PubMed Health⌕ Search

Biomedical subjects

E Estey

Publications and source records attributed to E Estey.

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

Cytomegalovirus pneumonia in adults with leukemia: an emerging problem.

Cytomegalovirus (CMV) pneumonia is reportedly unusual among adults with leukemia who have not undergone transplantation. To assess the frequency of CMV pneumonia and its outcome during the present time, we reviewed the experience of 2136 hospitalized adults with leukemia. Sixty-one patients (2.9%) had CMV pneumonia diagnosed. The frequency doubled from 1.4% in 1992--1994 to 2.8% in 1995--1997 (P<.05). Fifty-four patients (89%) had received treatment with an immunosuppressive chemotherapeutic regimen that contained fludarabine (n=37), high-dose cytoxan (n=17), or both (n=10), and 15 patients (25%) had received granulocyte transfusions that were stimulated with hematopoietic growth factors from unscreened donors. The overall CMV pneumonia--associated mortality rate was 57%. Among autopsied patients who had leukemia, the frequency of CMV pneumonia increased from 0%, 2.3%, and 0% in 1992, 1993, and 1994, respectively, to 4.6%, 6.5%, and 16% in 1995, 1996, and 1997, respectively (P<.05). CMV has emerged as an important cause of life-threatening pneumonia in adults with leukemia who have received potent immunosuppressive therapies and stimulated granulocyte transfusions from unscreened donors.

Adult↗
PubMed2001

Treatment of newly diagnosed and relapsed acute promyelocytic leukemia with intravenous liposomal all-trans retinoic acid.

A novel intravenous liposomal formulation of all-trans retinoic acid (ATRA) was evaluated in 69 patients with acute promyelocytic leukemia (APL): 32 new diagnoses, 35 relapses, and 2 oral ATRA failures. Liposomal ATRA (90 mg/m(2)) was administered every other day until complete remission (CR) or a maximum of 56 days. Treatment following CR was liposomal ATRA with or without chemotherapy. In an intent-to-treat (ITT) analysis of all patients, CR rates were 62%, 70%, and 20% in newly diagnosed, group 1 first relapses (ATRA naive or off oral ATRA more than or equal to 1 year), or group 2 relapses (second or subsequent relapse or first relapses off oral ATRA less than 1 year), respectively. In 56 evaluable patients (receiving 4 or more doses), CR rates for the same groups were 87% (20 of 23), 78% (14 of 18), and 23% (3 of 13). Remission failure in newly diagnosed patients was not from resistant disease. Several patients in CR became polymerase chain reaction (PCR) negative for promyelocytic leukemia/retinoic acid receptor-alpha (PML/RARalpha) after liposomal ATRA alone. Toxicity was generally mild, most commonly headaches (67. 5%). Eighteen patients (26%) had ATRA syndrome develop during induction. One-year survival of ITT patients was 62%, 56%, and 20% for newly diagnosed, group 1, and group 2, respectively. The medium duration of CR has not yet been reached and was 18 and 5.5 months in the same groups. These results demonstrate that liposomal ATRA is effective in inducing CR in newly diagnosed or group 1 APL patients. It provides a reliable dosage of ATRA for patients with APL unable to swallow or absorb medications and can induce molecular remissions without chemotherapy.

Adolescent↗
PubMed2001

Reducing mortality associated with immediate treatment complications of adult leukemias.

Analysis of data from 806 patients with newly diagnosed adult acute myelocytic leukemia (AML) (not including acute promyelocytic leukemia [APL] patients) treated at M.D. Anderson Cancer Center from 1995 through 1999 indicated that among patients entering a particular week of induction therapy, mortality rates were 6%, 8%, 6%, 9%, and 6% during weeks 1 to 2, 3 to 4, 5 to 6, 7 to 8, and 9 to 10, respectively. Because the mortality rate was not higher in the period immediately after treatment began, a definition of the period covered by the term "immediate" is somewhat arbitrary rather than "biologic," as might be the case if the early weeks were distinguished by a particularly high mortality rate. M.D. Anderson researchers have focused on the treatment complications and deaths occurring in the first 4 weeks after the beginning of induction therapy. In the first week, infection contributed to 71% of the deaths and pulmonary hemorrhage associated with diffuse alveolar damage contributed to 44%; the incidence of infection rose while the incidence of hemorrhage decreased during weeks 2 to 4. The associations between 4-week mortality rates with age, performance status, and white blood cell (WBC) count are well known. Study data suggest that elevated pretreatment levels of uric acid and tumor necrosis factor-alpha (TNF-alpha) levels are similarly associated with 4-week mortality. The prognostic significance of hyperuricemia appears independent of WBC, creatinine, and TNF-alpha. M.D. Anderson investigators have studied the roles of pheresis, TNF-alpha receptor-blocking agents, continuous venovenous dialysis, and newer antifungal agents in reducing early mortality. In particular, data from a retrospective M.D. Anderson analysis of pheresis (146 patients with WBC > 50,000 +/- microL) suggest that the value of this procedure is questionable. Preliminary data also point to the potential value of the TNF-alpha alpha receptor blocker etanercept (Enbrel, Immunex Corp, Seattle, WA) in patients at high risk of early death. Data from a randomized M.D. Anderson trial suggest that oral fluconazole plus itraconazole capsules are equivalent to liposomal amphotericin in antifungal prophylaxis. Because neither alternative appears satisfactory, researchers at M.D. Anderson are examining the role of intravenous itraconazole, which produces higher concentrations than itraconazole capsules in prophylaxis, and the role of FK 463 in treatment of fungal infections.

Adult↗
PubMed2001

Phase I study of irofulven (MGI 114), an acylfulvene illudin analog, in patients with acute leukemia.

Irofulven (MGI 114, 6-hydroxymethylacylfulvene, HMAF) is a semisynthetic illudin analog with broad in vitro anti-neoplastic activity. In this leukemia phase I study, we investigated the toxicity profile and activity of Irofulven in patients with primary refractory or relapsed acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), or myelodysplastic syndromes (MDS). Irofulven was given as an intravenous infusion over five minutes daily for five days. The starting dose was 10 mg/m2/day (50 mg/m2/course). Courses were scheduled to be given every 3-4 weeks according to toxicity and antileukemic efficacy. Twenty patients [AML: 17 patients; MDS: one patient; ALL: one patient; mixed lineage acute leukemia: one patient] were treated. Nausea, vomiting, hepatic dysfunction, weakness, renal dysfunction, and pulmonary edema were dose limiting toxicities, occurring in two of five patients treated at 20 mg/m2/day and two of three patients treated at 12.5 mg/m2/day. The MTD was defined as 10 mg/m2/day for five days. One patient with primary resistant AML achieved complete remission. Proposed phase II studies will further define the activity of Irofulven in patients with better prognosis AML and in other hematological malignancies, both as a single agent and in combination regimens, particularly with topoisomerase 1 inhibitors.

Adolescent↗
PubMed2001

Comparison of outcome in acute myelogenous leukemia patients with translocation (8;21) found by standard cytogenetic analysis and patients with AML1/ETO fusion transcript found only by PCR testing.

Patients with normal-karyotype acute myelogenous leukemia (NKAML) may have undetected genetic abnormalities that could affect prognosis. Screening for known AML-specific genetic abnormalities using the reverse transcription polymerase chain reaction (RT-PCR) may help in arriving at a more definitive prognosis. To test this hypothesis, 104 patients without translocation (8;21) and inversion(16), as shown by standard cytogenetic (SC) analysis, were screened for these two genetic abnormalities using RT-PCR. Western blot analysis for the AML1/ETO fusion protein and fluorescent in situ hybridization (FISH) analysis for t(8;21) were performed in patients for whom we had samples. The characteristics and outcome after high-dose cytarabine containing treatments in five patients with t(8;21) shown by RT-PCR alone were then compared to 21 patients with t(8;21) detected using SC analysis. Eight of the 104 patients had masked t(8;21) and none had masked inv(16), as shown by RT-PCR. Five of 54 patients with NKAML had a detectable AML1/ETO fusion RNA transcript. Western blot analysis showed the AML1/ETO fusion protein in four of the seven patients for whom we had samples among the eight with masked t(8;21) shown by RT-PCR. All patients with t(8;21) shown by RT-PCR had negative FISH results. Ninety percent (n=19) of the patients with t(8;21) shown by SC analysis and 40% (n= 2) of the patients with t(8;21) shown by RT-PCR alone achieved a complete remission (P value 0.03). These data suggest that the outcome of NKAML patients with t(8;21) shown by RT-PCR is not equivalent to patients with t(8;21) by SC studies.

Adult↗
PubMed2001

Plasma hepatocyte growth factor is a prognostic factor in patients with acute myeloid leukemia but not in patients with myelodysplastic syndrome.

Hepatocyte growth factor (HGF) is a potent angiogenic factor. The aim of our study was to evaluate plasma HGF levels and their prognostic significance in patients with newly diagnosed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The sandwich enzyme immunoassay technique was used to quantify HGF in stored samples obtained before treatment from patients with AML (59 patients) and MDS (42 patients) treated at The University of Texas MD Anderson Cancer Center. HGF levels were significantly higher in patients with AML or MDS than in healthy individuals (P < 0.0001). Higher HGF levels in both AML and MDS correlated significantly with white blood cell (P = 0.000001 for both groups) and monocyte counts (P = 0.0004 and 0.003, respectively), and with poor performance status (P = 0.03 and 0.001, respectively). Using Cox proportional hazard model and HGF levels as a continuous variable, plasma levels of HGF correlated with shorter survival of AML (P = 0.001), but not MDS (P = 0.34) patients. No significant correlation was observed between HGF levels and complete remission rate or duration. In the multivariate analysis HGF retained its significance as prognostic factor in AML (P = 0.02), along with age (P = 0.0005).

Acute Disease↗
PubMed2001

Significance of angiogenin plasma concentrations in patients with acute myeloid leukaemia and advanced myelodysplastic syndrome.

Human angiogenin is a potent inducer of angiogenesis. The association between angiogenin and cancer progression and poor outcome in solid tumours has been documented, but its significance in leukaemias has not been evaluated. We evaluated plasma angiogenin levels in 101 previously untreated patients with acute myeloid leukaemia (AML) (59 patients) and advanced myelodysplastic syndrome (MDS) (42 patients). Angiogenin levels were significantly higher in AML and advanced MDS patients than in healthy individuals (P < 0.00001). Angiogenin levels were also significantly higher in advanced MDS than in AML (P = 0.001). Higher levels of angiogenin correlated with prolonged survival periods in both AML and advanced MDS patients (P = 0.02 and 0.01 respectively). We found no correlation between angiogenin plasma level and various patient characteristics, including age, performance status, antecedent haematological disorder, haemoglobin, white blood cell and platelet counts, and poor prognosis cytogenetics. There was no significant correlation between angiogenin level and complete remission rate and duration in AML or advanced MDS patients. In multivariate analysis, angiogenin concentration retained its significance as a prognostic factor in AML (P = 0.03), together with age (P = 0.00007) and haemoglobin (P = 0.03).

Acute Disease↗
PubMed2001

Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia.

The mitogen-activated protein kinase (MAPK) pathway regulates growth and survival of many cell types, and its constitutive activation has been implicated in the pathogenesis of a variety of malignancies. In this study we demonstrate that small-molecule MEK inhibitors (PD98059 and PD184352) profoundly impair cell growth and survival of acute myeloid leukemia (AML) cell lines and primary samples with constitutive MAPK activation. These agents abrogate the clonogenicity of leukemic cells but have minimal effects on normal hematopoietic progenitors. MEK blockade also results in sensitization to spontaneous and drug-induced apoptosis. At a molecular level, these effects correlate with modulation of the expression of cyclin-dependent kinase inhibitors (p27(Kip1) and p21(Waf1/CIP1)) and antiapoptotic proteins of the inhibitor of apoptosis proteins (IAP) and Bcl-2 families. Interruption of constitutive MEK/MAPK signaling therefore represents a promising therapeutic strategy in AML.

Apoptosis↗
PubMed2001

Treatment of newly-diagnosed acute promyelocytic leukemia with liposomal all-trans retinoic acid.

It has been postulated that recurrence of disease in some patients with newly-diagnosed APL induced into CR, and subsequently maintained, with single agent oral ATRA results from the decline in ATRA levels that occurs with repeated dosing. Administration of liposomal ATRA (lipoATRA) circumvents, for perhaps several months, the decrease in ATRA levels and produces CRs in patients with relapsed APL. These findings led us to administer lipoATRA "monotherapy" to patients with newly-diagnosed APL. Patients received lipoATRA (90 mg/m2) for induction and continued to receive the drug, by itself, for 9 months unless 2 PCR tests done within 2-4 weeks of each other at a sensitivity level of 10(-4) were positive at 3 or 6 months from CR date, in which case idarubicin was added to lipoATRA. If the PCR test was negative 9 months from CR date, treatment stopped. 34 patients were enrolled, of whom 79% entered CR. The PCR test at time of CR was positive in 23/24 patients, but was negative in 24/26 (92%) 3 months later. Of most interest 11 of the 26 evaluable responding patients have remained PCR negative (tested Q 3 months) with a median follow-up of 18 months (range up to 34 months). It is generally believed that this type of result would be unlikely with oral ATRA monotherapy. Recurrence of morphologic APL has occurred in 4 patients, at 5, 6, 12, and 12 months, with a median follow-up time of 18 months in the patients remaining alive in CR. Comparison of this lipoATRA +/- idarubicin trial with oral ATRA + idarubicin induction and idarubicin + POMP maintenance, our previous trial, indicates similar survival, CR, and DFS in CR rates, with a suggestion that lipoATRA may produce lower CR rates and hence shorter survival in patients with high-risk disease (wbc count > 10,000/microliter. Nonetheless, the rates and duration of PCR negativity produced by lipoATRA monotherapy suggest that lipoATRA is a superior anti-APL agent than oral ATRA.

Administration, Oral↗
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↗
PubMed2001

Comparison of amphotericin B lipid complex (ABLC) vs. ambisome in the treatment of suspected or documented fungal infections in patients with leukemia.

Fungal infections remain a major cause of treatment failure and death in acute leukemia. New liposomal preparations of amphotericin B are now available. While less toxic, their comparative efficacy and toxicity profiles are unknown. In this study the comparative efficacy and safety of ABLC vs. AmBisome was evaluated in seventy-five patients with leukemia who developed 82 episodes of suspected or documented mycosis, and were treated (1:1) with either ABLC (n=43) or AmBisome (n=39). Both drugs were dosed accordingly from 3 to 5 mg/kg/day. Using an intent-to-treat analysis, the overall response to therapy was 27/43 (63%) for ABLC and 15/39 (39%) for AmBisome (p=0.03). Median dose and duration of treatment was 10 days at 3 mg/kg for ABLC and 15 days at 4 mg/kg for AmBisome. Acute, not dose-limiting infusion side effects were seen in 70% vs. 36% (p=0.002), ABLC vs. AmBisome. Increase of bilirubin > 1.5 times from baseline was 38% vs. 59%, ABLC vs. AmBisome (p=0.05). ABLC and AmBisome were equally effective for the treatment of suspected or documented fungal infections. While, acute infusion-toxicity was greater with ABLC, infusion toxicity requiring discontinuation was similar for both drugs. AmBisome was better tolerated than ABLC but was associated with mild abnormalities in liver function tests at the end of therapy.

Acute Disease↗
PubMed2001

Leukapheresis reduces early mortality in patients with acute myeloid leukemia with high white cell counts but does not improve long- term survival.

PURPOSE: Current published data on therapeutic leukapheresis in hyperleucocytic AML does not define the impact on survival from this procedure. Between 1992 and 1999 we saw 146 patients with newly-diagnosed AML (APL excluded) and an initial WBC count > 50 x 10(9)/L of whom 71 underwent leukapheresis at the discretion of their treating doctors. We compared outcome (early mortality, CR, and overall survival) rates in the patients who were and were not pheresed. After accounting for covariates relevant to these outcomes, including age, performance status, and cytogenetics, there was evidence (p = .006) that pheresis reduced 2-week mortality rate and a suggestion (p = .06) that this resulted in a higher CR rate. However there was no evidence that pheresis lengthened longer-term or overall survival; if anything the suggestion was the converse (p = .06). These data may reflect the fact that the patients chosen to have pheresis were prognostically unfavorable as defined by variables that were not captured in our data set, since the alternative explanation i.e. that pheresis per se shortens overall survival seems less likely. Whether the above justifies the use of pheresis in the absence of evidence from a randomized trial is doubtful, but it seems likely that any long-term benefit to be derived from this procedure must await further advances in anti-leukemia therapy.

Acute Disease↗
PubMed2000

The prognostic significance of p16(INK4a)/p14(ARF) locus deletion and MDM-2 protein expression in adult acute myelogenous leukemia.

BACKGROUND: The p16(INK4a) locus encodes two distinct proteins, p16(INK4a) and p14(ARF). Although p16(INK4a) and p15(INK4b) are involved in the phosphorylation of the retinoblastoma (Rb) protein, p14(ARF) interacts with the MDM-2 oncoprotein antagonizing its function as a suppressor of p53. The role of deletions of p16(INK4a)/p14(ARF) and p15(INK4b) and expressions of MDM-2 in myeloid leukemias and its influence on prognosis remain unclear. METHODS: The authors analyzed deletions of p16(INK4)/p14(ARF) and p15(INK4b) in 74 adults with acute myeloid leukemia (AML) by Southern blotting. Western blotting was used to determine Rb protein phosphorylation in patients with deletions of p16(INK4)/p14(ARF) and p15(INK4b). Then, they analyzed the levels of MDM-2 protein expression and correlated it with prognosis in an expanded population of 79 adults with AML by immunoblot analysis and solid-phase radioimmunoassay. RESULTS: Deletions of p16(INK4a)/p14(ARF) and/or p15(INK4b) occurred in 4 of 74 patients (5%) (hemizygous in 3, homozygous in 1 patient). Although the complete remission (CR) rate was similar (79% vs. 50%; P = 0.187), CR duration (10 vs. 46 weeks; P < 0.001), event free survival rate (EFS; 6 vs. 85 weeks; P < 0.004) and overall survival rate (11 vs. 86 weeks; P = 0.001) were significantly shorter in patients with deletions of p16(INK4a)/p14(ARF) and/or p15(INK4b). Thirty-seven (47%) of 79 patients studied for MDM-2 showed increased MDM-2 expression. These patients had a significantly shorter EFS rate (50 vs. 64 weeks; P = 0.023) and a trend for shorter CR duration (24 vs. 53 weeks; P = 0.07). Overall survival rate was not significantly different (50 vs. 84 weeks; P = 0.136). CONCLUSIONS: The authors concluded that 1) deletions of p16(INK4a)/p14(ARF) and/or p15(INK4b) occur with low incidence in patients with AML; 2) patients with deletions of p16(INK4a)/p14(ARF) and/or p15(INK4b) have a significantly shorter CR duration, EFS rate, and overall survival rate than do patients without deletions; (3) overexpression of MDM-2 is common in AML and is associated with shorter CR duration and EFS rate. Mechanisms other than p14(ARF) deletion are responsible for MDM-2 overexpression, and this overexpression may play a role in the biology of the disease.

Adult↗
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

Increased CD38 expression is associated with favorable prognosis in adult acute leukemia.

CD38 is expressed in acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML) blasts and its prognostic significance is unknown. We investigated CD38 expression in 304 AML and 138 ALL patients. CD38 was lower in AML-M3 compared to other FAB subtypes (5% vs. 41%; P < 0.001), but was similar among ALL subtypes (56.6%; P = 0.69). Ph + ALL and AML with t(15; 17) patients showed lower CD38 expression than the other cytogenetic groups. Overall survival favored AML and ALL patients with higher CD38 levels. Multivariate analysis revealed CD38 expression to be an independent outcome predictor in AML, but not in ALL.

ADP-ribosyl Cyclase↗