimulating factor (G-CSF) on the period of neutropenia, number of days of hospitalization, and delays in subsequent administration of chemotherapy in a cohort of patients with T-cell leukemia (T-ALL) or advanced stage lymphoblastic lymphoma (ASLL). PATIENTS AND METHODS: This open-label, randomized trial incorporated r-metHuG-CSF into the induction and two consecutive continuation-therapy cycles of our intensive program for T-cell malignancies. In the induction phase, r-metHuG-CSF was given after two different combinations of chemotherapy, one of which included vincristine, prednisone, cyclophosphamide, and adriamycin and the other a continuous infusion of high-dose ara-C and L-asparaginase. In the two continuation-therapy cycles, r-metHuG-CSF was given following the combination of vincristine, adriamycin, prednisone, and 6-mercaptopurine (MP) and after continuous infusion of high-dose cytarabine (ara-C). RESULTS: Fifty-six patients with T-ALL and 33 with ASLL were enrolled onto study from April 1994 to December 1995. Our data show no significant difference in number of days of absolute neutrophil count (ANC) less than 500/microL, hospitalizations, or delays in therapy in the induction phase. However, in the continuation-therapy phase the number of days of ANC less than 500/microL was significantly shorter (P = .017) on the G-CSF-arm without significantly affecting the number of days of hospitalizations or delays in therapy. CONCLUSION: r-metHuG-CSF did not significantly affect the period of neutropenia, hospitalization, or delays in therapy in the induction phase, whereas in the two cycles of continuation therapy, it significantly shortened the period of neutropenia.

Juvenile chronic myeloid leukemia: therapeutic insights.

Twelve children with juvenile chronic myeloid leukemia (JCML) received chemotherapy or bone marrow transplants. The median survival of the patients treated with myelosuppressive agents was 19 months. These results demonstrate that intensive chemotherapeutic and supportive measures can prolong survival in JCML but do not affect ultimate outcome. Purported differentiation inducers--low dose ara-C and 13-cis-retinoic acid--were not effective in two patients. Two patients were prepared for bone marrow transplantation with standard antileukemic cytoreduction regimens; one died very early post-transplant, and the other had early reemergence of his disease. The third transplant patient underwent transplantation after his disease had entered an accelerated phase. He received a different immunosuppressive pretransplant regimen, but the leukemia recurred. The latter two patients initially engrafted with mismatched T cell-depleted marrow grafts, but had recurrence of the disease. Our data suggest that marrow transplantation is possible for JCML patients without HLA-identical donors, but for successful marrow transplantation different measures are necessary to eradicate the abnormal stem cell compartment.

Transient therapy-related myelodysplastic syndrome associated with monosomy 7 and 11q23 translocation.

Secondary acute myelocytic leukemia (AML) and myelodysplastic syndromes (MDS) are known to develop in patients previously treated with different chemotherapeutic regimens. Nonrandom chromosomal abnormalities have been demonstrated in these therapy-related myeloid disorders which often evolve into refractory AML. The prognosis of these patients with conventional chemotherapy has been dismal and only allogeneic bone marrow transplantation offers a potential cure. We describe two patients who developed MDS after chemo/radiotherapy and had a spontaneous recovery. One patient was treated with MOPP-ABVD hybrid therapy for Hodgkin's disease, developed pancytopenia, marrow hypoplasia and dyserythropoiesis associated with monosomy 7. The other was treated with a combination of chemotherapy including VP-16 for Ewing's sarcoma, developed thrombocytopenia, marrow hypoplasia and dyserythropoiesis associated with an 11q23 translocation. Both patients received rhG-CSF after their cycles of chemotherapy and were considered for a bone marrow transplant. Marrow aspirates at frequent intervals showed gradual disappearance of the abnormal clone with parallel normalization of the peripheral count. In both patients G-CSF might have played a role in the development of the abnormal clone. We suggest that patients with therapy-related MDS without excess of blasts could be closely monitored for karyotypic and hematological improvement rather than transplanted immediately.

Effects of cranial radiation in children with high risk T cell acute lymphoblastic leukemia: a Pediatric Oncology Group report.

Contemporary chemotherapy has significantly improved event-free survival among patients with T cell-lineage acute lymphoblastic leukemia (T-ALL). Unlike B-precursor ALL, most investigators are still using cranial radiation (CRT) and are hesitant to rely solely on intrathecal therapy for T-ALL. In this study we assessed the effects of CRT upon event-free survival and central nervous system (CNS) relapses in a cohort of children with high risk features of T cell leukemia. In a series of six consecutive studies (1987-1995) patients were non-randomly assigned their CNS prophylaxis per individual protocol. These protocols were based on POG 8704 which relied on rotating drug combinations (cytarabine/cyclophosphamide, teniposide/Ara-C, and vincristine/doxorubicin/6-MP/prednisone) postinduction. Modifications such as high-dose cytarabine, intermediate-dose methotrexate, and the addition of G-CSF, were designed to give higher CNS drug levels (decreasing the need for CRT), to eliminate epidophyllotoxin (decreasing the risk of secondary leukemia), and to reduce therapy-related neutropenia (pilot studies POG 9086, 9295, 9296, 9297, 9398). All patients included in this analysis qualified for POG high risk criteria, WBC >50000/mm3 and/or CNS leukemia. Patients without CNS involvement received 16 doses of age-adjusted triple intra-thecal therapy (TIT = hydrocortisone, MTX, and cytarabine) whereas patients with CNS disease received three more doses of TIT during induction and consolidation. Patients who received CRT were treated with 2400 cGy (POG 8704) or 1800 cGy (POG 9086 and 9295). CNS therapy included CRT in 144 patients while the remaining 78 patients received no radiation by original protocol design. There were 155 males and 57 females with a median age of 8.2 years. The median WBC for the CRT+ and CRT- patients were 186000/mm3 and 200000/mm3, respectively. CNS involvement at diagnosis was seen in 16% of the CRT+ and 23% of the CRT- groups. The complete continuous remission rate (CCR) was not significantly different for the irradiated vs. non-irradiated groups (P = 0.46). The 3-year event-free survival was 65% (s.e. 6%) and 63% (s.e. 4%) for the non-irradiated vs. the radiated group. However, the 3-year CNS relapse rate was significantly higher amongst patients who did not receive CRT; 18% (s.e. 5%) vs. 7% (s.e. 3%) in the irradiated group (P = 0.012). Our analysis in a non-randomized setting, suggests that CRT did not significantly correlate with event-free survival but omitting it had an adverse effect on the CNS involvement at the time of relapse.

Intensive high-dose asparaginase consolidation improves survival for pediatric patients with T cell acute lymphoblastic leukemia and advanced stage lymphoblastic lymphoma: a Pediatric Oncology Group study.

This study was designed to test the hypothesis that high-dose asparaginase consolidation therapy improves survival in pediatric patients with T cell acute lymphoblastic leukemia and advanced stage lymphoblastic lymphoma. Five hundred and fifty-two patients (357 patients with T cell acute lymphoblastic leukemia (ALL) and 195 patients with advanced stage lymphoblastic lymphoma) were enrolled in POG study 8704 (T-3). Treatment included rotating combinations of high-dose myelosuppressive chemotherapy agents proven to be effective in T cell ALL in other POG group-wide or local institutional protocols (including vincristine, doxorubicin, cyclophosphamide, prednisone, asparaginase, teniposide, cytarabine and mercaptopurine). After achieving a complete remission (CR), patients were randomized to receive or not receive high-dose intensive asparaginase consolidation (25,000 IU/m2) given weekly for 20 weeks by intramuscular injection. Intrathecal chemotherapy (methotrexate, hydrocortisone and cytarabine) was given to prevent CNS disease, and CNS irradiation was used only for patients with leukemia and an initial WBC of >50,000/microl or patients with active CNS disease at diagnosis. CR was achieved in 96% of patients. The high-dose asparaginase regimen was significantly superior to the control regimen for both the leukemia and lymphoma subgroups. Four-year continuous complete remission rate (CCR) for the leukemia patients was 68% (s.e. 4%) with asparaginase as compared to 55% (s.e. 4%) without. For the lymphoma patients, 4-year CCR was 78% (s.e. 5%) with asparaginase and 64% (s.e. 6%) in the controls. The overall one-sided logrank test had a P value <0.001 favoring asparaginase, while corresponding values were P = 0.002 for ALL and P = 0.048 lymphoblastic lymphoma. Toxicities were tolerable, but there were 18 failures due to secondary malignancies (16 with non-lymphocytic leukemia or myelodysplasia). Neither WBC at diagnosis (leukemia patients) nor lymphoma stage were major prognostic factors. We conclude that when added to a backbone of effective rotating agents, repeated doses of asparaginase during early treatment improve the outcome for patients with T cell leukemia and advanced stage lymphoblastic lymphoma.

Study of early hematopoietic precursors in human cord blood.

Human cord blood is a source of transplantable stem cells. These stem cells express the antigen CD34, are resistant to treatment with 4-hydroperoxycyclophosphamide (CD34+/4-HCres), and do not give rise to colonies when plated in clonogenic assays. We studied the number of CD34+ cells present in cord blood and developed a two-step assay for early precursors (pre-colony-forming units, pre-CFU) capable of giving rise to committed progenitors. In this assay CD34+/4-HCres cord blood cells were cultured in suspension with different growth factors. After 7 days in suspension the remaining cells were plated in clonogenic assays, for granulocyte-macrophage colony-forming units (CFU-GM), erythroid burst-forming units (BFU-E), and mixed lineage colony-forming units (CFU-MIX), in the presence of pure factors or a combination of recombinant human (rh) interleukin 3 (IL-3) and medium conditioned by the PU34 primate cell line. Pre-CFU for all precursors were identified. These pre-CFU developed into committed progenitors in response to rhIL-3. The combinations of rhIL-3 plus rh interleukin 1 (IL-1) or rhIL-3 plus rh interleukin 6 (IL-6) did not enhance recovery of progenitors. The developing CFU-GM were responsive to rh granulocyte-macrophage colony-stimulating factor (GM-CSF) and rh granulocyte colony-stimulating factor (G-CSF) but much less so to rhIL-3. BFU-E and CFU-MIX developed in suspension but could only be detected when cells were replated in the presence of a combination of rhIL-3 and PU34 but not rhIL-3 alone. This assay may be useful in evaluating the number of early hematopoietic precursors present in cord blood samples and in defining growth factor combinations that could enhance hematopoietic recovery after cord blood stem cell transplants.

Effects of recombinant human Steel factor (c-kit ligand) on early cord blood hematopoietic precursors.

The purpose of this study was to define the effects of recombinant human Steel factor (rhSF) (c-kit ligand) on early and late cord blood hematopoietic progenitors. In the presence of recombinant human erythropoietin (rhEpo), rhSF supported the development of granulocyte/macrophage, erythroid, and mixed colonies from CD34-positive cord blood cells. With increasing concentrations of rhSF, an increase in the number of mixed colonies was observed. This increase was paralleled by a decrease in the number of erythroid colonies, such that the total number of the two colony types was always constant. Similar results were observed when CD34+ cells were cultured in the presence of a combination of rhEpo, rhSF, and rhIL-3. These results indicate that the presence of rhSF enhanced the detectability of the nonerythroid components of mixed colonies. The effect of rhSF on early progenitors (pre-colony-forming units [pre-CFU]) was studied in a two-step assay. In this assay, cells positive for CD34 and resistant to treatment with 4-hydroperoxycyclophosphamide (CD34+/4-HCres) were cultured in suspension for 7 days with rhSF, rhIL-3, or rhSF plus rhIL-3 and then plated in clonogenic assays. Before suspension culture, CD34+/4-HCres cells had a low clonogenic potential (0.37%). After being cultured in suspension, however, these cells gave rise to a large number of colonies of all types when replated. Cells cultured in suspension with the combination of rhSF and rhIL-3 increased significantly in number and gave rise to more colonies, when compared to cells cultured with either factor alone (synergistic effect). In identical experiments, such as effect had not been observed with combinations of rhIL-3 and either rhIL-1 or rhIL-6. Thus, rhSF supports the expansion and differentiation of early progenitors in human cord blood.

NK cell colony formation from human fetal thymocytes.

We established a clonal cell culture system for human natural killer (NK) cells from fetal thymocytes. Thymocytes of 16 to 22 gestational weeks were cultured in methylcellulose in the presence of interleukin (IL)-7, IL-15, and steel factor (SF). After 14 days in incubation, large, diffuse colonies consisting of small cells were identified. Cells in the colonies were medium- to large-sized granular lymphocytes, expressing CD56 but not CD3, and revealed lytic activity against K562 cells. Colony-forming units (CFU)-NK were enriched in lineage negative (Lin- ) CD34++ subpopulations of fetal thymocytes, whereas a smaller number of CFU-NK also existed in Lin-CD34+ and Lin-CD34- subpopulations. Cytokine requirement for the NK cell colony formation was examined under serum-free conditions. As a single agent, only IL-15, but not IL-2, IL-7, or SF, supported NK cell colony formation. IL-15 had synergy with IL-7 and SF independently, and the maximal number of colonies were obtained when the three cytokines were present. IL-2 also supported NK cell colony formation in the presence of SF. When IL-2 was added to cultures containing IL-15 alone, IL-15 plus SF, or IL-15, SF, and IL-7, the numbers of NK cell colonies were reduced relative to those without IL-2. These results indicate that IL-2 may regulate IL-15-responsive NK cell progenitors. This clonal culture system will be a useful tool in the investigation of NK cell ontogeny.

Characterization of c-kit expression by primitive hematopoietic progenitors in umbilical cord blood.

Human umbilical cord blood (CB) appears to be an exciting new source of transplantable stem cells for a variety of clinical conditions. In this study, we have attempted to further characterize the primitive progenitors in CB. First we analyzed the effects of early-acting growth factors on blast cell colony formation from CD34+ progenitors. Addition of Steel factor (SF), interleukin-6 (IL-6), or granulocyte colony-stimulating factor (G-CSF) to cultures containing interleukin-3 enhanced blast cell colony formation. These results indicated that cell cycle-dormant progenitors are present in CB. Next, based on results obtained in the murine system, we tested whether c-kit expression could separate the CB progenitors into cycle-dormant vs. cycle-active progenitors. Cells were separated into CD34+ c-kit-, c-kitlow, and c-kithigh. The results suggested that the c-kitlow population contains the majority of cycle-dormant progenitors and the c-kithigh population contains most of the forming cells were in the c-kitlow population, while the opposite is true for other colony-forming cells. Expression of c-kit may be useful in identifying CB progenitors with long-term engraftment capability.

Rapid exit from G0/G1 phases of cell cycle in response to stem cell factor confers on umbilical cord blood CD34+ cells an enhanced ex vivo expansion potential.

Currently, the most commonly used grafts of progenitor and stem cells for patients undergoing bone marrow transplantation (BMT) are derived from large collections of autologous or allogeneic adult human bone marrow (BM). The feasibility of using human umbilical cord blood (HUCB), normal peripheral blood (PB), and smaller collections of BM as sources of hematopoietic stem cell grafts for adult patients remains questionable. We investigated the ex vivo proliferative potential of HUCB CD34+ cells as a means of expanding HUCB grafts, thereby making them more acceptable for clinical transplantation. HUCB-derived CD34+HLA-DR+ cells, maintained for 5 days in suspension cultures supplemented with 10% HUCB plasma and a combination of stem cell factor (SCF) and interleukin-3 (IL-3), displayed a 10-fold increase in the total number of CD34+ cells. In contrast, only a four-fold increase was observed in identical cultures initiated with BM-derived CD34+HLA-DR+ cells. Whereas BM CD34+ cells failed to proliferate in response to SCF alone, HUCB CD34+ cells expanded 5.6-fold by day 5, thus demonstrating an enhanced response to SCF. When the effects of SCF on the exit of HUCB cells from G0/G1 phases of cell cycle were investigated, we found that although HUCB CD34+HLA-DR+ cells were more quiescent than BM CD34+HLA-DR+ and BM CD34+HLA-DR- cells (97.5% of HUCB CD34+HLA-DR+ in G0/G1 vs. 88.6% of BM CD34+HLA-DR+ and 92.0% of BM CD34+HLA-DR- [p < 0.005]), HUCB CD34+HLA-DR+ cells exited from dormancy more rapidly than BM cells, such that by 36 to 48 hours following exposure to SCF, only 55% remained in G0/G1. Furthermore, an 8.4-fold increase in the number of HUCB CD34+ cells still residing in G0/G1 was observed on day 5 in cultures supplemented with SCF and IL-3, suggesting the generation of large numbers of primitive hematopoietic progenitor cells (HPC) in vitro. When the contribution of HUCB plasma to the exist of HUCB CD34+HLA-DR+ cells from G0/G1 phases of cell cycle was investigated, it was found that in serum-free media supplemented with only SCF or IL-3, HUCB cells did not exist G0/G1 as rapidly as when HUCB plasma or SCF plus IL-3 was present. In contrast, when HUCB plasma was added to any cytokine combination, it did not enhance the exist of BM CD34+HLA-DR+ cells from G0/G1 phases of cell cycle.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of CD34+ selection and T cell immunodepletion on cord blood hematopoietic progenitors: relevance to stem cell transplantation.

Cord blood (CB) has been used recently for stem cell transplantation. We have investigated two different approaches to deplete CB samples of T cells capable of mounting graft-vs.-host disease (GVHD). The methods used were selection of CD34+ cells using avidin-biotin columns (CellPro) and T cell immunodepletion with T10B9 monoclonal antibody (mAb) plus complement. Using the avidin-biotin columns, 10.3% of the original CD34+ cells were recovered. Although this technique yielded a population containing 60 +/- 5.5% CD34+ cells, about 1 log of CFU-GM progenitors were lost. In contrast, after the T10B9 mAb and complement immunodepletion, 75 +/- 19% and 62 +/- 7% of the CD34+ cells and CFU-GM were recovered, respectively. T cell depletion was 3.6 logs using the CellPro columns and 2.2 logs after immunodepletion. To investigate whether cell losses following T cell depletion could be overcome by ex vivo expansion, cells were cultured in the presence of recombinant human interleukin-3 (rhIL-3) and recombinant human c-kit ligand (stem cell factor [rhSCF]) for 7 days. There were 14- and six-fold expansions in the number of progenitors recovered after CellPro and immunodepletion, respectively. To asses the engraftment potential of expanded cells, we used a murine transplantation model in which the presence of human cells was identified by the anti-CD45 mAb. Cells expanded in vitro engrafted in irradiated BNXid mice as efficiently as nonexpanded cells, suggesting that expansion did not affect their transplantability. This study shows that both techniques resulted in significant T cell depletion of CB. Furthermore, in vitro expansion could overcome cell losses sustained during the separation techniques without impairing the engraftment potential of the expanded cells.

Evaluation of the in vitro behavior of phenotypically defined populations of umbilical cord blood hematopoietic progenitor cells.

Umbilical cord blood (CB) has been identified as a potential source of hematopoietic stem cells suitable for clinical transplantation. We used long-term cord blood cultures (LTCBC) to evaluate the hematopoietic potential of populations of umbilical CB cells phenotypically defined and isolated by flow cytometry. LTCBC initiated with CD34+HLA-DR+ and CD34+HLA-DR- CB cells were examined over a period of 8 weeks for the production of assayable burst-forming units-erythroid (BFU-E), colony-forming units-granulocyte/macrophage (CFU-GM), and colony-forming units-mixed (CFU-GEMM) in response to repeated additions of stem cell factor (SCF), interleukin-3 (IL-3), IL-6, and either erythropoietin (Epo) or granulocyte-macrophage colony-stimulating factor (GM-CSF). The LTCBC-initiating cell (LTCBC-IC) appeared to be present among CD34+HLA-DR+ cells, in contrast to our previous findings in adult bone marrow (BM), where the long-term culture initiating cells were shown to be CD34+HLA-DR-. In addition, production of BFU-E, CFU-GM, and CFU-GEMM in CB CD34+HLA-DR+ cells displaying low uptake of the supravital dye rhodamine 123 (Rh123) exceeded those detected in the fraction of cells with high uptake of Rh123. Furthermore, on day 21 of LTCBC, the production of the high proliferative potential colony-forming units (HPP-CFC) by CB CD34+HLA-DR+Rh123dull cells was five-fold greater than that detected in cultures initiated with their Rh123bright counterparts. Collectively, these data show that, contrary to what has been documented in adult human BM, LTCBC-IC and presumably CB cells capable of in vivo engraftment reside in the CD34+HLA-DR+Rh123dull fraction of CB. Although the functional significance of these differences between the in vitro behavior of phenotypically defined populations of CB and BM remains to be determined, these findings constitute an objective parameter with which the suitability of CB for clinical transplantation may be assessed.

Hyperfractionated total lymphoid irradiation and cyclophosphamide for preparation of previously transfused patients undergoing HLA-identical marrow transplantation for severe aplastic anemia.

PURPOSE: To assess the immunosuppressive capacity of hyperfractionated total lymphoid irradiation and cyclophosphamide for transplantation of unmodified allogeneic marrow in sensitized aplastic anemia patients. METHODS AND MATERIALS: From February 1983 to September 1990, 23 multiply transfused aplastic anemia patients underwent unmodified bone marrow transplantation from HLA genotypically identical sibling donors following preparation with 6 Gy hyperfractionated total lymphoid irradiation and 160 mg/kg cyclophosphamide. Graft-versus-host disease prophylaxis included steroids in one patient, methotrexate in four, cyclosporine in seven, and methotrexate/cyclosporine in 12. There were 17 males and 6 females with a median age of 13 (range: 2.5-32). RESULTS: One patient died early before engraftment of bacterial sepsis. Twenty-two patients were evaluable for engraftment. Three experienced graft failure including one primary, and two late graft failures associated with cyclosporine withdrawal. Acute graft-versus-host disease occurred in 7/22 (> or = grade II in 6), and chronic graft-versus-host disease in 3/17 patients. Except for a patient who received total body irradiation for a second transplant, no patient in this series developed interstitial pneumonia. Fifteen patients are alive with follow-up of 38-125 months (median 68). The overall actuarial survival at 5 years is 69%, at 8 years it is 60%, with one late death. The survival of adult patients was similar to that of younger patients (> or = 16 years old: 63%, < 16 years old: 55%). The development of acute graft-versus-host disease adversely influenced survival (88% with Grade 0-I, 17% with grade II-IV; p = 0.002). No hypothyroidism or secondary malignancies have been documented in this series. CONCLUSION: Pretransplant immunosuppression with 6 Gy of hyperfractionated total lymphoid irradiation and 160 mg/kg CY reduces but does not eliminate the incidence of graft failure in sensitized aplastic anemia patients. The dose and the mode of administration of total lymphoid irradiation in this trial may be associated with a lower incidence of late side effects. Survival is comparable to that obtained using preparative regimens without radiation.

Effects of low dose rate irradiation on human marrow hematopoietic and microenvironmental cells: sparing effect upon survival of stromal and leukemic cells.

The effects of different dose rates of in vitro irradiation on the proliferative capacity of marrow stromal, hematopoietic and leukemic colony-forming cells (CFC) are described. Marrow cell suspensions, HL-60 cells and trypsin-dispersed fibroblasts were irradiated at 5 or 45 cGy/min and then assayed for CFC. Irradiation at low (5 cGy/min) compared to high (45 cGy/min) dose rate showed a significant difference in survival of stromal and of HL-60 cells, but not of hematopoietic progenitors: the respective D0 values were 170 and 120 (p = 0.003) for marrow fibroblastic progenitors (CFU-F); 145 and 110 (p = 0.005) for passaged marrow fibroblasts (CFU-F); 170 and 140 (p = 0.045) for HL-60 cells; 85 and 85 for multipotential CFC (CFU-mix); 125 and 120 for erythroid progenitors (BFU-E); and 115 and 120 for granulomonopoietic progenitors (CFU-GM) (p = 0.5 for hematopoietic clonogenic cells). Marrow suspensions did not establish confluent stromal layers in long-term marrow cultures following irradiation with 600 cGy at 45 cGy/min, whereas after 840 cGy at 5 cGy/min confluent stromal layers were obtained. This indicates that low dose rate-sparing effect applies to all stromal cell progenitors. Confluent stromal layers derived from progenitors surviving irradiation sustained hematopoiesis as well as controls when co-cultured with fresh hematopoietic cells. Adherent layers in long-term marrow cultures irradiated after establishment with doses less than or equal to 1500 cGy at 5 or 45 cGy/min also showed normal hematopoietic supportive function when co-cultured with freshly isolated hematopoietic cells.(ABSTRACT TRUNCATED AT 250 WORDS)

T-cell lymphoma in a child after heart transplantation.

Lymphoproliferative disease remains a small but worrisome problem after organ transplantation. This disorder is often a B-cell proliferation associated with Epstein-Barr virus. This article describes the unusual association of Epstein-Barr virus with a T-cell lymphoma in a child after heart transplantation and ultimately an atypical rejection episode with an increased number of eosinophils.

Effects of radiation and 4-hydroperoxycyclophosphamide on production of G- and GM-CSF by stromal cells.

The effects of in vitro radiation and exposure to 4-hydroperoxycyclophosphamide (4-HC) on the production of G- and GM-CSF by different components of the human hematopoietic microenvironment are described. The marrow microenvironment is composed of fibroblasts, endothelial cells, macrophages, and adipocytes. To study the effects of radiation/4-HC on colony-stimulating factor (CSF) production by stromal cells, confluent layers of umbilical cord endothelial cells (EC), marrow fibroblasts (MF), and heterogeneous adherent layers (HAL) derived from long-term marrow cultures were established. These layers were exposed to radiation up to 3000 cGy and/or 100 mumol/ml of 4-HC and subsequently stimulated with IL-1 beta on day 0, 7, or 14 after radiation/4-HC. Following IL-1 exposure conditioned medium (CM) was collected and G- and GM-CSF levels were measured by ELISA and their ability to support colony formation was assessed. G- and GM-CSF levels after exposure to 4-HC and radiation were 12,460 +/- 172 pg/ml and 2268 +/- 160 pg/ml for EC, 2214 +/- 94 pg/ml and 263 +/- pg/ml for MF, and 3168 +/- 316 pg/ml and 356 +/- 34 pg/ml for HALs, respectively. For each cell group there was no significant difference between levels obtained without exposure and levels after exposure to 4-HC and/or radiation (p > 0.6). Comparison of levels obtained from different cell groups showed significant differences with EC media being the highest (p < 0.0001). To test the activity of these measured factors, CM of different sources was used in colony assays of CD 34+ cord blood progenitors.(ABSTRACT TRUNCATED AT 250 WORDS)

Progressive autologous graft-versus-host disease induced by cyclosporin A.

The development of graft-versus-host disease (GVHD) in patients undergoing allogeneic bone marrow transplantation for leukemias and lymphomas has been associated with a lower incidence of relapse. This phenomenon is thought to be secondary to the anti-tumor effect of adoptively transferred cells. Cyclosporin A (CsA) therapy is known to cause autologous and syngeneic GVHD in experimental models and humans, and has been used in patients undergoing autologous bone marrow transplantation. It has been the consensus to date that CsA-induced autologous GVHD is generally mild, confined to the skin, self-limiting and non-life-threatening. We report by case of severe and progressive GVHD induced by CsA in a child following autologous bone marrow transplantation for acute lymphoblastic leukemia in second remission.