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1.
ESMO Open ; 8(6): 102064, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37977001

ABSTRACT

BACKGROUND: Molecular informed therapy changed treatment patterns of metastatic colorectal cancer (mCRC). Recently KRAS G12, the most prevalent RAS mutation in mCRC, was investigated to be a negative predictive marker for the efficacy of trifluridine/tipiracil (FTD/TPI). Whether this proposed selectivity remains when FTD/TPI is combined with bevacizumab remains elusive. We aimed to describe the efficacy of FTD/TPI + bevacizumab depending on the RAS mutational status in a real-world population. PATIENTS AND METHODS: Patients from five different cancer centers in Austria who received FTD/TPI + bevacizumab in any treatment line having available information on their molecular profile were eligible. Data were retrospectively collected by chart review. Survival data were compared using log-rank test. Multivariate Cox regression models included several established covariates. RESULTS: One hundred and twenty-three patients with mCRC were included in this study. Median overall survival (OS) was highly similar in the RAS wild type (WT) [9.63 months (95% confidence interval [CI] 8.055-13.775 months)] and the RAS mutant cohorts [8.78 months (95% CI 8.055-11.014 months)], which was confirmed in a multivariable model adjusting for potential confounders; hazard ratio (HR): 1.05 (95% CI 0.618-1.785; P = 0.857). In addition, no effect of KRAS G12 status on patient outcome was observed. In detail, OS was 8.88 months (95% CI 7.332-12.921 months) in patients with KRAS G12 mutation, compared to 9.47 months (95% CI 8.088-11.375 months) in patients with RAS WT/no-KRAS G12 disease [HR: 0.822 (95% CI 0.527-1.282; P = 0.387)]. CONCLUSION: This real-world study indicates that the efficacy of FTD/TPI + bevacizumab is independent of RAS mutational status and that bevacizumab may therefore mitigate the potentially limited efficacy of FTD/TPI monotherapy in the KRAS G12-mutated population.


Subject(s)
Colonic Neoplasms , Colorectal Neoplasms , Frontotemporal Dementia , Humans , Bevacizumab/pharmacology , Bevacizumab/therapeutic use , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Uracil , Retrospective Studies , Trifluridine/pharmacology , Trifluridine/therapeutic use , Proto-Oncogene Proteins p21(ras)/genetics
2.
Eur J Clin Invest ; 39(5): 395-405, 2009 May.
Article in English | MEDLINE | ID: mdl-19320940

ABSTRACT

BACKGROUND: The mammalian target of rapamycin (mTOR) has recently been implicated in leukaemic cell growth, tumour-associated angiogenesis and expression of vascular endothelial growth factor (VEGF). We examined whether mTOR plays a role as regulator of growth and VEGF-expression in acute myeloid leukaemia (AML). Three mTOR-targeting drugs, rapamycin, everolimus (RAD001) and CCI-779, were applied. The effects of these drugs on growth, survival, apoptosis and VEGF expression in primary AML cells and various AML cell lines were examined. MATERIALS AND METHODS: Growth of AML cells and AML-derived cell lines was assessed by (3)H-thymidine incorporation, survival was examined by light- and electron microscopy, by Tunel assay and by AnnexinV-staining, and the expression of VEGF by Northern blotting, RT-PCR and ELISA. RESULTS: Rapamycin was found to counteract growth in the AML cell lines U937 and KG1a as well as in primary AML cells in 14/18 patients examined. The effects of rapamycin and its derivatives were dose-dependent (IC(50): 10 pM-100 nM). It was also found that exposure to mTOR-targeting drugs resulted in apoptosis and in decreased expression of VEGF in leukaemic cells. CONCLUSIONS: mTOR-targeting drugs exert antileukaemic effects on AML cells in vitro through multiple actions, including direct inhibition of proliferation, induction of apoptosis and suppression of VEGF. Based on this study and other studies, mTOR can be regarded as a potential drug target in AML.


Subject(s)
Antibiotics, Antineoplastic/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Leukemia, Myeloid, Acute/metabolism , Protein Kinases/metabolism , Sirolimus/pharmacology , Vascular Endothelial Growth Factor A/metabolism , Adult , Aged , Apoptosis/drug effects , Dose-Response Relationship, Drug , Female , Humans , Leukemia, Myeloid, Acute/genetics , Male , Middle Aged , Protein Kinases/genetics , TOR Serine-Threonine Kinases , Tumor Cells, Cultured , Vascular Endothelial Growth Factor A/genetics
3.
Eur J Clin Invest ; 38(11): 869-73, 2008 Nov.
Article in English | MEDLINE | ID: mdl-19021706

ABSTRACT

BACKGROUND: Systemic mastocytosis (SM) is a mast cell neoplasm in which neoplastic cells usually display the D816V-mutated variant of KIT. Cladribine (2CdA) and dasatinib are two drugs that counteract the in vitro growth of neoplastic mast cells in SM. However, only little is known about the in vivo effects of these drugs in SM. PATIENT AND METHODS: We report on a patient with highly aggressive interferon-alpha-resistant SM who was treated with 2CdA and dasatinib. In vitro pretesting revealed a response of neoplastic mast cells to both compounds with reasonable IC(50) values. RESULTS: The patient was treated with six cycles of 2CdA (0.13 mg kg(-1) intravenously daily on 5 consecutive days). Despite a short-lived major clinical response and a decrease in serum tryptase, the patient progressed to mast cell leukaemia after the sixth cycle of 2CdA. The patient then received two further courses of 2CdA followed by treatment with dasatinib (100 mg per os daily). However, no major response was obtained and the patient died from disease progression after 2 months. CONCLUSIONS: In a patient with rapidly progressing aggressive SM, neither 2CdA nor dasatinib produced a long-lasting response in vivo, despite encouraging in vitro results. For such patients, alternative treatment strategies have to be developed.


Subject(s)
Antineoplastic Agents/therapeutic use , Cladribine/therapeutic use , Leukemia, Mast-Cell/drug therapy , Mastocytosis, Systemic/drug therapy , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Thiazoles/therapeutic use , Aged , Dasatinib , Disease Progression , Drug Therapy, Combination , Fatal Outcome , Female , Humans , Leukemia, Mast-Cell/pathology , Mastocytosis, Systemic/blood , Treatment Failure , Tryptases/blood
4.
Eur J Clin Invest ; 38(1): 43-52, 2008 Jan.
Article in English | MEDLINE | ID: mdl-18173550

ABSTRACT

BACKGROUND: Recent data suggest that the mammalian target of rapamycin (mTOR) is involved in the regulation of growth of neoplastic cells in chronic myeloid leukaemia (CML). PATIENTS AND METHODS: We treated six patients with imatinib-resistant CML in haematological relapse (leukocytes > 20,000 microL(-1)) with rapamycin at 2 mg per os daily for 14 consecutive days, with dose-adjustment allowed to reach a target rapamycin serum concentration of 10-20 pg mL(-1). RESULTS: A major leukocyte response with decrease to less than 10,000 microL(-1) was obtained in two patients, and a minor transient response was seen in two other patients. In responding patients, we also observed a decrease in vascular endothelial growth factor (VEGF) mRNA levels in circulating leukaemic cells. Side effects during rapamycin treatment were mild in most patients. In one patient, pneumonia developed. Rapamycin was also found to counteract growth of CML cells in vitro as determined by (3)H-thymidine incorporation. Moreover, rapamycin inhibited the growth of Ba/F3 cells exhibiting various imatinib-resistant mutants of BCR/ABL, including the T315I variant that exhibits resistance against most currently available BCR/ABL kinase inhibitors. CONCLUSIONS: Rapamycin shows antileukaemic effects in imatinib-resistant CML in vitro and in vivo. Larger trials with rapamycin or rapamycin-derivatives in combination with other targeted drugs are warranted to further determine clinical efficacy in CML.


Subject(s)
Antibiotics, Antineoplastic/therapeutic use , Antineoplastic Agents/therapeutic use , Leukemia, Myeloid, Chronic-Phase/drug therapy , Piperazines/therapeutic use , Pyrimidines/therapeutic use , Sirolimus/therapeutic use , Aged , Benzamides , Drug Evaluation , Drug Resistance, Neoplasm , Female , Humans , Imatinib Mesylate , Male , Middle Aged , Pilot Projects , RNA, Messenger/metabolism , RNA, Neoplasm/metabolism , Treatment Outcome , Vascular Endothelial Growth Factor A/metabolism
5.
Int J Immunopathol Pharmacol ; 20(3): 421-34, 2007.
Article in English | MEDLINE | ID: mdl-17880756

ABSTRACT

Traditionally, mast cells (MCs) have been considered to play an important role in allergic disorders and helminth infections. More recently, MCs have been implicated in a variety of different infectious diseases including life-threatening disorders caused by viruses and bacteria. Apart from recognition through specific IgE, MCs are considered to recognize such bacteria and viruses via specific cell surface binding sites. In addition, MCs interact with diverse components and cells of the immune system and thereby may facilitate the targeting and the elimination of invading microbes in the tissues. The current article provides an overview on MC antigens contributing to microbe recognition and targeting as an important element of natural host-defense.


Subject(s)
Antigens, CD/immunology , Host-Pathogen Interactions/immunology , Immunity, Innate/immunology , Infections , Mast Cells/immunology , Binding Sites/immunology , Humans , Immunoglobulin E/immunology , Infections/immunology , Infections/microbiology , Infections/parasitology , Infections/virology
6.
Eur J Clin Invest ; 37(10): 808-13, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17727673

ABSTRACT

BACKGROUND: Central nervous system (CNS) relapse in chronic myeloid leukaemia (CML) is rare and if recorded is usually found to occur in patients with lymphoblastic transformation. The BCR/ABL tyrosine kinase inhibitor imatinib is highly effective in patients with CML, but hardly crosses the blood-brain barrier. PATIENTS AND METHODS: We report on two CML patients who developed a myeloid CNS relapse during treatment with imatinib. One patient was in major cytogenetic response at the time of CNS relapse. In both cases, the myeloid origin of neoplastic cells in the cerebrospinal fluid (CSF) was demonstrable by immunophenotyping, and their leukaemic origin by detection of the BCR/ABL oncoprotein. No BCR/ABL kinase domain mutations were found. Both patients received intrathecal liposomal cytarabine (50 mg each cycle; 6 cycles). In one patient, additional CNS radiation was performed, whereas in the other, consecutive treatment with dasatinib (70 mg per os twice daily) was started. RESULTS: In response to therapy, the clinical symptoms resolved, and the leukaemic cells in the CSF disappeared in both cases. After three months of observation, both patients are in complete cytogenetic and major molecular response, without evidence for a systemic or a CNS relapse. CONCLUSIONS: 'Anatomic' resistance against imatinib in the CNS can lead to a myeloid CNS relapse. Liposomal cytarabine with or without radiation is effective as local therapy in these patients. For systemic treatment and prophylaxis, BCR/ABL kinase inhibitors crossing the blood-brain barrier such as dasatinib should be considered in patients with CNS relapse.


Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Central Nervous System Neoplasms/drug therapy , Cytarabine/administration & dosage , Cytarabine/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Protein Kinase Inhibitors/therapeutic use , Aged , Benzamides , Central Nervous System Neoplasms/secondary , Dasatinib , Drug Therapy, Combination , Female , Humans , Imatinib Mesylate , Liposomes , Male , Middle Aged , Piperazines/therapeutic use , Pyrimidines/therapeutic use , Thiazoles/therapeutic use , Treatment Outcome
7.
Eur J Clin Invest ; 34 Suppl 2: 2-11, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15291801

ABSTRACT

Chronic myeloid leukaemia (CML) is a stem cell disease characterized by an increased production and accumulation of clonal BCR/ABL-positive cells in haematopoietic tissues. The chronic phase of CML is inevitably followed by an accelerated phase of the disease, with consecutive blast crisis. However, depending on genetic stability, epigenetic events, and several other factors, the clinical course and survival appear to vary among patients. Recent data suggest that angiogenic cytokines such as vascular endothelial growth factor (VEGF), are up-regulated in CML, and play a role in the pathogenesis of the disease. These factors appear to be produced and released in leukaemic cells in patients with CML. In line with this notion, increased serum-levels of angiogenic growth factors are measurable in CML patients. In this study we provide an overview of angiogenic growth factors expressed in CML cells, discuss the possible pathogenetic role of these cytokines, the biochemical basis of their production in leukaemic cells, and their potential clinical implications.


Subject(s)
Genes, abl/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Angiopoietin-1/metabolism , Fibroblast Growth Factor 2/metabolism , Genetic Therapy/methods , Hepatocyte Growth Factor/metabolism , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/metabolism , Platelet-Derived Growth Factor/metabolism , Vascular Endothelial Growth Factor A/metabolism
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