A Hochhaus

..In CML, blood but not bone marrow samples have been examined using RNA stabilization in previous studies. Therefore, we sought to investigate the applicability of the PAXgene system for bone marrow samples in CML...

..This trial was registered at www.clinicaltrials.gov as CA180013...

..This article reviews the current role of allo-SCT, imatinib, and IFN-alpha in treating newly diagnosed chronic-phase CML, highlighting the benefits and challenges of long-term patient management, and discusses emerging trends...

..Side effects of dasatinib, including pleural effusions, are manageable with modification of dose or schedule. Phase III dose optimisation studies and future indications are also discussed...

..Adverse events experienced with dasatinib include myelosuppression and fluid retention (e.g., pleural effusions), which were manageable with dose adjustment or treatment...

..Management of resistance may include therapeutic strategies such as dose escalation to achieve individual optimal levels, combination therapy, as well as treatment interruption...

..Cytogenetic and molecular analyses at the time of resistance are suggested to guide therapy...

..The impact of the various treatment modalities (imatinib, interferon alpha, ara-C, allogeneic stem cell transplantation) will be elucidated. The recruitment of newly diagnosed CML patients into CML-study IV is recommended...

..Additional strategies include imatinib dose escalation, combination therapy, and treatment interruption to stop clonal selection of resistant cells...

..The estimated overall survival was 88% -- or 95% when only CML-related deaths were considered. This 6-year update of IRIS underscores the efficacy and safety of imatinib as first-line therapy for patients with CML...

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..In blast crisis, 29% achieve hematologic remission which may be durable. CONCLUSION: The available data represent response rates. Until survival data are available, the evidence-based recommendations will remain valid...

..Clinical responses to STI571 in various malignancies may stimulate greater interest in the clinical use of tyrosine kinase inhibitors...

..Pleural effusions were classified as grade 3 in 6% of reported events, with no incidence of grade 4. Dasatinib is associated with high response rates in patients with imatinib-resistant or -intolerant CP-CML...

..1% are associated with continuous remission...

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..0006). This is the first analysis of gender aspects in CML using randomized trials. It demonstrates the relevance of analyses of gender differences in CML and in malignant disease at large...

..The resulting expression signature point to involvement of BCR-ABL-independent mechanisms of resistance...

..001) and correspondingly >0% Ph+ (34% of pts; 5-year OS: 91%) compared with 0% Ph+ (66% of pts; 5-year OS: 97%; P=0.015). Treatment optimization is recommended for pts missing these landmarks...

..However, patients with clonal evolution are more likely to have BCR-ABL-independent mechanisms of resistance. The observations warrant trials combining imatinib with other agents...

..The established regimen was well tolerated and the preliminary efficacy data in this heavily pre-treated patients population appears to be promising...

..We provide recommendations for the propagation of the IS by national or regional laboratory networks...

..The favourable safety profile and promising activity of the capecitabine/mitomycin C combination, even in heavily pretreated patients, warrant further evaluation in patients with advanced colorectal and gastric cancers...

..We therefore conclude that allogeneic HSCT in CyR should be investigated prospectively as an alternative treatment option in defined patient groups...

..Preliminary antitumour activity has been observed in patients with pretreated pancreatic cancer and in untreated gastric cancer...

..We conclude that the course of CML is not different in the elderly. They require lower IFN doses, achieve the same hematologic and cytogenetic response rates and the same survival advantage at comparable toxicity...

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..We suggest that for patients who reach CR, IFN should be continued at least until relatively low levels of residual leukemia are achieved. (Blood. 2000;95:62-66)..

..Because of progressive disease treatment with the tyrosine kinase inhibitor imatinib (STI571, Glivec (R)) had been started 9 months before. She had achieved complete hematological remission within 8 weeks, but not a cytogenetic response...

..The variability in the anatomy of the FIP1L1-PDGFRA fusion has important implications for strategies to detect the fusion at diagnosis or for monitoring response to treatment...

..This report evaluates the influence of preoperative intensified radiochemotherapy on the rate and outcome of surgical complications...

..In view of the data of CML-study I, these results suggest that IFN/HU is also superior to IFN alone. HU should be combined with IFN in IFN-based therapies and for comparisons with new therapies...

..Comparable results were achieved using G6PD transcripts as standard. We conclude that the new PAXgene stabilization method could improve RNA quality and the comparability of molecular monitoring within and between multicenter trials...

..The local recurrence and distant failure rates observed after a median 28 months are low compared with standard 5-fluorouracil based therapy...

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..The clinical benefits may therefore be outweighed by the dose-limiting toxicity for both application forms. Combinations with other drugs, e.g., STI571 or homoharringtonine, have shown promising early results in vitro and in vivo...

..Restoration of defective cell adhesion mediated via the CD62L pathway may be one mechanism of action of imatinib in BCR-ABL-positive leukemias...

..MMR at 12 months was associated with a longer duration of CCyR. Overall, this analysis shows that dasatinib treatment results in high MMR rates in patients with CML-CP after imatinib failure...

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..We conclude that outcome after BMT is not compromised by pretreatment with IFN if it is discontinued at least 3 months before transplantation. Clear candidates for early transplantation should not be pretreated with IFN...

..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...

..In terms of antitumor activity, BBR 3438 was found to be ineffective in the treatment of gastric cancer...

..We conclude that the use of a common control plasmid does indeed improve comparability of BCR-ABL mRNA quantification results. However, further standardizing efforts like introducing a calibrator and regular control rounds are needed...

..MYO18A-FGFR1 is structurally similar to other fusion tyrosine kinases and is likely to be the causative transforming lesion in this unusual MDS/MPD...

..Capecitabine and MMC act synergistically due to an upregulation of the thymidine phosphorylase activity by MMC in a human xenograft model...

..CONCLUSIONS: The data emphasized the need for a prolonged follow-up of patients treated with imatinib to define the clinical potential of the drug and to establish methods to optimize therapy...

..These data confirmed the long-term efficacy of imatinib for PDGFR-rearranged CEL patients, and also showed that a minority of HES cases without known molecular aberrations may benefit from imatinib...

..We sought to improve the diagnostic armamentarium by screening and to analyze the dynamics of mutated clones in chronic myeloid leukemia patients who experienced hematologic or cytogenetic relapse...

..Combination therapy from the start of treatment to reduce the frequency of resistance is currently being evaluated with several drugs...

..In the present analysis, we sought to evaluate the potential association of HFSR and survival in German patients with metastatic colorectal cancer and locally advanced rectal cancer treated with cape in clinical trials...

..They may be considered as the driving force of disease progression and could serve as future prognostic markers...

..We conclude that allo SCT could become the preferred second-line option after imatinib failure for suitable patients with a donor. The study is registered at the National Institutes of Health, http://clinicaltrials.gov: NCT00055874...

..Up to 87% of patients achieve complete cytogenetic remission, therefore we provide guidance for monitoring disease status. Many trials of new drugs and combination therapies that include imatinib are underway...

..5 mL samples tested positive. For higher dilutions, a PB volume of 5 or 10 ml was required to improve sensitivity. The study showed the feasibility of RQ-PCR standardization independent of the PCR machine used...

..The definition of 'undetectable BCR-ABL' in an individual patient should take these preanalytical parameters into consideration...

..We here report on two out of four melanoma patients treated with high-dose imatinib presenting with severe and strongly dose-dependent skin eruptions, suggesting a cutaneous reactivity pattern different from allergic hypersensitivity...

..Monitoring the actual BCR-ABL inhibition in nilotinib treated patients using pCRKL as a surrogate is a means to establish effective dosing and to characterize resistance mechanisms against nilotinib...

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..Seventy-one patients treated with dasatinib after imatinib failure for a median of nine months were evaluated. Novel aberrations within Ph positive and negative clones appeared in six and three patients, respectively...

..Overall, dasatinib has durable efficacy in patients with or without BCR-ABL mutations. All trials were registered at http://www.clinicaltrials.gov as NCT00123474, NCT00101660, and NCT00103844...

..These data provide a rationale for the clinical development of optimized ATO-based regimens through incorporation of GSH-modulators in CML treatment...

..The definition of molecular surrogate endpoints beyond CCR for studies which are currently planned demands standardization of the nomenclature and of technologies to measure these targets...

..5 years, compared with earlier time points. Imatinib continues to be an effective and safe therapy for patients with CP CML after failure of IFN...

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..These data suggest that BCR/ABL leads to an enhanced cell cycle activation of CD34+ cells, which seems to be, at least in part, independent of additional factors provided by the bone marrow microenvironment...

..We retrospectively analyzed the impact of different adjuvant chemotherapy regimens in a group of patients treated for glioblastoma compared to patients receiving only postoperative radiotherapy...

..Imatinib has demonstrated synergistic effects in vitro with mitoxantrone, etoposide, and cytarabine...

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..Our data suggest that distinct tyrosine kinases likewise targeted by both drugs are essential actuators in maintenance of centrosome and karyotype integrity...

..Dasatinib is a multitargeted inhibitor of ABL, the SRC family, and other tyrosine kinases. We sought to evaluate the effects of this drug on cell proliferation, centrosomes, mitotic spindles, and cell cycle progression in vitro and in vivo...

..Despite good response and acceptable tolerability, little is known concerning long-term toxicity. Furthermore, the influence of these inhibitors on disease-unrelated cells is not investigated yet...

..Patients with PDGFRB fusions genes are excellent candidates for treatment with imatinib; complete cytogenetic and even molecular remissions are common while primary or secondary resistance seems to be very rare...

..Novel point mutations should be confirmed by analyzing the normal ABL alleles to exclude polymorphisms...

..Meanwhile, virtually all anti-cancer drugs have been encapsulated in liposomes using different technologies. This review will summarize preclinical and clinical data of approved and exemplary emerging liposomal anti-cancer agents...

..032). The general recommendation of HSCT as first-line treatment option in chronic phase CML can no longer be maintained. It should be replaced by a trial with modern drug treatment first...

..Efficacy and toxicity data are comparable to 5-FU/irinotecan combinations, although the likelihood of severe diarrhea appears to be higher with capecitabine/irinotecan...

..This phase I/II dose-finding study evaluated gefitinib in combination with a 5-fluorouracil (5-FU)/folinic acid (FA)/irinotecan (FOLFIRI-AIO) regimen in patients with metastatic colorectal cancer...

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..These findings are consistent with the hypothesis that the t(15;17) occurs by nonhomologous recombination of DNA after processing of the double-strand breaks by a dysfunctional DNA damage-repair mechanism...

..Therefore, we have established a combination regimen of these drugs (DocMitoCape), which demonstrated preliminary activity especially in bile duct and pancreatic carcinoma...

..Anal cancers universally express the epidermal growth factor receptor (EGFR) and KRAS mutations have not been reported in anal cancer thus far...

..conventional three-dimensional conformal radiotherapy (3D-CRT) and standard chemotherapy in these patients while maintaining or reducing renal toxicity...

..He was treated with capecitabine and oxaliplatin-based combination therapy. A long-lasting major remission was observed resulting in a survival of 18.5 months...

..We sought to determine the maximum tolerated dose and the dose-limiting toxicities (DLT) of these drugs in combination with intensity-modulated radiotherapy...