bluuebunny/crossref_metadata_2025_split huggingface dataset:
A prospective translational study investigating molecular predictors of resistance and response to regorafenib (REG) monotherapy in RAS mutant (mt) metastatic colorectal cancer (mCRC): Initial magnetic resonance imaging (MRI) sub-study result.
Authors: Khan Khurum Hayat , Rata Mihaela , Koh Dow-Mu , Tunariu Nina , Collins David J. , Chau Ian , Watkins David J. , Starling Naureen , Rao Sheela , Peckitt Clare , Fotiadis Nicos , Begum Ruwaida , Saffery Claire , Thomas Janet , Gerlinger Marco , Valeri Nicola , Cunningham David 
Published: February 2017

580 Background: REG that has single agent efficacy in patients (pts) with refractory mCRC, is known to have anti-angiogenic activities. The benefit of REG in unselected pts is modest. Thus, the identification of predictive biomarkers is critical for treatment stratification. PROSPECT-R study aims to identify genetic and radiological mechanisms of primary and acquired REG resistance in RAS mt mCRC patients. Methods: Multiparametric MRI studies including dynamic contrast enhancement (DCE)-MRI and diffusion weighted imaging (DWI) were acquired pre- and at day 15 post-treatment on a 1.5T Siemens Avanto MR scanner. Regions of interest of the entire chosen target metastatic lesion were drawn by a senior radiologist and the following imaging parameters were generated: volume transfer constant (Ktrans) derived from a pharmacokinetic analysis based on the extended Kety model and apparent diffusion coefficient (ADC) calculated using a mono-exponential fitting algorithm; median values of ADC and Ktrans were reported. Results: The first seven enrolled pts were analysed; a single target lesion per patient was chosen (5 liver and 2 pelvic metastases). At day 15 post treatment, a marked decrease (68-81%) of median tumour Ktrans was observed in 4 out of 7 pts; the remaining 3 patients showed no significant median Ktrans change (-36 to + 17%). Overall, the cohort average Ktrans decreased from 0.17 to 0.07 min-1(58%). No significant ADC changes were observed at day 15. Of the 4 pts with Ktrans reduction on day 15, 1 achieved RECIST 1.1 partial response (38% reduction in target lesions), 2 had stable disease and 1 progressed, based on CT assessments performed at 8 weeks of REG therapy; 3/7 pts with no Ktrans change progressed within 2 months of initiating REG. When modified Choi criteria were applied, 3/4 pts with Ktrans reduction were classified as responders. Conclusions: REG may have early anti-angiogenic affects; DCE-MRI could be a potential predicting biomarker in pts treated with REG. Further analysis within PROSPECT-R may elucidate genetic biomarkers to validate these findings. Clinical trial information: EUDRACT No: 2014- 003579-51.
Tumor site, clinicopathological characteristics, and survival of patients undergoing primary elective colorectal cancer resection.
Authors: Park James Hugh , Edwards Joanne , Roxburgh Campbell S.D. , Mcmillan Donald C. , Horgan Paul G. 
Published: February 2017

585 Background: Cancers arising in the proximal and distal colorectum differ in embryological origin, predisposing genetic and epigenetic mutations, clinicopathological characteristics and survival. However, the effect of tumor site on the prognostic value of clinicopathological characteristics and systemic inflammatory responses (SIR) is not known. The present study aims to examine the relationship between tumor site, clinicopathological characteristics and cancer-specific survival (CSS) in patients undergoing elective colorectal cancer (CRC) resection. Methods: Patients who had undergone elective, primary resection of stage I-III CRC (1997-2013) were included. Tumors were categorized as proximal (cecum to splenic flexure) or distal (splenic flexure to rectum) based on pathological reports. SIR was assessed using modified Glasgow Prognostic Score (mGPS; 0-CRP < 10mg/L, 1-CRP > 10mg/L, 2-CRP > 10mg/L and albumin < 35g/L). Results: 796 patients were included; 302 tumors were proximal and 494 were distal to the splenic flexure. Proximal location was associated with advanced age, T stage, poor differentiation, greater lymph node yield, peritoneal involvement and an increased mGPS (all P< 0.01). In all patients, on multivariate survival analysis, distal tumor site, advanced age, T stage, N stage, venous invasion, margin involvement and mGPS were independently associated with reduced CSS (all P< 0.05). In patients with proximal cancer, only age (HR 1.8, P= 0.001), T stage (HR 1.9, P= 0.009), N stage (HR 1.9, P< 0.001) and mGPS (HR 1.6, P= 0.004) were associated with CSS, whereas in patients with distal CRC, T stage (HR 1.4, P= 0.024), N stage (HR 1.5, P= 0.001), venous invasion (HR 1.5, P= 0.038), margin involvement (HR 4.1, P< 0.001) and mGPS (HR 1.5, P= 0.003) were associated with survival. Conclusions: In the present study, tumor site was associated with distinct clinicopathological characteristics. Furthermore, the prognostic value of pathological characteristics currently employed in tumor staging, such as venous invasion and margin involvement, differed with tumor site, whereas evaluation of the SIR was similarly prognostic in patients with proximal and distal CRC.
Palliative treatment of obstructive esophageal cancer by vascular targeted photodynamic therapy (VTP): Preclinical study in orthotopic rat model.
Authors: Uzana Ronny , Preise Dina , Agemy Lilach , Elmoalem Rachel , Belkin Varda , Sasson Keren , Yechezkel Tamar , Salomon Yoram , Scherz Avigdor Joshua 
Published: February 2017

59 Background: Vascular targeted photodynamic therapy (VTP) based on local sensitization of circulating WST11 (Pd-bacteriochlorophyll), enables effective focal ablation of solid tumors. WST11 clears from the circulation with t1/2 ~40 min (in humans) and does not accumulate in tissues which assures high level of safety and minimal adverse effects. Here we evaluate WST11-VTP for the treatment of obstructive esophageal cancer aiming at developing clinically relevant protocol. Methods: Using endoscopy guided procedure rat esophageal cancer cells (JA) were implanted in the mid esophagus. Following intravenous infusion of WST11, established tumors were illuminated by cylindrical fiber using the same endoscope sleeve. Safety and efficacy were evaluated by monitoring animal weight shift and histology of treated esophageal tissues. Treated animals included control (light/no WST11 or WST11/no light), WST11-VTP and WST11-VTP following treatment with bevacizumab at day -3. Results: WST11-VTP on esophageal tissues resulted in coagulative necrosis of the tumor graft and prolonged survival as evident by Kaplan—Meyer curves. The impact was confined to the illuminated site without signs of perforation or death. Following Bevacizumab, WST11-VTP showed similar results while control groups showed no effect. All treated animals started to regain weight at day 7 after VTP. Esophageal tissue and function was completely restored. Conclusions: WST11-VTP could be safely applied for the treatment of esophageal tumors, with only transient and mild adverse effect that are not affected by previous, clinically relevant treatment such as Bevacizumab application. Importantly, VTP effectively eradicated established esophageal tumors and could be translated into a clinical treatment protocol.
Assessing intratumor heterogeneity and evolutionary distance in exome sequencing of colon cancer.
Authors: Popper Ulrich , Rumpold Holger 
Published: February 2017

590 Background: Carcinogenesis is considered to be an evolutionary process by natural selection of cell clones which have acquired advantageous heritable characteristics. This adaption process, which resembles Darwin’s evolutionary theory, has also been suggested as a potential mechanism promoting resistance to anti-cancer treatment. Methods: We performed whole exome sequencing of four colon cancers at five morphologically different loci of the primary tumor tissue. To investigate intratumor heterogeneity we conducted structural variant analysis, copy number analysis and ploidy profiling. We propose an evolutionary distance of the tumor samples based on a distance function in copy number space. Results: Copy number and phylogenetic analysis demonstrated substantial intratumor heterogeneity, with all 20 samples (5 loci for 4 tumors) possessing a unique copy number profile. Our analysis further revealed cancer-specific, tumor-specific and locus-specific copy number variants. We found that at least one copy of 18q, including the genes DCC and SMAD4, as well as 8p, carrying the CSMD1 gene, was missing in all tumors. Additionally, gains of chromosome 7,8q, 13q, 20q and losses of 4q and 21q were frequent. Using our distance measure in copy number space, phylogenetic analysis grouped together the five loci of one tumor and showed their evolutionary branching. We found that our distance measure in copy number space is superior to a distance measure in SNV space for colon cancer. Conclusions: Our analysis reveals that the landscape of the tumor genome cannot be captured by single tumor-biopsy, which is one of the challenges to personalized-medicine as heterogeneity can lead to therapeutic failures. However, there can be characteristics of the tumor genomes that are stable across samples which can potentially be used as biomarkers. Nonetheless variability of copy number profiles of colorectal cancers might suggest a personalized therapy.
Long-term effect of Wnt/β-catenin small molecule inhibitor CWP232291 on intestinal carcinogenesis in novel GEM model deficient in Smad4 and p53.
Authors: Park Jun Won , Park Jung Min , Green Jeffrey E. , Kim Hark K. 
Published: February 2017

594 Background: We have established and characterized a novel genetically-engineered mouse (GEM) model for colorectal cancer by performing intestinal epithelium-specific knockout of Smad4 and p53 under Villin promoter. CWP232291 (JW Pharmaceutical Corporation, Seoul, Korea) is a potent Wnt/ β-catenin small molecule inhibitor currently tested in several Phase I trials. We evaluated chemopreventive efficacy of long-term CWP232291 treatment for intestinal carcinogenesis in our novel GEM model. Methods: Three-week-old GEM mice were intraperitoneally injected BIW for 17 weeks with 100 mg/kg CWP232291 (n = 19) or vehicle normal saline (n = 27) and then sacrificed. Results: All Villin-Cre;Smad4F/F;Trp53F/F mice developed multiple spontaneous intestinal tumors with the high proliferative activity and the activation of Wnt signaling pathway (median adenocarcinoma-free survival, 5.4 months; incidence of adenocarcinoma, 75.9 %). Whereas, Villin-Cre;Smad4F/F or Villin-Cre;Trp53F/F micedidn’t develop any intestinal tumors until 20 weeks. A histological assessment showed that tumor-bearing mice were significantly reduced after CWP232291 treatment (CWP232291, 50.0% vs vehicle, 84.0%; P < 0.01). More importantly, CWP232291 showed significant decrease in the incidence of malignant tumors (CWP232291, 37.5% vs vehicle, 78.3%; P < 0.05). In addition, tumor multiplicity is significantly decreased in CWP232291-treated mice (CWP232291, 1.2 ± 0.4 vs vehicle, 2.8 ± 0.4, P < 0.01). Immunohistochemistry showed that CWP232291 treatment reduced β-catenin, myc and cyclin D1 levels in tumors. In-vivo limiting dilution assay using primary mouse cancer cells showed that the frequency of cancer stem cells (CSCs) was 1/3,223 for the untreated group and 1/48,069 for the CWP291-treated group (p < 0.001). Conclusions: These results showed that CWP232291 inhibited Wnt signaling and reduced the CSCs through down-regulation of β-catenin and Wnt target genes and exerted a chemopreventive effect in our GEM model. This suggests that CWP232291 may be a promising candidate for colorecal cancer chemoprevention and maintenance.
Serum leucine-rich alpha-2-glycoprotein-1 with fucosylated triantennaryN-glycan as a novel tumor marker for colorectal cancer.
Authors: Shinozaki Eiji , Tanabe Kazuhiro , Akiyoshi Takashi , Tsuchida Tomohiro , Miyazaki Yuko , Kojima Nozomi , Igarashi Masahiro , Ueno Masashi , Suenaga Mitsukuni , Mizunuma Nobuyuki , Nakayama Konosuke , Iijima Sadayo , Yamaguchi Toshiharu 
Published: February 2017

595 Background: CEA and CA19-9 are measured widely in daily practice for colorectal cancer to monitor the condition of treatment, though its specificity and sensitivity is not satisfied enough. While, the innovation of mass spectrometry in this decade is dramatically. The revolutionized approach for the screening of glycomarkers provides a chance to discover more desirable tumor markers. We focused on glycan alterations of serum glycoproteins and tried to find new markers which are more specific and sensitive than the current markers. Methods: Sera of 80 CRC patients and 50 healthy volunteers were analyzed in this study. Glycopeptides were prepared from serum proteins by trypsin digestion, enriched by filtration and aleuria aurantia lectin(AAL), and then applied to liquid chromatography time-of flight mass spectrometry* (*LC-TOF-MS). Data was analyzed with our newly developed software, which calculates all of peak intensities and positions (m/z and elution time), aligns all peaks for all samples, and finally screens markers from a million of candidates. Results: Leucine-rich alpha-2-glycoprotein-1 with fucosylated triantennary N-glycan (LRG-FTG) was discovered as a new CRC marker from over 100,000 candidate glycopeptide peaks. The level of LRG-FTG in CRC patients (1.25 ± 0.973 U/ml) was much higher than that of healthy parsons (0.496 ± 0.433 U/ml, p < 10-10). Its sensitivity and specificity exceeded those of CA19-9. CEA and LRG-FTG levels were moderately correlated (r = 0.61), however their relation was independent and complementary. Combination marker of LRG-FTG and CEA showed 84% of sensitivity, 90% of specificity and 0.91 of AUC (ROC analysis), and responded well to the efficacy of chemotherapy. Conclusions: Serum LRG-FTG was significantly elevated in CRC patients compared to healthy volunteers. The combination with CEA is expected to be an alternative diagnostic marker which distinguishes CRC from healthy persons and a sensitive monitoring marker for evaluation of efficacy during chemotherapy. Further validation study is warranted to evaluate serum LRG-FTG combination test compared with conventional tumor markers.
Does pre-operative aspirin and statin prescription modulate the post-operative systemic inflammatory response following surgery for colorectal cancer?
Authors: Watt David G. , Park James Hugh , Ng Shoukee K , Horgan Paul G. , McMillan Donald C 
Published: February 2017

596 Background: Aspirin use has been reported to reduce the pre-op systemic inflammatory response (SIR) in patients with colorectal cancer (CRC). Moreover, an exaggerated post-op SIR, evidenced by C-reactive protein (CRP) concentrations, is associated with poorer short and long term outcomes, highlighting the importance of CRP as a potential therapeutic target for improving outcomes following surgery for CRC. Drugs such as corticosteroids, aspirin and statins may modulate the post-op SIR, but there is little current evidence supporting this hypothesis. Therefore, the aim of the present study was to determine whether pre-op prescription of aspirin or statins modulated the post-op SIR in patients undergoing surgery for CRC. Methods: Included patients were obtained from a prospectively maintained database of CRC resections from a single institution (2010-2014). The relationship between pre-op aspirin and statin prescription and post-op CRP concentrations was examined. Results: 446 patients were included. The majority of patients were > 65 yrs (64%), male (57%) and underwent elective surgery (91%). 120 patients were prescribed aspirin and 187 prescribed statins with 100 patients prescribed both. Patients prescribed aspirin had a reduced post-op SIR particularly on day 3 (p = 0.009), 4 (p = 0.003) and 5 (p = 0.005). This effect was also observed following elective surgery (n = 402) on day 3 (p = 0.014), day 4 (p = 0.009) and day 5 (p = 0.019). Patients prescribed a statin also had a reduced post-op SIR, particularly on days 3 (p = 0.010), 4 (p = 0.006) and 5 (p = 0.017) and also following elective surgery on day 3 (p = 0.039) and day 4 (p = 0.039). The combination of aspirin and statin, compared with none or each on its own, resulted in the lowest post-op SIR, particularly on day 3 (p = 0.015), day 4 (p = 0.006) and day 5 (p = 0.023). Conclusions: Pre-op prescription of aspirin or statins resulted in a reduced post-op SIR following surgery for CRC. Therefore, pre-op use of these medications may be of benefit in improving outcomes, by reducing the post-op SIR – a reported predictor of both long and short term outcomes, following surgery for CRC.
The prevalence RAS and BRAF mutations among patients in the Middle East and Northern Africa with metastatic colorectal cancer.
Authors: Garawin Tamer , Lowe Kimberly , Kafatos George , Murray Samuel 
Published: February 2017

598 Background: Anti-EGFR therapies are recommended for metastatic colorectal cancer (mCRC) patients with confirmed wild-type RAS (exons 2, 3, 4 of KRAS and NRAS) status. There is limited published information on the prevalence of RAS mutations using real world data. The objective of this study was estimate the prevalence of RAS and BRAF mutations among patients with mCRC in the Middle East and Northern Africa (MENA) in an effort to inform the rationale for biomarker testing and treatment choice. Methods: The study included 1,669 patients from August 2013 to July 2015 with mCRC from Algeria, Bahrain, Egypt, Jordan, Kuwait, Lebanon, Libya, Morocco, Oman, Qatar, Saudi Arabia, and the United Arab Emeritus. Information on RAS mutation status was obtained from one pathology lab using High Resolution Melting Analysis. Extended RAS analysis was conducted in a subset of patients, including: overall RAS (exon 2, 3, 4 of KRAS and NRAS; n = 750), KRAS exon 2 (n = 750), KRAS exon 3 and 4 (n = 507), NRAS exon 2, 3, and 4 (n = 507), and BRAF exon 15 (n = 78). The proportion of patients with each mutation was summarized. Results: The overall RAS mutation in the full sample was 35.3% (n = 589/1669). The observed mutation for KRAS exon 2 in a subset of patients with extended RAS analysis (n = 750) was 32.4% (243/750). Out of the subjects with wild-type exon 2 (n = 507), the observed mutations rates were as follows: KRAS exon 4 (20/507 = 3.9%), KRAS exon 3 (13/507 = 2.6%), NRAS exon 2 (7/507 = 1.4%), NRAS exon 3 (6/507 = 1.2%), and NRAS exon 4 (0%). The prevalence of BRAF exon 15 was 3.8% (3/78). The most robust data on specific RAS mutations was obtained from Algeria, Egypt, and Saudi Arabia. The prevalence of KRAS exon 2 mutations in these countries was as follows: Algeria (n = 33/86 = 38.4%), Egypt (n = 83/303 = 27.4%), Saudi Arabia (n = 85/245 = 34.7%). Conclusions: To our knowledge, this is the first study to evaluate the prevalence of RAS and BRAF mutations in the Middle East using real world data. The results of this descriptive study illustrate that there is variation in the prevalence of RAS and BRAF mutations in MENA.
Liquid biopsy leads to a paradigm shift in cancer treatment.
Authors: Suzuki Koichi , Takayama Yuji , Ichida Kosuke , Fukui Taro , Kakizawa Nao , Muto Yuta , Watanabe Fumiaki , Hasegawa Fumi , Tsujinaka Shingo , Kaneda Yuji , Miyakura Yasuyuki , Noda Hiroshi , Kiyozaki Hirokazu , Konishi Fumio , Rikiyama Toshiki 
Published: February 2017

602 Background: Liquid biopsy represents an ideal non-invasive tool allowing multiple testing over time, monitoring real time changes occurring within the tumor and evaluation of therapeutic response. Here we show monitoring of KRAS mutation in detection of circulating tumor DNA (ctDNA) during treatments for metastatic colorectal cancer patients (pts). Methods: 238 plasma samples were collected from 57 pts who underwent chemotherapy. KRAS mutant ctDNA (MctDNA) was determined by digital PCR as a tool of Liquid biopsy, detecting rare mutant clones in blood. Results: KRAS assessment in tumor tissues showed 19 pts with mutation (M) and 38 without mutation (W). Among 19 pts with M, 12 pts displayed MctDNA at the initial assessment and 7 pts showed no MctDNA. Then, one (M*) of 7 pts exhibited MctDNA during treatments. While 38 pts with W showed no MctDNA before chemotherapy except one pt (M**), 4 pts exhibited MctDNA after treatments with different regimens. MctDNA was detectable in the blood of these 4 pts prior to radiographic detection of disease progression. Regardless of KRAS status in tumor tissues, poor response was seen in pts with MctDNA. Conclusions: Liquid biopsy provides us a circulating biomarker for monitoring treatment response and choice of optimal regimens. [Table: see text]
Perioperative chemotherapy with S-1 plus oxaliplatin (SOX) for stage III colorectal cancer patients.
Authors: Aisu Naoya , Yoshida Yoichiro , Komono Akira , Yamada Teppei , Kojima Daibo , Mera Toshiyuki , Tanimura Syu , Yamashita Yuichi 
Published: February 2017

603 Background: Neoadjuvant chemotherapy (NAC) has a potential to increase the curative resection rate and reduce the recurrence rate. The purpose of this study was to evaluate the safety and efficacy of S-1 plus oxaliplatin (SOX) regimen as neoadjuvant (4 courses) and adjuvant (4 courses) for the treatment of patients with Stage III colorectal cancer (anyT and N+). Methods: We have treated patients with Stage III colorectal cancer undergone operation after NAC (SOX 4 courses) and adjuvant chemotherapy (SOX 4 courses) at Fukuoka University Hospital. SOX regimen (S-1 80 mg/ m2 : day1~14 and oxaliplatin 130 mg/m2 : day1) was administrated every 3 weeks. The primary endpoint was response rate and safety. Results: Of the 21 patients enrolled between September 2012 and December 2014. The median age was 62 years (range, 43–87), and 57% were female. Eastern Cooperative Oncology Group performance status scores were 0, 1, and 2 in 50%, 40%, and 10% of the patients, respectively. The patients received median 4(1-4) courses of NAC and median 4(0-4) courses of adjuvant chemotherapy. The cumulative median dose of oxaliplatin was 1204 (210-1841) mg/body. In NAC, 4 patients required treatment interruption because of the toxicity [grade2 gastrointestinal bleeding (n = 1), grade 3 thrombocytopenia (n = 2), and grade4 ileus (n = 1)]. A complete response according to Response Evaluation Criteria in Solid Tumors ver.1.1 was observed in a patient (4.8%) and a partial response was observed in 15 patients (71.4%) and a stable disease was 5 patients (23.8%). The response rate and tumor control rate were 76.1% and 100%. Curative resection was performed in all patients. No perioperative complications more than grade3 as Clavien Dindo classification was observed in all patients. The observed adverse events of Grade 3 or higher were thrombocytopenia (n = 4), neutropenia (n = 3), diarrhea (n = 1), and ileus (n = 1). Conclusions: Perioperative chemotherapy with SOX is safe and effective. Further studies are warranted to confirm the safety and efficacy of this method. A single-arm phase II trial of perioperative chemotherapy (SOX) and operation for stage III colorectal cancer patients (FUTURE1104 SOS3).