bluuebunny/crossref_metadata_2025_split huggingface dataset:
Second-line therapy of KRAS-mutated (KRASm) metastatic colorectal cancer (CRC) with the MEK inihibitor selumetinib ([SEL], AZ6244, ARRY-142886) in combination with irinotecan (IRI): An AGICC study.
Authors: Hochster Howard S. , Messersmith Wells A. , O'Neil Bert H. , Groshen Susan G. , Cohen Deirdre Jill , Denlinger Crystal Shereen , Gold Philip Jordan , Eckhardt S. Gail , Locker Gershon Y. , Ames Patricia , McKinley Marti , Leichman Lawrence P. ,   Academic GI Cancer Consortium
Published: February 2017

380 Background: 2nd-line therapy of KRASm CRC is limited; targeting downstream signal transduction enzymes is rational here. Use of the MEK inhibitor SEL is supported by preclinical and clinical evidence. We designed a dose-finding/phase II study of IRI plus SEL in KRASm CRC. Methods: Eligibility included: KRASm or BRAFm CRC with measurable disease progressing after 1st-line therapy with an oxalipatin-based chemo + bevacizumab regimen, PS 0-1, acceptable organ function. Patients were treated with IRI 180 mg/m2 iv q2w and SEL 50-75 mg po bid. First 3 patients of run-in portion were treated with SEL 50 mg and if no DLTs, next 3-6 patients at 75 mg po bid. If no DLTs, then phase II dose of SEL 75 mg po bid would be used. Primary endpoint was RECIST 1.0, investigator determined response rate (RR). As compared to the historical RR of 4% (and median PFS 2.5 mos) for 2nd-line FOLFIRI (Tournigand), with alpha 0.10 & beta 0.90, a sample size of 45 would have the power to detect improvement in RR to 15%, and 79% power to demonstrate improved med PFS to 4.0 mos. Early stopping would occur for responses of 0 of 20 patients. Results: 32 patients were entered and treated. Median age was 54 (40-71) yrs, 18 were male and 22 Caucasian, all KRASm. The first 3 tolerated SEL 50 mg bid without SAE and the remaining 29 were treated at 75 bid. Median number of cycles on study was 3.5 and median TTP approximately 4.0 months. Observed grade 3 AEs included: diarrhea 3, fatigue 2, neutropenia 2, and 1 each PLTS, enteritis, GI bleed, rash; one grade 4 ANC. Grade 2 AEs: diarrhea 12, rash 8 pts. Best response (investigator reported) included 3 (9%) confirmed PR and 15 (47%) SD [including 2 unconfirmed PR] of 32 entered. Six patients were on study for > 6 months (6, 6, 8, 9, 12.5, 14.5 months). The study was terminated early due to non-protocol considerations. These data are not yet verified. Conclusions: Despite early termination, the higher RR and PFS noted for 32 patients with KRASm CRC treated with IRI and SEL as 2nd-line therapy of CRC (and treated for up to 14.5 months), are promising compared with historical controls. The strategy of MEK inhibition in KRAS mutated CRC should be explored further. Clinical trial information: NCT01116271.
Mice on trial: Are xenografts using human tissue a better model of cancer than xenografts formed from cell lines?
Authors: Sadadcharam Gaitri , McCourt Morgan , Ryan Ciara , O'Connor Kate , Bennett Michael William , Power Derek Gerard , O'Reilly Seamus , Wang Jinghuai , Redmond Henry Paul , Andrews Emmet J 
Published: February 2017

386 Background: Xenograft tumours are validated models using either patient samples (primary xenografts) or cell lines (secondary xenografts) grown in a murine host. Repeated culturing of cancer cell lines results in epigenetic changes and subsequent behaviour changes distinct from primary human cancers. The aim of this study is to form both models and compare their responses to chemotherapy agents. Methods: Fresh primary colorectal adenocarcinoma tissue or colorectal cell lines (SW480 non metastatic line / SW620 metastatic line) were inoculated subcutaneously into immunodeficient mice to form primary and secondary xenografts respectively. Both models were subjected to either a 5-fluorouracil (5-FU) or irinotecan trial. The clinical response and biological features were evaluated. Results: Secondary xenografts were more aggressive with a shorter time to tumour formation, higher uptake rate and more aggressive histological features. The mice were randomised to either the control group (saline) or to the treatment group [60mg/kg of 5FU (SW620 / primary xenografts) or 60 mg/kg of Irinotecan (SW480 / primary xenografts)] via intraperitoneal injection. In the 5FU group, the primary xenografts began regressing after Day 2 but the secondary xenografts continued to grow until Day 8. The decrease from the maximal tumor volume to the study end point (Day 12 in primary xenograft group and Day 10 in secondary xenograft group) was evaluated with primary xenografts showing a greater decrease compared to secondary xenografts (56.6% vs. 10.4%; p =0.002). Conclusions: We demonstrated the ability to grow tumours in mice from fresh human colonic adenocarcinomas. Tumours formed in mice from patient derived adenocarcinomas produce more clinically accurate testing than tumours formed from cell line and may allow for drug screening in order to personalise an individual’s chemotherapy regime.
Expression analysis of MET, EGFR, and HER2, and K-ras mutation status in patients with stage II/III gastric cancer enrolled in the ACTS-GC study.
Authors: Ochiai Atsushi , Kitada Koji , Ichikawa Wataru , Terashima Masanori , Kurahashi Issei , Katai Hitoshi , Kushima Ryoji , Sasako Mitsuru 
Published: February 2017

40 Background: Exploratory biomarker analysis was conducted to identify factors related to outcomes of patients enrolled in the ACTS-GC study, a randomized controlled trial comparing surgery followed by adjuvant S-1 therapy with surgery alone in 1,059 patients with stage II/III gastric cancer. Methods: Formalin-fixed paraffin-embedded specimens obtained from 105 patients, an institutional subset of this biomarker study of 829 patients, were extensively examined for EGFR and HER2 by immunohistochemistry (IHC), MET amplification by FISH, and K-ras mutation status (codon 12, 13) by PNA-enriched direct sequencing. The expressions of 63 genes involved in pyrimidine metabolic pathway, growth factor signaling pathway, apoptosis, DNA repair, etc., were measured by quantitative real-time RT-PCR. The relations of the expressions of these genes to clinicopathological features such as histological type, T grade, N grade, tumor stage, gender, and age were also investigated. Results: The rates of K-ras mutation, EGFR overexpression, HER2 overexpression, and MET amplification were 6.7% (7/105), 14.3% (15/105), 11.4% (12/105), and 21.0% (22/105), respectively. These factors were almost mutually exclusive. Co-expressions were seen in 2 (EGFR & HER2), 4 (HER2 & MET), 5 (MET and EGFR) and 1 (EGFR & HER2 & MET) of the 105 patients. MET amplification and EGFR overexpression were associated with worse outcomes. In contrast, KRAS and HER2 status were not associated with overall survival or relapse-free survival. Expression levels of PCAM1, ESR1, MUC2, CAV1, ITGB3, and APC mRNA were significantly higher in diffuse-type cancer than in intestinal-type cancer, whereas expression levels of HER2, E2F1, LDHA and TOP2A mRNA were significantly higher in intestinal-type than in diffuse-type cancer (FDR P<0.05). Associations of other clinically significant genes with clinicopathological features other than histologic type were not screened. Conclusions: Many clinical, pathological, molecular, and genetic factors have been investigated with a growing understanding of the molecular pathogenesis of gastric cancer. We review and discuss such prognostic markers in the ACTS-GC study.
Investigation of a possible link between epithelial four-and-a-half LIM domains protein 2 expression and prognosis in colorectal cancer.
Authors: Verset Laurine , Tommelein Joke , Moles Lopez Xavier , Decaestecker Christine , Mareel Marc , Bracke Marc , Salmon Isabelle , De Wever Olivier , Demetter Pieter 
Published: February 2017

401 Background: Four-and-a-half LIM domains protein 2 (FHL2) is a component of the focal adhesion structures and has been suggested to play a role in cancer progression. It has been shown to be overexpressed in colorectal cancer (CRC). Here we examined a possible prognostic value of FHL2 in CRC. Methods: Immunohistochemistry for FHL2 was performed on 296 CRCs without distant metastases at time of surgery. Staining in the epithelial compartment was quantitatively evaluated using image analysis, and results were related to clinical variables. Antibody specificity was tested using siRNA transfection in hTERT-immortalised myofibroblasts. FHL2 expression was investigated also by Western blotting in sporadic (HT29) and HNPCC-derived (HCT116 and HCT8/E11) colon cancer cell lines. Results: Varying degrees of cytoplasmic FHL2 expression by neoplastic epithelial cells were detectable in all cases. Higher FHL2 expression in the epithelial compartment was an independent adverse prognostic factor. Expression in the tumour invasion front (p < 0.001) as well as in the centre of the tumour (p < 0.001) was associated with metachronous metastases. No relation between FHL2 expression and microsatellite instability could be demonstrated. Conclusions: Higher FHL2 expression is involved in CRC progression and correlates with the development of metachronous metastases, suggesting that FHL2 is an independent adverse prognostic indicator for CRC.
The critical role of dysregulated FOXM1–PLAUR signaling in human colon cancer progression and metastasis.
Authors: Li Dawei , Wei Ping , Peng Zhihai , Huang Chen , Tang Huamei , Jia Zhiliang , Cui Jiujie , Le Xiangdong , Huang Suyun , Xie Keping 
Published: February 2017

405 Background: The mammalian Forkhead Box (Fox) transcription factor FOXM1 is implicated in tumorigenesis including mouse intestinal cancer. However, the clinical significance of FOXM1 signaling in human colorectal cancer (CRC) pathogenesis remains unknown. Methods: We investigated FOXM1 expression in 203 cases of primary colon cancer and matched normal colon tissue specimens and explored the underlying mechanisms of altered FOXM1 expression and the impact of this altered expression on colon cancer growth and metastasis using in vitro and animal models of colon cancer. Results: We found weak expression of FOXM1 protein in the colon mucosa, whereas we observed strong FOXM1 expression in tumor-cell nuclei of colon cancer and lymph node metastases. A Cox proportional hazards model revealed that FOXM1 expression was an independent prognostic factor in multivariate analysis. Experimentally, overexpression of FOXM1 by gene transfer significantly promoted the growth and metastasis of colon cancer cells in orthotopic mouse models, whereas knockdown of FOXM1 expression by small interfering RNA did the opposite. Promotion of colon tumorigenesis by FOXM1 directly and significantly correlated with activation of urokinase plasminogen activator receptor (PLAUR) expression and elevation of invasion and metastasis. Conclusions: Given the importance of FOXM1 in regulation of the expression of genes key to cancer biology, dysregulated expression and activation of FOXM1 may play important roles in colon cancer progression and metastasis.
Evaluating variability in fluorouracil (FU) exposure in obese and non-obese patients with colorectal cancer using full weight-based dosing.
Authors: Patel Jai Narendra , Deal Allison Mary , McLeod Howard L. , O'Neil Bert H. , Walko Christine Marie 
Published: February 2017

409 Background: Approximately 30% of cancer patients are obese. Controversy exists on how to best use body weight to safely and effectively dose chemotherapy. Additionally, body surface area (BSA)-based dosing is associated with high pharmacokinetic (PK) variability and is a poor indicator of optimal drug exposure. Methods: We estimated FU exposure post cycle 1, as indicated by area under the curve (AUC), in 58 colorectal cancer patients receiving mFOLFOX6 (FU 2400 mg/m2 [BSA calculated using actual body weight (ABW)] over 46 hours) +/- bevacizumab. AUCs were determined using an immunoassay at Myriad Laboratories. The primary objective was to identify variability in FU exposure in obese and non-obese patients using body mass index (BMI), BSA, and ABW. Groups were compared using two group t-tests. Results: No significant difference in AUC was observed between obese (BMI ≥ 30 kg/m2) and non-obese (< 30 kg/m2) patients. A significantly lower AUC was observed in patients with a BSA ≥ 2.0 m2 compared to those < 2.0 m2 (p=0.02). The AUC for obese and non-obese patients ranged from 7-34 and 12-38 mg*hr/L, respectively. Only 32% and 28% of obese and non-obese patients, respectively, were within the previously reported therapeutic target AUC 20-25 mg*hr/L. Males had significantly lower AUCs compared to females (mean 18.7 v 22.4, p=0.03). FU AUC was not strongly correlated with BMI, BSA, or ABW (Pearson correlation of -0.03, -0.26, and -0.15, respectively). Conclusions: BSA-based dosing is associated with variable FU exposure. Lower AUCs in patients with a BSA ≥ 2.0 m2 supports both ASCO recommendations for full-weight-based dosing in obese patients and the value of dosing assessment across patient populations. Further study of AUC-based dosing is warranted as our data do not support a reduction in variable exposure based on BMI, BSA, or ABW dosing. [Table: see text]
Can systemic inflammation at diagnosis predict benefit from primary resection in metastatic colorectal cancer (mCRC)?
Authors: Tran Ben , Wong Hui-Li , Desai Jayesh , Tie Jeanne , Field Kathryn Maree , Kosmider Suzanne , Bae Susie , Wong Shu Fen , Gibbs Peter 
Published: February 2017

410 Background: In CRC, the tumor associated immune response can manifest as, (1) a good prognostic anti-tumor local (intra-tumoral) inflammatory response; or (2) a poor prognostic tumor promoting systemic inflammatory response. As suggested for renal cancer, the survival advantage associated with primary resection in mCRC patients (pts) might relate to modification of the tumor associated immune response, through reduction in tumor bulk and the resulting reduction in tumor promoting cytokines. We examine if systemic inflammation at diagnosis predicts benefit from primary resection in mCRC. Methods: A prospectively collected multi-disciplinary CRC database was used to explore clinicopathological data from pts diagnosed with de novo mCRC from Jan 2009 to Jul 2012. Evidence of systemic inflammation was defined as serum albumin (SA) <35g/L or neutrophil-lymphocyte ratio (NLR) >4 at diagnosis. Pts with primary resection >42 days from diagnosis were excluded. Survival analyses utilised the Kaplan-Meier method and log-rank test. Results: Of 212 pts diagnosed with mCRC, 154 (72%) had de novo mCRC. 92 (60%) of these underwent primary resection, 62 (40%) had primary left in situ. SA was available in 141 pts, 71 (50%) had SA <35g/L. NLR was available in all pts, 93 (60%) had NLR >4. Primary resection was associated with superior overall survival (OS): median 32.5mo v 8.4mo (HR 0.29, p<0.001). Systemic inflammation was associated with inferior OS using either SA <35g/L (median 8.4mo v 19.8mo, HR 2.54, p<0.001) or NLR >4 (median 16.8 mo v 13.1 mo, HR 1.59, p=0.03). There was no difference in OS advantages associated with primary resection in pts with SA <35g/L (HR 0.25, p<0.001) compared to normal SA (HR 0.28, p<0.001) at diagnosis; a non significant difference was observed for NLR ≤4 (HR 0.15, p<0.001) compared to NLR >4 (HR 0.42, p=0.001). Data regarding resolution of systemic inflammation following primary resection will be presented. Conclusions: Our study confirms the OS benefit from primary resection in mCRC and the adverse prognostic impact of systemic inflammation. Based on our current data, any benefit from primary tumour resection cannot be explained by an impact on the tumor associated immune response.
Impact of DNA mismatch repair deficiency on relapse rate in early-stage, sporadic colorectal cancer.
Authors: Buxhofer-Ausch Veronika , Bauer Heike , Mollik Marina , Reiner-Concin Angelika , Nirnberger Guenther , Sebesta Christian , Kriwanek Stephan , Zeillinger Robert , Ausch Christoph A. 
Published: February 2017

415 Background: 15-20% of sporadic colorectal cancers (CRC) are characterized by DNA mismatch repair (MMR) deficiency resulting in the phenomenon of microsatellite instability (MSI). There is evidence that CRC with MSI have a significant better prognosis compared to those with intact MMR. We investigated MMR gene expression in patients (pat.) with CRC and correlated it with early relapse rate. Methods: The study relates to 146 pat. with primary CRC UICC stage 0-II who underwent surgical resection at the Donauspital in Vienna and had a complete follow up of at least 60 months. Expression of the MMR genes MLH1, PMS2, MSH2, MSH6 was detected by immunohistochemical staining. Expression of MMR genes was correlated with pat. and disease characteristics as well as relapse frequency within the first 5 years after diagnosis. Chi-squared test was used to compare the distribution of the given variables between MMR gene proficient and deficient pat. Results: Mean age of the total group was 66.14 years, 45.2% were females and 54.8 males. Localization of the tumor was the colon in 69.2% and the rectum in 30.8% of pat., respectively. 33.6% of diseases were classified as UICC stage 0-I, and 66.4% as UICC stage II. 37/ 146 pat. experienced relapse, mean duration to relapse was 2.17 years. 13.7% of all pat. displayed a MMR deficient state. All MMR deficiencies occurred in the colon, none in rectum tumors. MLH1 was always associated with PMS2 deficiency and occurred in 9.6% of pat. There was a significant difference in sex distribution between the proficient and deficient group with 71.4% females with MLH1/PMS2 deficiency (p= 0.038). MSH2 deficiency was detected in 1 pat. only. MSH6 deficiency occurred in 5.5% of pat., none of the variables was significantly different distributed between the proficient and deficient group. None of the MMR deficiencies correlated with relapse rate. Conclusions: Our data suggest that the supposed better prognosis of MMR deficient compared to proficient pat. might not be explained by a different relapse rate within 5 years from diagnosis. Larger and prospective trials are warranted to elucidate plausible explanations for the proposed survival benefit of a MMR deficient state.
HER-2 in high risk rectal cancer patients treated in EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab.
Authors: Sclafani Francesco , Roy Amitesh Chandra , Chau Ian , Wotherspoon Andrew , Peckitt Clare , Dewdney Alice , Oates Jacqueline Rose , Cunningham David 
Published: February 2017

420 Background: HER-2 is a well established therapeutic target in breast and gastric cancer. The role of HER-2 in rectal cancer is unclear, as conflicting data on prevalence of HER-2 expression in this disease have been reported. This analysis evaluates the prevalence of HER-2 and its impact on the outcome of high risk rectal cancer patients treated with neoadjuvant CAPOX and CRT ± cetuximab in the EXPERT-C trial. Methods: Eligible patients with available tumour tissue for HER-2 analysis were included. HER-2 expression was determined by immunohistochemistry (IHC) in biopsy and/or surgical specimens (score 0 to 3+). Tumours with equivocal IHC result (2+) were tested for HER-2 amplification by B-DISH. Tumours with IHC 3+ or B-DISH ratio ≥2.0 were classified as HER-2 positive. The impact of HER-2 on primary (CR) and secondary endpoints (RR, PFS, OS) of the study was analyzed. Results: Of 164 eligible study patients, 104 (63%) biopsy and 114 (69%) surgical specimens were available for analysis. Only 3/104 (2.9%) and 3/114 (2.6%) were HER-2 positive, respectively. In 77 patients with paired specimens, concordance for HER-2 status was found in 74 (96%), with 3 patients with discordant results (1 patient with HER-2 negative biopsy/positive surgical specimen, 2 patients with HER-2 positive biopsy/negative surgical specimen). Overall 141 patients were assessable for HER-2; 6/141 (4.3%) had a HER-2 positive tumour in at least 1 specimen. The median follow-up was 58.7 months. HER-2 expression or amplification was not associated with a difference in outcome for any of the study endpoints, including in the subset of 90 KRAS/BRAF wild type patients treated ± cetuximab. Conclusions: Based on the low prevalence of expression as recorded in the EXPERT-C trial, HER-2 does not appear to represent a useful therapeutic target for high-risk rectal cancer. However, the role of HER-2 as prognostic factor and potential predictive biomarker for cetuximab-based treatment in rectal cancer warrants further investigation. A more comprehensive B-DISH analysis in IHC 0/1+ tumours is currently ongoing and data will be presented at the meeting.
Analysis of predictive and prognostic value of clinical and pathological factors in locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (CRT): Bologna multidisciplinary rectal cancer group study (BMRG-B01-Study).
Authors: Pini Sara , Di Fabio Francesca , Ceccarelli Claudio , Iacopino Bruno , Lecce Ferdinando , Cuicchi Dajana , Ugolini Giampaolo , Varrese Francesco , Guido Alessandra , Rojas Llimpe Fabiola Lorena , Giaquinta Stefania , Pinto Carmine 
Published: February 2017

421 Background: Preoperative fluoropyrimidine based CRT is standard treatment in LARC patients. The aim of this study was to evaluate prognostic and predictive role of clinical and pathological factors in this setting Methods: Between December 2001 and January 2012 we evaluated 149 pts with cT3-T4 N-/+ rectal adenocarcinoma located ≤12 cm from the anal margin. Preoperative CRT consisted of radiotherapy 50.4 Gy in 28 daily fractions + 5-fluorouracil or capecitabine +/- oxaliplatin. Rectal surgery with total mesorectal excision was performed 6-8 weeks after the end of neoadjuvant treatment. Pathological examination of surgical specimens included TRG according to the Dworak criteria. TS, EGFR, Ki-67, p53, Bcl-2, MLH1 and MSH2 were immunohistochemically determined in pre-treatment biopsies and surgical specimens. For immunohistochemistry evaluation serial sections of formalin-fixed, paraffin-embedded tissues were stained with specific antibodies using a biotin-free ready-to-use amplification system Results: After a median follow-up of 60 months (2-122) we observed 4.7% local recurrences, 12.7% distant recurrences, and 13.4% deaths. In surgical specimens TRG 1, 2, 3 and 4 were observed respectively in 22.5%, 35.3%, 25.6% and 16.6% of patients. ypN and TRG were independent prognostic factors of DFS (p=0.020, p=0.027). CRM and TRG were independent prognostic factors of OS (p=0.016, p=0.010). High pre-treatment biopsy expression of TS was associated with poor TRG (0-1) (p=0.007); high biopsy expression of Ki-67 was associated with good TRG (2-4) (p=0.039); decrease between pre-treatment biopsy and surgical specimen of Ki-67 (Δ Ki-67 ≥ 0) was associated with good TRG (2-4) (p=0.02). Decrease in Ki-67 (Δ Ki-67 ≥ 0) was associated with good DFS (p=0.011) and confirmed by multivariate analysis as an independent prognostic factor (p=0.035). Conclusions: In our analysis ypN, CRM and TRG were independent prognostic factors; baseline expression of TS, Ki-67 and decrease in Ki-67 were predictive of TRG; decrease in Ki-67 was an independent prognostic factor of DFS.