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PubMed2003

[The early efficacy of imatinib in the treatment of 54 cases of chronic myeloid leukemia].

OBJECTIVE: To observe the early outcome of imatinib in the treatment of chronic myeloid leukemia (CML). METHODS: There were 54 CML patients including 17 patients in chronic phase (CP), 13 patients in accelerated phase (AP) and 24 patients in blast crisis (BC). The dosage of imatinib is 400 mg/day for CP patients and 600 mg/day for AP and BC patients. The prescribed dose was administrated orally, once daily after a meal with a large glass of water. Before starting the imatinib administration, all the patients had thorough physical examination as well as blood and bone marrow examination, Ph chromosome and or the bcr/abl fusion-gene detection. Blood picture was examined twice a week in the first month of administration and thereafter weekly or fortnightly in the following days. Hepatic and renal function was tested fortnightly or every four weeks. Patients had bone marrow examination, Ph chromosome and or the bcr/abl fusion-gene detection again when they achieved a hematological response (CR). Dose was adjusted from time to time according to the results of blood examination and the patients tolerance to the drug. RESULTS: After a median 5-month period of follow-up, all the 17 CP patients achieved complete hematological response, including 6 cases (35.2%) whose Ph chromosome turned negative after treatment. 8 (61.5%) out of the 13 AP patients and 9 (37.5%) out of the 24 BC patients returned to chronic phase respectively. Adverse events included myelosuppression, periorbital edema or edema of the lower limbs, myalgia and muscle cramps, nausea, vomiting, low fever, tetter and bilirubin increasing. CONCLUSIONS: imatinib has good early efficacy in the treatment of CML and the therapeutic result is the best in the CP patients, next in the AP patients and relatively poor in the BP patients. The long term outcome of imatinib needs further observation. Patients have a good tolerance to imatinib.

Adolescent↗
PubMed2003

Cytogenetic and molecular mechanisms of resistance to imatinib.

Selective inhibition of the BCR-ABL tyrosine kinase by imatinib (Gleevec) (formerly STI571) is a promising new therapeutic strategy in patients with chronic myelogenous leukemia (CML). Despite significant hematologic and cytogenetic responses, resistance occurs in patients with chronic phase (CP) and advanced disease. A cohort of 72 patients with CML in myeloid blast crisis (BC) (n = 34), lymphoid BC (n = 2), accelerated phase (AP) (n = 16), CP (n = 18), and BCR-ABL(+) acute lymphoblastic leukemia (ALL) (n = 2) resistant to imatinib were investigated. Median levels of BCR-ABL transcripts, determined by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR), were not significantly changed at the time of resistance, but seven of 55 patients showed a greater than 10-fold increase in BCR-ABL levels. Genomic amplification of BCR-ABL was found in two of 32 patients evaluated by fluorescence in situ hybridization (FISH). Additional chromosomal aberrations were observed in 19 of 36 patients and point mutations of the ABL tyrosine kinase domain resulting in reactivation of the BCR-ABL tyrosine kinase were detected in 29 of 72 patients. Resistance may be caused by BCR-ABL-independent or BCR-ABL-dependent mechanisms. A thorough evaluation of resistant cases is required to suggest therapeutic measures in the individual case. Clonal selection of resistant cells harboring a BCR-ABL mutation might be reversed by stopping imatinib therapy and switching to chemotherapy. Combination therapy from the start of treatment to reduce the frequency of resistance is currently being evaluated with several drugs.

Benzamides↗
PubMed1991

Abnormal methylation of the calcitonin gene marks progression of chronic myelogenous leukemia.

The clinical aspects of disease progression in chronic myelogenous leukemia (CML) are well established, but the nature of the molecular events responsible is not known. We have previously reported a consistent pattern of novel sites of methylation in the 5' region of the calcitonin (CT) gene and other chromosome 11p loci in acute myelogenous and and lymphoid leukemias. In the present study, CT gene methylation patterns were investigated in peripheral blood from 51 patients with CML. Abnormal patterns were found in only 2 of 31 patients in chronic phase, but in 5 of 8 patients in accelerated phase, and in 11 of 12 patients in blast crisis (P less than .005). For one patient studied in blast crisis, abnormal CT gene methylation was found in the peripheral blast cells but not in the granulocytes. In two of three patients studied with CML and having normal peripheral cell patterns, abnormal patterns were found in marrow blast cells. In one patient, only partial normalization of the CT gene methylation pattern was seen after chemotherapy induction of a second chronic phase and the patient relapsed 5 months later. Our findings indicate that abnormal methylation of the 5' region of the CT gene is regularly a marker of disease progression in CML which may prove clinically useful. This abnormal methylation site is part of an imbalance in DNA methylation that may play a role in the progressive genetic instability which characterizes the advancing stages of CML.

Biomarkers, Tumor↗
PubMed2005

Validation of the EBMT risk score in chronic myeloid leukemia in Brazil and allogeneic transplant outcome.

BACKGROUND AND OBJECTIVES: The management of chronic myeloid leukemia (CML) has changed radically since the introduction of imatinib therapy. The decision of whether to offer a patient a hematopoietic stem cell transplant (HSCT) must be based on the probability of success of the procedure. The aim of this retrospective analysis of 1,084 CML patients who received an allogeneic HSCT in 10 Brazilian Centers between February 1983 and March 2003 was to validate the EBMT risk score. DESIGN AND METHODS: The study population comprised 647 (60%) males and 437 (40%) females, with a median age of 32 years old (range 1 - 59); 898 (83%) were in chronic phase, 146 (13%) were in accelerated phase and 40 (4%) were in blast crisis; 151 (14%) were younger than 20 years old, 620 (57%) were between 20 and 40 and 313 (29%) were older than 40; 1,025 (94%) received an HLA fully matched sibling transplant and only 59 (6%) received an unrelated transplant. In 283 cases (26%) a male recipient received a graft from a female donor. The interval from diagnosis to transplantation was less than 12 months in 223 (21%) cases and greater in 861 (79%). The overall survival, disease-free survival, transplant-related mortality and relapse incidence were 49%, 50%, 45% and 25%, respectively. RESULTS: Of the 1084 patients, 179 (17%) had a risk score of 0 or 1, 397 (37%) had a score of 2, 345 (32%) had a score of 3, 135 (12%) had a score of 4 and 28 (2%) a score of 5 or 6. The overall survival (OS) rate in patients with risk scores 0-1 and 2 was similar (58% and 55%, respectively) but significantly better than that in patients with scores 3 or more (score 3 - 44%, 4 - 36 % and 5-6 - 27%, respectively) pp<0.001). Disease-free survival (DFS) and transplant related mortality (TRM) in a patients with a score of 3 or more were 46% and 49%, respectively and the relapse rate beyond score 5-6 was 77%. Disease status had a negative impact on all outcomes (OS, DFS, TRM, and relapse). The OS rate for male recipients of a graft from a female donor was 40% compared to 52% among the other donor-recipient pairs (p=0.004). DFS and TRM were significant for disease phase and female donor-male recipient (p<0.001 and p<0.003, respectively). In our experience, age and interval between diagnosis and transplant did influence OS, DFS, TRM, and relapse rate. INTERPRETATION AND CONCLUSIONS: Our results validate the EBMT risk score in the context of a developing country and confirm its usefulness for making point decisions in the imatinib era.

Adolescent↗
PubMed1995

Interferon-alpha and interleukin-2 as treatment for leukemia relapse after allogeneic bone marrow transplantation.

We treated 12 patients with leukemia relapse after allogenic bone marrow transplantation with a combination of interferon-alpha (IFN-alpha) ((2.5-5.0) x 10(6) u/m2 subcutaneously three times a week) and interleukin-2 (IL-2) ((1.8-3.6) x 10(6) IU/m2 subcutaneously five times a week) to determine the toxicity and efficacy of combination cytokine therapy in this setting. The median age of the patients was 39 years (range: 16-50). There were nine females and three males. The median time to relapse from BMT was 98 days (range: 0-963). At the time of relapse, six patients had AML, four patients had CML (two in blast crisis and two in chronic phase with clonal evolution), and one patient had lymphoblastic lymphoma. Combination cytokine therapy was started a median of 108 days post BMT (range: 37-2404). Nine patients treated at the higher dose level required a 50% dose reduction because of toxicity or GVHD (three CNS, two GVHD, one high fever, one diarrhoea with hypotension, and one pericarditis). At a lower dose level, 2 of 10 patients had their treatment discontinued because of toxicity or GVHD. Six patients developed clinical findings consistent with acute GVHD while on combination cytokine therapy. Two patients responded to combination cytokine therapy: one with CML and one with AML. Combination cytokine therapy is feasible in the setting of relapse post allogeneic BMT. The combination of IL-2 1.8 x 10(6) IU/m2 five times a week with IFN-2 2.5 x 10(6) U/m2 three times a week seems to be tolerable, and merits further study in this setting.

Acute Disease↗
PubMed2001

Increased myeloperoxidase index and large unstained cell values can predict the neutropenia phase of cancer patients treated with standard dose chemotherapy.

OBJECTIVE: The objective of this study was to better understand neutropenia induced by standard dose chemotherapy and to verify if there are any hematological parameters for defining the phase and possibly the duration of neutropenia. METHODS: The kinetics of large unstained cells (LUCs) and lymphocytes was evaluated in 324 blood counts of 56 chemotherapy cycles through the use of a Technicon H2 or an ADVIA 120 hematology analyzer. Blood samples collected during the neutropenia phase were also studied by flow cytometry using a large panel of monoclonal antibodies. Parametric and nonparametric statistics were employed to compare the different variables analyzed. A linear regression between each variable before and after nadir and a simple linear correlation among the same variables in the neutropenic and recovery phase were performed. RESULTS: The percentage of LUCs reaches the higher value at nadir and the difference between the mean value of prenadir and nadir is statistically significant (P <.01). The number of LUCs increases during the pre and postnadir phase. Lymphocytes number appears stable in the prenadir phase. The MPXI index increases in the prenadir phase and falls at nadir and this difference is statistically significant(P <.01). LUCs are correlated with blasts and CD34+ cells in the pre and postnadir phase, with CD3+/CD4+ cells in the prenadir phase, and with CD2+/CD56+ in the postnadir phase. CONCLUSIONS: Our data have shown that the estimation of both percentage of LUCs and MPXI can predict the neutropenia phase and orient for its duration. The lymphocyte number may be regarded as a parameter of risk of fever after day 5 of chemotherapy and the number of blood CD34+ cells may be predicted by LUC count.

Adult↗
PubMed1999

Chromosomal aberrations during progression of chronic myeloid leukemia identified by cytogenetic and molecular cytogenetic tools: implication of 1q12-21.

To study the genomic abnormality underlying the acute transformation of chronic myeloid leukemia (CML), 15 CML patients in blast crisis (BC), 3 in accelerated phase (AP), and 20 in chronic phase (CP) were analyzed by conventional cytogenetics, comparative genomic hybridization (CGH), and dual-color chromosomal painting. Philadelphia (Ph) chromosome was identified in every case studied. Only 5 among 20 CP patients had additional abnormalities while 13 of 18 patients with disease progression (BC + AP) showed extra numerical and/or structural chromosomal aberrations. Cytogenetically, the most common chromosome gains during BC and AP were double or triple Ph chromosomes (5 of 14 cases) and trisomy 8 (5 of 14 cases). Trisomies 7 and 17 (1 of 14 cases each) were also observed. CGH analysis detected genetic imbalances in eight cases. Gains of chromosome 20 (3 cases) and 17q (2 cases) were observed, respectively. The recurrent chromosome loss was the deletion of the short arm of chromosome 17, seen in one case with i(17)(q10) and one case with an unbalanced translocation (1;17). In one case, a very complex chromosomal rearrangement, del(3),del(6),der(6)t(17;3;6),der(17)t(6;17), was seen. A novel finding of this work is the involvement of chromosome 1(q12-21qter) in CML disease progression. Overrepresentation of 1(q12-21qter) region was detected by CGH in one case which had a derivative chromosome 17. This abnormal chromosome was later confirmed by fluorescence in situ hybridization (FISH) painting to be a fusion between chromosome 1 and 17 to form the der(17)t(1;17) (q12-21;p11). Two other cases showed the same region being involved in translocations, t(1;10)(q12-21;q26) and t(1;11)(q12-21;p15). It is possible that one or more genes residing on chromosome 1q12-21 may be important in the acute transformation of CML. In conclusion, we find that the combined use of CGH, chromosome painting, and classic cytogenetic analysis allows a better evaluation of the genomic aberration involved in CML blastic transformation, and offers new directions for its further molecular investigations.

Adult↗
PubMed1999

Malignancy: A New Approach to the Analysis of Apoptosis in the Leukemic Subpopulation by Flow Cytometry Using a CD45 Gating Strategy.

Bone marrow and peripheral blood are heterogeneous tissues containing cells of different hematopoietic lineages. It is possible to detect leukemic cells by flow cytometry using a gating strategy, which combines CD45 expression on the cell surface with right angle light scatter (SS). This approach was applied to 15 cases of AML. Myeloblasts had the lowest CD45 fluorescence intensity of any of the cells in the myeloid series and also had the lowest SS, approximately equivalent to monocytes, but greater than lymphoblasts and lymphocytes. Using this gating strategy in each sample we could identify up to 5 separate cell compartments. Our results showed good correlation between the flow differential and the manual differential cell count. However in some cases, especially when a sample became hypocellular, the flow differential was more sensitive in identifying leukemic blasts. Total apoptosis (i.e. apoptosis in all cell populations combined) varied during the treatment between 0-34%. In the blood, the highest percentage of total apoptotic cells usually occurred between day 3-5 of treatment. The percentage of apoptotic cells varied depending on the cell type on a percentage basis. The leukemic population was lesslikely to undergo apoptosis compared to the lymphocytes, monocytes and more mature myeloid cells. In normal cells, apoptosis occurred mostly in G(1) and S phases of the cell cycle. Apoptosis among CD45-blasts usually varied between 0-5%. Myeloblasts also had a tendency to undergo apoptosis in G(1) and S phases of the cell cycle. The CD45-blast apoptotic peak in the blood occurred between day 5-7 of treatment. Analysis of drug-induced apoptosis in bone marrow seems to provide more information than such measurements in peripheral blood.

Journal Article↗
PubMed1979

Premature chromosome condensation studies in human leukemia. I. Pretreatment characteristics.

The phenomenon of premature chromosome condensation (PCC) was used to compare the bone marrow proliferation characteristics of 163 patients with various forms of leukemia prior to the initiation of new therapy. The proliferative potential index (PPI, or fraction of G1 cells in late G1 phase) and the fraction of cells in S phase was determined and compared to the type of disease and the bone marrow blast infiltrate for each patient. Previously untreated patients with acute leukemia exhibited an average PPI value three times that of normal bone marrow (37.5% for acute myeloblastic leukemia [AML], acute monomyeloblastic leukemia [AMML], or acute promyelocytic leukemia [APML] and 42% for acute lymphocytic leukemia [ALL] or acute undifferentiated leukemia [AUL]). Untreated chronic myelogenous leukemia (CML) patients showed intermediate PPI values (25.2%), whereas CML patients with controlled disease exhibited nearly normal PPI values (14.6%). On the other hand, blastic-phase CML patients exhibited PPI values closer to that observed in patients with acute leukemia (35.4%). Seven patients with chronic lymphocytic leukemia (CLL) exhibited even higher PPI values. No correlations were observed between PPI values, fraction of cells in S phase, and marrow blast infiltrate. For untreated acute disease patients, PPI values were prognostic for response only at low and high PPI values. These results suggest that the PCC-determined proliferative potential is a biologic reflection of the degree of malignancy within the bone marrow.

Bone Marrow↗
PubMed1975

Antibody responses to leukemia-associated antigens during immunotherapy of chronic myelocytic leukemia.

We have studied immunologic reactivity to leukemia-associated antigens in patients with chronic myelocytic leukemia (CML) treated with chemotherapy and adjunctive immunotherapy. All patients were immunologically competent as measured by skin test reactivity to dinitrochlorobenzene. Immunotherapy consisted of allogeneic irradiated leukemic myeloblasts injected intradermally, with BCG vaccine (Research Foundation, Chicago, Ill.) given by multiple puncture at the same site. 10(9) cells plus BCG were given weekly for 4 wk, and 10(8) cells plus BCG were given at monthly intervals thereafter. Eight patients judged clinically to be in the stable phase of their disease developed circulating antibody against the immunizing blast cells demonstrable by cytotoxicity and immunofluorescence assays. The antibody also showed reactivity against a panel of myeloblasts (12 paients) but not against the corresponding remission lymphocytes (five patients) or normal lymphocytes (20 donors). In two cases the antibody showed reactivity against the patient's own leukemic blasts. Seven of these eight patients have maintained a steady clinical course ranging from 20 to 40 mo, while one entered the blastic phase and died. Six patients were judged to be in the aggressive phase of CML because of progressive leukocytosis and splenomegaly or increasing myeloblastosis; five died an average of 16 mo after diagnosis. Humoral antibodies were not detected in these patients after repeated courses of BCG and allogeneic leukemic cells. We conclude that specific active immunotherapy of patients with CML can abet the production of humoral antibody against blast cell antigens and that this response may be impaired during the aggressive phase of the disease.

Adult↗
PubMed2006

Gene expression profiling of CD34+ cells identifies a molecular signature of chronic myeloid leukemia blast crisis.

Despite recent success in the treatment of early-stage disease, blastic phase (BP) of chronic myeloid leukemia (CML) that is characterized by rapid expansion of therapy-refractory and differentiation-arrested blasts, remains a therapeutic challenge. The development of resistance upon continuous administration of imatinib mesylate is associated with poor prognosis pointing to the need for alternative therapeutic strategies and a better understanding of the molecular mechanisms underlying disease progression. To identify transcriptional signatures that may explain pathological characteristics and aggressive behavior of BP blasts, we performed comparative gene expression profiling on CD34+ Ph+ cells purified from patients with untreated newly diagnosed chronic phase CML (CP, n=11) and from patients in BP (n=9) using Affymetrix oligonucleotide arrays. Supervised microarray data analysis revealed 114 differentially expressed genes (P<10(-4)), 34 genes displaying more than two-fold transcriptional changes when comparing CP and BP groups. While 24 of these genes were downregulated, 10 genes, especially suppressor of cytokine signalling 2 (SOCS2), CAMPATH-1 antigen (CD52), and four human leukocyte antigen-related genes were strongly overexpressed in BP. Expression of selected genes was validated by real-time-polymerase chain reaction and flow cytometry. Our data suggest the existence of a common gene expression profile of CML-BP and provide new insight into the molecular phenotype of blasts associated with disease progression and high malignancy.

Adult↗
PubMed1997

Tandem duplication of the MLL gene in myelodysplastic syndrome-derived overt leukemia with trisomy 11.

Trisomy 11 as a sole chromosomal abnormality is a rare aberration observed in myelodysplastic syndrome (MDS) or acute myeloblastic leukemia (AML). Recently a partial tandem duplication of the MLL gene, located on chromosome band 11q23, has been identified in de novo AML with trisomy 11. We describe a 72-year-old woman suffering from MDS-derived overt leukemia with trisomy 11 and a tandem duplication of the MLL gene. At first the patient was found to have myeloblasts with Auer rods in the peripheral blood and diagnosed as MDS, refractory anemia with excess of blasts in transformation (RAEB-T). After 2 months a picture of overt leukemia (AML; M2) developed as shown by an increased number of myeloblasts. Various chemotherapy regimens had little effect, and she died of disease progression 15 months after admission. During her clinical course, the chromosome analyses consistently showed 47,XX, +11. Southern blot analysis of leukemic blasts on admission and in accelerated phase revealed identical rearranged bands of the MLL gene. Fluorescence in situ hybridization analysis excluded the possibility of masked translocation of the MLL gene to other chromosomes. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis using a forward exon 6 primer and a backward exon 3 primer demonstrated an in-frame fusion of exon 8 with exon 2. Our results indicated that a partial tandem duplication of exons 2-8 of the MLL gene could be observed in MDS-derived overt leukemia as well as de novo AML with trisomy 11.

Aged↗
PubMed2002

Multicolor COBRA-FISH analysis of chronic myeloid leukemia reveals novel cryptic balanced translocations during disease progression.

During the initial indolent chronic phase of chronic myeloid leukemia (CML), the t(9;22)(q34;q11), resulting in the Philadelphia chromosome (Ph), is usually the sole cytogenetic anomaly, but as the disease progresses into the accelerated phase (AP), and eventually into aggressive blast crisis (BC), secondary aberrations, mainly unbalanced changes such as +8, i(17q), and +Ph, are frequent. To date, molecular genetic studies of CML BC have mainly focused on alterations of well-known tumor-suppressor genes (e.g., TP53, CDKN2A, and RB1) and oncogenes (e.g., RAS and MYC), whereas limited knowledge is available about the molecular genetic correlates of the unbalanced chromosomal abnormalities. Balanced secondary changes are rare in CML AP/BC, but it is not known whether cryptic chromosomal translocations, generating fusion genes, may be responsible for disease progression in a subgroup of CML. To address this issue, we used multicolor combined binary ratio fluorescence in situ hybridization (FISH), which allows the simultaneous visualization of all 24 chromosomes in different colors, verified by locus-specific FISH in a series of 33 CML cases. Two cryptic balanced translocations, t(7;17)(q32-34;q23) and t(7;17)(p15;q23), were found in two of the five cases showing the t(9;22) as the only cytogenetic change. Using several BAC clones, the breakpoints at 17q23 in both cases were mapped within a 350-kb region. In the case with the 7p15 breakpoint, a BAC clone containing the HOXA gene cluster displayed a split signal, suggesting a possible creation of a fusion gene involving a member of the HOXA family. Furthermore, one case with a partially cryptic t(9;11)(p21-22;q23) and an MLL rearrangement as well as a previously unreported t(3;10)(p22;p12-13) were identified. Altogether, a refined karyotypic description was achieved in 12 (36%) of the 33 investigated cases, illustrating the value of using multicolor FISH for identifying pathogenetically important aberrations in CML AP/BC.

Adolescent↗
PubMed1988

Expression of membrane activation antigens on murine B lymphocytes stimulated with lipopolysaccharide.

The expression of two membrane glycoproteins, RL388 antigen and transferrin receptor (TfR), was examined on murine B cells stimulated with lipopolysaccharide (LPS) in vitro. Immunofluorescent staining with monoclonal antibodies and flow cytofluorometric analysis were used to monitor the expression of these markers as a function of the time in culture, the state of membrane Ia antigen expression, the position in cell cycle, and the degree of B-cell differentiation. Freshly explanted splenic B cells expressed low levels of RL388 antigen and TfR. Following LPS stimulation, increased expression of RL388 antigen was detectable by 8 to 12 hr of culture, a time span characterized by increased Ia antigen expression, blast transformation, and G0 to G1 phase transition. The increased expression of TfR was apparent later and correlated with entry into late G1 phase and the onset of S phase. LPS-stimulated cell cultures treated with actinomycin D (G0/G1 block) exhibited increased expression of Ia antigen, but neither RL388 antigen nor TfR, whereas hydroxyurea treatment (G1/S block) allowed expression of all three markers. These results indicate that hyperexpression of RL388 antigen and TfR occurs during G1 phase and that these events are subsequent to Ia antigen hyperexpression. Finally, B cells in late G1 through M phase of the cell cycle simultaneously express high levels of RL388 antigen and TfR. These findings suggest that the expression patterns of RL388 antigen and TfR might be useful parameters for defining compartments of the murine B-cell cycle.

Animals↗
PubMed2005

Intermittent hypoxia causes REM sleep deficits and decreases EEG delta power in NREM sleep in the C57BL/6J mouse.

BACKGROUND AND PURPOSE: Obstructive sleep apnea (OSA) severely impairs sleep architecture. We hypothesized that both intermittent hypoxia (IH) and non-hypoxic arousals of OSA result in significant disruption of non-rapid eye movement sleep (NREMS) and rapid eye movement sleep (REMS). PATIENTS AND METHODS: Polysomnography was performed in C57BL/6J mice (n=5) exposed to IH (cycling of FIO2 from 20.9 to 5.0%) or sleep fragmentation (SF: high flow air blasts) throughout the 12-h light phase over 5 consecutive days. RESULTS: Both IH and SF induced arousals from sleep. On Day 1 of exposure, total NREMS during the light phase decreased comparably during IH (44.1+/-7.8%/12h, P<0.05) and SF (43.7+/-3.3%/12h, P<0.05) but returned to baseline levels of 62.0+/-7.8%/12h by Day 5 of exposure under both conditions. During IH, however, the electroencephalographic (EEG) delta power of NREMS remained impaired throughout the 5-day period of IH with a nadir of 65.4+/-5.6% relative to baseline (P=0.01), and REMS was effectively abolished during the light phase. In contrast, SF did not cause a significant reduction in either EEG delta power or REMS during the light phase. CONCLUSIONS: Thus, hypoxic exposure, but not arousals, caused overall deficits in the EEG delta power of NREMS and marked deficits in the total amount of REMS. We propose that hypoxic arousals may have a more severe impact on sleep architecture in patients with OSA than non-hypoxic arousals.

Animals↗
PubMed2003

Gemtuzumab ozogamicin, fludarabine, cytarabine and cyclosporine combination regimen in patients with CD33+ primary resistant or relapsed acute myeloid leukemia.

Clinical resistance to gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukemia (AML) is associated with blast multidrug resistance (MDR) phenotype. A Phase II study of Mylotarg, fludarabine, ara-C and the MDR-modifier, cyclosporine (CSA) (MFAC) was conducted in 32 patients with primary resistant (11, 34%) or relapsed (21, 66%) AML. Nine (28%) patients obtained complete remission (CR), two (6%) CR with incomplete platelet recovery. Overall median survival was 5.3 months, 12-month survival rate 19%. Fourteen patients (44%) developed grade 3/4 hyperbilirubinemia; six (18%) grade 3/4 hepatic transaminitis; three (9%) hepatic veno-occlusive disease (VOD). CSA inclusion in gemtuzumab ozogamicin-based regimens is feasible. MFAC is an effective regimen for refractory AML.

Acute Disease↗
PubMed2002

Expression of CD4 on peripheral blood granulocytes. a novel finding in a case of myelodysplastic syndrome in association with t(5;12).

Myelodysplastic syndromes (MDS) are associated with cell maturation defects that can manifest as abnormal surface antigen expression. We describe a patient with refractory anemia with excess blasts, who presented with infection and extensive dysplastic features in peripheral blood granulocytes. The granulocytes expressed CD11b, CD13, CD15, CD33, and CD43. The granulocytes also expressed CD4 antigen. Cytogenetic analysis showed a clonal t(5;12)(q33;p13). The patient improved on antibiotics with partial improvement in the dysplastic features. However, shortly after, the patient experienced paravertebral extramedullary blast transformation followed by a leukemia phase of acute monoblastic leukemia. The patient died a few days later. This is the first report describing anomalous expression of CD4 on granulocytes in MDS. Since the breakpoint on chromosome 12 is near the CD4 gene, which is mapped to 12p12, we hypothesize that dysregulation of the CD4 gene may have occurred resulting in its persistent expression on mature and maturing granulocytes.

CD4 Antigens↗
PubMed2003

Molecular pathogenesis of chronic myeloid leukaemia.

The abnormal haemopoietic precursor cells of chronic myeloid leukaemia (CML) carry the cytogenetic abnormality [t(9;22)(q34;q11)]--a reciprocal translocation that results in the expression of a chimaeric protein derived from the fused BCR and ABL genes. This Bcr-Abl protein tyrosine kinase mediates an array of effects on signal transduction pathways affecting cell survival, proliferation, adhesion and genetic stability. The end-result of these abnormal signalling processes is a bi- or triphasic clinical disease. Initially, CML is characterised by the presence of an excess of myeloid progenitor cells and their mature progeny. This chronic phase of CML is followed, either directly or with an intervening 'accelerated phase', by a stage where primitive blast cells predominate (acute transformation). This review discusses the role of Bcr-Abl-mediated signalling events in cellular transformation, genetic instability and disease progression in CML, and describes current developments in CML treatment using a Bcr-Abl inhibitor.

Chromosome Mapping↗