bluuebunny/crossref_metadata_2025_split huggingface dataset:
The association between smoking and LINE-1 hypomethylation (global DNA hypomethylation) in normal esophageal epithelium of patients with esophageal squamous cell carcinoma.
Authors: Iwagami Shiro , Baba Yoshifumi , Watanabe Masayuki , Shigaki Hironobu , Miyake Keisuke , Ida Satoshi , Nagai Yohei , Ishimoto Takatsugu , Iwatsuki Masaaki , Sakamoto Yasuo , Miyamoto Yuji , Baba Hideo 
Published: February 2017

41 Background: DNA methylation is a major epigenetic mechanism in X-chromosome inactivation, imprinting and repression of transposable elements and endogenous retroviral sequences. Global DNA hypomethylation appears to play an important role in genomic instability, leading to cancer development. DNA methylation in the long interspersed nucleotide element-1, L1 (LINE-1) repetitive element is a good indicator of global DNA methylation level. Smoking and alcohol is extremely important as the etiology of esophageal squamous cell carcinoma. Nonetheless, whether or not smoking and alcohol affect LINE-1 methylation level in normal esophageal epithelium of esophageal cancer patients remains uncertain. Methods: We quantified LINE-1 methylation of normal esophageal mucosa using pyrosequencing technology in 118 resected esophageal squamous cell carcinomas. The data on smoking (Brinkman index, absence or presence) and alcohol amount are available in all cases. We excluded preoperatively treated cases. Results: LINE-1 methylation in normal esophageal epithelium of esophageal cancer patients ranged from 57.1 to 92.8 of 0-100 scale (N=118; mean 81.2; median 80.0; standard deviation 7.2). LINE-1 methylation level (continuous variable) was significantly associated with Brickman index (continuous variable) (r=0.12, p=0.0002); heavy smoker had lower LINE-1 methylation level of normal esophageal mucosa. LINE-1 methylation level was lower in patients with smoking history (mean 79.7) than in patients without smoking history (mean 83.2) (p=0.034). Alcohol assumption was not associated with LINE-1 methylation level (r=0.003, p=0.58). Conclusions: Smoking was associated with LINE-1 hypomethylation in esophageal normal epithelium, suggesting the possibility of epigenetic field effects caused by cigarette in esophageal tumorigenesis. Considering that DNA methylation alterations are reversible and can thus be targets for chemoprevention, our findings may have clinical implication.
Distance-to-care: Stage at diagnosis for New Mexico (NM) residents with colorectal cancer (CRC).
Authors: Mason Meredith C. , Bruner Andrew , Meisner Angela W. , Morris Katherine T. , Nir Itzhak , Rajput Ashwani , Wiggins Charles 
Published: February 2017

421 Background: CRC is a leading cause of morbidity and mortality among NM’s American Indians, Hispanics, and non-Hispanic whites. Previous studies have shown that rural residents are more likely than urban dwellers to be diagnosed with late stage disease. Geographically New Mexico is the 5th largest state with a population of 2 million, many of whom reside in rural regions. This study was designed to characterize the association between distance-to-care and stage of disease at diagnosis in NM. Methods: The population-based NM Tumor Registry was used to identify records for all incident cases of CRC between 2001-2008. Latitude and longitude were determined for the place of residence for cancer cases and for the facility where each case was diagnosed. The “Great Circles” algorithm was used to estimate the distance from place of residence to the diagnosing facility. The percentage of cases diagnosed with early stage vs. other stages (i.e., regional, distant, and unknown stages-combined) was assessed by quartile of distance-to-care with the use of the chi-squared test for trend. Multiple logistic regression was used to characterize the association between stage and quartile of distance-to-care while controlling for other factors know to be associated with stage at diagnosis. Results: Analysis was based on 6,291 incident cases of CRC that were diagnosed among NM residents. Latitude and longitude for both place of residence at diagnosis and location of diagnosing facility were available for 4,385 (69.7%) of all incident cases. The percentage of cases diagnosed at early stage was inversely related to the distance between the place of residence at diagnosis and the facility where the cancer was diagnosed, as follows: 41.4% of cases in Quartile 1 (shortest distance-to-care); 39.9% in Quartile 2; 37.8% in Quartile 3; and 35.3% in Quartile 4 (p=0.002).By multiple logistic regression, distance-to-care was a significant predictor of stage at diagnosis after adjustment of sex, age and race/ethnicity. Conclusions: Rural residents of NM who must travel relatively long distances to receive medical care are at increased risk of being diagnosed at late stage colorectal cancer.
Is PET/CT useful in the staging of anal cancer?
Authors: Bhuva Neel , Glynne-Jones Robert , Harrison Mark 
Published: February 2017

422 Background: The use of 18flurodeoxyglucose PET or PET/CT in staging of anal cancer is becoming increasingly fashionable. However, evidence endorsing it as a definitive staging modality it is still emerging. The largest published series to date from the UK found sensitivity of PET to be superior for detection of regional nodal metastases and overall PET changed stage in 23% and management in 16% of cases [de Winton E et al. The impact of 18-fluorodeoxyglucose positron emission tomography on the staging, management and outcome of anal cancer. BJR 2009; 100: 693-700]. We initially performed a retrospective pilot feasibility study for the period 2009-2010 and found that PET/CT altered staging in 42% of the 43 patients included, predominantly upstaging nodal status. We continue our analysis and report this prospective series - to assess the usefulness of PET/CT in the staging of anal cancer. Methods: 47 patients were treated radically for anal cancer at Mount Vernon Cancer Centre (UK) between January 2010 and July 2011, of which 27 had PET/CT scans. Staging was compared following conventional modalities and PET/CT. The TNM clinical staging system was used. Results: In 9 patients the PET/CT stage differed from MRI staging. In total, there were 4 ‘T stage’ changes and 8 ‘N stage’ changes. Of these, 1 case showed a difference in ‘T’ staging alone 5 showed a change in ‘N’ staging alone and 3 showed a change in ‘T’ and ‘N’ staging. PET/CT altered staging in 33% of patients. Conclusions: We conclude that PET/CT alters staging in a significant number of cases correlating with the literature and our own retrospective analysis. Furthermore there is agreement that PET/CT shows greater sensitivity for detection of lymph nodes. Although PET/CT cannot replace CT/MRI as the optimal modality for planning, it can reveal useful information regarding tumour extent, nodal involvement and distal metastases. PET/CT can account for greater definition of dose delivery, and more accurately ascertain the need to include/exclude pelvic lymph nodes. With more precise staging, acute and late toxicity profiles will be greatly influenced, especially with more advanced radiotherapy techniques such as Intensity Modulated Radiotherapy (IMRT), whilst maintaining satisfactory outcomes.
Measurements of 5-FU levels in plasma of patients with gastrointestinal cancer.
Authors: Blaschke Martina , Cameron Silke , Blumberg Jutta , Wegner Ulrike , Ramadori Giuliano 
Published: February 2017

437 Background: 5-fluorouracil (5-FU) 50 years after its first introduction into therapy of gastrointestinal tumors is still one of the most effective anticancer drugs. Due to large interindividual metabolism optimal dosing has not yet been established. As 5-FU is mostly used in combination with other drugs elevated serum levels could be responsible for severe side effects. The aim of this study was to analyse intra- and interindividual variability of 5-FU levels in patients with 5-FU infusional therapy. Methods: 230 blood samples were obtained from 31 gastrointestinal cancer patients (esophagus (8), stomach (10), ileum (1), colorectum (12)) treated with 5-FU-infusional regimens, based on a 24 or 48 hour AIO treatment schedule. 5-FU was delivered using a Baxter pump. Intra- and interindividual differences in 5-FU plasma concentrations were analysed before (0h; n=115), at 2-3 hours after start of infusional 5-FU treatment (n=19) (early sampling) and towards the end of the infusion (n=96) (late sampling). 5-FU plasma concentrations were measured using an immunolinked Elisa assay (Saladax 5-FU PCM). Results: Early blood sampling resulted in lower 5-FU plasma concentrations (541±126,9 ng/ml) due to NaCl prefilling (4,5 ml) of the 5-FU tubing, as the Baxter pump delivers 4ml/h. Blood sampling at the later time-point resulted in reliable values (971±81,1 ng/ml). 5-FU concentrations did increase with elevated 5-FU doses. Measurements of 5-FU plasma concentrations lead to reproducible results. 5-FU concentrations were dose-dependent with low intra- and interindividual variability. However, care has to be taken, as the results can be influenced by inaccurate blood sampling (e.g at the port), early blood sampling (steady state-levels not reached), too late sampling (folfusor-pump already empty, i.e. in summer with elevated temperature), delayed centrifugation or hemolysis. Critical analysis of the measurements and correct performance of the sampling is therefore necessary. Conclusions: Measurement of 5-FU plasma concentrations may in the future allow to optimize the 5-FU dosing and to identify the cause of toxicity. Changes of 5-FU clearance in long-term therapy have to be studied.
Obturator canal lymph node metastasis from rectal carcinoid tumor.
Authors: Wang Yi-Zarn , Hall Michael Anthony 
Published: February 2017

440 Background: The optimal treatment option for rectal carcinoid tumor remains unsettled. Trans-anal excision has been accepted for small tumors (< 1-2 cm in size) without lymph node involvement. Larger tumors, and those with lymph node metastasis, however, are usually treated via low anterior resection (LAR) with total mesorectal excision (TME). Midgut carcinoid tumors have been found to have the tendency to obstruct lymphatic flow and create a detour in lymphatic passage. We hypothesize that rectal carcinoid may have similar potential to develop alternative lymphatic pathways outside of the mesorectal envelope, thus escaping surgical removal with traditional TME. Methods: A retrospective chart review of rectal carcinoid patients who underwent radical LAR with TME between 2006 and 2011 was conducted to determine if any extra-mesorectal metastasis had occurred. Results: 19 patients who underwent LAR with TME for rectal carcinoid were identified. 14 patients had radio-guided surgery (RGS). 12 of which, were injected with TC-99 intra-operatively and 2 had a preoperative injection of In-111 for octreotide scan. 6 of the 19 patients (31.5%) were found to have obturator canal lymph node metastasis, confirmed by final pathologic review. 5 of these 6 patients had the nodal metastasis to the right obturator canal. Of note, 4 of the 6 patients complained of debilitating foot and medial thigh pain on the affected side, with complete symptom resolution after surgical excision. Conclusions: Up to 31.5% of rectal carcinoid patients can have extra-mesorectal lymph node metastasis that could easily be missed by the traditional TME. Preoperative octreotide scanning with In-111 injection or intra-operative Tc-99 peri-tumor injection, with concomitant RGS can easily identify and remove such metastasis. Symptomatic improvement can be accomplished with its removal. The effect of such extra-mesorectal metastasis on patients’ long term or disease free survival is yet to be determined.
KRAS mutation as a prognostic factor in patients undergoing hepatic resection for metastatic colorectal cancer.
Authors: Baker Justin John , Aufforth Rachel , Auman James Todd , Eil Robert , McLeod Howard L. , Kim Hong Jin , Meyers Michael O. , Calvo Benjamin F. , Yeh Jen Jen 
Published: February 2017

444 Background: It is well known that KRAS mutations limit the efficacy of anti-EGFR therapy in patients with metastatic colorectal cancer (mCRC). However the role of KRAS mutations in patients who undergo a curative liver resection for mCRC is less clear. The purpose of our study was to evaluate the relationship between KRAS mutation status and survival in this patient population. Methods: We examined an IRB approved tissue repository and retrospective database of 129 patients from 1998-2010 who underwent curative liver resection for mCRC. Tumors were sequenced for KRAS codons 12, 13, and 61 mutations using pyrosequencing. Overall survival (OS) and disease-free survival (DFS) were analyzed using the Kaplan-Meier method and compared using the log-rank test. Multivariate analysis was performed using the Cox proportional hazards regression method. Results: The median follow-up for our cohort was 20.4mo (0.4-112). Mean age was 61.4±12.3. Prior to surgical resection 55 (43%) patients received chemotherapy. 35 (27%) tumors were KRAS mutant (mt), 83 (64%) were wild-type (wt), and 11 (9%) were not characterized. Median OS for KRAS wt patients was 40.3mo vs. 27.1mo for KRAS mt patients (p=0.046). Median DFS for KRAS wt was 13.6mo vs. 7.7mo for KRAS mt patients (p=0.037). 8 patients received cetuximab post–operatively. Cetuximab status was unknown in 50 patients. When we excluded those treated with cetuximab, the median OS was 40mo for KRAS wt vs. 25mo for KRAS mt patients (p=0.007). There were no differences in OS or DFS in patients who received cetuximab (p=0.7). In a multivariable model with pre-operative chemotherapy (p=0.2), extent of resection (p=0.053), and cetuximab therapy (p=0.7), the presence of KRAS mutation was independently associated with poor prognosis (HR=2.7 [1.3-5.5]). Conclusions: In patients undergoing curative liver resection for mCRC, KRAS mutation status is independently predictive of a worse outcome regardless of cetuximab therapy. KRAS status may be associated with more aggressive tumor biology. Our data supports the critical need to define KRAS mutation status and to develop therapies against KRAS and its downstream effectors.
Use of FoxP3+ and cytotoxic CD8+ T lymphocytes to identify a patient subgroup with a favorable prognosis similar to colon cancers with deficient DNA mismatch (dMMR) repair.
Authors: Yoon Harry H. , Orrock Jared M , Foster Nathan R. , Sargent Daniel J. , Smyrk Thomas C. , Sinicrope Frank 
Published: February 2017

460 Background: The immune response has emerged as a strong prognostic factor in colon cancer. Whereas CD8+ T cells mediate antitumor response, regulatory T cells expressing FoxP3+ can antagonize this effect, though prognostic data conflict. These markers have yet to be analyzed with MMR status, which is important since dMMR tumors show enhanced immune response. Methods: CD8+ and FoxP3+ density were analyzed by immunohistochemistry (IHC) in resected stage II and III colon carcinomas (N = 216) from participants in phase III adjuvant 5-fluorouracil-based trials. High vs low immune density was dichotomized at the median. MMR status, determined by IHC or analysis of microsatellite instability, was categorized as dMMR (12%) or proficient MMR (pMMR). Cox models, stratified by study, were adjusted for age, stage, grade and, where noted, MMR. Results: The association of FoxP3+ density with overall survival (OS) differed by CD8+ density (P for interaction = .040). By multivariable analysis, FoxP3+high was significantly associated with improved OS in CD8+low tumors (hazard ratio 0.43 [95% confidence interval 0.19 – 0.95]; P = .030], but not in CD8+high tumors (P = .91). Results were consistent after MMR adjustment. We then determined their prognostic impact in the larger pMMR subset (N = 119). Tumors with high FoxP3+ were associated with improved OS in cases with low, but not high, CD8+ density ( Table ). These patients (FoxP3+high, CD8+low) had similar 5-year OS rates as 107 dMMR cases from parent studies (89% vs 80%; P = .74), despite having distinct clinicopathologic features. Conclusions: The prognostic impact of FoxP3+ T cells depends on CD8+, indicating the importance of analyzing both in combination. High FoxP3+ exerts a paradoxically favorable survival impact, but only when CD8+ is low. Survival in pMMR tumors with high FoxP3+ and low CD8+ was similar to that of dMMR tumors, indicating that a favorable pMMR subset can be identified. [Table: see text]
LMTK3 polymorphism in patients with metastatic colon cancer.
Authors: Loupakis Fotios , Zhang Wu , Gerger Armin , Yang Dongyun , Bohanes Pierre Oliver , Labonte Melissa Janae , Benhaim Leonor , Wakatsuki Takeru , Ning Yan , Wilson Peter M.D. , El-Khoueiry Rita , El-Khoueiry Anthony B. , Iqbal Syma , Barzi Afsaneh , Giamas Georgios , Stebbing Justin , Lenz Heinz-Josef 
Published: February 2017

471 Background: LMTKs are a family of serine-threonine-tyrosine kinases. LMTK3 isoform is a potent regulator of estrogen receptor activity LMTK3 gene polymorphisms affect DFS and OS of breast cancer patients. Cumulative evidence implies that estrogen receptor signalling plays a role in colon carcinoma development and progression. We investigated whether the LMTK3 rs9989661 SNP is a prognostic factor in patients with advanced colon cancer. Methods: 318 patients with metastatic colon cancer treated at the USC/Norris Comprehensive Cancer Center or the LA County/USC Medical Center were included in this study. Genomic DNA was extracted from white blood cells of peripheral blood samples using the QiaAmp kit (Qiagen, Valencia, CA). The LMTK3 polymorphism was genotyped by PCR-RFLP. The association between the LMTK3 polymorphism and overall survival was examined using the log-rank test and multivariate Cox-model. Results: There were 141 females and 177 males, with a median age of 58 years (range 25-86). The cohort comprised 234 whites, 43 Asians, 15 Blacks, 24 Hispanics, and 2 Native Americans. The median survival was 13.7 months with a median follow-up of 2.3 years. The median overall survival was 16.6 vs. 12.8 months for patients with C/- vs. patients with T/T (HR=0.78; 95% CI: 0.56-1.08; p=0.055). At a multivariate analysis restricted to subjects with left-sided disease (n=126) the median OS for patients with C/- genotype was 23.8 months compared to 14.9 months of T/T patients (HR=0.51; 95%CI: 0.28-0.91; p=0.014). Conclusions: This study suggests that LMTK3 may be an independent prognostic factor for patients with metastatic colon cancer and raise the issue of possible disparities according to primary tumor location. Our group produced similar results also in the adjuvant setting. Functional correlative preclinical analyses and external clinical validation studies are currently ongoing.
Role of polymorphic fc gamma receptor II/III in the efficacy of cetuximab in KRAS-NRAS-BRAF-PI3K mutated.
Authors: Garcia-Foncillas Jesus , Rodriguez Javier , Boni Valentina , Sola Iosu , Honorato Beatriz , Zarate Ruth , Bandres Eva 
Published: February 2017

477 Background: The immunoglobulin G1 (IgG1) monoclonal antibody (MoAb) cetuximab is active in metastatic colorectal cancer (mCRC) as first or subsequent lines of therapy. Efficacy seems restricted to KRAS wild-type tumors. IgG1 may also induce antibody dependent cell mediated citotoxicity (ADCC) by recruitment of immune effector cells. ADCC is influenced by FcγR polymorphisms. We investigated the association of FcγR polymorphisms and disease control rate (DCR) in mCRC patients treated with chemotherapy plus cetuximab. Methods: Tumor tissues from 106 patients were screened for KRAS codon 12 and 13 mutations using a sensitive multiplex assay (DxS, Manchester. UK). NRAS (codons: 12, 13 and 61), PI3K (exon 20) and BRAF (exon 15) were analysed by direct sequencing. Fcγ RIIa and Fcγ RIIIa polymorphisms were genotyped by TaqMan assays. Results: DCR was significantly higher in KRAS wild-type tumors (61% vs 39%, p=0.049). In EGFR downstream-mutated mCRC patients, those harbouring a FcγRIIa H/H genotype had a higher DCR than alternative genotypes (67% vs 33%, p=0.017). By multivariate analysis, FcγRIIa-131H/H remained significantly correlated with DCR (p=0.008). Conclusions: FcγR polymorphisms may play a role in the clinical efficacy of cetuximab in EGFR downstream mutated mCRC patients. Further research into cetuximab immune-based mechanisms in KRAS-mutated patients seems warranted.
Association of the expression of CD133 in locally advanced rectal cancer with tumor regression and survival after neoadjuvant radiochemotherapy.
Authors: Sprenger Thilo , Conradi Lena , Beissbarth Tim , Rüschoff Josef , Ghadimi B. Michael , Rödel Claus , Becker Heinz , Rödel Franz , Liersch Torsten 
Published: February 2017

479 Background: CD133 has been described as a stem cell marker in colorectal cancer and is associated with higher tumorigenic potential and resistance to radiochemotherapy (RCT). In this study the expression of CD133 was evaluated in pre-treatment tumor biopsies and corresponding post-treatment surgical specimens of locally advanced rectal cancer patients undergoing multimodal therapy and was correlated to histopathological features and clinical follow-up. Methods: 97 patients with UICC II/III rectal cancer treated with preoperative 5-FU based RCT within the German Rectal Cancer Trials were investigated. Pre- and post-treatment CD133 expression levels were determined using immunhistochemistry and correlated with histopathologic parameters, tumor regression, tumor recurrence and disease-free survival (DFS). Results: As compared to pre-treatment biopsies we observed a significantly higher CD133 expression in post-treatment tumor specimens (p=0.01). There was, however, no correlation for both biopsies and tumor specimens between CD133 expression levels, pathological characteristics and survival. In matched analyses of corresponding biopsy/tumor pairs, patients with a decreased number of CD133 positive cells after preoperative RCT showed significantly lower post-treatment tumor stages (p=0.03) and higher histopathological tumor regression (p<0.01). Moreover, these patients had a significantly improved DFS in uni- (p<0.001) and multivariate analyses (p=0.001). Conclusions: CD133 expression displays a marker with prognostic and monitoring validity in rectal cancer patients. A decrease of the CD133 positive cell fraction in post-treatment tumor tissue is associated with a more favorable outcome after preoperative RCT.