bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of IMP3 on epithelial-to-mesenchymal transition and the function of colon cancer stem cells.
Authors: Wei Ping , Li Dawei , Xu Ye , Cai Sanjun , Du Xiang 
Published: February 2017

631 Background: EMT could promote the acquisition of stem-like properties in cancer cells and cancer stem cell (CSC) has EMT properties. However, the underlying mechanism of the interaction between EMT and CSC still remain unclear. We previously identified Insulin-like growth factor-II mRNA-binding protein 3 (IMP3) plays a vital role in colon cancer carcinogenesis. Here, we aimed to identify the gene function between EMT and CSC in colon cancer. Methods: The expression of IMP3 was analyzed in human tumor tissues. Colonospheres were isolated from colon cancer cell lines and the biological features of IMP3 were investigated in the process of EMT and colonoshpere cells. Results: Increased IMP3 levels were significantly correlated with higher clinical stage, T classification, LNM, presence of distant metastasis. Patients with IMP3-positive localized tumors had lower 5-year disease-free survival (DFS) and overall survival (OS) than those with IMP3-negative tumors. Multivariate survival analysis showed that IMP3 was an independent prognostic marker for DFS and OS. Expanded colonospheres contained cells that expressed high levels of CD133 and had the ability to promote migration and activate the epithelial-mesenchymal transition. Down regulation of IMP3 in HCT116 cells inhibited the invasion, migration ability and epithelial-mesenchymal transition and the properties of colonospheres. Conclusions: These findings suggest that IMP3 plays an important role in colon cancer tumorigenesis and metastasis through transactivation of colon CSC with EMT property, which is helpful to identify critical marker and therapeutic target.
K-ras mutational status and its clinical implications in Korean colorectal cancer patients.
Authors: An Ho Jung , Gye Bong-Hyeon , Kim Hyung Jin , Jung Ji Han , Lee Jong Hoon , Kim Sung Whan , Cho Hyun Min , Shim Byoungyong 
Published: February 2017

641 Background: The incidence of K-ras mutation of exon 2 was reported between 30-40% in colorectal cancer, and it is well known predictive biomarker for EGFR monoclonal antibody. However, its prognostic role has not been defined so far, especially in Eastern country. Methods: From January 2007 to September 2013, patients who were diagnosed as colorectal cancer and examed K-ras exon 2 mutation in Saint Vincent’s hospital were retrospectively reviewed. Results: Among 436 patients, 343 patients with sufficient clinical information were analyzed. The median follow up period was 13.0 (0.2-94.8) months. The incidence of K-ras mutation was 37.9% (codon 12 mutation: 28.6%, codon 13 mutaiton: 9.0%, both: 0.3%). Codon 12 p.G12D was most frequent (52.3%), and codon 13 p.G13D was the next (22.3%). The presence of K-ras mutation was associated with old age (p=0.038), female gender (p=0.034), lesser nodal involvement (p<0.001), but not related to stage, tumor site, and histology. There is no significant clinical differences between codon 12 and 13 mutations. The recurrence free survival in patients who received curative resection was worse in patients with K-ras mutation (p=0.001). The prognostic role of K-ras mutation was more prominent in colon cancer, while it lost its prognostic significance in rectal cancer. Conclusions: The prognostic role of K-ras mutation was different according to primary tumor sites in colorectal cancer.
Improving neoadjuvant chemoradiotherapy for rectal cancer with CRLX101, a nanoparticle-drug conjugate, with a camptothecin payload.
Authors: Wang Andrew , Tian Xi , Nguyen Minh , McRee Autumn Jackson , Sanoff Hanna Kelly , O'Neil Bert H. , Hennessy Meliessa G. , Eliasof Scott , Garmey Edward Graeme , Tepper Joel E. 
Published: February 2017

645 Background: There has been great interest in developing novel agents and strategies to improve chemoradiotherapy (CRT) for locally advanced rectal cancer. Irinotecan, a camptothecin (CPT) analogue, held high potential, but the combination was clinically infeasible due to severe gastrointestinal toxicities. CRLX101, a dynamically tumor targeted nanoparticle-drug conjugate differentially delivers CPT into cancer cells and appears to durably suppress HIF-1α as well as topoisomerase 1, but with less gastrointestinal toxicities than irinotecan. We therefore hypothesized that the addition of CRLX101 to CRT may further improve the therapeutic index in this setting. Methods: CRLX101 was evaluated using murine flank xenograft models (SW480 and HT29) of colorectal cancer alone or in combination with radiotherapy (XRT) and/or 5-FU and compared to CPT plus CRT. Skin toxicity and hematologic toxicity were also studied. In addition, a Phase Ib/II clinical trial (LCCC1315) evaluating the addition of CRLX101 to CRT in the neo-adjuvant treatment of rectal cancer is currently underway. A standard 3 + 3 design was used for the phase Ib with a CRLX101 starting dose of 12 mg/m2 in the first cohort escalating to the CRLX101 monotherapy MTD of 15 mg/m2 in the second. The primary phase 2 end-point is the pathological complete response (pCR) rate from treatment. Results: In the HT29 xenografts model, CRLX101+5FU+XRT delayed tumor growth significantly more than the other treatment regimens evaluated. In the SW480 xenografts model, both CRLX101+5FU+XRT and CRLX101+XRT delayed tumor growth more than other regimens, but there was no statistical advantage to the addition of 5-FU to CRLX101+XRT in this model. The addition of CRLX101 to 5FU+XRT did not increase hematologic or skin toxicities. In the ongoing clinical trial, none of the first 3 patients enrolled (the first dosing cohort) have experienced dose limiting toxicities and 1 out of 3 patients had a pCR. Conclusions: CRLX101 has been shown in preclinical experiments to improve the therapeutic index of CRT for rectal cancer. Preliminary clinical data suggest that CRLX101+5FU+XRT treatment is well tolerated. Clinical trial information: NCT02010567.
Novel mechanism linking noncanonical Wnt ligand induction to suppression of colorectal cancer cell proliferation.
Authors: Braun Donald Peter , Fagla Bani M , Ali Irshad 
Published: February 2017

648 Background: Malignant tissues are characterized by uncontrolled proliferation and dysfunctional differentiation. A central pathway in the control of proliferation and differentiation is the Wnt pathway. Wnt function is mediated by a canonical pathway (CP) which utilizes β-catenin and stimulates cell proliferation, and a non-canonical pathway (NCP) independent of β-catenin involved with differentiation. Studies suggest that dysfunctional Wnt signaling results from imbalance of CP components. The possibility that modulation of NCP components are involved in this process has not been studied comprehensively. Given their importance in constraining CP signaling and proliferation, the purpose of this study was to determine the capacity of NCP components to suppress human colorectal cancer (CRC) proliferation. Methods: Short term, primary CRC lines were established from resected tumors from patients with metastatic and/or recurrent disease. CRC were treated with LiCl, an activator of the CP, Dkk1, an inhibitor of the CP, and IWP-2, a pan inhibitor of CP and NCP Wnt ligand secretion. CRC proliferation and Wnt pathway gene expression were determined by MTS assays and quantitative gene expression respectively. Results: Unexpectedly, CRC proliferation was inhibited significantly (p<0.01) by LiCl and stimulated modestly (ns) by Dkk1. This was associated with a 20 fold increase in gene expression for the NCP ligand, Wnt9A. LiCl treated cells incubated with IWP-2 reversed the unexpected LiCl-mediated suppression of CRC proliferation. Conclusions: The unexpected finding that LiCl suppresses proliferation and Dkk1 has the opposite effect indicate dysregulation of the Wnt pathway in CRC. Further support for this hypothesis is the fact that Wnt 9A, an NCP ligand is increased by LiCl in CRC, an effect that is not expected in non-malignant cells. That IWP-2, a pan Wnt ligand secretion inhibitor reverses these effects is consistent with these observations. This study is the first to demonstrate a correlation between NCP ligand induction and suppression of CRC proliferation and suggests that control of CRC proliferation may be achieved in patients by modalities that activate the NCP Wnt pathway.
Prognostic and predictive values of APC and WNT pathway mutations in MSS colorectal cancers.
Authors: Kothari Nishi , Yue Binglin , Teer Jamie K. , Schell Michael J. , Kim Richard D. 
Published: February 2017

652 Background: WNT signaling is abnormal in many inherited and acquired colorectal cancers, through mutations in APC and other components of the pathway including beta catenins and AXINs. Aspirin and other COX-2 inhibitors have been hypothesized to decrease WNT pathway activity in preclinical models, potentially leading to improved survival. We evaluated APC and WNT pathway mutations as potential prognostic and predictive biomarkers for ASA use in a cohort of colorectal cancer patients. Methods: We analyzed tumor samples collected from 468 CRC patients diagnosed between 1998 and 2010 as part of a multi-institutional observational study. We performed targeted exome sequencing using the Illumina NGS platform with 50-100X coverage of mutations. The BWA/GATK pipeline was used to identify variants and indels. Matched normal samples were not available for comparison to identify somatic mutations, so filtering of normal variants was performed using 1000 Genomes. One or 2 mutations in the APC gene were counted as mutant. Additional WNT pathway mutations included AXIN1, AXIN2, CTNNB1, WNT1, and WNT2. Variants identified in 1000 Genomes with an MAF <0.01 were filtered. ASA use data was collected through retrospective chart review. Results: MSI-H tumors were excluded. 356 patients were eligible for analysis. 258 patients had APC mutations and 20 patients had other WNT pathway mutations including CTNNs, WNTs, AXINs, and TCF7L2. 140 patients had metastatic disease. Aspirin users had a median age of 70 compared to non-users at 63. Patients with APC mutations had improved overall survival compared to wild type patients for early stage disease (p = 0.03) with a trend towards improvement in survival for metastatic patients. Additional WNT pathway mutations did not strengthen this relationship. ASA use was not associated with improved OS in the APC or WNT pathway mutant patients. Conclusions: In this population, APC mutations had positive prognostic value, which was more pronounced in early stage disease. There was limited predictive value for ASA use in APC mutant patients. However, aspirin users tended to be older which might have confounded the association.
Correlation of overexpression of ATPase Na+/K+ transporting alpha 1 polypeptide with the diagnosis and clinical staging of esophageal cancer: A translational study.
Authors: Wu I-Chen 
Published: February 2017

66 Background: This study aims to identify the novel and potential upregulated genes related to secretionary or membranous proteins for the clinical diagnosis and staging of esophageal squamous cell carcinoma (ESCC). Methods: By combining microarray-based screening, which contained at least 25,000 DNA oligonucleotide probes, of esophageal tumors from both N-nitrosomethylbenzylamine- and arecoline-induced F344 rats and 17 human ESCC specimens, we further confirmed the potential candidate genes by tissue arrays in 243 cancer tissues and 126 normal tissues of esophagus from Taiwan, Korea, and USA and by ELISA in 78 serum specimens of ESCC patients from Taiwan. Results: Four candidate genes, including ATP1A1, SPINT2, CMTM8, and AGR2, were chosen due to their up-regulation in more than half of 17 paired tissues from 17 ESCC patients in the microarray-based screening. The four genes were verified by RT-PCR and immunohistochemical (IHC) staining in ESCC tissue specimens and only ATP1A1 (ATPase Na+/K+ transporting alpha 1 polypeptide) expression was consistent and further studied. Among the 243 cancer tissues and 126 normal tissues of esophagus, we found that the positive expressions of ATP1A1 by IHC staining were 207 (85%) of 243 in cancer tissues and 88 (70%) of 126 in normal tissues. After adjusted for age and sex, ATP1A1 overexpression had a 3.2-time (95% CI = 1.8-5.6) to be likely in cancer tissues than in normal tissues. ATP1A1 expression was also correlated to the tumor stage by IHC staining. Using the median level of 1,465.0 pg/mL of serum ATP1A1 protein expression as the cut-off point, we found that patients with stage III-IV had a 2.91-fold (1.12-7.36) likely to have high serum ATP1A1 levels than those with stage I-II after adjusting for age and sex. Conclusions: ATP1A1 overexpression may serve as a potential noninvasive marker of the clinical diagnosis and staging for ESCC patients.
The clinical utility of a tumour microenvironment-based histopathological score in patients with primary operable colorectal cancer.
Authors: Park James Hugh , Mcmillan Donald C. , Horgan Paul G. , Roxburgh Campbell S.D. 
Published: February 2017

664 Background: The tumor microenvironment is increasingly recognized as an important determinant of disease progression and outcome in colorectal cancer (CRC). The aim of the present study was to examine the clinical utility of a novel histopathological prognostic score based on both the tumor inflammatory cell infiltrate and the tumor stroma percentage, termed the Glasgow Microenvironment Score (GMS), in patients with primary operable CRC. Methods: Using routine H&E pathological sections, Klintrup-Mäkinen (KM) grade was graded as strong or weak, and tumor stroma percentage (TSP) was assessed as high (>50%) or low (≤50%) retrospectively in 319 patients undergoing resection of stage II-III CRC. The relationship between a cumulative score based on these factors and cancer-specific survival (CSS) was examined. Results: Median survival of survivors was 122 months with 106 cancer deaths. 63% of patients had stage II CRC. 5-year CSS of patients with stage II and stage III CRC was 82% and 58% respectively (p<0.001). 33% of patients were GMS=0 (strong KM/high or low TSP), 47% were GMS=1 (weak KM/low TSP), and 20% GMS=2 (weak KM/high TSP), with 5-year CSS of 86%, 74%, and 48% (p<0.001) respectively. On multivariate analysis, GMS was associated with CSS (HR 1.77, p<0.001), independent of age, emergency presentation, TNM stage and venous invasion (all p<0.01), and peritoneal involvement (p<0.05). The combination of TNM and GMS stratified 5-year CSS from 92% (stage II, GMS=0) to 35% (stage III, GMS=2) (Table). Conclusions: The present study shows the clinical utility of a novel, routinely available assessment of the tumor microenvironment in patients undergoing curative resection of CRC. [Table: see text]
Improving safety in first-line metastatic colorectal cancer (MCRC) therapy with bevacizumab: Modified FOLFOX7 versus XELOX2—Results of the induction phase of the GERCOR DREAM randomized phase III study.
Authors: Tournigand Christophe , Chibaudel Benoist , Samson Benoit , Scheithauer Werner , Lledo Gérard , Artru Pascal , Viret Frédéric , RAMEE Jean-Francois , Tubiana-Mathieu Nicole , Dauba Jérôme , Dupuis Olivier , Rinaldi Yves , Mabro May , Aucoin Nathalie , Bonnetain Franck , Louvet Christophe , Larsen Annette K. , André Thierry , De Gramont Aimery ,   GERCOR, Groupe Coopérateur Multidisciplinaire en Oncologie
Published: February 2017

670 Background: FOLFOX7 is an oxaliplatin FOLFOX regimen without 5FU bolus, first used in the OPTIMOX1 MCRC study (Tournigand, JCO 2006). Modified (m) FOLFOX7 has a reduced dose of oxaliplatin (100 mg/m²) and has been used in the OPTIMOX2 trial (Chibaudel, JCO 2009). XELOX2 derived from the bi-weekly XELOX regimen with oxaliplatin 85 mg/m² (Scheithauer, JCO 2003). Methods: First-line induction therapy (IT) allocation was randomized in unresectable MCRC patients with performance status (PS) 0-1 between 6 cycles of mFOLFOX7 with bevacizumab (B) or 6 cycles of XELOX2 with B. Stratification criteria were: center, age, ECOG PS, number of metastatic sites and LDH level. After 3-month IT, a second randomization for maintenance therapy allocation was done in non-progressive patients between B or B-erlotinib. mFOLFOX7-B consisted in B 5 mg/kg followed by folinic acid (FA) 400 mg/m² and oxaliplatin 100 mg/m² followed by 5-flurouracil (5FU) 2,400 mg/m² 46h-infusion. XELOX2-B consisted in B 5 mg/kg followed by oxaliplatin 100 mg/m² followed by capecitabine 1,250 mg/m² twice daily for seven days. Cycles were repeated every two weeks. The objective was to compare the safety and efficacy of XELOX2-B to mFOLFOX7-B (secondary objective of the study). Results: 156 patients were randomized to mFOLFOX7-B and 154 to XELOX2-B. Medians (mFOLFOX7/XELOX2) were: PFS 7.9/8.7 months (HR 0.98, CI 0.74-1.31; p=0.918), OS 26.6/23.4 months (HR 1.24, CI 0.98-1.59; p=0.075). RR (mFOLFOX7/XELOX2) was 50.0%/49.3%. Main grade 3/4 toxicities (mFOLFOX7/XELOX2) were neutropenia 9.2%/2.6% (p=0.018), diarrhea 5.2%/18.3% (p<0.001), asthenia 2.6%/11.8% (p=0.003), all 27.5%/37.6% (p=0.068). Conclusions: Both regimens have the same activity as the parent regimens with a reduced toxicity, especially mFOLFOX7-B. These regimens could be good backbones for future combinations with other agents and are well suited for frail and elderly patients. Clinical trial information: NCT00265824.
Observational study of first-line therapy, including cetuximab in cases of nonresectable colorectal cancer: CORAL (interim report).
Authors: Hashida Hiroki , Muro Kei , Itabashi Michio , Ohashi Yasuo , Sugihara Kenichi 
Published: February 2017

681 Background: Cetuximab (Cmab) + chemotherapy is now indicated in various treatment guidelines as a first-line therapy for non-resectable metastatic colorectal cancer (mCRC). The efficacy of Cmab + FOLFIRI has been demonstrated in CRYSTAL, but its efficacy and safety in combination with other regimens is unclear. There are few reports on Cmab combination therapy as first-line chemotherapy in Japan, and there are no reports of treatment results in the ESMO guideline groups 1, 2, and 3. Therefore an observational study was planned to evaluate the efficacy and safety of first-line therapy including Cmab, and to clarify the treatment results by group. This study received support from the Public Health Research Foundation’s Comprehensive Support Project for Oncology Research (CSPOR). Methods: The subjects were mCRC patients who received Cmab as first-line therapy either as combination therapy or monotherapy. Endpoints were response rate, PFS, and reason for discontinuation of first-line treatment (curative resection, PD, adverse events). To evaluate safety, skin conditions (incidence, degree, previous history) and other adverse events were investigated. Results: Among 579 patients enrolled at 158 institutes from January 2012 until June 2013, 575 were subjected to analysis. Background factors were PS 0/1/2 at 406/143/26, males females at 368/207, median age of 65 (31-88), groups 1/2/3 at 172/229/174, and concomitant drugs were oxaliplatin/irinotecan/others at 377/173/25. Response rate in the evaluable cases was 57%, and in groups 1/2/3 was 65%/54%/53%. The 1-year survival rate in groups 1/2/3 was 93%/61%/78%. In adverse events, the incidence of skin conditions (rash acneform) at 8 weeks/16 weeks was 69%/60% in patients with no history of acne vulgaris (2%/8% at G3 or higher) and 83%/81% in those with a previous history (13%/14% at G3 or higher). Conclusions: We reported treatment results according to ESMO guideline groups on the efficacy and safety of Cmab as first-line therapy in mCRC patients. Response rate and survival were higher in group 1. Survival outcomes after 1 year will be followed up. Clinical trial information: UMIN000007275.
Impact of duration of neoadjuvant radiation on rectal cancer survival.
Authors: Kumar Aalok , Peixoto Renata D'Alpino , Kennecke Hagen F. , Speers Caroline , Cheung Winson Y. 
Published: February 2017

682 Background: The utility of neoadjuvant radiation (XRT) for the treatment of stages II-III rectal cancer has been demonstrated previously. However, the optimal amount and duration XRT in this setting remains unknown. Using a population-based cohort of stage II and II rectal cancer (RC) patients treated with curative intent including XRT, our aims were to 1) examine the patterns in XRT use and 2) explore the relationship between XRT course and survival. Methods: We analyzed patients diagnosed with clinical stage II-III RC from 2006 to 2010 and treated with long course 45-50.4 Gray (LC) or short course 25 Gray (SC) XRT at any 1 of 5 regional cancer centers in British Columbia. Logistic regression models were constructed to determine the factors associated with the course of XRT given, LC vs. SC. Kaplan-Meier methods and Cox regression that accounted for known prognostic factors were used to evaluate the relationship between XRT course and disease-free (DFS), overall survival (OS), local recurrence free survival (LRFS) and distant recurrence free survival (DRFS). Results: 427 patients were identified: median age 65 years (range 31 to 94), 67% men, 87% T3/4 tumors, and 74% with N1 or N2 disease. Among them, 240 (56%) received SC and 187 (44%) received LC. Adjusting for confounders, patients with N1 or N2 disease were more likely to receive LC (OR for LC 5.08, 95% CI, 2.51-11.22, p<0.0001 and 8.35, 95% CI, 3.35-22.39, p<0.0001, respectively), while older age patients were less likely to receive LC (OR 0.95, 95% CI, 0.94-0.98, p<0.0001). On univariate analysis, there was no significant difference seen in DFS, OS, LRFS, and DRFS between LC and SC. Similarly, in multivariate analyses comparing LC vs. SC, the course of XRT was not associated with differences in DFS (HR 1.06, 95% CI, 0.68-1.64, p=0.80), OS (HR 0.91, 95% CI, 0.61-1.37, p=0.66), LRFS (HR 0.79, 95% CI, 0.39-1.57, p=0.50) and DRFS (HR 0.99, 95% CI, 0.60-1.61, p=0.95). Additional baseline clinical and tumor characteristics did not influence outcomes (all p>0.05). Conclusions: Appropriate pre-operative selection of SC vs. LC neoadjuvant XRT for early stage RC based on patient and tumor characteristics was not associated with differences in survival outcomes.