• [Liposomal daunorubicin and interferon-alfa in combination with all-retinoic acid--a new regime for the treatment of acute promyelocytic

• Colony-stimulating factors: beyond the effects on hematopoiesis.

• A graft-versus-tumor effect in a patient with ependymoma who received an allogenic bone marrow transplant for therapy-related leukemia. Case

• Targeted removal of PML-RARalpha protein is required prior to inhibition of histone deacetylase for overcoming all-trans retinoic acid

• Complete remission through blast cell differentiation in PLZF/RARalpha-positive acute promyelocytic leukemia: in vitro and in

• Phase I study of temozolomide in relapsed/refractory acute leukemia.

• Advances in the management of acute promyelocytic leukemia and other hematologic malignancies with arsenic trioxide.

• Molecular targets of arsenic trioxide in malignant cells.

• Factors affecting long-term outcome after allogeneic haematopoietic stem cell transplantation for acute myelogenous leukaemia: a retrospective

• Appearance of del(11q) in two patients with acute promyelocytic leukaemia treated with all-trans retinoic acid and combination

• Effect of additional chromosomal abnormalities in acute promyelocytic leukemia treated with all-trans-retinoic acid: a report of 17 patients.

• Phase 3 study of the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age and older with acute

• Targeted alpha particle immunotherapy for myeloid leukemia.

• Second malignancy after treatment of acute promyelocytic leukemia: experience of GIMEMA trials. Gruppo Italiano Malattie Ematologiche

• Activity of all-trans-retinoic acid in a case of central nervous system extramedullary relapse of acute promyelocytic leukemia.

• Therapy-related MDS and AML in acute promyelocytic leukemia.

• All-trans retinoic acid (ATRA) differentiates acute promyelocytic leukemia cells independently of P-glycoprotein (P-gp) related multidrug

• Financial analysis of patients with newly diagnosed acute myelogenous leukemia on protocol or standard therapy.

• Impact of combinations of antineoplastic drugs on intestinal microflora in 9 patients with leukaemia.

• Serum levels of angiogenin, basic fibroblast growth factor and endostatin in patients receiving intensive chemotherapy for acute

• Arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: a single center experience.

• High expression of Bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy.

• In vitro comparative antileukemic activity of various glucocorticoids in childhood acute leukemia.

• Transient dilated cardiomyopathy in a newborn exposed to idarubicin and all-trans-retinoic acid (ATRA) early in the second trimester of

• Acute megakaryoblastic leukemia: experience of GIMEMA trials.

• Therapy-related myelodysplastic syndrome or acute myelogenous leukemia in patients with acute promyelocytic leukemia (APL).

• Atypical blasts and bone marrow necrosis associated with near-triploid relapse of acute promyelocytic leukemia after arsenic trioxide

• Effect of slow lymphocyte recovery and type of graft-versus-host disease prophylaxis on relapse after allogeneic bone marrow transplantation for

• Superior effect of 9-cis retinoic acid (RA) compared with all-trans RA and 13-cis RA on the inhibition of clonogenic cell growth and the

• Cancer chemoprevention by hydroxytyrosol isolated from virgin olive oil through G1 cell cycle arrest and apoptosis.

1
UI - 12181827
AU - Savchenko VG; Parovichnikova EN; Isaev VG; Shuravina EN; Demidova IA;
TI - Ol'shanskaia IuV [Liposomal daunorubicin and interferon-alfa in combination with all-retinoic acid--a new regime for the treatment of acute promyelocytic leukemia]
SO - Ter Arkh 2002;74(7):11-8
AIM: To define duration and schemes of maintenance therapy, to evaluate cytarabine demand while treatment of acute promyelocytic leukemia (APL) with an original program 5D + Ifa + AT RA. MATERIAL AND METHODS: The above treatment was conducted in 7 patients with APL (1 male, 6 females, 18-45 years, leukocytes 1.2-15.0 x 10(9)/l). RESULTS: Induction by 5D program was performed in 5 patients. A complete remission was achieved in 4 of them, molecular--in 3. One woman died. 5D consolidation was performed in 6 patients. After the first course of consolidation all the patients achieved molecular remission. Maintenance of remission with Ifa + ATRA was made in 5 patients. In one female the remission came to the end. Mean time of the follow-up was 18 months. The remission lasted 5-36 months. Monitoring of molecular remission has not found marker PML/RARa. CONCLUSION: Daunozom monotherapy leads to a complete remission after the first course in most of the patients. In the majority of them it was molecular. Maintenance with If + ATRA for 2 years maintains molecular remission for 5-36 months.

2
UI - 11944610
AU - Stull DM
TI - Colony-stimulating factors: beyond the effects on hematopoiesis.
SO - Am J Health Syst Pharm 2002 Apr 1;59(7 Suppl 2):S12-20
AD - Department of Pharmacy, New York-Presbyterian Hospital, 525 East 68th Street, Room K 04, New York, NY 10021, USA. dmstull@nyp.org
The effects of sargramostim and filgrastim on hematopoietic cells are described. Filgrastim is a lineage-specific colony-stimulating factor (CSF), mainly affecting neutrophils. In addition to enhancing neutrophil recovery, filgrastim may also enhance neutrophil functional activity. Filgrastim does not have any meaningful effect on monocytes or macrophages; however, recent data indicate that filgrastim has a stimulatory effect on Th2 lymphocyte-inducing dendritic cells. These dendritic cells facilitate humoral immune responses, but they also produce inhibitory cytokines that diminish cell-mediated immunity. Sargramostim is a multilineage CSF, affecting neutrophils, monocytes, macrophages, and dendritic cells. Sargramostim has a greater impact on Th1 lymphocyte-inducing dendritic cells, which facilitate cell-mediated immune responses, including antitumor activity. The broader activity of sargramostim on both types of antigen-presenting cells (macrophages and dendritic cells) may account for the reports of benefit beyond enhanced neutrophil recovery that have been seen in clinical trials of patients with leukemia and patients undergoing stem-cell transplantation. Given the disparate activity of these two CSFs on the immune system and the types of immune responses generated, it is prudent for clinicians to consider these effects when choosing an agent for enhancing neutrophil recovery in various clinical settings.

3
UI - 12186480
AU - Tanaka M; Shibui S; Kobayashi Y; Nomura K; Nakanishi Y
TI - A graft-versus-tumor effect in a patient with ependymoma who received an allogenic bone marrow transplant for therapy-related leukemia. Case report.
SO - J Neurosurg 2002 Aug;97(2):474-6
AD - Division of Neurosurgery, National Cancer Center Hospital, Tokyo, Japan. mntanaka-nsu@umin.ac.jp
Graft-versus-leukemia effect is an immune-mediated antitumor phenomenon associated with allogenic bone marrow transplants (BMTs) for hematological malignancies, and recent findings have indicated that a similar effect could occur in some solid tumors such as breast cancers. The authors report on a 42-year-old man with a recurrent ependymoma who received an allogenic BMT for therapy-related leukemia. After transplantation, the patient developed chronic graft-versus-host disease, which was controlled with steroid agents. Interestingly, the recurrent ependymoma regressed steadily over the next 21 months posttransplant, until the tumor became almost undetectable on magnetic resonance images. This case indicates that the graft-versus-tumor effect, mediated by cytotoxic T cells, may be able to target intraparenchymal neuroepithelial tumors, despite the brain's generally recognized status as an immunoprivileged organ.

4
UI - 12130515
AU - Jing Y; Xia L; Waxman S
TI - Targeted removal of PML-RARalpha protein is required prior to inhibition of histone deacetylase for overcoming all-trans retinoic acid differentiation resistance in acute promyelocytic leukemia.
SO - Blood 2002 Aug 1;100(3):1008-13
AD - Division of Medical Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029-6547, USA. yongkui.jing@mssm.edu
All-trans retinoic acid (tRA)-induced differentiation in NB4 cells, a cell line derived from an acute promyelocytic leukemia patient with t(15;17) translocation, is markedly facilitated by sodium butyrate (NaB), a histone deacetylase inhibitor (HDACI), or by hexamethylene bisacetamide (HMBA), a non-HDACI tRA-differentiation inducer, as determined by nitroblue tetrazolium reduction. The tRA-induced expression of RIG-G, Bfl-1/A1, and p21(waf1) and, to a lesser extent, of CCAAT/enhancer binding protein-epsilon (C/EBPepsilon) are also enhanced by such combined treatments. Both responses are associated with a facilitated diminution of the leukemogenic PML-RARalpha protein and retained DeltaPML-RARalpha, a cleavage product. Treatment with tRA in tRA differentiation-resistant NB4 subclones R4 and MR-2 does not result in PML-RARalpha diminution and the tested gene expressions. Moreover, the addition of HMBA or NaB with tRA results in only minimal increase of differentiation in the tRA differentiation-resistant subclones. The increases in acetylated histone H3 (AcH3) and AcH4 in NaB-treated NB4, R4, and MR-2 cells are similar and do not correlate with the extent of differentiation induction when NaB and HMBA are given in combination with tRA. Arsenic trioxide (As2O3) treatment results in the total degradation of PML-RARalpha without increasing AcH3 or AcH4 or inducing differentiation in R4 cells. As2O3 in combination with tRA induces gene (Bfl-1/A1 and C/EBPepsilon) expression and partial differentiation. Both NaB and HMBA addition to As2O3-plus-tRA-treated R4 cells further enhances differentiation. These results suggest that elimination of the dominant negative PML-RARalpha protein is required prior to inhibition of histone deacetylase to fully overcome tRA-differentiation resistance in APL cells.

5
UI - 12130525
AU - Petti MC; Fazi F; Gentile M; Diverio D; De Fabritiis P; De Propris MS;
TI - Fiorini R; Spiriti MA; Padula F; Pelicci PG; Nervi C; Lo Coco F Complete remission through blast cell differentiation in PLZF/RARalpha-positive acute promyelocytic leukemia: in vitro and in vivo studies.
SO - Blood 2002 Aug 1;100(3):1065-7
AD - Hematology section, Regina Elena Cancer Institute, Department of Cellular Biotechnology, University La Sapienza, Rome, Italy.
Acute leukemia with the t(11;17) expressing the PLZF-RARalpha gene fusion is a rare variant of acute promyelocytic leukemia (APL) that has been associated with poor clinical response to all-trans retinoic acid (ATRA) treatment. However, some recent reports have put into question the absolute refractoriness of this leukemia to ATRA. We describe here a patient with PLZF/RARalpha APL who was treated at relapse with ATRA and low-dose hydroxyurea. Complete hematologic remission was obtained through differentiation of leukemic blasts, as proven by morphologic, immunophenophenotypic, and genetic studies carried out in sequential bone marrow samples. Moreover, in vitro studies indicated that blast differentiation was potentiated by the addition of the histone deacetylase inhibitor tricostatin A, but not of hydroxyurea, to ATRA. Our findings indicate that the maturation block may be overcome and terminal differentiation obtained in this leukemia subset and support the view that sensitivity/refractoriness of this form to ATRA should be revisited.

6
UI - 12149298
AU - Seiter K; Liu D; Loughran T; Siddiqui A; Baskind P; Ahmed T
TI - Phase I study of temozolomide in relapsed/refractory acute leukemia.
SO - J Clin Oncol 2002 Aug 1;20(15):3249-53
AD - Department of Medicine, Zalmen A. Arlin Cancer Institute, Munger Pavilion Room 250, New York Medical College, Valhalla, NY 10595, USA. karen_seiter@nymc.edu
PURPOSE: To determine the dose-limiting toxicity and maximum-tolerated dose of temozolomide in patients with acute leukemia. PATIENTS AND METHODS: Twenty patients (16 with acute myelogenous leukemia, two with acute lymphoblastic leukemia, and two with chronic myelogenous leukemia in blastic phase) received 43 cycles of temozolomide. Patients began treatment at two different dose levels: 200 mg/m(2)/d for 7 days or 200 mg/m(2)/d for 9 days. RESULTS: Prolonged aplasia was the dose-limiting toxicity, and the maximum-tolerated dose was 7 days of temozolomide. Overall treatment was well tolerated: hospitalization was required in only nine of 43 courses, and there were no treatment-related deaths. Two patients obtained a complete response, and two others met criteria for complete response except for platelet recovery. Overall, nine of 20 patients had a significant decrease in bone marrow blasts after temozolomide treatment. CONCLUSION: Temozolomide was well tolerated and had significant antileukemic activity when administered as a single agent. Further studies of temozolomide in hematologic malignancies are indicated.

7
UI - 11961204
AU - Slack JL; Waxman S; Tricot G; Tallman MS; Bloomfield CD
TI - Advances in the management of acute promyelocytic leukemia and other hematologic malignancies with arsenic trioxide.
SO - Oncologist 2002;7 Suppl 1():1-13
AD - Department of Hematologic Oncology, Roswell Park Cancer Institute, Buffalo, New York, USA.
Acute promyelocytic leukemia (APL), once considered the most devastating subtype of acute myeloid leukemia, is now the most treatable of all subtypes as a result of intensive research into its molecular pathogenesis. This research has led to a rational approach to treatment in which the use of the differentiating agent all-trans-retinoic acid (ATRA) has proven to be effective first-line treatment for inducing complete remission. Arsenic trioxide (ATO) is currently used to treat relapsed disease, further enhancing survival rates in a patient population for which limited salvage options exist. This review discusses the molecular mechanisms responsible for development of APL and the evolution of treatment options over the last three decades, including the major advances using ATRA and ATO in the last 12 years. The mechanism of action of ATO is also described in view of this agent's potential for broader therapeutic application in a variety of hematologic malignancies.

8
UI - 11961205
AU - Miller WH Jr
TI - Molecular targets of arsenic trioxide in malignant cells.
SO - Oncologist 2002;7 Suppl 1():14-9
AD - Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital and McGill University Department of Oncology, Montreal, Quebec, Canada. Wmiller@ldi.jgh.mcgill.ca
Arsenic trioxide (As2O3; ATO) has considerable efficacy in the treatment of relapsed acute promyelocytic leukemia (APL), inducing partial differentiation and promoting apoptosis of malignant promyelocytes. Although initial studies focused on the role of the characteristic APL fusion protein, PML-RARalpha, in mediating response to ATO, subsequent investigations have revealed that ATO acts on numerous intracellular targets. ATO broadly affects signal transduction pathways and causes a wide range of alterations leading to apoptosis. Key mediators of sensitivity to ATO-induced apoptosis include intracellular glutathione and hydrogen peroxide (H2O2). The loss of inner mitochondrial membrane potential is also an important step in ATO-mediated cell killing. Cellular and physiologic pathways affected by ATO provide some clues as to the mechanisms for the biologic effects of ATO. Recent research has shown that hematologic cancers other than APL and solid tumors derived from several tissue types may be responsive to monotherapy or combination therapy with ATO. A better understanding of the mechanisms of action of ATO may help guide the use of ATO for the treatment of a wide variety of malignancies and allow its potential in cancer therapy to be fully realized.

9
UI - 12060131
AU - Greinix HT; Nachbaur D; Krieger O; Eibl M; Knobl P; Kalhs P; Lutz D;
TI - Linkesch W; Niederwieser D; Hinterberger W; Lechner K; Rosenmayr A; Gritsch B Factors affecting long-term outcome after allogeneic haematopoietic stem cell transplantation for acute myelogenous leukaemia: a retrospective study of 172 adult patients reported to the Austrian Stem Cell Transplantation Registry.
SO - Br J Haematol 2002 Jun;117(4):914-23
AD - Department of Medicine I, Bone Marrow Transplantation Unit, University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. hildegarde.greinix@akh.wien.ac.at
Between 1982 and 2000, 172 patients with acute myelogenous leukaemia (AML) received haematopoietic stem cell transplants (SCT) from related (n = 132) or unrelated (n = 40) donors at four Austrian transplant centres and their results were reported to the Austrian Stem Cell Transplantation Registry. Conditioning for SCT consisted of cyclophosphamide and total body irradiation in 156 (91%) patients. Graft-versus-host disease (GVHD) prophylaxis was with standard cyclosporine and methotrexate in 95 (55%) patients. Median post-transplant follow-up was 5.6 years (range, 0.2--16.7). Multivariate analysis of transplant-related mortality (TRM) identified four variables associated with a lower risk: disease status of first complete remission (CR) at SCT, patient age of 45 years and younger, transplant performed during or after 1995, and lack of acute GVHD. Variables associated with significantly improved leukaemia-free survival were: bone marrow as the stem cell source, disease status of first CR at SCT, and occurrence of chronic GVHD. In multivariate analysis, transplantation performed during or after 1995, first CR at SCT, occurrence of limited chronic GVHD and lack of acute GVHD grades III to IV were associated with increased overall survival. Based on these analyses, options for the improvement of results obtained with allogeneic SCT in patients with AML could be defined.

10
UI - 12100154
AU - Campbell LJ; Rayeroux KC; Arkell K; Catalano JV; Cole-Sinclair MF
TI - Appearance of del(11q) in two patients with acute promyelocytic leukaemia treated with all-trans retinoic acid and combination chemotherapy.
SO - Br J Haematol 2002 Jul;118(1):243-5
AD - Victorian Cancer Cytogenetics Service, St. Vincent's Hospital, Melbourne, Australia. campbelj@svhm.org.au
Two acute promyelocytic leukaemia patients, treated with all-trans retinoic acid and combination chemotherapy, acquired a deletion of 11q within 12 months of diagnosis. One patient died in relapse, with both t(15;17) and del(11q) cell lines co-existing. Patient 2 remains in remission with del(11q) in 70% metaphases, despite normal marrow morphology. No deletion of the MLL gene was identified in the latter patient. The early appearance of a del(11q) is unusual, particularly without morphological evidence of myelodysplasia. We hypothesize that the del(11q) was therapy-induced but the absence of other genetic lesions has resulted in no accompanying morphological changes.

11
UI - 11503965
AU - Okoshi Y; Akiyama H; Kono N; Matsumura T; Mizuchi D; Mori S; Ohashi K;
TI - Sakamaki H Effect of additional chromosomal abnormalities in acute promyelocytic leukemia treated with all-trans-retinoic acid: a report of 17 patients.
SO - Int J Hematol 2001 Jun;73(4):496-501
AD - Hematology Division, Tokyo Metropolitan Komagome Hospital, Japan.
Seventeen cases of acute promyelocytic leukemia (APL) treated with all-trans-retinoic acid (ATRA) and combination chemotherapy at Tokyo Metropolitan Komagome Hospital between 1992 and 1999 were reviewed, and divided into 2 karyotype-based cytogenetic groups. One group comprised 7 patients with either the typical t(15;17) alone or a normal karyotype, and the other group comprised 10 patients with additional karyotypic abnormalities. No patient had received prior chemotherapy or irradiation, and no cases were complicated by a history of myelodysplastic syndrome before the diagnosis of APL. There were no significant differences in clinical characteristics at disease presentation. Complete remission was achieved in all 17 patients and karyotypes of bone marrow cells normalized in all cases. No differences were found in relapse rate, overall survival, or disease-free survival between the 2 groups. The analysis did not reveal any significant effect of additional chromosomal abnormalities on the prognosis of APL patients undergoing treatment with ATRA. However, a small number of patients were assessed in this study, and further cumulative studies are needed.

12
UI - 12149202
AU - Baer MR; George SL; Dodge RK; O'Loughlin KL; Minderman H; Caligiuri MA;
TI - Anastasi J; Powell BL; Kolitz JE; Schiffer CA; Bloomfield CD; Larson RA Phase 3 study of the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age and older with acute myeloid leukemia: Cancer and Leukemia Group B Study 9720.
SO - Blood 2002 Aug 15;100(4):1224-32
AD - Roswell Park Cancer Institute, Buffalo, NY 14263, USA. maria.baer@roswellpark.org
The Cancer and Leukemia Group B conducted a phase 3 trial of the P-glycoprotein modulator PSC-833 in untreated acute myeloid leukemia patients aged 60 years and older. Patients were randomized to 1 of 2 regimens, with doses determined in a prior phase 1 study, consisting of cytarabine 100 mg/m(2)/d by 7-day infusion, with daunorubicin 60 mg/m(2) and etoposide 100 mg/m(2) daily for 3 days (ADE), or daunorubicin 40 mg/m(2) and etoposide 60 mg/m(2) for 3 days with PSC-833, 2.8 mg/kg over 2 hours, and then 10 mg/kg/d by 3-day infusion (ADEP). The ADEP arm was closed after randomization of 120 patients (61 to ADE and 59 to ADEP) because of excessive early mortality. Rates of complete remission, nonresponse, and death were 46%, 34%, and 20% for ADE, versus 39%, 17%, and 44% for ADEP (P =.008). Nevertheless, disease-free survival (median 7 vs 8 months; P =.38) and overall survival (approximately 33% alive at 1 year) did not differ and were similar to historical results. Although the number of patients was limited, ADE patients whose pretreatment cells exhibited PSC-833-modulated dye efflux in vitro (n = 22) had worse outcomes than those without efflux (n = 11) (complete remission, nonresponse, and death rates of 41%, 41%, and 18%, compared with 91%, 9%, and 0%; P =.03), but with ADEP outcomes were nearly identical. Moreover, for patients with PSC-833-modulated efflux, median disease-free survival was 5 months with ADE and 14 months with ADEP (P =.07). Further modulation trials in older patients must await the design of less-toxic regimens.

13
UI - 12149203
AU - Jurcic JG; Larson SM; Sgouros G; McDevitt MR; Finn RD; Divgi CR;
TI - Ballangrud AM; Hamacher KA; Ma D; Humm JL; Brechbiel MW; Molinet R; Scheinberg DA Targeted alpha particle immunotherapy for myeloid leukemia.
SO - Blood 2002 Aug 15;100(4):1233-9
AD - Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Medical College of Cornell University, New York, NY 10021, USA. jurcicj@mskcc.org
Unlike beta particle-emitting isotopes, alpha emitters can selectively kill individual cancer cells with a single atomic decay. HuM195, a humanized anti-CD33 monoclonal antibody, specifically targets myeloid leukemia cells and has activity against minimal disease. When labeled with the beta-emitters (131)I and (90)Y, HuM195 can eliminate large leukemic burdens in patients, but it produces prolonged myelosuppression requiring hematopoietic stem cell transplantation at high doses. To enhance the potency of native HuM195 yet avoid the nonspecific cytotoxicity of beta-emitting constructs, the alpha-emitting isotope (213)Bi was conjugated to HuM195. Eighteen patients with relapsed and refractory acute myelogenous leukemia or chronic myelomonocytic leukemia were treated with 10.36 to 37.0 MBq/kg (213)Bi-HuM195. No significant extramedullary toxicity was seen. All 17 evaluable patients developed myelosuppression, with a median time to recovery of 22 days. Nearly all the (213)Bi-HuM195 rapidly localized to and was retained in areas of leukemic involvement, including the bone marrow, liver, and spleen. Absorbed dose ratios between these sites and the whole body were 1000-fold greater than those seen with beta-emitting constructs in this antigen system and patient population. Fourteen (93%) of 15 evaluable patients had reductions in circulating blasts, and 14 (78%) of 18 patients had reductions in the percentage of bone marrow blasts. This study demonstrates the safety, feasibility, and antileukemic effects of (213)Bi-HuM195, and it is the first proof-of-concept for systemic targeted alpha particle immunotherapy in humans.

14
UI - 12184278
AU - Pagano L; Pulsoni A
TI - Second malignancy after treatment of acute promyelocytic leukemia: experience of GIMEMA trials. Gruppo Italiano Malattie Ematologiche dell'Adulto.
SO - Blood 2002 Aug 15;100(4):1514-5

15
UI - 12144538
AU - Patriarca F; Fili C; Geromin A; Sperotto A; Prosdocimo S; Fanin R
TI - Activity of all-trans-retinoic acid in a case of central nervous system extramedullary relapse of acute promyelocytic leukemia.
SO - Eur J Haematol 2002 May;68(5):310-3
AD - Division of Hematology, Department of Bone Marrow Transplantation, Udine University Hospital, P. le S. Maria della Misericordia, I-13300 Udine, Italy. ematologia@dmm.uniud.it
We describe a patient with an acute promyelocytic leukemia (APL) previously treated with two courses of cytarabin, idarubicin and all-trans retinoic acid (ATRA), who presented a medullary and meningeal relapse after 8 months of complete remission. A diagnosis of central nervous system (CNS) involvement was based on the appearance of APL blasts in the cerebrospinal fluid (CSF); magnetic resonance (MR) imaging was negative. The neurological symptoms were not evident at the time of recognition of the medullary recurrence, but appeared a few days later, when the patient had already received a reinduction treatment. When the CSF was first examined, showing atypical promyelocytes, there was no excess of blasts on bone-marrow examination. The patient was treated with ATRA and intrathecal administrations of cytoxic drugs, achieving a complete long-lasting CNS remission. The appearance of mature myeloid cells in the CSF during this treatment suggested a possible differentiating effect of ATRA towards extramedullary relapse.

16
UI - 12211197
AU - Andersen MK; Pedersen-Bjergaard J
TI - Therapy-related MDS and AML in acute promyelocytic leukemia.
SO - Blood 2002 Sep 1;100(5):1928-9; discussion 1929

17
UI - 11697504
AU - Takeshita A; Shigeno K; Shinjo K; Naito K; Ohnishi K; Hayashi H;
TI - Tanimoto M; Ohno R All-trans retinoic acid (ATRA) differentiates acute promyelocytic leukemia cells independently of P-glycoprotein (P-gp) related multidrug resistance.
SO - Leuk Lymphoma 2001 Aug;42(4):739-46
AD - Department of Medicine III, Hamamatsu University School of Medicine, Japan. akihirot@hama-med.ac.jp
Here the relationship between all-trans retinoic acid (ATRA)-resistance and P-glycoprotein (P-gp)-associated multidrug resistance (MDR) is discussed in acute promyelocytic leukemia (APL). First, the remission rates of ATRA therapy are similar in relapsed/refractory APL to the preceding chemotherapy given and in newly diagnosed APL. Second, MDR1 cDNA-transduced NB4 (NB4/MDR) cells accumulate less Rhodamine-123 (Rh123) than NB4 cells, but there is no difference in the intracellular ATRA concentration between them. PSC833 or MS209. MDR modifiers, increases the intracellular accumulation of Rh123 in NB4/MDR and APL cells expressing P-gp, but not of ATRA. Third, the expression of CD11b, the NBT reduction activity, the proportion of apoptotic cells and the morphology are not different between NB4/MDR and NB4 cells, and between APL cells expressing P-gp and not. APL cells express little P-gp, and mainly express CD33 but no CD34. Despite previous reports that ATRA-resistant APL cells express more P-gp than ATRA-sensitive ones, P-gp and ATRA-resistance seems to exist independently.

18
UI - 12209692
AU - Berman E; Little C; Teschendorf B; Jones M; Heller G
TI - Financial analysis of patients with newly diagnosed acute myelogenous leukemia on protocol or standard therapy.
SO - Cancer 2002 Sep 1;95(5):1064-70
AD - Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York City, New York 10021, USA. bermane@mskcc.org
BACKGROUND: Medicare and third-party payers may be reluctant to pay for investigational (protocol) therapy for patients with cancer on the premise that such treatment is more expensive than standard therapy. However, prior studies that have attempted to compare protocol therapy with standard therapy have been difficult to interpret because of the assortment of malignancies studied and the lack of suitable control groups of patients who received standard therapy. METHODS: In the current study, the authors conducted a retrospective review of the financial charges associated with protocol or nonprotocol (standard) chemotherapy in patients with a single malignancy, newly diagnosed acute myelogenous leukemia (AML), who received their initial course of chemotherapy ("induction") at the Memorial Sloan-Kettering Cancer Center (MSKCC) between 1996 and 1999. Protocol and nonprotocol groups were analyzed according to clinical characteristics and standard prognostic features to determine whether the two groups were comparable. Median charges for all patients were determined using a database that linked clinical information, financial data, and clinical outcomes. RESULTS: A total of 353 patients with newly diagnosed AML were registered at MSKCC during the time period studied; of these, 79 patients (22%) received all of their care at the institution. Thirty patients (38%) received treatment on an investigational protocol. Forty-nine patients (62%) did not receive protocol therapy for the following reasons: 10 patients (20%) did not meet eligibility criteria, 4 patients (8%) were eligible for protocol therapy but declined, and 35 patients (71%) met protocol criteria but were not offered protocol therapy based on the judgment of their primary oncologist. The groups were not comparable because patients treated with standard therapy were older and had a poorer initial Eastern Cooperative Oncology Group (ECOG) performance status. Overall median charges for patients in the nonprotocol group were higher than for patients treated on a protocol although charges were not related to age, initial ECOG performance status, or cytogenetic risk group. CONCLUSIONS: Although charges for the nonprotocol group were higher, specific factors responsible for this difference were not identified. This study emphasizes the problems inherent in assembling suitable groups of patients for comparison. Copyright 2002 American Cancer Society.

19
UI - 11874159
AU - Nyhlen A; Ljungberg B; Nilsson-Ehle I; Nord CE
TI - Impact of combinations of antineoplastic drugs on intestinal microflora in 9 patients with leukaemia.
SO - Scand J Infect Dis 2002;34(1):17-21
AD - Department of Infectious Diseases, University Hospital of Lund, Sweden.
The impact of antineoplastic drugs on the intestinal microflora was studied in 9 patients with acute leukaemia during chemotherapy and in 5 patients also during chemotherapy-induced neutropenia. Quantitative and qualitative microbiological analyses of faecal samples obtained before and during chemotherapy showed significantly increased counts of Bacteroides spp. in 3/9 patients and, during neutropenia, significantly increased counts of yeasts in 2/5 patients; however, the intestinal microflora was stable in most patients.

20
UI - 12209593
AU - Glenjen N; Mosevoll KA; Bruserud O
TI - Serum levels of angiogenin, basic fibroblast growth factor and endostatin in patients receiving intensive chemotherapy for acute myelogenous leukemia.
SO - Int J Cancer 2002 Sep 1;101(1):86-94
AD - Section for Hematology, Department of Medicine, Haukeland University Hospital and the University of Bergen, Norway. nils.idar.glenjen@haukeland.no
Angiogenesis seems to be important both in the pathogenesis of acute myelogenous leukemia (AML) and for the susceptibility of AML blasts to chemotherapy. Recent clinical studies even suggest that antiangiogenic therapy can induce disease control in patients with AML relapse. In this context we have investigated the profile of the systemic component of angiogenic regulation in AML by characterizing the serum levels of (i) the angiogenic regulators angiogenin, basic fibroblast growth factor (bFGF) and endostatin; (ii) the endothelial cell marker soluble (s) E-selectin. Patients with untreated AML had increased levels of angiogenin, endostatin and sE-selectin, whereas the levels of bFGF were not significantly altered. The systemic levels of the proangiogenic bFGF, the antiangiogenic endostatin and the endothelial cell marker sE-selectin showed significant correlations, whereas angiogenin and sE-selectin levels were not correlated. Furthermore, intensive chemotherapy resulted in decreased systemic levels of the 2 proangiogenic mediators angiogenin and bFGF, whereas endostatin levels remained high after treatment. Although angiogenin normally is a part of the acute phase reaction, its systemic levels were not altered when patients with chemotherapy-induced cytopenia developed complicating bacterial infections. Our results suggest that intensive chemotherapy can modulate the systemic component of angiogenic regulation in AML patients. Copyright 2002 Wiley-Liss, Inc.

21
UI - 12210810
AU - Mathews V; Balasubramanian P; Shaji RV; George B; Chandy M; Srivastava A
TI - Arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: a single center experience.
SO - Am J Hematol 2002 Aug;70(4):292-9
AD - Department of Haematology, Christian Medical College and Hospital, Vellore, India. vikrammathews@hotmail.com
Arsenic trioxide (As(2)O(3)) has been found effective in the treatment in the treatment of acute promyelocytic leukemia (APML). Most studies with As(2)O(3) involve patients with APML who have relapsed following recruited for an ongoing trial of As(2)O(3) in the treatment of newly diagnosed APML. Arsenic trioxide was administered at a dose of 10 mg/day until complete remission (CR) was achieved. Afterward, a consolidation course and a maintenance schedule consisting of As(2)O(3) as a single agent were administered over 6 months. There were 3 early deaths related to intra-cerebral hemorrhage: two on day 3 and one on day 4. Of the 11 evaluable patients, one died on day 21 secondary to uncontrolled sepsis, while the remaining 10 (91%) have attained CR. The average time to CR was 52.3 days (range: 34-70 days). One patient developed an isolated central nervous system (CNS) relapse and subsequently went into a second CR following therapy with triple intrathecal chemotherapy, cranial irradiation, and an additional 4-week course of systemic As(2)O(3). This patient, as well as the remaining nine, has continued to remain in CR at a median follow up of 15 months (range: 2-33 months). Eight out of 10 patients achieved molecular remission at variable periods during their consolidation and maintenance schedules. One patient developed an ATRA syndrome and was administered daunorubicin (40 mg/day) for 2 days. The side effects with this therapy were minimal and did not require cessation of therapy in any patient. There was no significant hepatic toxicity. In our experience, arsenic trioxide is effective in inducing and maintaining remission in patients with APML with minimal side effects. The optimal regimen and total dose required need to be defined. Copyright 2002 Wiley-Liss, Inc.

22
UI - 12097997
AU - Tothova E; Fricova M; Stecova N; Kafkova A; Elbertova A
TI - High expression of Bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy.
SO - Neoplasma 2002;49(3):141-4
AD - Department of Hematology; Medical Faculty Hospital and UPJS, Kosice, 040 66 Slovakia. etothova@post.sk
Flow cytometric expression of bcl-2 protein was analyzed in 67 newly diagnosed acute myeloblastic leukemia (AML) patients using an anti-bcl-2 monoclonal antibody by direct immunofluorescence technique and results were correlated with FAB subtype, CD34 expression and clinical outcome. The number of bcl-2+ cells in each sample was heterogenous (range, 19% to 96%), with a mean of 81%. The percentage of bcl-2+ cells was higher in M0 and M1 types according to French-American-British classification. The mean fluorescence index (MFI), expressed as the ratio of sample channel:control mean channel was significantly higher (p=0.01) in M0 (19.0) and M1 (17.6) than M4 (11.7) and M5 (8.9) cytotypes. In addition, bcl-2 MFI significantly correlated both with CD34 positivity and with CD34 MFI. High percentage expression of bcl-2 and MFI index of bcl-2 was associated with a low complete remission rate after intensive chemotherapy (40.4% in cases with 20% and more positive cells vs 72% in cases with less than 20% positive cells). By statistical analysis we also demonstrated that both bcl-2 high MFI (>16) and CD34 expression are independent prognostic factors for achieving CR in AML.

23
UI - 12098004
AU - Styczynski J; Wysocki M; Balwierz W; Rokicka-Milewska R; Matysiak M;
TI - Balcerska A; Kowalczyk A; Wachowiak J; Sonta-Jakimczyk D; Chybicka A In vitro comparative antileukemic activity of various glucocorticoids in childhood acute leukemia.
SO - Neoplasma 2002;49(3):178-83
AD - Department of Pediatric Hematology and Oncology; Medical University Bydgoszcz, Bydgoszcz, 85-094 Poland. jan@styczynski-kki.net.pl
Resistance to glucocorticoids is nowadays one of the strongest adverse risk factors in the treatment of childhood acute lymphoblastic leukemia (ALL). Differential in vitro antileukemic activity of various glucocorticoids and their cross-resistance pattern in childhood acute lymphoblastic and myeloblastic leukemia was determined by means of the MTT assay in 49 successfully tested samples of childhood acute leukemia. The equivalent antileukemic concentrations of respective drugs against lymphoblasts in de novo ALL samples were: 35 microM of hydrocortisone; 8 microM of prednisolone; 1.6 microM of methylprednisolone; 0.47 microM of dexamethasone and 0.23 microM of betamethasone. In comparison to initial ALL samples, the group of relapsed ALL was more resistant to: prednisolone (38-fold, p=0.004), dexamethasone (>32-fold, p=0.004), methylprednisolone (37-fold, p=0.039), betamethasone (38-fold, p=0.018) and hydrocortisone (33-fold, p=0.030). The group of acute myeloid leukemia (AML) samples were resistant to: prednisolone (>83-fold, p<0.001), dexamethasone (>32-fold, p<0.004), methylprednisolone (>65-fold, p=0.003), betamethasone (>66-fold, p=0.004) and hydrocortisone (61-fold, p=0.007), when compared to ALL at presentation. A significant cross-resistance between all used glucocorticoids as well as between glucocorticoids and other tested anti-leukemic drugs was found. In some individual cases in vitro glucocorticoid cross-resistance was less pronounced and relatively good antileukemic activity of betamethasone was observed.

24
UI - 12144690
AU - Siu BL; Alonzo MR; Vargo TA; Fenrich AL
TI - Transient dilated cardiomyopathy in a newborn exposed to idarubicin and all-trans-retinoic acid (ATRA) early in the second trimester of pregnancy.
SO - Int J Gynecol Cancer 2002 Jul-Aug;12(4):399-402
AD - Department of Pediatrics (Cardiology), Texas Children's Hospital, 6621 Fannin, MC 19345-C, Houston, TX 77030, USA.
Acute promyelocytic leukemia was diagnosed in a 28-year-old pregnant woman at 13 gestational weeks. She was immediately started on idarubicin and all-trans-retinoic acid (ATRA) and achieved remission after her fourth cycle of treatment. Serial fetal ultrasonograms throughout pregnancy did not reveal any intrauterine growth retardation or other obvious malformations. The mother delivered a term (36.7 gestational weeks), 2720-gram female neonate. The infant was admitted to the intermediate care nursery for observation due to transient mild respiratory distress during the peripartum period. Because of right ventricular hypertrophy on an electrocardiogram, an echocardiogram was performed on the first day of life which showed moderate dilation of the right atrium and right ventricle with mildly depressed function, two small secundum atrial septal defects, and a small patent ductus arteriosus. The neonate remained hemodynamically stable and no arrhythmias were detected. The remainder of the hospital course was uneventful. When reassessed 1-1/2 months later, she was doing well and did not show any signs of congestive heart failure. A repeat echocardiogram at that time demonstrated complete resolution of the right heart enlargement and closure of the ductus arteriosus with persistence of the small and hemodynamically insignificant secundum atrial septal defects.

25
UI - 12200673
AU - Pagano L; Pulsoni A; Vignetti M; Mele L; Fianchi L; Petti MC; Mirto S;
TI - Falcucci P; Fazi P; Broccia G; Specchia G; Di Raimondo F; Pacilli L; Leoni P; Ladogana S; Gallo E; Venditti A; Avanzi G; Camera A; Liso V; Leone G; Mandelli F; GIMEMA Acute megakaryoblastic leukemia: experience of GIMEMA trials.
SO - Leukemia 2002 Sep;16(9):1622-6
AD - Cattedra di Ematologia, Universita Cattolica S. Cuore, Roma, Italy.
The objective of the study was to evaluate the incidence, characteristics, treatment and outcome of acute megakaryoblastic leukemia (AMeL) in patients enrolled in GIMEMA trials. Between 1982 and 1999, 3603 new consecutive cases of AML aged over 15 years were admitted to GIMEMA trials. Of them, 24 were AMeL. The incidence of AMeL among AML patients enrolled in GIMEMA trials was 0.6% (24/3603). Diagnosis was based on morphological criteria. Out of 11 cytogenetic studies performed two presented chromosome 3 abnormalities. Twelve patients (50%) reached a CR, five (21%) died in induction and seven (27%) were unresponsive. The median duration of CR was 35 weeks (range 10-441). Seven patients underwent transplantation procedures (1 BMT, 4 aBMT, 2 aPBSCT). Four patients died in CR due to chemotherapy-related complications. Comparing the CR rate between AMeL and the other cases of AML enrolled in GIMEMA trials, no differences were observed. These results were mirrored for different age groups. The median survival was 40 weeks. At present, after a follow-up of a minimum of 2 years, only two patients are alive in CR, all the others having died. A 5-year Kaplan-Meier curve shows a disease-free survival of 17% and an actuarial overall survival of 10%. AMeL is a rare form of AML. The CR duration and the overall survival in this group of patients are very poor, even if similar to those observed in other AML. Furthermore, a high number of deaths in CR were observed. On the basis of these data, a specific therapeutic approach, possibly with innovative treatments, should be evaluated.

26
UI - 12200720
AU - Garcia-Manero G; Kantarjian HM; Kornblau S; Estey E
TI - Therapy-related myelodysplastic syndrome or acute myelogenous leukemia in patients with acute promyelocytic leukemia (APL).
SO - Leukemia 2002 Sep;16(9):1888

27
UI - 12203219
AU - Chim CS; Lam CC; Wong KF; Man C; Kam S; Kwong YL
TI - Atypical blasts and bone marrow necrosis associated with near-triploid relapse of acute promyelocytic leukemia after arsenic trioxide treatment.
SO - Hum Pathol 2002 Aug;33(8):849-51
AD - Department of Medicine and Pathology, Queen Mary Hospital and Department of Pathology, Queen Elizabeth Hospital, Hong Kong.
The pathologic features of acute promyelocytic leukemia (APL) with t(15;17)(q22;q21) are highly characteristic, which with few exceptions enable a firm diagnosis to be made on morphologic grounds. An APL patient in first relapse presented with large, bizarre circulating blasts and bone marrow necrosis 2 weeks after chemotherapy consolidation for an arsenic trioxide-induced remission. Although a morphologic diagnosis could not be reached, cytogenetic investigations showed a near-triploid clone with t(15;17), confirming APL in second relapse. This case showed that clonal evolution with additional karyotypic aberrations might alter the blast morphology and pathologic features in APL. Copyright 2002, Elsevier Science (USA). All rights reserved.

28
UI - 11753550
AU - Kumar S; Chen MG; Gastineau DA; Gertz MA; Inwards DJ; Lacy MQ; Tefferi
TI - A; Litzow MR Effect of slow lymphocyte recovery and type of graft-versus-host disease prophylaxis on relapse after allogeneic bone marrow transplantation for acute myelogenous leukemia.
SO - Bone Marrow Transplant 2001 Nov;28(10):951-6
AD - Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Allogeneic BMT is potentially curative for patients with acute myelogenous leukemia (AML) in first remission. However, many patients relapse after transplantation. Various immunotherapeutic options have been attempted with variable success in preventing relapse. Early identification of patients at high risk for relapse could allow prompt intervention. We examined the effect of slow lymphocyte recovery after sibling-matched allogeneic BMT on the risk of relapse in patients with AML. We also examined the effect of prednisone-containing GVHD prophylaxis on the rate of lymphocyte recovery. Patients with absolute lymphocyte count (ALC) <150 x 10(6)/l by day +30 had a 3.5-fold higher risk of relapse (P = 0.0088) and a lower overall survival (P = 0.0079) than patients with a higher ALC. We did not find correlation between lymphocyte count determined earlier in the post-transplantation course (day +21) and the risk of relapse. Patients receiving prednisone had a significantly lower ALC at day +30 than those who did not receive prednisone (289 vs 549 x 10(6)/l, P = 0.002). We conclude that a slow lymphocyte recovery after allogeneic BMT for AML is strongly predictive of subsequent relapse and that the type of GVHD prophylaxis should be considered when analyzing lymphocyte recovery.

29
UI - 12139723
AU - Koistinen P; Zheng A; Saily M; Siitonen T; Mantymaa P; Savolainen ER
TI - Superior effect of 9-cis retinoic acid (RA) compared with all-trans RA and 13-cis RA on the inhibition of clonogenic cell growth and the induction of apoptosis in OCI/AML-2 subclones: is the p53 pathway involved?
SO - Br J Haematol 2002 Aug;118(2):401-10
AD - Department of Internal Medicine, University Hospital of Oulu, PO Box 20, 90029 Oulu, Finland. pirjo.koistinen@ppshp.fi
In the present study, the effects of 9-cis retinoic acid (RA) and 13-cis RA on acute myeloblastic leukaemia (AML) cell growth and the induction of apoptosis as well as its relationship with bcl-2 and p53 were compared with those of all-trans RA (ATRA). The study was performed with the subclones of the retinoid-sensitive OCI/AML-2 cell line. The most prominent inhibitory effect on clonogenic cell growth and morphological apoptosis was shown by 9-cis RA. In addition, Western blotting revealed the most obvious translocation of p53 from cytosol to nucleus in the case of 9-cis RA, which was the only retinoid able to change the conformation of p53 from mutational to wild type, as demonstrated by flow cytometry. There was no difference between the retinoids in the downregulation of bcl-2 as analysed by Western blotting and flow cytometry. The RA receptor (RAR)-alpha antagonist had no effect on apoptosis in any of the three retinoids studied using the annexin V method. In conclusion, this study shows that 9-cis RA was a more potent agent than ATRA or 13-cis RA in inducing growth arrest and apoptosis in the OCI/AML-2 subclones. The effect was associated with the downregulation of bcl-2 and was hardly mediated through the RAR-alpha receptor, but might be related to the activation of p53.

30
UI - 12195161
AU - Fabiani R; De Bartolomeo A; Rosignoli P; Servili M; Montedoro GF;
TI - Morozzi G Cancer chemoprevention by hydroxytyrosol isolated from virgin olive oil through G1 cell cycle arrest and apoptosis.
SO - Eur J Cancer Prev 2002 Aug;11(4):351-8
AD - Dipartimento di Scienze Biochimiche e Biotecnologie Molecolari, Sezione di Scienze Igienistiche e Ambientali, Universita di Perugia, Via del Giochetto, 06126 Perugia, Italy.
Recent epidemiological evidence and animal studies suggest a relationship between the intake of olive oil and a reduced risk of several malignancies. The present study assesses the effect of hydroxytyrosol, a major antioxidant compound of virgin olive oil, on proliferation, apoptosis and cell cycle of tumour cells. Hydroxytyrosol inhibited proliferation of both human promyelocytic leukaemia cells HL60 and colon adenocarcinoma cells HT29 and HT29 clone 19A. The con-centrations of hydroxytyrosol which inhibited 50% of cell proliferation were approximately 50 and approximately 750 micromol/l for HL60 and both HT29 and HT29 clone 19A cells, respectively. At concentrations ranging from 50 to 100 micromol/l, hydroxytyrosol induced an appreciable apoptosis in HL60 cells after 24 h of incubation as evidenced by flow cytometry, fluorescence microscopy and internucleosomal DNA fragmentation. Interestingly, no effect on apoptosis was observed after similar treatment of freshly isolated human lymphocytes and polymorphonuclear cells. The DNA cell cycle analysis, quantified by flow cytometry, showed that the treatment of HL60 cells with hydroxytyrosol 50-100 micromol/l arrested the cells in the G0/G1 phase with a concomitant decrease in the cell percentage in the S and G2/M phases. These results support the hypothesis that hydroxytyrosol may exert a protective activity against cancer by arresting the cell cycle and inducing apoptosis in tumour cells, and suggest that hydroxytyrosol, an important component of virgin olive oil, may be responsible for its anticancer activity.

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