bluuebunny/crossref_metadata_2025_split huggingface dataset:
An individual patient data (IPD) meta-analysis of the impact of thrombocytosis (?plts) on overall survival (OS) whilst using an intermittent chemotherapy (iCTx) strategy in advanced colorectal cancer (aCRC).
Authors: Adams Richard , Goey Kaitlyn , Chibaudel Benoist , Koopman Miriam , Punt Cornelis J. A. , Arnold Dirk , Hinke Axel , Hegewisch-Becker Susanna , De Gramont Aimery , Labianca Roberto , Tveit Kjell Magne , Wasan Harpreet Singh , Diaz-Rubio Eduardo , Kaplan Richard S. , Maughan Tim , Brown Louise C , Fisher David ,   ARCAD Group
Published: September 2018

e15044 Background: iCTx in pts with aCRC offers potential for improvement in QoL. The COIN trial is the largest study to compare iCTx v. continuous strategies in aCRC, a pre-specified subgroup analysis of 16 baseline factors was undertaken among pts with stable or responding disease after 3 mths of first-line therapy to see if the relative treatment effect differed by subgroup. Baseline ⇡plts alone identified a group of pts with significantly worse OS when an iCTx strategy was applied. Here we seek to validate this finding in other intermittent strategy trials. Methods: Published RCTs of iCTx in aCRC were identified via literature review. Eligible trials could allow one or more re-introductions of “full” initial regimen either upon progression or after a set period of time. Outcome and platelet data were requested and collated into a central database. The COIN trial was declared the discovery dataset and other eligible trials the validating datasets. Two co-primary hypotheses were agreed based upon the COIN trial results: Hypothesis 1: In pts with baseline ⇡plts, any planned complete stop of all therapyis detrimental to OS when compared to any maintenance strategy. Hypothesis 2: In pts with baseline ⇡plts, any planned stop of oxaliplatin(Ox) therapy is detrimental to OS when compared to any equivalent strategy where Ox is maintained. Unadjusted IPD meta-analysis was performed according to a pre-specified statistical plan. Results: All trials had broadly similar inclusion criteria . Incidence of ⇡plts range 17-32%. ⇡plts was a poor prognostic marker. Combining IPD from all trials, iCTx was not detrimental to OS. Hypothesis 1 included AIO-0207, CAIRO3, COIN B, OPTIMOX 2 and GISCAD with 1622 pts, HR for interaction of ⇡plts with treatment strategy 0.97 (0.66-1.40), p = 0.78. Hypothesis 2 included TTD MACRO, NORDIC VII and OPTIMOX I, with 1268 pts, HR for interaction 1.36 (0.71-2.62), p = 0.18. Conclusions: These IPD meta-analyses do not validate COIN trial findings that showed reduced OS in pts with baseline ⇡plts who are given a planned treatment break. Sensitivity analyses will be presented, including impact of RAS mut status.
Impact of metastasectomy in the multimodality approach for BRAFV600E metastatic colorectal cancer (mCRC): The Mayo Clinic experience.
Authors: Johnson Benny , Jin Zhaohui , Truty Mark J. , Smoot Rory L. , Kendrick Michael L. , Nagorney David M. , Grothey Axel 
Published: September 2018

e15045 Background: BRAF V600E mutations are present in 7% of mCRC patients (pts) and portend a poor prognosis. Data guiding initial treatment decisions are limited. This study investigates the management approach and clinical impact of utilizing metastasectomy for pts with BRAF V600E mCRC. Methods: By using prospective clinical and molecular data from Mayo Clinic, pts with BRAF V600E mCRC were analyzed for clinical characteristics, treatment and survival outcomes. Statistical analyses utilized Kaplan-Meier method, Log-rank test, and Cox proportional hazards models. Results: 164 pts with BRAF V600E mCRC were identified between 6/1999-8/2015. Complete follow up data were available for 52 pts. Median age of 65 years, 61% female, ECOG PS ≤ 1, 71% of pts had right sided tumors and 28% presented with liver limited metastasis. Only 7% (4/52) received FOLFOXIRI/BEV (average of 8 cycles). Peripheral neuropathy, pending BRAF status , and prior progression on FOLFOX, were the most common reasons documented for avoiding FOLFOXIRI/BEV. FOLFOX/BEV was the most common 1st line regimen used (32% of pts). Median overall survival (mOS) for all 52 pts was 25 months (mo) with median progression free survival (PFS) of 9.3 mo, reflecting worse survival when compared to BRAF wild-type control patients treated at Mayo Clinic (249 pts, mOS: 43 mo). With median follow up of 18.3 mo, 21 pts who underwent metastasectomy had improved OS (29.1mo vs. 22.7mo, HR = 0.33; CI: 0.12-0.78; p = 0.01) and PFS (13.6mo vs. 6.2mo, HR = 0.53, CI: 0.28-0.97; p = 0.03) when compared to the non-metastasectomy cohort, respectively. In multivariate analysis, metastasectomy remained statistically significant for improved survival outcomes (HR 0.52; 95% CI 0.07-1.02; p = 0.02). Median relapse-free survival after metastasectomy was 9.7 mo (95% CI, 5.5 mo-19.5 mo). Only 2 pts remain disease free at the time of last follow up, with 1 pt without recurrent disease for greater than 2 years (28.9 mo). Conclusions: The use of multimodality therapy incorporating metastasectomy for BRAF V600E mCRC is a critical component for enhanced survival outcomes.
Characteristics of Turkish colorectal cancer patients and bevacizumab preference.
Authors: Cicin Irfan , Gumus Mahmut , Uncu Dogan , Ozkan Metin , Kilickap Saadettin , Elkiran Tamer E. , Isikdogan Abdurrahman , Karaoglu Aziz , Oksuzoglu Berna , Ozdemir Feyyaz , Turna Hande , Kara Oguz , Ozyilkan Ozgur , Guducu Merve , Erdogan Alper , Uslu Ruchan 
Published: September 2018

e15055 Background: The aim of this registry was to collect demographic, diagnostic, treatment, and outcome information about Turkish patients with colorectal cancer (CRC). Methods: It was designed as a multicenter, cross-sectional, non-interventional study conducted on new and previously diagnosed CRC cases applied to 28 medical oncology outpatient clinics between 2012 and 2015. A total of 7547 male (n = 4314) and female (n = 3233) patients > 18 years were included. Results: The mean age at diagnosis was 57.7±12.4 years. There was no familial or other primary cancer history in majority of patients. 22.9% of patients (n = 1579) were diagnosed at Stage 4. In 73,7% of patients (n = 5492), tumor was left-sided. Lymphovascular invasion was determined in 34.3% of patients, 87.6% had surgery. Liver-only metastasis rate was 53.1%. KRAS was tested in 717 of 1579 mCRC patients and mutation was positive in 39.3% of cases (n = 282). BRAF and KRAS tests were performed at 3.5% (n = 83) and 49.2% (n = 1158) for first line, whereas at 5.5% (n = 54) and 63.9% (n = 630) for second line metastatic treatments, respectively. In 25,5% of stage 4 bevacizumab users, bevacizumab was used both for first and second line treatment (n = 83). In KRAS mutant stage 4 patients bevacizumab was used 67% of first line (n = 185), and 40.2% of second line treatments (n = 51). In KRAS wild stage 4 patients bevacizumab was used 46,8% of first line (n = 197), and 24,5% of second line treatments (n = 58). Conclusions: In this study we found that 22.9% of Turkish colorectal patients were diagnosed at Stage 4. 45% of stage 4 patients were tested for KRAS and mutatian rate was 39.3%. BRAF testing rate was low in Turkish centers. Bevacizumab was a preferred agent both for KRAS mutant and WT patients.
The prognostic value of serum IL-6 and YKL-40 in patients with metastatic colorectal cancer.
Authors: Jensen Benny Vittrup , Holsey Gramkow Mathias , Mosgaard Camilla Stedstrup , Dehlendorff Christian , Pfeiffer Per , Qvortrup Camilla , Yilmaz Mette K. N. , Larsen Finn Ole , Bojesen Stig Egil , Schou Jakob Hagen Vasehus , Boisen Mogens Karsbol , Nielsen Dorte , Johansen Julia S. 
Published: September 2018

e15060 Background: The prognostic value of serum IL-6, YKL-40 and CEA before first (1) and third line therapy (3LT) in metastatic colorectal cancer (mCRC) is lacking and was evaluated in this study. Methods: From 2004 to 2015 serum samples were collected from 160 and 255 patients with mCRC before 1LT and 3LT, respectively. Median age was 64 years (range 33-87) and male/female ratio 243(59%)/172(41%). Serum IL-6 (R&D, UK) and YKL-40 (Quidel, USA) were determined by ELISA. Progression-free (PFS) and overall survival (OS), crude and adjusted hazard ratios (HR) and corresponding 95% confidence intervals (CI) were estimated with Cox regression analysis. CEA, IL-6 and YKL-40 were included as log2-transformed continuous variables with mutual adjustment between CEA, IL-6 and YKL-40, primary tumor location, sex and age. Results: In 3LT IL-6, YKL-40 and CEA levels were higher (P < 0.001) than in 1LT (IL-6: 9.5 pg/ml [IQR4.2-18.5] vs. 4.6 [2.5-10.5]; YKL-40: 140 ng/ml [77-272] vs. 101 [62-172]; and CEA: 59 ug/l [14-288] vs. 23[5.8-153]). In 3LT univariate analysis showed that increased levels of IL-6, YKL-40 and CEA were associated with shorter PFS (IL-6: HR = 1.19, 95% CI 1.07-1.31, P < 0.01; YKL-40: HR = 1.13, 1.04-1.24, P = 0.01; CEA: HR = 1.05, 1.00-1.09, P = 0.04). In 1LT only high IL-6 was associated with shorter PFS (HR = 1.09, 1.01-1.17, P = 0.03). In a multivariate analysis only high IL-6 was significantly associated with shorter PFS in 3LT (HR = 1.15, 1.03-1.29, P < 0.01) and none of the biomarkers in 1LT. In 3LT univariate analysis showed that increased levels of all 3 biomarkers were associated with a shorter OS (IL-6: HR = 1.36, 1.23-1.51, P < 0.01; YKL-40: HR = 1.21, 1.10-1.33, P < 0.01; CEA: HR = 1.11, 1.06-1.16, P < 0.01). In 1LT high levels of IL-6 (HR = 1.17, 1.08-1.27, P < 0.01) and YKL-40 (HR = 1.18, 1.00-1.38, P = 0.05), but not CEA, were associated with short OS. In 3LT the multivariate analysis showed that both higher IL-6 (HR = 1.34, 1.20-1.50, P < 0.01) and CEA (HR = 1.09, 1.03-1.14, P < 0.01), but not YKL-40 were significantly associated with a shorter OS. In 1LT only higher IL-6 was associated with a shorter OS (HR = 1.19, 1.08-1.31, P < 0.01) Conclusions: Serum IL-6 and YKL-40 may be useful prognostic biomarkers in combination with CEA in patients with mCRC
RNAi-mediated beta-catenin knockdown in the gastrointestinal mucosa (GI) of patients with familial adenomatous polyposis (FAP): Results of START-FAP trial.
Authors: Hwang Larn , Fein Seymour H. , Ng Kevin , D'Cruz Osmond , Qazi Sanjive , Wang Wen , Nam David , Fong Annie 
Published: September 2018

e15065 Background: FAP is an inherited GI disorder that predisposes patients to early-onset of colorectal cancer due to mutations in the APC gene resulting in accumulation of β-catenin contributing to the formation of polyps. CEQ508 is a novel agent using live-attenuated bacteria genetically engineered to produce and deliver β-catenin short-hairpin RNA into the GI mucosa. Methods: A dose-escalating Phase I study (START-FAP) evaluated the safety and tolerability of single daily oral doses of CEQ508 in FAP patients (3 each in Cohort 1 and 2 with 108 and 109 CFU for 28 days). The primary objective was to establish safety of oral CEQ508. The secondary objective was to test the effectiveness of CEQ508 in targeting β‐catenin gene in GI mucosa. GI tissues (duodenum, ileum, colon, antrum) obtained during endoscopy exam at baseline and end-of-treatment (EOT) were measured using qPCR and analyzed with ViiA™ 7 Real-Time system. Ct values were normalized to 2 of 3 housekeeping genes (EIF2B1, HPRT1, GUSβ). A mixed Nested-ANOVA model was used to evaluate β-catenin knockdown in normal mucosa and polyps. Results: Oral dosing of 108 and 109 CFU of CEQ508 for 28 days was well-tolerated. Histological evaluation of polyps and normal mucosa at baseline and EOT indicated minimal changes in tissue morphology or inflammation. β-catenin knockdown differed significantly between tissue types, with duodenum exhibiting the highest and antrum with the lowest (~2-fold difference). No significant effects from CEQ508 treatment were observed in normal mucosa. Significant reduction was observed in overall β-catenin expression in polyps at EOT (P = 0.0005). Patient to patient variation accounted for 8.2% of total variations. Reduction was observed primarily in the duodenum (39.3% decrease, P < 0.0001) and ileum (28.8% decrease, P = 0.012). Conclusions: Bacterial delivery of RNAi via CEQ508 in FAP patients demonstrated an acceptable safety profile at the two bacterial dose levels tested, with no MTD having been identified. START-FAP achieved both the primary endpoint of safety and secondary endpoint of β-catenin knockdown. Clinical development of CEQ508 with Celecoxib/Lisinopril (IT-102) for FAP is planned.
c-Cbl expression as a novel predictive marker of survival in patients with metastatic colorectal cancer.
Authors: Lee Shin Yin , Kolachalama Vijaya B. , Tapan Umit , Weinberg Janice , Francis Jean M. , Zhao Qing , Hartshorn Kevan L. , Rahimi Nader , Chitalia Vipul 
Published: September 2018

e15090 Background: Aberrant hyperactive Wnt/ß-catenin signaling is critical in colorectal cancer (CRC) tumorigenesis. Casitas B-lineage Lymphoma (c-Cbl) is a negative regulator of Wnt signaling, and functions as a tumor suppressor. The objective of this study was to evaluate c-Cbl expression as a predictive marker of survival in patients with metastatic CRC (mCRC). Methods: Patients with mCRC treated at Boston University Medical Center between 2004 and 2014 were analyzed. c-Cbl and nuclear ß-catenin expression was quantified in explanted biopsies using a customized color-based image segmentation pipeline. Quantification was normalized to the total tumor area in an image, and deemed ‘low’ or ‘high’ according to the mean normalized values of the cohort. A supervised machine-learning model based on bootstrap aggregating was constructed with c-Cbl expression as the input feature and 3-year survival as output. Results: Of the 72 subjects with mCRC, 52.78% had high and 47.22% had low c-Cbl expression. Patients with high c-Cbl had significantly better median overall survival than those with low c-Cbl expression (3.7 years vs. 1.8 years; p = 0.0026), and experienced superior 3-year survival (47.37% vs 20.59%; p = 0.017). Intriguingly, nuclear ß-catenin expression did not correlate with survival. No significant differences were detected between high and low c-Cbl groups in baseline characteristics (demographics, comorbidities), tumor-related parameters (primary tumor location, number of metastasis, molecular features) or therapy received (surgery, chemotherapy regimen). A 5-fold cross-validated machine-learning model associated with 3-year survival demonstrated an area under the curve of 0.729, supporting c-Cbl expression as a predictor of mCRC survival. Conclusions: Our results show that c-Cbl expression is associated with and predicts mCRC survival. Demonstration of these findings despite the small cohort size underscores the power of quantitative histology and machine-learning application. While further work is needed to validate c-Cbl as a novel biomarker of mCRC survival, this study supports c-Cbl as a regulator of Wnt/ß-catenin signaling and a suppressor of other oncogenes in CRC tumorigenesis.
Role of fibrinolysis and α2-macroglobulin in growth of primary adenocarcinoma and rectal polyps.
Authors: Kolesnikov Evgeniy N. , Nikipelova Elena Alekseevna , Frantsiyants Elena Mikhaylovna , Kozlova Larisa , Kaplieva Irina V. , Trepitaki Lidia K. , Tkalya Lyudmila Dmitriyevna , Snezhko Alexander V. , Averkin Michail , Kozhushko Mikhail Anatolievich , Sanamyanc Sergey Vladimirovich , Myagkov Roman E. , Kharin Leonid , Trifanov Vladimir , Kit Oleg I. 
Published: September 2018

e15093 Background: An important role in tumor angiogenesis induction is played by hydrolytic systems, in particular plasmin one which provides degradation of the extracellular matrix, activates growth factors and metalloproteinases. Our purpose was to analyze the tissue fibrinolytic system and α2-macroglobulin (α2M) in primary adenocarcinoma (PA) and polyps (P) of the rectum (R). Methods: Tissues of tumors (РА, G2, T2-3N0M0, 42-73 years) and their perifocal zone (PZ) in R (n = 24) and Р (n = 27) were studied by ELISA; the result was calculated per 1 mg of tissue. Results: Resection line (RL) tissues contained levels of tРА antigen and its active form (tРА-Ag and tРА-act) 6.7 and 33.8 times higher than prourokinase and urokinase levels (uPA-Ag and uPA-act). RL tissues in P did not differ significantly from R tissues at PA resection. uPA-act in PA was higher than in RL by 3.2 times, uPA-Ag - 8 times higher, tРА-act - 2.3 times lower; tPA-Ag was similar to RL tissue values. Plasmin-α2-antiplasmin complex (PAP) in PA was 1.4 times higher than in RL. Plasminogen (PG) in PA was 1.5 times lower than in RL (p < 0.01). Activity of α2M in PA and RL did not differ. PAP and α2М in PA PZ were similar to RL, and PG did not differ from PA. Other indices were between tumor and RL levels. P tissue did not show changes in uPA; tPA-act activity was 1.3 times lower than in RL, and tPA-Ag 1.3 times higher (p < 0.01). PAP in tissues of 88.2% P was 1.5 times higher than in RL and 1.7 times lower than in PA. PG and α2М were similar in P and RL. PAP in PZ of P was 2.3 times higher than in RL and 1.5 times higher than in PA PZ. PG in P PZ was 1.4 times lower than in RL (p < 0.01). α2М activity in P PZ was higher than in RL and P by 5.4 times on average. uPA in P PZ did not differ from RL; tРА-Ag and tРА-act were higher than in RL by 1.5 and 1.9 times and exceeded P by 2.1 and 1.5 times (p < 0.01). Prevalence of uPA, activation of PG in PA and its PZ indicated degradation of the extracellular matrix compared with the corresponding P tissues. Conclusions: The role of R tumor PZ as a "metabolic" tumor field in neoplasm progression was confirmed. Activation of fibrinolysis in PA and its PZ with a deficiency of inhibitors stimulates the migration and proliferation of cells. Increasing tРА, РАР and α2М in PZ of polyps has a protective effect.
Whole exome sequencing identifies novel prognostic biomarker in colon cancer.
Authors: Shen Yinchen , Han Xiaohong , Wang Zheng , Liu Dongge , Sun Yongkun , Wang Jianfei , Qian Xiaoyan , Yang Hongying , Shi Yuankai 
Published: September 2018

e15098 Background: The incidence and mortality of cancer have been increasing in China, of which colorectal cancer (CRC) is ranking the fifth and among the leading cause of cancer-related deaths .Prognostic biomarker for colon cancer treated with standard adjuvant chemotherapy was rare and inconsistent, as gene mutations accumulation contribute to the carcinogenesis, available biomarkers may emerge by genome investigation. Methods: Whole exome sequencing was performed in 13 stage III colon cancers to identify gene alternations in patients with different outcomes, followed by 350 stage II-III colon cancers samples, of which clinicopathological characteristics and survival information were collected simultaneously to evaluate the clinical relevance in this cohort for evaluation of novel gene biomarkers. Results: Eight genes (CD97, ZNF568, WARS2, IL6R, APPL2, C9orf117, ANKRD32, ZNF443) were identified as differently expressed between two groups of good (DFS > 60 months) and poor (DFS < 25 month) separated according to treatment outcomes. ZNF443 was detected in 81.7% (286/350) samples, and ZNF443 (CA) was more common in male compared with female (56.0% vs 40.8%, P = 0.011).ZNF443 (CA) distribution differed related to different N stage, only stage N0 shared a higher frequency over 50% (P = 0.026).ANKRD32 was detected in 212 (93.8%) tumors, and ANKRD32 (CA) appeared more in left sites (included left colon and sigmoid colon, 61.1% vs 41.9%, P = 0.006). Moreover, ANKRD32 (CA) was significantly associated with superior disease-free survival (DFS) in stage III colon cancer patients (P = 0.044, HR 0.49, 95% CI0.24-0.98).Tumor nodal stage appeared as independent prognostic factor for DFS and over-all survival (OS) in stage II-III colon cancer (P < 0.05), and low tumor differentiation indicated a worse OS for colon cancers. While no other significant association was obtained between genes and survival in present study. Conclusions: Whole exome sequencing was efficient in discovering novel gene biomarkers in clinical evaluation. ANKRD32 was independently prognostic for DFS in stage III colon cancer.
Differences in plasminogen activation in primary rectal adenocarcinoma with and without liver metastasis.
Authors: Kolesnikov Evgeniy N. , Nikipelova Elena Alekseevna , Frantsiyants Elena Mikhaylovna , Kozlova Larisa , Bandovkina Valeria , Kaplieva Irina V. , Trepitaki Lidia K. , Tkalya Lyudmila Dmitriyevna , Snezhko Alexander V. , Averkin Michail , Kozhushko Mikhail Anatolievich , Sanamyanc Sergey Vladimirovich , Myagkov Roman E. , Kharin Leonid , Trifanov Vladimir , Kit Oleg I. 
Published: September 2018

e15111 Background: Plasminogen activators play a key role in the cascade fibrinolytic system as they catalyze plasmin formation from plasminogen (PG). Plasminogen activators together with plasmin are directly or indirectly involved in tumor growth. The purpose of the study was to compare the plasminogen activation system in primary adenocarcinomas (РА) of the rectum (R) with and without liver metastases (LM). Methods: Tissues of tumors (РА, st. III, G2, 38-74 years) and their perifocal zone (PZ) with LM (T2-3NхM1, n = 24) and without them (T2-3N0M0, n = 32) were studied by ELISA. Results: The studied parameters did not differ in apparently intact R tissues in the resection line (RL) with and without LM. Plasmin-α2-antiplasmin complex (PAP) was 1.4 times higher in PA with LM than without LM (p < 0.05). Prourokinase and urokinase levels (uPA-Ag and uPA-act) were 12.4 and 3.7 higher than in RL. uPA-Ag and uPA-act in PA+LM were higher than without LM by 1.4 and 1.6 times. PG levels and α2-macroglobulin (α2M) activity in PA+LM were lower by 1.5 and 2.7 times than in PA without LM and lower than in RL (p < 0.01). All studied parameters, except α2M, in PA+LM were activated more than in PA without LM. Low α2M content supposed realization of effects of uPA and plasmin in insufficient inhibitory control. Most parameters in PZ+LM were between the levels in PA and RL being significantly different from both and significantly exceeding the values in PZ of PA without LM. α2М was an exception being 1.8 times lower in PZ of PA+LM than in PZ of PA without LM. The results demonstrated higher uPA and РАР levels in PA and its PZ with LM than without them, with increased PG consumption and decreased α2M activity in these parts of the rectum. Activation of plasminogen system in tissues of PA+LM and in PA without LM was unidirectional. Conclusions: Levels of uPA and PAP, as well as low α2M content in PA and PZ with LM can be used as an indicator of tumor metastatic activity.