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Biomedical subjects

Michael Keating

Publications and source records attributed to Michael Keating.

53 records · Page 3Linked to original sources
PubMed2003

Use of plasma DNA in detection of loss of heterozygosity in patients with multiple myeloma.

BACKGROUND: Deletions or structural abnormalities in chromosomes 11 and 13 have been shown to be important in predicting clinical behavior in patients with multiple myeloma (MM). However, cytogenetic analysis in MM is frequently difficult because of poor yield of informative metaphases and the disease is frequently patchy, which complicates fluorescent in situ hybridization studies. OBJECTIVES: The purpose of this study was to explore the potential of using peripheral plasma DNA for the detection of loss of heterozygosity (LOH) in chromosomes 11 and 13 in patients with MM. METHODS: Peripheral blood (PB) plasma of 81 patients with MM, was used as a source of DNA for the detection of LOH at chromosomes 13q14 (D13S319 and D13AFMaw301wb5), and 11q21 (D11S2179) using polymerase chain reaction. RESULTS: Only 62 of the studied patients were informative for the two 13q microsatellite markers and 16 (26%) of these patients showed LOH. Only seven (11%) of 61 patients with informative D11S2179 microsatellite maker showed LOH. Purified plasma cells (PCs) from six bone marrow (BM) samples using anti-CD138-coated magnetic beads showed identical results to those detected in DNA isolated from PB plasma. Three patients with LOH underwent autologous BM transplantation, and two of three reverted to a normal state (no LOH) after transplantation. Seven of the patients with 13q LOH in PB plasma had <10% PCs (PCs) in their BM at the time of testing. CONCLUSION: PB plasma appears to be enriched by tumor-specific DNA and can be used to detect chromosomal abnormalities in patients with MM. Further studies are needed to establish the clinical relevance of this approach in comparison with other techniques.

Adult↗
PubMed2003

Plasma interleukin 8 level predicts for survival in chronic lymphocytic leukaemia.

The malignant B cells of patients with chronic lymphocytic leukaemia (CLL) constitutively express interleukin 8 (IL-8) and IL-8 receptors. Ex vivo culture with exogenous IL-8 enhances IL-8 expression and prolongs leukaemia cell survival, partly through increased bcl-2 expression. IL-8 may function as an autocrine growth and apoptosis resistance factor in CLL. Therefore, we evaluated the prognostic relevance of plasma IL-8 levels in 151 CLL patients [median age 61 years (range, 32-84 years), median plasma IL-8 level 18.9 pg/ml (9.1-89.1 pg/ml)]. All Rai stages were represented; advanced stage was associated with significantly higher plasma IL-8 levels (P < 0.0001, Kruskal-Wallis). Also, plasma IL-8 level was correlated with serum beta2-microglobulin (beta2-M) (R = 0.24, P = 0.0081), haemoglobin (R = -0.39, P < 0.0001) and platelet count (R = -0.23, P = 0.0049) by Spearman's rank correlation. Univariate analysis using Cox proportional hazards models identified elevated IL-8 and beta2-M as significant prognostic factors with relative risks of 7.43 (P = 9.1 x 10(-9)) and 16.40 (P = 5.9 x 10(-10)) respectively. High levels of IL-8 were associated with shorter survival independent of beta2-M level. Using recursive-partitioning procedures, an IL-8 cut-off point of 26.2 pg/ml segregated a group of CLL patients with significantly shorter survival (median 9.3 months) (P < 0.0001). In conclusion, plasma IL-8 level in CLL patients correlates with other prognostic factors, such as Rai stage and beta2-M, and is associated with increased risk of death in CLL patients. The role of IL-8 inhibitors in the treatment of patients with CLL should be explored.

Adult↗
PubMed2003

Single agent thalidomide in patients with relapsed or refractory acute myeloid leukaemia.

Thalidomide is a putative anti-angiogenesis agent that has significant anti-tumour activity in haematological malignancies with increased bone marrow angiogenesis, including multiple myeloma (MM) and myelodysplastic syndromes (MDS). Increased levels of the mitogen for angiogenesis, vascular endothelial growth factor (VEGF), correlate with worse survival in acute myeloid leukaemia (AML). A phase II trial of thalidomide was conducted in patients with relapsed- or refractory-AML previously treated with cytarabine-containing regimens. A total of 16 patients with refractory- or relapsed-AML were treated with thalidomide 200-800 mg orally daily (median dose 400 mg daily) for a median of 27 d (range, 3-94 d). Overall, one patient (6%) achieved complete remission (CR) lasting for 36 months, and two patients had a transient reduction in marrow blasts from 8% and 7% to less than 5% in both cases. There was no correlation between reduction in levels of angiogenesis markers and response. Toxicities related to thalidomide were significant, and precluded dose escalation beyond 400 mg orally daily in most patients. Although there appears to be some evidence of biological activity, single agent thalidomide is not an optimal choice of therapy for salvaging patients with relapsed- or refractory-AML. Thalidomide analogues with more potent immunomodulatory activities and more favourable toxicity profiles may offer more promise as anti-AML therapy.

Acute Disease↗
PubMed2003

CD79b expression in chronic lymphocytic leukemia. Association with trisomy 12 and atypical immunophenotype.

CONTEXT: CD79b is a relatively newly characterized B-cell marker that is expressed in a minority of chronic lymphocytic leukemia (CLL) cases. OBJECTIVE: To systematically correlate CD79b expression with specific morphologic and immunophenotypic findings and trisomy 12. DESIGN: We assessed CD79b expression in 100 consecutively accrued CLL cases that were also analyzed by conventional cytogenetics. Based on the association between trisomy 12 and CD79b expression, we then assessed 43 additional CLL cases with trisomy 12. CD79b expression was correlated with morphology and expression of other immunophenotypic markers. RESULTS: Eighteen (18%) of 100 consecutively accrued cases were CD79b positive. No significant association was found between CD79b expression and atypical morphology. CD79b expression correlated with CD22 and FMC7 positivity. Eight (8%) cases had trisomy 12; 4 (50%) of these were CD79b positive, suggesting an association with trisomy 12. Examination of a second group of 51 CLL cases with trisomy 12 (including 8 cases from the initial study group) showed that CD79b was positive in 26 cases (49%), a frequency significantly higher than that of the consecutively accrued CLL cases without trisomy 12 (P <.05). CONCLUSIONS: We conclude that CD79b immunoreactivity is positive in approximately 20% of CLL cases and that expression correlates with trisomy 12 and atypical immunophenotypic findings.

Adult↗
PubMed2002

Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia.

Micro-RNAs (miR genes) are a large family of highly conserved noncoding genes thought to be involved in temporal and tissue-specific gene regulation. MiRs are transcribed as short hairpin precursors ( approximately 70 nt) and are processed into active 21- to 22-nt RNAs by Dicer, a ribonuclease that recognizes target mRNAs via base-pairing interactions. Here we show that miR15 and miR16 are located at chromosome 13q14, a region deleted in more than half of B cell chronic lymphocytic leukemias (B-CLL). Detailed deletion and expression analysis shows that miR15 and miR16 are located within a 30-kb region of loss in CLL, and that both genes are deleted or down-regulated in the majority ( approximately 68%) of CLL cases.

Adult↗
PubMed2002

Recombinant human soluble tumor necrosis factor (TNF) receptor (p75) fusion protein Enbrel in patients with refractory hematologic malignancies.

PURPOSE: Tumor necrosis factor-alpha (TNF-alpha) is an important effector and regulatory cytokine involved in the pathophysiology of hematologic malignancies, including hairy cell leukemia (HCL), chronic lymphocytic leukemia (CLL), agnogenic myeloid metaplasia (AMM) and Philadelphia-negative myeloproliferative disorders (MPD). We conducted a pilot study to assess the safety of the soluble TNF receptor, etanercept (p75 TNFR:Fc; Enbrel) in patients with refractory hematologic malignancies. METHODS: Patients were eligible if they had refractory HCL, CLL, AMM, or Philadelphia-negative MPD. Enbrel was administered twice weekly at a dose of 25 mg subcutaneously for a minimum of eight doses, and was continued in patients without overt progression. RESULTS: Among the 26 patients enrolled on study, 25 patients were evaluable. Nine patients had AMM, eight CLL, three HCL, and five Philadelphia-negative MPD. Their median age was 60 years (range 30-83 years). A total of 70 courses consisting of 486 doses of Enbrel were administered. Enbrel was well tolerated, without any overt increase in infectious episodes. Stable disease/no objective response was seen in 22 patients (88%) and progression in 3 patients (12%). Three patients with AMM improved (two showed hematologic improvement, and one showed a reduction in liver and spleen size), and two patients (one with CLL and one with Philadelphia-negative MPD) showed improvement in disease-related symptoms. CONCLUSIONS: Enbrel was well tolerated, but no responses were noted in these immunosuppressed patients with refractory hematologic malignancies.

Adult↗
PubMed2002

Simultaneous homoharringtonine and interferon-alpha in the treatment of patients with chronic-phase chronic myelogenous leukemia.

BACKGROUND: Homoharringtonine (HHT) has antileukemic activity in patients with Philadelphia chromosome (Ph) positive chronic myelogenous leukemia (CML). Combinations of HHT, interferon-alpha (IFN-alpha), and cytarabine (ara-C) have been studied in various CML phases. The objectives of this study were to evaluate the efficacy and toxicity profiles of a combination regimen of simultaneous HHT and IFN-alpha therapy in patients with chronic-phase CML who were not exposed previously to either agent. METHODS: Forty-seven patients were treated: 37 patients with early chronic-phase CML (2 patients with clonal evolution) and 10 patients with late chronic-phase CML. Their median age was 62 years (range, 23-73 years). HHT was given at a dose of 2.5 mg/m(2) by continuous intravenous infusion over 24 hours daily for 5 days every month, and IFN-alpha was given daily at a target dose of 5 x 10(6) units/m(2) subcutaneously. Response, survival, and treatment toxicity were analyzed. RESULTS: Overall, the complete hematologic response (CHR) rate was 85%; the cytogenetic response rate was 66%, with major cytogenetic responses (Ph positive in < 35% of metaphases) in 49% of patients and complete cytogenetic responses in 21% of patients. The CHR rate, cytogenetic response rate, and major cytogenetic response rate were 84%, 69%, and 52%, respectively, in patients with early chronic-phase CML. Among the 10 patients with late chronic-phase CML, the CHR rate, cytogenetic response rate, and major cytogenetic response rate were 80%, 50%, and 40%, respectively. Response rates in patients age > 60 years were 84%, 62%, and 49% for CHR, cytogenetic response, and major cytogenetic response. Myelosuppression was frequent but manageable: Anemia with hemoglobin < 8.0 g/dL occurred in 36% of patients, requiring dose adjustments and erythropoietin therapy. Nonhematologic toxicities were mainly fatigue, aches, and gastrointestinal disturbances. Dose reductions with multiple courses were significant and were due to myelosuppression: After 6-24 courses, the median daily IFN-alpha dose was 1 MU/m(2), and the median number of days on HHT per month was 2 days. With a median follow-up of 26 months, the estimated 2-year survival rate was 90% (95% confidence interval, 79-100%). CONCLUSIONS: The simultaneous combination of HHT and IFN-alpha is safe and effective, but the dose schedules that actually were delivered were significantly lower than the planned dose schedules. With the availability of signal-transduction inhibitor 571 (imatinib mesylate), studies of combination of HHT and IFN-alpha chemotherapy in patients with CML who have disease that fails to respond to imatinib mesylate and of combinations with imatinib mesylate need to be explored.

Adult↗
PubMed2002

The clinical and diagnostic relevance of CD23 expression in the chronic lymphoproliferative disease.

BACKGROUND: CD23 antigen is a cell surface protein considered important in the differentiation of chronic lymphocytic leukemia (CLL) from other lymphoid leukemias. METHODS: To better clarify CD23 role as a diagnostic tool, the authors retrospectively evaluated clinical and laboratory features of 372 patients who were referred to M.D. Anderson Cancer Center with a diagnosis of CLL or B-cell chronic lymphoproliferative disease. RESULTS: Most of the patients (91%) were CD19+/CD5+. Only 6% of these CD19+/CD5+ patients were CD23-. Overall, CD23- patients had the worse prognostic features compared with CD23+ cases, including anemia (P = 0.03), massive splenomegaly (P = 0.000), high lactate dehydrogenase (P = 0.007), high beta2-microglobulin (P = 0.006), older age (P = 0.001), and male gender (P = 0.02). Surface immunoglobulin expression was moderate/strong in 19 (82%) patients, and FMC-7 was positive in 22 (96%) patients. None of the 13 patients tested for CD10 expressed the antigen. Based on morphology, of the CD23, 16 (70%) were diagnosed with mantle cell leukemia (MCL) was diagnosed in 16 (70%) CD23- patients, 3 (13%) with splenic marginal-zone leukemia, 3 (13%) with prolymphocytic leukemia (PLL) or PLL/CLL, and 1 (4%) with CLL. No cyclin D1 protein expression was noted by Western blot analysis in the one case that showed typical CLL morphology, and this patient did not require therapy. On the whole, the survival rate of CD23- patients was significantly worse than that of patients with CD23+. In contrast, 15 of 32 (49%) CD19+/CD5- patients were CD23-. CD23 negativity in this group was not associated with distinct clinical features or outcome. Eleven (73%) of these patients were classified as having splenic marginal-zone lymphoma and 4 as having follicular lymphoma. CONCLUSIONS: These data indicate that CD23 negativity is rare in typical B-cell CLL, and CD23 negativity in patients with CD19+/CD5+ is suggestive of mantle cell leukemia a more aggressive disease with poor response to conventional therapy in which newer chemotherapy regimens such as hyper-CVAD may be more effective.

Adult↗
PubMed2002

Chronic lymphocytic leukemia presenting in association with aplastic anemia.

An unusual case of chronic lymphocytic leukemia presenting in association with aplastic anemia is discussed, along with a review of the few previously reported cases. Possible humoral and cellular autoimmune mechanisms are examined as possible causes of marrow aplasia in this setting.

Adrenal Cortex Hormones↗
PubMed2002

Proliferation and apoptosis in acute and chronic leukemias and myelodysplastic syndrome.

Clonal expansion of leukemic cells is thought to be due to proliferation in excess of apoptosis. To define and compare proliferation and apoptosis between various leukemias and myelodysplastic syndrome (MDS), we measured proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine (BrdU) incorporation as surrogate markers for proliferation and caspase 3 activity and annexin V surface binding as surrogate markers for activation of the apoptotic cascade in patients with MDS, chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML). We found high proliferation in bone marrow cells from MDS and CMML as measured by PCNA and BrdU incorporation. The lowest level of proliferation was found in CLL. Apoptosis was also highest in MDS and CMML as measured by annexin V and caspase 3 activity. Unexpectedly, we found no significant difference in proliferation in bone marrow CD34+ cells from various leukemias or MDS. Apoptosis was significantly higher in bone marrow CD34+ cells from MDS and CML in chronic phase as compared to CD34+ cells from AML patients. Our results illustrate differences in proliferation and apoptosis between acute and chronic leukemias and MDS. These differences may have diagnostic and therapeutic implications.

Acute Disease↗
PubMed2002

Clinical relevance of vascular endothelial growth factor receptors 1 and 2 in acute myeloid leukaemia and myelodysplastic syndrome.

We have previously reported that high levels of cellular vascular endothelial growth factor (VEGF) protein correlated with short survival of patients with acute myeloid leukaemia (AML). As VEGF exerts its effects via two receptors, VEGF receptor 1 (VEGFR-1) and VEGFR-2, we evaluated the significance of VEGFR-1 and VEGFR-2 protein levels in AML and myelodysplastic syndrome (MDS), and their relationship to VEGF protein levels. Western blot analysis and radioimmunoassay confirmed and quantified specific protein levels in bone marrow samples from 41 MDS and 66 AML previously untreated patients. VEGFR-1 levels were significantly higher in AML than in MDS (P = 0.0004), but no significant difference was found in the VEGFR-2 levels (P = 0.5). No significant correlation between VEGFRs levels and duration of survival was found. VEGF protein levels were significantly higher in MDS than in AML (P < 0.0001). A Cox proportional-hazard regression model showed increasing VEGF levels to significantly correlate with shorter survival of patients with MDS (P = 0.008), a finding similar to our previous report of the inverse relationship between VEGF levels and survival of AML patients. We found a significant correlation between VEGF and VEGFR-2 levels in both AML and MDS (P < 0.0000001 andP < 0.0002 respectively) but not between VEGF and VEGFR-1 levels. These data suggest that VEGF expression, rather than the expression of its receptors, is the determining factor in the biological behaviour of AML and MDS, and that VEGFRs are differentially expressed in AML and MDS.

Acute Disease↗
PubMed2002

Successful treatment of refractory disseminated Mycobacterium avium complex infection with the addition of linezolid and mefloquine.

Execpt in patients with AIDS, disseminated MAC infection has been rare. We describe a patient with chronic lymphatic leukemia who developed disseminated cutaneous MAC lesions refractory to conventional antimycrobial therapy. The lesions responded to the addition of compounds that were recently discovered to have anti-MAC activity (linezolid, moxifloxacin) as well as GM-CSF.

Acetamides↗
PubMed2002

Differences in CD33 intensity between various myeloid neoplasms.

We measured the concentration of CD33 antigen on the surface of cells in 315 bone marrow (BM) samples and 114 corresponding peripheral blood (PB) samples from patients with various leukemias (acute myeloid leukemia [AML], chronic myelogenous leukemia [CML], myeloproliferative disorder [MPD] other than CML, myelodysplastic syndrome [MDS]) and from control subjects. Overall CD33 intensity in total CD33+ cells was significantly higher in BM than in PB. CD33 intensity in total BM CD33+ cells differed significantly with the type of disease. The median number of CD33 molecules per cell was highest in AML, followed by MDS, CML, and control subjects and lowest in MPD. When only CD34+/CD33+ cells were examined, CD33 molecules per cell were highest in CD34+ cells in AML and lowest in MPD (P = .027). Patients with AML or MDS younger than 60 years had significantly higher intensity of CD33 expression on CD34+ cells than patients 60 years or older. Levels of CD33 intensity did not correlate with cytogenetics in patients with AML or MDS. There was no correlation between CD33 intensity and response to therapy or overall survival in 35 patients treated with protocols including Mylotarg. These data demonstrate variation in CD33 intensity between various leukemias.

Aminoglycosides↗
PubMed2002

Clinical effects of alemtuzumab (Campath-1H) in B-cell chronic lymphocytic leukemia.

Alemtuzumab (Campath-1H) is a monoclonal antibody (MAb) that shows its most powerful effects in clearing malignant CD52-bearing cells from the blood and bone marrow. Attention had therefore focused on the use of alemtuzumab in the treatment of B-cell chronic lymphocytic leukemia (B-CLL), in which symptoms are the result of an expansion of a CD1a+/CD5+/CD23+/CD52+ malignant clone, causing lymphocytosis in the circulation and pervasive infiltration of the bone marrow. In clinical trials, in heavily pretreated patients, alemtuzumab was effective, producing responses in about one-third of patients who had failed to respond previously to chemotherapy, including fludarabine. In addition, there was an even higher clinical effect in the bone marrow. Alemtuzumab treatment has also allowed patients with advanced disease to proceed to stem cell transplantation, and preliminary data indicate that alemtuzumab is highly effective in previously untreated patients with B-CLL.

Adult↗
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↗