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Biomedical subjects

R J Jones

Publications and source records attributed to R J Jones.

At least 91 records · Page 5Linked to original sources
PubMed1994

Biology of chronic myeloid leukemia and its relevance to autologous bone marrow transplantation.

Because of the relative resistance of chronic myeloid leukemia (CML) progenitors to most standard cytotoxic agents, marrow-ablative doses of drugs or radiotherapy followed by allogeneic bone marrow transplantation (BMT) remain the only curative option for patients with CML. However, the effectiveness of allogeneic BMT is limited by the toxicity of graft-versus-host disease and the lack of histocompatible donors for most patients. Although it avoids these major obstacles of allogeneic BMT, autologous BMT has not been effective in CML because of the inability to purge CML from the autologous graft and the absence of the allogeneic immunologic antitumor activity. Techniques that allow the clinical isolation of normal stem cells from CML marrow combined with novel posttransplantation immunotherapeutic approaches should make autologous BMT a curative treatment for CML in the near future.

Bone Marrow Transplantation↗
PubMed1994

Phase I and pharmacodynamic study of the topoisomerase I-inhibitor topotecan in patients with refractory acute leukemia.

PURPOSE: To determine the feasibility of escalating the hydrophilic topoisomerase I (topo I)-inhibitor topotecan (TPT) above myelosuppressive doses in adults with refractory or relapsed acute leukemias and to assess pharmacodynamic determinants of TPT action. PATIENTS AND METHODS: Seventeen patients received 33 courses of TPT as a 5-day infusion at doses ranging from 0.70 to 2.7 mg/m2/d. Pharmacologic studies were performed to determine the TPT concentrations at steady-state (Css) and to examine parameters in the patients' leukemic blasts ex vivo that may be related to TPT sensitivity, eg, topo I content, p-glycoprotein (Pgp) expression, and the inhibitory effects of relevant TPT concentrations on the growth of blast colonies in clonogenic assays relative to the range of TPT Css values achieved. RESULTS: Severe mucositis of the oropharynx and perianal tissues was intolerable at TPT doses greater than 2.1 mg/m2/d, the recommended dose for phase II studies in leukemia. One complete response (CR) in a patient with chronic myelogenous leukemia in blast crisis (CML-B) and one partial response (PR) in a patient with acute myelogenous leukemia (AML) were noted. Significant reductions in circulating blast-cell numbers occurred in all courses, and complete leukemia clearance from the peripheral blood, albeit transient, was noted in 11 courses. TPT Css values ranged from 4.8 to 72.5 nmol/L. Colony-forming assays showed that the TPT LD90 (dose that inhibits the growth of leukemia blast colonies by 90%) values for blasts varied from 6 to 22 nmol/L, a range that overlapped with TPT Css values. In view of these variations in TPT sensitivity, several aspects of topo I-mediated drug action were also studied. In 10 of 11 samples, the multi-drug resistance (Mdr) modulator quinidine altered nuclear daunorubicin (DNR) accumulation and whole-cell TPT accumulation by less than 15%, which suggests that Pgp-mediated effects on drug efflux are insufficient to explain the fourfold range of TPT sensitivities in the colony-forming assays. Immunohistochemistry showed that topo I was expressed in all of the blasts from individual patients without detectable cell-to-cell heterogeneity in each marrow. Western blots indicated that topo I content varied over a 10-fold range. Although the sample size was small, topo I content appeared to be higher in acute lymphoblastic leukemia (ALL), intermediate in AML, and lower in CML-B. Topo I content did not appear to be related to the proliferative status of the blasts. CONCLUSION: These results indicate that substantial dose escalation of TPT above myelosuppressive doses reached in solid-tumor patients is feasible in patients with refractory leukemia, that biologically relevant TPT Css values are achievable, and that further developmental trials are warranted.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Phase I trial of interferon gamma to potentiate cyclosporine-induced graft-versus-host disease in women undergoing autologous bone marrow transplantation for breast cancer.

PURPOSE: We investigated if interferon gamma (IFN-gamma) could augment cyclosporine (CSA)-induced graft-versus-host disease (GVHD) following autologous bone marrow transplant in women with metastatic breast cancer and defined the toxicities of this therapy. PATIENTS AND METHODS: Thirty-six women with advanced breast cancer were treated with CSA 2.5 mg/kg daily for 28 days and IFN-gamma 0.025 mg/m2 subcutaneously (SC) every other day, days 7 to 28 following autologous bone marrow transplantation and monitored for induction and severity of GVHD and toxicity of therapy. RESULTS: GVHD was induced in 56% of patients. The severity of GVHD was greater than in a historic control population treated with CSA alone. Stage III rash was seen in 36% of patients, compared with 3% in the historic control population. Fourteen of 36 patients required therapy with topical corticosteroids and two of 36 required systemic treatment. Only three of 31 historic controls needed topical corticosteroids and no patient was treated systemically. There was no severe visceral GVHD. Hematopoietic recovery was not delayed. There were three toxic deaths. CONCLUSION: CSA-induced GVHD can be safely augmented by IFN-gamma in women treated with high-dose alkylating agents and autologous bone marrow transplantation. There is little evidence of increased toxicity. Evidence of antitumor efficacy awaits further investigation.

Adult↗
PubMed1993

BCR-ABL gene rearrangement and expression of primitive hematopoietic progenitors in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is characterized by an initial chronic phase of expanded yet orderly clonal hematopoiesis that is distinguished by the BCR-ABL gene rearrangement. We found that although the mature myeloid compartment in patients with CML was expanded and entirely derived from the dominant leukemic clone, the primitive hematopoietic progenitor compartment did not show a corresponding expansion and was substantially enriched for cells without the BCR-ABL gene rearrangement. More importantly, primitive progenitors exhibiting the BCR-ABL gene rearrangement did not express either the BCR-ABL hybrid mRNA or fusion protein (P210). Expression of P210 protein and BCR-ABL mRNA increased with myeloid commitment in vivo as well as with growth factor-induced proliferation and differentiation of the primitive CML progenitors in vitro. This differential expression of BCR-ABL between primitive and mature CML progenitors may explain the expansion of the leukemic clone at the level of mature myeloid progenitors and granulocytes without a concomitant expansion of primitive CML progenitors. Because BCR-ABL mRNA is minimally expressed or may be absent in primitive CML progenitors, these cells may escape detection by reverse transcriptase-polymerase chain reaction and eradication by antisense oligonucleotides targeted against BCR-ABL mRNA.

Base Sequence↗
PubMed1993

Autologous graft-versus-host disease: immunotherapy of breast cancer after bone marrow transplantation.

Clinical and laboratory evidence of a dose-response relationship has prompted the investigation of high-dose therapy with bone marrow transplantation in the treatment of women with metastatic breast cancer. Remission rates are high, but only a small proportion appear durable. An antitumor effect is associated with allogeneic graft-versus-host disease (GVHD) as well as with a similar syndrome that can be induced following autologous transplantation (autologous GVHD) by treatment with cyclosporine A following marrow infusion. The clinical manipulation of autologous GVHD may increase the potency of high-dose therapy. Clinical studies indicate that autologous GVHD can be induced in women with breast cancer and can be augmented by the administration of interferon gamma. Preliminary evidence indicates associated antitumor activity in vitro.

Animals↗
PubMed1993

The establishment of provisional quality assurance guidelines for assessing the hygienic adequacy of the lamb carcass cooling process.

The hygienic consequence of a lamb carcass cooling process can be assessed by evaluating the product's time-temperature history at a site within the carcass cavity adjacent to the 5th and 6th lumbar vertebrae. From these data, a numerical value, the process hygiene index, is generated which reflects the amount of potential bacterial growth the process allows and is proposed as an alternative quality assurance tool for assessing lamb cooling processes. Two hygienically acceptable lamb cooling processes, one producing carcasses destined for freezing and the other producing carcasses destined for chilled processing, were monitored. Acceptable cooling processes can be conveniently described in terms of a three class sampling plan where the maximum acceptable value (M) is the highest value obtained and the target value (m) is determined as the 80th percentile value of the pooled data from acceptable runs. The number (c), the proportion of sample values that may lie between (m) and (M), is determined from the acceptable run with the highest sample values. For the process yielding carcasses destined for freezing M = 15, m = 14 and c = 20% while for that producing carcasses for chilled processing M = 9, m = 6 and c = 60%. For both processes a minimum of five samples was tested per process run. Based on these values, provisional processing guidelines for the hygienic cooling of lamb carcasses are suggested.

Journal Article↗
PubMed1993

Autologous bone marrow transplantation.

Very high-dose cytotoxic therapy requiring bone marrow transplantation is the most active treatment for most hematologic malignancies and appears to be the treatment of choice for most patients with these diseases at relapse. Autologous bone marrow transplantation and allogeneic bone marrow transplantation can generally be expected to yield similar results in patients with lymphoma or acute leukemia; autologous bone marrow transplantation offers the advantage of greater availability and less toxicity but with a higher rate of tumor recurrence. Novel approaches that can increase the antitumor activity of autologous bone marrow transplantation without increasing the toxicity are being investigated. Dose intensification followed by autologous marrow rescue is also very active against responsive solid tumors, eg, breast cancer, ovarian cancer, testicular cancer, and pediatric solid tumors. However, it is difficult to demonstrate that autologous bone marrow transplantation has yet to lead to an improvement in disease-free survival for patients with solid tumors. Therefore, the exact role autologous bone marrow transplantation should play in the treatment of solid tumors remains to be established.

Bone Marrow Transplantation↗
PubMed1993

Screening for a raised rectal temperature in Africa.

The main purpose of this study was to compare rectal and axillary temperature measurements in African children. Altogether 573 sick children were seen in an outpatient setting in rural West Africa. Rectal and axillary temperatures were measured and the parent or guardian was asked if they thought that the child had a raised body temperature. Normal ranges were defined from an age matched population of 203 healthy children. A raised axillary temperature predicted a raised rectal temperature with a sensitivity of 98% and a specificity of 88%. The parents' impression that their child had a fever was a less sensitive (89%) and less specific (59%) indicator of raised rectal temperature. A raised axillary temperature is a good screening test for a raised rectal temperature in African children.

Axilla↗
PubMed1993

Cyclosporine-induced graft-versus-host disease after autologous bone marrow transplantation for acute myeloid leukemia.

Rodents given cyclosporine (CSP) for several weeks after autologous or syngeneic bone marrow transplantation develop a syndrome that mimics allogeneic graft-versus-host disease (GVHD). Autologous GVHD has also been reported after administration of CSP in patients who have received autologous bone marrow transplantation (ABMT) with untreated marrow for lymphoma or acute myeloid leukemia (AML). Our study was designed to determine whether CSP administration is associated with appearance of autologous GVHD in patients with AML receiving ABMT with 4-hydroperoxycyclophosphamide (4HC)-purged marrow and whether there was a dose-dependent effect of CSP on development of the syndrome. Thirty-three patients with AML (18 in first remission [CR1], 10 in CR2, and 5 in CR3) received intravenous CSP, beginning on the day of ABMT, after a preparative regimen of busulfan and cyclophosphamide and ABMT with 4HC-treated marrow. Skin biopsies were obtained weekly after ABMT or on appearance of rash and were graded for GVH changes. In the first phase of this study, groups of patients received CSP dosages of either 1 mg/kg/day (7 patients), 2.5 mg/kg/day (8 patients), or 3.75 mg/kg/day (6 patients) for 28 days. Sixteen of the 21 patients (76%) developed cutaneous histopathologic grade 2 GVHD at a median of 34 days (range, 14-49) after ABMT, and cutaneous manifestation were present at time of positive biopsy in 11 of the 16 patients. There was no apparent difference in frequency, time to onset, or duration of GVHD among the three CSP dosage groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

BMT for severe aplastic anemia using cyclosporine.

Between 1984 and 1991 24 patients with severe aplastic anemia (SAA) were transplanted with HLA identical sibling donor BM. The overall long-term survival was 79 +/- 8%. The average age was 21 years (range 4-53 years) and the median pre-transplant disease duration was 35 days (range 12-2998 days). Over one-half (15 of 24) of the patients had received > 10 units of blood product transfusions prior to BMT. The pre-transplant conditioning regimen consisted of 200 mg/kg cyclophosphamide (CY). Cyclosporine (CYA) was administered from 2 days prior to BMT and continued for 6-12 months. Two of the 24 patients failed to achieve primary engraftment (FTE). One of these patients had autologous recovery of BM function and is alive and well. Five of the 22 patients who engrafted failed to sustain engraftment (FTSE). Of these, three are alive and well following a second BMT or marrow boost. Only 1 of the 22 patients who engrafted had clinically significant (i.e. Stage II-IV) acute GVHD. No patient developed chronic GVHD. Our results indicate that BMT following a regimen consisting of CY with the continuous use of CYA in the post-transplant period is well tolerated and associated with excellent long-term survival. The high incidence of secondary graft instability (i.e. FTSE), however, suggests that future studies should focus on post-transplantation immunomodulation.

Adolescent↗
PubMed1992

Impaired erythropoietin response to anemia after bone marrow transplantation.

Delayed erythroid recovery is common after bone marrow transplantation (BMT), with some patients continuing to require red blood cell (RBC) transfusion support for as long as 1 year. While the etiology is multifactorial, inadequate stimulation of erythroid progenitors by the erythroid growth factor, erythropoietin, may play a role. In this study, the erythropoietin response to anemia of 70 consecutive patients undergoing BMT at the Johns Hopkins Oncology Center was compared with the erythropoietin response in uncomplicated iron deficiency anemia. Erythropoietin levels were elevated for the degree of anemia early after BMT; however, at the time of marrow recovery, erythropoietin levels were significantly suppressed in both allogeneic and autologous BMT patients compared with the iron-deficient patients. Patients with acute graft-versus-host disease (GVHD) had a more marked suppression of the erythropoietin response to anemia. In the patients who remained anemic for extended periods of time (up to 12 months after BMT), an inadequate erythropoietin response to anemia persisted. Delayed erythroid recovery after BMT is associated with inadequate erythropoietin levels. Therefore, recombinant human erythropoietin may be useful in the treatment of the anemia associated with both autologous and allogeneic BMT.

Anemia↗
PubMed1992

Optimization of busulfan dosage in children undergoing bone marrow transplantation: a pharmacokinetic study of dose escalation.

Busulfan (BU) is a widely used myeloablative and antineoplastic agent in clinical bone marrow transplantation (BMT). The lower incidence of BU-associated toxicities and lower therapeutic effectiveness in young children given BU doses based on body weight (ie, 16 mg/kg) is associated with altered pharmacokinetics of BU; the area under the curve (AUC) of BU concentration versus time is significantly less in these patients than those observed in older children and adults. To optimize BU dosage in young BMT recipients, we developed a dosage regimen based on body surface area (BSA) and determined BU pharmacokinetics and BU-associated toxicities. Seven children (median age, 3.9 years, range, 1.1 to 5.7) undergoing allogeneic or autologous BMT for leukemia received 40 mg/m2/dose BU every 6 hours for 16 doses; BU concentrations were measured in the plasma, and AUCs were determined for each patient after the first and 13th doses. Expressed as a function of body weight, the median BU dosage was 26.4 mg/kg (range, 24.3 to 28.2), a 60% increase over the BU dosage based on body weight. Four patients developed mucositis, and one of them also developed nonfatal hepatic veno-occlusive disease (VOD). No patients receiving 40 mg/m2 BU developed neurotoxicity (eg, seizures) or interstitial pneumonitis. Prompt and sustained engraftment was observed in the allogeneic BMT recipients, and late graft failure was not seen. The mean BU AUCs were 1,105 mumol/L.min (range, 790 to 2,080) after the first dose and 1,022 mumol/L.min (range, 632 to 1,860) after the 13th dose of BU, comparable to the AUCs in adults given 16 mg/kg of BU. These studies suggest that, in young children, BSA-based dosing of BU (40 mg/m2) provides drug exposures (AUCs) closer to adult values with acceptable toxicities and may improve therapeutic effects.

Bone Marrow Transplantation↗
PubMed1992

Induction of cutaneous graft-versus-host disease by administration of cyclosporine to patients undergoing autologous bone marrow transplantation for acute myeloid leukemia.

Cutaneous graft-versus-host disease (GVHD) has been reported after administration of cyclosporine (CSP) after autologous bone marrow transplantation (ABMT) with unpurged marrow in patients with lymphoma. To determine whether GVHD can be induced after ABMT with chemopurged marrow in acute myeloid leukemia (AML), we administered intravenous CSP for 28 days (beginning on the day of ABMT) to 19 patients with AML (12 in first remission [CR1], six in CR2, and one in CR3) who received busulfan (16 mg/kg) and cyclophosphamide (200 mg/kg) and ABMT with 4-hydroperoxycyclophosphamide (4HC)-treated marrow. In this dose-escalation trial, CSP daily doses were 1 mg/kg in seven patients, 2.5 mg/kg in eight patients, or 3.75 mg/kg in four patients. Skin biopsies were obtained weekly after ABMT or on appearance of rash and were graded for GVH changes. Overall, 15 of 19 patients (79%) had cutaneous histopathologic grade 2 GVHD at a median of 33 days (range, 14 to 49) after ABMT; in 10, cutaneous manifestations were present at time of positive biopsy. The frequency, time to onset, and duration of GVHD were similar among the three CSP dosage groups. No patients had hepatic or gastrointestinal dysfunction attributable to GVHD or required specific therapy for GVHD. Positive biopsies for GVHD were seen in seven of eight patients who received full-course, full-dose CSP and 8 of 11 patients who had CSP discontinued or dosage reduced because of renal insufficiency. Three patients (one with positive biopsy) died with ABMT-related complications. Seven patients (four CR1, three CR2) relapsed with AML at a median of 411 days (range, 178 to 549) after ABMT; six of seven had positive biopsies for cutaneous GVHD. Nine patients (seven CR1, one CR2, and one CR3) are alive without relapse at a median of 501+ days (range, 252+ to 811+) after ABMT; eight of nine had cutaneous GVHD. Short-course CSP can induce autologous GVHD in recipients of chemopurged marrow autografts for AML, but randomized prospective trials are needed to determine whether this immunologic reaction is associated with alterations in leukemic relapse rate and disease-free survival after ABMT in AML.

Adolescent↗
PubMed1992

Phase I-II trial of erythropoietin in the treatment of cisplatin-associated anemia.

BACKGROUND: Cancer patients undergoing chemotherapy with cisplatin-containing regimens often develop anemia. Although the cause is multifactorial, erythropoietin deficiency appears to play an important role. Recombinant human erythropoietin (epoetin) has been reported to be effective in reversing cisplatin-associated anemia in animal studies but not in clinical trials. PURPOSE: This pahse I-II clinical trial was designed to assess the safety and efficacy of treatment with epoetin for anemia associated with cisplatin chemotherapy. METHODS: Twenty-one cancer patients treated with cisplatin and manifesting anemia (hemoglobin level less than 110 g/L) received epoetin at escalating doses (25, 50, 100, or 200 U/kg body weight) intravenously five times a week for 4 weeks. RESULTS: Epoetin was well tolerated, and a maximal tolerated dose was not reached. Two patients experienced hypertension, which responded to standard antihypertensive therapy. No dose-dependent severe toxic effects were seen. The increase in hemoglobin levels from baseline on day 1 of the study was statistically significant after 4 weeks of epoetin therapy in the groups receiving 100 U/kg (mean change +/- SD = 19 +/- 13 g/L; P = .03) or 200 U/kg (mean change = 24 +/- 17 g/L; P = .007). A clinical response--an increase in hemoglobin level greater than 10 g/L--was achieved in 12 patients after 4 weeks of treatment. For these responders, the mean increase in hemoglobin level was 25 +/- 3.3 g/L over the level observed at the same time in the chemotherapy cycle preceding epoetin treatment, and this increase was statistically significant (P = .0001). Neither serum erythropoietin level nor hemoglobin level predicted a patient's response to epoetin. CONCLUSIONS: These preliminary findings suggest that epoetin is effective and well tolerated for the reversal of cisplatin-associated anemia, with the 100-U/kg and 200-U/kg dose levels offering optimal clinical response. IMPLICATIONS: We are conducting a phase III trial to determine the effect of epoetin on transfusion requirements in patients undergoing chemotherapy.

Adult↗
PubMed1992

Fluorescence in situ hybridization to determine engraftment status after murine bone marrow transplant.

The mouse Y-specific DNA sequence pY2 was used as a probe for fluorescence in situ hybridization (FISH) to evaluate murine hematopoietic tissues after sex-mismatched bone marrow transplant (BMT). The pY2 probe was localized to the long arm of the Y chromosome on BM metaphases. Hybridization of pY2 in FISH of interphase cells from BM, spleen, and thymus after BMT was compared with Southern blot analysis; both methods gave comparable results. Only FISH was able to analyze post-BMT peripheral blood (PB) samples successfully, and provides a useful method for following engraftment status in the mouse on an ongoing basis.

Animals↗
PubMed1992

Autologous graft-versus-host disease: a novel approach for antitumor immunotherapy.

Autologous bone marrow transplantation (BMT) is a therapeutic option for the treatment of lymphohematopoietic malignancies and solid tumors. Despite the intensive cytoreductive therapy, however, the rates of tumor recurrence after autologous BMT remain unacceptably high. Current studies suggest that the administration of cyclosporine (CsA) disrupts the reconstitution of self-tolerance following autologous BMT leading to the induction of an autoimmune graft-versus-host disease (GVHD). Studies in a rat tumor model and preliminary clinical trials suggest that this autoimmune or autologous GVHD provides a significant antitumor effect. Moreover, the antitumor effect of autologous GVHD can be enhanced by administration of gamma-interferon, which upregulates the antigen recognized by the autoreactive effector cells of autologous GVHD. These studies indicate that the induction of an autoimmune GVHD after autologous BMT may be a promising immunotherapeutic approach for treatment of certain neoplastic diseases.

Animals↗