Biomedical subjects

Francis J Giles

Publications and source records attributed to Francis J Giles.

143 records · Page 8Linked to original sources

PubMed2002

Oral mucositis: time for more studies.

Oral Mucositis (OM) is a frequent cause of severe morbidity in patients receiving chemotherapy and/or radiotherapy. The pathophysiology of OM involves direct cytotoxic effects, local inflammatory responses, and alterations in oral microflora. There are currently no approved agents for the prevention or treatment of OM. In this review we briefly describe current knowledge of the pathophysiology, clinical presentation, and management of OM. We then discuss investigational agents being studied in OM with a particular focus on local antimicrobial agents, hemopoietic growth factors, and cytokines. Measures to reduce the incidence of OM and/or alleviate its clinical sequelae should be incorporated into all chemotherapy or radiotherapy studies.

Antineoplastic Agents↗

PubMed2002

Essential thrombocythemia (ET): moving from palliation to cure.

Essential thrombocythemia (ET) is a clonal hematopoietic stem cell myeloproliferative disorder characterized by megakaryocytic hyperplasia and persistent thrombocytosis. The clinical presentation and evolution of ET are heterogeneous. This review highlights the current treatment options in the management of ET, including hydroxyurea, anagrelide and both regular and pegylated interferons. Anagrelide, while very effective at controlling counts and symptoms in most patients, may not consistently reduce the bone marrow megakaryocyte mass. Interferon is very effective and not associated with leukemogenesis, but has not been proven to restore polyclonal hematopoiesis and has significant dose-related adverse events. Pegylated interferon represents a significant improvement over the unmodified interferon preparations. Novel therapeutic options directed towards eradication of the malignant ET clone are required.

Female↗

PubMed2002

Phase II study of fludarabine, cytarabine (Ara-C), cyclophosphamide, cisplatin and GM-CSF (FACPGM) in patients with Richter's syndrome or refractory lymphoproliferative disorders.

A phase II study was conducted to evaluate the safety and efficacy of fludarabine, cytarabine (ara-C), cyclophosphamide, cisplatin and GM-CSF (FACPGM) treatment in patients with Richter's syndrome (RS), refractory prolymphocytic leukemia (PLL) or refractory non-Hodgkin's lymphoma (NHL). Twenty-two patients with RS, refractory PLL, or refractory NHL were entered into this trial between March 1997 and February 2001. Median age was 62 years (42-74); 77% were over 60 years of age. Histologic diagnosis was large cell NHL transformation in 15 patients with CLL, immunoblastic transformation of CLL in one, refractory PLL in three, and refractory NHL in three patients. Treatment consisted of fludarabine 30mg/m2 (days 1-3), ara-C 0.5g/m2 (days 3-4), cyclophosphamide 250 mg/m2 (days 2-4), cisplatin 15 mg/m2 IV CI (days 1-4) with GM-CSF 250 microg/m2 from day 5 to recovery of neutrophils and antibiotic prophylaxis. Patients with response were to receive a maximum of six cycles of therapy. Eighteen patients were evaluable for response; one patient achieved a complete remission (5%), 12 stable disease/no response (67%) and five patients had progressive disease (28%). The median survival was 2.2 months (range, 1-19); the median failure-free survival was 1.5 months (range, 0.5-18.6). Grade III/IV toxicities were as follows: anemia in 62% of cycles; leucopoenia in 66%; granulocytopenia in 90%; thrombocytopenia in 83%; hyperbilirubinemia in 14%; hyperuricemia in 17%; hyponatremia in 17%; hypokalemia in 14%; hypophosphatemia in 10%; hypoalbulinemia in 14%; hypocalcemia in 7%; and hypercalcemia in 3%. One (3%) patient developed cardiac failure. Forty-one percent of the cycles were complicated with fever, 34% with non-neutropenic fever, and 55% cycles with infections (fungal 31%; bacterial 57%; HSV 6%; VZV 6%). FACPGM had very limited activity and significant toxicity in a cohort of patients with heavily pretreated refractory lymphoproliferative disorders.

Adult↗

PubMed2002

Novel agents for the therapy of acute leukemia.

The leukemias are complex diseases with a wide range of clinical, morphologic, biologic, molecular, and clinical features and a consequent array of possible responses to any given intervention. Although progress has been made in the management of the leukemias, most patients who fail to respond to front-line therapies or who relapse after an initial response die from progressive disease. The balance between efficacy and toxicity of traditional cytotoxic therapies is increasingly unacceptable. As a consequence, the search for therapeutic advances is more focused on affecting the critical steps involved in the development, propagation, and mutation of malignant clones. This article briefly reviews current data on some agents being developed for the treatment of patients with leukemia, with an emphasis on modulators of angiogenesis, inhibitors of the ubiquitin-proteasome pathway, novel nucleoside analogues, and gene hypomethylation agents.

Angiogenesis Inhibitors↗

PubMed2002

Acute myeloid leukemia.

In this chapter, Drs. Keating and Willman review recent advances in our understanding of the pathophysiology of acute myeloid leukemia (AML) and allied conditions, including the advanced myelodysplastic syndromes (MDS), while Drs. Goldstone, Avivi, Giles, and Kantarjian focus on therapeutic data with an emphasis on current patient care and future research studies. In Section I, Dr. Armand Keating reviews the role of the hematopoietic microenvironment in the initiation and progression of leukemia. He also discusses recent data on the stromal, or nonhematopoietic, marrow mesenchymal cell population and its possible role in AML. In Section II, Drs. Anthony Goldstone and Irit Avivi review the current role of stem cell transplantation as therapy for AML and MDS. They focus on data generated on recent Medical Research Council studies and promising investigation approaches. In Section III, Dr. Cheryl Willman reviews the current role of molecular genetics and gene expression analysis as tools to assist in AML disease classification systems, modeling of gene expression profiles associated with response or resistance to various interventions, and identifying novel therapeutic targets. In Section IV, Drs. Hagop Kantarjian and Francis Giles review some promising agents and strategies under investigation in the therapy of AML and MDS with an emphasis on novel delivery systems for cytotoxic therapy and on targeted biologic agents.

Acute Disease↗

PubMed2002

Iseganan HCl: a novel antimicrobial agent.

Iseganan HCl is an antimicrobial peptide under development for the prevention of oral mucositis, a severe consequence of some chemotherapy and radiation therapy regimens. Several attributes of iseganan make it an optimal candidate for study in this clinical situation where both local and systemic host defenses may be impaired. These include broad spectrum and rapid bactericidal activity, a lack of observed resistance and cross-resistance and stability in biological fluids. Clinical trials of patients receiving stomatotoxic chemotherapy followed by a haematopoietic stem cell transplant show iseganan reduces the occurrence of oral mucositis and ameliorates sequelae such as mouth pain, throat pain and difficulty swallowing. Iseganan is well-tolerated, which is partly attributable to a lack of systemic absorption following topical oral administration. Other promising areas of investigation include topical oral application for the prevention of ventilator-associated pneumonia and nebulisation for treatment of chronic lung infection in patients with cystic fibrosis. Future studies will expand on the role of iseganan as a novel antimicrobial.

Animals↗

PubMed2002

Troxacitabine-based therapy of refractory leukemia.

Unique among currently approved or in-development nucleoside analogs, troxacitabine (Troxatyl) is an L-nucleoside with significant cytotoxic activity. Its stereochemistry and cellular transport characteristics render it insensitive to some tumor cell mechanisms of resistance to D-nucleosides, such as cytarabine and fludarabine. Troxacitabine's dose-limiting toxicities were mucositis and hand-foot syndrome in patients with refractory leukemia. Three complete and one partial remissions were observed in 30 patients with refractory acute myeloid leukemia on a Phase I study. Significant activity in blastic phase of chronic myeloid leukemia was seen on a Phase II study. Combinations of troxacitabine with ara-C, topotecan and idarubicin are active in patients with refractory acute myeloid leukemia (AML). Phase II studies in patients with refractory lymphoproliferative diseases are ongoing. Troxacitabine merits further study in patients with hematological malignancies.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2002

TNF-alpha targeted therapeutic approaches in patients with hematologic malignancies.

Tumor necrosis factor (TNF)-alpha is a major effector and regulatory cytokine with a pleiotropic role in the pathogenesis of several immune-regulated diseases, including graft versus host disease (GVHD) and hematologic malignancies, such as multiple myeloma (MM), myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). Curative treatment for the above diseases are not currently available for most patients. Therapeutic approaches inactivating or blocking TNF-alpha are being evaluated in clinical trials. This review describes the development of the soluble TNF-alpha receptor (p75 TNF-R: Fc; etanercept) and other agents inactivating or blocking TNF-alpha in the management of patients with hematologic malignancies. The satisfactory safety profile of etanercept--as demonstrated in patients with autoimmune diseases--has been confirmed in patients with hematologic malignancies and GVHD. Studies to assess whether etanercept, either as a single agent or in combination with cytotoxic and/or immune therapy, may increase response rates and/or survival in patients with MM, MDS, AML and other hematologic malignancies are now warranted.

Antineoplastic Agents↗

PubMed2002

Evolving role of ribonucleoside reductase inhibitors in hematologic malignancies.

Ribonucleotide reductases catalyze the de novo biosynthesis of deoxyribonucleosides for DNA synthesis. Increased ribonucleotide reductases activity has been associated with malignant transformation and tumor cell growth. The ribonucleotide reductases inhibitors may bind with the R1 subunit of the enzyme (Class 1) or the nonheme iron (Class 2). This review focuses on the therapeutic use of ribonucleotide reductases inhibitors in hematologic malignancies. Hydroxyurea, fludarabine and cladribine have established roles in the management of hematologic malignancies, while other ribonucleotide reductases inhibitors, such as gemcitabine, tezacitabine and heterocyclic carboxaldehyde thiosemicarbazones (e.g., triapine) are being evaluated in clinical trials.

Antineoplastic Agents↗

PubMed2002

Gemtuzumab ozogamicin: promise and challenge in patients with acute myeloid leukemia.

CD33 is a suitable target to guide delivery of a toxic moiety to most acute myeloid leukemia cells. Gemtuzumab ozogamicin (Mylotarg) is a humanized antiCD33 monoclonal antibody covalently linked to a derivative of a cytotoxic antibiotic, calicheamicin. As a single agent, gemtuzumab ozogamicin has activity (complete remission rate of 15-20%) in patients with relapsed disease. Gemtuzumab ozogamicin-based combinations are being studied as induction, maintenance and relapse regimens. The chemical hepatotoxicity often observed with gemtuzumab ozogamicin therapy is of little clinical consequence. However, hepatic veno-occlusive disease is a relatively frequent and serious toxicity for which no clear risk factors, other than stem cell transplantation, have been defined. Gemtuzumab ozogamicin-based regimens may be particularly worthy of study in patients with acute promyelocytic leukemia. Gemtuzumab ozogamicin is approved as single-agent therapy for patients over the age of 60 years in first relapse who are not considered candidates for cytotoxic therapy. The administration of gemtuzumab ozogamicin should be carried out under a level of supervision commensurate with that afforded other intensely myelosuppressive agents. Gemtuzumab ozogamicin-based combinations should not be prescribed outside the research setting until further data is available.

Acute Disease↗

PubMed2002

The emerging role of angiogenesis inhibitors in hematologic malignancies.

Angiogenesis is an important component of the pathogenesis of hematologic malignancies. A negative prognostic implication of increased angiogenesis has been established for acute and chronic myeloid and lymphocytic leukemias, myeloproliferative diseases, multiple myeloma, non-Hodgkin's lymphoma (NHL), and hairy cell leukemia. An association between the return of increased marrow vascularity to normal levels and durability of response has been established in some of these diseases. Elevated levels ofproangiogenic factors have been associated with a poor prognosis in the acute and chronic leukemias, multiple myeloma, and NHL. These data lend support to the reduction of activity of proangiogenic factors as a therapeutic modality. Vascular endothelial growth factor (VEGF) has been implicated as the major proangiogenic factor that regulates multiple endothelial cell functions, including mitogenesis. A direct relationship between VEGF and leukemic blasts and malignant plasma cells has been established, but VEGF may have a function distinct from its role in angiogenesis. Current protocols with anti- VEGF agents in patients with hematologic malignancies involve the use of monoclonal antibody, blockers of the VEGF-receptor tyrosine kinase pathway, thalidomide (Thalomid) and its analogs, and cyclooxygenase inhibitors. The receptor tyrosine kinase inhibitors also affect platelet-derived growthfactor, c-kit, and Flt-3 to varying degrees, considerably broadening their potential efficacy. This review will summarize several angiogenesis inhibitors in clinical development.

Angiogenesis Inhibitors↗

PubMed2002

Phase I and pharmacokinetic study of DX-8951f (exatecan mesylate), a hexacyclic camptothecin, on a daily-times-five schedule in patients with advanced leukemia.

PURPOSE: DX-8951f is a novel hexacyclic camptothecin-analogue topoisomerase I inhibitor with both in vitro antileukemic activity and myelosuppression as a dose-limiting toxicity in solid tumor Phase I studies. DX-8951f is active in a human acute myeloid leukemia (AML) severe combined immunodeficient mouse model. In a leukemia Phase I study, we investigated the toxicity profile and pharmacokinetics of DX-8951f in patients with primary refractory or relapsed AML or acute lymphocytic leukemia, myelodysplastic syndromes, or chronic myelogenous leukemia in blastic phase (CML-BP). EXPERIMENTAL DESIGN: DX-8951f was given as an i.v. infusion over 30 min daily for 5 or 7 days. The starting dose was 0.6 mg/m(2)/day for 5 days (3.0 mg/m(2)/course). Courses were given every 3-4 weeks according to toxicity and antileukemic efficacy. RESULTS: Twenty-five patients (AML, 21 patients; myelodysplastic syndrome, 1 patient; acute lymphocytic leukemia, 2 patients; CML-BP, 1 patient) were treated. Stomatitis was the dose-limiting toxicity, occurring in two of two patients treated at 1.35 mg/m(2)/day for 5 days, two of three treated at 1.2 mg/m(2)/day for 5 days, and one of six treated at 0.9 mg/m(2)/day for 7 days. The recommended Phase II dose was 0.9 mg/m(2)/day for 5 days. The pharmacokinetics of DX-8951 was linear and well fit by a two-compartment model. CONCLUSIONS: Phase II studies are warranted to further define the activity of DX-8951f in patients with hematological malignancies.

Acute Disease↗

PubMed2002

Treatment of philadelphia chromosome-positive, accelerated-phase chronic myelogenous leukemia with imatinib mesylate.

PURPOSE: Imatinib mesylate, a specific Bcr-Abl tyrosine kinase inhibitor, has shown encouraging activity in chronic myelogenous leukemia (CML). EXPERIMENTAL DESIGN: We treated 237 patients (median age, 50 years; age range, 18-82 years) with Philadelphia chromosome (Ph)-positive accelerated-phase CML with oral imatinib mesylate at daily doses of 400 mg (26 patients) or 600 mg (211 patients) and evaluated response and survival characteristics in univariate and multivariate analyses. RESULTS: Among the 200 patients with accelerated-phase CML for whom follow-up was 3 months or more, rates of complete and partial hematological response were 80% and 10%. Cytogenetic responses were evident in 90 patients [45%; complete response in 47 patients (24%) and partial response (Ph 1-34%) in 21 patients (11%)]. The estimated 18-month survival rate was 73%. The estimated complete hematological response rate at 18 months was 68%; that for cytogenetic response was 82%. In multivariate analyses, a diagnosis-to-treatment interval of 3 years or more, splenomegaly, and peripheral blasts predicted poor major cytogenetic response; age >60 years, marrow basophilia, and clonal evolution predicted poor survival. The 600-mg drug dose was associated with better cytogenetic response and survival in univariate analysis (P < 0.01) but not in multivariate analysis. Landmark analysis showed that achieving a cytogenetic response at 3 months or a major cytogenetic response (Ph < 35%) at 6 months was associated with better long-term survival. Seven of 15 patients who were in a second chronic phase achieved major cytogenetic response. The incidence of severe nonhematological toxic effects was 23%; drug discontinuation for severe toxicity was needed in 3% of patients. CONCLUSIONS: Imatinib mesylate was active against Ph-positive, accelerated-phase CML, and the prognostic factors identified in this study could aid in tailoring treatment strategies to specific risk groups.

Adolescent↗

PubMed2002

Imatinib mesylate for Philadelphia chromosome-positive, chronic-phase myeloid leukemia after failure of interferon-alpha: follow-up results.

We treated 261 patients with Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) in chronic phase after failure of IFN-alpha with the Bcr-Abl tyrosine kinase inhibitor imatinib mesylate (400 mg/day given p.o.) and analyzed hematological and cytogenetic responses, long-term prognosis, factors associated with achievement of major cytogenetic response and survival, and comparative survival in similar patients treated with other regimens. Median patient age was 55 years; 34% were 60 years or older, and median chronic-phase duration was 33 months. Overall, 94% achieved a complete hematological response, and 71% had a cytogenetic response [major (Ph+ cells <35%) in 62% and complete in 45%]. At a median follow-up of 17 months, 241 patients (92%) were still taking imatinib mesylate; estimated 18-month freedom from progression and survival rates were 93 and 96%. Multivariate analysis of factors associated with major cytogenetic response identified long chronic phase, marrow basophilia, high percentage of Ph+ cells before therapy, and prior hematological resistance to IFN-alpha as being adverse factors. This model was used to generate good-, intermediate- and poor-risk subgroups who had estimated major cytogenetic response rates of 93, 53, and 34%, respectively. Univariate analysis in terms of survival identified leukocytosis, high percentages of peripheral and marrow blasts, marrow basophilia, and the presence of cytogenetic clonal evolution as being adverse factors. Achieving a cytogenetic response at 3 or 6 months of therapy was associated with prolonged survival. In a subset analysis, survival rates among 161 patients with Ph-positive CML after hematological or cytogenetic failure after IFN-alpha who had been treated with imatinib mesylate were better than those for similar patients treated previously with other regimens. In summary, imatinib mesylate is highly effective in chronic-phase CML after IFN-alpha failure. We identified pretreatment and treatment-associated factors that were associated with higher major cytogenetic response rates and with improved survival.

Benzamides↗

PubMed1997

Biology and treatment of chronic myelogenous leukemia.

Chronic myelogenous leukemia (CML) involves the clonal expansion of hemopoietic progenitor cells associated with a characteristic translocation between chromosomes 9 and 22, resulting in the generation of an aberrant bcr-abl protein with enhanced tyrosine kinase activity. Although the precise molecular events leading to malignant expansion of the myeloid cell line are as yet undetermined, bcr-abl can induce cell proliferation, transformation of immature hemopoietic cells, and suppression of apoptosis in vitro. Abnormalities of stromal/progenitor cell interaction may be central to the pathogenesis of the abnormal hemopoiesis in CML. In chronic-phase CML, therapy with interferon-alfa (Intron A, Roferon-A) produces hematologic responses in up to 70% to 80% of patients and partial or complete cytogenetic responses in up to 50%, with many studies showing a significant overall survival advantage for responding patients. Allogeneic marrow transplantation can result in long-term survival and cure in patients with CML, particularly younger patients transplanted early in the course of the disease, and unrelated-donor or autologous marrow transplantation may be an option for patients without a matched sibling donor. Future therapy will likely involve selection and ex vivo expansion of nonleukemic stem cells for reinfusion as part of a strategy for autologous marrow transplantation.

Antineoplastic Agents↗

PubMedDate not supplied

Pattern of gene expression and immune responses to Semenogelin 1 in chronic hematologic malignancies.

Normal testicular-specific proteins are frequently aberrantly expressed by tumor cells. Based on this, we have investigated Semenogelin 1, a major protein of human semen coagulum thought to be highly specific to seminal vesicles, in leukemic cells. Using reverse transcription-polymerase chain reaction, Semenogelin 1 gene was frequently expressed in chronic myeloid leukemia (5 of 8, 62.5%) and chronic lymphocytic leukemia (5 of 12, 41.7%) but rarely in multiple myeloma (2 of 30, 6.7%). The gene was not expressed in bone marrow or peripheral blood from healthy donors. Semenogelin 1 expression is normally confined to the testis, suggesting that it is a novel Cancer-Testis (CT) antigen. Translation of the mRNA to Semenogelin 1 protein was confirmed by Western blot analysis of tumor cell lysates and by immunocytochemistry. The recombinant Semenogelin 1 protein was used with a control Escherichia coli-derived recombinant protein in ELISA and Western blot analysis to show that high titer IgG antibodies against Semenogelin 1 were detected in some patients, suggesting the in vivo immunogenicity of the protein. Immune responses predicted gene expression by the leukemia cells. Semenogelin 1 was also frequently coexpressed with other CT antigens, Sperm protein 17 and SPAN-Xb. These results therefore indicate that Semenogelin 1 is a novel CT antigen capable of inducing B-cell responses in vivo in chronic leukemias.

Biomarkers, Tumor↗

PubMedDate not supplied

Richter's syndrome: biology and therapy.

Richter's syndrome, that is, transformation of chronic lymphocytic leukemia to a large cell or immunoblastic lymphoma, occurs in up to 10% of patients with chronic lymphocytic leukemia. The onset of Richter's syndrome is characterized by worsening systemic symptoms, rapid tumor growth, and/or extranodal involvement. Median survival with conventional chemotherapy is less than 6 months. Therapy with more recent therapeutic regimens, such as hyperCVXD (fractionated cyclophosphamide, vincristine, liposomal daunorubicin, and dexamethasone), augmented hyperCVXD, and yttrium-90 ibritumomab tiuxetan, has not produced major improvements in response rates or overall survival. Improvement in the outcome of patients with Richter's syndrome may be aided by a more comprehensive understanding of the pathogenesis of Richter's syndrome; therapy could then be targeted against specific abnormalities. Current data indicate that the transformation of chronic lymphocytic leukemia to a large-cell or immunoblastic lymphoma is associated with abnormalities in cell cycle regulation (e.g., loss of the cell cycle inhibitors p16(INK4a) and p27(KIP1) ) and DNA repair (e.g., mutations and/or deletions of the p53, ATM, and p14(ARF) genes and epigenetic silencing of the MLH1 gene). However, the critical event leading to transformation is unclear. Given the poor prognosis of patients with Richter's syndrome, every effort should be made to enroll these patients into clinical trials evaluating novel agents with the appropriate correlative studies.

Antineoplastic Combined Chemotherapy Protocols↗