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Biomedical subjects

M Keating

Publications and source records attributed to M Keating.

At least 37 records · Page 2Linked to original sources
PubMed2001

The use of a bioactive skin substitute decreases length of stay for pediatric burn patients.

BACKGROUND: To optimize burn care for children, the authors introduced a protocol incorporating the use of a bioactive skin substitute, TransCyte (Advanced Tissue Sciences, La Jolla, CA). This study was designed to determine whether this management plan was safe, efficacious, and decreased hospital inpatient length of stay (LOS) compared with conventional burn management in children. METHODS: All pediatric burns greater than 7% total body surface area (TBSA) that occurred after October 1999 underwent wound closure with TransCyte (n = 20). These cases were compared with the previous 20 consecutive burn cases greater than 7% TBSA that received standard therapy. Standard therapy consisted of application of antimicrobial ointments and hydrodebridement. The following information was obtained: burn mechanism, age, size of burn, requirement of autograft, and LOS. Data were analyzed using the student's t test. RESULTS: Data for age, percent TBSA burn and LOS are reported as means +/- SEM. The children who received standard therapy were 2.99 +/- 0.7 years compared with those receiving TransCyte were 3.1 +/- 0.8 years. There was no difference between the treatment groups with regard to percent TBSA burn: standard therapy, 14.3 +/- 1.4% TBSA versus TransCyte, 12.7 +/- 1.3% TBSA. There was no difference in the type of burns in each group, the majority were liquid scald type, 70% in the standard therapy group versus 90% in the TransCyte group. Only 1 child in the TransCyte group required autografting (5%) compared with 7 children in the standard therapy group (35%). Children treated with TransCyte had a statistically 6 significant decreaed LOS compared with those receiving standard therapy, 5.9 +/- 0.9 days versus 13.8 +/- 2.2 days, respectively (P =.002). CONCLUSIONS: This is the first study using TransCyte in children. The authors found that this protocol of burn care was safe, effective, and significantly reduced the LOS. This new approach to pediatric burn care is effective and improves the quality of care for children with burns.

Burn Units↗
PubMed2001

Cytogenetic findings in mantle cell lymphoma cases with a high level of peripheral blood involvement have a distinct pattern of abnormalities.

We compared conventional cytogenetic findings in mantle cell lymphomas (MCLs) having an absolute peripheral lymphocytosis of more than 10,000/microL (>10 x 10(9)/L) at diagnosis ("leukemic"; n = 30) with those in cases having no or minimal lymphocytosis ("nodal"; n = 19). Only cases positive for t(11;14) were included for study. Forty-six cases (94%) had abnormalities in addition to t(11;14). The most frequent abnormalities involved chromosome 13 (26 cases [53%]), followed by chromosomes 1, 3, 7, 8, 9, 10, 12, 15, 17, and 21 (11-18 cases [22%-37%]). There was no difference in the number of aberrations between the 2 groups. Abnormalities of chromosomes 17, 21, and 22 were more frequent, and breakpoints involving 8q24, 9p22-24, and 16q24 were found exclusively in leukemic MCL. Chromosome 17 aberrations involved were structural (breakpoints involving 17p13, 17p11.2, 17q) in leukemic MCL but were only numeric in nodal MCL. Thus, leukemic MCL differs from nodal MCL in their cytogenetic profiles, which may contribute to the clinical presentation.

Adult↗
PubMed2001

Results of therapy with interferon alpha and cyclic combination chemotherapy in patients with philadelphia chromosome positive chronic myelogenous leukemia in early chronic phase.

The objective of the study was to investigate the toxicity and efficacy of cyclic combination therapy offered to patients with Ph-positive CML having a sub-optimal response to IFN-alpha. Patients in early chronic phase CML were treated with IFN-alpha at 5MU/m(2) daily. Patients who did not achieve cytogenetic response after 6 months of IFN-alpha therapy, or Ph-suppression to less than 35% Ph-positive cells (partial cytogenetic response) after 12 months of therapy were offered cyclic intensive chemotherapy every 6 months, with IFN-alpha maintenance between cycles. The initial 3 cycles included daunorubicin, vincristine, cytosine arabinoside (ara-C) and prednisone (DOAP). Later cycles were given with cyclophosphamide replacing daunorubicin (COAP). Of 74 patients treated, 61 (82%) achieved complete hematologic response (CHR): 51 (69%) had a cytogenetic response, which was major (Ph < 35%) in 31 (42%), and complete in 23 (31%). Fifty-five patients (74%) achieved CHR by 6 months of therapy, 38 (69%; 51% of total) with a cytogenetic response - 13 (24%) had a major cytogenetic response. Seventeen patients received at least 1 course of DOAP therapy. Median survival of the overall cohort of patients was 120 months. With a median follow-up of 145 months (103+ to 155+ months), 40 patients (54%) have died. The median duration of cytogenetic response was 35 months (range 3 to 149+ months) and the estimated 10-year cytogenetic response rate was 37%. A durable complete cytogenetic response was observed in 16 patients (20%) with a median duration of 139+ months (range 12+ to 149+ months), 11 of them (15%) are now off IFN-alpha therapy for a median of 57+ months (range 12+ to 128+ months). The projected 10-year survival was 50% for the study group versus 35% for 208 patients who received other IFN-alpha based regimens at the MD Anderson Cancer Center (p<.01). In conclusion, the addition of intensive chemotherapy may improve survival in patients with CML who have not obtained an adequate cytogenetic response on an IFN-alpha-based regimen.

Actuarial Analysis↗
PubMed2001

High expression of the receptor tyrosine kinase Tie-1 in acute myeloid leukemia and myelodysplastic syndrome.

The tyrosine kinase receptor Tie-1 has been shown to play a role in angiogenesis and hematopoiesis. We evaluated the level of expression and clinical significance of Tie-1 protein in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We used western blot analysis to confirm and radioimmunoassay to quantify Tie-1 protein expression in bone marrow samples obtained from untreated patients having AML (66 patients) or MDS (29 patients). Samples obtained from these patients contained significantly higher levels of Tie-1 protein than did control samples (P < 0.001). Also, Tie-1 levels were significantly higher in AML patients than MDS patients (P < 0.0001). Tie-1 levels did not correlate with complete remission or survival duration in patients having either disease. These data suggest that Tie-1 expression is increased in AML and MDS but that the level of expression does not influence the response to current therapy. The role of Tie-1 overexpression in the reported increased vascularity in the bone marrow of AML and MDS patients requires further investigation.

Acute Disease↗
PubMed2000

Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes.

Angiogenesis has been associated with the growth, dissemination, and metastasis of solid tumors. The aims of this study were to evaluate the vascularity and the levels of angiogenic factors in patients with acute and chronic leukemias and myelodysplastic syndromes (MDS). The numbers of blood vessels were measured in 145 bone marrow biopsies and the levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), tumor necrosis growth factor-alpha (TNF-alpha), tumor growth factor-alpha (TGF-alpha), and hepatocyte growth factor (HGF) were determined in 417 plasma samples. Except for chronic lymphocytic leukemia (CLL), vascularity was significantly higher in all leukemias and MDS compared with control bone marrows. The highest number of blood vessels and largest vascular area were found in chronic myeloid leukemia (CML). VEGF, bFGF, and HGF plasma levels were significantly increased in acute myeloid leukemia (AML), CML, CLL, chronic myelomonocytic leukemia (CMML), and MDS. HGF, TNF-alpha, and bFGF but not VEGF were significantly increased in acute lymphoblastic leukemia (ALL). TNF-alpha levels were significantly increased in all diseases except for AML and MDS. No significant increase was found in TGF-alpha in any leukemia or MDS. The highest plasma levels of VEGF were in CML, and the highest plasma levels of bFGF were in CLL. The levels of HGF were highest in CMML. These data suggest that vascularity and angiogenic factors are increased in leukemias and MDS and may play a role in the leukemogenic process.

Acute Disease↗
PubMed2000

Clinical relevance of intracellular vascular endothelial growth factor levels in B-cell chronic lymphocytic leukemia.

Strong evidence exists for an association between high vascular endothelial growth factor (VEGF) levels and poor prognoses in patients with solid tumors and acute leukemia. Using Western blot analysis and solid-phase radioimmunoassay, we measured cellular VEGF levels in B-cell chronic lymphocytic leukemia (CLL) samples from 225 patients and correlated these levels with disease characteristics and prognoses. The median VEGF level in CLL samples was 7.26 times the median level detected in normal peripheral blood mononuclear cells. Patients with lower levels of VEGF protein showed a trend toward shorter survival (P =.07). However, in a subgroup of CLL patients with good prognoses or early-stage disease (Rai stages 0-II, Binet stages A,B; beta2-M </= 2.8 mg/dL), lower levels of VEGF were associated with shorter survival times. For the entire group of patients, no correlation was found between VEGF levels and beta2-M levels or Rai and Binet stage. Most samples from patients with CLL expressed the 43-kd VEGF isoform in addition to the commonly expressed 45-kd isoform. It remains to be seen whether the expression of the 43-kd isoform is responsible for this reversed correlation with outcome. (Blood. 2000;96:768-770)

Adult↗
PubMed2000

Deletions in the 13q14 locus in adult lymphoblastic leukemia: rate of incidence and relevance.

BACKGROUND: A putative tumor suppressor gene involved in chronic lymphocytic leukemia (CLL) has been localized to the 13q14 locus. Microsatellite analysis was used to test whether this locus also is involved in acute lymphoblastic leukemia (ALL) and its prognostic relevance determined. METHODS: The authors analyzed 49 patients with adult ALL for deletions at the 13q14 locus using a battery of 6 microsatellite markers corresponding to this region (D13S260, STR257, D13S263, D13S153, D13S319, and AFMa301wb5). RESULTS: Five of the 49 adult ALL patients analyzed (10%) showed loss of heterozygosity (LOH) or deletions at 13q14. Similar to CLL, the significant minimal deletions appeared to be localized between D13S260 and AFMa301wb5 and did not involve the retinoblastoma or BRCA2 genes. Among newly diagnosed patients, LOH was associated with shorter survival (P = 0.007). CONCLUSIONS: These data suggest that the 13q14 gene, commonly deleted in CLL patients, also is deleted in some patients with adult ALL. Although the number of the cases in the current study is small, 13q deletions in ALL patients may play a role in the clinical behavior of this disease.

Adult↗
PubMed2000

ATM gene deletion in patients with adult acute lymphoblastic leukemia.

BACKGROUND: Loss of heterozygosity (LOH) at the ATM gene (mutated in ataxia telangiectasia [AT] patients) and ATM protein deficiency occur in 14% and 34%, respectively, of patients with chronic lymphocytic leukemia (CLL). ATM protein deficiency also is associated with aggressive disease and worse patient survival. Considering the aberrations in the ATM gene in CLL and the high rate of incidence of lymphoid neoplasias in AT patients, the authors investigated its incidence rate and significance in patients with adult acute lymphoblastic leukemia (ALL). METHODS: Samples from 36 adults with ALL were analyzed for LOH and homozygous deletion (HD) using a panel of three microsatellite markers located at the ATM gene (D11S2179), the MLL gene (D11S1356), and the BCL1 gene (D11S987) loci. These markers are located within the 11q13-q23 locus. RESULTS: Of the 36 informative cases, 10 (28%) showed deletions (7 LOH and 3 HDs) at the D11S2179 marker. In two patients, the deletions were extended to the MLL gene locus. These deletions were submicroscopic because only 3% (1 of 36) of patients showed abnormalities involving 11q23 using cytogenetic studies. The authors also estimated the levels of ATM protein in 15 ALL patients and 12 healthy volunteers by radioimmunoassay. The ATM protein levels in cases with LOH at the ATM gene were between 15-50% of those from normal bone marrow. In contrast to CLL patients, patients with LOH or HD at the ATM gene locus showed better survival compared with patients without ATM gene deletions (P = 0.003). CONCLUSIONS: LOH of the ATM gene and protein deficiency are common in adult ALL, are not demonstrated at the cytogenetic level, and are associated with a favorable prognosis. The authors speculate that ATM deficiency may increase the sensitivity of leukemic blasts to the chemotherapy used during induction and after disease remission in patients with adult ALL. The relatively high frequency of deletion of the D11S2179 marker compared with the D11S1356 marker suggests that ATM is the target gene of the deletion at the 11q23 locus, and that such deletions may play a role in the pathogenesis of ALL.

Adult↗
PubMed2000

Variations in the low levels of cyclin D1/BCL1 have prognostic value in chronic lymphocytic leukemia.

Cyclin D1 (CyD1)/BCL1 (PRAD1) is expressed at high levels in almost all cases of mantle cell leukemia/lymphoma (MCL) and in rare cases of chronic lymphocytic leukemia (CLL). The CyD1/BCL1 protein plays an important role in the progression of cells through the G1 phase of cell cycle. Most of the CyD1/BCL1 protein expression studies are performed using immunohistochemistry. We used a sensitive solid-phase radioimmunoassay (RIA) to quantify CyD1 protein expression in 199 patients with CLL. Of these 137 patients were previously untreated with the rest having had standard chemotherapeutic regimens including alkylating agents and fludarabine before being referred to our center. Median white cell count in these patients was 49x10(3) /microl (range 3.0-438.5x10(3)/microl), hemoglobin level 13.1 g/dl (range 5.2-17.3 g/dl), platelet count 157x10(3) /microl (range 10-377x10(3) /microl), age 58 (range 26-89), and beta2-microglobulin 2.75 mg/dl (range 1.1-14.3). The median radioactivity (CPM) of mononuclear cells obtained from 56 normal individuals was assigned a value of 1. There was no significant variation in CyD1 levels among normal individuals (SD=0. 12). While most CyD1 levels in MCL varied from 6.5 to 15.6, the median CyD1/BCL1 in CLL was 1.4 with 75th percentile under 2.12. Rare CLL cases (3.5%) showed levels between 4 and 8.83. When divided into two groups at the median level, patients with higher CyD1/BCL1 expression had shorter survival (P = 0.03). This remained true when applied only to the previously untreated patients (P=0.05). Despite the relatively low expression, the CyD1/BCL1 levels in univariate analysis were as good or better predictors of survival than Binet (P = 0.03) or Rai (P = 0.05) staging. Furthermore, CyD1/BCL1 levels correlated with serum beta2-microglobulin (P = 0.001), white blood cell count (P = 0.004) and hemoglobin levels at the time of collection (P = 0.0003) but not with lymphocyte count, platelet count or age. The data demonstrate that CyD1/BCL1 is likely to play a significant role in the biology of CLL and can be used as a prognostic indicator. Further studies to clarify the role of CyD1 in the biology of CLL and its value as a prognostic indicator at the time of diagnosis are encouraged.

Adult↗
PubMed2000

11q23 abnormalities in patients with acute myelogenous leukemia and myelodysplastic syndrome as detected by molecular and cytogenetic analyses.

11q23 chromosomal abnormalities and rearrangement of the mixed lineage leukemia (MLL) gene are important prognostic factors in acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). However, the presence of 11q23 abnormalities does not always correlate with that of MLL gene rearrangement. We retrospectively compared the occurrence of 11q23 abnormalities (measured by karyotyping) and MLL gene rearrangement (measured by Southern blotting) in bone marrow from 311 consecutive adult patients with AML or MDS. 11q23 abnormalities were found in 18 patients (5.8%), of whom 7 (39%) did not have the MLL gene rearrangement. MLL gene rearrangement was detected in 35 patients (11.2%). Of these 35 patients, only 11 (31%) had cytogenetic evidence of 11q23 abnormalities. None of the 21 patients with chronic myelomonocytic leukemia had 11q23 abnormalities or MLL gene rearrangement. 11q23 abnormalities were associated with shorter survival than was a diploid karyotype. Both cytogenetic and molecular studies should be performed to detect 11q23 abnormalities in patients with AML or MDS.

Adolescent↗
PubMed2000

Cyclophosphamide, ara-C and topotecan (CAT) for patients with refractory or relapsed acute leukemia.

Topotecan is a topoisomerase I inhibitor with significant activity in patients with myelodysplastic syndrome and chronic myelomonocytic leukemia. Pre-clinical data suggest a synergistic activity with DNA damaging agents such as cyclophosphamide, where topotecan might prevent the repair of cyclophosphamide-induced DNA damage. We thus designed a combination including cyclophosphamide 500 mg/m2 every 12 hours given on days 1 to 3; topotecan 1.25 mg/m2/day by continuous infusion on days 2 to 6, and cytosine arabinoside (ara-C) 2 g/m2 over 4 hours daily for 5 days on days 2 to 6 (CAT). Sixty six (63 evaluable) patients were treated. Fifty two patients had refractory (n=12) or relapsed (n=40) acute myelogenous leukemia (AML), and eleven had acute lymphocytic leukemia (ALL) (refractory n=3, relapsed n=8); their median age was 57 years (range, 18 to 79 years). Eleven patients (17%) achieved a complete remission (CR), and two patients (3%) had a hematologic improvement (HI; met all criteria for CR except for platelets < 100x10(9)/L), for an overall response rate of 20%. Responses occurred in 12 of 52 AML patients (23%), including 10 CR (19%) and 2 HI (4%), and in 1 of 11 patients with ALL (9%). Myelosuppression was universal; there were 23 episodes of pneumonia or sepsis and 18 episodes of fever of unknown origin complicating 74 courses of CAT. Non-hematologic toxicity was mostly gastrointestinal, including nausea, vomiting, diarrhea and mucositis, but was severe in only 8%. In summary, the CAT regimen is well tolerated and has significant anti-leukemia activity which warrants further investigation.

Acute Disease↗
PubMed2000

Terminal deoxynucleotidyl transferase-negative acute lymphoblastic leukemia.

OBJECTIVE: Terminal deoxynucleotidyl transferase (TdT) is a useful marker in the diagnosis of acute lymphoblastic leukemia (ALL) (French-American-British [FAB] L1 and L2) and is most useful in distinguishing ALL from mature B-lymphoid neoplasms, such as Burkitt lymphoma (FAB L3) and other lymphoid malignancies. The frequency of TdT-negative ALL is not known. Here we report 3 TdT-negative ALL cases that met the criteria for T-cell ALL. DESIGN: We reviewed approximately 200 cases of ALL retrieved from the database at our institution. All cases were evaluated using Wright-Giemsa, myeloperoxidase, butyrate, and TdT staining; immunophenotyped using flow cytometry; and studied using Southern blot analyses for T-cell receptors and immunoglobulin gene rearrangement. RESULTS: All ALL cases (L1 and L2) were TdT-positive, except for 3 cases that were of early T-cell lineage. None of the 3 cases demonstrated positivity for TdT in immunofluorescence staining with polyclonal antibodies or flow cytometry with monoclonal antibodies. Flow cytometric analysis confirmed a pre-T-cell immunophenotype in all 3 cases. One of the cases showed rearrangement of a T-cell antigen receptor and immunoglobulin heavy chain (J(H)). A second case showed germline configuration of T-cell receptors, but also showed rearrangement of the J(H), despite the expression of T-cell markers only.

Adult↗
PubMed2000

Novel therapies for chronic lymphocytic leukemia in the 21st century.

Chronic lymphocytic leukemia (CLL) is one of the most common types of leukemia diagnosed in the Western Hemisphere. Introduction of the purine analogs has improved outcome for patients with CLL as measured by improvements in disease-free survival and has made it possible to attain a complete remission in a minority of patients with this disease. The therapeutic success with the purine analogs in CLL has led to preclinical and early clinical investigation of a variety of other therapeutic agents. This, combined with advances in the understanding the genetic and immunobiology of CLL, leaves hope that CLL may become a curable disease in this century.

Antibodies, Monoclonal↗
PubMed2000

High-dose rituximab therapy in chronic lymphocytic leukemia.

Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA and IDEC Pharmaceutical Corporation, San Diego, CA) is a chimeric monoclonal antibody that targets mature B cells in most lymphoid B-cell malignancies. Rituximab is approved by the US Food and Drug Administration for therapy for recurrent B-cell lymphoma. In initial clinical trials the activity in small lymphocytic lymphoma, the counterpart of chronic lymphocytic leukemia (CLL), was less than 20%. In an attempt to increase the level of rituximab activity in CLL, we conducted a phase I dose-escalation study to overcome both the lower CD20 antigen density on CLL cells compared with lymphoma cells and the shorter half-life of rituximab in small lymphocytic lymphoma. Cohorts of patients were treated with escalated doses on weeks 2, 3, and 4 after an initial rituximab dose of 375 mg/m2 on day 1. The maximum dose of rituximab evaluated was 2,250 mg/m2. There is clear evidence of a dose-response relationship. Severe toxicity (grades 3 and 4) noted following the first dose of therapy in variant forms of CLL, namely mantle cell lymphoma and prolymphocytic leukemia, was uncommon in typical CLL. No unusual toxicity was noted at higher doses. Further exploration of the dosing schedule of rituximab in CLL and development of combination therapies is necessary. This agent shows promise for interaction in combined chemoimmunotherapy strategies for front-line and relapsed patients with CLL.

Aged↗
PubMed2000

Use of ICPs to manage unpredictable situations.

An ICP sets out best practice guidance. One health-care team applied ICPs to stroke care, which can be unpredictable. Stroke care was arranged in 'bite-sized chunks' with ICPs for each separate aspect.

Benchmarking↗
PubMed1999

A phase I-II trial of escalating doses of mitoxantrone with fixed doses of cytarabine plus fludarabine as salvage therapy for patients with acute leukemia and the blastic phase of chronic myelogenous leukemia.

BACKGROUND: Cytarabine is an essential drug for inducing remission of acute myelogenous leukemia, and it is also one the most effective drugs used as salvage therapy for patients with all types of relapsed acute leukemia. Nevertheless, there is considerable room for improvement in the treatment of patients with relapsed leukemia in terms of both the reinduction rate and the duration of response. Fludarabine has been shown to augment responses to cytarabine, possibly by increasing the intracellular concentrations of the active metabolite cytarabine triphosphate. Higher-than-standard doses of mitoxantrone have been shown to augment responses to cytarabine, possibly by increasing the DNA strand breaks induced by topoisomerase II; these strand breaks cannot be effectively repaired in the presence of cytarabine triphosphate. This preliminary study was designed to determine whether moderately high doses of mitoxantrone could be added to the combination of fludarabine and cytarabine in an attempt to improve the combination's antileukemic efficacy. METHODS: Fifty-five adults with relapsed or refractory acute leukemia or the blastic phase of chronic myelogenous leukemia (CML) received salvage therapy with the FLAM regimen, which consisted of fludarabine, cytarabine, and increasing doses of mitoxantrone. RESULTS: Even with doses of mitoxantrone escalated to as much as 60 mg/m(2) over 4 days, dose-limiting toxicity was not observed. Overall, the complete response rate was 27.3% (15 of 55 patients, including 4 of 17 with acute myelogenous leukemia [AML], 4 of 12 with acute lymphocytic leukemia [ALL], and 7 of 26 with the blastic phase of CML). The median time to complete response was 42 days. Toxicity other than myelosuppression was manifested primarily as hyperbilirubinemia, which was reversible in all cases. Poor performance status and undifferentiated blastic phase of CML were poor prognostic factors for response to FLAM. CONCLUSIONS: The FLAM regimen is an active salvage regimen and should be formally evaluated in Phase II studies of patients with AML, ALL, and the myeloid and lymphoid blastic phases of CML.

Adolescent↗