bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular characterization of colorectal tumors in young patients compared with older patients and impact on outcome.
Authors: Heeke Arielle Celeste , Xiu Joanne , Reddy Sandeep K. , Jiang Jiji , Wang Hongkun , Marshall John , Salem Mohamed E.
Published: February 2017

505

Background: The incidence of colorectal cancer (CRC) among young individuals is rising. The effect of an individual’s age on their tumor molecular profile is unknown. Methods: Molecular profiles of 4,821 tumors obtained from younger and older CRC patients (pts) were reviewed and correlated with pt outcome. Protein expression (IHC), gene amplification (ISH), sequencing (NGS and Sanger), and fragment analysis were performed. T and Fisher’s exact tests determined differences between age groups; Kaplan-Meier methodology estimated survival. Results: Tumors from 1,277 younger (median age 40; range 15-45 yr) and 3,544 older (72; 65-98) pts were studied. Most frequently mutated genes included TP53, APC, KRAS, PIK3CA, SMAD4, and BRCA1/2. Mutation rates for BRAF (14.4% vs. 4.8%, p < 0.001), APC (62% vs. 54%, p = 0.0034), FBXW7 (9.6% vs. 5.5%, p = 0.01), and KRAS (45% vs. 41%, p = 0.02) were higher in older pts; NRAS mutation rates (4.5% vs. 3.9%) were similar in both groups. Younger pts had higher overexpression rates of HER-2/neu (3.2% vs. 1.8%, p = 0.017) and MGMT (64% vs. 58%, p = 0.001). Microsatellite instability (MSI), determined by IHC (MLH1, MSH2, MLH6 and PMS2) and fragment analysis, was similar between cohorts (10.3% vs. 8.1%), but somatic MSI high (determined by concurrent BRAF mutation) was higher in older pts (6% vs. 0%, p < 0.0001). There was no difference in TS (37% vs. 34%), ERCC1 (25% vs. 26%) or TOPO1 (49% vs. 46%) expression between age groups. Older pts showed a trend toward higher PD-L1 expression (2.9% vs. 0.7%, p = 0.0512) but there was no difference in the frequency of PD-1 expression on tumor-infiltrating lymphocytes (39% vs. 43%). Outcome was evaluable for 82 pts (younger, 47; older, 35). Most pts received FOLFOX + Bev as first line Rx. Median OS was worse in younger pts (p = 0.03). Low ERCC1 expression was associated with prolonged survival in older (p < 0.01) but not in younger (p = 0.3) pts. There was no association between TOPO1 expression and OS (p = 0.8). Pts with low TS expression showed a trend toward longer OS (p = 0.08). Conclusions: Young pts with CRC may carry genetic alterations that are distinct from older pts. A better understanding of disease biology may help to identify therapeutic targets for younger pts.
Small RNA sequencing of colorectal cancer to reveal differences in microRNA expression between normal and tumor tissue.
Authors: Mjelle Robin , Sjursen Wenche , Thommesen Liv , Hofsli Eva
Published: February 2017

506

Background: MicroRNAs (miRNAs) are promising biomarkers and therapeutic agents for colorectal cancer (CRC). However, much remains to be known about the biology of miRNAs and miRNA variants in tumor tissue and why the expression differs from normal tissue. Methods: RNA from 48 normal and 48 cancer tissue samples were sequenced using the Illumina small RNA sequencing protocol. Samples were taken from both male and female patients with tumor stage 1-4. Results: We show that almost 50% of microRNAs (miRNAs) are differentially expressed between normal and cancer tissue. When analyzing pre-miRNAs that map to genomic clusters, so-called clustered miRNAs, we show that miRNAs in the same cluster often have similar expression profiles. This shows that common changes in co-expressed miRNAs seem to explain some of the miRNA expression changes between normal and tumor samples and indicates that altered pri-miRNA transcription is the mechanism for at least some of the miRNA changes. Analyses of miRNA variants, so-called isomiRs, revealed large variations between tumor and normal samples, similar to those observed for the canonical miRNAs. Different isomiR types show different expression profiles in tumor vs normal samples, indicating that miRNA processing is altered in tumor cells. Finally, we show that several canonical miRNAs and isomiRs correlate with genetic signatures in the tumor samples, including KRAS and BRAF mutation, Microsatellite instability and MLH1 methylation, indicating that tumor subtypes have different miRNA expression. Conclusions: Our results show that miRNA expression predicts tumor subtypes with different genetic signatures. We show that some of the changes in miRNA expression are due to different transcription programs in cancer vs normal tissue.
Verification of T-plus staging system for colorectal cancer based on nomogram analysis of single center’s 25-year follow-up.
Authors: Ding Ke-Feng , Li Jun , Kong Xiang-Xing , Tang Ke-Jun , Bei Di-Kai , Yuan Ying , Zhang Su-Zhan , Zheng Shu
Published: February 2017

516

Background: We proposed T-plus staging system which abandon the criterion to discriminate stage II/III by lymph node status and strengthens weighting of the T stage according to cluster analysis of the summary survival data of SEER. In this study, this principle of the T-plus staging system was verified with single center data by nomogram analysis. Methods: The 1,099 patients with colorectal cancer diagnosed before 2005 were analyzed to build a novel staging system based on nomogram (nomo-staging system). The remaining 981 patients diagnosed after 2005 were used to test the performance of nomo-staging system, T-plus staging system and the 7th edition TNM staging system by Akaike information criteria (AIC), Harrell’s c-index and the area under the curve (AUC) of Receiver Operating Characteristic to predict 5-year overall survival. A smaller AIC, higher c-index and higher AUC indicated a better staging system. Results: The nomo-staging system and T-plus staging system were listed in Table 1. The validation found that the 7th edition TNM staging system showed the weakest performance. For AIC, both nomo-staging system and T-plus staging system showed smaller value than the 7th edition TNM staging system (3214.912 vs. 3224.643 vs. 3229.810). For Harrell’s c-index, both the T-plus staging system and nomo-staging system showed higher value than the 7th edition TNM staging system (0.6814 vs. 0.6787 vs. 0.6778). For AUC to predict 5-year OS, the T-plus staging system and nomo-staging system showed slightly higher value than the 7th edition TNM staging system (0.6944 vs. 0.6924 vs. 0.6913). Conclusions: We propose replacement of lymph node status as the criterion to discriminate colorectal cancer stage II/III with greater weighting of the T stage. [Table: see text]
Racial and sex disparities in changing trends of squamous cell cancer of the anus (SSCA).
Authors: Gupta Arjun , Zhu Hong , Christie Alana , Meyer Jeffrey John , Khan Saad A. , Beg Muhammad Shaalan
Published: February 2017

520

Background: Squamous cell carcinoma of the anus (SSCA) is one of only few cancers with rising incidence in the United States (US). This is believed to represent changing epidemiology of human papillomavirus (HPV) and Human Immunodeficiency Virus (HIV). We explored the racial and sex disparities in the rising incidence of SSC. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify subjects with SCCA from 2000-2012. Age-standardized incidence rates (IR) per 100,000 for 2000-2012 time period were generated in Rate Session in SEER for white males (WM), white females (WF), black males (BM) and black females (BF). The 2000 US standard population was used for age standardization. The trend of change of IR between groups was compared by testing the interaction between time and group in the linear regression model. SAS 9.4 was used for analysis Results: Among 11,739 new cases of SSCA racial and sex distribution of cases was WM:32%, WF:54%, BM:5.4%, BF:5.4%. Median overall survival (OS) was WM:101 months (m), WF:139 m, BM: 71 m, BF 103 m (p < 0.005). The IR had the highest rate of increase for WF and BM (0.06/100,000 cases annually) while rates for BF and WM increased by 0.04 and 0.02/100,000 cases annually respectively. The overall test for difference in trend among WF, WM, BF and BM groups had a p-value of 0.0099. Conclusions: The rate of increase of SSCA IR is highest for WF and BM. Additionally WF have the highest age standardized incidence of SCCA as well as the highest OS compared to other groups. These data support disparities in epidemiology and survival of anal cancer.
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]
The effect of Wnt9A induced by lithium chloride on β-catenin and colorectal cancer cell proliferation.
Authors: Braun Donald Peter , Ali Irshad
Published: February 2017

631

Background: Malignant tissues are characterized by uncontrolled proliferation and dysfunctional differentiation which often results from dysregulated Wnt signaling. β-catenin, a second messenger upregulated in neoplastic tissues is utilized by the canonical Wnt pathway (CWP) to promote cellular proliferation. In healthy tissues CWP is stringently controlled by components of the non-canonical Wnt pathway (NCWP). The NCWP, which does not utilize β-catenin for its activity, acts in concert with the CWP to maintain homeostasis in healthy tissues. Our recent studies in CRC cells indicate that LiCl increases expression of the NCWP ligand, Wnt9A leading to activation of the NCWP. Suppressing Wnt9A significantly attenuates LiCl-mediated inhibition of CRC cell proliferation. The present study investigated the capacity of Wnt9A to directly modulate expression of β-catenin mRNA and/or protein levels in CRC cells, and the effects on proliferation and apoptosis. Methods: Primary CRC lines established from resected tumors of 5 patients with metastatic disease were treated with LiCl and Wnt9A protein. Cellular proliferation and apoptosis were determined by MTS and caspase 3 assays. Total and activated β-catenin protein were determined by ELISA and Wnt pathway genes and β-catenin mRNA were determined with PCR arrays. Results: LiCl inhibited CRC proliferation (p<0.001) and increased apoptosis (p<0.01) which coincided with a 23-fold (p<0.025) increase of the NCWP ligand Wnt9A. LiCl decreased β-catenin mRNA (p<0.03) and suppressed protein levels of the total (p<0.025) and the activated form of β-catenin. Recombinant Wnt9A protein emulated LiCl effects by inhibiting proliferation (p<0.001), increasing apoptosis (p<0.03) and suppressing activated β-catenin protein (p<0.001) in CRC cells. Conclusions: This study demonstrates a novel mechanism for inhibiting CRC cell proliferation through suppression of activated β-catenin levels by the non-canonical Wnt ligand, Wnt9A. These results suggest that in CRC tumors that are driven by β-catenin, activation of the non-canonical pathway and/or direct induction of or treatment with Wnt9A protein may be therapeutically beneficial.
Cost-effectiveness analysis of radiofrequency ablation (RFA) and stereotactic body radiotherapy (SBRT) in patients with isolated hepatic metastases from colorectal cancer (CRC).
Authors: Kirichenko Vladimir , Thai Ngoc , Morris William , Heenan Amy , Parda David S.
Published: February 2017

639

Background: Systemic therapy combined with surgery may prolong survival of patients with isolated hepatic metastases from CRC, however, only 10-25% are resectable. We applied a Markov model to estimate and compare cost effectiveness for the two competing treatments of SBRT and RFA in management of unresectable isolated hepatic metastases. Methods: We developed a multistate Markov decision model with probabilistic sensitivity analysis to simulate a randomized controlled trial for SBRT and RFA and compare respective cost effectiveness (in dollars per quality adjusted life years, or QALY). Model assumptions were based on extensive literature search of utilities and recurrence risks, including published data from our institution. Costs were taken from the 2013 Medicare reimbursement tables. In order to reflect reported patient selection variability across literature, two mortality rates due to hepatic metastases were considered for both treatment modalities: 50% probability of death in 1.5 years and 60% in 5 years. Sensitivity analysis was performed to model uncertainty in these parameters. Results: For patients with 5-year life expectancy, Markov cohort analysis demonstrated QALY-adjusted survival advantage of SBRT over RFA with QALY 4.35 vs. 3.89 respectively. This difference was marginal for patients with 1.5-year life expectancy. Physician-hour involvement was less in SBRT group. The incremental cost adjusted effectiveness (Cost/QALY) for SBRT over RFA was $2,379 in the 5-year life expectancy cohort, and $2,216 for SBRT over RFA in the 1.5-year cohort. Sensitivity analysis demonstated robustness of these results across a range of utility values, costs, recurrence rates, and procedure-related morbidity. Conclusions: In comparison to RFA, SBRT was more cost-effective modality for unresectable or potentially resectable hepatic metastases over a wide range of treatment and disease assumptions, including recurrence rates, and procedure-related morbidity. Additionally, SBRT is a relatively fast outpatient procedure requiring less physician-hour involvement.
Prognostic value of isolated peritoneal versus other metastatic sites in colorectal cancer (CRC) patients treated by systemic chemotherapy: Findings from 9,265 pts in the ARCAD database.
Authors: Franko Jan , Shi Qian , Meyers Jeffrey P. , Heinemann Volker , Falcone Alfredo , Tebbutt Niall C. , Maughan Tim , Seymour Matthew , Saltz Leonard , Tournigand Christophe , Diaz-Rubio Eduardo , Sougklakos Ioannis , Chibaudel Benoist , Moen Joseph , De Gramont Aimery , Adams Richard A. , Sargent Daniel J. , Grothey Axel
Published: February 2017

656

Background: Patients (pts) with peritoneal metastases from CRC (pmCRC) have reduced OS compared to mCRC pts without peritoneal involvement. Here we further investigated the impact of number and location of metastases among pts receiving first-line systemic chemotherapy. Methods: Individual patient data were available on 9,265 pts (median age 64; 63% male; 93% ECOG PS 0-1; 68% colon primary tumor; brain metastases excluded) enrolled onto 12 first-line randomized trials (4 tested targeted regimens). Stratified multivariable Cox models were used to assess the associations with overall survival (OS); adjusted hazard ratios (HRadj) and 95% confidence intervals are reported (CI). Results: There were 7,963 (86%) pts with non-pmCRC (3,904 with one disease site; 4,059 with ≥2 disease sites), 191 (2%) pts with isolated pmCRC, and 1,111 (12%) non-isolated pmCRC. These groups were similar in age, race, and use of targeted chemotherapy. Compared to non-pmCRC, pts with pmCRC were more likely to be female (41% vs. 36%, p<.001), have colon primary tumors (85% vs. 67%, p<.0001), and have PS2 (10% vs. 6%, p<.0001). Compared to isolated pmCRC, pts with solitary non-peritoneal sites (both M1a) had significantly better OS (HRadj=0.78; CI, 0.64-0.94, p=.009) while pts with ≥2 non-peritoneal sites had similar OS (HRadj=1.06; CI 0.88-1.28, p=.535). OS of pts with pmCRC with a single other disease site (n=446) was similar to isolated pmCRC (HRadj=1.13; CI 0.91-1.40, p=.28), but those with pmCRC + ≥2 additional disease sites (n=665) had shortest survival (HRadj=1.44; CI 1.17-1.77, p<.001). A combination of peritoneal and liver metastases (n=821; HRadj=1.37, CI 1.12-1.67, p=.002) was associated with poorer survival compared with isolated pmCRC; but combination with extrahepatic sites (n=290; HRadj=1.15, CI 0.91-1.45, p=.25) was not. Conclusions: pmCRC pts have significantly worse survival than those with other solitary site mCRC. Among those with multiple disease sites, poorer survival is a function of increased number of metastatic sites and peritoneal involvement, which indicates prognostic heterogeneities among M1b pts.
Comprehensive genomic profiling (CGP) to assess mutational load in gastric and esophageal adenocarcinomas: Implications for immunotherapies.
Authors: Frampton Garrett Michael , Schrock Alexa Betzig , Chalmers Zachary Rockow , Sun James , Ennis Riley , Gowen Kyle , Beg Muhammad Shaalan , Rubinson Douglas Adam , Yelensky Roman , Stephens Philip J , Miller Vincent A. , Ross Jeffrey S. , Ali Siraj Mahamed , Klempner Samuel Jacob
Published: February 2017

66

Background: Gastroesophageal cancer (GEC) present a management challenge, particularly when ERBB2 is not amplified and cytotoxic therapy has failed. Tumor mutational load is linked to predicted benefit from immune checkpoint inhibitors in advanced cancers. Using CGP we assessed the relationship between mutational burden and clinically relevant genomic alterations in GEC samples in the course of routine clinical care. Methods: DNA was extracted from 40 microns of FFPE sections from patients with GEC. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of greater than 500x for 236 or 315 cancer-related genes. Mutational load was characterized as the number of somatic base substitutions and short indels per megabase. Samples were stratified by histologic subtype, and presence or absence of therapeutically relevant receptor tyrosine kinase (RTK) alterations. The majority of samples were from patients with advanced disease. Results: The genomic profiles from a total of 736 gastric and 862 esophageal carcinomas were assessed. Median patient age was 57 for gastric and 60 for esophageal cases. There was no significant difference in mutational load between gastric and esophageal samples. 10th, 25th, median, 75th, and 90th percentiles of mutation load were 1.3, 2.7, 6.3, 11.3, and 20.0 for gastric cancers and 1.8, 3.6, 6.4, 11.3, and 17.5 for esophageal cancers. 27 (3.7%) gastric and 20 (2.3%) esophageal cases had alterations in mismatch repair genes MLH1, MSH2, MSH6 which was associated with ~2.5 fold increased mutational load. Mutational load was not significantly associated with the presence of RTK alterations, which occurred in 155 (21%) gastric and 355 (41%) esophageal cases. Conclusions: CGP in the course of clinical care can be used to assess mutational load in GEC. Alterations in RTKs were not exclusive of the high mutation subgroup, contrary to some previous reports. Mutations in DNA mismatch repair genes were associated with higher mutation burden as expected. Incorporation of CGP into ongoing prospective immunotherapy trials and clinical practice is needed to refine these relationships.
Impact of 18F-fluorodeoxyglucose position emission tomography/computed tomography on radiotherapy treatment planning and outcomes in esophageal cancer.
Authors: Ng Sweet Ping , Tan Jennifer , Osbourne Glen , Williams Luke , Bressel Mathias , Hicks Rodney J , Lau Eddie , Chu Julie , Ngan Sam , Leong Trevor
Published: February 2017

67

Background: Currently there is no universally accepted method to accurately delineate the gross tumor volume (GTV) of primary esophageal cancer in patients undergoing radiotherapy. This prospective study aims to determine the impact of PET/CT on radiotherapy planning and outcomes in patients with localized esophageal cancer. Methods: 54 patients were recruited between June 2003 - May 2008. All underwent PET/CT scanning in the radiotherapy treatment position and received treatment planned using the PET/CT dataset. Of these, 13 (24.1%) had metastatic disease detected on PET and 3 patients had no radical radiotherapy, while another 3 patients had missing planning PET/CT data (excluded from planning component analysis). GTV was defined separately on PET/CT (GTV-PET) and CT (GTV-CT) data sets. A corresponding planning target volume (PTV) was generated for each patient. Volumetric and spatial analysis quantified the proportion of FDG-avid disease not included in CT-based volumes. Clinical data was collected for 38 patients treated radically to determine locoregional control and overall survival rates. Results: Mean age was 67 years (range:32 - 88). Median follow up was 4 years (range:2.7 – 6.8). FDG-avid disease would have been excluded from GTV-CT in 29 patients (79%) with a mean volume of 17% (range:1-100%). In 5 patients, FDG-avid disease would have been completely excluded from the PTV-CT (median volume missed = 6%, range:2-92%). For 8 patients, less than 95% of PTV-PET would have received at least 95% of prescription dose based on the CT-based plan. GTV-CT underestimated the cranial and caudal extent of FDG-avid tumor in 14 (36%) and 10 (26%) patients respectively. There were no significant differences in radiation doses to the lungs and liver. 5-year overall survival and locoregional failure free survival were 24%, and 42% respectively. Conclusions: PET/CT prevented futile radiotherapy for 1 in 4 patients and avoided geographic misses without significant impact on normal tissues in apparently localized esophageal cancer. However, survival remains suboptimal and indicates the need for further improvement in planning and therapeutic paradigms.
A national survey on the management of liver metastases from colorectal cancer (CRC): Comparison of perspectives and expectations among medical oncologists and hepatobiliary surgeons across Canada.
Authors: Ho Maria Yi , Cleary Sean P. , Mazurek Matthew , Ghosh Sunita , Cheung Winson Y.
Published: February 2017

690

Background: To compare the perspectives of medical oncologists versus hepatobiliary surgeons in the management of liver metastases from CRC. Methods: Medical oncologists and hepatobiliary surgeons across Canada were surveyed to evaluate for criteria used to determine resectability of liver metastases from CRC and availability of multidisciplinary clinics. Results: Of 220 experts surveyed, 145 (66%) responded. 137 (95%) had received specialized training in oncology. Only 37 (26%) respondents reported access to both multi-disciplinary tumor boards and clinics. 109 (75%) reported lack of institutional criteria. Oncologists and surgeons disagreed with regard to absolute contraindications for resection of hepatic metastases. More oncologists reported a higher percentage of liver parenchyma involvement (70% vs. 45%), proximity to major vessels and poor performance status as contraindications compared to surgeons (p < 0.05). All physicians deemed CT as the preferred first-line imaging study for evaluating CRC liver metastases with significantly more surgeons indicating the need for MRI of the liver (p < 0.05). Oncologists and surgeons also showed high discordances with respect to both clinical and radiographic findings in terms of their influence on surgical decision regarding resection of liver metastases (Table). Conclusions: Medical Oncologists and surgeons have discordant criteria with respect to resection of hepatic metastases and the roles they play in the management of these complex patients. Uncertainties and discordances can lead to deficiencies in care, supporting the need for a standardized clinical preoperative risk scoring system for resection of liver metastases from CRC. [Table: see text]