PubMed Health⌕ Search

Biomedical subjects

R J Jones

Publications and source records attributed to R J Jones.

At least 109 records · Page 6Linked to original sources
PubMed1992

Purging with 4-hydroperoxycyclophosphamide.

Over the past 10 years, very-high-dose cytotoxic therapy with rescue of marrow function by autologous bone marrow transplantation (BMT) has been shown to be effective treatment for patients with lymphomas and acute leukemias. However, a major concern has been that infusion of occult tumor cells with the autologous marrow will contribute to relapse. Accordingly, multiple techniques for treating autologous marrow grafts in vitro, to remove or "purge" occult tumor, have been developed. Despite controversy regarding the necessity and efficacy of purging, most autologous transplants for acute leukemia and many for lymphoma are currently purged. Most studies have used immunologic or cytotoxic agents for purging. The most widely used cytotoxic purging agents have been the cyclophosphamide congeners, 4-hydroperoxycyclophosphamide (4-HC) and mafosfamide. Since the first 4-HC-purged autologous marrow transplant was performed in 1980, over 700 patients have received 4-HC-purged autologous bone marrow transplants at Johns Hopkins alone. This review will chronicle the development of 4-HC as a purging agent.

Acute Disease↗
PubMed1992

Plastid DNA in developing maize endosperm : genome structure, methylation, and transcript accumulation patterns.

Amyloplasts in storage organs such as maize (Zea mays L.) endosperm are plastid-derived, nonphotosynthetic, starch-accumulating organelles. This study was initiated to characterize the plastid genome in maize endosperm cells containing differentiated amyloplasts and to determine whether plastid genes are transcribed during the period of amyloplast biogenesis in endosperm development. Four cosmid clones representing the total sequence diversity of the maize plastid genome were hybridized to restriction digests of total cellular DNA from isolated 16-day-old endosperms. The hybridization patterns indicated that the plastid DNA present in endosperm tissue was indistinguishable from that in leaf total DNA. Methylation of maize endosperm amyloplast DNA or leaf chloroplast DNA was not detected with the methylation-sensitive enzymes HpaII and EcoRII. Transcripts homologous to the 17 specific plastid DNA BamHI fragments tested were detectable in total RNA prepared from 16-day-old endosperm tissue. Compared with leaf transcripts, the abundance of endosperm transcripts was substantially lower for transcripts detected by 12 different BamHI fragments and was similar or relatively higher for some transcripts homologous to five BamHi fragments. Transcripts homologous to genes for plastid ribosomal small subunit proteins 7 and 12 on fragments 10 and 23 and to an open reading frame on fragment 14 accumulated primarily as unprocessed or partially processed species in endosperm RNA. The demonstration that maize endosperm cells contain an intact, transcriptionally active plastid genome indicates that plastid genes could contribute to amyloplast biogenesis, although no transcripts unique to endosperm were identified.

Journal Article↗
PubMed1992

A comparison of prospective and retrospective diary methods of assessing alcohol use among university undergraduates.

The objective of this study is to compare data about the quantity of alcohol consumed by university undergraduates using a prospective diary with those data collected using a retrospective diary. Five hundred and ninety-eight subjects were randomly selected and divided into two groups matched for age, sex, year of study and subject group; one group received a prospective and one a retrospective questionnaire-301 students received prospective and 297 retrospective questionnaires. Sixty-eight per cent responded to the prospective and 75 per cent to the retrospective survey. There was no significant difference in the median alcohol consumption detected for men or women in this study (p = 0.13; p = 0.47). However, the prospective diary recorded a greater proportion of heavy drinkers, this difference being significant for men and women (p less than 0.05). The quantitative results of the retrospective diary are similar to those obtained by a similar method in a previous survey. The conclusion is that a prospective diary detects a greater proportion of heavy drinkers than a retrospective diary. The prospective survey may be the most appropriate method for assessing alcohol use in certain situations.

Adult↗
PubMed1992

Hexamethylene bisacetamide in myelodysplastic syndrome: effect of five-day exposure to maximal therapeutic concentrations.

The efficacy of hexamethylene bisacetamide (HMBA), a potent polar-planar solvent which is capable of differentiating leukemias and solid tumors in vitro at clinically achievable concentrations, was studied in 16 patients with severe myelodysplastic syndromes (MDS). An adaptive control dosing algorithm was used to maintain HMBA steady-state concentrations (Css) within a narrow therapeutic window (1-2 mM) for five days every four weeks. Despite achieving the target HMBA Css during at least two courses in each of 15 patients, HMBA did not produce clinically relevant improvements in blood cell counts nor in other functional indices. Instead, HMBA induced cytopenias in the majority of these patients, most of whom had preexisting cytopenias and limited hematopoietic reserves. These disappointing results correlated with concurrent in vitro bone marrow studies from these patients in which both the HMBA concentrations that were optimal for differentiation in vitro (2-5 mM) and the HMBA Css that were achieved in this study (1-2 mM) substantially inhibited the growth of granulocyte-macrophage colony-forming units and erythroid burst-forming units. Although the mechanism responsible for the anti-proliferative effects of HMBA on hematopoietic progenitors (cytotoxicity versus terminal differentiation) could not be determined, the induction of cytopenias and lack of significant clinical improvements suggest that HMBA is cytotoxic and will not be useful alone as a differentiating agent on this schedule of administration in the treatment of MDS.

Acetamides↗
PubMed1991

Correlation of occult clonogenic leukemia drug sensitivity with relapse after autologous bone marrow transplantation.

Despite initial complete remission rates exceeding 70%, the majority of patients with acute myeloid leukemia (AML) and adults with acute lymphocytic leukemia (ALL) eventually relapse. Improving the therapeutic results in acute leukemia requires detecting, and understanding the biology of, the minimal residual leukemia remaining after therapy and responsible for relapse. To investigate the biologic relevance of an in vitro assay for clonogenic leukemia (leukemia colony-forming units [CFU-L]) as a measure of minimal residual leukemia, we studied 58 consecutive patients with acute leukemia in complete remission undergoing autologous bone marrow transplantation (BMT) with cyclophosphamide-based therapy. CFU-L were cultured from the pretransplant remission marrows in 45 of 58 patients: 35 of 43 patients with AML and 10 of 15 with ALL. Clonal rearrangements, identical to the patients' overt leukemia when available, were detected in the occult CFU-L from four of the eight patients with ALL in whom adequate DNA for analysis could be obtained from the CFU-L. None of the uncultured pretransplant remission marrows from the 15 ALL patients showed clonal gene rearrangements. We also determined the in vitro sensitivity of the occult CFU-L to 4-hydroperoxycyclophosphamide (4HC), and correlated these results with the outcome of the patients. The sensitivity of the occult CFU-L to 4HC was the only factor that predicted relapse following BMT. The actuarial probability of relapse was 18% in the 23 patients whose CFU-L were sensitive to 4HC compared with 77% in the 22 patients whose CFU-L were resistant (P less than .001). The only factor that influenced the CFU-L sensitivity to 4HC was the type of leukemia. The CFU-L from the AML patients were more sensitive to 4HC than the CFU-L from the ALL patients (P = .001). Occult CFU-L genetically and functionally represent occult leukemia. Therefore, the CFU-L assay should provide a means for studying the biology of minimal residual leukemia and improving the therapeutic results in patients with acute leukemia.

Adolescent↗
PubMed1991

Evidence of a graft-versus-lymphoma effect associated with allogeneic bone marrow transplantation.

The existence of an immunologic antileukemia reaction associated with allogeneic bone marrow transplantation (BMT) is well established. However, a similar graft-versus-tumor effect against lymphomas has not been demonstrated. We analyzed the results of BMT in 118 consecutive patients with relapsed Hodgkin's disease or aggressive non-Hodgkin's lymphoma. The 38 patients less than 50 years of age with HLA-matched donors had allogenic marrow transplants, and the other 80 patients received purged autologous grafts. The median age was 26 years in both the allogeneic and the autologous graft recipients. The patient's response to conventional salvage therapy before transplant was the only factor that influenced the event-free survival after BMT (P less than .001). Both the patient's response to salvage therapy before BMT (P less than .001) and the type of graft (P = .02) significantly influenced the probability of relapse after BMT. The actuarial probability of relapse in patients who responded to conventional salvage therapy before BMT was only 18% after allogenic BMT compared with 46% after autologous BMT. However, the actuarial probability of event-free survival at 4 years was the same, 47% versus 41%, for patients with responsive lymphomas who received allogeneic and autologous transplants, respectively (P = .8). The beneficial antitumor effect of allogeneic BMT was offset by its higher transplant-related mortality (P = .01), largely resulting from graft-versus-host disease. Allogeneic BMT appears to induce a clinically significant graft-versus-lymphoma effect. The magnitude of this effect is similar to that reported against leukemias.

Adolescent↗
PubMed1991

Oral mucositis after bone marrow transplantation. A marker of treatment toxicity and predictor of hepatic veno-occlusive disease.

Oral mucositis and hepatic veno-occlusive disease (HVOD) are common complications after bone marrow transplantation (BMT). Forty-seven patients were prospectively examined for development of ulcerative oral mucositis (UOM) and HVOD after allogeneic BMT. In 17 patients (36%) UOM developed between 2 days before and 18 days after transplant (median 4 days after BMT). In seven patients (15%) HVOD developed with onset between 3 and 21 days after transplant (median 18 days after BMT). In a time-dependent analysis, in patients given busulfan plus cyclophosphamide or busulfan, etoposide, and cyclophosphamide UOM was 19 times more likely to develop than in patients treated by cyclophosphamide plus total body irradiation or by cyclophosphamide alone (p less than 0.001). Patients in whom UOM developed were 6.5 times more likely to develop HVOD than those in whom UOM did not develop (p less than 0.03). The sensitivity (86%), specificity (73%), and negative predictive value (97%) of UOM to predict HVOD were high, but the positive predictive value (35%) was low. The association of UOM and HVOD support the concept that both are toxic effects of treatment. Patients with hepatic abnormalities but without UOM are unlikely to have HVOD, and other causes of the hepatic dysfunction should be investigated.

Adolescent↗
PubMed1991

Autologous bone marrow transplantation in hematologic malignancies.

Autologous bone marrow transplantation (BMT) has become effective therapy for high-risk hematologic leukemias with long-term disease-free survivals and apparent cure in a substantial fraction of patients with relapsed aggressive non-Hodgkin's lymphoma, relapsed Hodgkin's disease, and the acute leukemias. Preliminary reports suggest autologous BMT may also be useful treatment for low-grade non-Hodgkin's lymphomas, chronic myelogenous leukemia, and multiple myeloma. Recent studies have begun to address the role autologous BMT should play in these diseases, especially relative to conventional-dose therapy and allogeneic BMT. Relapse remains the major cause for failure following autologous BMT. Novel approaches that can increase the antitumor effect of this treatment without increasing toxicity are being investigated.

Bone Marrow Transplantation↗
PubMed1991

CT of lymphoma: spectrum of disease.

Computed tomography (CT) is the study of choice for the detection and staging of Hodgkin and non-Hodgkin lymphoma. CT enables accurate measurement of both tumor extent and volume and provides information that can be used to plan an appropriate therapeutic regimen as well as follow patient response to therapy. This article presents a systematic review of the common and uncommon appearances of lymphoma in the chest and abdomen. Potential pitfalls and limitations of CT in staging and follow-up are also addressed.

Hodgkin Disease↗
PubMed1991

Treatment of chemotherapy-induced anemia with recombinant human erythropoietin in cancer patients.

Thirty patients with chemotherapy-induced anemia were treated with recombinant human erythropoietin for 4 weeks. In this dose-escalation study, cohorts of five to eight patients were treated per dose level. The doses of erythropoietin were 25, 50, 100, 200, or 300 IU/kg/d given intravenously for 5 days each week. Of 30 patients, 15 (50%) had a greater than 10% increase of their hemoglobin (Hb) values and were considered responders. At the two highest dose levels, 11 of 13 patients (85%) responded. In the 15 responding patients, the mean Hb level increased by 1.7 g/dL from baseline compared with an average decrease of 1.5 g/dL in the previous cycles of chemotherapy without erythropoietin administration. Recombinant human erythropoietin is effective in ameliorating chemotherapy-induced anemia when administered in adequate doses.

Adult↗
PubMed1991

Phase I study of combination drug purging for autologous bone marrow transplantation.

In a phase I clinical trial of autologous bone marrow transplantation, we determined the feasibility of ex vivo purging with high concentrations of pharmacologics in combination. Light-density cells isolated from the grafts of 26 patients with acute leukemia or lymphoblastic lymphoma were treated with 4-hydroperoxycyclophosphamide (4-HC; 30 to 60 micrograms/mL), vincristine (Vcr; 1.5 to 3.0 micrograms/mL), and methylprednisolone sodium succinate (MP; 5 mg/mL). All patients received marrow-lethal induction therapy followed by infusion of the treated grafts. Three patients died of transplant-related complications before achieving peripheral blood recovery of greater than 0.5 x 10(9) granulocytes per liter. All other patients achieved this parameter of engraftment at a median of 35 days after marrow infusion. The median time to last platelet transfusion was 45 days. These durations of aplasia were similar to those experienced by other patients receiving density-gradient separated grafts treated with 60 micrograms/mL of 4-HC as a single agent. No patient required infusion of untreated reserve marrow because of engraftment failure. The colony-forming unit-granulocyte macrophage (CFU-GM) content of the grafts after purging predicted these parameters of engraftment. Colony-forming unit-leukemia (CFU-L) cultured from the grafts of 12 of the patients treated for acute lymphoblastic leukemia (ALL) were considerably more sensitive to the combination regimen than to 4-HC alone; the sensitivity of CFU-GM from these patients did not differ between the two regimens. The results of this trial indicate the feasibility of treating autologous bone marrow grafts with high concentrations of pharmacologics in combination. The use of combinations may increase the efficacy of ex vivo purging without increasing the toxicity to normal hematopoietic cells.

Adolescent↗
PubMed1991

Analysis of factors predicting speed of hematologic recovery after transplantation with 4-hydroperoxycyclophosphamide-purged autologous bone marrow grafts.

We previously described the predictive value of graft colony-forming units granulocyte macrophage (CFU-GM) content after 4-hydroperoxycyclophosphamide (4-HC) purging for the duration of aplasia after autologous bone marrow transplantation. Despite the uniform 4-HC concentration, we observed heterogeneity in CFU-GM survival and the kinetics of engraftment. We have now analysed patient and graft characteristics for 154 patients undergoing autologous transplantation with 4-HC purged grafts to further define this heterogeneity. Patients transplanted for the treatment of malignant lymphoma reached a peripheral blood granulocyte count of greater than 0.5 x 10(9)/l (median, 20 versus 40 days; p less than 0.001) and platelet transfusion independence (median, 30 versus 70 days; p less than 0.001) significantly faster than patients transplanted for acute non-lymphoblastic leukemia. Other diagnostic groups were intermediate. These differences were independent of graft CFU-GM content. Multiple other patient and graft factors including patient age, peripheral blood counts on day of harvest, and amounts of other hematopoietic progenitors also predicted the kinetics of engraftment in univariate and multivariate analysis. Cytomegalovirus infection during the aplastic period predicted a delay in granulocyte (p = 0.024) but not platelet recovery (p = 0.174). This analysis demonstrates that multiple patient, graft, and post-transplant factors predict the engraftment capacity of autografts, and the kinetics of engraftment with 4-HC purged grafts. The multiple predictive factors explain a significant portion of the variability in engraftment kinetics observed after transplantation with 4-HC purged autografts.

Adolescent↗
PubMed1990

Effects of the differentiating agent hexamethylene bisacetamide on normal and myelodysplastic hematopoietic progenitors.

Hexamethylene bisacetamide (HMBA; NSC 95580) is a potent polar-planar differentiating agent of leukemia and solid tumor cell lines in vitro at clinically achievable concentrations. HMBA is currently being studied in patients with myelodysplastic syndrome. Previous phase I trials have demonstrated that HMBA produces hematologic toxicity in morphologically normal bone marrows of patients with solid tumors. Because of concern that HMBA may produce more severe myelotoxicity in patients with myelodysplastic syndrome since these patients have limited hematopoietic reserves, we studied the effects of HMBA on myelodysplastic and normal hematopoietic progenitors in vitro. HMBA concentrations that are optimal for differentiation in vitro (2 to 5 mmol/L) and HMBA concentrations that are being achieved in clinical trials (1 to 2 mmol/L) inhibited the growth of granulocyte-macrophage colony-forming units and erythroid burst-forming units from all 15 patients with myelodysplastic syndrome and all 4 normal subjects, HMBA did not induce proliferation of myelodysplastic or normal progenitors at any concentration; rather, it produced nearly identical inhibition of normal and myelodysplastic hematopoietic progenitors. HMBA also produced quantitatively similar inhibition of clonogenic leukemic growth of two myeloid leukemia cell lines. For a differentiating agent to be effective, it will likely have to either produce both differentiation and proliferation of abnormal hematopoietic progenitors or show selective inhibitory effects on abnormal as compared with normal progenitors. Although the mechanisms responsible for the antiproliferative effects of HMBA cannot be determined from this study, similar inhibitory effects of HMBA on normal and abnormal hematopoietic progenitors suggest that HMBA may be of limited utility in producing and sustaining elevations of peripheral blood cell counts in patients with myelodysplastic syndrome.

Acetamides↗
PubMed1990

Separation of pluripotent haematopoietic stem cells from spleen colony-forming cells.

Long-term reconstitution of the lymphohaematopoietic cells of a mouse after lethal irradiation requires the transplantation of at least (5-10) x 10(3) bone marrow cells. Several cell-separation techniques based on cell-surface characteristics have been used in attempts to identify the pluripotent haematopoietic stem cells (PHSC), and have allowed the long-term engraftment of lethally irradiated mice with an enriched fraction of fewer than 200 marrow cells. But these techniques enrich not only for PHSC but also for haematopoietic progenitors, especially day-12 spleen colony-forming units (CFU-S). Although day-12 CFU-S have been postulated to be primitive multipotential haematopoietic progenitors, with day-8 CFU-S representing later, more committed progenitors, recent evidence suggests that neither of these CFU-S represents mouse PHSC. Here we report that counterflow centrifugal elutriation, which sorts cells on the basis of size and density, can separate PHSC from these less primitive progenitors. The fraction containing the largest cells was enriched for the granulocyte-macrophage colony-forming units (CFU-GM), but gave only transient, early engraftment and was therefore depleted of PHSC. The intermediate fraction was enriched for CFU-S, but depleted of CFU-GM. Despite being devoid of CFU-GM and CFU-S, the fraction consisting of only morphological lymphocytes gave sustained, albeit delayed, reconstitution of all lymphohaematopoietic cells, and was therefore enriched for PHSC. We conclude that there are two vital classes of engrafting cells: committed progenitors, which provide initial, unsustained engraftment, and PHSC, which produce delayed, but durable, engraftment. Therefore for late haematological reconstitution, PHSC must be transplanted with a distinguishable source of early engrafting cells, thereby allowing the lethally irradiated host to survive initial aplasia.

Animals↗
PubMed1990

The action of bryostatin on normal human hematopoietic progenitors is mediated by accessory cell release of growth factors.

Since enrichment of human bone-marrow hematopoietic progenitors is becoming more feasible and since purified growth factors are now available, we sought to study the action of growth factors on CD34-positive enriched cultures of human bone-marrow cells. We tested the effect of recombinant human (rh) granulocyte-macrophage colony-stimulating factor (GM-CSF), rh interleukin-3 (IL-3), or a unique biologic response modifier, bryostatin 1, on the growth of purified CD34 cells obtained by limiting dilution in single-cell cultures. We have shown previously that bryostatin 1 stimulates both myeloid and erythroid progenitors of human origin in vitro. In this study both IL-3 and GM-CSF supported colony formation from 500, 100, or single-cell cultures at equivalent plating efficiences, suggesting a direct action of these factors on hematopoietic cell growth. Conversely, bryostatin 1 did not support the growth of CD34 cells in single-cell cultures, and the cloning efficiency increased with increasing the number of cells in the culture. To test whether the indirect action of bryostatin 1 might be mediated through the production of growth factors by accessory cells, studies were performed using antibodies directed against human IL-3 and GM-CSF in culture with bryostatin 1 and normal human bone-marrow cells. Results are consistent with the hypothesis that bryostatin 1 could have a stimulatory effect on the accessory cell populations to produce either IL-3 or GM-CSF. Further support for this notion was obtained by demonstrating that T cells, which are cells known to be able to produce IL-3 and GM-CSF, are stimulated by bryostatin 1 to express messenger RNA (mRNA) for specific growth factors, including GM-CSF. These results provide further support that bryostatin 1 may be a useful clinical agent to stimulate hematopoiesis in vivo.

Antibodies↗