Current Issue : January - March Volume : 2015 Issue Number : 1 Articles : 6 Articles
Background: Patients with Ewing sarcoma family of tumors (ESFT) who are resistant even to salvage chemotherapy,\nhave dismal prognoses and few therapeutic options. Because the docetaxel/irinotecan (DI) combination has not been\npreviously evaluated in ESFT, we prospectively evaluated its use in patients with recurrent or refractory ESFT.\nMethods: Patients aged <30 years with ESFT, who failed ? third-line therapy, were eligible. They received docetaxel\n100 mg/m2 intravenously on day 1, and irinotecan 80 mg/m2 on days 1 and 8, of a 21-day cycle up to 15 cycles or until\ndisease progressed. The primary objective was objective response rate (ORR); secondary objectives were progression-free\nsurvival (PFS) and safety.\nResults: We enrolled nine patients (median age: 13 years); four were male. Two patients had recurrent disease and\nseven had progressive disease. This group had undergone a median of four prior chemotherapy regimens (range: 3-6),\nand received a total of 51 DI cycles (median: three cycles/per person; range: 1-15 cycles). The nine patients showed\none complete response (CR), two partial responses (PRs), one stable disease, and five progressive diseases, for an ORR\n(CR + PR) of 3/9 (33.3%). Two patients with PR achieved CR with subsequent surgery. Overall median PFS was\n2.2 months (range: 0.5-16.9 months). All nine patients had grade 4 neutropenia (100%); grade 3 diarrhea or grade 2/3\nneuropathy each occurred in two patients (22%). All toxicities were manageable without serious morbidities or\ntreatment-related mortality.\nConclusions: The DI combination may be effective and tolerable for patients with heavily pre-treated ESFT.\nTrial registration: NCT01380275. Registered June 21, 2011....
Background: Many advanced human tumors, including hepatocellular carcinomas (HCC) are auxotrophic for\narginine due to down-regulation of argininosuccinate synthetase (ASS1), the rate-limiting enzyme in arginine\nsynthesis. The arginine-lowering agent PEGylated arginine deiminase (ADI-PEG 20) has shown efficacy as a\nmonotherapy in clinical trials for treating arginine-auxotrophic tumors and is currently being evaluated in\ncombination with cisplatin in other cancer types. Epigenetic silencing via methylation of the ASS1 promoter has\nbeen previously demonstrated in other cancer types, and a reciprocal relationship between ASS1 expression and\ncisplatin resistance has also been observed in ovarian cancer. However, the mechanism of ASS1 down-regulation, as\nwell as the correlation with cisplatin resistance has not been explored in HCC. The present study investigates\nADI-PEG 20 and cisplatin sensitivities in relation to ASS1 expression in HCC. In addition, we show how this\nbiomarker is regulated by cisplatin alone and in combination with ADI-PEG 20.\nMethods: ASS1 protein expression in both untreated and drug treated human HCC cell lines was assessed by\nwestern blot. The correlation between ASS1 protein levels, ADI-PEG 20 sensitivity and cisplatin resistance in these\ncell lines was established using a luminescence-based cell viability assay. Epigenetic regulation of ASS1 was\nanalyzed by bisulfite conversion and methylation-specific PCR.\nResults: A good correlation between absence of ASS1 protein expression, ASS1 promoter methylation, sensitivity\nto ADI-PEG 20 and resistance to cisplatin in HCC cell lines was observed. In addition, cisplatin treatment\ndown-regulated ASS1 protein expression in select HCC cell lines. While, at clinically relevant concentrations, the\ncombination of ADI-PEG 20 and cisplatin restored ASS1 protein levels in most of the cell lines studied.\nConclusion: ASS1 silencing in HCC cell lines is associated with simultaneous cisplatin resistance and ADI-PEG 20\nsensitivity which suggests a promising combination therapeutic strategy for the management of HCC....
Background: Colorectal cancer (CRC) is a disease that can be prevented through early detection. Through the use\nof effective educational tools, individuals can become better informed about CRC and understand the importance\nof screening and early detection. The walk through Inflatable Colon is an innovative educational resource developed to\nengage and educate communities on CRC and the importance of receiving screening at the appropriate ages.\nMethods: The Inflatable Colon Assessment Survey (ICAS) assessed knowledge and behavioral intentions to obtain\nscreening and promote CRC awareness. New Mexico State University faculty, staff, and students completed a consent\nform, took the pre-ICAS, toured the Inflatable Colon, and completed the post-ICAS. The majority of participants (92%)\nwere young adults, mostly college students, under the age of 30 yrs.\nResults: Overall, participants demonstrated increases in CRC knowledge and awareness after touring the inflatable\ncolon (p-values < 0.001). Interestingly, both males and Hispanics had lower CRC awareness at pre-test, but exhibited\nmaximum awareness gains equal to that of females and non Hispanic Whites after touring the IC. Behavioral intentions\nto obtain CRC screening in the future and to promote CRC awareness also increased (p-value < 0.001). Gender differences\nin behavioral intentions to act as advocators for CRC education were found (p < 0.05), with females being more likely to\neducate others about CRC than males.\nConclusion: Educational efforts conducted in early adulthood may serve to promote healthier lifestyles (e.g., physical\nactivity, healthy nutrition, screening). These educated young adults may also serve to disseminate CRC information to\nhigh-risk friends and relatives. The walk through Inflatable Colon can increase CRC knowledge and intentions to get\nscreened among a young and diverse population....
Background: Macrophage migration inhibitory factor (MIF) is a widely expressed cytokine involved in a variety of\ncellular processes including cell cycle regulation and the control of proliferation. Overexpression of MIF has been\nreported in a number of cancer types and it has previously been shown that MIF is upregulated in melanocytic\ntumours with the highest expression levels occurring in malignant melanoma. However, the clinical significance of\nhigh MIF expression in melanoma has not been reported.\nMethods: MIF expression was depleted in human melanoma cell lines using siRNA-mediated gene knockdown and\neffects monitored using in vitro assays of proliferation, cell cycle, apoptosis, clonogenicity and Akt signalling. In silico\nanalyses of expression microarray data were used to correlate MIF expression levels in melanoma tumours with\noverall patient survival using a univariate Cox regression model.\nResults: Knockdown of MIF significantly decreased proliferation, increased apoptosis and decreased\nanchorage-independent growth. Effects were associated with reduced numbers of cells entering S phase\nconcomitant with decreased cyclin D1 and CDK4 expression, increased p27 expression and decreased Akt\nphosphorylation. Analysis of clinical outcome data showed that MIF expression levels in primary melanoma\nwere not associated with outcome (HR = 1.091, p = 0.892) whereas higher levels of MIF in metastatic lesions\nwere significantly associated with faster disease progression (HR = 2.946, p = 0.003 and HR = 4.600, p = 0.004, respectively\nin two independent studies).\nConclusions: Our in vitro analyses show that MIF functions upstream of the PI3K/Akt pathway in human melanoma\ncell lines. Moreover, depletion of MIF inhibited melanoma proliferation, viability and clonogenic capacity. Clinically, high\nMIF levels in metastatic melanoma were found to be associated with faster disease recurrence. These findings support\nthe clinical significance of MIF signalling in melanoma and provide a strong rationale for both targeting and\nmonitoring MIF expression in clinical melanoma....
Background: The role of pERK, pAKT and p53 as biomarkers in patients with advanced pancreatic cancer has not\nyet been defined.\nMethods: Within the phase III study AIO-PK0104 281 patients with advanced pancreatic cancer received an\nerlotinib-based 1st-line regimen. Archival tissue from 153 patients was available for central immunohistochemistry\nstaining for pERK, pAKT and p53. Within a subgroup analysis, biomarker data were correlated with efficacy endpoints\nand skin rash using a Cox regression model.\nResults: Fifty-five out of 153 patients were classified as pERKlow and 98 patients as pERKhigh; median overall survival\n(OS) was 6.2 months and 5.7 months, respectively (HR 1.29, p = 0.16). When analysing pERK as continuous variable,\nthe pERK score was significantly associated with OS (HR 1.06, 95% CI 1.0-1.12, p = 0.05). Twenty-one of 35 patients\nwere pAKTlow and 14/35 pAKThigh with a corresponding median OS of 6.4 months and 6.8 months, respectively\n(HR 1.03, p = 0.93). Four out of 50 patients had a complete loss of p53 expression, 20 patients a regular expression\nand 26 patients had tumors with p53 overexpression. The p53 status had no impact on OS (p = 0.91); however, a\nsignificant improvement in progression-free survival (PFS) (6.0 vs 1.8 months, HR 0.24, p = 0.02) and a higher rate of\nskin rash (84% vs 25%, p = 0.02) was observed for patients with a regular p53 expression compared to patients with\na complete loss of p53.\nConclusion: pERK expression may have an impact on OS in erlotinib-treated patients with advanced pancreatic\ncancer; p53 should be further investigated for its potential role as a predictive marker for PFS and skin rash.\nTrial registration: NCT00440167 (registration date: February 22, 2007)....
Background: Ovarian tumors create a dynamic microenvironment that promotes angiogenesis and reduces\nimmune responses. Our research has revealed that threonyl-tRNA synthetase (TARS) has an extracellular angiogenic\nactivity separate from its function in protein synthesis. The objective of this study was to test the hypothesis that\nTARS expression in clinical samples correlates with angiogenic markers and ovarian cancer progression.\nMethods: Protein and mRNA databases were explored to correlate TARS expression with ovarian cancer. Serial\nsections of paraffin embedded ovarian tissues from 70 patients diagnosed with epithelial ovarian cancer and 12\ncontrol patients were assessed for expression of TARS, vascular endothelial growth factor (VEGF) and PECAM using\nimmunohistochemistry. TARS secretion from SK-OV-3 human ovarian cancer cells was measured. Serum samples\nfrom 31 tissue-matched patients were analyzed by ELISA for TARS, CA-125, and tumor necrosis factor-? (TNF-?).\nResults: There was a strong association between the tumor expression of TARS and advancing stage of epithelial ovarian\ncancer (p < 0.001). TARS expression and localization were also correlated with VEGF (p < 0.001). A significant proportion of\nsamples included heavy TARS staining of infiltrating leukocytes which also correlated with stage (p = 0.017). TARS was\nsecreted by ovarian cancer cells, and patient serum TARS was related to tumor TARS and angiogenic markers, but did not\nachieve significance with respect to stage. Multivariate Cox proportional hazard models revealed a surprising inverse\nrelationship between TARS expression and mortality risk in late stage disease (p = 0.062).\nConclusions: TARS expression is increased in epithelial ovarian cancer and correlates with markers of angiogenic\nprogression. These findings and the association of TARS with disease survival provide clinical validation that TARS is\nassociated with angiogenesis in ovarian cancer. These results encourage further study of TARS as a regulator of the tumor\nmicroenvironment and possible target for diagnosis and/or treatment in ovarian cancer....
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