bluuebunny/crossref_metadata_2025_split huggingface dataset:
Smoking and the risk of anal cancer recurrence: The Addenbrookes Hospital experience.
Authors: Bowzyk Al-Naeeb Anna , Barnett Gill , Wilson Charles 
Published: February 2017

439 Background: Anal cancer, a tumour induced by the human papilloma virus (HPV) is highly responsive to chemoradiation. Smoking appears to be an important cofactor in its development, possibly through immunomodulatory mechanism and has been reported to have a negative effect on prognosis. Objective is to evaluate the relation between smoking and the outcome in patients receiving radical chemoradiotherapy (50.4 Gy/ 28f with concomitant 5FU/Mitomycin) for squamous carcinoma of the anus. Methods: 109 patients treated with radical intent from January 2009- Feb 2013 were retrospectively analysed. Details of staging, smoking history, HIV status, response to treatment, follow up time and recording of persistent or recurrence were collected. High risk disease (HR) was defined as any T3/T4 disease or TxN2+, standard risk (SR) as T1/2 N0-1. Results: 68 females and 41 males with an age range 38-83 (median 61).Data about smoking status was available in 74 patients: 28 smokers, 8 ex-smokers, and 38 non-smokers. 54/109 (49%) had high risk disease (HR), and the distribution was balanced across the groups. 4 patients were HIV positive. Median follow up time was 23 months. Complete clinical response was achieved in 101/109 (93%), 1 patient died (cause unknown), and 7 had persistent disease. Of these 6 were smokers (2 SR, 3HR, 1 HR and HIV+) 1 was a non-smoker (1 HR). 9 patients developed recurrent disease: 5 smokers (2 SR, 3 HR), 1 ex-smoker (HR), 3 unknown (2HR, 1SR). 11/16 patients who had a local failure were persistent smokers. Using ordinal logistic regression, smoking increases the risk of recurrence with an Odds ratio of 17.4 (p=0.008). Conclusions: This retrospective series suggest that smoking is associated with a higher risk of local recurrence following chemoradiotherapy. One of the hypothesis is that tissue hypoxia may impact on the oxygen dependent effect of chemoradiation. Patients should be encouraged to stop smoking and smoking may need to be considered as a factor defining a higher risk category which may benefit from dose escalation.
Are the survival benefits associated with primary resection in de novo metastatic colorectal cancer (mCRC) mediated by reversal of systemic inflammation?
Authors: Tran Phillip V. , Samanthaby Mathu , Wong Hui-li , Desai Jayesh , Tie Jeanne , Field Kathryn M. , Kosmider Suzanne , Bae Susie , Gibbs Peter , Tran Ben 
Published: February 2017

464 Background: Despite reported survival benefits for primary tumor resection in de novo mCRC, its use remains controversial, particularly as the biological explanation remains unclear. We explored whether reversal of systemic inflammation, a marker of a tumor-promoting immune response and poor prognosis, is associated with improved survival in pts undergoing primary resection. Methods: We identified pts who underwent primary resection for de novo mCRC from a prospective CRC database, excluding pts who had metastatectomy. Neutrophil-lymphocyte ratio (NLR) was used to represent systemic inflammation. Survival differences associated with reversal of systemic inflammation, as defined by NLR falling from an elevated level (> 5) at diagnosis to ≤ 5 postoperatively, were examined. Associations between falling NLR and primary tumor bulk (maximal length assessed by pathologist) as well as metastatic burden (maximal axial diameter of largest metastasis assessed by radiologist) were explored. Results: Baseline and postoperative NLR were examined in 156 pts with median age 69y and median overall survival (OS) 18.3 mo. Baseline NLR was elevated in 66 (42%) pts; primary resection resulted in falling NLR in 37 of these pts (56%). Compared to pts with persistent NLR >5, a falling NLR was significantly associated with improved OS (HR 0.53, p = 0.012). Falling NLR was also associated with larger primary tumors, although this was not significant (median length 55mm vs. 45mm, p = 0.059). In a preliminary analysis of 26 pts with retrievable radiology, falling NLR was associated with lower metastatic burden compared to an unchanged NLR (median diameter 29mm vs. 41mm, p = 0.046). Conclusions: Our data demonstrates improved OS in pts who have reversal of systemic inflammation following primary resection in de novo mCRC. The possible associations between reversed systemic inflammation with larger primary tumors or a lower metastatic burden suggest an immune mediated response to reduced tumour bulk as an explanation for the reported survival advantage associated with primary resection. If confirmed, this might define a subgroup of pts who might benefit most from primary resection.
Detection of potential actionable targets in appendiceal cancer detected by immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), and mutational analysis.
Authors: Borazanci Erkut , Kimbrough Jeffery , Sachdev Jasgit C. , Millis Sherri Z. , Ejadi Samuel , Burnett Ken , Ratliff Stephanie , Von Hoff Daniel D. , Ramanathan Ramesh K. 
Published: February 2017

469 Background: Appendiceal cancers are rare and there are no established guidelines for adjuvant treatment and metastatic disease. Methods: Samples were identified from > 60,000 global tumors analyzed at a referral molecular profiling CLIA certified laboratory (Caris Life Sciences) for biomarkers of drug sensitivity, under an approved protocol. 285 samples with primary tumor sites of appendix were identified (M/F ratio of 38%/62%; mean age of 55). Approximately 80% of samples were adenocarcinomas, 10% carcinoids, and 10% of indeterminate histology. IHC assays (n=273) were performed with up to 30 biomarkers; FISH (n=39) for c-Myc, cMET, EGFR, HER2 and/or TOPO2A gene copy amplifications; and sequencing done ( n= 223) for KRAS, EGFR, PIK3CA, and BRAF. Results: Targets on IHC: 97% high BCRP; 16% high KIT; 80% high COX-2; 50%high EGFR; 30% low MGMT, 81% high MRP1, 35% high PDGFR, 82% low PTEN, 27% high RRM1, 39% high SPARC; 67% high TLE3, 27% high TOPO2A ; 63% high TOPOI, and 99% negative TS. Targets on FISH: 5% amplified EGFR and 0% amplified Her2/Neu. Sequencing results: 53% mutated KRAS and 2% mutated BRAF. Conclusions: The high levels of drug resistance proteins (BCRP and MRP1) highlights the difficulty in treating these tumors. The incidence of KRAS mutations (53%) and low expression of TS (99%) is noteworthy, and points towards using 5FU/capecitabine as a backbone of therapy. Therapeutic options are varied and options include TOPO1 inhibitors (irinotecan/topotecan), EGFR inhibitors (erlotinib, cetuximab), PDGFR antagonists (regorafenib, axitinib), MGMT (temazolamide), BRAF inhibitors (vemurafenib, dabrafenib) and SPARC (nab-paclitaxel). These findings indicate the need to evaluate patient samples for patterns in marker expression and alteration, in order to better understand the molecular biology and formulate a personalized therapy approach in these difficult to treat cancers, and to pursue whole genomic sequencing. Supported by a grant from Caris Life Sciences.
Immune response and its correlation with the disease activity in patients with advanced colorectal cancer (aCRC): Results from a prospective observational study.
Authors: Ahmed Shahid , Wei Guojian , Lim June , Arnold Florence Pilar M. Plaza , Abbas Tahir , Iqbal Nayyar , Dwernychuck Lynn , Sami Amer , Haider Kamal , Yadav Sunil , Bretscher Peter 
Published: February 2017

471 Background: Currently limited biomarkers are available to monitor disease status in cancer patients. Although host factors are critical in regulating cancer, the role of immune responses in aCRC is less clear. A predominant T helper 1 (Th1) response may be more effective to contain cancer than one with a substantial Th2 component. The Th1/Th2 phenotype can be inferred from relative prevalence of IgG isotypes among anti-cancer antibodies and may provide an innovative way to assess disease activity. The study aims to develop an ELISA assay to monitor IgG1:IgG2 and its utility in predicting disease status in aCRC. Methods: A validated ELISA assay (Bertech Pharma) utilizing CRC cell lines was developed to measure IgG1 (Th2) and IgG2 (Th1) levels. A sample size of 44 (24 CRC and 20 healthy control [HC]) was estimated to achieve 80% power and α error of 0.05 assuming that the assay correctly detect CRC specific antibody in > 80% cases. The IgG1:IgG2 was compared between/within groups with HC and aCRC. Results: Samples were collected from 62/66 individuals recruited at 2:1 over 1 yr. 43 CRC patients had median age of 65 yrs (39-86) and M:F 2.3:1. 25 had >1 metastatic site, 31 underwent primary tumor resection and 37 received chemotherapy. Using standard criteria, 14/43 (33%) CRC patients had elevated 1gG1 titer compared with 2/19 (10%) HCs (p = 0.06). Mean IgG1 of CRC group was 0.18±0.05 compared with 0.15±0.01 in HC (p = 0.01). Conversely, mean IgG2 level of CRC group was 0.26±0.11 compared with 0.38±0.15 in HC (p = 0.003). Mean IgG2:IgG1 of CRC group was 1.5±0.35 compared with 2.5±0.97 in HC (p < 0.001). Among 43 CRC patients, 7/12 (58%) with disease progression (DP) had elevated IgG1 compared 7/31 (23%) with stable disease (p = 0.03). Strikingly, 9/12 (75%) patients who died had elevated IgG1 compared with 5/31 (16%) who were alive during the follow up, p = 0.001. Logistic regression revealed positive association among elevated IgG1 and DP, HR:4.8 (95% CI:1.2-19.9) and mortality, HR:15 (95% CI:3.1-78.8). Conclusions: Our results revealed that patients with aCRC have abnormal IgG1:IgG2 compared with HC and elevated IgG1 (a predominant Th2 response) levels in aCRC correlate with DP and mortality.
A phase I/II study of azacitidine and capecitabine/oxaliplatin (CAPOX) in refractory CIMP-high metastatic colorectal cancer.
Authors: Overman Michael J. , Eng Cathy , Kee Bryan K. , Fogelman David R. , Shroff Rachna T. , Fark Christine , Moinova Helen , Lutterbaugh Jim , Issa Jean-Pierre J. , Markowitz Sanford D. , Kopetz Scott 
Published: February 2017

488 Background: Hypermethylation of promoter CpG islands (CIMP) has been strongly implicated in chemotherapy resistance and both clinical and preclinical studies have shown the ability to restore platinum sensitivity with the reversal of hypermethylation. CIMP is implicated in the pathogenesis of a subset of colorectal cancers termed CIMP-high. Methods: The primary objectives were as follows: phase I—MTD and DLTs; phase II—RECIST response rate. Prior progression on fluoropyrimidine/oxaliplatin-based treatment was required (RECIST criteria progression in 21 pts). The phase II portion was restricted to patients with CIMP-high (≥ 2/6 methylation-specific PCR markers: hMLH1, P16, P14, MINT1, MINT2, and MINT31). Pre-treatment, C1D5, C2D1, C2D5, and at restaging blood samples were collected. Results: 26 pts [M/F 15/11, median age: 66 yrs (range: 34-75), ECOG PS 0/1: 1/25, median number of prior therapies: 4.5] were enrolled from 8/2010 to 12/2012. The phase I portion enrolled 15 pts (12 treated at MTD), of which 3 were CIMP-high. No DLTs were observed with the MTD determined to be azacitidine (75 mg/m2, SQ D1-5), oxaliplatin (110 mg/m2 IV D2), and capecitabine (1500 mg/m2/d, PO divided BID, D1-14) q21 days. The phase II portion enrolled 11 CIMP-high pts and closed due to lack of an objective response. Common grade 3-4 treatment-related toxicities were neutropenia in 10 pts (38%) and diarrhea in 3 pts (12%). Grade 2 fatigue occurred in 14 pts (54%). No responses were seen. Stable disease (SD) occurred in 7 of 15 phase I pts and 10 of 11 phase II pts (p=0.04) with median PFS of 2.5 and 4.5m (p=0.04), respectively. SD >6 months was seen in 2 phase II pts (6.8m and 8.5m). Median OS and median post-study OS were 9.4m and 5.3m, respectively, and were similar between phase I and phase II portions. Post-study therapy was given to 14 patients: 12 progressed, 1 on active treatment, 1 lost to f/u. Conclusions: Azacitidine and CAPOX were well tolerated with high rates of stable disease in CIMP-high pts, but no objective responses. Improved activity from post-study treatment was not seen. Ongoing correlative work evaluating quantitative changes in methylation from circulating free tumor DNA will be presented. Clinical trial information: NCT01193517.
Plasma cell-free DNA and fraction of circulating KRAS mutations as prognostic in patients with metastatic colorectal cancer.
Authors: Sefrioui David , Vasseur Nasrin , Sesboüé Richard , Blanchard France , Oden-Gangloff Alice , Sabourin Jean-Christophe , Frébourg Thierry , Michel Pierre , Di Fiore Frédéric 
Published: February 2017

490 Background: It has been suggested that detection of circulating tumor DNA may be relevant in patients with metastatic colorectal cancer (mCRC). The main objective of the present study was to evaluate a method based on the TaqMan Mutation Detection Assay (TMDA) for the detection of circulating KRAS mutations in mCRC patients. Moreover, we also investigated the prognostic impact of the plasma cell-free DNA and the fraction of circulating KRAS mutations. Methods: The study was conducted from April to July 2013 and plasma samples were prospectively collected in a series of 35 mCRC patients treated with chemotherapy (CT). QIAamp Circulating Nucleic Acid kit was used for DNA extraction and Quant-iT High Sensitivity dsDNA Assay for cf-DNA quantification. Detection of circulating tumor DNA was based on the KRAS mutations detected in tumour and was performed in plasma by the castPCR Technology TMDA. Response to CT was assessed according to RECIST criteria. The results of plasma cf-DNA and level of mutant DNA fragments were correlated with response and 3-months survival. Results: We isolated and quantified plasma cf-DNA in all patients with a mean concentration of 106 ng/mL. Among them, 18 were wild-type and 17 mutated for KRAS in the tumour. Detection of circulating KRAS mutations was performed with TMDA in 23 patients (10 KRAS wild-type and 13 KRAS mutated). The sensitivity was 62% (8/13) and specificity 100% (0/10) with a level of circulating mutant DNA fragments ranging from 0 to 29%. Plasma cf-DNA and level of circulating mutant DNA were both significantly correlated with the 3-months survival (mean 36 versus 524 ng/mL, p=0.0015 and 2% versus 29%, p<0.0001). There was a non significant trend for response to CT (respectively p=0.14 and p=0.12). Conclusions: TMDA method is a simple, accurate and non-invasive tool for the detection of circulating tumor DNA. Our preliminary results also suggest that plasma cf-DNA and fraction of mutant DNA fragments could be prognostic markers in mCRC patients.
Correlation of lymphovascular invasion and staging in patients undergoing lymphatic mapping for colon cancer.
Authors: Korant Alpesh K. , Dhar Vikrom K. , Johnston Gregory , Saha Supriya Kumar , Shaik Mohammed , Wiese David , Saha Sukamal 
Published: February 2017

498 Background: Lymphovascular invasion (LVI) is known as a negative prognostic factor in colon cancer (CCa) patients (pts). Sentinel lymph node mapping (SLNM) is known to upstage more pts than conventional surgery. A retrospective study was undertaken to determine the relationship between LVI and other known prognostic factors in CCa pts undergoing SLNM. Methods: Pts with CCa underwent SLNM. Data was collected for tumor (T) and node (N) stage, distant metastasis (M), size, grade, recurrence, and 5-year overall survival (5yrOS). Chi-square analysis was used to calculate the association between categorical variables with a p value of 0.05 as significant. Kaplan-Meier method was used to calculate 5yrOS. Results: We studied 310 CCa pts undergoing SLNM. Success rate was 100%. Nodal positivity was 46%. LVI was present in 34% of pts overall, in 66% node +ve pts versus only 7% in node -ve pts (p<0.001). Pts with LVI were proportionately of higher grade, larger size, higher T-stage, node +ve and higher AJCC stage. Pts with LVI had significantly higher recurrence and lower 5yrOS (Table). Conclusions: Presence of LVI positively correlated with all known prognostic factors in CCa pts undergoing SLNM, with higher recurrence and significantly lower 5yrOS. [Table: see text]
Concordance of ColoPrint and MSI-print classification in paired endoscopic-surgical specimens of stage I-III colorectal cancer (CRC).
Authors: Garcia-Carbonero Rocio , Sanchez-Simon Inmaculada , Bozada Juan M. , Araujo Miguez Angela , De la Portilla Fernando , Nieboer Frank , Stork Lisette , Simon Iris M. 
Published: February 2017

501 Background: ColoPrint is a gene expression classifier that has demonstrated improved prognostic accuracy over conventional clinical and pathological factors in patients with stage II-III CRC (Salazar et al, JCO 2011). MSI-Print is a gene classifier that identifies patients with deficient mismatch repair system and MSI-H status (Tian et al. J Pathol 2012). The gene signatures have been validated in several independent patient cohorts. The aim of this study was to assess the performance of ColoPrint and MSI-Print in fresh-frozen endoscopic samples obtained by colonoscopy. Methods: A pilot study was initiated to address the concordance of gene signatures in paired endoscopic-surgical fresh-frozen samples from patients with stage I-III CRC. RNA was isolated from samples with > 30% tumor cells. Nineteen paired samples passed quality control and were hybridized to the diagnostic microarrays. Results: Patient characteristics–median age: 74 years (range:49-84); male/ female: 58/42(%); ECOG 0-1/2-3: 84/16(%); stage I/II/III: 21/47/32(%). ColoPrint risk classification was highly concordant between paired endoscopic and surgical specimens from the same patient. 14 cases were equally classified as low risk; 3 cases were equally classified as high risk; 2 cases were not concordant but the risk score was close to the cut-off value between low and high risk for both matched pairs (borderline samples). A similar high concordance was observed for the MSI signature in paired endoscopic-surgical samples (13 cases were equally classified as MSS, 5 equally classified as MSI, and 1 case had borderline results (both samples close to the cut-off between MSS/MSI). Conclusions: These encouraging preliminary results suggest endoscopic procedures may be valuable, non-invasive and widely available tools to obtain adequate tumor tissue for molecular assays, and can allow for easy implementation of genomic signatures in patients not amenable to surgical resection (i.e., advanced disease) and/or in less complex community sites for routine clinical practice.
A proprietary multianalyte test for predicting extreme resistance to neoadjuvant 5-FU based chemoradiation (CTRT) in esophageal adenocarcinoma (EC).
Authors: Shan Weiwei , Lassen Natalie , Johnson Clare , Biermann-Harrar Yaeli , Oelschlager Kristen M. , Cook Robert W. , Rosen Daniel , Badve Sunil S. , Kessler Kenneth , Saxena Romil 
Published: February 2017

51 Background: Standard of care for localized EC is neoadjuvant CTRT followed by surgery. Although 5-FU based regimens are still commonly used, other regimens (CROSS) are also prescribed. Published EC studies report 20-25% of patients exhibit extreme resistance (exCTRT) to 5-FU based neoadjuvant treatment (NT); these patients may benefit from alternative treatment regimens. We have developed a proprietary assay using a training set of 167 patients to accurately identify patients with exCTRT (ROC 0.96). The results presented herein constitute an independent clinical validation. Methods: Biopsy samples from 71 pts diagnosed to have EC and who had undergone surgical excision following NT were obtained. IHC detection of NF-kB, SHH, and Gli-1 proteins in FFPE sections was performed in a CLIA approved lab. A GI pathologist and an expert clinical scientist blindly evaluated resection specimens and assigned a labeling index (LI) score. The LI for each case was compared to the established training set and the predicted response determined using a logistic regression algorithm. Blinded pathology scoring for exCTRT vs. non-exCTRT was performed for all samples using both CAP Tumor Response Grade (TRG) and the Rohatgi research scale. Results: Of the 71 EC cases in the clinical validation cohort, 24 had an outcome of exCTRT (<50% reduction in tumor following neoadjuvant treatment; TRG 3) and 47 had an outcome of non-exCTRT (>50% reduction in tumor; TRG 0-2). ROC for the validation cohort was 0.85. The positive predictive value for the validation study was 83%, reflecting an assay that can accurately predict those likely to have some degree of response to chemotherapy / radiation. Conversely, a negative predictive value of 83% with specificity of 94% was achieved indicating accurate identification of those not likely to benefit from neoadjuvant treatment. Conclusions: The analysis of NF-kB, SHH, and Gli-1 in EC tissue can accurately identify patients unlikely to respond to 5-FU based NT. These results are now confirmed using a CLIA accredited lab and a multicenter independent validation cohort of esophageal adenocarcinoma biopsies.
TRP genes family expression in colorectal cancer and its relationship with prognostic factors.
Authors: Kalender Mehmet Emin , Sozucan Yilmaz , Sari Ibrahim , Suner Ali , Oztuzcu Serdar , Bozgeyik Ibrahim , Cengiz Beyhan , Igci Yusuf Z , Balakan Ozan , Camci Celaletdin 
Published: February 2017

513 Background: Different factors are effective in the development of colorectal cancer (CC). With the discovery of that TRP (transient receptor potential) genes family is an important component of calcium channel, about 30 members of the family of TRP ion channel in mammals have been determined up to the present. TRP channels are associated with many pathological conditions like cancer and cardiovascular diseases as well as the physiological significance of them.. The aim of this study is to investigate TRPM, TRPV and TRPC gene expression levels in tumor tissues of CC patients and to analyze the relationship of expression in tumor tissue of colorectal cancer with other known prognostic factors. Methods: In this study, 93 CC patients whose follow-up and treatment realized in Medical Oncology Department of Gaziantep University Medical Faculty Hospital were analyzed retrospectively. Level of TRP gene expression in paraffin blocks of normal and cancerous colorectal tissue samples of 93 patients were studied at the level of mRNA with real-time PCR. Results: From normal and cancerous colorectal tissues of 37 female and 56 male patients diagnosed with colorectal cancer, expressions of TRPV3, TRPV4, TRPV5, TRPM4, and TRPC6 genes in tumor tissue were detected lower when compared to normal tissue (p < 0.05). When expression levels of other TRP genes in tissues were compared, any significant difference was not found (p > 0.05). There was no meaningful difference between prognostic factors and gene expressions of tumor tissues statistically (p > 0.05). Conclusions: Expression of many proteins in cancer cells compared to normal cells increases or decreases. In CC, TRPV3, TRPV4, TRPV5, TRPM4, and TRPC6 genes of which expression in cancerous tissue decreases may be thought as potential genes contributing to tumorigenesis. To verify this hypothesis, it should be supported with further studies.