bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential expression and prognostic value of ERCC1 and thymidylate synthase in resected gastric adenocarcinoma.
Authors: Squires Malcolm Hart , Fisher Sarah B. , Fisher Kevin E. , Patel Sameer H. , Kooby David A. , Staley Charles A. , Farris Alton B. , Maithel Shishir K.
Published: February 2017

38

Background: Excision repair cross complementing gene-1 (ERCC1) and thymidylate synthase (TS) are key regulatory enzymes whose expression patterns are variably associated with overall survival (OS) in several malignancies. For example, in lung cancer, high ERCC1 expression is inversely associated with OS depending on whether or not patients receive perioperative chemotherapy with surgery. The expression pattern and prognostic value of ERCC1 and TS in resected gastric adenocarcinoma (GAC) are not known. Methods: 109 patients who underwent resection of GAC between 1/00-6/11 had tissue available for analysis. Primary objective was to assess for differential expression of ERCC1 and TS using immunohistochemistry. Secondary objective was to assess for association of ERCC1 and TS expression with OS. Results: Median age was 64yrs. Median FU was 21.2mos and median OS was 28.8mos. Resected GAC exhibited differential expression of ERCC1 (23% high, n=25) and TS (43% high, n=47). ERCC1 and TS expression were not associated with OS. In a planned subset analysis, however, of patients who received chemotherapy (n=73), high ERCC1 expression was associated with decreased OS (16.7 vs. 53.8mos; p=0.03). After controlling for tumor size, margin, grade, T-stage, lymph node involvement, and presence of lymphovascular or perineural invasion, the negative prognostic value of high ERCC1 expression persisted on multivariate Cox regression analysis (HR 2.5; 95%CI: 1.03-6.0; p=0.04). By contrast, in patients who underwent resection only (n=35), high ERCC1 expression was associated with improved OS (40.4 vs. 12.7mos; p=0.10). This finding persisted on multivariate analysis (HR 0.20; 95%CI: 0.04-.86; p=0.03). Conclusions: Resected gastric adenocarcinoma exhibits differential expression of TS and ERCC1. TS expression is not associated with OS. However, similar to what is reported in lung cancer, high ERCC1 tumor expression is associated with decreased OS in patients receiving chemotherapy, but is associated with increased OS in those treated with surgery alone. ERCC1 expression has prognostic value in resected gastric cancer and further investigation is warranted.
Circulating angiogenic factors as predictors of benefit from bevacizumab (bev) beyond progression in metastatic colorectal cancer (mCRC): Translational analyses from the phase III BEBYP trial.
Authors: Cremolini Chiara , Loupakis Fotios , Bocci Guido , Fioravanti Anna , Masi Gianluca , Salvatore Lisa , Marmorino Federica , Orlandi Paola , Schirripa Marta , Di Desidero Teresa , Antoniotti Carlotta , Canu Bastianina , Danesi Romano , Falcone Alfredo
Published: February 2017

382

Background: TML and BEBYP trials demonstrated that the strategy of prosecuting bev beyond progression is effective in mCRC. Previous analyses from phase II studies showed that a dynamic modulation of plasma angiogenic factors occurs during first-line treatment with chemotherapy (CT) plus bev and a wide variability in soluble Vascular Endothelial Growth Factor Receptor 2 (sVEGFR2) levels was observed at the time of progression. Moving from preliminary analyses in murine models we selected a pool of candidate ligands to be tested in the clinical setting. Methods: sVEGFR2, Placental Growth Factor (PlGF), Platelet-Derived Growth Factor-C, basic Fibroblast Growth Factor, Angiopoietin-2 and sTie-2 were assessed by ELISA on plasma samples collected at baseline in a cohort of 59 patients enrolled in phase III BEBYP trial of 2nd-line CT ± bev beyond progression to a bev-containing first-line regimen. Plasma levels were defined high or low adopting the median as cut-off. Results: A significant interaction between treatment arm and baseline sVEGFR2 levels was observed (p=0.036). Among 30 patients with high sVEGFR2 levels, the prosecution of bev was associated with a significant benefit in terms of PFS (median: 10.4 vs 3.4 months, HR 0.37 [95%CI:0.10-0.58], p=0.0015), that was not evident among 29 patients with low sVEGFR2 levels (5.4 vs 5.0 months, HR 0.98 [95%CI:0.45-2.11], p=0.956). Despite a trend towards a greater benefit from bev among 30 patients with high PlGF levels (HR 0.45 [95%CI: 0.13-0.86]), no interaction between treatment arm and baseline PlGF levels was observed (p=0.210). Combined analysis of sVEGFR2 and PlGF showed that prosecuting bev provided a substantial benefit in PFS in the subgroup with high levels of both ligands (10.5 vs 2.3 months, HR 0.25 [95%CI:0.01-0.45], p=0.043). Conclusions: sVEGFR2 levels at the time of first progression may predict benefit from the prosecution of bev. Impressive results deriving from concomitant testing of sVEGFR2 and PlGF may be affected by excessive subgrouping and should be considered cautiously. Given their potential clinical value these data need prospective confirmation. Clinical trial information: NCT00720512.
Increased gene copy number and amplification of FGF2 and FGFR1 in metastatic colorectal cancer.
Authors: Lieu Christopher Hanyoung , Varella-Garcia Marileila , Xu Liang Guo , Jiang Zhi-Qin , Eckhardt S. Gail , Messersmith Wells A. , Maru Dipen M , Kopetz Scott
Published: February 2017

402

Background: Fibroblast growth factors (FGFs) and their receptors (FGFRs) play essential roles in tightly regulating cell proliferation, survival, migration, and angiogenesis in cancers. However, gene copy number and amplification of FGF2 and FGFR1 have not been extensively evaluated in patients with metastatic colorectal cancer (CRC). Methods: Two tissue microarrays (TMA) were constructed with resected CRC liver metastases from 120 patients. The TMAs included duplicated intratumoral regions and the invasive margin between tumor and normal hepatic parenchyma. Patients were either untreated, or previously treated with FOLFIRI or FOLFOX +/- bevacizumab. The TMA slides were subjected to a two-color FISH assay using a mixture of FGF2 and FGFR1 in-house developed probes. Results: Results were obtained from 118 patients. The analysis detected an average of 1.90 copies of FGF2 signal per cell (range, 1.10-3.46 copies) and an average of 2.27 copies of FGFR1 signal per cell (range, 1-12-7.14 copies). Three control specimens from each slide were also scored, with an average of 1.74 copies of FGF2 and 1.73 copies of FGFR1. High copy number per cell (mean > 2.5 copies) was detected in 9.3% of specimens for FGF2 and 27.9% for FGFR1, including 2 patients (1.7%) for FGF2 and 5 (4.2%) for FGFR1 with focal amplification, defined by ≥ 10% cells with > 4 copies. Additionally, duplications of gene signals in the same locus were detected in 10 samples (8.5%) for FGF2 and 19 (16.1%) for FGFR1. Intratumoral heterogeneity was rare (detected in 3 patients). There was no statistically significant correlation between FGF2 or FGFR1 gene copy number and prior treatment, pathologic response, relapse free survival, or overall survival, though there was a trend towards higher FGFR1 gene copy number in patients previously receiving bevacizumab (p=0.07). Conclusions: Both FGF2 and FGFR1 display variable copy number among resected CRC liver metastases, with larger variability detected for FGFR1. Gene amplification was rare but detected in several patients for both FGF2 and FGFR1. Follow up studies will investigate higher FGFR1 gene copy number in patients previously treated with bevacizumab, perhaps reflecting a potential escape or resistance mechanism.
Identification of synthetic lethal interactions with the BRAF oncogene in colorectal cancer.
Authors: Vecchione Loredana , Gambino Valentina , d'Ario Giovanni , Tian Sun , Simon Iris , Popovici Vlad Calin , Delorenzi Mauro , Bernards Rene , Tejpar Sabine
Published: February 2017

403

Background: Approximately 8-15% of colorectal (CRC) patients carry an activating mutation in BRAF. This CRC subtype is associated with poor outcome and with resistance, both to chemotherapeutic treatments and to tailored drugs. We recently showed that BRAF (V600E) colon cancers (CCs) have a characteristic gene expression signature (1, 2) which is found also in subsets of KRAS mutant and KRAS-BRAF wild type (WT2) tumors. Tumors having this gene signature, referred as “BRAF-like”, have a similar poor prognosis irrespective of the presence of the BRAF (V600E) mutation. By using a shRNA-based genetic screen in BRAF mutant CC cell lines we aimed to identify genes and pathways necessary for survival and growth of BRAFmutant CC. Such studies may reveal additional targets for therapy and potentially provide new biomarkers for patient stratification Methods: We identified 363 genes that are selectively overexpressed in BRAF mutant tumors as compared to WT2 type tumors, based on gene expression profiles of the PETACC3 (1) and Agendia (2) datasets. The TRC human genome-wide shRNA collection (TRC-Hs1.0) was used to generate a 1815 hairpins sub-library targeting those identified genes (BRAF library). BRAF(V600E) CC cell lines were infected with the BRAF library and screened for shRNAs that cause lethality. LIM1215 CC cell line (WT2) was used as a control. Cells stably expressing the shRNA library were cultured for 13 days, after which shRNAs were recovered by PCR. Deep sequencing was applied to determine the specific depletion of shRNA in BRAF(V600E) cells as compared to LIM1215 cells Results: Candidate genes were identified by using following filtering criteria: depletion in BRAF(V600E) cells by at least 50% and depletion in BRAF(V600E) cells 1, 5-fold higher than in control cells with the corresponding p-value to be ≤ 0.1. A total of 34 genes met our criteria of which 6 genes were presented with more than one hairpin and were concordant across the cell lines selected for validation. Conclusions: We identified candidate synthetic lethal genes in BRAF mutant CC cell lines. Functional analysis is ongoing. Data will be presented. References 1. J Clin Oncol 2012 Apr 20;30(12):1288-9 2. Gut (2012). doi:10.1136/gutjnl-2012-302423
The requirement for freshly isolated human tumor cells for the study of colorectal cancer stem cells.
Authors: Bellister Seth Albert , Fan Fan , Tozzi Federico , Lu Jia , Xia Ling , Zhou Yunfei , Bhattacharya Rajat , Ye Xiangcang , Ellis Lee M.
Published: February 2017

411

Background: Reliable methods for the isolation of an enriched cancer stem cell (CSC) population in colorectal cancer (CRC) may provide new approaches for the identification of therapeutic targets. There is no consensus regarding the best methods to isolate a CRC tumor cell population enriched for CSCs. The goal of this study was to determine the utility of various CSC markers in both established cell lines and freshly isolated patient-derived tumor xenografts in order to validate methods of CSC isolation. Methods: Established human CRC cell lines (HCT116, HT29, SW480) and three freshly isolated CRC cell lines were studied. Freshly isolated cell lines were generated by first injecting CRC cells derived from clinical specimens into nude mice. Xenografted tumors were resected and FAC-sorted to isolate human cells. These cells were FAC-sorted for CD133, CD44, and ALDH activity. Tumorsphere formation and in vivo dilutional and serial tumorigenicity studies were done to validate methods for CSC enrichment. Results: Using established human CRC cell lines, none of the markers studied could be used to enrich for the CSC population as assessed by sphere formation or tumor initiating capacity; this suggests that cells grown in culture for long periods of time lose their hierarchy. In the freshly isolated CRC cells, CD133 and CD44 were unable to enrich for CSC-ness. In contrast, freshly isolated CRC cells with high ALDH activity formed spheres whereas cells with low ALDH activity did not. In validation studies, freshly isolated cells from patient-derived xenografts with high ALDH activity demonstrated enhanced tumorigenic capacity in murine models. Furthermore, the tumorigenicity of ALDH high cells was maintained after serial passage of cells harvested from tumors generated by ALDH high cells, while ALDH low cells did not form tumors. Conclusions: CRC cells from patient-derived tumor xenografts can be used to study CSC properties using ALDH activity as a marker. In contrast, CD44 and CD133 are not reliable markers for enriching for the CSC population from established cell lines or patient xenografts. Established CRC cell lines should not be used to study CSC biology.
Gastrointestinal cancer risk in Irish hereditary breast ovarian cancer families.
Authors: Gogarty Darragh S , Lyons Tomas , Farrell Michael P. , Dorman Naoise Maria , Green Andrew J , Gallagher David J.
Published: February 2017

413

Background: Colorectal and breast cancer are linked in certain predisposition syndromes such as Cowden and Peutz-Jegers syndrome. Breast cancer risk also appears increased in certain Lynch syndrome kindreds. Original reports suggested an increased risk of colorectal malignancies in BRCA1/2 mutation carriers. Two large studies in Ashkenazi Jewish populations subsequently contradicted this early evidence, although neither study was powered to address effects if each gene independently, or other modifier effects in certain families. We report the Irish experience of colorectal and gastro-esophageal (GE) cancer in hereditary breast ovarian cancer (HBOC) families. Methods: 97 HBOC families at two tertiary referral centres were reviewed for the presence of early onset GE malignancies. The medical records of individuals with GE cancer were reviewed to determine carrier status. Clinical data including age of diagnosis, stage, treatment and outcome were extracted. Median age of diagnosis and outcome were compared among BRCA1/2 mutation carriers and non-carriers. Results: We identified 30 individuals with GE malignancies in 97 HBOC families (19 with colorectal, 11 with gastric). Two families were excluded as Lynch syndrome was also diagnosed in these families. Definitive carrier status was available on 8 individuals. Additional 7 individuals were obligate carriers. Age at diagnosis ranged from 27-84 years (median=60). Median age of CRC diagnosis among carriers was 54 compared with 61 among non-carriers (p=0.20). Median age of gastric diagnosis among carriers was 66 compared with 53 among non-carriers. Conclusions: Early onset colorectal cancer occurs in certain HBOC families and may be related to mutation status. No genotype-phenotype association was identified in this study. An additional 150 Irish HBOC families are being screened for early onset GI malignancies and updated data will be presented at the meeting.
Predicting overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC) treated with chemotherapy (CT): The British Columbia Cancer Agency (BCCA) mCRC score.
Authors: Gresham Gillian , Cheung Winson Y. , Chan Matthew , Kim Jason , Renouf Daniel John
Published: February 2017

419

Background: Median OS of mCRC is 2 years, but the prognosis of individual pts can be highly variable. Our study objective was to develop a scoring system to improve the prognostication of mCRC pts at baseline assessment. Methods: Pts diagnosed with mCRC from 2006 to 2008, referred to 1 of 5 regional cancer centers in British Columbia, and received CT were reviewed. Pts with ECOG >3 were excluded due to their uniform poor prognosis. Univariate analyses were performed on baseline variables and those significantly associated with prognosis were included in a multivariate stepwise selection. Each significant factor was given a weighted score (range 1-5) based on the regression coefficients. Patients were assigned a composite risk score (range 0-15) based on their baseline variables, and then separated into quartiles for OS using cut-point analysis and Kaplan-Meier methods. Validation was conducted with the bootstrap technique. C-index statistic was 0.75, which indicated good discrimination. Results: A total of 505 mCRC pts were included: median age 63 (range 22-86), 58% male, 75% ECOG 0-1, 58% colon primary, 34% >1 metastatic site, and 46% smokers. Median pre-treatment CEA was 16.8 ng/ml. In this cohort, 64% were metastatic at presentation, 81% underwent primary tumor resection, 23% received prior adjuvant CT, and 72% were treated with palliative CT. ECOG 2-3 (HR 3.1, 95%CI 2.4-4.2), no primary resection (HR 2.3, 95%CI 1.6-3.3), colon primary (HR 1.6, 95%CI 1.2-2.1), >1 metastatic site (HR 1.6, 95%CI 1.2-2.1), CEA level >4 ng/ml (HR 1.2, 0.8-1.6), male (HR 1.2, 95%CI 0.8-1.6), and smoker (HR 1.4, 95%CI 1.0-1.8) were significant in the multivariate model and assigned points corresponding to their effect size. Median OS varied significantly depending on the composite risk score (Table). Conclusions: In this population-based analysis, the BCCA mCRC score was a simple method that used baseline variables to improve the prognostication of mCRC pts. This model requires external validation. [Table: see text]
The role of NF-κB pathway in cancer inflammation of esophageal squamous carcinoma.
Authors: Tzao Ching , Cheng Li-Yuan , Chang Chien-Chih , Sun Guang-Huan
Published: February 2017

42

Background: Chronic inflammation plays an important role in tumorigenesis and tumor progression in human cancers. We aim to investigate the role of NF-kB in cancer inflammation of esophageal squamous cell carcinoma (ESCC). Methods: To generate M2-polarized macrophages, cells of human U937 monocyte cell line were treated with phorbol myristate acetate (PMA, 50 ng/ml) for 6 hours, and then cultured with PMA plus Th2 cytokines, IL-4 (20 ng/ml) and IL-13 (20 ng/ml), for another 18 hours. M2 phenotype was verified by flow cytometry and by cytokine profiling using enzyme-linked immunosorbent assay (ELISA). After co-culture with M2 macrophages, transcription nuclear factor-kB (NF-kB) activity was measured using quantitative polymerase chain reaction (Q-PCR), followed by reconfirmation with Western blot analysis for IkBα in KYSE-170 and -510 ESCC cell lines (kindly provided by Dr. Yutaka Shimada at Kyoto University, Japan). A selective inhibitor to NF-kB, Bay11-7082, was used to treat ESCC cell lines co-cultured with M2 macrophages, followed by cell proliferation, migration, invasion assays and vascular endothelial growth factor (VEGF) secretion by ELISA. The effect of Bay11-7082 (5 mg/kg) against growth of ESCC tumor was tested in xenografted tumors. Results: PMA plus Th2 cytokines treatment promoted differentiation of U937 cells into M2 macrophages. When treated with Bay11-7082, proliferation, migration, invasion and induction of VEGF expression was significantly inhibited in M2 macrophage co-cultured ESCC cells with a down-regulation of IkBα expression. Tumor growth was significantly increased in M2 macrophage co-cultured ESCC cells compared to that of the non-co-cultured controls, which was significantly retarded by treatment with Bay11-7082. Conclusions: NF-kB pathway was activated in ESCC cell lines co-cultured with M2 macrophages with an increase in cell proliferation, cell motility and angiogenic factor in vitro and tumor growth in vivo, which were significantly suppressed by a NF-kB inhibitor, Bay11-7082. These results suggest a role of M2 macrophage in promoting aggressiveness of ESCC cells, possibly through an activation of NF-kB pathway that may serve as a potential therapeutic target for ESCC.
Deepness of response: A quantitative analysis of its impact on post-progression survival time after first-line treatment in patients with mCRC.
Authors: Mansmann Ulrich Robert , Sartorius Ute , Laubender Ruediger Paul , Giessen Clemens Albrecht , Esser Regina , Heinemann Volker
Published: February 2017

427

Background: The extent of tumor shrinkage in patients (pts) receiving chemotherapy +/- monoclonal antibodies has prognostic value for PFS and OS. "Deepness of response (DpR)" is a new efficacy outcome measure that could explain the impact of tumor shrinkage on long-term survival outcome. If shrinkage takes place DpR is the percentage of tumor shrinkage observed at the nadir compared to baseline. DpR is 0 for no change and negative if the tumor load increases. Longest diameter (LD) based on RECIST or a calculated tumor volume (ASCO GI 2012 #635) can quantify the tumor load at distinct time points. A joint model was presented (ASCO GI 2012 #580, ASCO 2012 #3603) which allows us to relate DpR to individual post-progression survival (PPS) time. Methods: Based on the data from 2 randomized trials (CRYSTAL, n=1198; OPUS, n=337), 4 treatment regimens (FOLFIRI +/- cetuximab and FOLFOX4 +/- cetuximab) were studied. A joint model was used to quantify individual changes in tumor size over time and to relate these changes to PFS and OS. Relationships between baseline tumor load and DpR and PPS were studied. Proper scoring rules were used to assess whether the LD-based or the volume-based approach allowed a better prediction of individual prognosis. Results: Results are reported for the CRYSTAL study using LD-based measures for 663 pts with KRAS wild-type tumors and imaging data. The 348 pts treated with FOLFIRI alone had a mean DpR of 35.52% (Interquartile range [IR]:12.09%, 59.86%), minimum DpR -80%. The 315 pts treated with FOLFIRI + cetuximab had a mean DpR of 50.07% (IR: 22.87%, 79.55%) and a minimum DpR of -49%. The DpR was significantly different between the 2 groups (p<0.00001). Individual DpR is a significant prognostic factor for PPS time in both the LD-based (p=0.0023) and volume-based (p=0.0003) models. Proper scoring rules provided evidence of a more precise estimation of individual PPS time based on volume algorithm-measured DpR. Results of the OPUS study will be presented. Conclusions: Our results emphasize the value of the variable DpR as a new efficacy outcome measure for clinical trials. The tumor-shrinking capacity of cetuximab was shown to be associated with its ability to prolong PPS.
Plasma concentrations of 5-FU and creatinine clearance as predictive markers for severe toxicities of capecitabine in patients with colorectal cancer.
Authors: Makihara Katsuya , Mishima Hideyuki , Azuma Sayaka , Miyagi Kazuyo , Komori Katsuya , Hasegawa Hiroko , Yasui Masayoshi , Ikenaga Masakazu , Tsujinaka Toshimasa
Published: February 2017

428

Background: Pharmacokinetically guided dose adjustment of 5-fluorouracil (5-FU) are available but management of capecitabine has not been established. Patients with renal impairment often experience severe adverse events. The aim of this study is to assess the relationship between plasma concentration of 5FU, metabolites after administration of capecitabine, renal function and adverse events. Methods: Plasma concentration–time data for capecitabine, 5’-DFUR, 5’-DFCR and 5-FU were analyzed by blood samples within 60–180 min after administration of capecitabine on day 8 in colorectal cancer patients receiving capecitabine based regimen (capecitabine with or without oxaliplatin and bevacizumab). Concentrations of 5-FU were analized by a nanoparticle antibody-based immunoassay for 5-FU(My 5-FUR assay). Correlation between the peak concentration of capecitabine metabolites (Cmax) or creatinine clearance (Ccr) and toxicity (grade 3–4 diarrhea, grade 2-3 hand–foot syndrome and grade 3–4 anorexia) were assessed. When parameter of correlation exists, logistic regression analysis was done. ROC (receiver operating characteristic) analysis was conducted to explore the cut off value of the parameter associated with severe adverse events. Results: A total of 42 patients were analyzed. The Cmax of 5’-DFUR, 5-FU and Ccr were significantly correlated with the incidence of severe adverse events. Cmax of 5-FU (p = 0.015) and Ccr (p = 0.016) were also independent parameters. According to the ROC analysis, severe adverse events were observed in the patients whose Cmax of 5-FU was higher than 295 ng/mL and Ccr was lower than 64.8 mL/min. Conclusions: Plasma concentration of 5-FU and renal function are good predictive markers of adverse events after capecitabine administration. These results would lead to the appropreate indivisual dosage adjustment of capecitabine.
Tumor cancer stem cell genetic profile as predictor of relapse in stage II and III radically resected colon cancer patients.
Authors: Giampieri Riccardo , Scartozzi Mario , Loretelli Cristian , Mandolesi Alessandra , Bittoni Alessandro , Faloppi Luca , Bianconi Maristella , Bearzi Italo , Cascinu Stefano
Published: February 2017

429

Background: Although disease stage is the most relevant factor influencing treatment choice in locally advanced radically resected colon cancer, it is not uncommon to observe disease relapse in patients with apparent low risk stage that are usually excluded from an adjuvant therapy. On the contrary we also know that some patients with high risk stage are not likely to relapse, independently from medical treatment received. Preclinical data suggested that cancer stem cells may influence the biological behaviour of many solid tumours including colorectal cancer, we then tested a panel of genetic markers of stemness in resected Dukes stage B and C colorectal cancer patients in order to define a prognostic profile. Methods: We performed k-means unsupervised clustering (K=2) using the mRNA expression data of 66 genes. The algorithm divided the patients into two groups (A and B). Most patients clustered in a manner consistent with relapse free survival, defined as the time between primary surgery and first radiological sign of metastatic involvement or patients death, whichever came first. Results: A total of 62 patients were analysed (36, 58% stage II and 26, 41% stage III), 36 (58%) patients relapsed during the follow-up period (range 1.63-86.5 months). Respectively 12 (19%) and 50 (81%) patients were allocated into group A and B. A significantly different median relapse-free survival was observed between the 2 groups (22.18 vs 42.85 months, p=0.0296). Interestingly, even if group A had a worse outcome in terms of risk of relapse, an higher proportion of stage II patients could be found in this group (83%) when compared with the group B (52%). Among tested genes, those with the highest capability in determining allocation into one of the two groups were CD44, ALCAM, DTX2, HSPA9, CCNA2, PDX1, MYST1, COL1A1 and ABCG2. Conclusions: This analysis supports the idea that, other than (or maybe more than) stage, biological variables, such as expression levels of colon cancer stem cell genes, may be relevant in determining an increased risk of relapse in resected colorectal cancer patients. Our findings may also be relevant for new treatment strategies targeting tumour stem cells genetic profile.
Microenvironment and cytokines in pseudomyxoma peritonei.
Authors: Lohani Kush Raj , Shetty Shreya Jagadish , Judge Sean J. , Venkatesh Govindarajan , Thomas Peter , Loggie Brian W.
Published: February 2017

433

Background: Pseudomyxoma Peritonei (PMP), a peritoneal mucinous neoplasm of appendix origin, is associated with inflammation and fibrosis which is central to the disease biology. Here, we examine possible biomarkers or regulators of PMP biology in peritoneal tumor microenvironment and in serum. Methods: Ascites, peritoneal washings and serum were collected from PMP patients. Cytokines and C-reactive protein (CRP) levels were determined using Milliplex immunoassays. Immunohistochemistry (IHC) was performed on formalin-fixed tissue sections. Statistical analysis was performed by the Mann Whitney U test and Bivariate analysis. Results: Serum CRP was significantly elevated in PMP patients (n=29) versus controls (n=4) (0.124 vs 0.004 mg/dl, p = 0.003). CRP levels were lower in ascites (0.028 vs 0.124 mg/dl, p = 0.014), but correlated with serum levels (R = 0.65, p < 0.001). Cytokines typically elevated after infection or injury—TNF-α, IL-1α, IL-1β and γ INF—were not significantly elevated in PMP ascites; however, IL-6, IL-8, IP-10 and MCP-1 were consistently higher (p < 0.001) in PMP with ascites (n=29) when compared to control peritoneal washings (n=9). Both serum and ascites from 10 patients were evaluated for these four cytokines. Ascites levels were significantly elevated compared to their respective serum for IL-6 (1107 vs 3.18 pg/ml, p < 0.001), IL-8 (167 vs 1.59 pg/ml, p < 0.001), IP-10 (5454 vs 504 pg/ml, p < 0.001) and MCP-1 (2420 vs 234 pg/ml, p = 0.002) but the serum levels were not significantly elevated compared to controls (n=6) (p = 0.31, 0.2, 0.63, 0.37 respectively). IHC revealed staining for IL-6 and IL-8 in stromal cells and focal staining of tumor for IP-10 and MCP-1. Recombinant IL-6-treated LS174T cells (mucinous colon cancer cell line) showed increased proliferation (p<0.009) which was inhibited by anti-IL-6 antibodies (p<0.004). Conclusions: CRP, a liver-synthesized marker of systemic inflammation, is elevated in PMP, and may have clinical utility. The results support local synthesis for cytokines IL-6, IL-8, IP-10 and MCP-1 in the peritoneum. Interestingly, the pattern of cytokines appears to be distinct from those following injury or infection. Further studies may yield novel targets for future treatment.
Does conversion chemotherapy really improve survival in patients with colorectal liver metastases?
Authors: Kataoka Kozo , Kanazawa Akiyoshi , Iwamoto Shigeyoshi , Miyake Yasuhiro , Kato Takeshi , Nakajima Akio , Arimoto Akira , Kono Yukihiro
Published: February 2017

435

Background: Recently, liver resection becomes possible by intensive chemotherapy, i.e. conversion chemotherapy, in patients with initially unresectable colorectal liver metastases (CLM). But the criteria for non-resectability varies one team to another, and there are few reports about the clinical benefit of conversion chemotherapy followed by liver resection. Methods: Our criteria for resectability of CLM depends on the size of remnant liver volume (>30%) and expected function after the removal of all metastases, regardress of number and size of CLM. From December 2007 to September 2011, 113 patients were diagnosed as CLM without extra-hepatic metastases and received chemotherapy. 47 patients were initially diagnosed as resectable and received hepatic resection after chemotherapy (resected group). 66 patients were initially diagnosed as unresectable, but 11 patients become resectable after chemotherapy (conversion group) and 55 patients remain unresectable in spite of chemotherapy (unresecetd group). We assessed the survival benefit between these 3 groups, retrospectively. Results: 110 patients received oxaliplatin-based regimen and 3 irrinotecan-based regimen. In coversion group, 8 patients received cetuximab containing regimen and 2 received bevacizumab containing regimen. 46 of 47 patients in resected group received R0 resection and 7 of 11 patients in conversion group. No serious postoperative complications were observed in resected and conversion group, but the incidence of a surgical site infection in conversion group was somewhat higher than in resected group. Median disease-free survival was significantly higher in the resected group than conversion group (16.73 months [95% CI: 7.80~25.47] and 3.83 months [95% CI: 0.35~7.31 months]) (P=0.031). And median overall survival (OS) was also higher in resected group, but not significant. In resected and conversion group, median OS was significantly higher than in unresected group. (52.20 vs 39.37 vs 20.57 months (p <0.001)). Conclusions: The recurrence rate was higher in coversion group, but conversion chemotherapy followed by hepatic resection seems to be promising and feasible strategy in initially unresectable CLM patients.
Correlation of production of IL-17 with immune suppression relating myeloid-derived suppressor cells (MDSC) and nutritional damages in patients with digestive system cancer.
Authors: Gonda Kenji , Shibata Masahiko , Yazawa Takashi , Yashima Rei , Kimura Takashi , Kenjo Akira , Nakamura Izumi , Ohki Shinji , Anazawa Takayuki , Tsuchiya Takao , Shimura Tatsuo , Koyama Yoshihisa , Gotoh Mitsukazu , Takenoshita Seiichi
Published: February 2017

437

Background: Although a causal relationship between inflammation and innate immunity of cancer is more widely accepted today, many of the precise cellular mechanisms mediating this relationship remain unclear. Th17 cells, which produce the proinflammatory cytokine IL-17, have been recognized as one of the key factors in regulation of inflammatory bowel disease and rheumatoid arthritis. Methods: This study demonstrated that, in patients with digestive system cancers including 7 patients with esophageal, 14 with gastric, 20 with colorectal, 5 with hepatocellular, 7 with cholangiocellular, and 7 with pancreatic carcinomas, IL-17 production was correlated with MDSC level and with markers for nutritional impairment, immune suppression and chronic inflammation. Results: IL-17 production was significantly higher in patients with all types of digestive cancer than in normal volunteers. In addition, IL-17 production levels were significantly correlated with neutrophil counts and the neutrophil/lymphocyte ratio, and significantly inversely correlated with cell mediated immune response indicators (lymphocyte PHA-blastogenesis and IL-12 production) and patients’ nutritional status (prealbumin levels). Circulating MDSC levels were significantly correlated with IL-17 production. Conclusions: These results suggest that, in human gastrointestinal cancers, chronic inflammation involving IL-17 may be an important mechanism for disease progression through enhancement of immune suppression or cachexia. Controlling activation of Th17 cells may prove to be a valuable strategy for treatment of patients with gastrointestinal cancer.
Surgical practice patterns and long-term survival for early-stage rectal cancer.
Authors: Stitzenberg Karyn Beth , Penn Dolly , Sanoff Hanna Kelly , Meyers Michael O.
Published: February 2017

459

Background: Local excision (LE) is considered a standard option only for patients with T1N0 rectal cancer and those who are medically unfit for proctectomy. The growing numbers of case series suggest that use of LE may be increasing. The objectives of this study are to characterize practice patterns for surgical management of rectal cancer and determine the comparative effectiveness of LE versus proctectomy for overall survival (OS) for Stage I rectal cancer. Methods: National Cancer Database data were used to identify all patients with rectal cancer diagnosed from 1998-2010. Patient and tumor characteristics associated with procedure type were examined. Kaplan-Meier plots and Cox proportional hazards models, controlling for patient and tumor characteristics and receipt of radiation (XRT), were used to compare OS for Stage I cases from 1998-2005. Results: 147,553 (50%) of 296,068 cases were excluded due to prior malignancy, non-invasive disease, distant metastases, failure to receive definitive surgery, treatment indicated to be palliative, or receipt of neoadjuvant therapy. 76,756 (69%) cases were treated with proctectomy and 34,697 (31%) with LE. Use of LE steadily increased from 23% in 1998 to 41% in 2010, p<0.001. LE was most commonly used for Stage I cases. Women, older patients, patients with less comorbidities, black patients, uninsured patients, and those with T1 tumors were more likely to receive LE than other Stage I patients. Socioeconomic status and rurality were not associated with use of LE. Adjuvant XRT was used for 12% of T1 tumors and 46% of T2 tumors after LE and 5% of T1 tumors and 12% of T2 tumors after proctectomy. For patients with T1N0 tumors, adjusted OS was associated with receipt of proctectomy (HR 0.83; 95%CI 0.77, 0.89) but not XRT. For patients with T2N0 tumors, adjusted OS was associated with both proctectomy and XRT: LE only HR 1.0; proctectomy only HR 0.70; LE+XRT HR 0.70; proctectomy+XRT HR 0.70. Conclusions: Use of LE for rectal cancer is increasing. LE alone is associated with poorer long-term OS than proctectomy. For patients with larger tumors, those that receive adjuvant XRT in addition to LE have significantly better OS than those who receive LE alone.
Phase I study of the HSP90 inhibitor AUY922 in combination with capecitabine as treatment for patients with advanced solid tumors.
Authors: Bendell Johanna C. , Hart Lowell L. , Pant Shubham , Infante Jeffrey R. , Jones Suzanne Fields , Mohyuddin Adil , Murphy Patrick , Patton Jeffrey , Penley William Charles , Thompson Dana Shelton , Burris Howard A.
Published: February 2017

475

Background: Heat shock protein 90 (HSP90) is a molecular chaperone involved in the maintenance and function of client proteins, many of which are integral to key oncogenic processes. AUY922 is a competitive inhibitor of HSP90, with demonstrated activity in a variety of preclinical models. Further preclinical evidence suggests potential synergy between inhibition of HSP90 and fluorouracil treatment (Burkitt et al. 2007). This phase I study was designed to determine the maximum tolerated dose (MTD) of AUY922 in combination with standard dose of capecitabine as treatment for patients with advanced solid tumors. Methods: Patients with refractory solid tumors for which capecitabine was an appropriate therapy received AUY922 with capecitabine in a standard 3+3 dose escalation. Capecitabine 1000mg/m2 was administered twice daily for days 1-14 of 21-day cycles, with escalating doses of AUY922 administered by intravenous (IV) infusion on days 1, 8, and 15; the 6th dose level combined the MTD of AUY922 with capecitabine 1250mg/m2. Dose-limiting toxicities (DLTs), safety, and efficacy were evaluated. Results: 23 patients were treated at 6 dose levels: 22mg/m2 (n = 3); 28mg/m2 (n = 3); 40mg/m2 (n = 3); 55mg/m2 (n = 5); 70mg/m2 (n = 3); 70mg/m2 with capecitabine 1250mg/m2 (n = 6). There were no DLTs observed until the 6th dose level (grade 3 diarrhea). Common adverse events (all grades) included: diarrhea (61%), nausea (57%), fatigue (43%), hand-foot skin reaction (39%), anorexia (39%), vomiting (35%), rash (30%), and darkening vision (22%). Myelosuppression was uncommon, with no instances of grade ≥3 thrombocytopenia, and only 2 patients (9%) with grade 3/4 neutropenia (1 patient each). Of the 19 patients evaluable for response per RECIST 1.1, unconfirmed partial response (PR) was noted in 3 patients (13%; colorectal, 1; breast, 1; stomach, 1), with 1 additional confirmed PR (4%; colorectal); two of these had progressed on prior fluorouracil. Stable disease was noted in 8 patients (35%). Conclusions: The addition of AUY922 to standard dose capecitabine was well-tolerated at doses of up to 70mg/m2. Preliminary efficacy is encouraging, and warrants further investigation of this regimen. Clinical trial information: NCT01226732.
Preclinical activity of MM-111, a bispecific ErbB2/ErbB3 antibody in previously treated ErbB2-positive gastric and gastroesophageal junction cancer.
Authors: Lahdenranta Johanna , Paragas Violette , Kudla Arthur J. , Overland Ryan , Moyo Victor M. , Nielsen Ulrik , McDonagh Charlotte , Onsum Matthew
Published: February 2017

48

Background: ErbB2 (HER2) overexpression has been reported in 7-34% of gastric cancers. ErbB3 (HER3) is the preferred dimerization partner of ErbB2, and ErbB2/ErbB3 heterodimer activation is implicated in the progression and metastasis of ErbB2+ tumors. Activation of ErbB3 signaling is a postulated resistance mechanism to current ErbB2-directed therapies and select chemotherapies. In line with this research, ErbB3 levels are associated with poor prognosis in gastric cancers. MM-111 is a bi-specific antibody that docks to ErbB2 and inhibits ErbB3 signaling in cells that overexpress ErbB2. In this study, MM-111 was evaluated in ErbB2+ gastric cancer by testing the activity of MM-111 in ErbB2+ pre-clinical models of gastric cancer, and by assessing the prevalence of potentially predictive biomarkers in a panel of archived gastric and gastroesophageal junction (GEJ) tumors. Methods: MM-111 was tested in ErbB2+ gastric cancer xenografts that were either untreated or after tumors ceased to respond to trastuzumab/5-FU. Xenografts were analyzed at multiple time points for the expression of ErbB-receptor family members and their downstream signaling by Luminex -assays. Preclinical data indicate that ErbB2, ErbB3, and heregulin are predictive biomarkers for MM-111. In order to determine the prevalence of our potentially predictive biomarkers in gastric and GEJ cancers, we obtained commercially archived tumor tissue and assayed the tissue for ErbB2 and ErbB3 expression levels using quantitative IHC, and measured heregulin transcript levels by RT-PCR. Results: MM-111 synergizes with various treatment regimens in the 2nd line treatment setting in ErbB2+ gastric cancer xenografts. In our models, the combination of MM-111, trastuzumab, and paclitaxel is particularly effective after tumors progressed on trastuzumab/5-FU. MM-111 inhibits the activity of the ErbB –signaling axis in these models. In addition, 23% of GEJ tumor samples and 20% of gastric samples were positive for potentially predictive biomarkers. Conclusions: ErbB2+xenograft tumors that stop responding to trastuzumab-based therapies benefit from MM-111–based regimens.
Phase II study of sorafenib and capecitabine (SorCape) in previously treated metastatic colorectal cancer (mCRC): NCT01471353.
Authors: George Thomas J. , Ivey Alison Marguerite , Dang Long H. , Daily Karen Colleen , Hou Wei , Viviano Dana Lynn , Watson Scott , Granicz Renee , McEwan Margaret A. , Yan Hui , Allegra Carmen Joseph
Published: February 2017

489

Background: Sorafenib (Sor) is an oral multi-tyrosine kinase inhibitor (TKI) affecting tumor proliferation and angiogenesis through inhibition of the Ras/Raf/MEK/ERK, VEGF and PDGF pathways. Inhibition of the MEK/ERK pathway through Raf has been shown to resensitize tumor cells resistant to chemotherapy. A similar TKI, regorafenib, has recently demonstrated efficacy as monotherapy in advanced mCRC. Demonstrating activity of this class of compounds with standard cytotoxic therapy represents a clinical unmet need for patients (pts) with mCRC. Methods: Eligible pts had progressive mCRC after prior oxaliplatin and irinotecan, at least 1 measurable target lesion by RECIST, ECOG PS 0-1, and adequate organ function. Pts received Cape (1000mg/m2PO BID D1-14) and Sor (400mg PO BID max via dose escalation per cycle). Cycles were q21d with tumor assessments q9w. Endpoints included progression-free survival (PFS), objective and biochemical response rates, overall survival (OS), toxicity, and quality of life. Sample size was based on a 50% improved median PFS from 3 (historical) to 4.5 months (m). Results: 24 of 43 planned pts have received therapy. 19 were white and 17 male. Median age 61y (37-79). 14 (58%) were KRAS-mut. Median prior lines of therapy for mCRC was 3 (1-5). All but one had liver and/or lung metastases. Most frequently observed adverse events (AEs) included fatigue (29%), HTN (38%), and HFS (91%). 18 pts (75%) had a grade 3 AE (11/18 were HFS). There were no grade 4 or 5 toxicities. Preliminary PFS is 4.1m. 5/16 (31%) evaluable pts have radiographic stable disease. Conclusions: Enrollment continues with manageable AEs, despite the overlapping toxicity of HFS. Preliminary PFS data appears promising in this refractory mCRC population. Clinical trial information: NCT01471353.
Prospective analysis of UGT1A1 promoter polymorphism for irinotecan dose escalation in metastatic colorectal cancer patients treated with bevacizumab combined with FOLFIRI as the first-line setting.
Authors: Yeh Yung-Sung , Huang Meng-Lin , Lu Chien-Yu , Wang Jaw-Yuan
Published: February 2017

491

Background: Infusional fluorouracil/leucovorin plus irinotecan-based regimen (FOLFIRI) with bevacizumab has been widely used as first-line treatment for patients with metastatic colorectal cancer (mCRC). We prospectively analyzed the influence of uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) genotyping for irinotecan dose escalation in mCRC patients treated with combination of FOLFIRI and bevacizumab as the first-line setting. Methods: A total of 65 mCRC patients undergoing first-line treatment with FOLFIRI combined with bevacizumab were analyzed. Genotypes were performed by analyzing the sequence of TATA box of UGT1A1 of genomic DNA from the patients. Genotype and clinical parameters were compared by univariate analysis. The irinotecan dose is escalating form 180 mg/m2 to 260 mg/m2 in UGT1A1 6/6 or 6/7, and from 120 mg/m2 to 210 mg/m2 in UGT1A17/7. Results: The response rate was observed in 44 of 60 UGT1A1 6/6 or 6/7 (73.3%) in comparison to 1 of 5 UGT1A1 7/7 (20%) patients (p=0.013). The grade III-IV adverse events (AE) was observed in 4 of 60 UGT1A1 6/6 or 6/7 (6.7%) in comparison to 3 of 5 UGT1A1 7/7 (60%) patients (p<0.001), but it was not different between age of ≥ 70 and < 70 (p=0.559). Fifteen of 60 (20%) patients with UGT1A1 6/6 or 6/7 could be performed with liver or lung metastaectomy in comparison to none of 5 patients with UGT1A1 7/7. In addition, the disease control rate was significantly higher in irinotecan dose of ≥ 210 mg/m2 than irinotecan dose of < 210 mg/m2(p=0.015). Conclusions: UGT1A1 promoter polymorphism was found to be predictive of toxicity and efficacy in mCRC patients with first-line treatment of FOLFIRI combined with bevacizumab. The higher dose of irinotecan (≥ 210 mg/m2) may achieve a better disease control rate but do not increase the incidence of GR III-IV AE in mCRC patients of age ≥ 70 years.
Differences in outcome between right- and left-sided colon cancer: A population based study.
Authors: Aarts Frits , de Hingh Ignace , de Wilt Johannes HW , Lemmens Valery E. P. , Verhoeven Rob H.A.
Published: February 2017

493

Background: Colon cancer is the second most frequent cause of cancer death, with an increasing incidence during the last decade. Recently, there is an increased interest in possible differences in outcome after surgery between right- and left-sided colon carcinoma (RCC and LCC). Methods: A population based study was performed in the south part of the Netherlands covering a region with more than 2 million inhabitants. Patients suffering from either RCC or LCC, excluding rectal cancer, were compared with regard to epidemiological, clinical and histological parameters as well as survival data. A Cox proportional hazard model was used to estimate the impact of different parameters on survival. Results: The data of 12,731 patients with colon cancer from January first 2000 and December 31 2010 were analyzed. Of these, 42% was RCC and 55% was LCC. In the remaining 3% of patients the location was not otherwise specified. In comparison with LCC, the majority of RCC patients were female (53% vs. 46%) and older (42% vs 34% > 75 years). The majority of RCC (77%) and LCC (87%) was non-mucinous adenocarcinoma. In RCC, 18% of tumors were mucinous adenocarcinoma vs 10% in LCC, p< 0.001. Well differentiated tumors were more common in LCC, 70% vs 58% in RCC Moderately and poorly differentiated tumors were more present in RCC compared to LCC (23% vs 13%, p<0.0001). Stage I tumors were more common for LCC vs stage II-IV tumors in RCC, p<0.0001. In RCC 1-9 lymph nodes were found in 37% vs 51% in LCC. In RCC 49% >10 LN were found vs 34% in LCC. No difference was found between anatomical sites regarding tumor positive LN, nor in LN ratio. Synchronous distant metastases were present in 30% of RCC vs 25% in LCC. Median overall survival in RCC was 46 months vs 60 months in LCC, p<0.0001. Survival differed between age groups and location and was worse for RCC with age 45-59 yrs: RCC vs LCC p<0.0008, age 60-74 yrs: RCC vs LCC, p<0.0006). Also, in T4 tumors, survival was worse for RCC, p<0.007. Conclusions: Prognosis of colon carcinoma is correlated to anatomical distribution with a significantly worse prognosis for RCC patients. Since RCC is more common in people of older age and the incidence is increasing, these findings may have future implications for the planning of treatment strategies.