Table 2 - uploaded by Mario Scartozzi
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Table summarising main characteristics of the reported studies regarding gastric and pancreatic cancer.
Source publication
Introduction:
In the GI tumors area, key findings from the American Society of Clinical Oncology 2013 annual meeting were long awaited, particularly in colorectal, gastric and pancreatic cancer.
Areas covered:
The following pages briefly present and comment on a selection of those studies considered most relevant for clinical practice and future...
Citations
... Metastatic progression significantly favored CT (44%) over RTCT (60%, p = 0.04). Although the results of the LAP-07 trial discourage the inclusion of RTCT in the routine treatment for LAPC [56], the paper from Hammel et al. discusses balancing the role of RTCT by "confirming the safety of RTCT (with concurrent capecitabine)" and advocating the "need for further RT intensification", in particular, intensity-modulated RT (IMRT) and SBRT for the safe escalation of doses [55]. Again, the role of the RT-administered dose is of importance. ...
Pancreatic cancer represents a modern oncological urgency. Its management is aimed to both distal and local disease control. Resectability is the cornerstone of treatment aim. It influences the clinical presentation’s definitions as up-front resectable, borderline resectable and locally advanced (unresectable). The main treatment categories are neoadjuvant (preoperative), definitive and adjuvant (postoperative). This review will focus on i) the current indications by the available national and international guidelines; ii) the current standard indications for target volume delineation in radiotherapy (RT); iii) the emerging modern technologies (including particle therapy and Magnetic Resonance [MR]-guided-RT); iv) stereotactic body radiotherapy (SBRT), as the most promising technical delivery application of RT in this framework; v) a particularly promising dose delivery technique called simultaneous integrated boost (SIB); and vi) a multimodal integration opportunity: the combination of RT with immunotherapy.
... , the outcomes for CRC patients remain poor, and their average survival time is less than 30 months (Scartozzi et al., 2014). ...
Background
Abnormal methylation of TNFRSF10C was found to be associated with different types of cancers, excluding colorectal cancer (CRC). In this paper, the performance of TNFRSF10C methylation in CRC was studied in two stages.
Method
The discovery stage was involved with 38 pairs of CRC tumor and paired adjacent non-tumor tissues, and 69 pairs of CRC tumor and paired adjacent non-tumor tissues were used for the validation stage. Quantitative methylation specific PCR (qMSP) method and percentage of methylated reference (PMR) were used to test and represent the methylation level of TNFRSF10C , respectively. A dual-luciferase reporter gene experiment was conducted to evaluate the promoter activity of TNFRSF10C fragment.
Results
A significant association of TNFRSF10C promoter hypermethylation with CRC was found and validated (discovery stage: 24.67 ± 7.52 vs. 3.36 ± 0.89; P = 0.003; validation stage: 31.21 ± 12.48 vs. 4.52 ± 1.47; P = 0.0005). Subsequent analyses of TCGA data among 46 pairs of CRC samples further confirmed our findings (cg23965061: P = 4E − 6; cg14015044: P = 1E − 7). Dual-luciferase reporter gene assay revealed that TNFRSF10C fragment was able to significantly promote gene expression (Fold change = 2.375, P = 0.013). Our data confirmed that TNFRSF10C promoter hypermethylation can predict shorter overall survival of CRC patients ( P = 0.032). Additionally, bioinformatics analyses indicated that TNFRSF10C hypermethylation was significantly associated with lower TNFRSF10C expression.
Conclusion
Our work suggested that TNFRSF10C hypermethylation was significantly associated with the risk of CRC.
... Lapatinib, a small molecule, dual tyrosine kinase inhibitor targeting EGFR and HER2, was predicted to demonstrate significant clinical activity against gastric cancer, where HER2 is amplified and/or there is an overexpression of EGFR or HER2 (29,30). To date, lapatinib appears to have minimal activity as a single agent in first-line therapy of advanced/metastatic gastroesophageal junction and gastric cancer based upon preliminary data from phase II and III clinical studies (31)(32)(33). Although the study investigating lapatinib as first-line therapy in patients with advanced or metastatic gastric cancer met first-stage criteria and went on to complete enrollment (31), the study investigating lapatinib in relapsed adenocarcinoma of the esophagus stopped early because of rapid progression of disease. ...
Secondary objectives:
overall survival (OS), PFS, time-to-response, duration-of-response, toxicity and identify associations between lapatinib pharmacokinetics and biomarker endpoints. Primary biomarker objectives: modulation of 5-FU-pathway genes by lapatinib, effects of germline SNPs on treatment outcome, and trough steady-state plasma lapatinib concentrations. 68 patients were enrolled; (75% GC, 25% GeJ). 12 patients (17.9%) had confirmed partial response, 31 (46.3%) had stable disease, and 16 (23.9%) had progressive disease. Median PFS and OS were 3.3 and 6.3 months, respectively. Frequent AEs included diarrhea (45%), decreased appetite (39%), nausea (36%), and fatigue (36%). Lapatinib induced no changes in gene expression from baseline and no significant associations were found for SNPs analyzed. Elevated baseline HER3 mRNA expression was associated with a higher RR (33% vs 0%, p=0.008). Lapatinib plus capecitabine was well tolerated, demonstrating modest antitumor activity in patients with advanced GC. The association of elevated HER3 and RR warrants further investigation as an important player for HER-targeted regimens in combination with capecitabine.
... [2,3] Outcomes for patients with CRC remain poor, with an average survival of <30 months. [4] The development and progression of CRC is a multistep oncogenic process in which both genetic and epigenetic alterations accumulate in a temporal and spatial manner sequentially. [5] Although much effort was dedicated to explore the molecular mechanisms of CRC during the last two decades, the precise molecular pathogenesis of CRC remains unclear. ...
Objective:
The deregulation of microRNA-185 (miR-185) has been showed to be associated with many cancers and act as a tumor suppressor in many types of human malignancies. We hence tried to find out its role in human colorectal cancer (CRC).
Materials and methods:
miR-185 expression was investigated by real-time quantitative polymerase chain reaction. We carried out transfections to overexpress or knockdown of miR-185 by mimics or inhibitor, respectively. Functional study like cell counting kit-8 assay was performed to evaluate the proliferation. For addressing the impact of miR-185 on Wnt/β-catenin signaling, we further applied luciferase reporter assay and Western blotting for specific proteins in this pathway.
Results:
miR-185 was decreased in CRC cell lines when compared with corresponding control cell line. We also proved that its overexpression in LoVo cells could remarkably suppress cell proliferation whereas knocked it down in SW480 cells has the opposite effect in vitro. Mechanically, we demonstrated that miR-185 could suppress the Wnt/β-catenin signaling and modulate the transcription and translation level of downstream molecules of this pathway, including MYC and CCND1.
Conclusion:
Taken together, these results suggested that miR-185 exerts its tumor suppressor activities probably through a negative modulation of the Wnt/β-catenin pathway.
Objective:
Colorectal cancer (CRC) is one of the major healthcare problems worldwide. A lot of miRNAs are aberrantly expressed in CRC and involved in its development and progression. The purpose of this study was to investigate the expression and function of miR-503 in CRC.
Methods:
miR-503 expression was detected in CRC tissues and cell lines by Quantitative real-time PCR. Cell proliferation was assessed by MTT assay. Cell apoptosis and cell cycle distribution were measured by flow cytometry. Moreover, luciferase reporter assay and western blot were performed to determine the potential target of miR-503 in CRC cells.
Results:
miR-503 was significantly decreased in CRC tissues and cell lines in comparison with controls. Overexpression of miR-503 in CRC cells remarkably inhibited cell proliferation and induced apoptosis. Furthermore, E2F3 was identified as a direct target of miR-503 in CRC cells and down-regulation of E2F3 had a similar effect as miR-503 overexpression on CRC cells. In addition, the expression of E2F3 was negatively correlated with miR-503 level in CRC tissues.
Conclusions:
miR-503 inhibits cell proliferation and induces apoptosis by directly targeting E2F3 in CRC cells, indicating its potential application in CRC diagnosis and therapy.
Bevacizumab is frequently used in patients with progressive glioblastoma raising questions regarding frequency of treatments, dosage, duration of therapy and the possibility of tapering and discontinuation for selected patient groups. We retrospectively assessed the safety and outcome of tapering and discontinuation of bevacizumab therapy for reasons other than disease progression and toxicity in 19 patients with progressive glioblastoma receiving bevacizumab for at least 6 months. In 10 of the 19 patients tapering bevacizumab resulted in complete discontinuation and reinitiation after disease progression during halted treatment. As a comparison group 33 patients with bevacizumab for at least 6 months continuously dosed at 10 mg/kg every 2 weeks were selected. Age and Karnofsky performance status at start of bevacizumab were similar in both groups. Influenced by the selection process, progression-free survival (PFS) and overall survival (OS) were longer in the group receiving a tapered and discontinued bevacizumab regimen (PFS 22.7 versus 11.2 months, HR 0.33, p-value = 0.01; OS 29.9 versus 15.5 months, HR 0.22, p-value = 0.001) with a median time of discontinuation of 4.5 months (range: 1.9–44.2 months). Stable disease or partial response according to RANO at ≥3 months was achieved in 89 % of patients with reinitiated bevacizumab therapy after discontinuation. These data indicate that tapering and discontinuation of bevacizumab therapy for other reasons than progression is feasible without an increased risk for tumor rebound or unresponsiveness to reinitiated bevacizumab therapy.
Background: The biological axis of CXC chemokine ligand 12 (CXCL12)/CXC chemokine receptor 4 (CXCR4) plays an important role in the specific metastasis of tumors, whereas the mRNA expression of glycoprotein hormone receptor 5, a stem cell marker, exerts an important effects on tumor proliferation, invasion and metastasis. Objective: To investigate the expressions of CXCL12/CXCR4 and glycoprotein hormone receptor 5 in human colorectal cancer tissues as well as their relationship with clinical and pathological characteristics. Methods: Totally 100 colorectal cancer patients admitted at Liaoning Cancer Hospital & Institute from January to June 2013 were enrolled as experimental group, and another 100 healthy volunteers served as control group. Immunohistochemical SP method was used to detect the expression of CXCL12, CXCR4 and glycoprotein hormone receptor 5 mRNA in human colorectal cancer tissues. We analyzed the correlation of CXCL12, CXCR4 and glycoprotein hormone receptor 5 mRNA expression with colorectal cancer patients' age, sex, tumor size and site, lymphatic metastasis and prognosis Results and Conclusion: There was a higher expression of CXCR4 and glycoprotein hormone receptor 5 mRNA, but lower expression of CXCL12 mRNA in the human colorectal cancer tissues. The mRNA expression of CXCR4, CXCL12 and glycoprotein hormone receptor 5 showed no correlation with age, gender, tumor size and site of colorectal cancer patients, but was related to lymphatic metastasis. For colorectal cancer patients with lymphatic metastasis, the expression of CXCR4 and glycoprotein hormone receptor 5 mRNA was higher, but no change was found in the expression of CXCL12 mRNA. The expression of CXCR4 was increased with the degree of tumor malignancy as well as glycoprotein hormone receptor 5 expressed on the surface of gastrointestinal cancer and brain tumor stem cells. These findings indicate that the growth and metastasis of human colorectal cancer tissues are promoted by increasing the expression of CXCR4 and glycoprotein hormone receptor 5 in human colorectal cancer tissues; the CXCL12/CXCR4 biological axis and glycoprotein hormone receptor 5 are expected to become a new target therapy for tumor diagnosis and treatment.
Colorectal cancer (CRC) is the third most common cancer in western countries. Despite significant improvement in available treatment options, CRC still remains the second leading cause of cancer-related death. Traditionally, 5-fluorouracil has been used as the main chemotherapy drug for treatment of metastatic CRC (mCRC). However, during the last two decades more effective chemotherapeutic agents such as oxaliplatin, irinotecan and the monoclonal antibodies cetuximab, panitumumab and bevacizumab have been used in clinical practice. More recently, the therapeutic armamentarium has been supplemented by the monoclonal antibodies bevacizumab, cetuximab and panitumumab as well as the protein-trap aflibercept and the small molecule multi-kinase inhibitor regorafenib. One of the major problems for the management of CRC is the inherent or acquired resistance to therapeutic approaches. The discovery of microRNAs (miRNAs), a class of small, endogenous, non-coding, single-stranded RNAs that play a role as post-transcriptional regulators, has added new dimensions to the diagnosis and treatment of cancer. Because miRNAs are important regulators of carcinogenesis, progression, invasion, angiogenesis and metastases in CRC, they might serve as potential predictive and prognostic factors and even as therapeutic targets themselves. Several miRNAs are already known to be dysregulated in CRCs and have been linked to biological processes involved in tumor progression and response to anti-cancer therapies. This review summarizes current therapeutic approaches for treating CRC and highlights the role of miRNAs as novel predictive biomarkers and potential drug targets in CRC patients.
