bluuebunny/crossref_metadata_2025 huggingface dataset:
Cytologic and molecular characterizations of CTC detected in patients with metastatic colorectal carcinomas.
Authors: Coget Julien , Blanchard France , Lamy Aude , Toure Emmanuel , Di Fiore Frédéric , iwanicki-Caron Isabelle , Michel Pierre , Michot Francis , Sabourin Jean-Christophe
Published: February 2017

485

Background: Circulating tumor cells (CTC) appear to be associated with poor prognosis in patients with metastatic colorectal cancer (mCRC). ScreenCell technology, which is based on the separation of CTCs from other circulating cells by blood filtration, could allow clinical use of this new biomarker. The aim of our study was to demonstrate the feasibility of CTC filtration in a clinical situation and to compare CTC cytological/molecular characterizations.

Methods: Sampling of venous blood was performed in 39 patients with mCRC before starting chemotherapy regimen. For cytology, blood were filtered using ScreenCell Cyto devices. After staining with hematoxylin, each filter was analyzed by a cytopathologist. Cells visualized on the filter were considered as tumoral if they met the following morphological criteria: nuclear diameter >7micron, anisocytosis, membrane irregularities, presence of large nucleolus. For molecular biology, blood were filtered using ScreenCell MB columns: DNA was then extracted for KRAS genotyping. Prior to the clinical study, HCT116 cells were used in order to establish biological procedures.

Results: 3 samples were not analysed due to blood coagulation. The presence of CTC was identified in 23/36 patients with mCRC (64%). KRAS mutation was present in 40% of tumor patients. In those patients, no mutation was observed on CTC specimens even when using whole gene amplification and PNA selective PCR, whereas KRAS mutation was detected in 10 HCT116 cells diluted in 3ml of normal blood using this same procedure.

Conclusions: ScreenCell Technology allows cytological studies which appear to be fast and efficient for the detection of CTC in mCRC patients. Detection of CTC molecular abnormalities is a major challenge: implementation of molecular tests such as KRAS genotyping, allowing tumor characterization directly from minimally invasive blood sampling, could have tremendous clinical applications. Our first in vitro results highlight the fact that detection of somatic molecular alterations is feasible, from just a few tumoral cells diluted in blood, which encourages further developments using other molecular approaches.
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.
Radiofrequency ablation for unresectable colorectal hepatic metastases: Prognostic factors and the effect of postoperative chemotherapy on survival.
Authors: Ross Louis , Berber Eren , Mitchell Jamie , Siperstein Allan
Published: February 2017

581

Background: Radiofrequency ablation (RFA) is a recognized treatment modality in the management of patients with colorectal cancer liver metastasis (CRCLM). Our goal was to assess factors affecting long-term survival of patients undergoing RFA of CRCLM.

Methods: We prospectively evaluated patients with unresectable CRCLM that underwent laparoscopic RFA. Patients were assessed pre- and postoperatively using triphasic computed tomography (CT) and intraoperatively using laparoscopic ultrasound. All information was entered into an IRB approved database. Pre-operative predictors were identified using Cox modeling. Postoperative chemotherapy was analyzed for its affect on survival.

Results: 312 patients underwent 397 RFA sessions from 1999 to 2010. Patients averaged 2.7 lesions, with a dominant diameter of 3.4 cm and a preoperative CEA of 76. 28% had preoperative extrahepatic disease. Median survival on Kaplan-Meier analysis was 32 months, with 3 and 5 years survivals of 44% and 22%, respectively. The following were statistically significant on univariate and multivariable analysis: number of tumors (hazard ratio (HR) of 1.13 per tumor p=0.0002), dominate tumor diameter (HR 1.14 per cm p=0.03), pre-operative CEA (HR of 1.002 per one point rise p<.0001), and pre-operative extrahepatic disease (HR 1.4 p=0.05). Post-operative chemotherapy was shown to improve survival after controlling for the presence of new disease in follow-up.

Conclusions: To our knowledge, this is both the largest and longest follow-up of RFA for unresectable CRCLM. The number and size of tumors, and preoperative CEA value are strong predictors of survival whereas pre-operative extrahepatic disease had mild impact on survival. Post-operative chemotherapy was shown to improve survival after controlling for other factors.
Clinical research in surgical oncology: An analysis of clinicaltrials.gov.
Authors: Menezes Amber S , Barnes Alison , Scheer Adena S , Moloo Husein , Boushey Robin P , Auer Rebecca Ann C
Published: February 2017

591

Background: The conduction of randomized clinical trials has expanded in medical specialties, but to a far lesser degree in surgery. This is due to design challenges with standardization of treatment, blinding and lack of surgeon equipoise. The objective of this study was to assess the current landscape of clinical trials in surgical oncology registered at clinicaltrials.gov.

Methods: Data was extracted from clinicaltrials.gov using the following search engine criteria: ‘Cancer’ as Condition, ‘Surgery OR Operation OR Resection’ as Intervention, and Non-Industry sponsored. The search was limited to Canada and the United States and included trials registered from January 1, 2001 to January 1, 2011. The search was performed on March 23, 2011 by three investigators in parallel. The total number of oncology trials was also obtained.

Results: Of 9990 oncology trials, 1049 (10.5%) included any type of surgical intervention. Of these trials, 125 (11.9%; 1.3% of all oncology trials) manipulated a surgical variable, 773 (73.7%) assessed adjuvant/neoadjuvant therapies, and 151 (14.4%) were observational studies. Trials assessing adjuvant therapies focused on systemic treatment (362 trials, 46.8%) and multimodal therapy (129 trials, 16.7%). Of the 125 trials where surgery was the manipulated variable, 59 trials (47.2%) focused on surgical techniques (including minimally invasive) or devices, 45 trials (36.0%) studied invasive diagnostic methods, and 21 trials (16.8%) evaluated surgery vs. no surgery. The majority of the 125 trials were non- randomized (72, 57.6%), and Phase III trials accounted for less than one-quarter (29, 23.2%).

Conclusions: The number of registered surgical oncology trials is small in comparison to oncology trials as a whole. Clinical trials specifically designed to assess surgical interventions are vastly outnumbered by trials focusing on adjuvant therapies, and are frequently non-randomized. Randomized surgical oncology trials account for <1% of all registered cancer trials. Barriers to the design and implementation of randomized trials in surgical oncology need to be clarified to facilitate higher-level evidence in surgical decision making.
Characterization of colon cancer–associated antigens that would be key therapeutic targets in the prevention of disease relapse or progression.
Authors: Broussard Elizabeth Kyungsun , Coveler Andrew L. , Whiting Samuel H. , Kim Rachel , Rastetter Lauren , Gad Ekram , Higgins Doreen , Slota Meredith , Gyurkey Grace , Childs Jennifer , Disis Mary Lenora
Published: February 2017

594

Background: Colon cancer (CRC) is an immunogenic tumor and adaptive immunity may play a role in inhibiting disease relapse. A vaccine to boost cellular immunity in CRC patients could prevent disease recurrence, but there have been few defined immunogenic proteins identified as vaccine candidates. TVG has shown that overexpressed tumor associated proteins, abundant in the cancer state but expressed at basal levels in normal cells, can be immunogenic. We hypothesized that ideal candidate antigens would be ones already validated as prognostic markers in multivariate analysis.

Methods: From a directed literature review we selected antigens based on (1) incidence of expression, (2) independent predictor of poor prognosis or early disease recurrence, and (3) known biologic function in CRC pathogenesis. We identified peptides that were predicted to be high affinity binders across multiple HLA DR alleles. We evaluated immunogenicity of peptides with IFN-g ELISPOT assays in CRC and control patients. We then evaluated the efficacy of vaccination in reducing tumors in the AOM mouse model. We evaluated immunogenicity of peptides with IFN-g ELISPOT assays using vaccinated mice splenocytes. We quantified antigen protein expression in AOM tumors.

Results: The eight proteins are: CDC25B, COX-2, EBAG9, EGFR, Fascin-1, IGF-1R, PRL-3 and VCP. For all candidate antigens there was a greater IFN-g response in CRC patients than in controls. Four antigens (COX-2 p<.0001, CDC25B p<.0002, and EGFR p=.01, Fascin-1 p=.05) demonstrated a statistically significant reduction in the development of colon tumors compared to vaccination with adjuvant alone.

Conclusions: We conclude that: 1. biologically relevant CRC associated proteins can be identified that are associated with prognosis, 2. epitopes predicted to bind multiple DR alleles, derived from candidate antigens, elicit T cell responses greater in CRC patients than in normal controls, 3. vaccination with peptides derived from four antigens resulted in a statistically significant reduction in the development of colon tumors in a mouse model, and 4. these antigens may represent novel immunologic targets for CRC.
Outcome of trimodality-eligible esophagogastric cancer (EC) patients who declined surgery after preoperative chemoradiation.
Authors: Taketa Takashi , Correa Arlene M , Suzuki Akihiro , Blum Mariela Anabel , Lee Jeffrey Edwin , Welsh James , Lin Steven H. , Maru Dipen , Erasmus Jeremy J. , Bhutani Manoop S. , Weston Brian , Rice David C. , Swisher Stephen , Hofstetter Wayne Lewis , Ajani Jaffer A.
Published: February 2017

6

Background: Patients with localized EC eligible for resection at presentation should receive trimodality therapy (chemoradiation and surgery). However, surgical resection is not always performed in these patients because of poor performance status or reluctance in eligible patients to proceed with surgical resection after preoperative chemoradiation. Reports on the outcome of such patients are rare.

Methods: Between 2002 and 2010, we identified 599 trimodality-eligible EC patients in our prospective database. All patients had extensive baseline staging, preoperative chemoradiation, and preoperative staging that included endoscopic biopsy and PET-CT. Of 599 patients, 32 patients declined surgery.

Results: The median age was 70 years (range, 55-81), 29 patients (90.6%) were men and 30 (93.8%) were Caucasian. Majority had baseline stage II (44%) or III (38%) cancer. All 32 patients had an adenocarcinoma (moderate: 53.1%, poorly: 46.9%) and reached a clinical complete response (negative biopsy and PET in the physiologic range) post-chemoradiation. Four patients had salvage surgery and 3 are alive. Overall, 22 patients remain alive at a median follow up of 33.1 months (95% CI, 28.1-38.1). 3-year overall survival (OS) and relapse-free survival (RFS) were 65.1±10.4% and 37.5±10.3%. Median OS and RFS were 54.2 months (95% CI, 25.7-82.7), 30.4 months (95% CI, 16.3-44.5).

Conclusions: Although the outcome of patients with EC who decline surgical resection after chemoradiation is reasonable, the lack of a validated approach to esophageal preservation dictates that trimodality therapy remains the standard of care in patients with potentially resectable EC.
Phase I study of biweekly liposome irinotecan (PEP02, MM-398) in metastatic colorectal cancer failed on first-line oxaliplatin-based chemotherapy.
Authors: Chen Li-Tzong , Shiah Her-Shyong , Lin Peng-Chan , Lee Jenq-Chang , Su Wu-Chou , Wang Yi-Wen , Yeh Grace , Chang Jang-Yang
Published: February 2017

613

Background: PEP02 (MM-398) is a nanoliposomal formulation of irinotecan (CPT-11) that has improved pharmacokinetics (PK) and tumor distribution of CPT-11 and its active metabolite, SN-38. PEP02 single agent q3w has shown preliminary efficacy and safety in Phase II pancreatic and gastric cancer studies. Since irinotecan is approved for metastatic colorectal cancer (mCRC) and biweekly regimens are widely used, the aims of this study are to determine the maximum tolerated dose (MTD), characterize the PK and pharmacogenetics (PGx), and explore the efficacy of PEP02 q2w in mCRC.

Methods: Patients (pts) with disease progression after 1st-line oxaliplatin-based chemotherapy, ECOG PS 0-1, and without prior exposure to irinotecan were eligible. PEP02 was given on day 1 and 15 of each 28 day treatment cycle. The starting dose was 80 mg/m2 and escalated by 10 mg/m2 to the target dose of 100 mg/m2. PK was evaluated during the 1st cycle and the tumor response was assessed by RECIST.

Results: A total of 18 pts (M/F 9/9; median age 57.5) were enrolled, with 6 at each dose level. Dose-limiting toxicity manifested as G3 diarrhea was observed in one pt per dose level. The target dose of 100 mg/m2 was determined to be the MTD. Nine pts had dose delayed (4, 3, 2 at 80, 90, 100 mg/m2), mostly because of neutropenia. The PK and PGx are being analysed. As of August 2011, there are 3 pts still on study treatment and 17 pts evaluable for tumor response. Four pts (2 at 80 mg/m2, 1 each at 90 and 100 mg/m2) showed partial response (3 after 2 cycles and 1 after 8 cycles) and 8 pts (3 each at 80 and 90 mg/m2, 2 at 100 mg/m2) maintained stable disease for at least 2 cycles, which resulted in a response rate (RR) of 23.5% and a disease control rate (DCR) of 70.6%. Current median progression-free survival (PFS) is 4 months and 8 pts (47%) had PFS ≥ 6 months.

Conclusions: The MTD of biweekly PEP02 is 100 mg/m2. As a 2nd-line monotherapy after oxaliplatin-based chemotherapy, the efficacy results indicate the potential benefit of PEP02 for mCRC (FOLFIRI-1 achieved only 4% RR, 34% DCR, and 2.5 months PFS in FOLFOX pretreated pts). A randomized Phase II study evaluating PEP02 plus 5-FU/LV (FUPEP regimen) vs. FOLFIRI is currently ongoing in France.
Tumor shrinkage and overall survival (OS) from multicenter phase II study of modified FOLFOX7 (combination chemotherapy of infusional 5-FU/l-leucovorin and intermittent oxaliplatin) with bevacizumab in the first-line therapy of colorectal cancer: CRAFT trial.
Authors: Koda Keiji , Ishida Hideyuki , Katoh Ryoji , Maeda Kotaro , Tezuka Toru , Mishima Hideyuki , Tomita Naohiro , Saito Norio , Hamada Chikuma , Sakamoto Junichi
Published: February 2017

616

Background: Additional bevacizumab (BV) to FOLFOX has been established as a standard 1st-line therapy for mCRC. The intermittent administration of L-OHP can reduce the peripheral sensory neurotoxicity as reported in OPTIMOX and CONcePT study. CRAFT trial was conducted to confirm the effectiveness of stop and go strategy of mFOLFOX7+BV. We previously reported the feasibility and good progression free survival (PSF) in that study (K. Ishibashi et al. ECCO2011). This time, the overall survival (OS) and possibilities for conversion surgery were reported.

Methods: We administered 8cycles of mFOLFOX7/BV followedby 8 cycles of FULV/BV as a maintenance, and reintroduction of 8 cycles of mFOLFOX7/BV until disease progression. Patients who had progressive disease during maintenance phase are allowed to receive oxaliplatin ahead of schedule. The primary endpoint is the duration from the study enrollment to disease progression (PFS I). The secondary endpoints are survival time from the study enrollment to disease progression or death plus from 1st PD in the maintenance phase to 2nd PD (PFS II), tme to treatment failure (TTF) ,OS, and safety.

Results: Between March 2009 and June 2010, 52pts were enrolled. Median PFS I was 13.2 (95%CI,10.3-15.0) months. PFS II was 13.5(95%CI,12.5-15.1) months. Median, TTF was 10.3 (95%CI, 5.6-12.1) months, OS was 27.4 (95%CI, 21.0-32.8) months. There was no uncontrollable toxicity. The range of tumor shrinkage wasup to - 91.0% and 3 patients received conversion surgery.

Conclusions: This study met its primary endpoint PFS I (K.Ishibashi et al. ECCO 2011.). The current data indicated that stop and go strategy is effective to prolong the duration of 1st line treatment and to improve survival in mCRC. Tumor shrinkage data also suggested mFOLFOX7+BV has possibilities to make a conversion surgery. Water fall plot for all patients will be presented at the meeting.
Molecular predictors of treatment response in colon and gastric cancer.
Authors: Fanta Paul Timothy , Roeland Eric , Shen John P. , Shimabukuro Kelly Anne , Hwang Michael , Ramamoorthy Sonia , Lowy Andrew M.
Published: February 2017

619

Background: With the noted exception of KRAS mutational status, currently there exists limited data regarding the incorporation of tumor-derived biomarkers in the clinical management of gastrointestinal malignancies. High ERCC1 levels have been associated with inferior results in platinum-treated patients with non-small cell lung cancer, esophageal cancers, and head and neck cancer. Lenz et al. concluded ERCC-1 gene expression levels may allow the selection of patients who may benefit from FOLFOX chemotherapy in metastatic colon cancer. Low intra-tumoral ERCC1 mRNA expression predicted improved PFS and OS in patients with esophageal adenocarcinoma who were treated with tri-modality therapy in the SWOG 0356 correlative study.

Methods: To determine the prevalence and patterns of expression of select tumor biomarkers including ERCC1, TS, HER-2, KRAS, BRAF, and EGFR gene expression was measured in metastatic gastric and colorectal cancers using formalin fixed paraffin embedded tumor samples from 120 metastatic colorectal and 20 metastatic gastric cancer were dissected using laser-captured micro-dissection and analyzed for ERCC-1, TS, EGFR, RRM1, and VEGFR2a mRNA expression using a quantitative RT-PCR methodology. Gene expression values (relative mRNA levels) were recorded as ratios between the target gene and internal reference gene (beta-actin). A retrospective review of the patient’s response to therapy was planned.

Results: In colorectal patients, the incidence of KRAS mutations was 50%, specifically Gly12Ser 4%, Gly12Val 11%, Gly12Asp 20%, Gly12 Cys 7% Gly12Ala 2% and Gly13Asp 8%. BRAF expression analysis displayed 91% wild type with 9% V600E mutations. Median expression values for ERCC1, TS, EGFR, RRM1, and VEGFR2A expression levels using RT-PCR were 1.23, 2.28, 1.90, 1.05, and 1.61 respectively in the colorectal subset. In gastric cancer, ERCC1, TS, and Her-2 median expression levels using RT-PCR were 1.54, 3.56, and 0.08 respectively. Correlation with clinical outcome is pending and will be reported later.
Treatment of colorectal liver metastasis: Comparison of radiofrequency ablation and hepatic resection.
Authors: Yoon Min Yong , Kim Hyung Ook
Published: February 2017

637

Background: Hepatic resection is the mainstay of management for colorectal liver metastases. But, the treatment for colorectal liver metastases requires a multidisciplinary therapeutic strategy. The aim of this study was to compare recurrence and survival rates for patients treated with hepatic resection or radiofrequency ablation (RFA) for colorectal liver metastases.

Methods: Between July 2002 and September 2010, 52 patients underwent hepatic resection and 58 underwent RFA for synchronous or metachronous colorectal liver metastases. A retrospective analysis was performed. Patients with extrahepatic metastases were excluded.

Results: The two groups had similar mean age, comorbid medical conditions, primary disease stage, and number of tumors. Preoperative median serum carcinoembryonic antigen (CEA) level was significantly higher in the resection group (13.8 ng/mL vs. 3.1 ng/mL; p = 0.001). Median diameter of main tumors was significantly greater in resection group (4.1 cm vs. 2.0 cm; p = 0.002). Recurrence rate after treatment was 46.2% (24/52) in the resection group and 70.7% (41/58) in the RFA group. Marginal recurrence after resection or RFA was observed in 7.6% (4/52) and 46.6% (27/58), respectively (p = 0.003). Median recurrence free survival (28.0 vs. 12.0 months; p = 0.007) and median overall survival (43.0 vs. 26.0 months; p = 0.023) were significantly longer in the resection group.

Conclusions: Hepatic resection is the treatment of choice for colorectal liver metastases. RFA for colorectal liver metastases was associated with higher marginal recurrence rate and shorter recurrence free and overall survival.
Prevalence of bowel dysfunction in colorectal cancer survivors.
Authors: Sall Karanvir , Cheung Winson Y.
Published: February 2017

638

Background: There is limited research on the long-term bowel health outcomes of colorectal cancer (CRC) survivors even though colorectal surgery, radiation, and chemotherapy can pose significant morbidity for patients. Our aims were to characterize the prevalence of specific bowel complications in CRC survivors and to compare their outcomes with those of non-CRC survivors and non-cancer controls.

Methods: Using population-based data from the 2009 U.S. National Health and Nutrition Examination Survey, we identified 3 different groups of adult patients: CRC survivors, non-CRC survivors, and non-cancer controls. Weighted multivariate logistic regression models were constructed to determine the relationship between survivor status and bowel health outcomes, while controlling for patient and disease characteristics. Main outcomes included leakage of gas, mucus, liquid stool, and solid stool. Stratified analyses were subsequently conducted to assess for effect modification based on gender (men vs. women), age (≤ 60 vs. >60), and ethnicity (white vs. non-white).

Results: In total, 10,894 subjects were included: 75 CRC survivors, 910 non-CRC survivors, and 9909 non-cancer controls. Baseline characteristics were similar among all 3 patient groups. In univariate analyses, more CRC survivors reported bowel dysfunction, including leakage of: gas (15 vs. 12 vs. 10%, p=0.01), liquid stool (8 vs. 7 vs. 4%, p<0.001), and solid stool (2 vs. 0 vs. 0%, p<0.001) than non-CRC survivors and non-cancer controls. In multivariate analyses, CRC survivors continued to have significantly higher odds of solid stool incontinence (OR 2.09, 95% CI 1.24-3.53, p<0.05) when compared to the other groups. The association between surviving CRC and presence of bowel dysfunction was not modified by ethnicity, but specific outcomes, such as solid stool leakage, were more prominent in women (p=0.003) and those who were aged >60 years (p=0.002).

Conclusions: Bowel problems are significantly more frequent among CRC survivors than non-CRC survivors and non-cancer patients, especially for women and the elderly. Studies to develop interventions that minimize these bowel complications are needed in order to improve the long-term health and quality of life for CRC survivors.
Colorectal treatment effectiveness in a population-based registry: A 1991-1994 and 2001-2005 comparison.
Authors: Lin Ge
Published: February 2017

647

Background: Providing state and regional cancer treatment prognoses, and comparing them over time are important for both local patients and physicians. The present study is the first in Nebraska, US to compare the change in prognostic factors for five-year survival of CC patients to those of RC patients from two time periods, 1991-1994 to 2001-2005.

Methods: CC and RC Patients aged 19 years and older were selected from the Nebraska Cancer Registry the two time periods. The outcome variable was five-year survival (survived or not) from the date of diagnosis up to five years or more. Treatment was divided into five groups: surgery alone, surgery with chemotherapy and radiation therapy (S+CT+RT), surgery with chemotherapy (S+CT), other treatments, and no treatment. Multivariate logistic regression analysis was used to examine the effect of prognostic factors on five-year survival.

Results: There was a 7% five-year survival improvement in RC patients from time 1 to time 2 but no survival improvement in CC patients. Younger age, female, being married, and early stage at diagnosis were associated with CC survival advantage in time 1 and time 2. In contrast, for RC patients, female had no survival advantage in time 2 while those in the 65-74 age group showed improved survival with time. With regard to treatment, surgery alone was the most consistent prognostic factor through time, while S+ CT+RT became the most important prognostic factor for survival in RC in time 2, and S+CT became the most important prognostic factor for survival in CC in time 2.

Conclusions: There was marked change in treatment modalities for both CC and RC patients between the 1991-1995 and 2001-2005 periods, with a general trend toward better five-year survival prognosis. The most effective treatments for CC and RC patients in the most recent period are Surg+CT and S+CT+RT, respectively.