bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical significance of serum angiopoietin-like protein 2 in colorectal cancer patients.
Authors: Kitajima Takahito , Toiyama Yuji , Shimura Tadanobu , Ide Shozo , Imaoka Hiroki , Kondo Satoru , Kawamura Mikio , Okugawa Yoshinaga , Kawamoto Aya , Hiro Junichiro , Saigusa Susumu , Ohi Masaki , Tanaka Koji , Inoue Yasuhiro , Mohri Yasuhiko , Kusunoki Masato 
Published: February 2017

417 Background: Angiopoietin-like protein 2 (ANGPTL2) is a secreted protein belonging to the angiopoietin family. It has been reported to act as a causative mediator of chronic inflammation and metabolic abnormalities. ANGPTL2 increases inflammatory carcinogenesis in several cancers, and its expression in tumor cells is highly correlated with the frequency of tumor cell metastasis through increased tumor angiogenesis and tumor cell epithelial-to-mesenchymal transitions. However, to our own knowledge, clinical significance of serum ANGPTL2 in cancer patients remains unknown. The aim of this study was to quantify serum ANGPTL2 level using ELISA, and to evaluate its clinical and prognostic significance in patients with colorectal cancer (CRC). Methods: We quantified serum ANGPTL2 levels from 194 CRC patients and normal 48 controls (NC) by ELISA. Next, we investigated ANGPTL2 expression in matched CRC tissues (n=194) by immunohistochemistry (IHC) to identify the source of circulating ANGPTL2. The IHC score of ANGPTL2 was determined on the basis of both staining intensity and the percentage of positive cells. Results: Serum ANGPTL2 levels were significantly higher in CRC than in NC (p<0.01) and gradually increased according to TNM stage progression. Serum ANGPTL2 levels discriminated CRC from NC with high accuracy (AUC=0.837). High serum ANGPTL2 was significantly associated with larger tumor size (p=0.03), undifferentiated adenocarcinoma (p=0.03), advanced T stage (p<0.01), peritoneal metastasis (p<0.01). In addition, Kaplan–Meier curves revealed that high serum ANGPTL2 were significantly associated with poor disease free survival (p=0.01) and overall survival (p=0.03). Interestingly, ANGPTL2 levels in serum from CRC patients closely correlated with IHC scores of cytoplasmic ANGPTL2 expression in matched CRC tissues (r=0.14, p=0.03). Conclusions: Serum ANGPTL2, which might be derived from primary CRC tumor, has strong potential to serve as a noninvasive biomarker for CRC diagnosis and prognosis.
Are immunohistochemical (IHC)/microsatellite instability (MSI) testing necessary as part of Lynch syndrome work-up in the era of multiplex genetic testing?
Authors: Idris Ahmad Fitri , Hooper Simon D. , Farrell Michael P. , Nolan Carmel , Clarke Roisin , Berkley E , Gallagher David J. 
Published: February 2017

425 Background: IHC for mismatch repair proteins and MSI are commonly used to direct genetic testing for Lynch Syndrome. Abnormal results in the setting of a positive family history often lead to genetic testing for Lynch syndrome. The often cumbersome process of completing IHC/MSI requires obtaining stored tissue +/- blood from a family member affected with cancer. Upfront genetic testing is not favoured due to concerns about identifying variants of uncertain significance. We performed a review of Lynch syndrome work-up in Ireland, and propose a model that is the reverse of the current international standard, and may expedite and simplify work up of these families. Methods: Data was ascertained from three cancer genetics services in Dublin and included the following variables: date of birth, date of request and reporting results for IHC, MSI and genetic tests. Time intervals were determined for LS work-up for all patients who had the process initiated in these 3 centres. Results: Probands from 50 families referred for LS work-up were included.The median time from date of IHC request to date of IHC report (total of 50 patients) was 4 weeks (range: 4 days to 36 weeks). The median time between date of IHC request to date of MSI report (n = 32 patients) was 20 weeks (range: 4 to 56 weeks). The median time from date of genetic test request to date of result (n = 9 patients) was 9 weeks (range: 2 to 26 weeks). The median time for completion of all 3 tests in one individual (n=3 patients) was 14 weeks (range: 10 to 60 weeks). Conclusions: The diagnostic pathway for Lynch syndrome is cumbersome and often lengthy. Appropriate upfront multiplex genetic testing would expedite the identification of mismatch repair gene mutation carriers. IHC/MSI testing could be used to characterise variants of uncertain significance.
Strenghening and protecting families: How to handle the familial colorectal cancer risk—A prospective observational study in Upper Bavaria.
Authors: Mansmann Ulrich Robert , Woelke Gabriele , Engel Jutta , Stausberg Juergen 
Published: February 2017

427 Background: Lynch defines patients with familial colorectal cancer (CRC) risk as those with two or more first- or second-degree relatives (or both) with CRC. They make up about 20 percent of all CRC patients. Also, first degree relatives of CRC patients have an increased CRC risk. It is our goal to create population based data on familial CRC risk in a German population. Methods: Incident CRC cases in Upper Bavaria are collected and their family trees constructed. The patient’s relatives are documented by name, address and date of birth, but without health related information. Cancer history is added to a family by a record linkage procedure combining members of the family trees with cancer histories in the Munich CancerRegistry (MCR). A specific data protection concept guarantees anonymity for families and their cancer histories. Prevalence of familial CRC risk in upper Bavaria and the posterior probability of a family to carry CRC risk can be inferred from the anonymous data. Strength of simple familial CRC risk detection tools can also be assessed. Results: Per year, 141 clinical departments and 24 oncological practices report about 1300 incident CRC cases (below 70 years) to the MTR. Recruitment of patients started in September 2012. During the first year, we recruited 456 patients in 27 clinical departments and 6 oncological practices and contacted 1,600 relatives. Participation of relatives is reluctant in spite different information sources (leaflet, call center, internet) on the study purpose are provided. Record linkage creates an anonymous collection of CRC family histories. 37 families with a CRC patient below the age of 50 are recorded. They are recruited into a psycho-oncological substudy. First risk estimates will be available end of 2013. Conclusions: For the first time, the study offers population based data on familial CRC risk in a German population of 4.6 mio. people. The results strengthen the concept of familial CRC risk for the development of appropriate preventive screening strategies.
Mutations within the EGFR signaling pathway: Influence on efficacy in FIRE-3—A randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients.
Authors: Stintzing Sebastian , Jung Andreas , Rossius Lisa , Modest Dominik Paul , Fischer von Weikersthal Ludwig , Decker Thomas , Kiani Alexander , Al-Batran Salah-Eddin , Vehling-Kaiser Ursula , Heintges Tobias , Moehler Markus , Scheithauer Werner , Kirchner Thomas , Heinemann Volker 
Published: February 2017

445 Background: The FIRE-3 study (AIO KRK-0306) was designed as a randomized multicenter trial to compare the efficacy of FOLFIRI plus cetuximab (cet) to FOLFIRI plus bevacizumab (bev) as first-line treatment in KRAS WT mCRC patients. FOLFIRI plus cet as first-line treatment of KRAS WT mCRC patients resulted in comparable overall response rates (ORR) and progression free survival (PFS) when compared to FOLFIRI plus bev. Overall survival (OS) was significantly longer in the FOLFIRI plus cet arm. Methods: In a preplanned analysis, the effect of mutations within the EGFR dependent pathway were investigated. Next to mutations within KRAS (exon 2, 3, 4), NRAS (exon 2, 3, 4) and BRAF (V600E), mutations within PIK3CA (exon 9 and 20) and Akt were investigated and their impact on ORR, PFS and OS within the FIRE-3 population was evaluated. The analysis of all mutations was carried out employing pyrosequencing. Results: The ITT population consisted of 592 KRAS WT (exon 2) patients. The current analysis includes 488 cases (82.4%) with tumor tissue available. In 407 pts sequencing of all RAS mutations was possible. The ORR within the WT RAS patient group was higher in the FOLFIRI plus cet arm (65.5% vs 59.6%; Fisher´s p: 0.157). HRs (cet; bev) for pts with WT RASwere 0.93 (95% CI, 0.74-1.17; p = 0.54) for PFS and 0.70 (95% CI, 0.53-0.92; p = 0.01) for OS. PIK3CA mutation did not influence PFS nor OS when compared to the RAS wt population. Conclusions: ORR and OS were increased in patients with cet plus FOLFIRI as compared to bev plus FOLFIRI in patients without RAS mutations. Exclusion of patients with RAS mutations identifies a population which is more likely to benefit from cetuximab. Clinical trial information: NCT00433927.
Discovery of prognostic and predictive tissue biomarkers in patients with resectable esophageal cancer.
Authors: MacGregor Thomas P. , Gillies Richard S. , Sahgal Natasha , Chetty Runjan , Wang Lai-Mun , Turkington Richard Calvin , Maynard Nicholas D. , McHUGH Peter J. , Kennedy Richard D. , Middleton Mark R. , Sharma Ricky A. 
Published: February 2017

45 Background: Patients with operable esophageal adenocarcinoma have a poor prognosis (median survival <2 years). We aimed to discover novel prognostic and predictive biomarkers to be validated as tools for patient selection for optimal neo-adjuvant therapy. Methods: Protein levels of XPF, MUS81, Cyclins A, B1, D1 and E, and Ki67 were assessed by retrospective immunohistochemical analysis of baseline tumor biopsy samples from 3 groups of patients with operable esophageal adenocarcinoma: surgery alone (N=54), 2 cycles of cisplatin-fluorouracil chemotherapy followed by surgery (N=46), and 2 cycles of oxaliplatin-fluorouracil chemotherapy (N=38). Expression of 48,803 genes was studied by Illumina HT-12 chip array followed by functional pathway analysis in oxaliplatin-treated patients before and after chemotherapy (N=38). Results were tested for association with pathological response (Mandard regression grading) (Chi-square test), disease free survival (DFS) and overall survival (OS) (Wilcoxon test). Results: High Ki67 protein levels were associated with worse OS (P=0.034; N=93). None of the markers were predictive of clinical endpoints following cisplatin chemotherapy. In oxaliplatin-treated patients (N=38), functional pathway analysis revealed associations between overexpression of cell cycle/DNA repair genes at baseline and worse clinical outcomes. Expression of 15 DNA repair (DNAR) genes was associated with DFS, and 16 DNAR genes with OS. Expression of 21 DNAR genes significantly increased after chemotherapy. Gene expression associations were validated at the protein level: high MUS81 at baseline predicted poor DFS (P=0.036) and poor OS (P=0.015) following oxaliplatin therapy; high XPF expression was associated with lack of pathological response (P=0.032); high Cyclin B1 predicted poor DFS (P=0.017). XPF protein levels increased following oxaliplatin (P=0.001, paired t-test). Conclusions: By confirmation of mRNA findings at the protein level, XPF, MUS81, and Cyclin B1 have been discovered as predictive biomarkers for response to oxaliplatin chemotherapy that merit prospective validation as tools for patient selection. Funded by Oxford NIHR Biomedical Research Centre and ECMC.
Effect of RAD21 overexpression on prognosis in KRAS-mutant colorectal carcinomas.
Authors: De Campos Silva Thomaz , Deb Siddhartha , Xu Huiling , Yan Yuqian , Fox Stephen B. , Mortensen Neil , McKay Michael 
Published: February 2017

453 Background: RAD21 is a component of the cohesion complex and is integral for chromosome segregation and error-free DNA repair. Early studies suggest RAD21 appears to be functionally important in tumour progression and we assessed its clinicopathological and prognostic significance in a cohort of colorectal adenocarcinoma (CRC), and its biological characteristics and cell cell chemosensitivity in vitro. Methods: A multi-institutional study examined RAD21 expression in 652 invasive CRC's. Correlation with clinicopathological factors including gender, differentiation, subtype, nodal status, metastasis and disease specific survival was performed. Correlation with BRAF and KRAS mutation status, p53 accumulation, microsatellite instability, and CpG island methylator phenotype was also undertaken. Cell clones with stable RAD21 knockdown were generated and tested for cellular sensitivity to conventional chemotherapeutic drugs. Results: High RAD21 expression correlated with male gender (56.7% vs. 43.3%), more well differentiated tumours (14.4% vs. 4.0%, p = 0.0001), higher T stage (36.1% vs. 27.0%, p = 0.01), and presence of metastasis (18.8% vs. 12.6%, p =0.03). Both on univariate and multivariate analysis, increased RAD21 expression correlated with worse DSS (hazards ration [HR] 1.4, 95% confidence interval [CI] 1.1 to 1.9, p = 0.01). Subgroup analysis showed RAD21 expression was prognostic in female patients (HR:1.6, 95%CI:1.1-2.3, p = 0.01) and tumours with nodal disease (HR:1.6, 95%CI:1.2-2.2, p = 0.003). RAD21 expression associates worse DSS in patients whose tumors carrying KRAS mutations (HR:2.6, 95%CI:1.4-4.3, p = 0.001), or p53 accumulation (HR:2.2, 95%CI:1.2-4.1, p = 0.02) and in patients receiving adjuvant chemoradiotherapy (HR:1.9, 95%CI:1.2-3.0, p = 0.005). Cells with reduced RAD21 expression exhibited enhanced sensitivity to 5-FU, alone or with Oxaliplatin. Conclusions: RAD21 expression in CRC is associated to advanced disease stage and confers poorer overall prognosis and resistance to chemoradiotherapy. RAD21 expression is of prognostic significance in tumours with somatic KRAS mutations or p53 accumulation. In these subgroups, RAD21 may be a novel important therapeutic target.
Associations between patient (pt) colorectal cancer (CRC) tumor KRAS and BRAF mutation (mut) status and overall survival (OS).
Authors: Hassabo Hesham M. , Sahin Ibrahim Halil , Kazmi Syed Mohammad Ali , Al Mutar Salwan S. , Bugano Diniz Gomes Diogo , Pini Tunghi May , Vilar Sanchez Eduardo , Dasari Arvind , Kopetz Scott , Overman Michael J. , Eng Cathy , Kee Bryan K , Vauthey Jean-Nicolas , Hassan Manal , Garrett Chris R. 
Published: February 2017

473 Background: Evolving information is emerging regarding patient tumor molecular data and associations with patient clinical characteristics and survival outcomes; we sought to evaluate pt clinical data with CRC tumor mut status. Methods: Since January 2008 tumor pts with stage IV CRC (principally primary tumors) were analyzed for KRAS (codon 12, 13, and 61) mut status as standard-of-care. A subset of pts tumors underwent BRAF and KRAS codon 164 mut testing. Results: 1,891 pts with CRC whose tumors underwent molecular mut analysis were identified from the clinical record. There was no statistically significant difference in pt overall survival from time of diagnosis for stages I/II (data not shown) and III; for stage IV pts there was an inferior OS associated with BRAF mut tumors (see Table). Tumor BRAF mut was significantly detected among ever smokers (10.2%) as compared to never smokers (5.4%), p < 0.001; meanwhile, tumor KRAS mut and wild type distribution were similar between ever smokers and never smokers. KRAS mut was significantly observed in CRC patients with distant lymph node, hepatic and lung metastasis, p < 0.001. Type 2 diabetes, intake of metformin or ACE inhibitors, were not significantly correlated with tumor KRAS or BRAF mut status. Conclusions: Pts with stage IV CRC BRAF mut tumors have a higher likelihood of prior or current smoking history in addition to having an adverse survival prognosis; pts with stage IV KRAS mut tumors have an increased association with distant lymph node, hepatic, and lung metastases as compared to KRAS wild type and BRAF mut tumors. Studies are ongoing to determine how tumor molecular characteristics may help to predict clinical outcomes and provide a useful to guide pt care. [Table: see text]
Association of human papillomavirus with unique clinicopathologic features in patients with metastatic squamous cell carcinoma of the anal canal.
Authors: Morris Van Karlyle , Rashid Asif , Rodriguez-Bigas Miguel A. , Das Prajnan , Wolff Robert A. , Chang George J. , Crane Christopher H. , Phillips Jonathan , Ohinata Aki , Rogers Jane , Eng Cathy 
Published: February 2017

479 Background: The incidence of anal carcinoma in the United States continues to increase steadily, and infection with the human papillomavirus (HPV) is an established risk factor for the development of anal carcinoma. However, clinicopathologic characteristics of patients with metastatic squamous cell carcinoma of the anal canal according to HPV status have thus far not been defined. Methods: Records of patients treated for metastatic squamous cell carcinoma of the anal canal at the MD Anderson Cancer Center between June 2005 and August 2013 were reviewed. Patients were tested for the presence of HPV DNA by in-situ hybridization and/or the p16 oncoprotein by immunohistochemistry. Associations between the presence of HPV and clinicopathologic attributes were measured by calculation of odds ratios, and survival was estimated according to the Kaplan-Meier method. Results: Patients were followed for a mean of 50.2 months, and the mean age at diagnosis was 54.0 years. Among the 43 patient records reviewed, 39 tumors (90.1%) tested positive for the presence of HPV. Patients with HPV-negative tumors were more likely to have a strong (> 30 pack-year) tobacco history (OR=18.5, p=0.018) and were more likely to develop brain metastases (OR=2.0, p=0.04). A faint association was observed between Caucasian ethnicity and HPV-positive tumors (OR=8.8, p=0.06). Median survival from the time of diagnosis of metastatic disease was 42.4 months, with a trend towards a worse survival seen among patients with HPV-negative tumors (HR for death 4.9, p=0.09). Conclusions: Differences in HPV status and prior tobacco exposure may identify two separate populations of patients with metastatic squamous cell anal carcinoma with different clinicopathologic phenotypes. Our results are similar to prior published data in patients with squamous cell carcinoma of the head and neck in which patients with HPV-positive tumors demonstrate improved survival outcomes. Data from additional patients will be presented.
Potential role of mTOR phosphorylation status as a negative predictor to everolimus plus octreotide in NETs.
Authors: Casanovas Oriol , Capdevila Jaume , Barriuso Jorge , Teule Alex , Castellano Daniel E. , Manzano Jose Luis , Lopez Carlos , Alonso Vicente , Garcia Carbonero Rocio , Dotor Emma , Martinez Alba , Salazar Ramon 
Published: February 2017

484 Background: Everolimus treatment is currently approved for a few tumor types and currently evaluated in several other malignancies, including NETs. Nevertheless, there is an urgent need for histological or molecular factors of prediction of response, as these would help discriminate subgroups of patients more likely to respond. Here we report on a biological sub-study on histological markers to unravel the relationship between the activation of the IGFR-mTOR-S6 signal transduction pathway with treatment response to everolimus plus octreotide combined therapy in patients with GI NETs. Methods: IGFR-1 (Abcam #54274), phospho-mTOR (Ser-2448, Cell Signaling #2976) and phospho-S6 (Ser-235/236, Cell Signaling #4857) were evaluated by immunohistochemistry (according to Choe G. et al, Cancer Research. 2003) from paraffin embedded blocks from patients with progressive locally advanced or metastatic non-functioning GI NETs, included in a national phase II clinical trial (EVERLAR, NCT01567488). Study endpoint was PFS, and 50% of the patients had progressed at the time of analysis. Univariant (Chi square) and multi-variant (COX) statistical analysis were performed. Results: 38 patients were evaluated with a median age of 62.7 years, balanced on gender (57 % vs. 42%), of which 76.3% were metastatic, mostly to liver. IGF1R positivity showed a nonsignificant trend to association to treatment response (50% progression vs. 21% progression, p=0.15). Nevertheless, mTOR activation (phospho-mTOR positivity) was associated with progression (median PFS of 100 days vs. 225 days, p=0.019). Multivariant COX regression analysis showed a Hazard Ratio of 2.96 [0.8-10.2] (p=0.087) for phospho-mTOR activation. Conclusions: Contrarily to expected results, mTOR activation status determined by phospho-mTOR immunohistological positivity seems to be associated to worse outcome in terms of progression to everolimus+somatostatin analogs in GI NETs patients. This could be indicative of a refractoriness or primary resistance to treatment based on a threshold of mTOR activation, possibly due to activation feedback-loops.
Influence of genetic variants of genes potentially associated with colorectal brain metastases on overall survival.
Authors: Stremitzer Stefan , Berghoff Anna Sophie , Volz Nico Benjamin , Zhang Wu , Yang Dongyun , Stintzing Sebastian , Ning Yan , Sunakawa Yu , Yamauchi Shinichi , Sebio Ana , El-Khoueiry Rita Elie , Birner Peter , Preusser Matthias , Lenz Heinz-Josef 
Published: February 2017

487 Background: Brain metastases (BM) in colorectal cancer (CRC) are rare, developing in only 0.3-9% of the patients, and considered a late-stage manifestation of the disease. The aim of this study was to investigate whether genetic variants of genes involved in BM-related pathways, such as integrin, invasion- and adhesion-mediating, angiogenic and tumor suppressing pathways, are associated with outcome. Methods: Genomic DNA was extracted from formalin-fixed paraffin embedded resected BM from 70 patients with histologically proven CRC. Single nucleotide polymorphisms (SNP) in seven genes (CXCR4, MMP9, ST6GALNAC5, ITGAV, ITGB1, ITGB3, KLF4) were analyzed by direct Sanger DNA sequencing and evaluated for association with overall survival (OS) from resection of BM. Only SNPs with an allele frequency of ≥ 10% were analyzed. Results: In univariate analysis, rs17577 (MMP9) and rs4642 (ITGB3) showed a significant difference in OS [(G/G 7.4 months, G/A 5.1 months; HR (95% CI) 1.83 (0.95-3.53), p = 0.0440) and (A/A 9.4 months, A/G 4.8 months, G/G 4.3 months; HR (95% CI) 0.81 (0.44-1.49) and 2.14 (0.98-4.67), p = 0.0354), respectively]. In multivariate analysis adjusted for baseline characteristics [primary tumor site (right colon, left colon, rectal), chemotherapy before BM (yes/no), BM location (supratentorial, infratentorial, both), Karnofsky performance status (<80, 80-100)], rs2236599 (KLF4), and rs10171481 (ITGAV) are significant in OS [(G/G 7.4 months, G/A or A/A 4.8 months; HR (95% CI) 3.19 (1.55-6.53), p = 0.0016) and (A/A 5.7 months, A/G 4.4 months, G/G 15.5 months; HR (95% CI) 0.61 (0.29-1.29) and 0.25 (0.10-0.60), p = 0.0082), respectively]. Conclusions: This study suggests for the first time a prognostic effect of the SNPs involved in the BM pathway. Further analyses are needed to confirm these findings.