bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pretreatment and postresection epidermal growth factor receptor (EGFR) pathway mutations in a prospective phase II trial (EXCITE) of preoperative cetuximab-containing chemoradiation (CRT) in locally advanced rectal cancer (LARC).
Authors: Gollins Simon , Quirke Philip , Myint Sun , Saunders Mark P. , Sebag-Montefiore David , Susnerwala Shabbir , Essapen Sharadah , Samuel Leslie M. , Sizer Bruce , Beare Sandy , Emma Lawrie , Jitlal Mark , West Nicholas 
Published: February 2017

458 Background: Little data exists comparing pre- and post-CRT EGFR pathway mutations in LARC. Methods: Patients had MRI-defined LARC threatening or involving the surgical resection margin. CRT used pelvic radiotherapy (RT) 45Gy in 25 daily fractions with concurrent capecitabine (650mg/m2 bid PO 5 days/week), IV cetuximab (400mg/m2 one week prior then weekly at 250mg/m2 weeks 1-5) and IV irinotecan (weekly at 60mg/m2weeks 1-4). Surgery was 8 weeks after CRT. EGFR pathway mutations were not assessed prospectively. After study completion DNA was extracted from pre-treatment biopsies and post-resection specimens by macrodissecting areas of greatest tumour cell density. KRAS codons 12, 13, 61, 146, NRAS codons 12, 13, 61, PIK3CA codons 542, 545, 546, 1047 and the BRAF V600E hotspot were then pyrosequenced. Results: From 04/09-10/11, 80 patients commenced RT. 76 patients had surgery, with pathological complete response (CR) in 14 (18%) and near-complete (microfoci) in 6 (8%). Four patients had no surgery due to clinical CR. Pre-treatment mutation status was available in 78 patients with a KRAS codon mutation in 34 patients, BRAF in 3, NRAS in 3, PIK3CA in 10 and pathway (any mutation) in 45 (58%). Post-resection data in 54 patients showed 35 mutated codons in 32 patients (59%). 18 patients (33%) showed a discrepancy compared to pre-treatment biopsy. In 17 this was at a single codon, from wild-type (wt) to mutant (mut) in 9 (7x KRAS 12, 1x KRAS 13, 1x PIK3CA 542), from mut to mut in 1 (KRAS 12 c.35G>A to c.34G>T) and mut to wt in 7 (1x KRAS 12, 2x KRAS 13, 2x KRAS 146, 1x PIK3CA 542, 1x PIK3CA 545). One patient changed in 3 codons (mut to wt at KRAS 146 and PIK3CA 545 and wt to mut at KRAS 12). In 12 patients (22%) this changed overall EGFR pathway status (6x wt to mut and 6x mut to wt). Conclusions: Intratumour heterogeneity may explain the EGFR pathway codon changes causing sequencing from single areas of macrodissection to underestimate the tumour genomic landscape and presenting a challenge to personalised medicine. Cetuximab may also drive growth of undetectable mutant clones to detectable levels on pyrosequencing. Clinical trial information: 2007-006701-25.
Prognostic role of microRNA-34a expression in colorectal cancer.
Authors: Lin Albert Y. , Kouzminova Natalia B. , Pollack Jonathan , Nuovo Gerard 
Published: February 2017

472 Background: Colorectal Cancer (CRC) is one of the leading causes of death worldwide. MicroRNA-34a (miR-34a), a tumor suppressor gene, is known to be down-regulated in CRC cell lines and recently shown to be a cell-fate determinant in early-stage dividing colon cancer stem cells. However, its prognostic significance is unclear. Methods: MiR-34a detection was performed by in situ hybridization on a CRC tissue microarray (n=127; stage I, 21 patients; II: 42; III: 33; IV: 31). Its expression was graded as negative (no signal), low (expression in 1-19% of cancer cells), moderate (20-49% of cancer cells), and strong (50-100% of cancer cells). The correlations between miR-34a expression and EGFR, osteopontin (OPN), p53, Ki67, LEF1, VEGF, COX2, MMR, stage and grade were evaluated by chi-squared test and Spearman's rank correlation coefficient. Kaplan-Meier survival analysis, log-rank test and Cox regression model were used to assess the association of miR-34a expression with recurrence-free survival (RFS) and disease specific survival (DSS). Results: MiR-34a expression had moderate positive correlation with genes associated with tissue proliferation and invasion, including Ki67 (Spearman's r=0.28, p=0.002), and weak correlation with EGFR (r=0.2, p=0.02) and LEF1 (r=0.18, p=0.039). In the subgroup of patients (n=75; stage II/III) with negative OPN expression (n=25), weak or negative miR-34a expression was associated with worse RFS (HR=4.1; 95%CI=1.1-15.9; p=0.036) and DSS (HR=10.5; 95%CI=1.2-94.5; p=0.036). Conclusions: Our results suggest that down-regulated or absent expression of miR-34a correlates with worse RFS and DSS in stage II - III CRC patients with negative OPN expression. Further investigation of miR34a in prospective randomized studies is warranted to establish its role as a prognostic factor for CRC outcome.
Retrospective evaluation of Middle Eastern patients (pts) with type II diabetes mellitus (DM) and colorectal cancer (CRC): Validation of metformin effect on overall survival (OS).
Authors: Al Omari Amal , Abdelkaleq Hadeel , Al-Hussaini Maysa , Turfa Rim , Awad Nour , Al Mutar Salwan S. , Hassabo Hesham M. , Sahin Ibrahim Halil , Hassan Manal , Garrett Chris R. 
Published: February 2017

478 Background: Epidemiologic data suggest that anti-DM medications may impact OS in CRC pts who have type 2 DM. Although type 2 DM and CRC are major health problems in the Middle East, little data exists on pts with both conditions from this region. Methods: Medical records from 1,835 CRC pts seen at King Hussein Cancer Center between 1/1/2004 and 12/31/2012 were evaluated for prevalence of type 2 DM; those with both conditions were evaluated for anti-diabetic therapy and treatment outcomes (OS and progression-free survival [PFS]). Results: 285 type 2 DM CRC patients were identified (prevalence 15.5%); 19 pts were censored as their anti-DM medications were not known. Median age of 266 pts analyzed was 62.1 years (± 8.9), M: F ratio 1.6:1, non-metformin (n = 109, 41%), metformin only (n = 43, 16%), metformin + insulin (n = 11, 4%), metformin + another oral agent (n = 104, 39%). Metformin use increased over time (19% in 2004 to 71% in 2012). Adjusting for age, gender, body mass index, and stage, type 2 DM pts treated with metformin had a 40% improvement in OS (hazard ratio 0.624, 95% confidence interval 0.44-0.97). Conclusions: These data support previous findings that metformin use in CRC pts with type 2 DM is associated with a superior PFS and OS. Contrary to previously published data there was a statistically significant OS benefit in stage IV pts, while the trend toward OS benefit in stage I-III pts was not statistically significant (see Table). This study was supported by the King Hussein Cancer Center/MD Anderson Sister Institution Network Fund. [Table: see text]
Use of the essential autophagy protein beclin 1 to regulate DNA damage response and predict response to chemoradiation in rectal cancer.
Authors: Tougeron David , Park Jae Myung , Okamoto Koichi , Huang Shengbing , Sinicrope Frank A. 
Published: February 2017

492 Background: Beclin 1 interacts with its cofactor UVRAG to promote autophagy, a cellular degradation process induced by cellular stress. While cells with defective autophagy are prone to genomic instability, it is unknown whether Beclin 1 and/or UVRAG can regulate DNA damage/repair. Methods: Colorectal cancer cell lines (HT-29, DLD1) with Beclin 1 or UVRAG siRNA were irradiated ± 5-FU. DNA damage (pATM, pH2Ax, 53BP1, RAD51), cell death (annexin V, caspase-3, clonogenic survival), and centrosome number (γ-tubulin staining), were determined. Beclin 1 protein expression was analyzed in pretreatment endoscopic biopsies from 96 rectal carcinoma patients who received radiation + 5-FU followed by surgery. Results: Beclin 1 or UVRAG knockdown was shown to enhance DNA double-strand breaks (DSBs) and cell death induced by radiation ± 5-FU. Suppression of either gene increased the percentage of irradiated cells with nuclear foci expressing 53BP1 (nonhomologous end joining), but not RAD51 (homologous recombination). Beclin 1 was shown to regulate UVRAG, and a UVRAG deletion mutant defective in Beclin 1 binding decreased protection against radiation-induced DSBs. Knockdown of Beclin 1 or UVRAG increased centrosome number in irradiated cells. While autophagy inhibition by ATG5 or LC3 siRNA enhanced radiation-induced DSBs, they did not alter centrosome number suggesting independence from autophagy. In rectal carcinomas, high vs low level Beclin 1 expression was detected in 56 (58.3%) and 40 (41.7%) tumors, respectively. Pre-treatment Beclin 1 was not associated with clinicopathological variables. However, high vs low Beclin 1 predicted a significantly reduced pathological response (macroscopic vs. microscopic or no residual tumor) to chemoradiation (high: 14.2% vs. low: 40%; p = 0.017). High vs low Beclin 1 was independently associated with poorer overall survival (HR, 4.30; 95% CI, 1.42-16.47; p = 0.009). Conclusions: Beclin 1 and UVRAG confer protection against radiation-induced DNA damage and maintain centrosome stability. The ability of Beclin 1 overexpression to confer resistance to chemoradiation, suggests its potential utility as a predictive biomarker in rectal cancer.
A randomized, placebo-controlled, double-blind phase II trial of peri-operative cimetidine in early colorectal cancer.
Authors: Jameson Michael B. , Findlay Michael P. N. , Bissett Ian , van Dalen Ralph , Lolohea Simione , Warren Judith , Romano Claudia 
Published: February 2017

509 Background: A Cochrane meta-analysis of randomised trials using histamine-type 2 receptor antagonists with surgery for colorectal cancer (CRC) demonstrated a hazard ratio of 0.53 for mortality if patients used cimetidine. The benefit is likely to be specific to patients whose tumours express the antigens that allow circulating cells to bind to endothelial selectin (E-selectin), the expression of which is induced by inflammatory cytokines perioperatively and inhibited by cimetidine. This trial sought to evaluate several key issues critical to informing the conduct of a phase 3 trial. Methods: Patients with non-metastatic CRC planned for curative-intent surgery were randomised to receive cimetidine 800mg BID or placebo orally for 5 weeks, starting 2-7 days preoperatively. A subset of patients had serial blood sampling for inflammatory cytokines. In addition to DFS and OS, endpoints assessed include treatment compliance and toxicity, recruitment issues, post-operative stay and complications, and tumour characteristics including expression of sialyl Lewis antigens and COX-2. Results: 123 patients (36% female) have been recruited in 4 centres over 3.5 years; another 4 are required to complete the planned 120 treated patients. The primary tumour was rectal in 45% and pathological postoperative tumour stage was 0-I, II, III, and IV in 29%, 33%, 35%, and 2% respectively. About 50% of CRC patients were eligible and fewer than half of those were recruited. Patient compliance was excellent with 89% of patients taking their medication orally in the first 2 days postoperatively. Inflammatory cytokines were commonly elevated postoperatively for up to 2 weeks but normalised by 4 weeks. Immunostaining for tumour antigens is in progress and will be presented. DFS and OS data are immature. Conclusions: Oral administration of cimetidine for 5 weeks is well-tolerated and feasible over the perioperative period, and covers the duration of elevated inflammatory cytokines. Correlative immunostaining studies will be presented. Clinical trial information: 12609000769280.
The effect of different doses of bevacizumab and irinotecan on tumor growth of nude mice bearing human colon cancer DLD-1.
Authors: Cong Luo 
Published: February 2017

518 Background: Anti-angiogenic therapy is an important therapeutic strategy in advanced colorectal cancer. However, the anti-angiogenic drug,such as bevacizumab(avastin) is expensive. So, clarifying whether different doses of avastin play the same effect in vivo is urgently needed. The aim of the study was to observe the different doses of avastin in combination with irinotecan in human colon tumor growth in nude mice and tumor angiogenesis. Methods: 21 nude mice inoculated with DLD-1 human colon cancer cells were randomly divided into four groups: sterile saline control (group A), 5mg/kg avastin plus irinotecan chemotherapy group (group B), 10mg/kg avastin plus irinotecan group (group C), and irinotecan chemotherapy group (group D). Drugs were administered in the first 1,5,9 days, mice were sacrificed in the 10th day after treatment, the tumor growth inhibitory rate was calculated and the tumor microvessel density (MVD) were detected by immunohistochemistry. Results: The tumor inhibition rate in groups B, C, and D were 62.85%, 47.91%, 39.59% respectively. A, B, C, and D groups’ MVD were 7.000 ± 0.71, 4.940 ± 0.58, 5.080 ± 1.25, 5.557 ± 2.04, The MVD in group B and C were significant different compared with group A by Dunnett's test, and the MVD expression difference between D, A groups and B, C groups did not reach statistical significance (P values were 0.086,0.083). Tissue necrosis was found in each group after HE staining of tumor tissue. Among them, the control group, mostly mild to moderate necrosis, and the necrosis area were increased after drug treatment. But there were no statistical differences of the necrotic area in drug treated groups graded by rank sum test (χ2 = 4.73, P = 0.193). And cell apoptosis was obviously seen in treated groups. Conclusions: Different doses of avastin with irinotecan inhibited the tumor growth on DLD-1 xenografted nude mice, Synergistic effects were observed in combination therapy, From cell morphology changes after staining with HE, we speculated that the mechanism may be related to the inhibition of tumor angiogenesis, and cell apoptosis increasing. The effect of 5mg/kg and 10mg/kg bevacizumab on tumor volume and MVD had no significant differences.
Early tumor shrinkage (ETS) and deepness of response (DoR) to predict progression-free, postprogression, and overall survival: Results from the phase III TRIBE trial.
Authors: Cremolini Chiara , Loupakis Fotios , Lonardi Sara , Trenta Patrizia , Antoniotti Carlotta , Masi Gianluca , Tomasello Gianluca , Ronzoni Monica , Ciuffreda Libero , Zaniboni Alberto , Carlomagno Chiara , Boni Corrado , Negri Francesca , Barone Carlo , Vitello Stefano , Giuntini Nicola , Bonetti Andrea , D'Amico Mauro , Boni Luca , Falcone Alfredo 
Published: February 2017

521 Background: The TRIBE trial demonstrated that first-line FOLFOXIRI plus bevacizumab (bev) improves PFS, response rate (RECIST), and OS in comparison to FOLFIRI plus bev (ASCO Annual Meeting 2013). Recent experiences evidenced that both ETS and DoR may implement the assessment of response and correlate with survival in metastatic colorectal cancer (mCRC). Methods: ETS was defined as the relative change in the sum of longest diameters of RECIST target lesions at week 8 compared to baseline. A 20% decrease was adopted as cut-off value to discriminate early responders and non-responders. DoR was defined as the relative change in the sum of longest diameters of RECIST target lesions at the nadir in the absence of new lesions or progression of non-target lesions compared to baseline. The median value was used as cut-off. Results: Out of 508 randomized patients, 443 and 484 patients were evaluable for ETS and DoR, respectively. Early responders achieved longer PFS (median PFS: 12.7 vs 10.0 mos, HR: 0.66 [0.52-0.79], p<0.0001), post-progression survival (median PPS: 17.1 vs 10.7 mos, HR: 0.64 [0.47-0.81], p=0.0005) and OS (median OS: 35.8 vs 22.4 mos, HR: 0.54 [0.39-0.67], p<0.0001). Patients achieving a DoR higher than the median reported longer PFS (median PFS: 13.1 vs 9.3 mos, HR: 0.61 [0.49-0.73], p<0.0001), PPS (median PPS: 18.4 vs 10.5 mos, HR: 0.58 [0.44-0.73], p<0.0001) and OS (median OS: 36.8 vs 21.3 mos, HR: 0.47 [0.35-0.58], p<0.0001). A significant correlation of DoR as a continuous variable with PFS (HR: 0.983 [0.979-0.986], p<0.0001), PPS (HR: 0.987 [0.984-0.991], p<0.0001) and OS (HR: 0.979 [0.975-0.983], p<0.0001) was observed. No differences across arms were reported. Conclusions: ETS and DoR predict PFS, PPS and OS. These findings support the hypothesis that the adoption of active upfront regimens, able to induce a rapid and deep tumor shrinkage, may positively affect the subsequent disease history, thus translating into an advantage in survival. Clinical trial information: NCT00719797.
Colorectal signet-ring cell carcinoma: Responsive to adjuvant chemotherapy but still a poor prognosis.
Authors: Hugen Niek , Verhoeven Rob H. A. , Lemmens Valery E. P. P. , Van Aart Carola J. C. , Elferink Marloes A. G. , de Wilt Johannes H. W. , Nagtegaal Iris D. 
Published: February 2017

529 Background: Colorectal signet-ring cell carcinoma (SRCC) has been associated with a poor survival compared to mucinous adenocarcinoma (MC) and the common adenocarcinoma (AC). Prognostic impact of tumor localization is unknown and efficacy of adjuvant chemotherapy in SRCC has never been assessed. This study analyses prognostic impact of SRCC and determines whether SRCC patients benefit from adjuvant chemotherapy for colon cancer equally compared with AC. Methods: Data on 196,757 patients with CRC in the Netherlands in the period 1989 and 2010 was included in this nationwide population-based study. Five-year relative survival estimates were calculated and multivariate relative survival analyses using a multiple regression model of relative excess risk (RER) were performed. Results: SRCC was found in 1.0% of CRC patients. SRCC patients presented more frequently with stage III or IV disease than AC (75.2% versus 43.6%, P<0.0001) and SRCC was more frequently found in the proximal colon (57.7% versus 32.0%, P<0.0001). SRCC patients had a poor 5-year relative survival of 31% in colon and 20% in the rectum compared to 57% and 59% in AC (P<0.0001). This poorer survival for SRCC was found in stage II, III and IV. In comparison with AC, there was no significant interaction between SRCC and adjuvant chemotherapy (RER 1.10, 95% CI 0.81-1.51), suggesting a comparable benefit from adjuvant chemotherapy in AC and SRCC. Conclusions: Prognostic impact of SRCC is dismal in both colon and rectal cancer patients, but colonic SRCC patients seem to benefit from adjuvant chemotherapy equally compared with AC. Reduced efficacy of adjuvant chemotherapy therefore does not seem to explain the poor outcome in SRCC patients. We recommend to adhere to adjuvant treatment guidelines for all histological subtypes, but encourage clinical trials to take histological subtype into account for stratification.
Outcome after liver transplantation compared with chemotherapy in colorectal cancer patients with nonresectable liver-only disease.
Authors: Dueland Svein , Guren Tormod Kyrre , Hagness Morten , Glimelius Bengt , Line Pål-Dag , Pfeiffer Per , Foss Aksel , Tveit Kjell Magne 
Published: February 2017

531 Background: Surgical treatment of colorectal liver metastases (CLM) is the only treatment option with curative potential; however, only about 10-20% of the patients are candidates for surgical resection. The majority of CLM patients has non-resectable disease, and receives palliative chemotherapy. These patients have poor prognosis with median OS of about 20-24 months after starting first-line chemotherapy and only about 10% survive five years. Methods: Individual data from patients with non-resectable liver only disease who had received liver transplantation (Ltx) (SECA-study, Hagness et al., Ann Surg. 2013) were compared to a similar group of patients with non-resectable liver only metastases included in the NORDIC VII study (first-line Flox chemotherapy ± Cetuximab, Tveit et al., J Clin Oncol. 2012). Twenty one patient included in the Ltx study were compared to 47 patients with liver only metastases included in the NORDIC VII study. All patients in the NORDIC VII study started first-line chemotherapy, whereas 57% of patients in the Ltx study had received second- or third-line chemotherapy at time of Ltx. Results: Median age of the Ltx group was 56 years (range 45-65 years) and 57 years (range 34-65 years) in the Nordic VII study. Median tumor size was 4.5cm (range 2.8-13.0cm) and 5.0cm (range 1.4-16.0cm) in the Ltx and Nordic VII groups, respectively. 5 year OS in the Ltx group was 60% compared to a 5 year OS of 9% in the NORDIC VII group. The 5 year OS of the 21 patients in the NORDIC VII data set with the longest OS was 19%. The patients in the Ltx study who had received only first-line chemotherapy at time of Ltx had a 5 year OS of 80%. Patients in the NORDIC VII study had an OS from end of second-line chemotherapy of 6-7 months. In comparison, patients with progressive disease on second-line/third-line chemotherapy at time of Ltx, had a median OS of 39 months and a 5 year OS of 30%. Conclusions: Patients with non-resectable CLMonly, has a dramatic improved OS after Ltx compared to chemotherapy. The difference could not be explained by patient selection. Selected patients with CRC obtain OS similar to Ltx patients transplanted for primary liver malignancies. Selected CRC patients should therefore be considered for Ltx. Clinical trial information: NCT01311453.
Meta-analysis of outcomes of VEGF and EGFR targeted biologic therapy in relapsed metastatic colorectal cancer (mCRC).
Authors: Chan David , Segelov Eva , Shapiro Jeremy David , Price Timothy Jay , Karapetis Christos Stelios , Tebbutt Niall C. , Pavlakis Nick 
Published: February 2017

534 Background: Biologic therapies used in treatment of mCRC are expensive and there is debate about their value. We examined the impact of biologic therapy on overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and grade 3/4 toxicity for patients beyond first-line treatment. Methods: MEDLINE, EMBASE, and Cochrane libraries were searched for randomized studies in relapsed mCRC comparing treatment containing targeted therapy to the same treatment without targeted therapy. Biologic agents were classed as: EGFR-inhibitors (EGFR-I), VEGF antibody/trap and VEGFR tyrosine kinase inhibitors (TKI). Only KRAS wild-type patients were included for EGFR-I analysis. Results were aggregated according to standard meta-analytic techniques. Results: 10 studies evaluating 5,847 patients were identified. Considering subgroups and lines, OS and PFS benefit was demonstrated in all groups across all lines except for OS in 2nd line EGFR-I use (which may be due to subsequent crossover). A benefit to ORR was seen with EGFR-I 2nd line (Pooled ORR benefit +24%, Odds Ratio (OR) 4.44, 95% CI 3.20-6.18), EGFR-I 3rd line and beyond (Pooled ORR benefit +16%), VEGF antibody/trap (Pooled ORR benefit +7.2%, OR 2.00, 95% CI 1.57-2.54) and VEGFR TKI (Pooled ORR benefit +1.9%, OR 2.05, 95% CI 1.27-3.30). The risk of grade 3/4 toxicity was greater with the addition of all targeted agents. Conclusions: The use of VEGF and EGFR targeted biologic agents beyond first-line setting in mCRC results in a benefit to OS, PFS and ORR for all agents except for OS benefit with second-line EGFR-I. This benefit comes at the cost of increased toxicity. [Table: see text]