bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serum C-reactive protein levels and colorectal cancer mortality.
Authors: Goyal Abhishek , Siegel Abby B. 
Published: February 2017

360 Background: Chronic inflammation has been causally linked to colorectal cancer (CRC), and use of NSAIDs has been associated with reduced risk. Prediagnostic C-reactive protien (CRP) levels, a highly sensitive marker of inflammation, have been weakly associated with increased CRC incidence. However, their relationship with CRC mortality has not been studied well. We hypothesized that elevated baseline CRP levels in general population will predict increased CRC mortality. Methods: This cohort study used CRP data from the Third National Health and Nutrition Examination survey, 1988-94 (NHANES III), with follow-up through 2006. Of the 15,832 eligible adults, NHANES III classified 65% as having CRP levels below detection (≤0.21mg/dL). Using this as the reference, we categorized the remaining participants in three approximately equal groups, and calculated hazard ratios for CRC, all-cancer mortality excluding CRC, and overall mortality due to non-cancer causes. Results: Median follow-up period was 14.2 years. In age adjusted (not shown) and multivariable adjusted models (Table), we observed strong, dose-response associations between CRP levels and CRC mortality. Associations between CRP levels and mortality due to other causes were much weaker. Conclusions: In this large, representative study of U.S. adults, we obtained significantly higher HRs for CRC mortality, as compared to mortality from other cancer and non-cancer causes, making these results unlikely to be explained by residual confounding or other biases. Further, since mortality is a function of both incidence and survival, it provides a more valid estimate of the prognostic value of CRP compared to incidence alone. Further evaluation of CRP may help stratify high risk groups for screening and prognosis, and potentially identify those who might benefit from anti-inflammatory therapy. [Table: see text]
Prostate cancer incidence in males with Lynch syndrome.
Authors: Haraldsdottir Sigurdis , Hampel Heather , Wei Lai , Wu Christina Sing-Ying , Bekaii-Saab Tanios S. , De La Chapelle Albert , Goldberg Richard M. 
Published: February 2017

366 Background: Lynch syndrome (LS) is caused by germline mutations in DNA mismatch repair (MMR) genes and increases the risk of colon and several other cancers. Prostate cancer is not currently considered part of the LS-tumor spectrum. The objective of this retrospective study was to assess whether the incidence of prostate cancer is increased above that of the general population in MMR mutation carriers. Methods: Patients who were identified as MMR mutation carriers and included in previous LS studies or evaluated at the genetics clinic at The Ohio State University were contacted and their cancer history documented. Follow-up time was defined as the time between their first index cancer or their entry onto the LS studies until the last date of follow-up or date of death, whichever came first. The prostate cancer incidence was adjusted for age and race and compared to that of the SEER registry of 1999-2009. A standardized rate ratio (SRR) was obtained by comparing the observed rate to the expected rate. Results: 186 males (median age 49 years, range 17-83) were identified as MMR mutation carriers either by testing (95%) or as obligate carriers (5%) in 94 families. Their mean follow-up time was 5.1 years (SD+/-6.0 years) with a total of 938 person-years (p-ys). Caucasians comprised 95.1% of the cohort, African-Americans 3.8% and Asians 1.1%. Of the patients who were tested for mutations, MSH2 was most commonly mutated (49.2%), followed by MLH1 (23.7%), PMS2 (14.7%) and MSH6 (12.4%). Ten patients (5.4%), all Caucasian, were diagnosed with prostate cancer at a median age of 59 years (range 52-82). 7 patients were identified as MSH2 carriers, 2 as MSH6 carriers and 1 as a PMS2 carrier. The observed incidence rate was 102.8 cases per 100,000 p-ys versus the expected number of 158.2 cases per 100,000 p-ys, the standardized rate ratio was 0.65 (95% CI 0.53-0.79). Conclusions: Prostate cancer incidence was not increased in this relatively large cohort of LS patients.
Long-term efficacy and pharmacodynamic parameter analysis in pretreated KRAS-mutant metastatic colorectal carcinoma (mCRC) patients treated with RG7160 (GA201), an antibody-dependent cellular cytotoxicity (ADCC)-enhanced monoclonal anti-EGFR antibody.
Authors: Delord Jean-Pierre , Tabernero Josep , Garcia-Carbonero Rocio , Cervantes-Ruiperez Andres , Gomez-Roca Carlos Alberto , Berge Yann , Capdevila Jaume , Corral Jaime Jesus , Roda Perez Desamparados , Golding Sophie , Oppenheim David , Soehrman Brossard Sophia , Mancao Christoph , Farzaneh Farzin , Passioukov Alexandre , Manenti Luigi , Ott Marion Gabriele , Soria Jean-Charles 
Published: February 2017

379 Background: EGFR-positive, KRAS-mutant mCRC patients (pts) do not benefit from anti-EGFR treatment. In this pt population we investigated the efficacy of single-agent GA201, a novel dual acting, anti-EGFR antibody which was glycoengineered to enhance ADCC on top of signaling blockage. This stimulation of immune effector cells may improve long term clinical outcomes. Methods: In an open-label, multicenter, non-randomized study, KRAS-mutant mCRC pts (1-2 prior chemotherapy lines) were treated with GA201 (1400 mg on day 1 and 8 then by 1400 mg q2W). The primary endpoint was to investigate tumor response. Here we report response rates, overall survival (OS) and pharmacodynamics analyses from archival, pre- and on-treatment biopsies and blood samples. Results: 25 pts received a median of 5 GA201 infusions (range 2–24), for up to 414 days. Median overall survival was 9.3 months (range 1.2 – 21.2). Best overall response was stable disease (40% of patients at 8 weeks), which was maintained in 24% of pts at 16 weeks, in 2 patients (8%) at 24 weeks and 1 pt (4%) at 42 weeks. Treatment-related adverse events were all manageable with rash (20% grade3), hypomagnesaemia (20% g3/4) and infusion-related reactions (4% g3) being the most common adverse events; none led to discontinuation or dose reduction. Comparison of pre- and post-treatment tumor biopsies evaluable for 11 pts revealed that tumor-infiltrating cell counts increased notably after one cycle of therapy (median composite immune reactive score of 1491 vs 898 cells/mm3 at baseline). In addition, it was noted that EGFR H-score in baseline tumor biopsies was notably higher than in archival tumors (median [range] 52 [13–161] vs 3 [1–81], respectively). High tumor immune cell infiltration at baseline might be associated with better treatment outcome and long-term survival. Conclusions: Encouraging OS is achieved with GA201 monotherapy in patients with KRAS-mutant tumors. The pharmacodynamics analyses support the hypothesis of triggering an enhanced long term immune response in this pretreated patient population. Clinical trial information: NCT00721266.
Blood-based screening for methylation changes in colorectal cancer patients using novel nanotechnologies.
Authors: Ahuja Nita , Kwak Ruby , Keeley Brian , Stark Alejandro , Guzzetta Angela Anna , Wolfgang Christopher Lee , Herman James Gordon , Iacobuzio-Donahue Christine A , Wang Tza Huei 
Published: February 2017

384 Background: Identification of blood-based biomarkers for cancer screening is essential in order to develop novel and minimally invasive methods for colorectal cancer screening. Our lab has successfully applied a novel nanotechnology that allows us to detect and amplify a single tumor DNA fragment in a plasma sample. This DNA is tested for methylation of several genes including TFPI2 which has shown to be highly sensitive and specific for the detection colorectal cancer in stool. Methods: Whole blood was obtained from 18 colorectal cancer patients and plasma was isolated. Plasma was processed using Methylation On Beads nanotechnology (MOB) and bisulfate treated. Methylation status was determined via quantitative PCR method. Results: Two genes, TFPI2 and IGFBP3, were detected with a high sensitivity. TFPI2, demonstrated a methylation frequency of 94.4%, which is concordant with the TFPI2 methylation frequency of 99% in primary colorectal cancer tissues. IGFBP3 showed the methylation frequency of 61.1%, which corresponds with the methylation frequency of 52% in retrospective colorectal cancer tissues in previous studies. Quantification using standard curves indicated a single copy level of DNA found in plasma. Conclusions: Blood-based screening is challenging due to extremely low quantities of circulating DNA in blood. Utilizing a novel nanotechnology that detects DNA at a single copy level, the methylation changes in colorectal cancer were successfully detected in plasmas at similar frequencies as in tissue samples. This study has demonstrated the feasablility and applicability to blood-based screening. Future studies will focus on improving the sensitivity and determining the specificity of this method.
Prediction of clinical outcome in stage II and III colon cancer by a common gene variant in AXIN2.
Authors: Szkandera Joanna , Absenger Gudrun , Weissmueller Melanie , Pichler Martin , Stotz Michael , Lax Sigurd , Leitner Gerhard , Asslaber Martin , Renner Wilfried , Gerger Armin 
Published: February 2017

387 Background: Recent evidence suggests that the Wnt and Notch signaling pathways are involved in colon cancer progression and tumor recurrence. There is substantial germline genetic variability in these pathways, including single nucleotide polymorphisms (SNPs). SNPs may alter transcription, translation or splicing, thereby causing inter-individual differences in a patient’s tumor recurrence capacity and chemoresistance. We hypothesized that SNPs analyzed in a comprehensive panel of Wnt and Notch pathway genes predict clinical outcome in patients with colon cancer. Methods: A total of 815 patients with stage II and III colon cancer treated at the Medical University of Graz were included in this retrospective study. FFPE tissue specimens from normal tissue adjacent to the tumor samples were available from 599 patients. 18 SNPs in Wnt and Notch pathway genes (SFRP, DKK2, DKK3, Axin2, APC, MYC, TCF7L2 and NOTCH-2) were determined by 5’-exonuclease assay (TaqMan). The primary endpoint of the study was disease-free survival (DFS). Results: The homozygous mutant variant of AXIN2 rs2240308 G>A was associated with a significantly increased median DFS (HR 0.638, 95% CI 0.432-0.942, p=0.024) in univariate analysis. Patients carrying at least one G allele in AXIN2 rs2240308 G>A showed a median DFS of 114 months. In contrast, patients with homozygous A/A showed a median DFS of 133 months. After Cox proportional hazards model adjustment for known prognostic markers this result remained significant (HR 0.671, 95% CI 0.453-0.992, p=0.046). Conclusions: To the best of our knowledge, this is the first study identifying a common genetic variant in AXIN2 as an independent prognostic marker in stage II and III colon cancer. Larger prospective trials are warranted to confirm these findings.
Plasma levels of TIMP-1 in chemo-naive patients with metastatic colorectal cancer treated with first-line FLOX with or without cetuximab: Results from the Nordic VII Study.
Authors: Tarpgaard Line Schmidt , Guren Tormod Kyrre , Glimelius Bengt , Sorbye Halfdan , Ikdahl Tone , Christensen Ib Jarle , Qvortrup Camilla , Kure Elin , Pfeiffer Per , Tveit Kjell Magne , Nielsen Hans J. , Brünner Nils 
Published: February 2017

392 Background: KRAS status is presently the best known biomarker to select patients with metastatic colorectal cancer (mCRC) for therapy with EGFR inhibition. However, in NORDIC VII a survival benefit of adding cetuximab to the Nordic FLOX regimen could not be confirmed. Plasma Tissue Inhibitor of MetalloProteinases-1 (TIMP-1) is a promising biomarker in patients with mCRC, and has multiple actions including regulation of apoptosis, angiogenesis, cell growth and differentiation. High levels of TIMP-1 associate with reduced sensitivity to irinotecan-based treatment in patients with mCRC. We investigated whether high plasma TIMP-1 also correlates with response rate, progression-free survival (PFS) and overall survival (OS) in patients with mCRC treated in NORDIC VII. Methods: In NORCIC VII 571 patients with mCRC were randomized to: (A) Nordic FLOX; (B) Nordic FLOX + cetuximab or (C) Nordic FLOX intermittently + cetuximab continuously. Baseline plasma samples for TIMP-1 analysis were available from 426 patients (79%). Plasma TIMP-1 was determined using the MAC15 antibody in-house validated kinetic Enzyme Linked Immunosorbent Assay. Results: Median plasma TIMP-1 was 296 ng/mL. The tumor was KRAS mutated in 149 patients (35%). Best response did not correlate to TIMP-1 values (OR=1.16, 0.91-1.49, p=0.22). High plasma TIMP-1 was associated with short PFS (HR=1.22, 1.07-1.39, p=0.003) and OS (HR=1.55, 1.36-1.80, p<0.0001). Multivariate analysis (TIMP-1, age, gender, KRAS, ALP, WBC, platelets, CRP, CEA, WHO PS, no. of metastatic sites) demonstrated that high plasma TIMP-1 was not an independent biomarker of PFS (HR=0.95, 0.76-1.18, p=0.65) or OS (HR=1.17, 0.91-1.50, p=0.22). Multivariate analysis retained CRP, PS and no. of metastatic sites in the final model for PFS and alkaline phosphates, PS and no. of metastatic sites for OS. Conclusions: Plasma TIMP-1 is a new prognostic biomarker in patients with mCRC treated with 1st line Nordic FLOX +/- cetuximab. Due to the design of NORDIC VII, a predictive effect of plasma TIMP-1 could only be estimated for cetuximab treatment and no significant treatment by marker intervention was observed.
Demonstration of subpopulations with differing cancer stem cell phenotypes in xenograft and in vitro models of colorectal liver metastases.
Authors: Sanford Dominic E. , Giorgi Andrew , Goetz Brian D. , Panni Roheena Z. , Hawkins William G. , Linehan David , Goedegebuure Peter S , Fields Ryan C. 
Published: February 2017

394 Background: Tumors are composed of heterogeneous cell populations, some of which demonstrate enhanced tumor-forming capabilities (so-called tumor initiating cells [TIC] or cancer stem cells). In colorectal cancer (CRC), CD133, 44, and 24 are cell surface markers that identify TIC. Therefore, we sought to determine if CRC liver metastases (CRC-LM) form xenografts (in vivo) and cell cultures (in vitro) with TIC markers. Methods: CRC-LM were grafted in NOD/SCID mice and passaged serially. Xenografts were mechanically dissociated and cultured under sphere forming conditions. Flow cytometry was performed for TIC phenotype. Results: 16 of 18 (89%) CRC-LM specimens formed tumors in mice. Xenografts formed EpCAM+ tumors and spheres. The frequency of CD133+, CD44+, and CD133+/CD44+ tumor cells were 55%, 33%, and 23%, respectively. There was a subpopulation of CD133+/CD44+ cells with elevated CD44 expression(CD44hi). This CD133+/CD44hi population was also CD24+; representing 5% of cells. Eight of eleven (73%) xenografts formed spheres in vitro. The frequency of CD133+, CD44+, and CD133+/CD44+ cells were 63%, 47%, and 26%, respectively. CD133+/CD44+/CD24+ cells made up 8% of sphere-forming cells. There was a non-significant trend towards increased frequency of CD133+, CD44+, and CD133/CD44 positive cells in the spheres compared to the xenografts. However, the percentage of CD133+/CD44+/CD24+ cells was significantly increased in spheres relative to xenografts (8% vs. 5%, respectively; p<0.05) (see Table). Conclusions: CRC-LM derived xenografts and spheres are composed of distinct cell populations with differing levels of TIC/cancer stem cells. Sphere cultures may enhance for the most enriched TIC population. Thus, xenografts and sphere cultures are important model systems to further study the importance of cancer stem cells in CRC progression and metastases. [Table: see text]
Association of CD133 expression levels with the k-ras mutation status in rectal cancers before and after preoperative radiochemotherapy.
Authors: Sprenger Thilo , Gaedcke Jochen , Conradi Lena-Christin , Jo Peter , Jung Klaus , Beissbarth Tim , Homayounfar Kia , Ghadimi B. Michael , Liersch Torsten 
Published: February 2017

400 Background: The role of the potential stem cell marker CD133 as a predictive or prognostic marker in multimodal rectal cancer treatment is currently under debate. While CD133 has been identified as a prognostic marker in rectal cancers after preoperative radiochemotherapy (RCT) it was recently characterized as a very unspecific feature for colorectal cancer stem cells. We therefore analyzed the association between CD133 expression and mutations in the proto-oncogenes K-Ras and PI3K in rectal cancer patients receiving neoadjuvant RCT. Methods: CD133 expression was evaluated immunhistochemically in pre-treatment biopsies and surgical specimens of 128 patients with locally advanced rectal cancers (cUICC II/III) treated with preoperative RCT within the phase-III German Rectal Cancer Trials. K-Ras mutations were analyzed by sequencing of exons 1, 2, and 3. PI3K mutations were detected by sequencing the p110α subunit (PIK3CA) and correlated with histopathologic parameters, tumor regression and survival. Results: CD133 expression was significantly associated with mutations in the K-Ras gene in both pre-treatment biopsies and post-treatment tumor specimens in uni- and multivariate analyses. However, no significant correlation was observed between CD133 and PI3K mutations. Post-treatment CD133 levels were correlated with neoadjuvant RCT (50.4 Gy/5-FU vs. 50.4 Gy/5-FU+Ox) and tumor regression grading. Anyway, there was no significant association between pre- and post-treatment CD133 expression and disease-free survival. Conclusions: CD133 expression levels are strongly associated with mutations in the K-Ras proto-oncogene in rectal cancers before and after preoperative RCT. Our results strengthen the hypothesis that CD133 is not a specific marker for colorectal stem cells but might be integrated in proliferation pathways like the ras-raf axis.
Micro-RNA-21 (miR21) expression in colorectal cancer (CRC) as a predictor for fluoropyrimidine-based adjuvant chemotherapy.
Authors: Lin Albert Y. , Kouzminova Natalia B. , Pollack Jonathan , Nuovo Gerard 
Published: February 2017

408 Background: Fluoropyrimidine-based adjuvant chemotherapy is a standard treatment option for patients with high risk II or stage III CRC. It is, however, unclear if a subset of patients will benefit from chemotherapy more than others. MiR21, a small non-coding RNA, has been associated with promotion of tumor cell growth and metastasis. To assess the effect of miR21 on chemotherapy, we analyzed the association of miR21 expression with clinical outcomes and known prognostic factors. Methods: MicroRNA detection was performed by in situ hybridization on a CRC tissue microarray containing specimens from 130 cases (stage I, 21 patients; II: 44; III: 33; IV: 32). MiR21 expression was graded as negative (no staining in all tissue cores), low (0-10% staining), moderate (20-40%) and strong (50-100%), and was analyzed with stage, grade, expression of VEGF, Ki67, LEF1, OPN and MSH2 by immunohistochemistry. Cox proportional hazards regression analysis was performed to assess the association of miR21 expression with 10-year recurrence-free survival in the subgroup of 77 stage II or III patients. Results: In all, miR21 expression had moderate positive correlation with genes associated with tissue proliferation and invasion, including Ki67 (Spearman's r=0.42, p<0.001), VEGF (r=0.32, p<0.001) and OPN (r=0.32, p<0.001), and weak correlation with LEF1 (r=0.22, p=0.012) and MSH 2 (r=0.18, p=0.039). In the subgroup of 36 patients treated with adjuvant therapy, low or negative miR21 expression (≤10%, n=15) was associated with increased recurrence (HR =3.5; p=0.05). In the multivariate Cox regression model including stage, grade and LEF1 expression, the association of low or negative miR21 with cancer recurrence remained significant along with grade and LEF1. Ki67 was excluded from the multivariate model because of significant association with miR21 (r=0.44, p=0.007) in the analyzed group. Conclusions: Our results suggest that low miRNA21 expression is associated with increased risk for recurrence in CRC patients received adjuvant chemotherapy. Further investigation of miR21 in randomized studies is warranted to establish its role as a predictor for CRC in the setting of adjuvant therapy.
Occurence of initiation and progression of colorectal cancer in the changed intestinal environment.
Authors: Ohigashi Seiji , Sudo Kazuki , Kobayashi Daiki , Takahashi Osamu , Takahashi Takuya , Asahara Takashi , Nomoto Koji , Onodera Hisashi 
Published: February 2017

416 Background: Use of new molecular biology–based methods of bacterial identification is expected to help elucidate the relationship between colorectal cancer (CRC) and intestinal microbiota. However, it remains unclear whether microbial dysbiosis is the cause or the result of CRC onset. We analyzed the intestinal environments to determine whether the changes differed with the stage of CRC or adenoma. Methods: We analyzed fecal microbiota, organic acid concentrations, and pH in CRC patients (n=93), individuals with adenoma (n=23), and individuals with normal intestinal tracts (n=27). After patient hospitalization, the feces of all subjects were collected before any administration of laxatives or antibiotics to prepare the bowel.Thirteen bacterial groups were enumerated in the fecal microbiota by using reverse transcription–quantitative PCR (RT-qPCR). Eight kinds of organic acid were quantified using high-performance liquid chromatography, and fecal pH was measured by pH meter. Results: The counts of total bacteria (10.3 ± 0.7 vs. 10.8 ± 0.3 log10 cells/g of feces; p<0.001), 5 groups of obligate anaerobe (Clostridium coccoides group, C. leptum subgroup, Bacteroides fragilis group, Bifidobacterium, and Atopobium cluster), and 2 groups of facultative anaerobes (Enterobacteriaceae and Staphylococcus) were significantly lower in the CRC group than in the healthy individuals. While the concentrations of organic acids—particularly short chain fatty acids (SCFAs) such as acetic acid, propionic acid, and butyric acid—were significantly decreased in the CRC group, the pH was increased in the CRC group (7.4 ± 0.8 vs. 6.9 ± 0.6; p<0.001). Comparison among the CRC, adenoma, and non-adenoma groups revealed that fecal SCFAs concentrations and pH in the adenoma group were intermediate to the CRC group and the non-adenoma group. Within the CRC group, no differences in microbiota or organic acids were observed among T-stages or Dukes stages. Conclusions: CRC patients showed significant differences in the intestinal environment, including alterations of microbiota, decreased SCFAs, and elevated pH. These changes are not a result of CRC progression but are involved in CRC onset.