National Cancer Institute®
Last Modified: February 1, 2002
UI - 11340522
AU - Viscoli C; Paesmans M; Sanz M; Castagnola E; Klastersky J; Martino P;
TI - Glauser M; International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer Association between antifungal prophylaxis and rate of documented bacteremia in febrile neutropenic cancer patients.
SO - Clin Infect Dis 2001 Jun 1;32(11):1532-7
AD - University of Genova and National Institute for Cancer Research, Genova, Italy. email@example.com
Published data have suggested a correlation between antifungal prophylaxis and bacteremia in febrile neutropenia. This correlation was investigated among 3002 febrile neutropenic patients enrolled in 4 trials during 1986-1994. Globally, 1322 patients (44%) did not receive antifungal prophylaxis; 835 (28%) received poorly absorbable antifungal agents and 845 (28%) received absorbable antifungal agents. The rates of bacteremia for these groups were 20%, 26%, and 27%, respectively (P=.0001). In a multivariate model without including antifungal prophylaxis, factors associated with bacteremia were: age, duration of hospitalization, duration of neutropenia before enrollment, underlying disease, presence of an intravenous catheter, shock, antibacterial prophylaxis, temperature, and granulocyte count at onset of fever. When antifungal prophylaxis was included, the adjustment quality of the model improved slightly (P=.05), with an odds ratio of 1.19 (95% confidence interval [CI], 0.92-1.55) for patients receiving nonabsorbable and 1.42 (95% CI, 1.07-1.88) for those who were receiving absorbable antifungal agents. Antifungal prophylaxis with absorbable agents might have an impact on the rate of documented bacteremia in febrile neutropenia. This effect should be confirmed prospectively.
UI - 11778550
AU - Chen Y; Miao J; Fang Z
TI - [Effects of PML and PML-RAR alpha antisense oligonucleotides on promyelocytic leukemia cell line NB4]
SO - Zhonghua Zhong Liu Za Zhi 2000 Jul;22(4):283-6
AD - Shanghai Institute of Hematology, Renji Hospital, Laboratory of Leukemia Research, Shanghai Second Medical University, Shanghai 200001, China.
OBJECTIVE: To investigate the different effects of anti-PML (promyelocytic leukemia) and anti-PML/RAR alpha (promyelocytic leukemia/retionic acid receptor alpha) antisense oligonucleotides on cell growth, expression of PML-RAR alpha mRNA and PML-RAR alpha/PML protein location of NB4 cell line. METHODS: RT-PCR was used for PML-RAR alpha mRNA expression, trypan blue exclusion for cell count, methylcellulose assay for leukemic colony forming unit, immuno-fluorescence for PML-RAR alpha/PML protein localization. RESULTS: Both anti-PML start codon region antisense (STAS) and anti-PML-RAR alpha fusion region antisense (FUAS) could inhibit cell growth and formation AML-CFU. Cells became partially differentiated on day 5, being more marked in FUAS-treated cells than in STAS-treated ones. Down regulated PML-RAR alpha mRNA expression occurred at 24 h was in STAS and FUAS-treated cells and maintained for up to 72 h. Immuno-fluorescence analysis with anti-PML monoclonal antibody showed a remarkable decrease to almost complete disappearance of microgranules. The residual granules became enlarged to become discrete dots (< 10 per cell), similar to normal POD structure in some STAS-treated cells at 24 h. AT 72 h, nearly all the granules disappeared. Similar changes were observed in FUAS-treated cells. CONCLUSION: Both PML and PML-RAR alpha antisense oligonucleotides can specifically block the expression of PML-RAR alpha at mRNA and protein levels. PML protein is implicated in the regulation of cell differentiation.
UI - 9354674
AU - Falini B; Flenghi L; Fagioli M; Lo Coco F; Cordone I; Diverio D;
TI - Pasqualucci L; Biondi A; Riganelli D; Orleth A; Liso A; Martelli MF; Pelicci PG; Pileri S Immunocytochemical diagnosis of acute promyelocytic leukemia (M3) with the monoclonal antibody PG-M3 (anti-PML).
SO - Blood 1997 Nov 15;90(10):4046-53
AD - Institutes of Hematology and Internal Medicine, University of Perugia, Perugia, Italy.
Acute promyelocytic leukemia (APL) is characterized by a reciprocal 15; 17 chromosomal translocation, which fuses the promyelocytic leukemia (PML) and retinoic acid receptor alpha (RARalpha) genes, leading to the expression of the PML/RARalpha fusion oncoprotein. Immunocytochemical labeling of the wild-type PML protein with the PG-M3 monoclonal antibody (MoAb) directed against the amino terminal portion of the human PML gene product, produces a characteristic nuclear speckled pattern that is due to localization of the protein into discrete dots (5 to 20 per nucleus), named PML nuclear bodies. The architecture of PML nuclear bodies appears to be disrupted in APL cells that bear the t(15; 17), thus resulting in a change of the nuclear staining pattern from speckled (wild-type PML protein) to microgranular (PML-RARalpha fusion protein). To assess whether the PG-M3 MoAb could assist in the diagnosis of APL (M3), bone marrow and/or peripheral blood samples from 100 cases of acute nonlymphoid leukemias of different subtypes were blindly immunostained with the PG-M3 MoAb, using the immunoalkaline phosphatase (APAAP) or immunofluorescence technique as detection system. Notably, the abnormal (micropunctate) pattern of the PML/RARalpha fusion protein (usually >/=50 small granules/per nucleus) was observed in APL (M3) samples, but not in other types of acute nonlymphoid leukemias. Immunocytochemical labeling with PG-M3 was particularly useful in the diagnosis of microgranular variant of APL (M3V) (three cases misdiagnosed as M4 and M5), and also to exclude a morphologic misdiagnosis of APL (six of 78 cases). In all cases investigated, immunocytochemical results were in agreement with those of reverse transcription-polymerase chain reaction (RT-PCR) for PML/RARalpha. Because the epitope identified by PG-M3 is located in the aminoterminal portion of PML (AA 37 to 51), the antibody was suitable for recognizing APL cases characterized by breakpoint occurring at different sites of PML (bcr 1, bcr 2 and bcr 3). In conclusion, immunocytochemical labeling with PG-M3 represents a rapid, sensitive, and highly-specific test for the diagnosis of APL that bears the t(15; 17). This should allow an easy and correct diagnosis of this subtype of acute leukemia to any laboratory provided with a minimal equipment for immunocytochemistry work.
UI - 9680345
AU - Diverio D; Rossi V; Avvisati G; De Santis S; Pistilli A; Pane F; Saglio
TI - G; Martinelli G; Petti MC; Santoro A; Pelicci PG; Mandelli F; Biondi A; Lo Coco F Early detection of relapse by prospective reverse transcriptase-polymerase chain reaction analysis of the PML/RARalpha fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter "AIDA" trial. GIMEMA-AIEOP Multicenter "AIDA" Trial.
SO - Blood 1998 Aug 1;92(3):784-9
AD - Dipartimento di Biotecnologie Cellulari ed Ematologia, Universita "La Sapienza", Rome, Italy.
Although the majority of patients with acute promyelocytic leukemia (APL) are potentially cured by treatments combining all-trans retinoic acid (ATRA) and chemotherapy (CHT), a sizable proportion (around 30%) will relapse during follow-up. Retrospective molecular monitoring studies using reverse transcriptase-polymerase chain reaction (RT-PCR) for the specific PML/RARalpha fusion gene, have shown that a positive test usually precedes the occurrence of hematologic relapse. Prospective RT-PCR analyses were performed since 1993 at diagnosis and at preestablished time intervals during follow-up in bone marrow (BM) samples of 163 patients with PML/RARalpha+ APL enrolled in the multicenter Gruppo Italiano Malattie Ematologiche Maligne dell' Adulto (GIMEMA) trial AIDA (All-trans retinoic acid plus Idarubicin). Treatment consisted of ATRA and idarubicin for induction followed by three polychemotherapy courses as consolidation. The sensitivity level of the RT-PCR assay for PML/RARalpha, as assessed by serial dilution experiments, was 10(-4). All patients were in hematologic remission and tested PCR- at the end of consolidation. Of 21 who converted to PCR-positive thereafter, 20 underwent hematologic relapse at a median time of 3 months (range, 1 to 14) from the first PCR+ result. Seventeen of these 21 (81%) PCR+ conversions were recorded within the first 6 months postconsolidation. Of 142 who tested persistently PCR- in >/=2 tests after consolidation, 8 had hematologic relapse and 134 remained in complete remission (CR) after a median follow-up of 18 months (range, 6 to 38) postconsolidation. Using a time-dependent Cox model, the relative risk of hematologic relapse of patients who converted to PCR+ was 31.8 (confidence limits 95%, 12.9 to 78.3). Our results indicate that conversion to PCR positivity for PML/RARalpha during remission is highly predictive of subsequent hematologic relapse and highlight the prognostic value of stringent molecular monitoring during the early postconsolidation phase in APL. As a result of the present study, salvage treatment in patients enrolled in the GIMEMA trial AIDA is now anticipated at the time of molecular relapse, defined as the conversion to PCR positivity in two successive BM samplings during follow-up. Copyright 1998 by The American Society of Hematology.
UI - 10720132
AU - Bolognesi E; Cimino G; Diverio D; Rapanotti MC; D'Alfonso S;
TI - Fleischhauer K; Migliaretti G; Momigliano-Richiardi P HLA class I in acute promyelocytic leukemia (APL): possible correlation with clinical outcome.
SO - Leukemia 2000 Mar;14(3):393-8
AD - Dipartimento di Scienze Mediche, Universita del Piemonte Orientale A Avogadro, Novara, Italy.
The majority of patients with acute promyelocytic leukemia (APL) possess either a bcr1 or a bcr3 type fusion between PML and RARalpha genes. The junction sequences may possibly be a target for immune response and influence susceptibility to the disease. In this case, HLA class I allele frequencies would be different between bcr1 and bcr3 patients. To test this hypothesis, we typed 102 APL patients for HLA-A, -B and -Cw alleles. The A*1, A*30, B*51, B*41, Cw*0602, and Cw*1701 alleles showed a different distribution between bcr1 and bcr3 patients, but in no case was this statistically significant after correction for the number of comparisons or was confirmed in an independent panel. Moreover, no difference was detected between bcr1 and bcr3 when HLA alleles were grouped according to their peptide binding specificities. Comparing HLA frequencies, clinical features at diagnosis and clinical outcome of the 64 patients homogeneously treated with all-trans retinoic acid and idarubicin (AIDA protocol) we observed a statistically significant association between HLA-B*13 and risk of relapse by univariate and multivariate regression analysis. Should this finding be confirmed in larger future studies, this observation would be of outmost importance in identifying patients at high risk of relapse in which more aggressive consolidation therapies should be used.
UI - 11698395
AU - Kwon SH; Ahn SH; Kim YK; Bae GU; Yoon JW; Hong S; Lee HY; Lee YW; Lee
TI - HW; Han JW Apicidin, a histone deacetylase inhibitor, induces apoptosis and Fas/Fas ligand expression in human acute promyelocytic leukemia cells.
SO - J Biol Chem 2002 Jan 18;277(3):2073-80
AD - Department of Biochemistry and Molecular Biology, College of Pharmacy and Department of Genetic Engineering, College of Life Science and Natural Resources, Sungkyunkwan University, Suwon 440-746, Korea.
We previously reported that apicidin arrested human cancer cell growth through selective induction of p21(WAF1/Cip1). In this study, the apoptotic potential of apicidin and its mechanism in HL60 cells was investigated. Treatment of HL60 cells with apicidin caused a decrease in viable cell number in a dose-dependent manner and an increase in DNA fragmentation, nuclear morphological change, and apoptotic body formation, concomitant with progressive accumulation of hyperacetylated histone H4. In addition, apicidin converted the procaspase-3 form to catalytically active effector protease, resulting in subsequent cleavages of poly(ADP-ribose) polymerase and p21(WAF1/Cip1). Incubation of HL60 cells with z-DEVD-fmk, a caspase-3 inhibitor, almost completely abrogated apicidin-induced activation of caspase-3, DNA fragmentation, and cleavages of poly(ADP-ribose) polymerase and p21(WAF1/Cip1). Moreover, these effects were preceded by an increase in translocation of Bax into the mitochondria, resulting in the release of cytochrome c and cleavage of procaspase-9. The addition of cycloheximide greatly inhibited activation of caspase-3 by apicidin by interfering with cleavage of procaspase-3 and DNA fragmentation, suggesting that apicidin-induced apoptosis was dependent on de novo protein synthesis. Consistent with these results, apicidin transiently increased the expressions of both Fas and Fas ligand. Preincubation with NOK-1 monoclonal antibody, which prevents the Fas-Fas ligand interaction and is inhibitory to Fas signaling, interfered with apicidin-induced translocation of Bax, cytochrome c release, cleavage of procaspase-3, and DNA fragmentation. Taken together, the results suggest that apicidin might induce apoptosis through selective induction of Fas/Fas ligand, resulting in the release of cytochrome c from the mitochondria to the cytosol and subsequent activation of caspase-9 and caspase-3.
UI - 11775836
AU - Hu J; Yu T; Zhao W; Gu B; Shen Z; Li X; Sun G; Chen S; Wang Z
TI - Impact of RT-PCR monitoring on the long-term survival in acute promyelocytic leukemia.
SO - Chin Med J (Engl) 2000 Oct;113(10):899-902
AD - Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Second Medical University, Ruijin Hospital-Samuel Waxman Cancer Research Foundation, Joint Center for Cancer Differentiation Therapy, Shanghai 200025, China.
OBJECTIVE: To evaluate the impact of kinetics of molecular remission via retro-transcriptase polymerase chain reaction (RT-PCR) assay on the long-term survival in patients with acute promyelocytic leukemia (APL). METHODS: Seventy patients with newly-diagnosed APL in remission were involved in this study. Monitoring of minimal residual disease (MRD) was performed regularly by RT-PCR assay for PML-RAR alpha during consolidation. RESULTS: A 5-year relapse-free survival (RFS) and overall-survival (OS) were estimated as 46.8% +/- 8.4% and 69.9% +/- 9.4% for the whole group. Fifty-two (74.3%) patients got negative RT-PCR result at least once. Serial monitoring of RT-PCR was available in 38 cases and 24 (63.2%) patients presented with persistent negative PCR results. The achievement and continuous negative RT-PCR result was significantly related to the RFS. CONCLUSIONS: Achievement of negative RT-PCR in remission is associated with favorable RFS and OS. Continuous negative RT-PCR results are associated with long-term relapse-free survival and may be considered as potentially curative. RT-PCR assay for detection of MRD should be performed regularly during post-remission period as an important prognostic factor.
UI - 11697646
AU - Stein RS; Wolff SN; Greer JP; Flexner JM; Goodman S; Jagasia M; Brandt
TI - SJ; Morgan DS; Arrowsmith E; McCurley TL Age and cytogenetics as predictors of event free survival in patients with acute non-lymphocytic leukemia receiving high dose cytosine arabinoside and daunorubicin as consolidation chemotherapy.
SO - Leuk Lymphoma 2001 Sep-Oct;42(5):913-22
AD - Department of Medicine, Vanderbilt University School of Medicine, and VA Medical Center, Nashville, TN, USA. firstname.lastname@example.org
Between 1991 and 1999, 67 patients with acute non-lymphocytic leukemia (ANLL) in complete remission received high dose cytarabine (HiDAC) 3 gm/m2 q12h x 12 doses followed by daunorubicin 45 mg/m2/day x 3 days as consolidation therapy. Five year actuarial event free survival (EFS) was 34% +/- 6%. Age was significantly associated with EFS. EFS was 60% +/- 15% in patients age 20 to 29, 48% +/- 16% in patients age 30 to 39, 23% +/- 10% in patients age 40 to 49, 31% +/- 11% in patients age 50 to 59, and 0% in patients age > or = 60. Contrary to other reports which have used different HiDAC regimens, we found no relationship between cytogenetics and EFS. Cytogenetics were defined as favorable risk: t(8;21), inv (16), and del (16); neutral risk: normal or t(15;17); and unfavorable risk: any abnormality not included in favorable risk or neutral risk. EFS was 29% +/- 17% in patients with favorable cytogenetics, 37% +/- 14% in patients with neutral cytogenetics, and 31% +/- 12% in patients with unfavorable cytogenetics. These differences were not statistically significant. Because of the successful use of allogeneic transplantation at relapse in patients with matched related donors, five year actuarial survival (S) in this series was 40% +/- 6%. Five year actuarial survival was 57% +/- 9% for patients age < or = 44 and 25% +/- 8% for patients age > or = 45. This difference is statistically significant, p < .025. Clinicians should be cautious about making clinical decisions regarding consolidation therapy of ANLL on the basis of the presence or absence of cytogenetic abnormalities as the importance of cytogenetics may depend on the specific therapy which is employed.
UI - 11835353
AU - Ito K; Kinjo K; Nakazato T; Ikeda Y; Kizaki M
TI - Expression and sequence analyses of p33(ING1) gene in myeloid leukemia.
SO - Am J Hematol 2002 Feb;69(2):141-3
AD - Division of Hematology, Keio University School of Medicine, Tokyo, Japan.
p33(ING1) is a novel candidate tumor suppressor gene which is involved in the regulation of apoptosis. p33(ING1) interacts with p53 signaling pathway and regulates cellular growth. It has reported that the expression of p33(ING1) mRNA was decreased in lymphoid malignancies. We thus investigated the potential involvement of p33(ING1) abnormalities in myeloid leukemias. However, the levels of p33(ING1) transcript were almost equal in 3 AML cell lines and 10 fresh AML samples. In addition, neither point mutations nor deletions in p33(ING1) gene were found in myeloid leukemias. These results suggest that p33(ING1) may not be a major candidate tumor suppressor gene in myeloid leukemias. Copyright 2002 Wiley-Liss, Inc.
UI - 11587217
AU - Preisler HD; Li B; Chen H; Fisher L; Nayini J; Raza A; Creech S;
TI - Venugopal P P15INK4B gene methylation and expression in normal, myelodysplastic, and acute myelogenous leukemia cells and in the marrow cells of cured lymphoma patients.
SO - Leukemia 2001 Oct;15(10):1589-95
AD - Rush Cancer Institute, Chicago, Illinois 60612, USA.
P15INK4B methylation and expression was studied in bone marrow cells obtained from normal individuals, from patients who had been cured of lymphoma, and from patients with either MDS or AML. The level of p15 methylation was very low in normal BM cells and in CD34+ and CD34- subpopulations (0-6.5%; med, = 2.5%). P15INK4B transcripts were present in each of these cell populations. In contrast, methylation was the usual situation in MDS and AML marrows. The presence of methylation of the p15INK4B gene did not always indicate an absence of expression nor was expression always present if methylation was absent. P15INK4B methylation was studied in the marrows of nine patients (one studied twice) who had been cured of lymphoma and in whom hemopoiesis was believed to be normal. Increased methylaton was present in all 10 marrows. These data indicate that p15INK4B methylation is likely to be a very early event in the development of the secondary hematologic disorders.
UI - 11587231
AU - Takagi K; Yoshida A; Yamauchi T; Yamashita T; Iwasaki H; Tsutani H;
TI - Maezawa Y; Baba H; Ueda T Successful treatment of Aspergillus spondylodiscitis with high-dose itraconazole in a patient with acute myelogenous leukemia.
SO - Leukemia 2001 Oct;15(10):1670-1
UI - 11801314
AU - Salido M; Sole F; Espinet B; Fernandez C; Zamora L; Woessner S; Florensa
TI - L Pentasomy 21 with two isochromosomes 21 in a case of acute myeloid leukemia without maturation.
SO - Cancer Genet Cytogenet 2002 Jan 1;132(1):71-3
AD - Laboratori de Citologia Hematologica, Escola de Citologia Hematologica S. Woessner-IMAS, Hospital del Mar, IMAS, IMIM, Barcelona, Spain. email@example.com
Here, we report a 72-year-old male patient with acute myeloid leukemia (AML) without maturation. Cytogenetic study of a bone marrow culture revealed the following karyotype: 47,XX,+21,+i(21)(q10)x2. Fluorescence in situ hybridization study with a locus specific probe for 21q22 verified a pentasomy of 21q as a sole clonal cytogenetic abnormality. To our knowledge, this is the first report of pentasomy 21q in AML without Down syndrome.
UI - 11721412
AU - Chen W; Zhang W; Zhu J
TI - [Homozygous deletion and methylation of p16 and p15 gene in acute leukemia]
SO - Zhonghua Xue Ye Xue Za Zhi 1999 Sep;20(9):474-6
AD - Beijing Red-cross Chaoyang Hospital, Capital University of Medical Sciences, Beijing 100020.
OBJECTIVE: To investigate the frequency of p16 and p15 gene inactivation in acute leukemia and to evaluate its clinical significance. METHODS: Fifty-six patients with newly diagnosed acute leukemia was studied. PCR technique was used to detect homozygous deletion of p16 and p15 gene, restriction enzyme-PCR technique was used to detect gene methylation, and TdT-mediated dUTP-digoxygenin end-labeling (TUNEL) technique was used to detect cell apoptosis. RESULTS: p16 and/or p15 gene inactivation was detected in 33 of the 56 patients, including 23/38 (60.5%) of the ALL patients (T-ALL 12/16, B-ALL 11/22) and 10/18 (55.5%) of the ANLL patients. For All patients, methylation was the major pathway of p16 and p15 gene inactivation. Patients with p16 and/or p15 gene inactivation had a delayed apoptosis, a poor response to chemotherapy, a lower remission rate and a shortened remission duration. CONCLUSION: The inactivation of p16 and p15 gene plays a key role in the pathogenesis of acute leukemia.
UI - 11845985
AU - Tothova E; Elbertova A; Fricova M; Kafkova A; Hlebaskova M; Svorcova E;
TI - Stecova N; Guman T; Raffac S P-glycoprotein expression in adult acute myeloid leukemia: correlation with induction treatment outcome.
SO - Neoplasma 2001;48(5):393-7
AD - Department of Hematology, Medical Faculty Hospital and UPJS, Kosice, Slovak Republic. firstname.lastname@example.org
Drug resistance has become a major cause of the treatment failure in patients with acute leukemia. P-glycoprotein (P-gp), which is associated with multidrug resistance (MDR) phenotype, has been reported to be an important predictor of the treatment outcome. The aim of this study was to analyze the value of P-gp expression in bone marrow cells as a predictor of the response to remission induction chemotherapy, as well as duration of remission in adult patients with newly diagnosed acute myeloid leukemia (AML). We examined the expression of P-gp in 31 patients using the monoclonal antibody UIC2. Direct immunofluorescent labeling was performed and samples were analyzed by flow cytomery. Kolmogorov-Smirnov test (D-value) was used to estimate UIC2 staining. A D > or = 0.3 for labeling of gated leukaemic blasts as compared to that of the isotypic control was defined positive (+) and compared to clinical data. P-gp expression was found in 14/31 (45.6%) patients, 17/31 (54.8%) of the samples were found P-gp negative(-). No correlation was found regarding age, sex and FAB subtype, altough 6/14 (43%) cases with more than 50% of cells having P-gp expression, were CD34+/CD7+. Complete remission rates were significantly lower in UIC2+ patients than in UIC2- cases (70% vs 35%, p < 0.01). Complete remission duration was also shorter in UIC2+ patients (6 vs 12.4 months). Our data indicate, that P-gp expression is a reliable marker of resistance to induction treatment in patients with de novo AML and can help to identify patients who may require alternative regimens designed to overcome therapy resistance.
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