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    Chronic myeloid leukemia in chronic phase (CML-CP) cells that harbor oncogenic BCR-ABL1 and normal ABL1 allele often become resistant to the ABL1 kinase inhibitor imatinib. Here, we report that loss of the remaining normal ABL1 allele in these tumors, which results from cryptic interstitial deletion in 9q34 in patients who did not achieve a complete cytogenetic remission (CCyR) during treatment, engenders a novel unexpected mechanism of imatinib resistance. BCR-ABL1–positive Abl1?/? leukemia cells were refractory to imatinib as indicated by persistent BCR-ABL1–mediated tyrosine phosphorylation, lack of BCR-ABL1 protein degradation, increased cell survival, and clonogenic activity. Expression of ABL1 kinase, but not a kinase-dead mutant, restored the antileukemic effects of imatinib in ABL1-negative chronic myelogenous leukemia (CML) cells and in BCR-ABL1–positive Abl1?/? murine leukemia cells. The intracellular concentration of imatinib and expression of its transporters were not affected, although proteins involved in BCR-ABL1 degradation were downregulated in Abl1?/? cells. Furthermore, 12 genes associated with imatinib resistance were favorably deregulated in Abl1?/? leukemia. Taken together, our results indicate that loss of the normal ABL1 kinase may serve as a key prognostic factor that exerts major impact on CML treatment outcomes. Cancer Res; 71(16); 5381–6. ©2011 AACR.
    cancerres.aacrjournals.org   ...Read On

    New pyrazolo[3,4-d]pyrimidine SRC inhibitors induce apoptosis in mesothelioma cell lines through p27 nuclear stabilization.

    Oncogene. 2011 Jul 25;

    Authors: Indovina P, Giorgi F, Rizzo V, Khadang B, Schenone S, Di Marzo D, Forte IM, Tomei V, Mattioli E, D'Urso V, Grilli B, Botta M, Giordano A, Pentimalli F

    Malignant mesothelioma (MM) is a highly aggressive tumor of the serous membranes for which there is currently no effective curative modality. Recent data suggest that hyperactivation of the tyrosine kinase SRC has a key role in MM development and therefore this kinase represents an important molecular target for MM therapy. We tested new pyrazolo[3,4-d]pyrimidine SRC inhibitors on a panel of MM cell lines expressing the active form of SRC. These SRC inhibitors exerted a significant proapoptotic effect on MM cells without affecting the normal mesothelial cell line MET-5A, supporting a possible use of these SRC inhibitors for a safe treatment of MM. We also showed that SRC inhibitor-induced apoptosis occurred concomitantly with an increase in the nuclear stability of the cyclin-dependent kinase inhibitor p27. This finding is remarkable considering that loss of nuclear p27 expression is a well-established adverse prognostic factor in MM, and p27 nuclear localization is crucial for its tumor-suppressive function. Consistently, SRC inhibition seems to promote the increase in p27 nuclear level also by inactivating the AKT kinase and downregulating cyclin D1, which would otherwise delay p27 nuclear import and provoke its cytoplasmic accumulation. To determine whether p27 stabilization has a direct role in apoptosis induced by SRC inhibition, we stably silenced the CDKN1B gene, encoding p27, in MSTO-211H and REN mesothelioma cells by transduction with lentiviral vectors expressing short hairpin RNAs against the CDKN1B transcript. Strikingly, p27 silencing was able to suppress the apoptosis induced by these SRC inhibitors in both MM cell lines, suggesting that p27 has a crucial proapoptotic role in MM cells treated with SRC inhibitors. Our findings reveal a new mechanism, dependent on p27 nuclear stabilization, by which SRC inhibition can induce apoptosis in MM cells and provide a new rationale for the use of SRC inhibitors in MM therapy.Oncogene advance online publication, 25 July 2011; doi:10.1038/onc.2011.286.

    PMID: 21785466 [PubMed - as supplied by publisher]

    www.ncbi.nlm.nih.gov


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    The Effect of Clinical Covariates on the Diagnostic and Prognostic Value of Soluble Mesothelin and Megakaryocyte Potentiating Factor.

    Chest. 2011 Jul 7;

    Authors: Hollevoet K, Nackaerts K, Thas O, Thimpont J, Germonpré P, De Vuyst P, Bosquée L, Legrand C, Kellen E, Kishi Y, Delanghe JR, van Meerbeeck JP

    ABSTRACT BACKGROUND: Soluble mesothelin (SM) and megakaryocyte potentiating factor (MPF) are serum biomarkers of mesothelioma. This study examined the effect of clinical covariates on biomarkers levels, their diagnostic and prognostic value. METHODS: 594 participants were included in a multicenter study, including 106 patients with mesothelioma and 488 controls. Multiple linear regression analyses were used to identify which covariates were independently associated with SM and MPF levels. The effect of these covariates on the diagnostic accuracy was evaluated with receiver operating characteristics (ROC) curve analysis. In patients with mesothelioma, survival analysis was performed with Cox regression. RESULTS: SM and MPF levels were independently associated with age, glomerular filtration rate (GFR) and body mass index (BMI) in controls, and GFR and tumor stage in patients with mesothelioma. The area under the ROC curves significantly differed with the distribution of these covariates in the study population. The patients with mesothelioma were best discriminated from the controls with either the youngest age, the highest GFR or the largest BMI. Furthermore, the controls were significantly better differentiated from stage II-IV than from stage I mesothelioma. MPF, not SM, was an independent negative prognostic factor, but only if adjusted for the biomarker-associated covariates. CONCLUSIONS: SM and MPF levels were affected by the same clinical covariates, which also had a significant impact on their diagnostic and prognostic value. To improve the interpretation of biomarker results, age, GFR and BMI should be routinely recorded. Approaches to account for these covariates require further validation, as does the prognostic value of SM and MPF.

    PMID: 21737491 [PubMed - as supplied by publisher]

    www.ncbi.nlm.nih.gov


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    Thyroid disease is a favorable prognostic factor in achieving sustained virologic response in chronic hepatitis C undergoing combination therapy: A nested case control study

    Interferon-alpha in combination with ribavirin is the current gold standard for treatment of chronic hepatitis C. It is unknown if the development of autoimmune thyroid disease (TD) during treatment confers an improved chance of achieving sustained virologic response.

    The aim of this study is to assess the chance of achieving sustained virologic response (SVR) in patients who developed TD during treatment when compared with those who did not.

    Methods: We performed a tertiary hospital-based retrospective nested case-control analysis of 19 patients treated for hepatitis C who developed thyroid disease, and 76 controls (matched for age, weight, gender, cirrhosis and aminotransferase levels) who did not develop TD during treatment. Multivariate logistic-regression models were used to compare cases and controls.

    Results: The development of TD was associated with a high likelihood of achieving SVR (odds ratio, 6.0; 95% confidence interval, 1.5 to 24.6) for the pooled group containing all genotypes.

    The likelihood of achieving SVR was increased in individuals with genotype 1 HCV infection who developed TD (odds ratio, 5.2; 95% confidence interval, 1.2 to 22.3), and all genotype 3 patients who developed TD achieved SVR.

    Conclusions: Development of TD during treatment for hepatitis C infection is associated with a significantly increased chance of achieving SVR. The pathophysiogical mechanisms for this observation remain to be determined.Trial RegistrationThe Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRB 12610000830099

    Author: Huy TranTracey JonesRobert GibsonGlenn Reeves
    Credits/Source: BMC Endocrine Disorders 2011, 11:10
    hepatitiscnewdrugs.blogspot.com


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    Clinical Implications of Bilateral Lateral Cervical Lymph Node Metastasis in Papillary Thyroid Cancer: A Risk Factor for Lung Metastasis.

    Ann Surg Oncol. 2011 May 7;

    Authors: Lee YS, Lim YS, Lee JC, Wang SG, Kim IJ, Son SM, Lee BJ

    BACKGROUND: Distant metastasis to the lung in papillary thyroid cancer (PTC) is rarely detected, but it is known to be an important prognostic factor associated with survival. We investigated risk factors for lung metastasis in PTC. MATERIALS AND METHODS: We performed a retrospective review of patients with PTC (n = 977) who were treated from January 2006 to August 2009. Enrolled patients received radioablation therapy followed by a radioiodine whole body scan. Lung metastasis was screened out with whole body scan or positron emission tomography/computed tomography (PET/CT) and confirmed with chest CT. Age, gender, extrathyroidal extension, central lymph node metastasis, lateral lymph node metastasis, and bilateral lateral cervical lymph node metastasis (BLNM) were investigated to analyze the relationship with lung metastasis. RESULTS: In total, 949 patients were enrolled. The median age was 49 years (±13 years) with 829 women. Lung metastasis was found in 20 patients (2.1%). Patients were divided into three groups by tumor size (?1 cm, 1-2 cm, >2 cm); the groups comprised 47.3%, 28.5%, and 24.1% of the patients, respectively. BLNM was identified in 4.4% (n = 43). In a univariate analysis, male gender, old age, large tumor, extrathyroidal extension, lymph node metastasis, lateral lymph node metastasis, and BLNM were significantly related to lung metastasis (P < 0.05). In a multivariate analysis, BLNM appeared to be the only significant risk factor for lung metastasis (P = 0.026; odds ratio = 10.219). CONCLUSIONS: BLNM may be a risk factor for lung metastasis. This indicates that careful examinations, including chest CT and positron emission tomography (PET), are recommended during the follow-up period when BLNM is suspected.

    PMID: 21553141 [PubMed - as supplied by publisher]

    www.ncbi.nlm.nih.gov


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