bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mucinous neoplasms of the appendix: A single-center experience.
Authors: Guo Sharon , Barry Maura Meredith , Hajdu Cristina , Cohen Deirdre Jill 
Published: February 2017

368 Background: Appendiceal neoplasms are poorly understood and represent less than 0.5% of all gastrointestinal cancers. We describe the presentation, pathologic characteristics, and treatment interventions that may have affected patient (pt) outcome. Methods: This is a retrospective review of pts with appendiceal neoplasms treated at NYU Medical Center and/or NYU Cancer Center between 2002-2011. Pt demographics and medical history were collected, including pathology reports, operative findings, imaging studies, treatment and outcomes. Results: 41 consecutive pts with varying stages of appendiceal cancer were identified (70.7% female, median age 57). Most common presentations included: 15 (36.6%) gynecologic complaints, 12 (29.2%) acute appendicitis, and 11 (26.8%) abdominal symptoms. Histologic subtypes were 27 (65.9%) mucinous cystadenomas and 14 (34.1%) adenocarcinomas of which 12 (29.3%) were mucinous adenocarcinoma and 2 (4.9%) were signet cell mucinous adenocarcinoma. Distribution of stages was: 27 (65.9%) stage 0, 2 (4.9%) stage I, 2 (4.9%) stage IIA/B, 6 (14.6%) stage IVA, and 4 (9.8%) stage IVB. All pts underwent one or more of the following procedures: appendectomy (n=39), colectomy (n=9), bilateral salpingo-oophorectomy (n=4), other (n=1). 9 of 10 stage IV pts underwent debulking, of those 2 had suboptimal debulking. 1 stage II pt and 4 stage IV pts (all mucinous adenocarcinoma subtype) received hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin-C (all female, median age 39). In contrast, 6 stage IV pts (2 signet cell adenocarcinoma, 4 mucinous adenocarcinoma subtypes) did not receive HIPEC (67% female, median age 80). 1 pt received systemic 5FU based chemotherapy in addition to HIPEC (female, age 39). Median overall survival (mOS) for all pts ≥ stage II is 32 months. mOS in pts ≥ stage II who did not receive HIPEC is 8 mo whereas mOS in pts ≥ stage II who received HIPEC has not been reached. Conclusions: Appendiceal cancer is frequently detected as an incidental finding for gynecologic and abdominal complaints or presents as acute appendicitis. Surgery is the mainstay of treatment for this disease. Additional therapy including HIPEC may be of benefit in select advanced stage patients.
Racial disparities and the outcome of metastatic (met) colorectal cancer (CRC).
Authors: Barzi Afsaneh , Shabihkhani Maryam , Yu Steven , Yang Dongyun , Ji Lingyun , Lenz Heinz-Josef 
Published: February 2017

373 Background: Over the past decade survival of patients (pts) with CRC has improved. Although, the mortality rate for CRC is lower in Hispanics (H) than Whites (W), the decrease in mortality has been smaller among H during this period. H are the largest and minority in U.S. and therefore it is important to explain the discordant improvement in their outcome from CRC. We conducted a retrospective review of our CRC pts to determine whether treatment (TX) related factors would explain the observed difference in the outcome. Methods: Data for pts treated with at least one cycle of chemotherapy (CT) in the first line setting for met CRC at Los Angeles County Hospital and Norris Cancer Center between 2004 and 2011 were collected. Pts, disease, and TX related factors were reviewed and included for analysis. H were compared to non-Hispanics (NH) including Asians (A), Blacks (B), and W as a group and to W. Descriptive statistics were used to describe the population and where appropriate chi-square, Wilcoxon, and log-rank tests were used for comparison between the groups. Results: A total of 190 pts, 53% H, 24% A, 10% B, and 13% W were included for analysis. The median age of the population was 55 (21-82) years. 72 % of pts had de-novo met disease. 47% of patients had left, 24% right sided, and 29% rectal cancer. One-third of the patients received bevacizumab in the first line setting. Median time (MT) from first symptom to presentation was 85 days (d); 87 d in H and 74 d in NH (P=0.57). MT from diagnosis to TX was 70 d; 72 d H and 69 d NH (P=0.79). The median time from first TX to progression (TTP) was 8.9 (95% CI: 9.9-12.9) months (m) in H, 11.5 m in NH (P=0.058), and 12.6 m in W (P=0.079). Median BMI was 25.6; 26.5 in H, 24.1 in NH (P=0.001). There was no significance statistical difference between site of the disease, type and number of cycles of CT among the groups. Conclusions: Despite similar access to care in H and NH in our cohort, TTP is shorter for H than NH and W. Although the P is nonsignificant in this small sample, the trend is intriguing. The results need to be confirmed in larger cohorts and prospective studies. Given that the TX for met CRC is mostly unchanged since 2004, the results suggest an inherent biological difference between H and NH with obesity playing a significant role in the outcome.
Stratification of patients with colorectal cancer of UICC stage II using prognostic mutations signatures obtained by deep amplicon sequencing of cancer genes.
Authors: Rosenthal Andre , Ridwelski Karsten , Marusch Frank , Pross Matthias , Mantke Rene , Manger Thomas , Pertschy Jörg , Buthut Thomas , Gellert Klaus , Gruetzmann Robert , Engelhardt Holger , Nartschik Peter , Koll Rainer , Kretschmar Karin , Kretschmar Karl-Heinz , Drescher Bernd , Stecker Katrin , Raspe Ricado , Klaßen Susanne , Adams Hans-Peter 
Published: February 2017

377 Background: Assignment of patients (pts) with UICC-stage II colorectal cancer (CRC) to adjuvant therapy remains controversial. The clinical utility of histo-pathological parameters (pT4, L+, V+) as well as tumor RNA expression signatures like Oncotype Dx Colon Cancer Assay, ColoPrint, or Predictor C is low given their positive predictive value (PPV) of 0.13, 0.22, 0.19, and 0.33, respectively, when adjusted to an incidence of 10% for occurrence of metastatic disease (mets) within 3 years after diagnosis. Methods: We applied deep amplicon sequencing of 48 well-known cancer genes to DNA samples of primary tumors from 173 pts with UICC-stage II CRC using the Illumina MiSeq technology. Patients were selected from a prospective, multicenter clinical diagnostic study named MSKK. More than 6,500 patients with CRC have been recruited into this study conducted by 39 hospitals in Germany. 79 of the 173 pts had progression of disease events within 3 years after R0 resection including 40 pts with mets, 12 pts with local recurrences, and 27 pts with secondary malignancies. 94 pts remained progression-free. Results: Deep sequencing revealed a total of 2,221 sequence variations (SV) including missense, stop, InDel, noncoding, nonsense SV. 401 SV were in COSMIC, 750 SV in normal tissue. The remaining 1471 SV served as basis for development of SV-signatures (SVS) for prediction of progression events in a classical double-nested bootstrap approach in order to generate second order unbiased estimates of performance of SVS, namely sensitivity(S+), specificity (S-), PPV, and negative predictive value (NPV). The best SVS for prediction of metastases contained SV in less than 15 genes and has a S+ of 0.41, S- of 0.93, PPV of 0.40, and NPV of 0.93 (incidence of metastasis: 10%). The best SVS for prediction any progression event has a S+ of 0.33, S- of 0.93, PPV of 0.54, and NPV of 0.84 (incidence for any progression = 20.5%). Conclusions: This deep sequencing based prognostic tissue test with a PPV of 40% and a NPV of 93% represents a milestone over prognostic tests based on RNA expression. The increased PPV leads to more patients being treated correctly with adjuvant therapy.
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.