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Biomedical subjects

R Costello

Publications and source records attributed to R Costello.

At least 37 records · Page 2Linked to original sources
PubMed1999

The immunophenotype of minimally differentiated acute myeloid leukemia (AML-M0): reduced immunogenicity and high frequency of CD34+/CD38- leukemic progenitors.

Minimally differentiated acute myeloid leukemia (AML-M0) is a rare FAB subtype (2-3% of AMLs) of poor prognosis. The aim of our study was to characterize AML-M0 expression and regulation of adhesion/costimulatory molecule involved in immune recognition, to test blast in vitro immunogenicity, and to determine the percentage of leukemia progenitor cells. Here, we demonstrate that alloimmune recognition of AML-M0 in primary mixed lymphocyte reaction, as evaluated by IL-2 secretion of responding T cells, is reduced in comparison with more differentiated subtypes (128 +/- 95 pg/ml vs304 +/- 159 pg/ml, P < 0.05). These data are in line with low blast cell expression of major histocompatibility complex (MHC) class II DR molecules, and of the CD28 ligand B7-2, which plays an important role in AML immune recognition. Adhesion/costimulatory molecules were up-regulated by leukemic cell stimulation via CD40, and, although less efficiently, by gamma-IFN; both stimuli improved blast cell immunogenicity. We also demonstrate that AML-M0 have a very high percentage (40% +/- 30) of CD34+/CD38- leukemic clonogenic precursors in comparison with more differentiated AMLs (2.5% +/- 2) or non-leukemic CD34+hematopoietic precursors (1.8% +/- 0.8). Since the presence of a leukemic cell population at an early differentiation stage has been identified as a poor prognostic factor, we conclude that the high frequency of CD34+/CD38- blasts in AML-M0 may converge with already identified poor prognosis factors such as chemotherapy resistance and cytogenetic abnormalities. The clinical implications of AML-M0 impaired in vitroimmunogenicity and a high percentage of CD34+/CD38- blasts will require comparative analysis of additional patients. The increased immunogenicity of blast cells after CD40 triggering provide interesting clues for AML-M0 immunotherapy, that have to be confirmed with an in vivo leukemia model in mice.

ADP-ribosyl Cyclase↗
PubMed1999

Phase II trial of docetaxel, cisplatin, fluorouracil, and leucovorin as induction for squamous cell carcinoma of the head and neck.

PURPOSE: To evaluate the toxicity and efficacy of a 4-day regimen of docetaxel, cisplatin, fluorouracil, and leucovorin (TPFL4) in patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Thirty previously untreated patients with stage III or IV SCCHN and Eastern Cooperative Oncology Group functional status of 2 or less were treated with TPFL4. Postchemotherapy support included prophylactic growth factors and antibiotics. Patients who achieved a complete response (CR) or partial response (PR) to three cycles of TPFL4 received definitive twice-daily radiation therapy. The primary end points were toxicity and response to TPFL4. RESULTS: Eighty-five cycles were administered to 30 patients. The major acute toxicities to TPFL4 were mucositis and nausea. One patient died of neutropenic sepsis during therapy. Additional major toxicities were neutropenia, anorexia, nephropathy, neuropathy, and diarrhea. Fourteen percent of all cycles were associated with hospitalization for toxicity. The overall clinical response rate to TPFL4 was 93%, with 63% CRs and 30% PRs. Primary tumor site clinical and pathologic response rates were 93% and 68%, respectively. CONCLUSION: TPFL4 has an acceptable toxicity profile in good-performance-status patients. Modification of the 5-day TPFL regimen (TPFL5: shorter chemotherapy infusion time, earlier intervention with growth factors and antibiotics) led to fewer episodes of febrile neutropenia and hospitalization. Response rates to TPFL justify further evaluation of combinations of these agents in the context of formal clinical trials.

Adult↗
PubMed1998

[Hodgkin's disease in patients infected with the human immunodeficiency virus].

INTRODUCTION: Hodgkin's disease in patients infected by the human immunodeficiency virus (HIV) is still not part of the definition of acquired immune deficiency syndrome. Nonetheless, this entity has a particular presentation when compared to the disease occurring in immune-competent patients. CURRENT KNOWLEDGE AND KEY POINTS: Increased frequency (> 75%) of advanced anatomical stages and extranodular localizations (Ann Arbor system stages III and IV) has been outlined in HIV-infected patients. Mediastinal involvement is more unusual in immunocompromised than in immune-competent patients. The presence of B symptoms (fever, weight loss, nocturnal sweats) is very frequent. Finally, the predominance of mixed cellularity (type 3) characterizes Hodgkin's disease in immunocompromised patients. Due to either the immunodeficiency, antiretroviral treatments, poor hematological tolerance in response to chemotherapy, or to advanced anatomical stages, disease management may be hampered. Current therapeutical approaches often obtain complete remission; however, some deaths are still related to the disease progression to acquired immune deficiency syndrome. FUTURE PROSPECTS AND PROJECTS: From these observations, Hodgkin's disease management in HIV-infected patients relies on therapeutical approaches similar to those used for non infected patients, with some specific recommendations. Chemotherapy should be conducted in the shortest time in order to minimize chemotherapy-induced immunosuppression. Simultaneous use of antiretroviral treatment and reinforced opportunistic infection prophylaxis are of pivotal importance. Finally, the use of hematopoietic growth factors appears to be safe regarding viral replication, but still requires further evaluation.

AIDS-Related Opportunistic Infections↗
PubMed1998

Induction chemotherapy with docetaxel, cisplatin, fluorouracil, and leucovorin for squamous cell carcinoma of the head and neck: a phase I/II trial.

PURPOSE: A phase I/II trial of docetaxel, cisplatin, fluorouracil (5-FU), and leucovorin (TPFL5) induction chemotherapy for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Twenty-three previously untreated patients with stage III or IV SCCHN and Eastern Cooperative Oncology Group functional status less than or equal to 2 were treated with TPFL5. Postchemotherapy home support included intravenous fluids, prophylactic antibiotics, and granulocyte colony-stimulating factor (G-CSF). Docetaxel dose was escalated to determine the maximum-tolerated dose (MTD). Fifteen patients were treated with three cycles of TPFL5 at MTD. Patients who achieved either a partial response (PR) or complete response (CR) to three cycles of TPFL5 then received definitive twice-daily radiation therapy. Toxicity and clinical and pathologic response to TPFL5 were assessed. RESULTS: Twenty-three patients received a total of 69 cycles of TPFL5. The MTD was determined to be docetaxel 60 mg/m2. Dose-limiting toxicity (DLT) was neutropenia. Additional significant toxicities at MTD were nausea, mucositis, diarrhea, peripheral neuropathy, and sodium-wasting nephropathy. The overall response rate to TPFL5 was 100%, which included 14 of 23 (61%) clinical CRs and nine of 23 (39%) clinical PRs. Primary-site clinical and pathologic CR rates were 19 of 22 (86%) CRs and 20 of 22 (91%) CRs, respectively. Eight patients had less than a CR in the neck to chemotherapy and, therefore, had postradiation neck dissections, four of which were positive for residual tumor. CONCLUSION: TPFL5 is a tolerable induction regimen in patients with good performance status. The DLT is neutropenia with significant mucositis, diarrhea, peripheral neuropathy, and sodium-wasting nephropathy. The high response rates to TPFL5 justify further evaluation of this combination of agents in the context of formal clinical trials.

Adult↗
PubMed1997

Reversible hypercapnia in chronic obstructive pulmonary disease: a distinct pattern of respiratory failure with a favorable prognosis.

PURPOSE: Hypercapnia is regarded as a poor prognostic indicator in chronic obstructive pulmonary disease (COPD), but many patients hospitalized with hypercapnia associated with an acute exacerbation of COPD revert to normocapnia during recovery. We wished to determine if this reversible hypercapnia represents a distinct pattern of respiratory failure in COPD, or simply a stage in the progression to chronic hypercapnia. We therefore compared the long-term clinical progression and survival of COPD patients with reversible hypercapnic respiratory failure (defined as type 2.1) to those with normocapnic (PaCO2 < 50 mm Hg; type 1) and also to those patients with chronic hypercapnic (PaCO2 > 50 mm Hg) respiratory failure (defined as type 2.2). PATIENTS AND METHODS: We prospectively followed for 5 years a cohort of 85 patients who had been admitted as emergencies during a 1-year period to the respiratory unit of a University teaching hospital with an exacerbation of COPD complicated by respiratory failure (PaO2 < 60 mm Hg). The main long-term outcome measures were survival and blood gas changes. RESULTS: Sixty-eight (80%) patients survived the initial admission, and 17 (27%) survived 5 years. PaCO2 rose substantially more during exacerbations in type 2.1 patients (mean 15.8 mm Hg), compared with type 2.2 (mean 6.8 mm Hg) and type 1 patients (mean 1.5 mm Hg). We analyzed 149 subsequent admissions among the survivors over the following 5 years. Type 2.1 patients had a better 5-year survival (28%) than type 2.2 (11% survival; P < 0.05), and similar to type 1 patients (33% 5-year survival). Only 24% of reversible hypercapnic patients developed chronic hypercapnia during long-term followup. CONCLUSIONS: The data support reversible hypercapnia being a distinct manifestation of respiratory failure in COPD, with a similar prognosis to that of normocapnic respiratory failure.

Aged↗
PubMed1997

Detection of CBFbeta/MYH11 fusion transcripts in acute myeloid leukemia: heterogeneity of cytological and molecular characteristics.

Pericentric inversion of chromosome 16, translocation (16;16) and del(16q), resulting in a chimerical fusion of CBFbeta and MYH11 genes, are typically seen in the M4Eo French-American-British (FAB) classification subset of acute myelogenous leukemia (AML). In this study, we analyzed 70 cases of acute non-lymphoblastic leukemia, mainly of the M4 or M5 type. We report the very unusual presence of the t(16;16) and CBFbeta/MYH11 fusion transcript in an M7 patient. Ten M4Eo and four non-M4Eo patients presented an inv(16), t(16;16) or CBFbeta/MYH11 fusion transcript. In most cases, the common 'A-type' CBFbeta/MYH11 fusion transcript was detected. In addition to the eight different breakpoints and the three alternative splicing variants already described, evidence of a new CBFbeta/MYH11 fusion transcript was found which involves a 785-bp deletion of MYH11. Moreover, two patients had an unusual transcript, to our knowledge only observed once. Only one patient had abnormal eosinophilic differentiation without chromosome 16 cytogenetic abnormalities or detectable CBFbeta/MYH11 fusion. Conversely, only one patient presented CBFbeta/MYH11 fusion without abnormal eosinophilic differentiation. Altogether, our data suggest a correlation between the CBFbeta/MYH11 fusion transcript and characteristic abnormal eosinophilic differentiation, whatever the FAB subtype or the percentage of abnormal eosinophils

Adult↗
PubMed1997

Effect of growth hormone on human alveolar macrophage oxidative metabolism.

BACKGROUND: Growth hormone (GH) has diverse immunological actions and has been shown to augment oxidative metabolism in rat peritoneal and porcine alveolar macrophages and both human and animal neutrophils. A study was performed to determine the effects of GH on human alveolar macrophages in vitro. METHODS: Macrophages were harvested from 10 patients undergoing bronchoalveolar lavage and incubated with 0, 10 and 100 nmol/ml GH for four hours. Oxidative metabolism was assessed by means of a fluorescent assay using FMLP and E coli as stimulants. Fluorescence was measured using flow cytometry. RESULTS: No difference in basal or stimulated oxidative metabolism was found between the GH and control groups. CONCLUSIONS: GH does not have a direct stimulatory action on human alveolar macrophages in vitro. However, this does not exclude an indirect effect in vivo. The results contrast with previous studies on animal alveolar macrophages.

Analysis of Variance↗
PubMed1997

Induction chemotherapy with cisplatin, fluorouracil, and high-dose leucovorin for squamous cell carcinoma of the head and neck: long-term results.

PURPOSE: A phase II trial of cisplatin, fluorouracil, and leucovorin (PFL) induction chemotherapy in patients with locally advanced squamous cell carcinomas of the head and neck region (HNCA). PATIENTS AND METHODS: One hundred two patients (stage III/IV, previously untreated) were treated with induction PFL. Patients with resectable primary tumor site lesions and clinical complete response (CR) were offered radiotherapy (RT) without surgery to the primary tumor site. Response, toxicity, local-regional therapy, survival, and preservation of the primary tumor site were assessed. RESULTS: Among 279 courses, the overall response rate was 81%. Nineteen (19%) failed to respond, including three who died during therapy. Sixty-seven (69%) of 97 with assessable primary lesions had a clinical CR at the primary tumor site. Pathologic CR was recorded in 46 of 55 (84%) clinical CR patients who had biopsies performed on the primary tumor site. Toxicities resulted in unexpected hospitalizations in 19% of cases. After definitive local-regional therapy, 84 (82%) were disease-free including 71 (69%) with preserved primary tumor site anatomy. With a median follow-up time of 63 months, the cause-specific, overall (OS), and failure-free survival (FFS) rates at 5 years are 58%, 52%, and 51%. Local failure occurred in 29 of 102 (29%) and the local control rate at 5 years was 68%. CONCLUSION: PFL has significant activity with acceptable toxicity in patients with advanced disease who have a good performance status. Preservation of the primary tumor site could be achieved without apparent loss of local control or survival. Management of neck disease by surgery or RT must be individualized and separate from management of primary tumor. Survival compares favorably with similar trials of induction chemotherapy or chemoradiotherapy.

Adolescent↗
PubMed1997

Clinical and biological aspects of Philadelphia-negative/BCR-negative chronic myeloid leukemia.

The Philadelphia (Ph) chromosome was the first chromosomal abnormality associated with a specific leukemia, chronic myeloid leukemia (CML). This chromosome arises from the t(9;22)(q34;q11) translocation which results in the juxtaposition of the bcr gene and the abl proto-oncogene. This BCR/ABL fusion gene encodes for a hybrid protein with the capacity of oncogenic transformation of hematopoietic cells. Nonetheless, very few myeloproliferative disorders (about 10%) included under the generic term of CML have no Ph chromosome. Half of these Ph-negative CML have the BCR/ABL fusion gene (BCR-positive) and are considered equivalent to Ph-positive CML. In contrast, the patients without detectable BCR/ABL fusion (BCR-negative) fulfil the criteria for atypical CML (aCML) of the French-American-British (FAB) classification, despite considerable variability at the individual level. Due to the very small number of patients with precise cytological descriptions already published, cooperative studies focused on aCML are warranted to draw definitive conclusions and to provide some pointers on physiopathology.

Adult↗
PubMed1996

[Chronic myeloid leukemia, biological aspects].

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of a stem cell, involving myeloid, erythroid, megacaryocyte, lymphoid B-cells and "natural killer" cells. The hallmark of CML is the Philadelphia (Ph) chromosome which is a shortened chromosome 22 (22q-) resulting from a reciprocal translocation involving chromosome 9 and chromosome 22, designed t (9;22) (q34;q11). This translocation juxtaposes parts of two genes; ABL on chromosome 9 and BCR (breakpoint cluster region) on chromosome 22. Transcription of the BCR/ABL fusion gene results in an hybrid mRNA that is translated into a 210 kDa or 190 kDa protein, depending on the location of the breakpoint in the bcr region. This protein plays a key role in CML: its tyrosine-kinase activity, that differs from the normal ABL product, may be involved in leukemic cell growth. Nonetheless, the loss of the negative cell growth regulation by c-ABL, or BCR/ABL fusion protein interaction with other cellular genes (such as RAS or c-MYC) could also be involved in CML pathophysiology. A better understanding of the molecular mecanisms of CML could lead to specific treatment, such as tyrosine-kinase inhibitors, synthetic oligodeoxynucleotides, or site-specific DNA-binding proteins designed against BCR/ABL oncogenic fusion sequence.

Cloning, Molecular↗
PubMed1996

Docetaxel: an active drug for squamous cell carcinoma of the head and neck.

PURPOSE: We conducted a phase II study designed to evaluate the activity, safety, and tolerability of docetaxel (Taxotere: Rhône-Poulenc Rorer Pharmaceuticals Inc, Collegeville, PA) in patients with advanced, incurable, or recurrent squamous cell carcinoma of the head and neck (SCCHN) who had not received prior palliative chemotherapy. PATIENTS AND METHODS: Thirty-one patients with measurable, locoregional, or metastatic SCCHN were treated with docetaxel, administered at a dose of 100 mg/m2 as a 1-hour intravenous (i.v.) infusion once every 21 days on an outpatient basis. All patients were premedicated with dexamethasone, diphenhydramine, and cimetidine. Prophylactic administration of growth factors or antiemetics was not permitted. RESULTS: Thirty-one patients were treated. Twenty-nine patients were assessable for response and 30 for toxicity. Four of 31 patients (13%) achieved complete response (CR), nine (29%) achieved partial response had stable disease (SD) and seven (23%) experienced progression of disease (PD). The major response rate was 42% (95% confidence interval [CI], 24% to 60%). The median duration of responses was 5 months (range, 2 to 14). The principal toxicity was leukopenia, which occurred with rapid onset and brief duration. Sixteen patients (53%) experienced nadir fever, and 13 required dose reduction. Hypersensitivity reactions occurred in four patients. Grade 3 peripheral neuropathy occurred in two patients; grade 2 or 3 fatigue occurred in six (20%) and 10 (33%), respectively. Minimal edema (grade 1) occurred in five patients (17%). Clinically significant mucositis, diarrhea, or dermatitis were not observed. CONCLUSION: Docetaxel has major activity against SCCHN. It appears to be well tolerated in this group of patients and can be safely administered on an outpatient basis. Premedication with dexamethasone, cimetidine, and diphenhydramine is associated with a reduced incidence of significant edema, hypersensitivity reactions, and dermatologic toxicities.

Adult↗