Current Issue : October - December Volume : 2015 Issue Number : 4 Articles : 6 Articles
Background: Based on the mechanism of action, combining somatostatin analogues (SSAs) with mTOR inhibitors\nor antiangiogenic agents may provide synergistic effects for the treatment of patients with neuroendocrine\ntumours (NETs). Herein, we investigate the use of these treatment combinations in clinical practice.\nMethods: This retrospective cross-sectional analysis of patients with NETs treated with the SSA lanreotide and targeted\ntherapies at 35 Spanish hospitals evaluated the efficacy and safety of lanreotide treatment combinations in clinical\npractice. The data of 159 treatment combinations with lanreotide in 133 patients was retrospectively collected.\nResults: Of the 133 patients, with a median age of 59.4 (16ââ?¬â??83) years, 70 (52.6 %) patients were male, 64 (48.1 %)\nhad pancreatic NET, 23 (17.3 %) had ECOG PS ?2, 41 (30.8 %) had functioning tumours, 63 (47.7 %) underwent surgery\nof the primary tumour, 45 (33.8 %) had received prior chemotherapy, and 115 (86.5 %) had received prior SSAs.\n115 patients received 1 lanreotide treatment combination and 18 patients received between 2 and 5 combinations.\nLanreotide was mainly administered in combination with everolimus (73 combinations) or sunitinib (61 combinations).\nThe probability of being progression-free was 78.5 % (6 months), 68.6 % (12 months) and 57.0 % (18 months) for\npatients who only received everolimus plus lanreotide (n = 57) and 89.3 % (6 months), 73.0 % (12 months), and 67.4 %\n(18 months) for patients who only received sunitinib and lanreotide (n = 50). In patients who only received everolimus\nplus lanreotide the median time-to-progression from the initiation of lanreotide combination treatment was\n25.8 months (95 % CI, 11.3, 40.3) and it had not yet been reached among the subgroup of patients only receiving\nsunitinib plus lanreotide. The safety profile of the combination treatment was comparable to that of the targeted\nagent alone.\nConclusions: The combination of lanreotide and targeted therapies, mainly everolimus and sunitinib, is widely\nused in clinical practice without unexpected toxicities and suggests efficacy that should be explored in\nrandomized prospective clinical trials....
Background: MicroRNAs (miRNAs) show differential expression across breast cancer subtypes and have both\noncogenic and tumor-suppressive roles. Numerous microarray studies reported different expression patterns of\nmiRNAs in breast cancers and found clinical interest for several miRNAs but often with contradictory results. Aim\nof this study is to identify miRNAs that are differentially expressed in estrogen receptor positive (ER+) and negative\n(ER?) breast primary tumors to better understand the molecular basis for the phenotypic differences between these\ntwo sub-types of carcinomas and to find potential clinically relevant miRNAs.\nMethods: We used the robust and reproductive tool of quantitative RT-PCR in a large cohort of well-annotated 153\nbreast cancers with long-term follow-up to identify miRNAs specifically differentially expressed between ER+ and ER?\nbreast cancers. Cytotoxicity tests and transfection experiments were then used to examine the role and the regulation\nmechanisms of selected miRNAs.\nResults: We identified a robust collection of 20 miRNAs significantly deregulated in ER+ compared to ER? breast\ncancers : 12 up-regulated and eight down-regulated miRNAs. MiR-190b retained our attention as it was the miRNA the\nmost strongly over-expressed in ER+ compared to ER? with a fold change upper to 23. It was also significantly upregulated\nin ER+/Normal breast tissue and down-regulated in ER?/Normal breast tissue. Functional experiments showed\nthat miR-190b expression is not directly regulated by estradiol and that miR-190b does not affect breast cancer cell lines\nproliferation. Expression level of miR-190b impacts metastasis-free and event-free survival independently of ER status.\nConclusions: This study reveals miR-190b as the highest up-regulated miRNA in hormone-dependent breast cancers.\nDue to its specificity and high expression level, miR-190b could therefore represent a new biomarker in hormonedependent\nbreast cancers but its exact role carcinogenesis remains to elucidate....
Background: The management of unresectable metastatic colorectal cancer (mCRC) is a comprehensive treatment\nstrategy involving several lines of therapy, maintenance, salvage surgery, and treatment-free intervals. Besides\nchemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), molecular-targeted agents such as anti-angiogenic agents\n(bevacizumab, aflibercept, regorafenib) and anti-epidermal growth factor receptor agents (cetuximab, panitumumab)\nhave become available. Ultimately, given the increasing cost of new active compounds, new strategy trials are needed\nto define the optimal use and the best sequencing of these agents. Such new clinical trials require alternative\nendpoints that can capture the effect of several treatment lines and be measured earlier than overall survival to\nhelp shorten the duration and reduce the size and cost of trials.\nMethods/Design: STRATEGIC-1 is an international, open-label, randomized, multicenter phase III trial designed to\ndetermine an optimally personalized treatment sequence of the available treatment modalities in patients with\nunresectable RAS wild-type mCRC. Two standard treatment strategies are compared: first-line FOLFIRI-cetuximab,\nfollowed by oxaliplatin-based second-line chemotherapy with bevacizumab (Arm A) vs. first-line OPTIMOX-bevacizumab,\nfollowed by irinotecan-based second-line chemotherapy with bevacizumab, and by an anti-epidermal growth factor\nreceptor monoclonal antibody with or without irinotecan as third-line treatment (Arm B). The primary endpoint is\nduration of disease control. A total of 500 patients will be randomized in a 1:1 ratio to one of the two treatment\nstrategies.\nDiscussion: The STRATEGIC-1 trial is designed to give global information on the therapeutic sequences in patients\nwith unresectable RAS wild-type mCRC that in turn is likely to have a significant impact on the management of this\npatient population. The trial is open for inclusion since August 2013....
Background: Tumor-induced lymphangiogenesis plays a crucial role in metastasis and tumor progression.\nHowever, the significance of intratumoral lymphovascular density (I-LVD) and peritumoral lymphovascular density\n(P-LVD) has been controversial in gastric cancer. The purpose of this study was to investigate the differences of\nclinicopathologic characteristics with respect to I-LVD and P-LVD in gastric cancer.\nMethods: Samples of I-LVD and P-LVD from 66 patients who had undergone radical gastrectomy for gastric cancer\nwere assessed after staining with D2-40, an immunostaining marker for lymphatic endothelium. The mean number\nof lymphatic vessels in three hotspots was calculated in intratumoral and peritumoral areas.\nResults: The peritumoral lymphatics were enlarged with dilated lumens compared to the intratumoral lymphatics.\nI-LVD was positively correlated with diffuse gastric cancer subtype, tumor stage, lymphovascular invasion, tumor\nnode metastasis stage, and overall survival (P <0.05). P-LVD was associated with lymphovascular invasion, node\nstage, and disease-free survival (P <0.05).\nConclusions: We conclude that P-LVD had an important role in lymph node metastasis, while I-LVD was more\nassociated with depth of tumor invasion. However, both LVDs contributed to gastric cancer progression and\nprognosis....
Background: TRAIL is a potent and specific inducer of apoptosis in tumour cells and therefore is a possible new\ncancer treatment. It triggers apoptosis by binding to its cognate, death-inducing receptors, TRAIL-R1 and TRAIL-R2.\nIn order to increase its activity, receptor-specific ligands and agonistic antibodies have been developed and some\ncancer types, including pancreatic cancer, have been reported to respond preferentially to TRAIL-R1 triggering. The\naim of the present study was to examine an array of TRAIL-receptor specific variants on a number of pancreatic\ncancer cells and test the generality of the concept of TRAIL-R1 preference in these cells.\nMethods: TRAIL-R1 and TRAIL-R2 specific sTRAIL variants were designed and tested on a number of pancreatic\ncancer cells for their TRAIL-receptor preference. These sTRAIL variants were produced in HEK293 cells and were\nsecreted into the medium. After having measured and normalised the different sTRAIL variant concentrations, they\nwere applied to pancreatic and control cancer cells. Twenty-four hours later apoptosis was measured by DNA\nhypodiploidy assays. Furthermore, the specificities of the sTRAIL variants were validated in HCT116 cells that were\nsilenced either for TRAIL-R1 or TRAIL-R2.\nResults: Our results show that some pancreatic cancer cells use TRAIL-R1 to induce cell death, whereas other\npancreatic carcinoma cells such as AsPC-1 and BxPC-3 cells trigger apoptosis via TRAIL-R2. This observation extended\nto cells that were naturally TRAIL-resistant and had to be sensitised by silencing of XIAP (Panc1 cells). The measurement\nof TRAIL-receptor expression by FACS revealed no correlation between receptor preferences and the relative levels of\nTRAIL-R1 and TRAIL-R2 on the cellular surface.\nConclusions: These results demonstrate that TRAIL-receptor preferences in pancreatic cancer cells are variable and that\npredictions according to cancer type are difficult and that determining factors to inform the optimal TRAIL-based\ntreatments still have to be identified....
Background: BRAF mutations are present in 40 % of human skin melanomas. Mutated tumors with an increased\npercentage of BRAF mutant alleles (BRAF-M%) may have a better response to RAF/MEK inhibitors. We evaluated the\nBRAF-M% in melanomas, and the genetic causes of its variation.\nMethods: BRAF-M% was quantified by pyrosequencing, real-time PCR (rtPCR) and/or picoliter-droplet PCR (dPCR).\nBRAF mutant expression was detected by immunohistochemistry. Chromosomal alterations were analyzed with\nfluorescence in situ hybridization (FISH), and single nucleotide polymorphism (SNP) arrays.\nResults: BRAF-M% quantification obtained with pyrosequencing was highly correlated (R = 0.94) with rtPCR, and with\ndPCR. BRAF-M% quantified from DNA and RNA were also highly correlated (R = 0.98). Among 368 samples with >80 %\ntumor cells, 38.6 % had a BRAFV600E mutation. Only 66.2 % cases were heterozygous (BRAF-M% 30 to 60 %). Increased\nBRAF-M% (>60 %) was observed in 19 % of cases. FISH showed a polysomy of chromosome 7 in 13.6 %, 35.3 %\nand 54.5 % of BRAF wild-type, heterozygous and non-heterozygous BRAF-mutated samples, respectively (P < 0.005).\nAmplification (5.6 %) and loss (3.2 %) of BRAF locus were rare. By contrast, chromosome 7 was disomic in 27/27\nBRAF-mutated nevi.\nConclusions: BRAF-M% is heterogeneous and frequently increased in BRAF-mutant melanomas. Aneuploidy of\nchromosome 7 is more frequent in BRAF mutant melanomas, specifically in those with high BRAF-M%....
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