bluuebunny/crossref_metadata_2025_split huggingface dataset:
Demographic, medical, and behavioral factors associated with colorectal cancer screening and diagnostic colonoscopy in Israel.
Authors: Gofine Miriam , Paltiel Ora , Manor Orly , Cohen Arnon , Elran Einat , Valinsky Liora , Matz Eran , Jaffe Dena Hirschfield 
Published: February 2017

557 Background: Colorectal cancer (CRC) is the third leading cause of cancer death worldwide and second leading cause of cancer death in Israel. Israel's universal health care system funds CRC screening (CRCS) (fecal occult blood testing or colonoscopy) for all adults aged 50-74. CRCS adherence is influenced by numerous factors including patient characteristics. In addition to screening asymptomatic individuals, those with anemia may have undiagnosed CRC and require aggressive case finding. This study’s goals were: 1) To compare the socio-demographic, health status, and health behavior characteristics of the eligible Israeli population who underwent any versus no CRCS (2009-2012); 2) To examine the relationship between anemia severity and CRCS likelihood; 3) To determine whether anemia status predicts time-to-CRCS. Methods: National retrospective cohort study of Israeli adults aged 51-71 on 1.1.2009 using electronic medical records from all 4 Israeli HMOs (n=1,009,898) over a 4-year period. Results: Differences in CRCS adherence were observed by patient characteristics. For example, ever-smokers comprised 17.9% of the screened population and 24.9% of the non-screened population (p<0.001). Increasing anemia severity was positively associated with any CRCS performance, especially colonoscopy. For example, severely anemic individuals (hemoglobin <10 g/dL for men, <8 g/dL for women) were significantly more likely to receive colonoscopy than those who were not anemic (OR = 3.23; 95% CI, 2.58-4.27). Anemia somewhat expedites CRCS. For example, 8.9% of those with anemia and 7.6% of those without anemia performed any CRCS within 30 days of hemoglobin level recording (p<0.001). Conclusions: Full CRCS adherence is not yet optimized in Israel. Particular attention directed at those at-risk for CRCS non-adherence may decrease CRC mortality. Although lower hemoglobin somewhat expedites colonoscopy performance, few individuals with anemia actually undergo colonoscopy. Further analysis accounting for confounding and effect modification is crucial for a more complete understanding of these relationships.
Metachronous cancer after endoscopic submucosal dissection of gastric neoplasia.
Authors: PARK Jae Myung , Yoon Seung Bae , Song Kyo Young , Lim Chun-Hyun , Cho Yu Kyung , Kim Sang Woo , Choi Myung-Gyu 
Published: February 2017

559 Background: Metachronous recurrence after endoscopic resection (ER) of gastric cancer is known to be high. However, recurrence rate of metachrous lesions after ER of gastric adenoma has not been studied well. The aim of the study was to compare the metachronous recurrence between gastric carcinoma and adenoma patients. Methods: Four hundred eight carcinoma and 539 adenoma patients were enrolled in this study, and median follow-up period was 27 months (IQR: 16-45 months). Clinicopathological characteristics were assessed. At the follow-up endoscopy, the whole gastric mucosa was examined thoroughly to detect any gastric neoplasia. All suspicious lesions were evaluated histologically on endoscopic biopsies. Surveillance endoscopic schedule was as follows: every 3–6 months within 1 year, then once every year. Results: Forty three metachronous recurrence was diagnosed in in carcinoma patients and 45 in adenoma patients. There was no significant difference in the incidence of recurrent metachronous neoplasm between carcinoma and adenoma patients (p=0.728, log-rank test). After excluding metachronous adenoma, cancer recurrence was not different either between two groups (p=0.943). After adjusting for age, sex, multiplicity, and Helicobacter pylori status, the risk of the metachronous development of gastric cancer in adenoma patients was similar with that in carcinoma patients (HR, 0.96; 95% CI, 0.63-1.45). Conclusions: Metachronous gastric cancer after ER of gastric adenoma was as high as that of gastric carcinoma. Similar endoscopic surveillance program should be applied for both gastric carcinoma and adenoma patients after ER.
Single-center early experience of optical coherence tomography (OCT) for evaluation of high-grade dysplasia or early cancer in Barrett's esophagus.
Authors: Pai Sachin Gopalkrishn , Fuloria Jyotsna , Joshi Virendra 
Published: February 2017

56 Background: Barrett’s esophagus is a well-known risk factor for esophageal cancer. Surveillance esophagogastroduodenoscopy (EGD) and procedures like endoscopic mucosal resection (EMR) and radio frequency ablation (RFA) are adopted to mitigate risk of evolution to high grade dysplasia and cancer. Newer imaging modalities are expected to improve diagnostic accuracy and guide management. Here we describe our early experience with optical coherence tomography (OCT) which is an near infra-red light imaging technique for diagnosing high grade dysplasia and early stage cancer in patients with Barrett’s esophagus. Methods: Patients who underwent EGD and diagnosed with Barrett’s esophagus and endoscopic features worrisome for high grade dysplasia or early cancer were selected for the procedure. Patients underwent OCT for further characterizations of these lesions. Clinical and endoscopic findings, imaging studies and OCT findings were recorded and analyzed. Results: 5 patients were studied in this early series and details are tabulated below. (OCT images will accompany final presentation.) Conclusions: Early detection of high grade lesions and early cancer with image directed therapy in Barrett’s esophagus may positively impact survival. Our early experience suggests OCT is helpful in detecting cryptic dysplastic changes, especially in the aftermath of previous ablation and can guide additional endoscopic treatment. Further studies are necessary to determine efficacy of such an approach. [Table: see text]
Proteomic signatures of colorectal cancer to identify distinct and reproducible subgroups independent of oncogenic mutations.
Authors: Lee Michael Sangmin , Clarke Callisia , Jiang Zhi-Qin , Manyam Ganiraju C. , Tian Feng , Lu Yiling , Morris Jeffrey , Broom Bradley McIntosh , Menter David , Vilar Sanchez Eduardo , Shureiqi Imad , Raghav Kanwal Pratap Singh , Eng Cathy , Chang George J. , Simon Iris , Bernards Rene , Mills Gordon B. , Overman Michael J. , Maru Dipen M. , Kopetz Scott 
Published: February 2017

580 Background: While colorectal cancer (CRC) has classically been categorized on the basis of oncogenic mutations such as KRAS and BRAF, proteomic analyses directly elucidate the functional state of the cancer cell’s protein signaling, as recently described in a pan-cancer cohort and with mass-spectroscopy in a small CRC cohort. We performed an antibody-based proteomic analysis (reverse-phase protein array; RPPA) of a large cohort at MD Anderson (MDACC) and The Cancer Genome Atlas (TCGA) to determine patterns of protein expression in CRC. Methods: 725 archived CRC tumor samples (263 MDACC discovery set, and 462 TCGA validation set) underwent protein extraction and RPPA at MDACC to determine levels of 127 proteins. With unsupervised hierarchical clustering, samples dichotomized with distinct patterns of protein expression. The proteins with highest discriminatory utility were identified by LIMMA in the discovery set and confirmed in the validation set. Clinical variables and DNA sequencing results were available for correlation. Results: Among the top 30 discriminant proteins for the dichotomized groups in each dataset, 18 were common to both and tended to correlate with each other. One group was notable for high EMT (high fibronectin and collagen VI, low E-cadherin), while the other group was notable for high Akt/TSC/MTOR (high AKT, MTOR, Tuberin), and high RTK pathway components (high BRAF, HER2, HER3). This latter group also was notable for elevated beta-catenin and low CHK1, implicating differential activation of Wnt and cell cycle pathways, and intriguingly had elevated phospho-AMPK and phospho-NFkB. In the MDACC cohort, this latter group was more likely to have mucinous histology (p=0.009 by Fisher’s exact test) and lack lymphovascular invasion (p=0.026). When both TCGA and MDACC cohorts were examined, there was no significant difference in microsatellite instability, PIK3CA, KRAS, or BRAF mutations between the two proteomic groups. Conclusions: CRCs appear to be classifiable into distinct subsets by proteomic features. These findings reflect distinct differences in cellular signaling that are independent of common oncogenic driver mutations.
Prognostic effect of a single nucleotide polymorphism (SNP) in MIR608 in patients with high-risk locally advanced rectal cancer (LARC): Results of the EXPERT-C trial.
Authors: Sclafani Francesco , Chau Ian , Cunningham David , Lampis Andrea , Hahne Jens , Braconi Chiara , Peckitt Clare , Gonzalez David , Hullki Wilson Sanna , Capdevila Jaume , Glimelius Bengt , Cervantes Andres , Begum Ruwaida , Brown Gina , Tait Diana M. , Wotherspoon Andrew , Eltahir Zakaria , Yusuf-Adam Sandra , Oates Jacqueline Rose , Valeri Nicola 
Published: February 2017

581 Background: An association between rs4919510, a SNP of mir-608, and prognosis of patients with colorectal cancer has been reported. However, no studies have analysed the role of this SNP in LARC. We conducted a pharmacogenomic analysis of rs4919510 in EXPERT-C, a randomised phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery and adjuvant CAPOX ± cetuximab in high-risk LARC. Methods: SNP analysis was performed on DNA extracted from tumour tissue. Kaplan-Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms. Results: A total of 155/164 (94.5%) patients had tumours assessable for rs4919510 genotyping. 95 (61.3%) were homozygous for CC, 55 (35.5%) heterozygous (CG) and 5 (3.2%) homozygous for GG with no deviation from the Hardy-Weinberg equilibrium (p=0.379). Genotypes were evenly distributed in the two treatment groups and no association with baseline clinico-pathological characteristics or tumour molecular status (including RAS) was observed. Complete response did not differ according to the tumour genotype in the entire population (14.7% for CC, 13.3% for CG/GG) and was not influenced by treatment (12.0% for CC and 14.3% for CG/GG in CAPOX, 17.8% for CC and 12.5% for CG/GG in CAPOX-C) (all p values>0.05). Median follow-up was 64.9 months. In the CAPOX arm the 5-yr PFS and OS rates were 54.6% and 60.7% for CC and 82.0% and 82.1% for CG/GG, respectively (HR PFS 0.13, 95% CI: 0.12-0.83, p=0.02, HR OS 0.38, 95% CI: 0.14-1.01, p=0.05). In the CAPOX-C arm the same survival figures were 73.2% and 82.2% for CC and 64.6% and 73.1% for CG/GG (HR PFS 1.38, 95% CI: 0.61-3.13, p=0.44, HR OS 1.34, 95% CI: 0.52-3.48, p=0.55). An interaction was found between study treatment and rs4919510 genotype for both PFS (p=0.02) and OS (p=0.07). Conclusions: This is the first study investigating rs4919510 in LARC. We found that the CC genotype was associated with worse prognosis compared to the CG/GG genotype in patients treated with chemotherapy alone but not in those treated with cetuximab. The addition of cetuximab to chemotherapy may mitigate the unfavourable prognostic associated with the CC genotype.
Phase II study of temozolomide (TMZ) in metastatic colorectal cancer (mCRC) patients molecularly selected by MGMT promoter hypermethylation.
Authors: Amatu Alessio , Bencardino Katia , Barault Ludovic , Cassingena Andrea , Bonazzina Erica , Ghezzi Silvia , Moutinho Catia , Tosi Federica , Ricotta Riccardo , Magni Elena , Gatto Rosalinda , Marrapese Giovanna , Esteller Manel , Bardelli Alberto , Di Nicolantonio Federica , Sartore-Bianchi Andrea , Siena Salvatore 
Published: February 2017

583 Background: O(6)-methylguanine-DNA-methyltransferase (MGMT) is a DNA repair protein. About 40% of mCRC display MGMT deficiency due to promoter hypermethylation, leading to susceptibility to treatment with cytotoxic alkylating agents. We previously reported that objective clinical response to dacarbazine is confined to tumors harboring MGMT promoter hypermethylation (Amatu et al. Clin Cancer Res 2013). Based on these findings, we conducted a phase II study with TMZ in MGMT-deficient mCRCs after failure of standard therapies (EudraCT 2012-003338-17). Methods: We screened mCRC patients for MGMT promoter hypermethylation on archival FFPE specimens by methylation-specific PCR (MSP). All eligible patients underwent tumor biopsy prior to start of treatment. Patients received TMZ 200 mg/m2 po qd days 1-5 q28 until progression or intolerable toxicity. We used a Fleming single-stage design to determine whether PFS rate at 12 week would be ≥35% (H0≤15%, type I error=0.059 (1-sided) and power=0.849). Secondary endpoints included response rate (RR), disease control rate (DCR), overall survival (OS), and association of clinical outcomes with quantitative MGMT evaluation in serum and fresh tissue. Results: 150 patients were screened: 54 (36%) presented MGMT promoter hypermethylation and 29 were eligible and enrolled from December 2012 to May 2014 (M 69%, median age 60y [38-77], mean number of previous treatment lines 5.6). A median of 2 cycles of TMZ were administered (range 1-5). Primary endpoint was not achieved, since PFS rate at 12 weeks was 10.3% (90% CI: 2.9-24.6). DCR was 48.3% (90% CI: 32.0-64.8), median OS 6.2 months (95% CI: 3.7-7.6), and median PFS 2.6 months (95% CI: 1.4-2.7). G3/4 toxicities occurring in ≥10% of patients included: thrombocytopenia (10.3/13.8%), neutropenia (0/10.3%) and increased bilirubin (11.1/0%). Exploratory MGMT quantitative analysis is in progress. Conclusions: In mCRC patients treated with TMZ, selection according to MGMT promoter hypermethylation by MSP did not provide meaningful PFS rate at 12 weeks. Biomarkers analyses on serum and fresh tumor biopsy are ongoing to identify the subgroup of mCRCs benefiting from treatment. Clinical trial information: 2012-003338-17.
The impact of oxaliplatin on the gonads: From bench to bedside.
Authors: Ben-Aharon Irit , Levi Mattan , Brenner Baruch , Purim Ofer , Amit Limor , Stemmer Salomon M. , Shalgi Ruth 
Published: February 2017

584 Background: Recent studies have indicated a significant increase of young colorectal cancer patients, who may then face unique survivorship issues as fertility concerns. The impact of oxaliplatin on gonadal function remains unclear. We prospectively evaluated oxaliplatin-induced gonadotoxicity in a cohort of young patients. In a preclinical setting, the impact of oxaliplatin on the gonads was prospectively studied in mice. Methods: Newly diagnosed female (< 43 years) and male (<45 years) patients who were candidates for oxaliplatin-based protocol were enrolled into the study. Hormonal profile (including AMH and menstrual pattern) was measured in female patients and in male patients at baseline and within 6 months post-treatment. In the pre-clinical setting, pubertal mice (female and male cohorts) were injected with oxaliplatin or saline (control) and sacrificed at various time-points (1 week, 1 or 3 months) post-treatment. Ovarian reserve was estimated by serial serum AMH. Testicular function was evaluated by serial serum inhibin and sperm count. Gonads had been retrieved at each time point for immunohistochemical study of apoptosis (TUNEL, Ki67) and repair (PCNA), ovarian reserve (AMH) and testicular reserve (DAZL). Results: Eighteen patients (10 women; 8 men) were enrolled. Median age for women was 34y (range 27-43) and for men 39y (33-44). AMH decreased in all women post-treatment, but was measurable in 8/10 patients (p<0.05). FSH was elevated yet in the premenopausal range in these patients. Three patients remain menstruating during treatment. Additional five patients resumed menstruation within 6 months post-treatment. In female mice oxaliplatin induced moderate apoptosis at 1-month post treatment with a recovery of the histology compared with control mice at later time points. Inhibin was slightly decreased in men post-treatment. In male mice oxaliplatin exerted moderate apoptosis and transient decrease in spermatocyte staining in histological sections and a non-significant decrease in sperm count. Conclusions: Our results in both the clinical and pre-clinical settings indicate that oxaliplatin exerts moderate transient gonadal toxicity. Future prospective large-scale studies are warranted in order to affirm these outcomes.
HER-2 as a potential target for rectal cancer treatment: Positivity rate in patients of the CAO/ARO/AIO-94 and -04 trial.
Authors: Conradi Lena-Christin , Storch Marcus , Nagelmeier Iris , Styczen Hanna , Wolff Hendrik A. , Gaedcke Jochen , Sprenger Thilo , Homayounfar Kia , Ghadimi Michael , Rüschoff Josef , Beissbarth Tim , Rödel Claus , Liersch Torsten 
Published: February 2017

585 Background: Members of the EGFR family are established targets for specific therapy approaches in a variety of malignancies. Especially HER-2 has been targeted for more than a decade in breast cancer and more recently in gastric cancer and adenocarcinomas of the gastroesophageal junction. Applying the HER-2 scoring algorithm established in gastric cancer we here investigated HER-2 expression in rectal cancer using FFPE tumor samples from both large trials of the German Rectal Cancer Study Group (GRCSG)-(CAO/ARO/AIO-94 and -04). Methods: Overall, FFPE samples from 839 patients from 63 sites were available. All patients received standardized multidisciplinary treatment according to protocols of the phase-III-trials. 104 patients were treated by primary tumor resection followed by adjuvant CRT, all other patients (n=547) had preoperative CRT either with concomitant 5-FU mono therapy (n=329, 60.1%) or a combination of 5-FU and oxaliplatin (n=218, 39.9%). The HER-2-status was determined in resection specimens using immunohistochemistry scoring and S-ISH-amplification detection. Tumors with IHC 3+ or S-ISH ratios of ≥2.2 were classified HER-2-positive; these results were correlated with clinicopathological parameters (e.g., resection status, nodal-status ((y)pN)), time to recurrence (TTR) and cancer specific survival (CSS). Results: Positive HER-2-status was found in 13.8% of resected specimens. Positivity rate in primary resection specimens was 11.5% (n=12), while after preoperative CRT 13.2% (n=78 ) patients showed a HER-2 positive tumor; 13.1% (n=43) after 5-FU mono and 13.3% (n=35) after combination of 5-FU and oxaliplatin. There was no prognostic difference according to the HER-2 status regarding TTR (p=0.90) and CSS (p=0.68) overall. However in the 5-FU mono subgroup the HER-2 expression was of prognostic relevance as measured by CSS (p=0.034). Conclusions: Analysis of 839 patients from the GRCSG validated a relevant HER-2 amplification of 13.8% in samples of rectal adenocarcinoma. Besides its potential as an independent predictor of survival HER-2 may represent a promising target for innovative therapies and should be further assessed.
Clinical and molecular characterization of refractory BRAF mutant metastatic colorectal carcinoma (mCRC): Vall d’Hebron Institute of Oncology phase I program cohort.
Authors: Sanz-Garcia Enrique , Elez Elena , Argiles Guillem , Hernandez-Losa Javier , Vivancos Ana , Moreno Debora , Macarulla Teresa , Capdevila Jaume , Alsina Maria , Sauri Tamara , Hierro Cinta , Azaro Analia , Cruz Zambrano Cristina , Vilaro Marta , Jimenez Jose , Landolfi Stefania , Nuciforo Paolo , Ramon y Cajal Santiago , Rodon Jordi , Tabernero Josep 
Published: February 2017

587 Background: BRAF mutation (mt) occurs in 5-8% of mCRC and its role as a negative prognostic factor is well known. The up-front detection of BRAF mt is not standardized beyond the boundaries of research. However, since novel emerging specific therapies are increasingly available in clinical trials, the prior determination of this mutation is now warranted. Methods: From 07/2010 to 01/2014, 581 patients (pts) with advanced refractory mCRCunderwent genetic tumor profiling as part of the VHIO Phase I Trial Molecular Prescreening Program. BRAF mt was determined by Sanger sequencing or multiplex PCR and mass detection (MassARRAY, Sequenom) of 268 frequent hotspots in 25 oncogenes including, KRAS, NRAS, and PIK3CA. PTEN status was also assessed by immunohistochemistry. Results: 581 samples were analyzed detecting BRAF mt in 56 (9.6%). In the BRAF mt population, median age was 61 years (45-80) and 54% had right-sided CRC. Metastatic sites were found at: liver 61%; peritoneum 52%; lung 39%. Median number of standard treatment was 4 (0-8) including cetuximab and/or panitumumab in 73%. BRAF V600E mutation was detected in 53 samples whereas V600K, D594V and D594G were seen in one sample each. PTEN was analyzed in 44.6% of samples resulting in low expression (H-score <50) in 56%. Other co-existing mutations were PIK3KCA H1047R, PIK3CA E545K, NRAS G12V, GNAS R201C and EGFR S768I. 22 pts were enrolled at least in one phase I trial with drugs targeting either BRAF alone (n=12) or combined with anti-EGFR (n=5), MEK (n=2), PI3K (n=1) inhibitors or double MEK/PI3K inhibition (n=2). Partial responses (PR) were seen in 3 pts (2 with BRAF inhibitor and EGFR inhibitor and 1 with BRAF inhibitor as a single agent). Conclusions: BRAF mt mCRC pts in our institution have a similar pattern to other series reported. Notably, PTEN low expression was present in almost half of the samples analyzed and other co-existent mutations in the ERK and PI3K pathways were detected. This observation, coupled with the clinical outcome observed with single agent BRAF inhibition in this population, suggests that these patients may derive greater benefit from dual BRAF and either EGFR, MEK or PI3K inhibition.
Ziv-aflibercept (Z) in combination with FOLFIRI for second-line treatment of patients with metastatic colorectal cancer (mCRC): Interim safety data from the global Aflibercept Safety and Quality-of-Life Program (ASQoP and AFEQT) in patients age 65 or older.
Authors: Bordonaro Roberto , Frassineti Giovanni Luca , Ciuffreda Libero , Aprile Giuseppe , Thomas Anne , Vishwanath Raghu L. , Zilocchi Chiara , Dochy Emmanuelle , Taïeb Julien , Sobrero Alberto F. 
Published: February 2017

588 Background: The prespecified analysis of patients (pts) ≥65 y in the VELOUR study demonstrated a safety profile similar to that of ziv-aflibercept (Z) (known as aflibercept outside the United States) plus FOLFIRI in the overall VELOUR population. The global ASQoP/AFEQT Program comprises 2 clinical studies (ASQoP [NCT01571284]; AFEQT [NCT01670721]) designed to capture QoL and safety data from a population similar to VELOUR but treated in a real-life setting. We report safety data from the fourth interim analysis of pts ≥65 y. Methods: ASQoP/AFEQT are single-arm, open-label trials evaluating Z in metastatic colorectal cancer pts previously treated with an oxaliplatin-containing regimen. Eligible pts received Z (4 mg/kg) q2w on day 1 of each cycle followed by FOLFIRI until disease progression, unacceptable toxicity, death, or investigator/pt decision. Initial starting doses of FOLFIRI and dose modifications are at treating physician’s discretion. The % of pts ≥65 y with grade (G) 3 or 4 AEs in the combined safety population of ASQoP/AFEQT are compared with the prespecified analysis in pts ≥65 y from the Z + FOLFIRI arm of VELOUR. Results: At data cutoff, the overall safety population comprised 688 pts with ≥1 completed treatment cycle; 303 (44.1%) were ≥65 y. In the overall safety population ≥1 G3/4 AE was reported in 72.2% of pts vs. 83.5% in overall VELOUR. Most G3/4 AEs were G3. There were no reports of G4 hypertension, diarrhea, or fatigue. Median number of cycles was 6 in ASQoP/AFEQT and 9 in the Z + FOLFIRI arm of VELOUR. Table shows summary of AEs in pts ≥65 y. Conclusions: This interim analysis from ASQoP/AFEQT in pts ≥65 y has identified no new safety signals and provides additional safety data suggesting an acceptable toxicity profile in this real-life setting. Clinical trial information: NCT01571284. [Table: see text]