bluuebunny/crossref_metadata_2025_split huggingface dataset:
Possible role of the systemic inflammatory reaction in defining tumor responder vs. nonresponder in cancer macrobead therapy.
Authors: Smith Barry H. , Andrada Zoe Padua , Nazarian Angelica , Ocean Allyson J. , Parikh Tapan , Lu Jia , Arreglado Anna , Fahey Thomas J. , Berman Nathaniel , Gazda Larry , Martis Prithy , Laramore Melissa , Akahoho Eugene , Thomas Joanne , Wolf David J. 
Published: February 2017

572 Background: Peritoneal implantation of mouse renal adenocarcinoma cell-containing (RENCA) Macrobead (MB) represents a cell-system-based approach to the treatment of advanced, mCRC that has been evaluated to date in Phase IIa trials. The data indicate that there are “responders” (R) and “non-responders”(NR) as reflected in overall survival (OS), where “response” is defined as a >20% decrease in either/both CEA or CA19-9 during the first 30 days after MB implantation. We analyzed whether the “response” is due to a post-implant systemic inflammatory response (SIR) or rather a direct inhibitory effect of the MB. Methods: Thirty-four treatment-resistant mCRC patients (pts) were implanted laparoscopically at least once with RENCA MB. Pts were considered R (n=25), or NR (n=9), based on tumor marker responses within the first 30 days. CRP, IL-6, TNF-alpha, and ESR, as measures of SIR, were measured at Day 14 and 30. Results: All 34 pts showed SIR to MB implantation, as indicated by transient rises in CRP, IL-6, TNF-a, and ESR. Baseline CRP values (R, mean 3.24+/-4.39 vs. NR, 2.96+/-3.43; t-test, p=0.86), Day 14 CRP values (R, mean 20.97 +/- 7.21 vs. NR, 14.5+/-8.78; t-test, p=0.04), Day 30 CRP values (R, mean 8.21+/-5.43 vs. NR, 10.76+/-6.92; t-test, p=0.27) and mean changes in IL-6 (baseline p=0.28; Day 14 p=0.36; Day 30 p=0.54), TNF-a (baseline p=0.37; Day 14 p=0.32; Day 30 p=0.29) did not show statistically significant differences between R and NR groups. Conclusions: Data suggest that early tumor marker decreases in R of RENCA MB are likely not due to the induced SIR, but rather a possibly direct anti-tumor-cell effect by factors released by MB. This supports the importance of the MB-induced changes in the MEF-2 pathway in the target colorectal cancer cell/tumor reported previously. Studies of clinical efficacy of MB continue in a Phase IIb clinical trial. Clinical trial information: NCT01053013.
The prognostic role of the host immune response in rectal cancer patients treated with neoadjuvant chemoradiation.
Authors: Sprenger Thilo , Wirtz Ralph M , Pektas Selcan , Bohnenberger Hanibal , Kauffels Anne , Conradi Lena-Christin , Homayounfar Kia , Liersch Torsten , Ghadimi Michael 
Published: February 2017

575 Background: The development of metachronous distant metastasis is – despite remarkable progress - still a challenging problem after multimodality treatment of rectal cancer. The host immune response has been identified as a valid prognostic marker in primary colon cancer but not in rectal cancer after neoadjuvant chemoradiotherpy so far. Methods: We analysed the mRNA and protein expression of the B- and T-cell chemokines CXCL13 and CXCL9 as well as the B-cell marker IGHM in 77 rectal cancer specimens undergoing preoperative chemoradiotherapy and investigated the role of the host immune response on the occurrence of distant metastasis and survival. Results: The intratumoral mRNA expression levels of the T-cell activator CXCL9 (p < 0.001) as well as the B-cell chemokine CXCL13 (p < 0.01) were inversely correlated with the development of distant metastasis. Patients with high CXCL9 (p < 0.0001) or CXCL13 expression (p < 0.01) had a significantly prolonged DFS. Moreover, patients with high mRNA levels of both CXCL9 and CXCL13 had an excellent DFS compared to patients without expression of any of the chemokines (p < 0.0001). Additionally, CXCL9 expression was correlated with an improved CSS (p < 0.05). There was no significant correlation between the B-cell marker IGHM and metastasis or survival. Conclusions: The host immune response represented by intratumoral expression levels of the lymphocyte-activating chemokines CXCL9 and 13 is associated with reduced rates of distant metastases and improved survival in rectal cancers after multimodality treatment. Further investigations are needed to prospectively validate these results and characterize the underlying cellular and molecular mechanisms.
Novel probe-based quantative image of mitochondria in live colon cancer tissues by multiphoton microscopy.
Authors: Kim Eun Sun , Chun Hoon Jai , Jeen Yoon Tae , Keum Bora , Choi Hyuk Soon , Kim Seung Han , Lee Jae Min , Yoo In Kyung 
Published: February 2017

581 Background: Multiphoton endomicroscopy is the recentely updated technique for endoscopy and virtual image and optical sectioning. However optimized probe has not been established for multiphoton endomicroscopic image. Therefore we developed novel probe for mitochondria and applied for colon neoplasm tissues. In cancer cell, abnormally increased mitochondrial replication is related mitochondrial dysfunction and Warburg effect. Methods: We used newly developed multiphoton probe for micochondria imaging which are made using benzofuran derivative (BFP, maximal multiphoton fluorescence at 570 nm). Fresh mucosal tissues of colonic adenoma and adenocarcinoma were obtained from endoscopic biopsy. Multiphoton probe BFP for mitochondria was stained for tissues and imaging performed using multiphoton microscopy. Results: BFP shows high enhancement factor upon binding mitochondria, good selectivity, cell permeability, and can readily detect mitochondria in human tissues by multiphoton microscopy. Mitochondria were detected in human colon mucosa tissues. Calculated mitochondria area were increased in adenocarcinoma tissues compared to normal mucosal tissues. Conclusions: Newly developed multiphoton probe for mitochondria are usable to image human live colon tissues.
Levels of oxidative stress and telomeres in Lynch syndrome-associated malignancies.
Authors: O'Kane Grainne , McGarrigle Sarah A. , Rehill Nadia , Farrell Michael P. , O'Sullivan Jacintha , Muldoon Cian , Mac Mathuna Padraic M. , Carney Desmond N. , Gallagher David James 
Published: February 2017

582 Background: Lynch Syndrome (LS) is caused by germline mutations in mismatch repair genes (MMR) genes which are critical in maintaining cellular integrity. Failure of the MMR pathway in LS culminates in the hypermutable phenotype of Microsatellite Instability. LS confers an increased risk of malignancy of which colorectal cancer (CRC) is most common. Carriers exhibit significant phenotypic variation in the age of onset of malignancy which cannot be predicted. Telomere length attrition is considered an early step in carcinogenesis and may be accelerated by oxidative stress. We investigated an association between relative telomere length (RTL) and levels of DNA oxidative damage in LS affected carriers (AC), unaffected carriers (UAC) and in patients with MMR- proficient colorectal cancer (MPC). Methods: Peripheral blood mononuclear cells were isolated from patients within each group. DNA was extracted and RTL measured by quantitative polymerase chain reaction (PCR). Real-Time PCR was used to quantitate expression levels of TERT, TERC and DKC1 (telomerase components) from RNA. Serum levels of 8-hydroxydeguanosine (8-OHdG) were measured from patients using the ELISA technique. Pearson’s correlation was used to compare mean RTL, telomerase levels and 8-OHdG between groups. Results: RTL and telomerase components were measured in 27 AC (median age 50yrs) 27 UAC (median age 40yrs) and 27 MPC (median age 66yrs). Corresponding RTLs were 0.89, 0.91 and 1.69 respectively. AC had significantly shorter RTL compared to UAC (p = 0.03) and MPC (p < 0.0001). There we no differences in the mean expression of TERT, TERC or DKC between groups. Younger age of tumour onset was associated with shorter telomere length in both AC (p = 0.0006) and MPC (p < 0.0001). 8-OHdG levels have been measured in 17 AC, 19 UAC and 14 MPC. The mean levels of AC and UAC were not statistically different. However the mean MPC level was significantly less than UAC (p = 0.03) and AC (p < 0.0001). Conclusions: Shortened telomere length is an important step in carcinogenesis. Affected LS patients have shorter telomeres and evidence of higher levels of DNA oxidative stress than patients with MMR-proficient CRC.
Therapeutic impact and timing of gastrointestinal malignancy genomic profiling: A single-institution experience.
Authors: Koenig Kristin Lynn , Burkart Jarred , Mikhail Sameh , Wu Christina Sing-Ying , Noonan Anne M. , Goldberg Richard M. , Bekaii-Saab Tanios S. , Ciombor Kristen Keon 
Published: February 2017

584 Background: Tumor genomic profiling has become critical in the identification of targeted therapeutic options for patients (pts) with advanced malignancies. Mutational frequencies and their therapeutic importance vary among tumor types. This analysis was undertaken to characterize the landscape of genomic alterations in gastrointestinal (GI) malignancies found in a large academic institutional practice, and to determine the frequency of alteration-specific targeted therapy selection based on genomic profiling. Methods: Adult pts with GI malignancies presenting to the Ohio State University Comprehensive Cancer Center oncology clinics were offered next generation sequencing through FoundationOne testing as part of routine clinical care. Institutional review board approval was obtained to retrospectively analyze results from FoundationOne testing performed between 2012 and 2015. Results: 265 pts with GI malignancies underwent successful genomic profiling. 1205 genomic alterations were found, with an average of 4.5 per tumor (range 0-20); 365 (30%) of these were potentially actionable and most often found in colorectal or gastroesophageal tumors. 14 pts (5.3%) had actionable alterations in MET, CDKN2A/B, FGFR2, KRAS, BRAF, or NF2 that led to enrollment in genotype-directed clinical trials or off label use of targeted therapies beyond standard of care. Pt performance status at the time of genomic alteration identification was a significant factor in precluding genotype-directed therapy. One variant of unknown significance involving FGFR2 identified at initial testing subsequently became actionable and led to pt enrollment on a clinical trial. One pt with rectal cancer was found to have a KRAS wild-type and BRAF mutant primary but KRAS mutant and BRAF wild-type liver metastasis. Conclusions: Genomic profiling of GI malignancies through next generation sequencing is feasible and can lead to genotype-directed therapy selection; however, it should be considered early in the pt’s course to optimize use of targeted therapies through clinical trials. Consideration should be given to serial tumor testing to identify emerging genomic alterations for optimal therapy selection.
Serum amyloid α (SAA-1) SNP rs12218 to predict outcome for mCRC patients treated with FOLFIRI and bevacizumab: Data from FIRE-3 trial.
Authors: Berger Martin D. , Stintzing Sebastian , Heinemann Volker , Yang Dongyun , Sunakawa Yu , Ning Yan , Matsusaka Satoshi , Okazaki Satoshi , Miyamoto Yuji , Suenaga Mitsukuni , West Jordan David , Zhang Wu , Petasis Nicos , Lenz Heinz-Josef 
Published: February 2017

586 Background: The formyl peptide receptor 2 (FPR2) plays a key role in regulating inflammatory processes and host defense by binding a variety of both pro- and anti-inflammatory ligands. As inflammatory mediators may represent a favourable soil for tumor initiation and progression, we hypothesize that genes encoding for FPR2 and its ligands may predict outcome in patients with metastatic colorectal cancer (CRC). Methods: Three hundred and one patients with CRC enrolled in the randomized phase III FIRE-3 Trial and treated with FOLFIRI and Bevacizumab were included in this study. Genomic DNA was extracted from formalin fixed paraffin embedded tissue. Eight functional SNPs in 8 genes (FPR2, ANXA1, ALOX5, ALOX12, ALOX15, SAA1, PLCB3 and PRKCB1) were analyzed by PCR-based direct sequencing. Candidate SNPs and their correlation with outcome were analyzed by uni- and multivariate analysis. Results: The SAA1 rs12218 variant showed significant association with progression-free survival (PFS). Patients harboring any T allele had a significantly longer PFS than those with a CC genotype in both univariate (p = 0.013) and multivariate analysis (p = 0.010). Conclusions: This is the first report demonstrating that the SAA1 polymorphism rs12218 might serve as a predictive marker in patients with metastatic CRC treated with FOLFIRI and Bevacizumab in the first line setting. Targeting SAA1, a proinflammatory ligand of FPR2, might be a promising approach to enlarge our treatment armamentarium against mCRC.
Predictive value of ERCC1 and KRAS in colorectal cancer patients with FOLFOX chemotherapy.
Authors: Lee In Kyu , Choi Sung-Bong , Cheung DaeYoung , Kim Jin Il 
Published: February 2017

588 Background: To determine the clinical significance of KRAS mutation and ERCC1 overexpression as a predictive factor of resistance in oxaliplatin based treatment. Methods: We retrospectively analyzed the clinicopathologic features, status of KRAS mutation and ERCC1 overexpression of 386 colorectal cancer patients who received curative intent surgery. Among them 84 patients were treated by FOLFOX regimen as the first line. Their disease-free survival and overall survival according to the KRAS and ERCC1 were analyzed. Results: About a quarter of patients (25.5%) were represented KRAS wild type with ERCC1 overexpression. Among the patients who treated by FOLFOX regimen, 73 patients were evaluated both of the KRAS and ERCC1. There were no significant differences of disease-free survival and overall survival according to KRAS status and ERCC1 expression each. Under the subgroup analysis, overall survival of ERCC1 overexpression group in wild type KRAS was poor than ERCC1 negative group (p=.029), but no significant difference was in mutant KRAS group (p=.671). Conclusions: Our results suggest that the KRAS wild type with ERCC1 overexpression would be associated with the resistance of oxaliplatin.If oxaliplatin based chemotherapy would beconsidered, status of KRAS mutation and ERCC1 overexpression should be evaluated.
Novel mutational and pathway signatures in relapsed/refractory colorectal cancer patients.
Authors: Johnson Benny , Cooke Laurence , Mahadevan Daruka 
Published: February 2017

591 Background: In the management of metastatic colorectal cancer (mCRC), all RAS (KRAS, NRAS) and BRAF V600E mutation status guides therapeutic options and identify a unique cohort of patients (pts) with a more aggressive clinical course. We hypothesized that relapsed/refractory CRC pts develop unique mutational signatures that guide standard and targeted therapy but also predict for therapeutic response, identify novel driver mutations and highlight key signaling pathways for clinical decision making. Methods: Relapsed/refractory mCRC pts (N=31) were molecularly profiled by NGS Caris Molecular Intelligence (IHC, FISH/CISH, NGS) and/or Foundation One (NGS, copy number). Samples were annotated by histology, primary and/or metastatic site, biopsy location, gene mutation, domain, topology, and mutation count. Web-based bioinformatics tools (Enrichr/IntAct) were utilized to analyze mutational profiles, identifying pathway-networks. Results: Pts included progressed on fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, cetuximab or panitumumab. Most common histology was adenocarcinoma followed by squamous cell carcinoma (colon N=28; rectal N=3). TP53 was the most common mutation followed by APC, KRAS, PIK3CA, BRAF, SMAD4, SPTA1, FAT1, PDGFRA, ATM, ROS1, ALK, CDKN2A, FBXW7, TGFBR2, NOTCH1 and HER3. Pts had on average >5 unique gene mutations. High mutational burden was not predictive for PD-1 (5 pts) or PD-L1 (1 pt) positivity. The most common activated signaling pathways were: ERRB2/HER2, FGFR, p38 activation through BRAF-MEK cascade via RIT and RIN, ARMS-mediated activation of MAPK cascade, and VEGFR2. Conclusions: Dominant oncogene mutations do not always equate with oncogenic dependence, therefore understanding the pathologic interactome in each patient is important to both identification of clinically relevant targets and choosing the next best therapy. Mutational signatures derived from corresponding ‘pathway-networks’ represent a meaningful tool to 1). Evaluate functional investigation in the laboratory, 2). Predict response to drug therapy, and 3). Guide rational drug combinations in relapsed/refractory mCRC pts entering targeted and immune checkpoint trials.
Post-operative C-reactive protein concentration: A potential therapeutic target following surgery for colorectal cancer?
Authors: Watt David G. , Park James Hugh , McSorley Stephen Thomas , Horgan Paul G. , McMillan Donald C 
Published: February 2017

597 Background: Post-operative C-reactive protein concentrations (CRP) have been reported to be associated with the development of complications following surgery for colorectal cancer (CRC). The development of complications and an exaggerated post-op CRP are associated with poor long term survival. However, whether this is due to the complication or to the CRP concentration remains unclear. Therefore, the aim of the present study was to determine whether post-op CRP concentrations, independent of post-op complications, were associated with poor long term survival following surgery for CRC. Methods: Included patients were obtained from a prospectively maintained database of CRC resections from a single institution (1999-2013). The relationship between post-op CRP concentrations and overall survival (OS) was examined using Cox regression analysis. Results: 813 patients were included. The majority of patients were > 65 yrs (67%), male (55%) and underwent elective surgery (90%). 257 patients (32%) suffered a complication. Median follow up was 49 months with 314 deaths. In those undergoing elective surgery, 508 patients had an uncomplicated post-op course. In these patients, post-op CRP was significantly lower, on post-op days 2, 3 and 4 (p < 0.001) compared to those with complications. On univariate survival analysis, CRP concentrations on day 2 (HR 1.003, p = 0.008), 3 (HR 1.003, p = 0.024) and 4 (HR 1.003, p = 0.019) were associated with poorer overall survival. On multivariate analysis, adjusting for age, sex and TNM stage, day 2 CRP (HR 1.003, p = 0.006), age (HR 1.70, p < 0.001) and TNM stage (HR 1.61, p < 0.001) were independently associated with poorer survival. On multivariate analysis, adjusting for age, sex and TNM stage, day 3 CRP (HR 1.003, p = 0.030), age (HR 1.70, p < 0.001) and TNM stage (HR 1.63, p < 0.001) were independently associated with poorer survival. Conclusions: In patients undergoing elective surgery for CRC who have an uncomplicated post-op course, the post-op day 2 and 3 CRP concentrations were independently associated with poorer survival. Therefore, CRP could be considered a potential therapeutic target in future attempts to try and improve outcomes following surgery for CRC.
Oxaliplatin associated neurotoxicity outcomes among older adults with colorectal cancer: A population-based study.
Authors: Raphael Michael J. , Fischer Hadas , Fung Kinwah , Austin Peter , Booth Christopher M. , Anderson Geoffrey , Singh Simron 
Published: February 2017

601 Background: The addition of oxaliplatin to fluorouracil-based regimens in the adjuvant treatment of colorectal cancer (CRC) has been shown to improve overall survival at the expense of increased toxicity. Toxicity may be higher among older patients who may also derive less benefit from oxaliplatin. The incidence of toxicity in the elderly is unknown. Methods: A cohort of patients ≥ 66 years old diagnosed with Stage II and III CRC between 2007 and 2011 in Ontario, Canada was identified using the Ontario Cancer Registry. Linked administrative databases were used to identify patients treated with oxaliplatin who were subsequently diagnosed with peripheral neuropathy (PN) or received a new prescription for a neuropathic pain medication. Patients were stratified into two age strata, ages 66-69 and ages ≥ 70, and each group was compared to a control cohort receiving non-oxaliplatin-based adjuvant chemotherapy (AC). Cause-specific hazard models were used to estimate the effect of Oxaliplatin exposure on the cause-specific hazard of PN and associated neurotoxicity outcomes after accounting for the competing risk of death. Results: We identified 3,607 patients aged ≥ 66 with Stage II and III CRC, of whom 1,541 were treated with an oxaliplatin-based AC regimen. Compared to control subjects receiving non-oxaliplatin based AC, patients ≥ 70 years old treated with oxaliplatin were more likely to be diagnosed with PN (cause-specific hazard ratio (CHR) age ≥ 70, 2.07 [95% CI, 1.43-3.00; p < 0.001]) and receive a new prescription for a neuropathic pain medication (CHR age ≥ 70, 1.86 [95% CI, 1.43-2.42;p < 0.001]). In patients aged 66-69, oxaliplatin use was not associated with a new diagnosis of PN (p = 0.903), but was associated with an increased likelihood of receiving a prescription for a neuropathic pain medication (CHR age 66-70, 1.92 [95% CI, 1.22-3.03; p = 0.005]). By the end of one year, the cumulative incidence of PN was 3.21% (95% CI, 2.02-4.81) for ages 66-69 and 5.51% (95% CI, 4.14-7.15) for age ≥ 70. Conclusions: In this population-based cohort of CRC patients ≥ 70 years old, treatment with oxaliplatin is associated with a significant risk of developing PN and requiring treatment with neuropathic pain medications.