bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of esophageal carcinoma for a radioresistant subpopulation with cancer stem cell characteristics.
Authors: Smit J. K. , Niemantsverdriet M. , van Os R. P. , Hollema H. , Plukker J. T. , Coppes R. P. 
Published: February 2017

36 Background: Neo-adjuvant chemoradiation is considered as standard treatment in esophageal cancer (EC). However, a significant proportion of these tumors do not respond well to radiotherapy. Here, we investigated the presence of radioresistant cells in EC with cancer stem cell characteristics. Methods: EC OE-33 adenotype and OE-21 squamous cell carcinoma cell-lines and fresh tumor material of EC patients were analyzed for common CSC-markers with Fluorecence Activated Cell Sorting (FACS) and immunohistochemistry. Subpopulations were tested for clonogenic survival to determine radioresistance. Non-adherent 3D sphere-cultures and xenograft tumors generated in NOD/SCID mice were performed to investigate stem cell properties. Results: Both cell lines lacked expression of CD133 and CD90, whereas the expression of EpCam overlapped with CD44 in OE-33. In sub-confluent cultures the expression of CD44+/CD24- was 5.6% SD ± 2.3 and 35.1% SD ± 1.3 in OE-33 and OE-21, respectively. In a clonogenic survival assay the CD44+/CD24- cells showed up to a 2-fold lower radiosensitivity compared to CD44+/CD24+ cells in both the OE-33 (p = 0.02) and the OE-21 cell line (p = 0.01). The CD44+/CD24- subpopulation had a 2.2-fold higher sphere-forming capacity compared to the CD44+/CD24+ subset (p = 0.01) in OE-33. Analysis of the spheres showed an enrichment in the CD44+/CD24- phenotype from 5.6% to 56.4% (p = 0.01) after 4 days of culturing as measured by FACS, but differentiated to a higher percentage of CD44+/CD24+ in time. Furthermore, CD44+/CD24- cells exhibited a greater in vivo tumor initiating capacity, shorter latency time and faster growth speed compared with unsorted or CD44+/CD24+ cells. Importantly, a clear CD44+/CD24- population could be identified in fresh EC biopsies of patients. Conclusions: EC appear to contain a radioresistant CD44+/CD24- subpopulation. This phenotype displays some CSC characteristics in vitro and in vivo and is present in human EC tumors. This marker could be used in future trials to predict tumor response. No significant financial relationships to disclose.
sFRP-1: A functional prognostic marker for gastric cancer?
Authors: Moran C. J. , Ray P. S. , Bagaria S. P. , Qu Y. , Fleisig A. J. , Sim M. , Turner R. R. , Cui X. 
Published: February 2017

37 Background: Despite being a leading cause of cancer-related death world wide, gastric adenocarcinoma (GA) lacks distinctive biomarkers and targeted therapies. Underexpression of the E-cadherin gene in GA is associated with an aggressive phenotype and a poor prognosis but the mechanisms of this difference are poorly understood. Developing effective therapies for GA requires identification of critical functional markers and deeper understanding of its pathophysiology. Methods: Unsupervised hierarchical clustering analysis of a publicly available 230-sample GA microarray dataset identified a prominent cluster (21.7%) associated with underexpression of E-cadherin and overexpression of a Wnt-family protein: secreted frizzled-related protein 1 (sFRP-1). Archival GA specimens were then assessed for the expression of sFRP-1 by immunohistochemistry. Prognostic significance was assessed using univariate and multivariate analyses. GA cell lines transfected with sFRP-1 were used to determine the role of sFRP-1 in gastric cancer. Results: 85 patients with GA underwent surgery with curative intent; 39 stained positive for sFRP-1 (46%). In this positive group, sFRP-1 staining was focal; was commonly found on the leading edge of the infiltrating tumor mass; and was not restricted to one histopathologic group, grade, or clinical stage. On univariate analysis T stage, nodal involvement, pathologic stage, nuclear grade, E-cadherin status and sFRP-1 status were predictive of overall survival. In a multivariate model, T stage (p < 0.001), nuclear grade (p < 0.001), E-cadherin status (p = 0.031) and sFRP-1 status (p = 0.0097) were predictive of overall survival. Overexpression of sFRP-1 in GA cell lines induced mesenchymal phenotype, enhanced growth and stem cell-like properties. sFRP-1 also attenuated Wnt signaling and E-cadherin expression, but potentiated Notch and Hedgehog signaling known to be involved in GA progression. These findings suggest a Wnt-independent mechanism mediated by sFRP-1. Conclusions: The aggressive biological subtype of gastric cancer may be linked to overexpression of sFRP-1. Our findings identify sFRP-1 as a functional prognostic biomarker for gastric cancer, which may serve as a potential therapeutic target. No significant financial relationships to disclose.
Association of use of bisphosphonates with risk of colorectal cancer.
Authors: Rennert G. , Pinchev M. , Rennert H. S. , Gruber S. B. 
Published: February 2017

371 Background: Bisphosphonates are commonly used for the treatment of osteoporosis and of bone metastases due to breast cancer and were recently reported to be associated with reduced risk of breast cancer, but their association with risk of other cancers is unknown. Methods: The Molecular Epidemiology of Colorectal Cancer (MECC) study is a population-based case-control study in northern Israel of colorectal cancer cases and age/sex/clinic/ethnic-group matched controls. Use of bisphosphonates prior to diagnosis was assessed in a subset of 933 pairs of post-menopausal female cases and controls, enrolled in Clalit Health Services (CHS), using computerized pharmacy records. Results: The use of bisphosphonates for more than one year prior to diagnosis, but not for less than a year, was associated with a significantly reduced relative risk of colorectal cancer (odds ratio=0.50, 95% CI: 0.35-0.71). This association remained statistically significant after adjustment for, vegetable consumption, sports activity, family history of colorectal cancer, , BMI, use of low-dose aspirin, statins, vitamin D and post-menopausal hormones (OR=0.40, 0.24-0.64). Concomitant use of bisphosphonates and statins did not further reduce the risk. Conclusions: The use of oral bisphosphonates for more than 1 year was associated with a 60% relative reduction in the risk of colorectal cancer similar to the recently reported association of this drug class with reduction in breast cancer risk. No significant financial relationships to disclose.
The added value of diffusion-weighted magnetic resonance imaging (DW-MRI) in the local staging of advanced colorectal pelvic cancer.
Authors: Georgiou P. A. , Tekkis P. P. , Patel U. , Antoniou A. , Darzi A. W. , Cunningham D. , Koh D. , Brown G. 
Published: February 2017

378 Background: Surgeons rely on imaging to plan exenterative pelvic surgery for locally advanced primary and recurrent rectal cancer. Accurate local staging is vital in this process, as it provides information about the extent of the disease, facilitating the planning of the operation required to achieve complete resection. DW-MR imaging is a functional radiological modality that can provide indirect informationabout the water proton mobility within biologic tissue, without the need of a contrast agent. The aim of the present study was to assess the diagnostic accuracy and added value of diffusion DW-MRI in detecting colorectal tumor invasion into seven intrapelvic compartments for planning exenterative pelvic surgery. Methods: Thirty three consecutive patients were preoperatively staged using DW-MRI to undergo exenterative surgery for locally advanced primary (n=12) and recurrent (n=21) colorectal pelvic cancer. Two radiologists reported tumor invasion for each of the seven anatomic surgical resection compartments and were blinded to histopathology and intraoperative reference standards. Accuracy, sensitivity, specificity and predictive values were calculated for the seven intrapelvic compartments. Interobserver agreement was assessed using Cohen's Kappa (k) coefficient for each compartment. Results: The sensitivity of DW-MRI when used alone was low for all the compartments except the central (92%). Its specificity was very high for all the compartment (≥89.5%). Combining DW-MRI with conventional MRI increased the sensitivity for the lateral compartment by 8.3% to 100% and the specificity for the anterior compartment below the peritoneal reflection by 9.1% to 90.9%. The overall incremental value for the lateral compartment was 3%. The interobserver agreement was either good or very good (k≥0.669; p<0001) for all the compartments. Conclusions: DW-MRI can improve the diagnostic accuracy of conventional MRI when staging patients with advanced colorectal pelvic cancer. Diffusion images are cheap and easy to obtain. Therefore DW-MRI should always be used in combination with conventional MRI when considering patients for exenterative pelvic surgery. No significant financial relationships to disclose.
Clinicopathologic and genetic features of Chinese hereditary nonpolyposis colorectal cancer (HNPCC).
Authors: Liu F. , Wei W. , Nan P. , Li X. , Xu Y. 
Published: February 2017

382 Background: Hereditary non-polyposis colorectal cancer (HNPCC) is the most common hereditary colorectal cancer (CRC). At least five mismatch repair genes, majorly hMLH1and hMSH2 gene mutations, are associated with this syndrome. Given the geographical and racial differences, Chinese HNPCC patients have some special characteristics compared with patients in West countries. Based on our former studies, we developed a criteria, the Fudan Criteria, for clinical diagnosis of Chinese HNPCC. The aim of this study is (1) to understand the relationship between genotype and phenotype in Chinese HNPCC; and (2) to investigate the clinical value of Fudan Criteria. Methods: 116 unrelated probands of HNPCC or suspected HNPCC families from the Fudan Colorectal Registry were studied. 32 families fulfilled the Amsterdam criteria (AC group), 28 families fulfilled the Fudan Criteria (FD group). 56 families met the revised Bethesda guideline (BG Group). Direct DNA sequencing of all exons of hMSH2 and hMLH1 genes were performed. Mutation and clinicalpathological features were compared between the groups. Results: 32 pathological germline mutations were identified. 16/32 mutations were located at hMLH1 and 16/32 located at hMSH2. The sensitivity of Amsterdam Criteria was 50%, specificity was 81% and Youden's index was 31%. The sensitivity of Fudan Criteria was 75%, specificity was 58% and Youden's index was 33%. In AC group, there were no significant clinicopathological differences in patients with or without mutation. However, families with hMSH2 mutation had a higher ratio of synchronous and metachronous CRC than families with hMLH1 mutation (33% vs. 6%; P=0.04). Families in AC group share the same clinicopathological features with families in FD group, except multiple relative tumors (21.6% vs.6%; P=0.001). Conclusions: There seems no close relation between genotype and phenotype, except patients with hMSH2 mutation more frequently harbor synchronous and metachronous CRC. Fudan Criteria had a little higher sensitivity and accuracy than Amsterdam Criteria for identification of Chinese HNPCC. No significant financial relationships to disclose.
Profile of the colorectal (CRC) cancer (Ca) patients (PTS) in Turkey: A cross-sectional disease registry study—A Turkish Oncology Group trial.
Authors: Aykan N. , Demir G. , Disci R. , Yalcin S. , Turhal N. S. , Ozdogan M. , Ozkan M. , Yaren A. , Camci C. , Akbulut H. ,   Turkish Oncology Group
Published: February 2017

394 Background: CRC Ca is one of the most common Ca worldwide. This study was designed to determine the profile of recently diagnosed CRC Ca pts in Turkey. Methods: In this national, multicenter cross-sectional disease registry study, data for 968 pts diagnosed CRC Ca were analyzed. This non-interventional study was supported by sanofi-aventis. Results: From October 2008 to October 2009, 662 colon (68%), 306 rectum (32%) Ca pts were registered from 21 centers in 7 geographic regions of Turkey. Characteristics are as follows. Male 61%, mean age was 60±12 for colon and 57±13 for rectum Ca. The ratio of colon and rectum Ca were equal in the Black Sea region, colon Ca was higher in the other 5 regions except Eastern Anatolia where the highest percentage of rectum Ca was observed (55% vs 45%). Red meat consumption was significantly high only in Eastern Anatolia (p<0.001). The consumption of alcohol, fruit and vegetables didn't show any difference. The percentage of smoking was slightly higher in the rectum Ca group (21% vs 16%, NS). The CRC family history was a risk factor in 7.4% colon, and in 5.6% rectum Ca pts. Among all pts, 1.5% had familial poliposis and only 0.4% had Lynch syndrome. Hypertension (29%) and diabetes mellitus (15%) were the most frequent concomitant diseases. Mean body mass index was 26 ± 4 in colon and 26 ± 5 in rectum Ca pts. Median time between the onset of symptoms and diagnosis was 3 months (mo) for colon and 4 mo for rectum Ca pts. For 46% of pts this time was longer than 4 mo. The mean weight loss in last 6 mo was slightly higher in colon Ca pts (3.9 vs 3.4 kg). Anemia was more frequent in colon Ca pts (p<0.05). Primary tumor location: sigmoid 37% for colon Ca, distal rectum 61% for rectum Ca. In total, 86% of pts were operated (88% of colon, 80% of rectum Ca). In 26% of pts emergency surgery was performed. AJCC staging at diagnosis: I-7%, II-26%, III-35%, IV-32% in colon and I-14%, II-22%, III-39%, IV:25% in rectum. Conclusions: This study showed that colon Ca was more frequent and most of the cases were operated. Data also revealed that pts were diagnosed at considerably later stages. The role of the consumption of red meat, obesity and smoking should be evaluated in larger trial in the future. [Table: see text]
Impact of early tumor shrinkage on long-term outcome in metastatic colorectal cancer (mCRC) treated with FOLFOX4 with or without cetuximab: Lessons from the OPUS trial.
Authors: Piessevaux H. , Bokemeyer C. , Schlichting M. , Heeger S. , Tejpar S. 
Published: February 2017

398 Background: The measurement of tumor shrinkage at the first evaluation (8 weeks) was reported to predict long-term outcome in mCRC treated with irinotecan-based chemotherapy (CT) + cetuximab (cet) in first-line and chemorefractory patients (pts). The predictive power of early tumor measurements was restricted to pts treated with CT + cet compared with CT alone but isn't known for cet with other CT regimens. This was investigated in pts treated with the FOLFOX4 regimen ± cet in the OPUS trial. Methods: Based on the 8-weekly radiological assessments reported by the investigator and reviewed by an independent review committee, relative changes in tumor size from baseline were computed and dichotomized using a 20% relative decrease cut-off value. Kaplan-Meier curves were constructed for progression-free survival (PFS) and overall survival (OS), stratified by treatment arm and KRAS status. Results: Tumor measurements at week 8 with KRAS status were available in 297 pts. Tumor shrinkage ≥20% was associated with significantly better PFS and OS in KRAS wild-type (wt) pts treated with FOLFOX4 + cet but not in those treated with CT alone (Table). Conclusions: When combining cet with FOLFOX4 in first-line KRAS wt mCRC, early tumor shrinkage is associated with long-term outcome. This finding is specific for the effect of cet, confirming this drug to have distinctive and rapid effects on tumor size leading to long-term outcome measures unrelated to the effect of CT. [Table: see text] [Table: see text]
Clinicopathological features in metastatic colorectal cancer patients with KRAS wild type compared with codon 12 and codon 13 mutant: Results from a multicenter, cross-sectional study by the Japan study group of KRAS mutation in colorectal cancer.
Authors: Yoshino T. , Watanabe T. , Yamazaki K. , Uetake H. , Ishiguro M. , Sugihara K. , Ohashi Y. ,   Japan Study Group of KRAS Mutation in Colorectal Cancer
Published: February 2017

407 Background: The KRAS mutation mainly located in the codon 12 and 13 indicates unresponsiveness of patients with metastatic colorectal cancer (CRC) to anti-epidermal growth factor receptor (EGFR) antibodies. Many studies have reported that approximately 30%-40% of CRC patients have KRAS mutations. However, the clinicopathological features of KRAS mutant CRC have not been fully clarified, especially in Asian populations. This study aimed to clarify the clinicopathological features of KRAS mutant CRC in comparison with KRAS wild type in large-scale Japanese population. Methods: The key eligibility criteria included histologically confirmed colorectal adenocarcinoma with adequate tumor samples. Formalin-fixed paraffin-embedded tumor blocks or thinly sliced tumor sections from 389 centers were sent to commercial laboratories. Almost all KRAS point mutations in the codon 12 and 13 were investigated by direct sequencing (96%). The logistic regression analysis was used to estimate the odds ratios (ORs) and compute 95% confidential intervals (CIs). Results: Of 5,887 registered tumor samples between Oct. 2009 and Mar. 2010, the KRAS testing were performed for 5,790 samples. As of the cut-off date, Sep. 2010, we have successfully determined the KRAS mutational status of 5,732 samples (99%).The median age was 65 years old, and 61% were male. The primary tumor site was right colon, left colon, and rectum in 30, 38, and 32% patients, respectively. The frequency of KRAS mutation was 37.6% (2,155/5,732), of which the 80% (1,714/2,155) mutations were located in codon 12. On logistic regression analysis, female gender (OR=1.212, 95% CI=1.083-1.356), older age > 50 years (OR=1.312, CI=1.056-1.628) and right colon (versus left: OR=2.177, CI=1.905- 2.489; versus rectum: OR=1.500, CI=1.308-1.720) were independent risk factors of KRAS mutant CRC. Clinicopathological features were similar between codon 12 and 13 mutant CRC. Conclusions: This study disclosed that KRAS mutant CRC was different from KRAS wild type CRC in terms of clinicopathological features. No significant financial relationships to disclose.
Use of genetic variations to predict toxicity associated with neoadjuvant chemoradiation for AJCC stage II/III rectal cancer.
Authors: Ho J. , Li W. , Duldulao M. P. , Chen Z. , Kim J. , Garcia-Aguilar J. 
Published: February 2017

411 Background: Genetic polymorphisms have been associated with toxicity from chemotherapeutic agents for colon cancer, but none has been identified for rectal cancer. We examined the association between polymorphisms in genes for DNA repair, cell cycle progression, angiogenesis, and drug metabolism with toxicity from neoadjuvant chemoradiation treatment (CRT) for rectal cancer. Methods: Patients with AJCC stage II/III rectal adenocarcinoma were enrolled in a phase II multicenter trial examining timing of rectal cancer response to neoadjuvant CRT. There were two treatment arms: (I) radiation (XRT) and 5-FU followed by surgery and (II) XRT/5-FU and FOLFOX followed by surgery. Treatment toxicity, classified by the NCI Common Terminology Criteria guidelines as grade 3 and above, was recorded. DNA was extracted from normal rectal mucosa and analyzed for 22 polymorphisms in 17 genes. Results: We evaluated 110 patients (group I, n = 52; group II, n = 58). A total of 19 patients experienced grade 3+ adverse events (AE) [group I, n = 10 (19%); group II, n = 9 (16%)]. Gastrointestinal symptoms were the most common AE [group I, n = 5 (10%); group II, n = 4 (7%)]. The detection of lys allele (lys/lys or lys/gln genotypes) at codon 751 of the Xeroderma pigmentosum group D (XPD) gene was associated with increased toxicity in group II (p = 0.03), whereas homozygosity for the arg allele (i.e., arg/arg genotype) at codon 399 of the X-ray cross-complementing protein 1 (XRCC1) gene was associated with a significant increase in toxicity in both treatment groups (p = 0.009). Conclusions: Genetic polymorphisms in DNA damage repair genes XPD and XRCC1 are associated with toxicity in rectal cancer patients receiving CRT. The identification of gene polymorphisms that predict adverse events may help to optimize patient therapy while minimizing morbidities. No significant financial relationships to disclose.
Differential expression of small ubiquitin-like modifier family of proteins in patients with colorectal adenocarcinoma.
Authors: Wiatrek R. , Duldulao M. P. , Chen Z. , Li W. , Kim J. , Li Y. , Chen Y. , Garcia-Aguilar J. 
Published: February 2017

420 Background: The cytotoxic effects of radiation and chemotherapy are mediated in part by DNA damage. The small ubiquitin-like modifier (SUMO) family of proteins regulates DNA repair pathways by activating factors involved in homologous recombination (HR) or non- homologous end joining (NHEJ). Our objective was to determine the potential role of SUMO proteins in patients with colorectal cancer. Methods: We first assessed two established colorectal cancer cell lines (HCT116 and HT29) and two normal colonic mucosa cell populations utilizing ultra high-throughput expression analysis (Solexa) to examine differential expression of genes involved in SUMOylation (SAE1, SAE2, PIAS-1, and DNAPKcs). To verify the clinical relevance of SUMOylation in colorectal cancer, we obtained archived specimens from patients with colorectal cancer (n=51) and examined the expression of these proteins in both benign and malignant tissue by immunohistochemistry (IHC). Results: Ultra high-throughput expression analysis of cancer and normal cells revealed a 10 to 15-fold upregulation of SAE2 (heterodimer of the E1 activation enzyme in SUMOylation), a 10 to 11-fold upregulation of DNAPKcs (catalytic subunit in NHEJ repair pathway), and a 6-fold upregulation of SAE1 in cancer cells. In contrast, PIAS-1 showed similar expression levels between cancer and normal colonic cells. By IHC, SAE1 and SAE2 were highly expressed in 65% and 53% of tumor specimens, respectively; but only in 7% and 0% of normal tissues, respectively. DNAPKcs was also highly expressed in tumor tissues (63%) with corresponding low expression (0%) in normal tissues. Corroborating the cell line results, PIAS-1 was infrequently expressed in both tumor (10%) and normal tissues (0%). Conclusions: We are the first to demonstrate the differential expression of SUMO proteins in colorectal cancer cell lines and in clinical specimens. SUMO proteins have a role in DNA repair and their expression in colorectal cancer may modify tumor response to chemoradiotherapy. No significant financial relationships to disclose.