Search PubMed⌕ Search

Biomedical subjects

F J Giles

Publications and source records attributed to F J Giles.

At least 73 records · Page 4Linked to original sources
PubMed1999

The potential of amifostine: from cytoprotectant to therapeutic agent.

BACKGROUND AND OBJECTIVE: Amifostine is an inorganic thiophosphate cytoprotective agent known chemically as ethanethiol, 2-[(3-aminopropyl)amino]dihydrogen phosphate. It is a pro-drug of free thiol that may act as a scavenger of free radicals generated in tissues exposed to cytotoxic drugs, and binds to reactive metabolites of such drugs. Amifostine was originally developed as a radioprotective agent in a classified nuclear warfare project. Following declassification of the project it was evaluated as a cytoprotective agent against toxicity of the alkylating drugs and cisplatin. In fact, pretreatment with amifostine was well tolerated and reduced the cumulative hematologic, renal and neurological toxicity associated with cisplatin, cyclophosphamide and vinblastine therapy of advanced and metastatic solid tumors. The objective of this review is to focus the importance of amifostine as a myeloprotective and cytoprotective drug during treatment with chemotherapeutics, presenting the most recent results, and to discuss the application of amifostine in the therapy of myelodysplastic syndromes. EVIDENCE AND INFORMATION SOURCES: The material analyzed in this study includes data published or under publication by the authors as full papers or clinical protocols. Articles and abstracts published in Journals covered by Medline constitute the other source of information. STATE OF THE ART AND PERSPECTIVES: Amifostine, formerly known as WR-2721, is an organic thiophosphate that was developed to protect normal tissues selectively against the toxicities of chemotherapy and radiation. Amifostine is a pro-drug that is dephosphorylated at the tissue site to its active metabolite by alkaline phosphatase. Differences in the alkaline phosphatase concentrations of normal versus tumor tissues can result in greater conversion of amifostine in normal tissues. Once inside the cell the free thiol provides an alternative target to DNA and RNA for the reactive molecules of alkylating or platinum agents and acts as a potent scavenger of the oxygen free radicals induced by ionizing radiation and some chemotherapies. Preclinical animal studies demonstrated that the administration of amifostine protected against a variety of chemotherapy-related toxicities including cisplatin-induced nephrotoxicity, cisplatin-induced neurotoxicity, cyclophosphamide- and bleomycin-induced pulmonary toxicity, and the cytotoxicities (including cardiotoxicity) induced by doxorubicin and related chemotherapeutic agents. Amifostine was shown to protect a variety of animal species from lethal doses of radiation. Studies in tumor-bearing animals demonstrated that the administration of amifostine results in cytoprotection without loss of antitumor activity. Multiple phase I studies were carried out with amifostine in combination with chemotherapy for various neoplasms. Appropriate doses of amifostine resulted to be 740-910 mg/m(2) in a single dose regimen, and 340 mg/m(2) in a multiple dose regimen. Amifostine afforded not only hematologic protection, but also other organ protection from cytotoxic agents such as nephrotoxicity, mucositis and peripheral neuropathy from cisplatin. Many studies have been performed to investigate cytoprotective efficacy of amifostine. In brief, amifostine gives hematologic protection from cyclophosphamide, carboplatin, mitomycin C, fotemustine and radiotherapy; renal and peripheral nerve protection from cisplatin; mucosa, skin, and salivary gland from radiotherapy. In phase I/II studies these properties have been confirmed, together with a generally good tolerability of the drug, hypotension being the most common side effect. It has been observed that amifostine possibly enhances the anti-tumor effect of carboplatin, nitrogen mustard, melphalan, and cisplatin combined with 5-FU or vinblastine. For all these characteristics, amifostine is at present broadly used as supportive treatment during chemotherapy, in lymphomas and solid tumors, and its spec

Amifostine↗
PubMed1998

Translocation (3;21;8)(q21;q22;q22) in a patient with acute myeloid leukemia. A case report and review of prognostic indicators.

We report a patient with acute myeloid leukemia (AML) and t(3;21;8)(q21;q22;q22). This translocation has not been previously described in de novo or relapsed AML. The patient is a 25-year-old woman who presented with WBC 6.2 x 10(9)/L, Hgb 10.2 g/dL, Hct 28.4%, and platelets 67 x 10(9)/L. A bone marrow biopsy revealed a 70% hematopoietic cellularity with 65% blasts. Immunophenotyping showed aberrant expression of lymphoid-associated marker CD19. Cytogenetic analysis on a 72-hour culture of bone marrow cells supplemented with conditioned media was evaluated by G-banding at about the 400-band level. The patient's age, cytogenetics, WBC, and immunophenotype at diagnosis would seem to suggest a favorable prognosis, according to previous studies of prognostic indicators. She was treated with induction and consolidation chemotherapy, followed by myeloablative conditioning and autologous peripheral blood stem cell transplant (PBSCT). Despite multiple favorable prognostic factors, the patient relapsed 7 months after PBSCT. Translocation of chromosomes 8 and 21 is common in AML and is generally considered a good prognostic factor. We suspect that the effect of the 3q21 translocation in an otherwise favorable translocation of chromosomes 8 and 21 may be responsible for this patient's early relapse.

Adult↗
PubMed1998

Clinical course and therapy of chronic myelogenous leukemia with interferon-alpha and chemotherapy.

This article begins with a review of the natural history of chronic myelogenous leukemia (CML), with an emphasis on prognostic features. Current standard therapy of CML with interferon-alpha based regimens, and interferon-alpha, in the context of allogenic stem cell transplantation is then discussed. Finally, some potentially effective novel agents including homoharringtonine, decitabine, ATRA, and topotecan are described.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Monocyte-macrophages, granulocyte-macrophage colony-stimulating factor, and prolonged survival among patients with acute myeloid leukemia and stem cell transplants.

Recombinant GM-CSF has been recently shown to prolong survival of elderly patients with acute myeloid leukemia (AML) by reducing the rate of induction therapy-related mortality. In a prospective, randomized, placebo-controlled, double-blind, multicenter study conducted by the Eastern Cooperative Oncology Group in the United States, granulocyte-macrophage colony-stimulating factor (GM-CSF) was given only to those patients who had hypocellular or remission marrow on day 10 of one or two cycles of standard induction therapy. Although the administration of GM-CSF significantly reduced a wide range of adverse events, the main benefit of this cytokine seems to be mediated by a reduction in sepsis. A similarly designed study, conducted by the Southwest Oncology Group in a directly comparable AML patient population with use of granulocyte colony-stimulating factor (G-CSF) as the supportive cytokine, showed no survival benefit and no reduction in the rates of serious or lethal sepsis. In most current clinical situations, GM-CSF and G-CSF are indistinguishable both in terms of efficacy and toxicity. GM-CSF and G-CSF have very different impacts on the survival of patients with AML. The stimulation of monocyte-macrophage function and proliferation by GM-CSF may mediate the selective benefit of GM-CSF in patients with AML and stem cell transplants. GM-CSF merits further study as therapy for and/or protection against opportunistic sepsis in patients with cancer and will be included in a number of International Oncology Study Group protocols.

Adult↗
PubMed1998

Results of topotecan single-agent therapy in patients with myelodysplastic syndromes and chronic myelomonocytic leukemia.

The activity of topotecan was evaluated in patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). Sixty patients with a diagnosis of MDS (n = 30) or CMML (n = 30) were treated. Their median age was 66 years, with 50 patients (83%) being over 60 years of age at time of study entry. Chromosomal abnormalities were present in 50% of patients and thrombocytopenia of less than 50 x 10(9)/L in 50%. Topotecan was administered as 2 mg/m2 by continuous infusion over 24 hours daily for five days (10 mg/m2 per course) every 4 to 6 weeks for two courses, then at maximum tolerated dose level (1-2 mg/m2 by continuous infusion over 24 hours daily for five days) once every 4-8 weeks for a maximum of 12 courses. Evaluation of outcome and of differences among subgroups was performed according to standard methods; the criteria for response were those used for acute leukemia. Nineteen patients (31%) achieved a complete response (CR). A CR was achieved in 11 of 30 patients with MDS (37%) and in eight of 30 with CMML (27%). A CR was achieved in 10 of 23 patients with previously untreated MDS (43%). Eight of 11 patients who presented with cytogenetic abnormalities (five of which involved chromosome 5 and/or 7 abnormalities) and achieved CR, were evaluated cytogenetically in CR: all were cytogenetically normal in CR. Characteristics associated with a higher CR rate were lack of previous chemotherapy, absence of ras oncogene mutations, and presence of less than 10% monocytes in either peripheral blood or bone marrow. In contrast, CR rates were similar by different agent groups, by different karyotype abnormalities, and by other pre-therapy peripheral blood counts. Non-myelosuppressive side effects were mucositis in 67% of patients (severe [grade 3-4] 23%), diarrhea in 38% (severe 17%), and nausea and vomiting in 28% (severe 5%). Febrile episodes during neutropenia occurred in 85% of patients and documented infections in 47 %. Mortality in the first four weeks was 20%. With a median follow-up duration of 31 months, the 12 month survival rate was 38%, median survival time 10.5 months, and median remission duration 7.5 months. In summary, topotecan has significant single-agent activity in MDS and CMML. Complete responses associated with topotecan therapy often involve the disappearance of abnormal, poor-prognosis karyotypes, which is particularly encouraging. Future strategies to optimize topotecan's role include combination regimens with topoisomerase II reactive agents, cytarabine, or hypomethylating agents (azacytidine and decitabine).

Adult↗
PubMed1998

Chronic lymphocytic leukemia in (Richter's) transformation.

Non-Hodgkin's lymphomas (NHL), Hodgkin's Disease (HD), and multiple myeloma (MM) develop as second malignancies in approximately 3%, 0.5%, and 0.1%, respectively, of chronic lymphocytic leukemia (CLL) patients. The true incidence may be higher, as postmortem examination is not performed in most patients, thus underestimating occult disease. As originally described, the term Richter's syndrome (RS) refers to the development of aggressive NHL during the course of CLL. The onset of RS is usually abrupt with clinical deterioration as manifested by worsening systemic symptoms, rapid tumor growth, and/or extranodal involvement. Diagnosis requires tissue biopsy. The NHL is usually diffuse large cell (LCL) or its immunoblastic variant. It is resistant to current therapies, and the median survival of patients who develop RS is approximately 6 months. The precise relationship between the cells of origin of CLL and LCL in RS patients is unknown with data suggesting either common (60%) or distinct (40%) clonal evolutions for these malignancies in different patients. Gene rearrangement studies and isotype analysis suggest that CLL and LCL in RS patients frequently share identical clonal origins. Purine analog therapy of CLL patients does not seem to affect the incidence or clinical behavior of RS. Despite increasing rates of achievement of complete remission in CLL associated with fludarabine-based regimens, RS still occurs, warranting continued surveillance of all CLL patients regardless of disease status. HD and MM in CLL patients are usually advanced at the time of presentation and have poor response and survival rates.

Humans↗
PubMed1997

Comparison of Technetium-99m sestamibi and indium-111 octreotide imaging in a patient with Ewing's sarcoma before and after stem cell transplantation.

BACKGROUND: We report the use of two novel nuclide agents, Technetium-99m (99Tc)sestamibi (MIBI) and indium-111 (In-111) octreotide, in comparison with conventional computed tomography (CT) imaging in a patient with metastatic Ewing's sarcoma (ES) before and after high dose chemotherapy with autologous peripheral stem cell transplantation (PSCT). MIBI is taken up actively by metabolically active tumor cells. Octreotide, a somatostatin analog, binds specifically to somatostatin receptors. METHODS: The patient was a 20-year-old male with recurrent metastatic ES to the lung. Before and sequentially after high dose chemotherapy and PSCT, the patient was imaged with MIBI. Whole body planar and single photon emission computed tomography (SPECT) images were obtained after the injection of 30 mCi of 99Tc MIBI. Prior to PSCT the patient was imaged with 6 mCi In-111 pentreotide. RESULTS: Conventional CT scans also were performed. Initial CT revealed pulmonary metastasis in the right lower lobe along with multiple left pleural-based lesions. These lesions were visualized clearly with MIBI. Octreotide detected only the left lung involvement. Sequential MIBI scans after PSCT correlated with tumor reduction in the right lung field and tumor progression in the left lung as well as the development of new pulmonary metastasis. These findings were confirmed on CT. CONCLUSIONS: MIBI imaging was highly concordant with CT scanning in the detection of metastatic ES. MIBI scanning holds promise for the direct detection of a variety of human malignancies, and may prove useful as a rapid whole body imaging modality.

Adult↗
PubMed1997

Serum levels of TNF, IL-6 and sCD23 correlate with changes in lymphocyte count in patients with B-cell chronic lymphocytic leukaemia receiving interferon-alpha therapy.

The control of cell growth and differentiation in B-cell malignancies may be regulated by the autocrine production of cytokines, several of which have been implicated in the growth and survival of B-cells. The effect of interferon-alpha (IFN) therapy in these disorders may be to disrupt autocrine growth or survival loops. We have measured levels of circulating IL-1b, IL-6, TNF-a and soluble CD23 (sCD23) in 8 patients with Binet stage A B-cell chronic lymphocytic leukaemia (B-CLL) receiving IFN therapy, and compared these with changes in the lymphocyte count following IFN therapy. Two patients developed anti-interferon antibodies while on IFN therapy, and in both them, the changes in lymphocyte count correlated significantly with the titre of anti-interferon antibodies, as well as serum levels of IL-6, TNF-a and sCD23. In one patient there was significant correlation with levels of IL-1b. One patient, who stopped and restarted IFN therapy, demonstrated correlation between lymphocyte count and levels of IL-6 and sCD23. In a further two patients, there was correlation with levels of sCD23 alone, while the remaining three patients showed no correlation between lymphocyte count and the serum cytokines measured. These results suggest that IFN therapy may alter levels of circulating cytokines in some CLL patients and that these effects may be associated with disease progression.

Humans↗
PubMed1996

Cost-effectiveness of interferon-alpha and conventional chemotherapy in chronic myelogenous leukemia.

OBJECTIVE: To compare the cost-effectiveness of interferon-alpha with that of hydroxyurea as initial therapy for patients with chronic myelogenous leukemia (CML) in the chronic phase. DESIGN: A decision analysis and Markov model that described the natural history of the therapeutic process. The Markov model contained two treatment arms (interferon-alpha and hydroxyurea) and eight states of health (complete hematologic remission with cytogenetic response, complete hematologic remission without cytogenetic response, partial hematologic remission, chronic phase without hematologic remission, accelerated phase, blast crisis, bone marrow transplantation, and death). Probabilities, costs, and utilities were obtained from published clinical studies and clinical investigators. MEASUREMENT: Quality-adjusted years of life saved and costs and qualities discounted at 5% per year. SETTING: University medical centers in North America and Europe. PATIENTS: Meta-analysis of results from patients studied in clinical trials. RESULTS: The model's predictions of median survival (69 months with interferon-alpha therapy and 58 months with hydroxyurea therapy) were derived from data in the recent literature. In patients 50 years of age, interferon-alpha improved life expectancy over hydroxyurea by approximately 18 months. The marginal cost-effectiveness of interferon-alpha (incremental discounted cost of interferon-alpha compared with that of conventional therapy) was $34800 per quality-adjusted year of life saved. The model was sensitive to the monthly cost of interferon-alpha therapy (if the cost of interferon-alpha is reduced by one third, the cost-effectiveness becomes $19300 per quality-adjusted year of life saved) but was not particularly sensitive to the costs associated with blast crisis or bone marrow transplantation. The other significant variable was quality of life during therapy with interferon-alpha; when this measure was varied from 70% to 100% of the quality of life during hydroxyurea therapy, cost-effectiveness changed from $123200 to $25620 per quality-adjusted year of life saved. When the quality of life associated with interferon-alpha was less than 62% of the quality of life associated with hydroxyurea, the discounted quality-adjusted life expectancy with interferon-alpha was less than that with hydroxyurea. CONCLUSION: Compared with hydroxyurea, interferon-alpha is, in most clinical scenarios, a cost-effective initial therapy for patients with chronic-phase CML who can tolerate the drug.

Antineoplastic Agents↗
PubMed1996

Translocation (12;15)(p13;q13) in a patient with relapsed acute myeloid leukemia.

We report a patient with a history of leukopenia who developed acute myeloid leukemia (AML) FAB M2 and was successfully treated with induction and consolidation chemotherapy. She relapsed 7 months after initial diagnosis. Peripheral blood cells at relapse showed a t(12;15)(p13;q13), which has not been previously described in de novo or relapsed AML.

Aged↗
PubMed1996

Cutaneous manifestation of leishmaniasis 40 years after exposure in a patient with chronic lymphocytic leukaemia.

Most individuals infected with the protozoan parasite Leishmania do not demonstrate overt disease, because of effective immune protection produced by T-cell mediated immunity. Acquired defects in T-cell responses may lead to emergence of leishmaniasis many years after exposure in endemic areas. We describe a case of a 75 year old man, who presented with a cutaneous manifestation of leishmaniasis 40 years after exposure, co-incident with the diagnosis of chronic lymphocytic leukaemia.

Aged↗
PubMed1996

Technetium-99m sestamibi scanning in multiple myeloma stem cell transplantation.

We report the use of technetium-99m sestamibi (MIBI) in a patient with multiple myeloma (MM) undergoing peripheral blood stem cell (PBSC) transplantation. MIBI is a radionuclide agent that is preferentially taken up by malignant tumors. Plain radiographs in a MM patient, taken prior to PBSC transplantation, showed a large right humeral lytic lesion that correlated with increased uptake of MIBI at the same location. MIBI uptake, demonstrating active MM bone disease, was also evident in areas which were normal on plain radiographs. Three months after PBSC transplant, the lytic lesion had healed by plain radiographs and repeat MIBI scan showed no uptake. MIBI scanning results have a positive correlation with plain radiographs, and more importantly, demonstrate active MM bone disease not yet detectable by plain radiographs. If MIBI proves more sensitive in the detection of MM bone disease than plain radiographs or bone scanning with traditional isotopes, it will have a significant role in the detection of early disease and in monitoring disease progression during and after therapy.

Aged↗
PubMed1995

Burkitt translocation (8;22)(q24;q11) in a patient with multiple myeloma.

The prevalence of chromosomal abnormalities in multiple myeloma (MM) has been difficult to detect by karyotyping primarily because of the low proliferative rate of malignant plasma cells. The reported incidences of abnormal karyotypes range from 24% to 63% in bone marrows obtained from MM patients, with the higher rates being seen in aggressive disease [1-8]. Detection of abnormal karyotypes in MM has been associated with a poor prognosis. We report a MM patient with an 8;22 Burkitt translocation, the first such reported case.

Bone Marrow↗
PubMed1995

Growth factors can protect B-chronic lymphocytic leukaemia cells against programmed cell death without stimulating proliferation.

The proliferation and survival of B-chronic lymphocytic leukaemia (B-CLL) cells may be regulated by autocrine growth factor loops. Furthermore, it has been suggested the reduction in lymphocytosis following therapy with interferon-alpha may be associated with the interruption of autocrine growth factor production. We have therefore examined the effects of a number of cytokines on the proliferation of B-CLL cells, and also on the regulation of programmed cell death, and the role of interferon-alpha in these systems. In the ten patients studied, neither interferon-alpha alone or together with either interferon-gamma, IL1, IL4, IL6, TNF, or serum containing high levels of soluble CD23 was able to induce proliferation of B-CLL cells. Incubation with TPA or IL2 resulted in variable proliferative responses. Co-incubation with interferon-alpha enhanced TPA-induced proliferation in 4 cases, but reduced IL2-induced proliferation in all cases studied. In contrast, all the cytokines studied were able to protect B-CLL cells against programmed cell death, both spontaneous and that induced by hydrocortisone, with the exception of TNF. These data suggest a role for interferon-alpha in disrupting autocrine survival pathways rather than inhibiting proliferation.

Apoptosis↗
PubMed1995

Current therapy of refractory multiple myeloma.

Induction therapy with standard regimens induces an average objective response (OR) rate (Southwest Oncology Group [SWOG] Criteria) of 40%-50% in patients with previously untreated multiple myeloma (MM) [1, 2]. The great majority of those who initially achieve remission eventually relapse, with less than 20% of patients being in ongoing remission at five years from time of initial therapy [1]. At least 30% of MM patients fail to adequately respond to induction chemotherapy [3, 4]. Patients may exhibit clinical deterioration, increasing paraprotein levels, increasing marrow suppression, refractory hypercalcemia or worsening renal failure while undergoing induction therapy. Patients who do not achieve an OR to induction therapy are sometimes described as "nonresponders." This group includes patients who are truly primarily resistant to front-line therapy, patients whose disease is in plateau phase at time of disease presentation, and patients who are slow responders to their induction therapy. The terms "refractory" or "advanced" are often applied to patients who have either primary resistant or relapsed disease. The lack of agreed terminology is a major stumbling block to data review and the logical planning of clinical studies. A classification of relapsed and resistant disease is proposed in Figure 1. Prolongation of median survival beyond one year in studies of therapy for refractory MM patients is rarely achieved [3-104]. Failure of current cytotoxic therapy has led to attempts to improve treatment by the investigation of mechanisms of cytotoxic drug resistance, the development of methods to identify drug-resistant MM cells, and attempts to either prevent or, once established, to circumvent drug resistance [105-109]. Recent data on cytotoxic and/or systemic radiation therapy will be reviewed.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Serum macrophage colony-stimulating factor (M-CSF) levels correlate with clinical response to interferon-alpha in patients with early-stage B-CLL.

Interferon-alpha (IFN-alpha) reduces peripheral lymphocyte counts in B-CLL (CLL). In eight patients with stage 0 CLL on IFN-alpha therapy, peripheral lymphocyte counts fell to 61.7 +/- 19.5% of baseline at week 2 (P < 0.01), while serum M-CSF levels rose from 455 +/- 183 U/ml to 686 +/- 110 U/ml (P < 0.05). Neopterin levels also showed a significant rise. M-CSF levels were correlated with clinical response in these patients. Increased production of M-CSF and the activation of mononuclear phagocytes may be involved in clinical responses to IFN-alpha in early-stage CLL.

Biopterins↗