bluuebunny/crossref_metadata_2025_split huggingface dataset:
Down expression of activin A receptor type 2A in relation to metastatic potential and prognosis of patients with colon cancer.
Authors: Zhuo Changhua , Hu Dan , Lin Xiandong , Chen Ying , Zheng Xiongwei , Yang Chunkang 
Published: January 2019

712 Background: The ACVR2A (activin A receptor type 2A) is a membrane receptor in TGF-β signal pathway, which is involved in the regulation of cell proliferation, migration and apoptosis. The expression profiles and biological functions of ACVR2A in colon cancer is largely unknown so far. Methods: ACVR2A expression was investigated using GSE39582 database and two validation cohorts. The in vitro study of the cell proliferation and migration of human colon cell lines was also performed. Results: In GSE39582 database (n = 497), lower mRNA expression of ACVR2A was identified as an inferior prognostic factor by linear regression analysis. In one validation cohort of 15 stage IV patients, the mRNA expression of ACVR2A was significantly reduced in metastatic lesions and primary tumors compared with adjacent normal controls (P = 0.001). In another validation cohort of tissue microarray (TMA) cohort consisting 193 cases, reduced ACVR2A expression was correlated with advanced N stage (P = 0.001) and positive lymphovascular invasion (P = 0.005). Strong correlations between lower ACVR2A mRNA or protein expression and worse survival were also observed in GSE39582 database and TMA validation cohort (all P< 0.05). Moreover, our in vitro studies showed a remarkable increase of cell migration in cell ACVR2A knockdown cells. Conclusions: Taken together, our findings indicate that loss of ACVR2A has an important role in cancer progression and distant metastasis, and may serve as a prognostic marker in patients with colon cancer. Keywords: Activin a receptor type 2A (ACVR2A), Colon Cancer, tissue microarray, Metastasis, Cell proliferation, Cell migration
Dynamic monitoring HER2 amplification of circulating DNA in metastatic colorectal cancer patients treated with cetuximab.
Authors: Chen Zhi-Yu , Liu Rujiao , Guo Weijian , Zhu Xiaodong , Zhao Xiaoying , Qiu Lixin , Zhang Xiaowei , Huang Mingzhu , Zhang Wen , Zhang Zhe , Li Wenhua 
Published: January 2019

714 Background: Addition of cetuximab has shown clinical benefit in RAS and BRAF wild-type (wt) patients with metastatic colorectal cancer (mCRC). Human epidermal growth factor receptor 2 ( HER2) amplification was reported to be one of the resistance mechanisms to cetuximab. We investigated whether monitoring of HER2 amplification in circulating DNA allows early detection of progression and informs about resistance to cetuximab. Methods: We analyzed HER2 amplification in circulating DNA by 8 week-interval using droplet digital polymerase chain reaction (ddPCR) from 30 RAS and BRAF wt patients, who progressed after failure of cetuximab-containing regimens between Jul 2015 and Jun 2017. Results: 16.7% (5/30) of patients exhibited dynamic fluctuations of HER2 amplification in plasma, one of whom was found to be positive for HER2 amplification in matched tumor tissue sample using FISH. Two patients had HER2 and c-MET co-amplification. All 5 primary sites were left side, 4 rectums and 1 descending colon. 3 patients received cetuximab as first line therapy, whereas 2 patients in the 2nd line setting. Among these 5 patients, changes in circulating DNA levels showed good agreement with changes in tumor volume. Furthermore, quantifications of HER2 amplification showed obvious increase with an average lead time of 2 months compared with CT documented progress. But interestingly, there was no difference in progression-free survival (PFS) between these 5 patients and the others without HER2 amplification (p > 0.05). Conclusions: Plasma HER2 amplification detected by ddPCR was showed dynamic changing over time and would predict resistance to cetuximab-containing treatment. Average 2 months lead time was observed and need to validate in the further study.
Effect of MMP-13 degraded SPARC on type I collagen and its biomarker potential in colorectal cancer.
Authors: Kehlet Stephanie Nina , Harling Henrik , Jørgensen Lars N , Karsdal Morten A , Willumsen Nicholas 
Published: January 2019

717 Background: Increased collagen deposition and remodeling of the extracellular matrix has been shown to play a role in the pathology of gastrointestinal cancer (GC). The matricellular protein SPARC (secreted proteome acidic and rich in cysteine) binds collagens and hereby regulates collagen fibrillogenesis. Matrix metalloproteinase (MMP) mediated cleavage of SPARC, increases the affinity for collagens up to 20-fold. SPARC has been shown to be overexpressed in GC patients and associated with GC cell invasion and metastasis. Increased expression and cleavage of SPARC might therefore be implicated in GC pathology by increasing collagen deposition. Here, we present the development and validation of a competitive enzyme-linked immunosorbent assay (ELISA) quantifying a specific MMP-13 generated fragment of SPARC - a cleavage site involved in increased collagen affinity. The biomarker potential of this fragment was examined in serum from colorectal cancer (CRC) patients and healthy controls. Moreover, we evaluated the ability of cleaved SPARC to prevent type I collagen degradation in vitro. Methods: A monoclonal antibody was raised against a MMP-13-generated neo-epitope of SPARC and a competitive ELISA assay (SPARC-M) was developed and technically validated. Serum levels were assessed in CRC patients (n=50) and healthy controls (n=30). The ability of cleaved SPARC to prevent collagen degradation was investigated using an ELISA assay measuring type I collagen degradation by MMP-9. Results: SPARC-M was technically robust and specific for SPARC cleaved by MMP-13. The fragment was elevated in CRC patients when compared to healthy controls (p=0.0097). When MMP-13 degraded SPARC was incubated with type I collagen and MMP-9, type I collagen degradation was completely inhibited suggesting that SPARC increases collagen deposition by preventing collagen degradation. Conclusions: SPARC-M was significantly elevated in CRC patients compared to healthy controls suggesting biomarker potential. Biologically, cleaved SPARC may prevent type I collagen degradation hereby leading to a pro-tumorigenic environment. Larger clinical studies are needed to validate the clinical use of this biomarker in GC.
Single nucleotide polymorphisms (SNPs) in COL4A2, PPP1R17, and ARHGAPP44 and prognostic value in metastatic colorectal cancer (mCRC).
Authors: Townsend Amanda Rose , Asher Rebecca , Price Timothy Jay , Lee Chee Khoon , Dorward Hilary , Gebski Val , Tomita Yoko , Tebbutt Niall C. , Hardingham Jennifer 
Published: January 2019

720 Background: Our previous study has identified COL4A2, PPP1R17 and ARHGAP44 SNPs using whole exome sequencing with potential prognostic significance (Townsend et al. ASCO GI 2017). COL4A2 encodes a subunit of type IV collagen, the C-terminal of which is an inhibitor of angiogenesis. We assessed prognostic impact of these variants in patients from the phase III MAX study (capecitabine +/- bevacizumab (+/- mitomycin C)). An analysis of predictive effect on bevacizumab was also undertaken. Methods: DNA was extracted from archival macrodissected formalin fixed paraffin embedded tumor tissue and genotyped using Agena Bioscience MassARRAY system (AGRF). Univariate association of variant group (WT versus mutation (MT)) with progression free survival (PFS) and overall survival (OS) was assessed using Kaplan-Meier curves and Cox regression models. Logistic regression models were used to assess association with response rate (RR). A cox regression model with treatment, variant status and their interaction investigated if variants were predictive of bevacizumab effect. Results: Of the available 145 of 471 (31%) patients in the MAX study, 25 (17%) had COL4A2 MT, 29 (20%) PPP1R17 MT, 14 (10%) ARHGAP44 MT. Patient demographics were comparable across treatment groups and outcomes similar to whole study population. On univariate analysis median PFS was numerically longer for WT vs MT in all 3 variants, but these differences were not significant (COL4A2 WT 8.4m v MT 6.0m, p=0.09; PPP1R17 WT 7.8m v MT 7.5m, p=0.76; ARHGAP44 WT 8.2m v MT 6.5m, p=0.86). There was also no significant association between variant type and OS. Multivariate analysis for COL4A2 MT v WT showed no significant difference in PFS or OS (HR 1.42; 95% CI 0.91-2.22, p=0.13 and HR 1.33; 95% CI 0.85-2.1, p=0.21). There was no association between treatment response and variant status. Variant status was not predictive of bevazicumab efficacy for treatment response, PFS or OS. Conclusions: There was no significant prognostic or predictive impact of novel gene variants in patients treated with bevacizumab. This may be due to small numbers of MT variants in this study and further studies in larger populations may be useful.
Regorafenib tolerance and outcomes in inner-city minority colorectal cancer population.
Authors: Ahmed Ahmed Tarig , Malapati Sindhu Janarthanam , Yim Barbara , Singh Sunny R K , Gupta Shweta 
Published: January 2019

722 Background: Regorafenib (REG) is an oral multikinase inhibitor used for treatment of metastatic colon cancer after progression on fluorouracil, oxaliplatin and irinotecan therapy. The FDA approval was based on CORRECT trial showing improvements in progression-free survival (PFS) and overall survival (OS). Another trial (CONCUR) showed similar results. However, these trials included predominantly Whites and Asians. Our study aimed to evaluate treatment outcomes in the underserved, mainly African Americans and Hispanics. Methods: Cook County hospital is the 3rd largest public hospital in the US. All patients with an order for REG were identified from our pharmacy database. Charts were retrospectively reviewed for cancer stage, age, ethnicity, previous treatments, PFS and OS. Patients with non-colorectal cancer, incomplete data, no evidence of REG usage were excluded. Statistical analysis was done by t-test on subgroups. Results: A total of 42 patients were screened and 30 were included in the study. A comparison of outcomes with CORRECT and CONCUR trials is presented in Table 1. Our study patients, despite being less heavily pre-treated, had a worse OS compared to the clinical trials, with similar PFS. There was a trend towards better PFS and OS in women in our study of 4.3 and 4.8 months compared to men with 1.9 and 3.3 months respectively (p = NS). Six (20%) patients discontinued REG due to intolerance within a median of 1.2 months. The intolerant patients had a significantly higher median BMI of 31 compared to 24.9 for patients who continued the medication to progression (p = 0.019). Conclusions: Compared to CORRECT and CONCUR trials, population of predominantly AA and Hispanics showed a trend towards worse OS despite being less heavily pre-treated indicating worse outcomes in minorities treated with REG. Women showed better PFS and OS compared to men in our study. Patients unable to tolerate REG had significantly higher BMI, indicating a need to study dosing in this subgroup. [Table: see text]
Evaluation of outcomes over time (1998-2009) of patients (pts) with stage III colon cancer receiving adjuvant FOLFOX: Analysis of 7,230 patients from MOSAIC, C07, C08, N0147, AVANT, and PETACC8 trials in the ACCENT Database.
Authors: Salem Mohamed E. , Yin Jun , Goldberg Richard M. , Pederson Levi , Wolmark Norman , Alberts Steven R. , Taieb Julien , Marshall John , Lonardi Sara , Yoshino Takayuki , Kerr Rachel , Yothers Greg , Grothey Axel , Andre Thierry , De Gramont Aimery , Shi Qian 
Published: January 2019

724 Background: Adjuvant FOLFOX is the standard of care for pts with stage III colon cancer and a platform to test new agents. Improvements in supportive care and development of newer treatments for metastatic disease impact the overall outcome of pts treated with adjuvant therapy. We examined the trend of disease-free survival (DFS), survival after recurrence (SAR), and overall survival (OS) of pts treated with FOLFOX over a ten-year period. Methods: Outcomes of colon cancer pts enrolled in 6 adjuvant trials receiving FOLFOX alone were analyzed. Pt enrollment period was dichotomized as old (1998 – 2003) vs. new era (2004 – 2009) based on the FDA approval date of bevacizumab. 3/5yr event-free rates were estimated by adjusted Kaplan-Meier methods. Outcomes were compared between the two eras by Cox model. To control for potential confounding effects, all analyses were adjusted for age, gender, performance score, T/N stage, tumor sidedness and histologic grade. Results: In total, 7,230 pts (stage II [n = 1122]; stage III [n = 6,108]) were identified; 32% and 68% were treated in the old and new era, respectively. Stage III pts enrolled in the new era were significantly younger, more likely to have T4/N2 disease, higher tumor grade, and left-sided tumors. After adjusting for pt characteristics, no difference in DFS was seen over time. However prolonged SAR and OS were observed in pts treated in the new era (Table). 5yr OS increased from 76% to 80% over time. Median SAR improved from 14.8 to 26.4 months. Conclusions: Stage III colon cancer pts who received adjuvant FOLFOX experienced significant improvements in SAR and OS—but not DFS—over time. In view of the improvements in OS and nearly doubled SAR, the optimal duration of OS follow-up to evaluate the benefits of adjuvant therapy (currently 5 years) should be reassessed, and ACCENT investigators are planning to conduct these additional analyses using their large pooled-trial database. [Table: see text]
Efficacy outcomes with bevacizumab added to chemotherapy (bev+CT) compared with chemotherapy alone (CT) in left- and right-sided tumors in metastatic colorectal cancer (mCRC).
Authors: Loupakis Fotios , Hurwitz Herbert I. , Saltz Leonard , Arnold Dirk , Grothey Axel , Nguyen Quynh Lan , Osborne Stuart , Yau Linda , Talbot Jonathan , Srock Stefanie , Lenz Heinz-Josef 
Published: January 2019

726 Background: Primary tumor location is an important prognostic factor in mCRC. Efficacy differences with EGFR antibodies by tumor location show a predictive effect (Arnold et al. Ann Oncol 2017). Two first-line (1L) pivotal bev trials showed the prognostic value of sidedness (Loupakis et al. J Natl Cancer Inst 2015). In this exploratory study, further analysis of the predictive effect of bev is presented. Methods: Data from two randomized phase III studies (NO16966 [NCT00069095], AVF2107g [NCT00109070]) of bev+CT vs CT-alone as 1L treatment for mCRC were analyzed retrospectively. Patients (pts) with sidedness information available were included; pts from NO16966 (part 1) randomized to CT only were excluded. Sidedness was identified by case report forms. Results: Sidedness was determined in 1590 pts (27% Right and 73% Left) out of 2214 pts total (Table). In the pooled analysis, PFS improved with bev+CT compared to CT only in both right-sided (HR=0.75; 95% CI 0.61, 0.93) and left-sided (HR=0.76; 95% CI 0.67, 0.86) mCRC with similar magnitude of benefit in both sides. OS also improved with bev+CT in right-sided (HR=0.82; 95% CI 0.65, 1.03) and left-sided (HR=0.85; 95% CI 0.74, 0.98) pts. Conclusions: This exploratory subgroup analysis of two pivotal studies indicates that the effect of bev is independent of tumor location in mCRC patients. Survival outcomes. Clinical trial information: NCT00069095 and NCT00109070. [Table: see text]
Outcomes over time (1998-2009) of stage II colon cancer patients (pts) receiving adjuvant FOLFOX: Pooled analysis of 1,122 pts in the ACCENT database.
Authors: Salem Mohamed E. , Yin Jun , Goldberg Richard M. , Pederson Levi , Wolmark Norman , Alberts Steven R. , Taieb Julien , Marshall John , Lonardi Sara , Yoshino Takayuki , Kerr Rachel , Yothers Greg , Grothey Axel , Andre Thierry , De Gramont Aimery , Shi Qian 
Published: January 2019

728 Background: Adjuvant FOLFOX therapy for stage II patients remains controversial, and selection criteria are imprecise. We examined the trend of disease-free survival (DFS: time to recurrence or death, whichever occurs first); time to recurrence (TTR: time to recurrence, censored at death without recurrence); survival after recurrence (SAR); and overall survival (OS) of pts treated with FOLFOX over a ten-year period. Methods: Outcomes of pts with stage II colon cancer enrolled in 6 adjuvant trials receiving FOLFOX alone were analyzed. Pt enrollment period was dichotomized as old (1998 – 2003) vs. new era (2004 – 2009) based on the FDA approval date of bevacizumab. 3/5yr event-free rates were estimated using adjusted Kaplan-Meier methods. Outcomes were compared between the two eras by multivariate Cox model. To control for potential confounding effects, all analyses were adjusted for age, gender, performance score, T stage, number of lymph nodes (LNs) examined, tumor side, and histologic grade. Results: In total, 1,122 pts with stage II were identified; 71% and 29% were treated in the old and new era, respectively. Pts enrolled in the new era were significantly younger and more likely to have higher tumor-grade and right-sided tumors compared to old era. More pts in the new era (71%) had ≥12 LNs examined compared to the old era (53%). After adjusting for potential confounding effects, no difference in DFS, TTR, SAR or OS between old and new eras was found (Table). Although median SAR increased from 13.6 to 26 months over time, this was not statistically significant, likely due to lack of power. An increased TTR over time (HRadj. 0.41, padj.= 0.002) was observed in pts with ≥12 LNs examined (3-yr TTR: 92% in old era vs. 96% in new era), but not pts with <12 LNs examined (pinteraction = 0.04). Conclusions: In stage II colon cancer pts who received adjuvant FOLFOX, no significant increase of DFS or OS was observed over time. However TTR was longer only in pts with ≥12 LNs examined. [Table: see text]
Three versus six months adjuvant oxaliplatin plus fluoropyrimidine chemotherapy for patients with stage III colon cancer: The Hellenic Oncology Research Group (HORG) participation to the International Duration Evaluation of Adjuvant (IDEA) chemotherapy project.
Authors: Souglakos John , Boukovinas Ioannis , Xynogalos Spyros , Kakolyris Stylianos , Ziras Nikolaos , Vaslamatzis Michael , Ardavanis Alexandros , Athanasiadis Athanasios , Androulakis Nikolaos E. M. , Kentepozidis Nikolaos K. , Christopoulou Athina , Makrantonakis Paris , Varthalitis Ioannis I. , Christofyllakis Charalampos , Emmanouilides Christos E. , Mavroudis Dimitrios , Prinarakis Efthimios , Kalisperi Aggeliki , Hatzidaki Dora , Georgoulias Vassilis 
Published: January 2019

730 Background: The IDEA international collaboration aimed to combine data from 6 randomized trials to investigate whether a 3-month (3m) of oxaliplatin/fluoropyrimidines-based adjuvant chemotherapy (CT) is non-inferior to the 6-month(6m) for 3-year disease free survival (DFS)in stage III colon cancer (CC). Methods: HORG-IDEA randomized patients between 3Mand 6M of CT with mFOLFOX6 or CAPOX. DFS was estimated using the Kaplan–Meier method and described using 3 years DFS rate. Results: In total708 patients were randomized between May 2009 and October2015, 354in each arm. Among them the basic characteristics was: median age 63.9 years; mFOLFOX6: 41.8% and CAPOX 58.2%, N1: 74.9%, N2: 25.2%; T1-3: 86.4%, T4: 13.6%. DFS median follow-up was 54.2 months. There were 214 DFS events (109in 3M and 105 in 6M arm) leading to a 3-year DFS rate of 73.2% in the 3M vs. 74.9% in the 6M (HR = 1.03; 95%CI 0.80–1.43, p = 0.622).For patients receiving mFOLFOX6, 3-year DFS rate was 71.8% in the 3M vs.77.7% in the 6M (HR = 1.18; 95%CI 0.74–1.88 p = 0.478). For patients receiving CAPOX 3-year DFS rate was 74.7% in the 3M vs. 74.8% in the 6M (HR = 0.99; 95%CI 0.69–1.45 p = 0.994).94.2% and 78.0% of pts completed 3 and 6 months of CT, respectively. Overall, 96.9% and 89.5% of patients completed 3 months (arm A) and 6 months (arm B) of CT, respectively. Median oxaliplatin doses intensity were 97.3% in 3M and 73.2% in 6M (505.0 and 738.3 mg/m2).Overall maximum neuropathy during treatment grade 2/3-4 was 23.9/5.9%in 3M and38.7/13.7%in 6M; p < 0.0001. In addition, worst grade 2/3-4 diarrhea was 11.1/4/0 in 3M and in 12.3/7.36M; p = 0.03. Conclusions: Since the HORG-IDEA study was designed in order to contribute patients in the IDEA project, the result on the study should be interpreted together with those of the whole IDEA project. Nevertheless, the results of the HORG-IDEA study are in line with those of the whole IDEA project, indicating that the results are depended on the administered adjuvant regimen, and the choice of regimen and duration should be depended on tumor characteristics and patient preference. Clinical trial information: NCT01308086.
Age, gender, and performance status effects on efficacy of 3 versus 6 months of adjuvant oxaliplatin and fluoropyrimidine chemotherapy for stage III colon cancer: Phase III ACHIEVE trial as part of the IDEA collaboration.
Authors: Kato Takeshi , Yoshino Takayuki , Yamanaka Takeharu , Kotaka Masahito , Manaka Dai , Eto Tetsuya , Hasegawa Junichi , Takagane Akinori , Nakamura Masato , Munemoto Yoshinori , Nakamura Fumitaka , Bando Hiroyuki , Taniguchi Hiroki , Gamoh Makio , Shiozawa Manabu , Saji Shigetoyo , Maehara Yoshihiko , Mizushima Tsunekazu , Ohtsu Atsushi , Mori Masaki 
Published: January 2019

731 Background: ACHIEVE, a part of the IDEA collaboration, was a multicenter trial randomizing patients with stage III resected colon cancer to either 3 versus 6 months of mFOLFOX6/CAPOX. The primary endpoint was disease-free survival (DFS). We previously reported that the hazard ratios (HRs) of 3 versus 6 months duration in this study according to risk stage (low-risk [T1-3 and N1] or high-risk [T4 or N2]) and regimen (mFOLFOX6 or CAPOX) as well as in overall population were consistent with those observed in the whole IDEA. Methods: ACHIEVE enrolled 1313 patients in Japan between August 2012 and June 2014, out of whom 1291 pts were analyzed for efficacy analysis. As of June 2017, 291 DFS events were observed with a median follow-up time of 39 months. The HR of DFS in the overall population was 0.95 (0.76—1.20) with a 3-year DFS of 80% in 3 months arm and 78% in 6 months arm. In the current study, we investigated subgroup analyses for DFS including age, gender, and ECOG performance status (PS). Results: Outcomes of subgroup analyses are summarized in the Table. With regard to HRs and upper bound on the confidence intervals, the trend of 3 months arm being slightly inferior to 6 months arm in patients with an age of ≥70, female gender, and an ECOG PS of 1; however, there was no evidence of significant interaction across treatment duration and the subgroups. Conclusions: The treatment duration effect did not depend on age, gender, and ECOG PS. Further results according to risk stage and regimen will be presented. Clinical trial information: UMIN 000008543. [Table: see text]