BACKGROUND: The category, cytology, cytogenetics (CCC) system for myelodysplastic syndrome (MDS) and the pediatric WHO system for MDS/myeloproliferative disorder (MPD) have recently been proposed to characterize these diseases in pediatrics. OBJECTIVE: We compare the CCC and pediatric WHO systems against each other and against the French, American, British (FAB) and adult WHO classifications in order to determine which more accurately classifies these diseases and predicts outcome. METHODS: An 18-year retrospective review identified patients less than 18 years of age meeting CCC and/or pediatric WHO criteria for the diagnosis of MDS or MPD. Resolution, stability, progression, and death in the subcategories of each system were compared. RESULTS: Twenty-eight patients were included in the study. Pediatric WHO: 17 patients met criteria, 10 died. Eight developed acute myelogenous leukemia (AML) (seven died), one juvenile myelomonocytic leukemia (JMML) (died), one chronic myelomonocytic leukemia (CMML) (currently in relapse), two died of complications, two responded to BMT, three have stable disease, one resolved. Eleven patients were not classifiable by the pediatric WHO system, one of which progressed to AML and died. CCC: 26 patients met criteria, 9 died. Nine developed AML (8 died), 1 died of complications, 10 responded to treatment (BMT and/or chemotherapy). Four are stable without treatment, two resolved. Two patients with MPD were not classifiable by the CCC system. CONCLUSIONS: Both the pediatric WHO and CCC systems are better able to classify MDS in children than the adult WHO and FAB classifications. The pediatric WHO system is more exclusive. Children meeting these criteria are more likely to progress to AML or death. The restrictive nature of the pediatric WHO system was unable to classify one case of fatal MDS. The CCC system is more inclusive and can stratify patients into a neutral or poor prognosis based upon outcome. However, the CCC system ignores those diseases with a myeloprolifferative component. This resulted in two cases of MPD that were unclassifiable by the CCC system. One of these patients died, the other is currently in relapse. Copyright 2004 Wiley-Liss, Inc.

BACKGROUND: Short, 21-mer, double-stranded/small interfering RNAs (ds/siRNAs) were designed to target bcr-abl mRNA in chronic myelogenous leukemia (CML) with a potential also to target c-abl mRNA. METHODS: ds/siRNAs were transfected into bcr-abl-positive K-562 cells (derived from blast-crisis) or bcr-abl-negative/c-abl-positive Jurkat cells (derived from acute lymphoblastic leukemia) using lipofectamine. ds/siRNAs intracellular uptake was detected by fluorescent confocal microscopy using fluorescein-labeled ds/siRNAs. The treatment was performed over 6 days with repetitive siRNA transfections. Efficiency of the siRNAs was determined 24 hours after single siRNA transfection and 6 days after repetitive siRNA transfections. RESULTS: Two of the designed ds/siRNAs decreased the target mRNA levels markedly (determined by reverse transcriptase-polymerase chain reaction analysis) and bcr-abl/c-abl oncoproteins (determined by flow cytometry using Fluor-488-labeled, anti-c-abl antibody as well as by Western blot analysis). These sequences also inhibited protein tyrosine kinase activity significantly and suppressed cell proliferation. One of the three selected ds/siRNAs expressed only slight effects on the bcr-abl/c-abl mRNA in K-562 cells (but not on the oncoprotein level), on protein tyrosine kinase activity, and on cell proliferation. The combination of the three ds/siRNA constructs provoked stronger decreases in bcr-abl/c-abl mRNAs and their respective oncoproteins and produced the strongest suppression of cell proliferation. CONCLUSIONS: The cross-talk between siRNA interference of bcr-abl oncogene and the expression of several apoptotic/antiapoptotic factors, cell proliferation factors, and other oncogenes exists and it was determined by microarray analysis in K-562 cells that were treated over 6 days. Cancer 2004. Copyright 2004 American Cancer Society.

Breast cancer resistance protein (BCRP) is an ATP binding cassette transporter that confers resistance to a series of anticancer agents such as 7-ethyl-10-hydroxycamptothecin (SN-38), topotecan, and mitoxantrone. In this study, we evaluated the possible interaction of gefitinib, a selective epidermal growth factor receptor tyrosine kinase inhibitor, with BCRP. BCRP-transduced human epidermoid carcinoma A431 (A431/BCRP) cells acquired cellular resistance to gefitinib, suggesting that BCRP could be one of the determinants of gefitinib sensitivity in a certain sort of cells. Next, the effect of gefitinib on BCRP-mediated drug resistance was examined. Gefitinib reversed SN-38 resistance in BCRP-transduced human myelogenous leukemia K562 (K562/BCRP) or BCRP-transduced murine lymphocytic leukemia P388 (P388/BCRP) cells but not in these parental cells. In addition, gefitinib sensitized human colon cancer HT-29 cells, which endogenously express BCRP, to SN-38. Gefitinib increased intracellular accumulation of topotecan in K562/BCRP cells and suppressed ATP-dependent transport of estrone 3-sulfate, a substrate of BCRP, in membrane vesicles from K562/BCRP cells. These results suggest that gefitinib may overcome BCRP-mediated drug resistance by inhibiting the pump function of BCRP. Furthermore, P388/BCRP-transplanted mice treated with combination of irinotecan and gefitinib survived significantly longer than those treated with irinotecan alone or gefitinib alone. In conclusion, gefitinib is shown to interact with BCRP. BCRP expression in a certain sort of cells is supposed to be one of the determinants of gefitinib sensitivity. Gefitinib inhibits the transporter function of BCRP and reverses BCRP-mediated drug resistance both in vitro and in vivo.

A 63-year-old woman presented to the internist with fatigue, cough, low-grade fever, splenomegaly and leucocytosis up to 130 x 10(9)/l. Although a diagnosis of chronic myelogenous leukaemia was initially entertained, she turned out to have a metastasised melanoma. The differential diagnosis and workup is discussed, as well as potential mechanisms by which the tumour could have induced the leucocytosis, such as the production of G-CSF or similar mediators, and the prognostic significance of this phenomenon.

The objective was to study the incidence and prognosis significance of -7/7q- abnormalities in acute leukemia and myelodysplastic syndrome. Conventional cytogenetic analysis of R-band was used to test -7/7q- chromosome abnormalities in 410 patients with acute leukemia (AL), in 71 cases of myelodysplastic syndrome (MDS) and in 36 cases of chronic myelogenous leukemia in accelerated phase (CML-AP). The results showed that the incidences of -7/7q- abnormalities in AL, MDS and CML-AP patients were 4.88%, 9.86% and 8.33% respectively. The -7/7q- abnormalities could be found in acute myeloblastic leukemia (AML) and acute lymphocytic leukemia (ALL), incidences of which were 4.70% and 6.25% (P > 0.05) respectively. 9 cases had -7 or 7q- as the sole chromosome abnormalities, 22 cases showed other additional chromosome abnormalities: -X, -5, +8, t(3; 3), t(11;16) and t(2;11). Monosomy -7 and 7q- abnormality clone was found in one patient with MDS-RAEB, and the number of cells with -7 abnormality was greater than that of 7q- abnormality cells. Four patients acquired CR among 7 patients with ALL after chemotherapy, but 2 out of 13 patients with AML achieved CR while 6 out of 7 patients with MDS transformed into AL. No patients with CML-AP achieved CR. In conclusion, -7/7q- is a frequent aberration in hematologic malignancies as well as AML and ALL. The monosomy -7 and 7q-abnormalities were detected in the same patient. The patients with -7/7q- abnormalities show poor prognosis.