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Biomedical subjects

R M Fox

Publications and source records attributed to R M Fox.

At least 19 recordsLinked to original sources
PubMed1997

Randomized, blinded, placebo-controlled phase I trial of pegylated recombinant human megakaryocyte growth and development factor with filgrastim after dose-intensive chemotherapy in patients with advanced cancer.

Thrombocytopenia caused by chemotherapy is an important cause of morbidity and mortality in the treatment of malignant disease. Recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) is a potent stimulator of megakaryocytopoiesis and prevents chemotherapy-induced thrombocytopenia in preclinical studies. We administered PEG-rHuMGDF with filgrastim after dose-intensive chemotherapy to 41 patients with advanced cancers to determine its safety and effects on hematologic recovery. Carboplatin 600 mg/m2 and cyclophosphamide 1,200 mg/m2 were administered to patients with advanced cancer. Patients were randomly assigned to receive blinded study drug, either PEG-rHuMGDF or placebo (3-to-1 ratio), commencing the day after chemotherapy. PEG-rHuMGDF was given at doses of 0.03, 0.1, 0.3, 1.0, 3.0, and 5.0 microg per kilogram body weight by daily subcutaneous injection for between 7 and 20 days. All patients received concurrent filgrastim 5 microg per kilogram body weight per day until neutrophil recovery. Fifteen patients had received PEG-rHuMGDF alone in a previous phase I study. Platelet function and peripheral blood progenitor cells (PBPC) were assessed. PEG-rHuMGDF enhanced platelet recovery in a dose-related manner when compared with placebo. The platelet nadir occurred earlier in patients given PEG-rHuMGDF (P = .002) but there was no difference in the depth of the nadir. Recovery to baseline platelet count was achieved significantly earlier following PEG-rHuMGDF administration compared with placebo (median, 17 days for PEG-rHuMGDF 0.3 to 5.0 microg/kg versus 22 days for placebo, P = .014). In addition, platelet recovery was faster in patients who had previously received PEG-rHuMGDF, suggesting that pretreatment might be beneficial. Platelet function did not change during or after administration of PEG-rHuMGDF. Levels of PBPC on day 15 after chemotherapy were significantly greater in patients administered PEG-rHuMGDF 0.3 to 5.0 microg/kg and filgrastim compared with those given placebo plus filgrastim. PEG-rHuMGDF was well tolerated at all doses. Two patients given PEG-rHuMGDF had a thrombotic episode. PEG-rHuMGDF accelerates platelet recovery after moderately dose-intensive carboplatin and cyclophosphamide, and is likely to be clinically useful in treatment of chemotherapy-induced thrombocytopenia. Because it enhances mobilization of PBPC by filgrastim, PEG-rHuMGDF might also allow more efficient collection of stem cells for autologous or allogeneic transplantation.

Adult↗
PubMed1997

Long-term survival advantage of MACOP-B over CHOP in intermediate-grade non-Hodgkin's lymphoma. The Australian and New Zealand Lymphoma Group.

BACKGROUND: The initial publication of the results of the Australian and New Zealand Lymphoma Group (ANZLG) randomized controlled trial comparing MACOP-B and CHOP in patients with intermediate-grade non-Hodgkin's lymphoma (NHL) showed equivalent complete response rates, time to treatment failure, and survival. Here we report the long-term follow-up of the 236 patients entered on that study to determine if there were any long-term advantages or disadvantages associated with MACOP-B. PATIENTS AND METHODS: Two hundred thirty-six eligible patients were randomized between October 1986 and June 1991. The median duration of follow-up has been extended from 3.2 years in our previous publication to 6.5 years. RESULTS: As previously reported, the complete response (CR) rate for MACOP-B and CHOP chemotherapy was 51% and 59%, respectively. The estimated failure-free survival rate for MACOP-B and CHOP patients was 42% and 30%, respectively, at 5 years (P = 0.045) and 37% and 25%, respectively, at 8 year (P = 0.057). The estimated overall survival rate at 5 years was 54% for MACOP-B and 41% for CHOP patients (P = 0.035) and at 8 years was 45% and 36%, respectively (P = 0.16). CONCLUSION: With this extended follow-up, we have shown a long-term survival advantage for MACOP-B chemotherapy over standard CHOP in patients with intermediate-grade non-Hodgkin's lymphoma.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

Thrombopoietic effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) in patients with advanced cancer.

BACKGROUND: Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) is a potent stimulator of megakaryocyte colony formation and platelet production. It is likely to be useful in the management of severe thrombocytopenia. To determine its clinical activity and safety, we gave it to patients with advanced cancer before chemotherapy. METHODS: Patients were randomly assigned to receive either PEG-rHuMGDF or placebo in a three to one ratio. PEG-rHuMGDF was given at a dose of 0.03, 0.1, 0.3, or 1.0 microgram/kg body weight. The study drug or placebo were administered daily by subcutaneous injection for up to 10 days or until a target platelet count was reached. FINDINGS: 17 patients, median age 59 years, received either PEG-rHuMGDF (13 patients) or placebo (four patients). PEG-rHuMGDF produced a dose-dependent increase in platelet counts. Patients given placebo. 0.03, and 0.1 microgram/kg of PEG-rHuMGDF had median increases in platelet counts of 16%, 12%, and 39%. Those receiving 0.3 and 1.0 microgram/kg of PEG-rHuMGDF had an increase in blood platelets of between 51% and 584%. Platelets rose from day 6 of PEG-rHuMGDF administration and continued to rise after stopping the drug. The platelet count peaked between days 12 and 18 and remained above 450 x 10(9)/L for up to 21 days. There were no alterations in white-blood-cell count or haematocrit, and low toxicity. Platelets taken from patients during PEG-rHuMGDF administration and at the time of peak platelet count were morphologically and functionally normal. INTERPRETATION: The potency with which PEG-rHuMGDF stimulates platelet production and its low toxicity indicate that this is likely to be a useful agent for the management of thrombocytopenia.

Dose-Response Relationship, Drug↗
PubMed1996

Administration of pegylated recombinant human megakaryocyte growth and development factor to humans stimulates the production of functional platelets that show no evidence of in vivo activation.

This report describes the effect of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) on platelet production and platelet function in humans. Subjects with advanced solid tumors received PEG-rHuMGDF daily for up to 10 days. There was no increase in circulating platelet count at doses of 0.03 or 0.1 microgram/kg/d by day 12 of study. At doses of 0.3 and 1.0 microgram/kg/d there was a threefold median increase (maximum 10-fold) in platelet count by day 16. The platelets produced in vivo in response to PEG-rHuMGDF showed unchanged aggregation and adenosine triphosphate (ATP)-release responses in in vitro assays. Tests included aggregation and release of ATP in response to adenosine diphosphate (ADP) (10, 5, 2.5, and 1.25 mumol/L), collagen (2 micrograms/mL), thrombin-receptor agonist peptide (TRAP, 10 mumol/L) and ristocetin (1.5 mg/mL). Administration of aspirin to an individual with platelet count of 1,771 x 10(3)/L resulted in the typical aspirin-induced ablation of the normal aggregation and ATP-release response to stimulation with arachidonic acid (0.5 mg/mL), collagen, and ADP (2.5 and 1.25 mumol/L). There was no change in the expression of the platelet-surface activation marker CD62P (P-selectin) nor induction of the fibrinogen binding site on glycoprotein IIb/IIIa as reported by the monoclonal antibody, D3GP3. An elevation of reticulated platelets was evident after 3 days of treatment with PEG-rHuMGDF and preceded the increase in circulating platelet count by 5 to 8 days; this reflected the production of new platelets in response to PEG-rHuMGDF. At later time points, the mean platelet volume (MPV) decreased in a manner inversely proportional to the platelet count. Levels of plasma glycocalicin, a measure of platelet turnover, rose 3 days after the initial increase in the peripheral platelet count. The level of plasma glycocalicin was proportional to the total platelet mass, suggesting that platelets generated in response to PEG-rHuMGDF were not more actively destroyed. Thus, the administration of PEG-rHuMGDF, to humans, increased the circulating platelet count and resulted in fully functional platelets, which showed no detectable increase in reactivity nor alteration in activation status.

Cohort Studies↗
PubMed1996

Molecular cloning of a novel human gene (D11S4896E) at chromosomal region 11p15.5.

A novel gene (GOK) has been cloned from human chromosome region 11p15.5 that is believed to contain a gene or genes associated with a number of pediatric malignancies, including Wilms tumor. A 4-kb cDNA has been cloned and it encodes a predicted protein of approximately 84 kDa that could be translated in vitro. Computer analysis predicted that the protein had a signal peptide and may contain a transmembrane helix. Restriction mapping by pulsed-field electrophoresis indicates that GOK is located 1.7 kb telomeric of RRM1, and both genes are transcribed in the same direction. GOK displays high evolutionary conservation: cloning and partial sequencing of a mouse genomic clone revealed 90% identity with the human gene at both the nucleotide and the predicted amino acid levels.

Amino Acid Sequence↗
PubMed1996

Laparoscopic liver biopsy to evaluate hepatic dysfunction in patients with hematologic malignancies: a useful tool to effect changes in management.

Hepatic dysfunction is common in patients who receive intensive chemotherapy and it is important to determine the etiology in order to institute appropriate therapy. The role of laparoscopic liver biopsy in patients with neutropenia, thrombocytopenia, or both was evaluated as a mean of making treatment decisions and as a determinant of clinical outcome. Laparoscopic liver biopsy was performed in 29 subjects who were receiving intensive cytotoxic therapy with or without bone marrow transplantation. One to three direct-vision laparoscopic liver biopsies were performed in each patient using a Tru-cut needle during general anesthesia. Platelet concentrate transfusions were usually given before, during, and immediately after biopsy. Bleeding was controlled with spatula electrocautery. Thirty-two biopsies were obtained in 29 patients. At the time of liver biopsy, white blood cell and platelet counts ranged from 0 to 14,300/microliters (median: 2500/microliters), and 1000 to 47,000/microliters (median: 20,000/microliters), respectively. Bleeding at the liver biopsy site was readily controlled during the procedure without clinical evidence of significant bleeding; no procedure-related complications were noted and no patients required re-exploration. All biopsies were informative and the lesions observed in 32 biopsies revealed graft-versus-host disease (n = 5), hepatic candidiasis (n =1), hepatic veno-occlusive disease (n = 3), cholestasis (n = 19), hemosiderosis (n = 26), toxic injury (n = 8), hepatic steatosis (n = 4), granuloma (n = 1), viral infection (n =1), and malignancy (n = 1). Laparoscopic liver biopsy has been proven to be an effective means of assessing the cause of liver dysfunction in patients who were thrombocytopenic and immunosuppressed. The diagnosis obtained at laparoscopic liver biopsy altered therapy in nine of 29 (31%) patients.

Adult↗
PubMed1995

Human gene for the large subunit of ribonucleotide reductase (RRM1): functional analysis of the promoter.

Ribonucleotide reductase comprises two nonidentical protein subunits R1 and R2, both of which are required for enzyme activity and show cell cycle-dependent regulation. The TATA-less promoter of the human RRM1 gene (encodes R1 protein) was examined with reference to regulatory domains upstream of the transcription start site. A region from nt -195 to +3 was found to give maximal expression of a reporter gene when transfected into the human cell line K562. Overall, this 198-bp region shows 58% identity with the equivalent region of the murine promoter; however, it contains two 22-bp domains that were 81 and 91% identical between species. Electrophoretic mobility shift assays were performed using a fragment of the domain closest to the transcription start site. These experiments revealed that several factors were able to bind this region in a sequence-specific manner. One of these factors was shown to be Sp1 by specific competition and supershift using antibody to Sp1. The data presented suggest that Sp1 is involved in the transcription of RRM1.

Animals↗
PubMed1995

Sequential changes in serum iron and ferritin in patients undergoing high-dose chemotherapy and radiation with autologous bone marrow transplantation: possible implications for treatment related toxicity.

In an effort to define the pattern of iron flux during high-dose chemotherapy or chemo/radiotherapy, we prospectively measured serum iron, iron binding capacity, and ferritin in patients undergoing autologous bone marrow transplantation for various malignancies. Sequential measurement of serum iron from days -7 to +12 was carried out in 88 evaluable patients, and simultaneous measurement of iron, ferritin, and total iron binding capacity was carried out in 32 patients. We found that there was a predictable rise in serum iron on day -2 or -3, and that this was accompanied by an increase in the saturation of transferrin. In addition, there was a similar increase in serum ferritin levels, which peaked by day +2. We suggest that the timing of this change in serum iron and saturation of transferrin may be important in mediating endothelial cell damage and, hence, organ toxicity in the setting of AuBMT. Based on these findings, we suggest that large clinical studies could be a source of patient samples to measure surrogate endpoints such as lipid peroxidation products (malondialdehyde or isoprostanes), or protein oxidation products following high-dose chemo/radiotherapy to determine the role of iron in cellular injury. It is possible that pharmacological manipulations to reduce free radical production or to chelate iron during the days prior to bone marrow reinfusion might help to reduce tissue injury in the setting of bone marrow transplantation.

Adolescent↗
PubMed1995

Acute cholecystitis after autologous bone marrow transplantation for acute myeloid leukemia.

BACKGROUND: We investigated the incidence of acute cholecystitis in patients with acute myeloid leukemia (AML) undergoing autologous bone marrow transplantation in complete remission. PATIENTS AND METHODS: Thirty-five consecutive acute myeloid leukemia patients were given oral busulfan 4 mg/kg/day for 4 days and IV cyclophosphamide 50 mg/kg/day for 4 days followed by reinfusion of autologous bone marrow purged with 4-hydroperoxycyclophosphamide. RESULTS: Five of 35 patients developed clinical evidence of acute cholecystitis, manifested by fever, nausea, vomiting, right-upper-quadrant pain, and abdominal guarding, within 18 days after autologous bone marrow infusion. Ultrasonography and CT scans of the abdomen supported the diagnosis of cholecystitis. Three patients underwent cholecystectomy, while two patients were treated medically; all recovered uneventfully. A review of 338 consecutive bone marrow transplant patients who underwent marrow transplantation for a variety of diseases and were treated with other high-dose cytotoxic regimens during the same time period revealed significantly fewer cases of cholecystitis, i.e. two, (p < 0.0001). CONCLUSIONS: Five of 35 AML patients undergoing autologous bone marrow transplant using busulfan, cyclophosphamide, and purged bone marrow developed evidence of acute cholecystitis. These findings suggest that the busulfan/cyclophosphamide preparative regimen may be associated with acute cholecystitis. The true incidence of this injury and its pathogenesis remain to be elucidated.

Acute Disease↗
PubMed1994

Filgrastim in patients with chemotherapy-induced febrile neutropenia. A double-blind, placebo-controlled trial.

OBJECTIVE: To determine if filgrastim (recombinant human methionyl granulocyte colony-stimulating factor) used in addition to standard inpatient antibiotic therapy accelerated recovery from infection associated with chemotherapy-induced neutropenia. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Hematology and oncology wards of four teaching hospitals. PATIENTS: 218 patients with cancer who had fever (temperature > 38.2 degrees C) and neutropenia (neutrophil count < 1.0 x 10(9)/L) after chemotherapy. INTERVENTION: Patients were randomly assigned to receive filgrastim (12 micrograms/kg of body weight per day) (n = 109) or placebo (n = 107) beginning within 12 hours of empiric therapy with tobramycin and piperacillin. Patients received treatment and remained in the study until the neutrophil count was greater than 0.5 x 10(9)/L and until 4 days without fever (temperature < 37.5 degrees C) had elapsed. MEASUREMENTS: Days of neutropenia and fever and days in the study (hospitalization); time to resolution of fever and febrile neutropenia; and frequency of the use of alternative antibiotics. RESULTS: Compared with placebo, filgrastim reduced the median number of days of neutropenia (3.0 compared with 4.0 days of a neutrophil count of < 0.5 x 10(9)/L; P = 0.005) and the time to resolution of febrile neutropenia (5.0 compared with 6.0 days; P = 0.01) but not days of fever (3.0 days for both groups). The frequency of the use of alternative antibiotics was similar in the two groups (46% compared with 41%; P = 0.48). The median number of days patients were hospitalized while on study was the same (8.0 days; P = 0.09); however, filgrastim decreased the risk for prolonged hospitalization (> 11 days, 4th quartile) by half (relative risk, 2.1 [95% CI, 1.1 to 4.1]; P = 0.02). In exploratory subset analyses, filgrastim appeared to provide the greatest benefit in patients with documented infection and in patients presenting with neutrophil counts of less than 0.1 x 10(9)/L. CONCLUSIONS: Filgrastim treatment used with antibiotics at the onset of febrile neutropenia in patients with cancer who have received chemotherapy accelerated neutrophil recovery and shortened the duration of febrile neutropenia.

Adolescent↗
PubMed1994

Human R1 subunit of ribonucleotide reductase (RRM1): 5' flanking region of the gene.

Ribonucleotide reductase is essential, in dividing cells, for the production of deoxyribonucleotides prior to DNA synthesis in S phase. Neither of its two subunits (R1 and R2) are detectable in quiescent cells. In cycling cells, RRM1 mRNA and R1 protein are present throughout the cell cycle. A fragment of the human cDNA was used to isolate a genomic clone that encompasses the 5' flanking region of human RRM1. Primer extension and PCR experiments were used to define six potential cap sites. The immediate upstream region does not have a TATA box and is not GC-rich. A 1.9-kb fragment (-1670 to +208) was able to direct transcription of a reporter gene in a transient expression system. Understanding the mechanisms regulating expression of this gene will provide insight into the processes involved in cell cycling and may be of particular importance in understanding the deregulated growth of transformed cells.

Amino Acid Sequence↗
PubMed1994

Marrow cellularity as a predictor of adequate cell yield for transplantation.

Clear correlations have not been established between bone marrow cellularity before or at marrow harvest and marrow cell yield for transplantation. The authors therefore retrospectively reviewed 204 marrow donations to ascertain whether biopsy cellularity was predictive of nucleated cell yield at harvest, as measured by final cell counts (FCC)/kg body weight. Preharvest and intraoperative biopsy cellularity were highly correlated with each other; moderate correlation was found between intraoperative biopsy cellularity and FCC. Mean cellularity was slightly but significantly higher in samples yielding an FCC greater than 2 x 10(8) nucleated cells/kg (P < 0.01). Biopsy cellularity less than 20%, seen in 4% of specimens, did not consistently correlate with low FCC, defined as less than 2 x 10(8) nucleated cells/kg. More than 2 x 10(8) cells/kg were consistently obtained only when biopsy cellularity was 65% or more. Marrow biopsies performed before harvest can be used to predict intraoperative cell counts at the time of marrow donation, although a cell yield of more than 2 x 10(8) nucleated cells/kg can be assured only with high marrow cellularity.

Adolescent↗
PubMed1994

Randomized comparison of MACOP-B with CHOP in patients with intermediate-grade non-Hodgkin's lymphoma. The Australian and New Zealand Lymphoma Group.

PURPOSE: To compare complete response rates, time to failure, survival, and toxicity for patients with intermediate-grade non-Hodgkin's lymphoma (NHL) treated with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) versus those treated with a regimen consisting of methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisolone, and bleomycin (MACOP-B), in a multicenter, randomized controlled trial performed by 22 centers of the Australian and New Zealand Lymphoma Group (ANZLG). PATIENTS AND METHODS: Between October 1986 and June 1991, 304 patients were randomized, of whom 236 were eligible for analysis. Eligibility criteria included diffuse small cleaved-cell, diffuse mixed small- and large-cell, follicular large-cell, diffuse large-cell, and large-cell immunoblastic, stages I bulky or II to IV. RESULTS: There was no significant difference in complete response rates (51% for MACOP-B v 59% for CHOP), failure-free survival, or overall survival in the two treatment arms. The rate of death of MACOP-B patients relative to CHOP patients was estimated to be 0.91 (P = .64) when stratified by prognostic group. There were no significant differences between the two regimens in any of the prognostic subgroups. Toxicity was significantly more severe with MACOP-B, particularly cutaneous toxicity, stomatitis, and gastrointestinal ulceration. The average relative dose-intensity (RDI) of MACOP-B was 0.91 and of CHOP was 0.90, indicating good dose delivery in this multicenter group setting. CONCLUSION: CHOP chemotherapy produced results equivalent to those of MACOP-B in patients with intermediate-grade NHL and with significantly fewer toxic complications. Despite relatively poor results in some patient subgroups, CHOP remains the standard chemotherapy for this disease, against which all new regimens should be compared.

Adolescent↗
PubMed1994

Hepatic dysfunction in patients with carcinoma who are severely thrombocytopenic and immunosuppressed.

BACKGROUND: The use of intensive cytotoxic drug therapy for malignant disorders often results in hepatic dysfunction. It is important to determine the cause of hepatic injury to institute appropriate therapy; however, neutropenia and thrombocytopenia may prevent performance of hepatic biopsy to establish a cause. STUDY DESIGN: We prospectively evaluated the cause of hepatic dysfunction using laparoscopic biopsy of the liver in 20 consecutive patients who were receiving intensive cytotoxic therapy, with or without bone marrow transplantation, or who were being treated for severe aplastic anemia. One to three direct-vision laparoscopic biopsies were performed in each patient during general anesthesia and bleeding was controlled with spatula electrocautery. Platelet concentrate transfusions were given before, during, and immediately after the biopsy. RESULTS: Platelet and leukocyte counts at the time of hepatic biopsy ranged from 1,000 to 83,000 per microL (median of 23,500 per microL) and zero to 14,300 per microL (median of 2,200 per microL), respectively. Nineteen of 20 patients had platelet counts of less than 68,000 per microL. Bleeding at biopsy site was controlled during the procedure without evidence of bleeding or complications after biopsy. Biopsy specimens revealed graft-versus-host disease (n = 2), hepatic veno-occlusive disease (n = 1), steatosis (n = 5), cholestasis (n = 19), hemosiderosis (n = 19), and granuloma (n = 1). CONCLUSIONS: In several patients, the knowledge derived from hepatic biopsy results altered the therapeutic strategy. The use of laparoscopic hepatic biopsy to assess the cause of hepatic dysfunction should be encouraged because it is a safe procedure, even in patients who are severely thrombocytopenic and immunocompromised.

Adolescent↗
PubMed1993

Calcium antagonists and Bay K8644 promote depolarization of the rat heart mitochondrial membrane potential. Further evidence for a role in alteration of oxidative metabolism.

Studies were carried out using a tetraphenylphosphonium (TPP+)-selective electrode to monitor the effect of selected calcium (Ca2+) antagonists and the dihydropyridine Ca2+ agonist Bay K8644 on membrane potential (psi) associated with isolated rat heart mitochondria. Verapamil and diltiazem (10-500 microM), standard Ca2+ antagonists, produced a depolarization of both liver and heart mitochondria at concentrations > 150 microM. In contrast, nitrendipine (10-200 microM), a dihydropyridine compound, produced a concentration-related inhibition of psi in mitochondria from both sources, effects which were statistically significant at concentrations > 50 microM. Cinnarizine (10-100 microM) and bepridil (10-100 microM) also produced inhibition of heart psi, these effects being particularly noted in the presence of bepridil, where depolarization of the membrane was statistically significant with only 10 microM drug. The results indicate the complexity of action of these drugs at the mitochondrial level. In general, drug actions on psi appear to be correlated with previously reported effects on Ca2+ transportation rather than oxidative phosphorylation associated with rat heart mitochondria. The findings also illustrate that the mitochondrial actions of cardiovascular compounds may be of relevance in situ, particularly during ischaemia/reperfusion when mitochondria become loaded with Ca2+.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗