Current Issue : January - March Volume : 2014 Issue Number : 1 Articles : 6 Articles
Background: The optimal choice of cytotoxic drugs for intraperitoneal chemotherapy (IPC) in conjunction with\r\ncytoreductive surgery (CRS) for treatment of peritoneal carcinomatosis (PC) is poorly defined. We investigated drug\r\nsensitivity ex vivo in patient samples of various PC tumor types and correlated clinical outcome to drug sensitivity\r\nwithin the subset of PC from colorectal cancer (CRC).\r\nMethods: PC tissue samples (n = 174) from mesothelioma, pseudomyxoma peritonei (PMP), ovarian cancer, CRC or\r\nappendix cancer were analyzed ex vivo for sensitivity to oxaliplatin, cisplatin, mitomycin C, melphalan, irinotecan,\r\ndocetaxel, doxorubicin and 5-FU. Clinicopathological variables and outcome data were collected for the CRC subset.\r\nResults: Mesothelioma and ovarian cancer were generally more drug sensitive than CRC, appendix cancer and\r\nPMP. Oxaliplatin showed the most favorable ratio between achievable IPC concentration and ex vivo drug\r\nsensitivity. Drug sensitivity in CRC varied considerably between individual samples. Ex vivo drug sensitivity did not\r\nobviously correlate to time-to-progression (TTP) in individual patients.\r\nConclusions: Drug-sensitivity varies considerably between PC diagnoses and individual patients arguing for\r\nindividualized therapy in IPC rather than standard diagnosis-specific therapy. However, in the current paradigm of\r\ntreatment according to diagnosis, oxaliplatin is seemingly the preferred drug for IPC from a drug sensitivity and\r\nconcentration perspective. In the CRC subset, analysis of correlation between ex vivo drug sensitivity and TTP was\r\ninconclusive due to the heterogeneous nature of the data....
Background: The mutation status of the BRAF and KRAS genes has been proposed as prognostic biomarker in\r\ncolorectal cancer. Of them, only the BRAF V600E mutation has been validated independently as prognostic for\r\noverall survival and survival after relapse, while the prognostic value of KRAS mutation is still unclear. We\r\ninvestigated the prognostic value of BRAF and KRAS mutations in various contexts defined by stratifications of the\r\npatient population.\r\nMethods: We retrospectively analyzed a cohort of patients with stage II and III colorectal cancer from the PETACC-3\r\nclinical trial (N = 1,423), by assessing the prognostic value of the BRAF and KRAS mutations in subpopulations\r\ndefined by all possible combinations of the following clinico-pathological variables: T stage, N stage, tumor site,\r\ntumor grade and microsatellite instability status. In each such subpopulation, the prognostic value was assessed by\r\nlog rank test for three endpoints: overall survival, relapse-free survival, and survival after relapse. The significance\r\nlevel was set to 0.01 for Bonferroni-adjusted p-values, and a second threshold for a trend towards statistical\r\nsignificance was set at 0.05 for unadjusted p-values. The significance of the interactions was tested by Wald test,\r\nwith significance level of 0.05.\r\nResults: In stage II-III colorectal cancer, BRAF mutation was confirmed a marker of poor survival only in\r\nsubpopulations involving microsatellite stable and left-sided tumors, with higher effects than in the whole\r\npopulation. There was no evidence for prognostic value in microsatellite instable or right-sided tumor groups. We\r\nfound that BRAF was also prognostic for relapse-free survival in some subpopulations. We found no evidence that\r\nKRAS mutations had prognostic value, although a trend was observed in some stratifications. We also show\r\nevidence of heterogeneity in survival of patients with BRAF V600E mutation.\r\nConclusions: The BRAF mutation represents an additional risk factor only in some subpopulations of colorectal\r\ncancers, in others having limited prognostic value. However, in the subpopulations where it is prognostic, it\r\nrepresents a marker of much higher risk than previously considered. KRAS mutation status does not seem to\r\nrepresent a strong prognostic variable...
The t(6;9)(p23;q34) chromosomal translocation is found in 1% of acute myeloid leukemia and\r\nencodes the fusion protein DEK-NUP214 (formerly DEK-CAN) with largely uncharacterized functions.\r\nMethods: We expressed DEK-NUP214 in the myeloid cell lines U937 and PL-21 and studied the effects on\r\ncellular functions.\r\nResults: In this study, we demonstrate that expression of DEK-NUP214 increases cellular proliferation. Western blot\r\nanalysis revealed elevated levels of one of the key proteins regulating proliferation, the mechanistic target of\r\nrapamycin, mTOR. This conferred increased mTORC1 but not mTORC2 activity, as determined by the\r\nphosphorylation of their substrates, p70 S6 kinase and Akt. The functional importance of the mTOR upregulation\r\nwas determined by assaying the downstream cellular processes; protein synthesis and glucose metabolism. A\r\nglobal translation assay revealed a substantial increase in the translation rate and a metabolic assay detected a shift\r\nfrom glycolysis to oxidative phosphorylation, as determined by a reduction in lactate production without a\r\nconcomitant decrease in glucose consumption. Both these effects are in concordance with increased mTORC1\r\nactivity. Treatment with the mTORC1 inhibitor everolimus (RAD001) selectively reversed the DEK-NUP214-induced\r\nproliferation, demonstrating that the effect is mTOR-dependent.\r\nConclusions: Our study shows that the DEK-NUP214 fusion gene increases proliferation by upregulation of\r\nmTOR, suggesting that patients with leukemias carrying DEK-NUP214 may benefit from treatment with\r\nmTOR inhibitors....
Background: Breast cancer incidence is increasing. The survival rate varies and is longer in high-income countries.\r\nIn Brazil, lower-income populations rely on the Unified Public Health System (Sistema �šnico de Saude, SUS) for\r\nbreast cancer care. The goal of our study is to evaluate the survival of patients with operable breast cancer stages\r\nI-III at a Brazilian public hospital that treats mostly patients from the SUS.\r\nMethods: A cohort study of patients who underwent surgery for breast cancer treatment at the Clinical Hospital of\r\nthe Federal University of Minas Gerais from 2001 to 2008 was performed, with a population of 897 cases.\r\nInformation on tumor pathology and staging, as well as patientsâ�� age and type of health coverage (SUS or private\r\nsystem) was collected. A probabilistic record linkage was performed with the database of the Mortality Information\r\nSystem to identify patients who died by December 31th, 2011. The basic cause of death was retrieved, and breast\r\ncancer-specific survival rates were estimated with the Kaplan-Meier method. The Cox proportional hazards model\r\nwas used for univariate and multivariate analysis of factors related to survival.\r\nResults: A total of 282 deaths occurred during the studyâ��s period, 228 of them due to breast cancer. Five-year\r\nbreast cancer-specific survival rates were 95.5% for stage I, 85.1% for stage II and 62.1% for stage III disease. Patients\r\nfrom the SUS had higher stages at diagnosis (42% was in stage III, and from the private system only 17.6% was in\r\nthis stage), and in the univariate but not multivariate analysis, being treated by the SUS was associated with shorter\r\nsurvival (hazard ratio, HR = 2.22, 95% CI 1.24-3.98). In the multivariate analysis, larger tumor size, higher histologic\r\ngrade, higher number of positive nodes and age older than 70 years were associated with a shorter breast cancerspecific\r\nsurvival.\r\nConclusions: Five-year breast cancer survival was comparable to other Brazilian cohorts. Patients treated by the\r\nSUS, rather than by the private system, had shorter survival times, mostly due to higher initial stage of the disease....
Background: Not only four but rather seven different human epidermal growth factor receptor related (Her)\r\nreceptor tyrosine kinases (RTKs) have been described to be expressed in a variety of normal and neoplastic tissues:\r\nHer1, Her2, Her3, and additionally four Her4 isoforms have been identified. A differential expression of Her4 isoforms\r\ndoes not, however, play any role in either the molecular diagnostics or treatment decision for breast cancer\r\npatients. The prognostic and predictive impact of Her4 expression in breast cancer is basically unclear.\r\nMethods: We quantified the Her4 variants JM-a/CYT1, JM-a/CYT2, JM-b/CYT1, and JM-b/CYT2 by isoform-specific\r\npolymerase chain reaction (qPCR) in (i) triple-negative, (ii) Her2 positive breast cancer tissues and (iii) in benign\r\nbreast tissues.\r\nResults: In all three tissue collectives we never found the JM-b/CYT1 or the JM-b/CYT2 isoform expressed. In\r\ncontrast, the two JM-a/CYT1 and JM-a/CYT2 isoforms were always simultaneously expressed but at different ratios.\r\nWe identified a positive prognostic impact on overall survival (OS) in triple-negative and event-free survival (EFS) in\r\nHer2 positive patients. This finding is independent of the absolute JM-a/CYT1 to JM-a/CYT2 expression ratio. In\r\nHer2 positive patients, Her4 expression only has a favorable effect in estrogen-receptor (ER)-positive but not in\r\nER-negative individuals.\r\nConclusion: In summary, JM-a/CYT1 and JM-a/CYT2 but not JM-b isoforms of the Her4 receptor are simultaneously\r\nexpressed in both triple-negative and Her2 positive breast cancer tissues. Although different expression ratios of\r\nthe two JM-a isoforms did not reveal any additional information, Her4 expression basically indicates a prolonged\r\nEFS and OFS. An extended expression analysis that takes all Her receptor homologs, including the Her4 isoforms,\r\ninto account might render more precisely the molecular diagnostics required for the development of optimized\r\ntargeted therapies....
Background: Tumor microenviroment is characteristic of inflammation, ischemia and starvation of nutrient. TNF-a,\r\nwhich is an extraordinarily pleiotropic cytokine, could be an endogenous tumor promoter in some tumor types.\r\nThe basic objective of this study was to investigate the effects of TNF-a on the cell viability and apoptosis of\r\nhepatocellular carcinoma cells under serum starvation, and to identify the molecular mechanisms involved.\r\nMethods: For this purpose, five different concentrations of TNF-a and two different serum settings (serum-cultured\r\nand serum-deprived) were used to investigate the effects of TNF-a on the cell viability and apoptosis of Hep3B and\r\nSMMC-7721 cells.\r\nResults: TNF-a (10 ng/ml) attenuated serum starvation-induced apoptosis of hepatocellular carcinoma cells, and\r\nautophagy conferred this process. BAY11-7082, a specific inhibitor of NF-?B, reversed the suppression of serum\r\nstarvation-induced apoptosis by TNF-a. Moreover, TNF-a-induced NF-?B transactivation was suppressed by autophagy\r\ninhibitor 3-MA. In addition, TNF-a up-regulated Ferritin heavy chain (FHC) transiently by NF-?B activation and FHC levels\r\nwere correlated with the TNF-a-induced protection against serum starvation-mediated apoptosis of hepatocellular\r\ncarcinoma cells. Furthermore, FHC-mediated inhibition of apoptosis depended on suppressing ROS accumulation.\r\nConclusions: Our findings suggested that autophagy conferred the TNF-a protection against serum\r\nstarvation-mediated apoptosis of hepatocellular carcinoma cells, the mechanism involved with the activation of\r\nthe TNF-a/ NF-?B /FHC signaling pathway....
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