bluuebunny/crossref_metadata_2025_split huggingface dataset:
ERCC1, KRAS mutation, and oxaliplatin sensitivity in colorectal cancer: Old dogs and new tricks.
Authors: Orlandi Armando , Di Salvatore Mariantonietta , Basso Michele , Bagalà Cinzia , Strippoli Antonia , Plastino Francesca , Dadduzio Enzo , Di Lascio Simona , Quirino Michela , Cassano Alessandra , Astone Antonio , Barone Carlo 
Published: February 2017

489 Background: Oxaliplatin is widely used in metastatic colorectal cancer, but currently there are not valid predictors of response to this drug. In our recent retrospective clinical study we have shown a greater efficacy of Oxaliplatin in patients with metastatic colorectal cancer with mutated (mt) K-RAS. We hypothesized that the mutational status of K-RAS could influence the expression of ERCC1, one of the main mechanisms of Oxaliplatin resistance. Methods: We used four cell lines of colorectal cancer: two K-RAS wild type (wt) (HCT-8 and HT-29) and two K-RAS mt (SW620 and SW480). We evaluated the sensitivity of these cell lines to Oxaliplatin by MTT-test and the ERCC1 levels before and after 24 h exposure to Oxaliplatin by Real-Time PCR. We silenced K-RAS in a K-RAS mt cell line to evaluate the impact on Oxaliplatin sensitivity and ERCC1 levels. We also silenced ERCC1 in order to confirm the importance of this protein as a Oxaliplatin resistance factor. Results: The K-RAS mt cell lines were more sensitive to Oxaliplatin (OR 2.68; IC 95% 1.511-4.757 p<0.001). The basal levels of ERCC1 did not show significant differences between K-RAS mt and wt cell line, however, after 24 h exposure to Oxaliplatin, only the K-RAS wt lines showed the ability to induce ERCC1, with a statistically significant difference (OR 42.9 IC 95% 17.260-106.972 p<0.0005). The silencing of K-RAS in K-RAS mt cell lines demonstrated to reduce sensitivity to Oxaliplatin associated with the acquisition of the ability to induce ERCC1. The silencing of ERCC1 in K-RAS wt cell lines enhance the sensibility to Oxaliplatin. Conclusions: The K-RAS mutated cell lines were more sensitive to Oxaliplatin. This feature seems to be secondary to the inability of these cells to induce ERCC1 after exposure to Oxaliplatin. K-RAS can thus be a predictor of response to Oxaliplatin in colorectal cancer representing a surrogate for ability to induce ERCC1.
Experience with colorectal cancer: Analysis of patient web forums.
Authors: Beusterien Kathy , Tsay Sarah , Su Yun , Corral Mitra , Gholizadeh Shadi , Wagner Samuel 
Published: February 2017

496 Background: Patient-reported outcomes are typically collected through structured questionnaires. Patient web forums provide a unique opportunity for patients to spontaneously post their experiences and thoughts about diseases and treatments. This study explored the impact of colorectal cancer (CRC) treatments in these forums. Methods: This was a cross-sectional qualitative analysis of web data. Two of the most active CRC web forums were identified using 4 criteria: site active for > 5 years, > 12,000 total posts on the forum, >20 individuals currently browsing, and > 10 new posts/day. All posts posted in Jul and Dec 2010 and Feb-Mar 2011 on the two forums were abstracted for review and coding using MaxQDA software. Results: A total of 1,654 posts, posted by 264 individuals, were identified on the two CRC web forums. Demographic and /or tumor information were identified for 83% of the posters. Of these, 83% were CRC patients and 17% were family members; 76% were females, and the mean age of the patients was 49 years. The majority had advanced cancer (44% stage IV or metastatic, 40% stage III). The most common topics were a variety of side effects (62.3% of posts), treatment response (13%), and impact on personal, social, and work lives, income and life styles, and resulting emotional distress (23.9%). The posters came to the online forums in part to have an emotional outlet. Another key motive was sharing experiences and seeking advice. Formal knowledge regarding the likelihood of response, magnitude of benefit, or side effects was absent however, leading to senses of uncertainty, anxiety, sometimes shock, and unrealistic expectations. On balance, although patients reported difficulties being on treatment, they also expressed resilience and appreciation for the availability of treatment options and the hope they provide. Conclusions: Online CRC communities provide patients with convenient and valuable emotional support and disease and treatment information. The profound impact of CRC and treatments goes beyond efficacy, toxicity, and structured quality of life scores. Systematic information and decision tools are needed to minimize uncertainties and help patients manage expectations and emotional distress.
Molecular dissection of effector mechanisms of RAS-induced resistance to monoclonal anti-EGFR antibodies.
Authors: Kasper Stefan , Breitenbuecher Frank , Markowetz Jeannette , Reis Henning , Meiler Johannes , Schmid Kurt W , Trarbach Tanja , Schuler Martin H. 
Published: February 2017

501 Background: RAS mutations are negative predictors of efficacy of anti-EGFR antibodies in patients with colorectal cancer (CRC). Oncogenic RAS activates the MAPK- and PI3K/AKT pathways, which are considered the main effectors of resistance. However, the relative impact of these pathways and their downstream effectors in RAS-mutant CRC is less defined. To this end we conducted functional studies using transgenic cancer models in vitro and in vivo. In addition, we analyzed pathway activation in primary tumor samples from metastatic CRC patients. Methods: Anti-EGFR-antibody sensitive cancer cell lines were retrovirally transduced to stably express (i) oncogenic RAS, (ii) conditionally active mutant RAF-1 or (iii) AKT. The impact of oncogene expression on cell proliferation, induction of apoptosis, clonal survival and tumor growth in NOD/SCID mice was analyzed in relation to treatment with cetuximab or panitumumab. Cell lines with endogenous KRAS or PI3KCA mutations were used as additional controls. Primary tumor samples from 47 patients with metastatic CRC were immunohistochemically analyzed for activation of the MAPK and PI3K/AKT pathways in relation to KRAS status. Results: Transgenic RAS, RAF-1 and AKT protected anti-EGFR-sensitive CRC cells against anti-proliferative and pro-apoptotic effects of the antibodies in vitro and in vivo. This was in line with immunohistochemical analyses of primary tumour samples, which revealed a strong correlation of MAPK and PI3K/AKT pathway activation and mutant KRAS (regression 0.921, p<0.0001). Sustained activation of both pathways caused upregulation of anti-apoptotic BCL-2 proteins. Transgenic expression of these BCL-2 proteins could substitute oncogenic RAS in mediating antibody resistance. Cotreatment with BH3 mimetics neutralizing anti-apoptotic BCL-XL and BCL-2 sensitized RAS-mutant cancer cells to anti-EGFR therapy. Conclusions: Activation of the MAPK and PI3K/AKT pathways mediates resistance to anti-EGFR therapies in cancer models in vitro and in vivo. Simultaneous or cross activation of both pathways is observed in KRAS mutant primary CRC. These results may guide clinical strategies to overcome RAS-mediated antibody resistance.
Selective PI3K inhibition by BKM120 and BEZ235 alone or in combination with chemotherapy in wild-type and mutated human gastrointestinal cancer cell lines.
Authors: Moehler Markus Hermann , Mueller Annett , Bachmann Erika , Schimanski Carl Christoph , Galle Peter Robert 
Published: February 2017

522 Background: New targeted agents against tyrosine kinases expand the standard therapy in oncology. However, tumor resistance is still a challenge, particularly induced by mutations in growth-related signalling cascades. 20% and 10% of patients with human colon and gastric cancer carry PI3K mutations and do not react to receptor blocking therapies. Recently, selective tyrosine kinase inhibitors have been generated which block PI3K signalling pathways in tumor cells. Their therapeutically role has not yet been clarified. Methods: To define inhibitory and pro-apoptotic effects of the 2 PI3K inhibitors BEZ235 and BKM120 3 human colon cancer (HT-29, HCT-116, DLD-1) and 3 gastric cancer cell lines (NCI-n87, AGS, MKN-45) with different PIK3CA mutation status were used. First, viability, apoptosis and caspase assays were performed during incubation with inhibitors alone or combined with cytotoxic agents. Second, molecular consequences for cell cycle and the signalling pathways were analysed by defining the protein levels by FACS and Western blot. Results: Both PI3K inhibitors BEZ235 and BKM120 induced concentration dependently a significant reduction in viability and an increase in apoptotic death, while mutated cells reacted more sensitive to treatment. BKM120 had a higher efficiency than the dual PI3K/mTOR inhibitor BEZ235. BEZ235 alone caused a G1 arrest in tumor cells. In contrast, BKM120 induced a G2 shift in all gastrointestinal cancer cells. There was a clear downregulation in AKT signalling, and for BEZ235 an additional inhibition of mTOR pathway. Furthermore, BEZ235 caused synergistic induction of apoptosis combined with irinotecan in colon cancer. Combinations with 5-fluoruracil and the 2 substances induced additive apoptotic effects. Human gastric cancer cells were less sensitive to BEZ235 and BKM120. Conclusions: In general, we found higher pro-apoptotic effects for all cell lines and in special cases a better response of resistant mutant cells. Our data support the clinical development of these PI3K inhibitors BEZ235 and BKM120 as potential targeting agents for patients with different wild-type or mutated gastrointestinal cancer cells.
MicroRNAs related to intrinsic resistance to oxaliplatin and the irinotecan metabolite SN-38 in 10 colorectal cancer cell lines.
Authors: Jensen Niels Frank , Soekilde Rolf , Stenvang Jan , Nielsen Birgitte Sander , Litman Thomas , Brünner Nils , Rømer Maria Unni 
Published: February 2017

524 Background: Chemotherapy of metastatic colorectal cancer is based on 5-flourouracil combined with either oxaliplatin or irinotecan (active metabolite: SN-38). Identification of predictive biomarkers of drug response is needed to provide a better personalized treatment. In this study we aimed to identify microRNAs related to intrinsic resistance to oxaliplatin or irinotecan in a panel of ten colorectal cancer cell lines. Methods: Drug sensitivity towards oxaliplatin and SN-38 was determined for ten colorectal cancer cell lines (Colo-205, DLD-1, HCC-2998, HCT-15, HCT-116, HT-29, KM12, LoVo, LS-174T, and SW620), using the cell viability MTT assay and the cell death LDH assay. In addition, two cell lines (DLD-1 and LoVo) were exposed to the drugs for 6, 24 or 48 hours. MicroRNA expression profiles were generated using the Exiqon miRCURY LNA microarray platform (including 840 microRNAs), and four differentially expressed microRNAs were validated by independent qRT-PCR measurements. Results: The drug sensitivities of the ten colorectal cancer cell lines varied about 50 times between the least and most sensitive cell lines. Correlation of drug sensitivity data to microRNA expression data across the ten cell lines yielded about 25 microRNA biomarker candidates, for each of the drug/assay combinations. Following short-term drug treatment 10-20 microRNAs were altered for each drug/cell line combination. Validation by qRT-PCR showed a very good correlation to the microarray data. MicroRNAs identified by correlation to drug sensitivity and by short-term treatment were compared, and less than 10% were identified by both approaches, perhaps representing the most promising candidates. These candidates are for SN-38 miR-15a, miR-22, miR-24, miR-98, miR-142-3p, miR-1290, and let-7b, and for oxaliplatin miR-23b, miR-27a, miR-192, miR-200a, miR-222, miR-886-5p, and miR-1308. Conclusions: In the present study we identified a number of microRNAs that are potentially involved in intrinsic resistance and/or could be predictive biomarkers for either irinotecan or oxaliplatin.
Survival outcome of bevacizumab followed by cetuximab in metastatic colorectal cancer patients.
Authors: Kataoka Kozo , Kanazawa Akiyoshi , Nakajima Akio , Hosogi Hisahiro , Kanaya Seiitirou , Kohno Yukihiro 
Published: February 2017

529 Background: The molecular targeted agents, such as bevacizumab and cetuximab have been shown to improve overall survival of metastatic colorectal cancer (mCRC) patients. However, we still do not know what sequence is best to use the molecular targeted agents for mCRC especially in K-ras wild case. In this analysis, we evaluate the benefits of using bevacizumab followed by cetuximab for mCRC patients retrospectively. Methods: From July 2006 to September 2010, 60 chemotherapy-naive patients who were diagnosed as mCRC, received oxaliplatin based regimen for first line, did not respond to bevacizumab containing regimen used for first line or second line, and received cetuximab or continued bevacizumab, were eligible for this analysis. 28 patients received cetuximab as third line or fourth line chemotherapy due to K-ras wild type (Group A). And 32 patients continued bevacizumab-containing regimen in spite of disease progression (Group B). Results: The median number of cycles of bevacizumab containing regimen were 9 (range, 2-30) in group A and 8 (range, 2-27) in group B, and cetuximab 12(range, 3-32) in group A. The difference of the rate of serious adverse effects was not significant between two groups. Median overall survival was significantly higher in Group A than Group B (31.2 months (95%CI: 23.2-39.3 months) and 27.0 month (95%CI: 17.2-37.6), respectively) (P<0.001). Partial response rate of cetuximab was 18%(5/28) in group A. Median progression free survival of cetuximab in group A was 4.3 months (95%CI: 2.62- 6.06). Conclusions: Using cetuximab after progression with bevacizumab might be effective sequence to improve the overall survival of K-ras wild mCRC patients. But we need further prospective study to look for the best sequence in chemotherapy for mCRC patients.
Lymph node metastasis in patients with early pathologic T-stage rectal cancers: What does local excision leave behind?
Authors: Russell Maria C. , Chiang Yj , Feig Barry W. , Chang George J. , Rodriguez-Bigas Miguel A. , Skibber John Michael , Chagpar Ryaz , Cormier Janice N. , You Y. Nancy 
Published: February 2017

537 Background: As the interest in local excision (LE) for rectal cancer increases, the risk of residual nodal disease and local failure must be considered. We utilized a nationwide cancer registry to establish incidence and predictors of nodal metastasis in early pathologic T stage rectal cancers. Methods: Early path T stage rectal cancers (1998-2007) were identified from the National Cancer Database (NCDB), including pT1-2 tumors in patients not receiving neoadjuvant therapy (NT), or ypT0-2 tumors after NT. Proctectomy was performed in 22,416 (74.7%) and LE in 7,589 (25.3%) without NT. After NT, 7,481 (96.1%) underwent proctectomy and 300 (3.9%) LE. Nodal metastasis rates were calculated from proctectomy patients. Factors associated with nodal metastases were analyzed among those with ≥12 nodes assessed. Results: The incidence of nodal positivity was 12.5% for pT1 and 26.8% for pT2 tumors. Among those with ≥12 nodes examined, these rates increased to 16.9% and 28.6% respectively. After receiving NT, nodal positivity rates were 8.6% for ypT0, 12.9% for ypT1, and 21.4% for ypT2 tumors. These rates increased to 13.5%, 16.9% and 28.3% respectively when ≥12 nodes examined. In multivariate analysis, female sex, age <50, higher T stage, higher histologic grade, mucinous/signet-ring features, and more than 12 nodes examined were all significantly associated with nodal metastases in both groups ( Table ). Conclusions: Among rectal cancers of early path T stages, the risk of nodal metastasis increases with higher path T stage and with greater number of nodes examined, regardless of receipt of NT. These findings must be carefully deliberated, given the current interests in expanding the role of LE based on pathologic T stage of rectal cancer. [Table: see text]
Short-term clinical outcomes from a randomized controlled trial to evaluate laparoscopic and open surgery for stage II-III colorectal cancer: Japan Clinical Oncology Group study JCOG 0404 (NCT00147134).
Authors: Yamamoto Seiichiro , Inomata Masafumi , Kitano Seigo , Katayama Hiroshi , Mizusawa Junki , Konishi Fumio , Sugihara Kenichi , Watanabe Masahiko , Shimada Yasuhiro , Moriya Yoshihiro ,   Colorectal Cancer Study Group of Japan Clinical Oncology Group
Published: February 2017

538 Background: The benefits of laparoscopic surgery (LAP) in comparison with open surgery (OP) have been suggested; however, the long-term survival after LAP for advanced colorectal cancer (CRC) requiring complete mesocolic excision is still unclear. We conducted a study to confirm the non-inferiority of LAP to OP in terms of overall survival with less frequent post-operative morbidity. The primary analysis is planned in 2014, and short-term outcomes including post-operative complications are presented here. Methods: Only accredited surgeons from 30 Japanese institutions participated. Eligibility criteria included histologically proven CRC; tumor located in the cecum, ascending, sigmoid or rectosigmoid colon; T3 or deeper lesion without involvement of other organs; N0–2 and M0; tumor size =<8 cm; patient age 20-75 years. Patients were randomized preoperatively by the minimization method. Patients with pathological stage III received adjuvant chemotherapy with fluorouracil plus leucovorin. The primary endpoint is overall survival, and the planned sample size was 1050. Results: A total of 1057 patients were randomized (OP: 528, LAP: 529) between October 2004 and March 2009. Patients assigned to LAP had less blood loss than those assigned to OP (median 30 ml vs 85 ml, p<0.001), although LAP lasted 52 minutes longer than OP (p<0.001). Radicality of resection, as assessed by the number of resected lymph nodes, did not differ between the two groups. LAP was associated with earlier recovery of bowel function (p<0.001), and with a shorter hospital stay (p<0.0001) than OP. Morbidity and mortality until discharge did not differ between the two groups, except for fewer wound-related complications in LAP (p=0.007). Conclusions: Short-term clinical benefits of LAP were demonstrated, and laparoscopic surgery for advanced CRC can be performed safely by experienced surgeons. If the non-inferiority of LAP in overall survival is demonstrated in the primary analysis planned in 2014, LAP will be the new standard surgical procedure for CRC.
Bevacizumab in the first-line treatment of elderly patients with metastatic colorectal cancer: Mature results from a large community-based observational study.
Authors: Hofheinz Ralf , Grothe Wilfried , Tummes Dirk , Kindler Manfred , Petersen Volker , Boszeit-Luft Stefanie , Seraphin Joerg , Hinke Axel , Arnold Dirk 
Published: February 2017

566 Background: In most patients (pts) with metastatic colorectal cancer, a 3-drug combination of a fluoropyrimidine, oxaliplatin (ox) or irinotecan (iri), and a monoclonal antibody is considered standard 1st-line treatment. However, in elderly pts this choice remains controversial. After registration of bevacizumab (bev) in Germany in 2005, this observational study was initiated in pts receiving bev with various first-line chemotherapy (CT) regimens to evaluate the disease profile and efficacy of bev in patients with metastatic colorectal cancer. Methods: Eligibility criteria focused on M1 disease without prior palliative CT. The choice of CT regimen was at the physician’s discretion. Predefined efficacy endpoints were: response rate (RR), progression-free survival (PFS) and overall survival (OS). Pts were followed for up to 6 years (y). Two pt subgroups were analyzed: ≥70 y and ≥75 y; the ≥75 y group is the focus of this abstract. Results: 1777 eligible pts were enrolled at 261 sites from Jan 2005 to June 2009, 206 (12%) of whom were aged ≥75 y. These elderly pts did not differ greatly vs younger pts in time from initial diagnosis or time to first relapse, pT, pN and M stage, site of metastasis, grading, CEA, WBC, blood pressure, or prior adjuvant therapy. However, fewer elderly pts had >1 involved organ site (28% of pts ≥75 y vs. 32% of pts ≥70 y) and elderly pts had significantly poorer performance status (ECOG 0 in 29% of pts ≥75 y vs. 39% of pts ≥70 y). Bev treatment duration was similar in elderly and younger pts, but differences in CT usage were observed (Table). Response and survival outcomes were significantly worse in those aged ≥75 y. Conclusions: Bev-based treatment combinations can be used successfully in pts aged ≥75 y. However, PFS and OS are significantly shorter in pts aged ≥75 y vs younger pts, probably because of greater comorbidity and possibly because of less intensive treatment in the elderly. [Table: see text]
Effect of a combination of aurora kinase A inhibitor MLN-8237 and cisplatin on gastrointestinal tumors.
Authors: Sehdev Vikas , Soutto Mohammed , Belkhiri Abbes , Ecsedy Jeffrey , El-Rifai Wael 
Published: February 2017

58 Background: Gastric cancers respond poorly to current chemotherapeutic protocols indicating active intrinsic mechanisms against drug induced cell death. We have previously reported that AURKA overexpression induces pro-survival (AKT and β-catenin) and inhibits apoptotic (p53 and p73) pathways. Methods: We evaluated the effect of AURKA specific inhibitor (MLN-8237) alone and/or in combination with cisplatin (CDDP) in gastrointestinal (GI) cancer cells. Following treatment with MLN-8237 and/or CDDP, cell survival, cell viability, western blot and qRT-PCR analyses were done on GI cancer cell lines. Additionally, tumor xenografted mice were treated with MLN (30mg/kg) and/or CDDP (2mg/kg) for 21 days and tumor volume was measured every alternate day. Results: The ATP-Glo cell viability and cell survival assay data indicated that in comparison to single agent treatments alone; the combination treatment with MLN-8237 (0.5µM) and CDDP (2.5µM) significantly increased inhibition of cellular viability and survival (p<0.05) in AGS, KATO-III, MKN28, FLO-1, OE-19 and OE33 cell lines. Similarly, the western blot data exhibited higher levels of p73, Puma, Noxa, cleaved caspase 3 and cleaved PARP with MLN (0.5µM) and CDDP (2.5µM) combination treatment, as compared to single agent treatments in AGS, FLO-1 and OE33 cell lines. The tumor growth results for OE33 mouse xenograft study demonstrate synergistic antitumor effect with MLN-8237 and CDDP combination in the following order of effectiveness: Control > CDDP > MLN-8237 > and MLN-8237/CDDP (p<0.01). Moreover, the qRT-PCR data from tumor xenograft samples treated with MLN-8237/CDDP combination showed significantly higher mRNA levels of p73 downstream transcriptional target genes (P21, PUMA, NOXA and BAX) (p<0.05). Conclusions: Our in vitro and in vivo data indicate that inhibition of AURKA with MLN-8237 in combination with CDDP enhances the antitumor activity of MLN-8237 against GI cancer cells. Therefore, our study demonstrates that MLN-8237 is an effective anti-tumor agent which can be potentially combined with CDDP for better therapeutic outcome in GI cancer patients.