bluuebunny/crossref_metadata_2025_split huggingface dataset:
Postcolonoscopy colorectal cancers in average-risk Korean subjects with a normal initial colonoscopy.
Authors: Lee Han Hee , Choi Hyun Ho , Lim Chun-Hyun , Kim Hyung-Keun , Kim Sung Soo , Chae Hiun-Suk , Cho Hyunjung , Cho Young-Seok 
Published: February 2017

526 Background: There are relatively few studies regarding the incidence of postcolonoscopy colorectal cancer (PCCRC) in Asian countries. We evaluated the characteristics of PCCRC in average-risk Korean subjects. Methods: This study included subjects who were ≥ 50 years of age and had undergone a first completed colonoscopy between January 2001 and December 2004, at which no baseline adenoma had been detected, followed by a second colonoscopy 1–5 years later. The incidence and characteristics of advanced neoplasia in these subjects were assessed. Results: A total of 343 subjects underwent follow-up colonoscopy within 5 years. Seventy-three (21.3%) subjects were found to have at least one adenoma upon follow-up colonoscopy. Advanced adenoma was found in eight (2.3%) subjects, and non-advanced adenomas were found in 65 (19.0%). Five patients (1.5%) were diagnosed with invasive CRC following a normal colonoscopy. The putative reason for the PCCRCs was missed lesions in two (40.0%) and new cancer in three (60.0%) cases. Conclusions: The risk of advanced neoplasia (including PCCRCs) within 5 years after a normal baseline colonoscopy in our cohort was not low. Considering that 40% of PCCRCs were attributable to missed lesions, our results emphasize the need for technical improvement of colonoscopic examinations to improve adenoma detection.
Methylated BCAT1 and IKZF1 DNA in tissue and plasma from colorectal cancer cases.
Authors: Symonds Erin L , Baker Rohan , Bastin Dawn , Bambacas Libby , Byrne Susan , Young Graeme P , Pedersen Susanne Kartin 
Published: February 2017

543 Background: We have previously described a 2-gene blood test based on the detection of methylated BCAT1 and IKZF1 for colorectal cancer (CRC). This study explored the relationship between the presence of these methylated DNA biomarkers in plasma and tissue from CRC patients. Methods: Blood (pre-resection) and samples of tumor and adjacent non-cancer tissue (NCT) were collected from 75 patients diagnosed with CRC. Extracted DNA was assessed for presence of methylated BCAT1 and IKZF1. Results: Methylated BCAT1 and IKZF1 were detected in 68 (91%) and 69 (92%) tumor tissues, respectively, with one or both methylation biomarkers being present in 74 (99%) of the 75 tumor tissues. Combined methylation levels (mean %methylated DNA per 5ng total DNA) were significantly higher in tumor than NCT: 56% methylated DNA (95%CI: 47-67) versus 3% (2.7-4) (t-test, p < 0.001). In the matching plasma samples, methylated BCAT1 and IKZF1 were detected in 35/75 and 36/75, respectively, with a combined presence of 48/75 (64%; 95%CI: 52-75). Appearance of methylated BCAT1/IKZF1 DNA in plasma and tissue was not significantly correlated (p > 0.05). Tissue methylation levels were independent of morphology, whereas the presence of biomarkers in plasma was associated with tumor size (Chi2 p = 0.02) and depth of invasion (Chi2 p = 0.003). There was no association with tumor differentiation, lymphovascularity or lymph node invasion. The one tumor tissue sample negative for BCAT1/IKZF1 methylation was also negative in plasma. For one metastatic case, primary tumor, plasma and liver samples were available and analysed, which confirmed methylated BCAT1/IKZF1 in all samples. It is worth noting that no methylation was detected in adjacent non-cancer liver tissue. Conclusions: BCAT1 and IKZF1 are highly methylated in tumor tissues, regardless of morphology. The low methylation levels in the surrounding NCT suggest that these changes are tumor specific with no obvious field effect. Appearance of the methylated biomarkers in blood depends on the primary tumor displaying invasive morphological features indicative of the tumor having access to shedding into the blood stream.
Morbidity and mortality of laparoscopic gastrectomy versus open gastrectomy for advanced gastric cancer: A single center, prospective, randomized trial.
Authors: Lin Jian-Xian , Huang Changming , Zheng Chaohui , Li Ping , Xie Jianwei , Wang Jiabin , Lu Jun , Chen Qiyue , Cao Longlong , Lin Mi 
Published: February 2017

55 Background: Laparoscopic-assisted distal gastrectomy (LADG) is rapidly gaining popularity. However, there is limited evidence regarding the safety for advanced gastric cancer (AGC). We therefore conducted a single center, prospective, randomized study comparing LADG with open distal gastrectomy (ODG) for AGC to evaluate the safety of this trial with respect to morbidity and mortality. Methods: The eligible criteria were pathologically-proven adenocarcinoma, 18 to 75 years of age, no history of other cancer, chemotherapy, or radiotherapy, preoperative stage T2-4aN0-3M0 with R0 resection. The primary end point was to determine whether there is a difference in overall survival between LADG and ODG groups. The morbidity and mortality were compared to evaluate the safety of this trial. Results: A total of 192 patients were randomized (96 cases in LADG Group; 96 patients in ODG Group) between July 1, 2011 and August 31, 2014. There were no significant differences between the two groups in the clinicopathological characteristics. Median number of retrieved lymph nodes per patient was 36, and the mean number of retrieved lymph nodes in LADG Group was more than that in ODG Group (39.8±11.1 vs. 35.4±14.8 per case, P = 0.021). The number of transfused units per patient and times to resumption of activities, resumption of soft diet, and post-operative stay were similar in the two groups; while the operation time, blood loss, and times to first flatus were significantly lower in the LATG Group (P < 0.05, respectively). The post-operative complication rates of the LADG and ODG groups were 19.8% (24/96) and 16.7% (16/96), respectively (P = 0.575). The postoperative mortality was 0% (0/96) and 1.0% (1/96) in the LADG and ODG groups (P = 0.316), respectively. Conclusions: There was no significance difference in the morbidity and mortality between LADG and ODG groups. A well-designed phase III multicenter, prospective, randomized trial comparing surgical outcomes and oncologic safety between laparoscopic and open gastrectomy for AGC can be carried out. Clinical trial information: ChiCTR-TRC-11001340.
KRAS testing disparities in the state of New Mexico.
Authors: Greenbaum Alissa , Wiggins Charles , Meisner Angela W. , Rojo Manuel , Kinney Anita , Rajput Ashwani 
Published: February 2017

551 Background: ASCO guidelines published in 2009 recommend all patients with metastatic colorectal cancer (CRC) receive KRAS testing to guide anti-EGFR monoclonal antibody treatment. Recent literature examining nation-wide trends via the Surveillance, Epidemiology, and End Results (SEER) database showed New Mexico to exhibit the highest KRAS rates of testing out of 18 registries. We aim to explore disparities in KRAS testing in the state of New Mexico. Methods: The New Mexico Tumor Registry (NMTR), a population-based cancer registry participating in the SEER Program, was queried to identify all incident cases of CRC among New Mexico residents from 2010 to 2013. Chi-square tests were used to identify disparity in KRAS testing with a p-value ≤ 0.05 considered significant. Results: A total of 637 patients were diagnosed with metastatic CRC from 2010-2013. As expected, KRAS testing in Stage 4 patients presented the highest frequency (38.4%), though testing in stage 3 (8.5%), stage 2 (3.4%) and stage 1 (1.2%) was also seen. In those with metastatic disease, younger patients (ages 22-39 and 40-64 years) were more likely to receive testing than patients 65 years and older (p < 0.0001). Patients living in or near a metropolitan center received KRAS testing more often than patients living in non-metro and rural areas (p = 0.016). There were no disparities in testing between male and female patients (39.1 v. 37.7%; p = 0.71) or amongst the predominant ethnic groups (p = 0.66). A small increase in the occurrence of KRAS testing was noted from 2010 to 2013 (34.2 to 42.2%); this trend approached though did not obtain significance (p = 0.07). In stage 4 patients, there were no significant differences in rates of wild-type versus mutant status when examined by age (p = 0.95), sex (p = 0.41), ethnicity (p = 0.41), by progressive years (p = 0.42) or geography (p = 0.35). Conclusions: New Mexico exhibits high rates of KRAS biomarker testing in patients with metastatic CRC. Age and geographic disparities exist in the rates of testing, while sex, ethnicity and the year tested showed no differences. Further study is required to explore the reasons for this disparity in KRAS testing, as well as to determine the motivation for testing in stage 1 through 3 CRC which is contrary to current treatment guidelines.
Disease control and survival outcomes for rectal adenocarcinoma (RA) managed with neoadjuvant chemoradiotherapy (nCRT): Performance of serum CEA changes as a biomarker.
Authors: Chang Tangel , Bhatia Sudershan , Berg Daniel James , Buatti John Michael , Watkins John 
Published: February 2017

552 Background: nCRT is commonly employed in advanced or distal RA, with validated associations between tumor response and disease control; however, the identification of patients likely to respond remains elusive. The present investigation seeks to determine whether absolute CEA levels and changes during treatment are associated with pathologic complete response (pCR), freedom from failure (FFF), disease specific survival (DSS), and overall survival (OS). Methods: Retrospective analysis of clinicopathologic and treatment factor association with outcomes. Eligible patients underwent nCRT followed by mesorectal resection; patients with pre-nCRT evidence of metastasis or who did not undergo resection were excluded. CEA levels were recorded at 3 times: pre-nCRT (C1), post-nCRT/pre-op (C2), and post-op (C3; < 45 days of surgery, or < 225 days if post-op C given). Univariate analysis was performed to identify clinicopathologic factor association with pCR, FFF, DSS, and OS. The absolute and relative changes in interval CEA levels were computed and included as factors in the analysis. Results: From 2003-11, 71 patients were eligible. At median follow-up of 57 months (range, 5-124), 20 patients had RA recurrence and 25 had died (19 recurrent). nCRT resulted in pCR for 19 patients (27%), which was associated with DSS (p = 0.04). The estimated 5-year FFF, DSS, and OS for the entire population were 69%, 77%, and 72%, respectively. Clinical and pathologic N-stage, nodal ratio, ypTNM stage, and stage migration post-CRT were significantly associated with FFF, DSS, and OS. The relative change from C1 to C2 was significantly associated with pCR (exp(b); p = 0.031). Absolute C3 was associated with FFF (1.091; 0.001), DSS (1.183; 0.018), and OS (1.092; 0.002); however, absolute and relative changes at C2 and C3 as compared with C1 did not demonstrate associations with disease control or survival endpoints. Conclusions: Within the present study, changes in CEA levels following CRT were associated with pCR. Additionally, initial post-op CEA demonstrated associations with disease control and survival endpoints.
Genomic profiling and efficacy of anti-EGFR therapy in appendiceal adenocarcinoma.
Authors: Braghiroli Maria Ignez Freitas Melro , Nash Garrett Michael , Morris Martin , Hechtman Jaclyn Frances , Vakiani Efsevia , Berger Michael F. , Solit David B. , Saltz Leonard , Cercek Andrea 
Published: February 2017

574 Background: Metastatic appendiceal adenocarcinoma (AAC) is a heterogenous disease and the majority of patients present with diffuse metastases in the peritoneal cavity. Cytotoxic and targeted therapies are typically extrapolated from colorectal adenocarcinoma (CRC), however, it is not known whether this is effective or not. Herein we investigated the genetic profiles of these tumors in an effort to identify molecular characteristics and potentially actionable mutations, as well as the response to anti-EGFR therapy in RAS/BRAF wild type (wt) AAC. Methods: We identified patients (pts) with ACC treated at MSKCC who had tumor who had undergone molecular profiling, either by next generation sequencing using our MSK-IMPACT platform, or by MALDI-TOF mass spectroscopy genotyping (Sequenom). MSK-IMPACT tumors and matched normal samples were analyzed either on 410 gene panel. Sequenom (provided an 8 gene panel including KRAS, NRAS, BRAF, and PIK3CA). Via an IRB approved waiver, we collected tumor histology and evaluated pts who were RAS/RAF wt and had been treated with anti-EGFR therapy. Results: We identified a total 97 AAC pts, of whom 60 had Sequenom testing and 37 had IMPACT. Among pts analyzed with IMPACT, 24 had mucinous adenocarcinoma, 3 adenocarcinoma with signet ring, 7 adenocarcinoma ex goblet cell carcinoid, 3 invasive adenocarcinoma. In total 159 alterations were identified with a median 4.2 alterations/patient (range 0-10). Alterations were seen most commonly in KRAS (21/37), GNAS (12/37), TP53 (10/37), SOX9 (5/37), and SMAD4 (4/37). Potentially treatable alterations were present in 15% of patients and included BRAF V600E (1), MTOR (2), ERBB2 (1) and NTRK(2). Of the total 97 pts, 50 (52%) were RAS/BRAF wt. Of those,13 evaluable patients received anti-EGFR therapy with either panitumumab or cetuximab. There were no responders. Conclusions: Mutational sequencing in AAC indicates that 16% have mutations in genes such as BRAFV600E, MTOR, ERBB2 and NTRK with the potential to expand investigational options through increased access to trials of selectively targeted agents. Additionally, in RAS/BRAF wt pts, panitumumab/cetuximab does not appear to have therapeutic efficacy comparable to historic controls in RAS/RAF wt CRC.
Prospective biomarker validation trial evaluating the prognostic role of the combined expression of phospho-insulin growth factor receptor-1 and matrilysin in KRAS (exon 2) wild-type (WT) metastatic colorectal cancer (mCRC) patients treated with FOLFOX-6 plus panitumumab as first-line therapy [PULSE trial (GEMCAD 09-03)].
Authors: Maurel Juan , Fernandez-Martos Carlos , Martin-Richard Marta , Alonso Vicente , Mendez Jose Carlos , Salud Antonia , Pericay Carles , Aparicio Jorge , Gallego Javier , Carmona Alberto , Casado Enrique , Manzano Hermini , Horndler Carlos , Rubini Michele , Cuatrecasas Miriam , Garcia-Albeniz Xabier , Feliu Jaime 
Published: February 2017

583 Background: Matrilysin can activate phospho-insulin growth factor receptor-1 (pIGF-1R) through IGFBP-3 degradation, releasing IGF-1. Matrilysin per se has shown poor prognosis in mCRC and the co-expression of matrilysin and pIGF-1R (double positivity, DP) correlates with poor prognosis in WT KRAS refractory patients (pts) treated with anti-EGFR in retrospective analyses. We performed a prospective clinical trial in WT KRAS (exon 2) pts, treated with FOLFOX plus panitumumab in first-line therapy to validate those findings. Methods: Positive cases were defined by immunohistochemistry as those with moderate or strong intensity (++/+++) and > 70% expression for both matrilysin and p-IGF-1R (antibody anti-pY1316). The primary end-point was progression-free survival (PFS). Seventy-eight pts and 56 events were required to have an 80% power to detect a difference in median PFS of 6 months (two-sided p< 0.05). Results: We screened 196 mCRC pts in 24 centers between Nov/2010 and Apr/2013 and 78 pts met inclusion criteria (42 non-DP and 36 DP). Median follow-up was 23 months. There were no differences in baseline characteristics [age, sex, liver metastases, lactate dehydrogenase (LDH) levels, performance status and BRAF mutational status] between both groups. There were no differences in the number of FOLFOX-6 and panitumumab cycles received. Cutaneous toxicity was more frequent in DP pts (p = 0.035). Response rate was 80.5% in non-DP and 72.2% in DP patients (p = 0.37). Median PFS (95% CI) was 7.4 months (95%CI 5.2-13.3) in non-DP and 9.6 months (95% CI 6.7-17.5, p = 0.15) in DP patients. Median overall survival was 19.8 months (11.5-26.3) in non-DP pts and 39.1 months (26-NE, p = 0.071) in DP pts. Adjusted HR for PFS was 0.68 (95% CI 0.41-1.12). Adjusted analysis for OS was 0.50 (95% CI 0.27-0.90). Conclusions: We found that co-expression of matrilysin and pIGF-1R is a novel strong prognostic biomarker of survival benefit in mCRC KRAS WT pts treated in first-line with FOLFOX-6 plus panitumumab. Clinical trial information: NCT01288339.
Microarray analysis of gene expression in gastric cancer cells from ascitic fluids before and after capecitabine and oxaliplatin (CapeOX).
Authors: Maeda Osamu , Ishiguro Kazuhiro , Funasaka Kohei , Miyahara Ryoji , Hirooka Yoshiki , Goto Hidemi , Ando Yuichi 
Published: February 2017

60 Background: Resistance to anti-cancer drugs is a critical issue in treatment of cancer. Alteration of gene expression profile accompanied with acquisition of drug-resistance is considered to be related with resistance mechanisms. Methods: 1. Ascitic fluids were collected before the beginning of CapeOX, during the treatment was effective, and after the disease was progressed. They were cultured for ten days and passed to new flasks, and were cultured in additional two weeks to remove normal cells including white blood cells and mesothelial cells. 2. AGS cells were cultured in medium with either fluorouracil or oxaliplatin, and fluorouracil- or oxaliplatin-resistant cells were established. AGS cells were also treated with a demethylating agent decitabine. 3. Expression of 25,147 genes was analyzed with microarray, and was compared among ascitic fluid cells before and after CapeOX, drug-resistant AGS cells, and decitabine-treated AGS cells. Results: Genes with alteration in expression due to CapeOX-resistance were classified into genes commonly changed with fluorouracil-resistant cells, those with oxaliplatin-resistant cells, and others. Among 873 genes with decreased expression after CapeOX, some genes including PCDH20 and DEFB4A have been reported as potential tumor suppressor genes. Expression of PCHD20 in AGS increased after treatment with decitabine. Conclusions: Drug-resistance in gastric cancer may be related with expression of genes including tumor suppressors regulated by epigenetic mechanisms. Repetitive collection of gastric cancer cells in ascitic fluids before and after chemotherapy is useful to understand drug-resistance mechanisms.
Limits on costs and values of anticancer drugs in metastatic colorectal cancer: Policies and proposal.
Authors: Guirgis Helmy M. 
Published: February 2017

607 Background: Guidelines from the National Institute of Health and Clinical Excellence (NICE) in the United Kingdom (UK) set limits on cost-effectiveness ratios (ACER) of 20,000-30,000 pound per quality of life-year gained (QALY). Bevacizumab (Bev) is not approved in UK in 1st-line metastatic colorectal cancer (mCRC). The objectives were twofold:1- Propose limits of 5,000 in Unites Sates dollars (US$) on 4-week drug costs and values 2- Weigh and compare drugs in various lines of mCRC. Methods: The 4-week costs (4wC) were calculated. Values were expressed as 4wC x hazard ratio of death (HR). Relative values (RV) were computed as 5,000/values. Results: In 1st-line, 4wC of Bev (5.0mg/Kg) was $4,620, values 3,049 and RV 1.64. Panitumumab (Pan) were $8,223, values 6,833 and RV 0.73 Cetuximab (Cet) were $9,775, values 7,820 and RV 0.64. In 2nd- line, 4wC of Aflibercept (Afl) was $5,000, RV 1.22, Bev (10 mg/KG) $9,240, RV 0.72 and Ramucirumab (Ram) $11,200 with RV 0.53. Regorafenib (Reg) in refractory disease had 4wC of $9,400, value 7,238 and RV 0.69. Trifluridine/tipiracil (TAS 102) at projected costs of $5,000 to $9,000, values were estimated at 3,400 to 6,120 with RV of 1.47 to 0.82. Conclusions: In 1st-line Bev had lower 4wC with higher values and RV than Pan, Cet and the $5,000 proposed limits. In 2nd-line, Afl was at the borderline of limits. Costs of Pan, Cet, Ram and Bev in 2ndand Reg in refractory disease were excessive and inflated for their values. Preliminary cost evaluation of TAS 102 seemed promising.
Correlation of the prognostic impact of Ki67/BCL2 index based on immunohistochemistry with poor clinical outcome in gastric cancer.
Authors: Son Byoung Kwan , Min Kyueng Whan , Kim Dong-Hoon , Kim Eun-Kyung , Ha Junghoon 
Published: February 2017

61 Background: Considering the heterogeneity of gastric cancer, it is particularly important to identify potential prognostic indicators. Ki67 and B-cell lymphoma 2 (BCL2) proteins are known prognostic markers in different types of cancer. Ki67 is associated with cell proliferation, whereas BCL2 has anti-proliferative roles. A combined marker based on these opposite functions might provide improved prognostic information in gastric cancer. The aim of this study is to investigate correlations between a combined marker using Ki67 and BCL2 and clinicopathologic parameters, and to evaluate the prognostic value of the combinatorial marker in patients with different types of gastric cancer. Methods: This study assessed Ki67 and BCL2 expression using tissue microarray obtained from 276 patients with adenocarcinoma of the stomach. A Ki67/BCL2 index based on the relative expression of each protein was divided into low- and high-risk groups using receiver operating characteristic (ROC) curves. Results: High Ki67/BCL2 index was significantly associated with advanced AJCC stage, high recurrence, diffuse or mixed type, high histological grade, and the presence of lymphatic and perineural invasion (all p < 0.05). Univariate and multivariate analyses revealed a significant relationship between disease-free or overall survival and Ki67/BCL2 index in intestinal-type gastric cancer(all p < 0.05). Conclusions: A combined marker using Ki67 and BCL2 could be a useful indicator for predicting survival in patients with intestinal-type gastric cancer.
BRAF mutations in colonic high-grade neuroendocrine carcinoma.
Authors: Padmanabhan Chandrasekhar , Dahlman Kimberly Brown , Berlin Jordan , Liu Eric , Gonzalez Raul S. , Guo Yan , Shi Chanjuan , Idrees Kamran 
Published: February 2017

612 Background: The WHO 2010 has classified GI neuroendocrine neoplasms into well-differentiated neuroendocrine tumor (NET) and high-grade neuroendocrine carcinoma (NEC). NEC is more aggressive than NET. Whole genome sequencing (WGS) has provided insight into the genetic underpinnings of NET but little is known about NEC. The aim of this study is to perform genomic profiling of NEC to better characterize the underlying mutations in this aggressive disease. Methods: We identified 9 patients who underwent biopsy or resection for NEC between 1/2005 - 6/2013 with histological blocks available. WGS was performed on DNA extracted from tissue from 2 patients with ≥80% tumor cellularity using the Illumina HiSeq 2500 platform. Validation and mutational analysis of the BRAF gene was performed on 2 WGS patients and an additional 7 patients via Sanger Sequencing of exon 11 and 15. Results: 7 of 9 patients (78%) presented with metastasis at initial diagnosis (Table). 8 patients died of disease within 25 months. In 2 NECs, we identified BRAF mutations on exon 15 by WGS. Patient S1 presented with cecal NEC and had an A1781G:p.D594G mutation on exon 15. Patient S2 presented with a descending colon NEC and had a c.1799T>A: p.V600E mutation on exon 15. An additional 7 colonic NECs were analyzed with Sanger Sequencing of exons 11 and 15. 2 had BRAFV600E mutations. Overall, BRAF mutations were present in 4 of 9 (44%) colonic NECs. The 3 cases with V600E mutations were large cell NECs, whereas the case with a D594G mutation was a small cell NEC. Conclusions: High grade colonic NEC is an aggressive tumor with high frequency (44%) of activating BRAF mutations. Further investigation is warranted to ascertain the incidence of BRAF mutations in a larger population as BRAF inhibition may be a potential avenue of targeted treatment for these patients. [Table: see text]