bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
N-myristoyltransferase 2: A novel marker for colorectal cancer screening.
Authors: Rathinagopal Jenny , Kuriakose Shiby , Bhanot Shiv , Min Jordan , Hu Nan , Bernstein Charles N , Fang John , Greene Tom H , Varma Shrivastav Shailly , Singh Harminder , Shrivastav Anuraag
Published: September 2018

e15114

Background: Colorectal cancer (CRC) is the second most common cause of cancer related deaths in North America. Most CRCs arise from pre-malignant adenomatous polyps with some of these polyps developing into cancer over years providing an ideal opportunity for detection and intervention. However, the unpleasant nature of the current screening methods often leads to non-compliance. N-Myristoyltransferase (NMT) has been reported to be overexpressed in CRC tissues. In this study we show that NMT2, an isoform of NMT, is overexpressed in peripheral blood mononuclear cells (PBMC) of individuals with colorectal adenomatous polyps or cancers compared to healthy controls. Methods: PBMC’s were isolated from blood samples of CRC patients (n = 14), individuals with - non-adenomatous polyps (n = 8); adenomatous polyps (n = 18) and healthy controls (n = 24). Immunohistochemistry (IHC) was used to determine the NMT2 expression in these samples. IHC-scores were derived from assessment of both staining intensity (scale 0-3) and percentage of positive cells (0-100%), which were multiplied to generate an IHC -score between 0-300. Observers calculating the IHC scores were unaware of the polyp/CRC status. A receiver operating characteristic (ROC) analysis was performed to assess the overall performance of the NMT2 test via the area under the curve (AUC). Results: NMT2 was significantly overexpressed in PBMC of CRC patients (median IHC score- 196) compared to control subjects (median IHC score- 50). In addition, IHC scores were significantly higher for adenomatous polyps (median IHC score- 165) compared to those with non-adenomatous polyps (median IHC score- 54.8). We included non-adenomatous polyps and healthy subjects in “controls” and adenomatous polyps in “cases” along with CRC in the ROC analysis. The ROC curve of NMT2 expression displayed substantial separation between controls/non adenomatous polyps compared to CRC/adenomatous polyps [AUC = 0.913 (95% CI: 0.830-0.994)]. Conclusions: Our results show an increase in NMT2 expression in PBMC of CRC patients and individuals with adenomatous polyps suggesting that NMT2 could be used as a novel blood based biomarker for the screening and early detection of CRC. Validation studies are the next step.
Correlation of pre- and post-induction plasma mutant allele fraction with progression-free survival (PFS) in STEAM, a prospective, randomized, multicenter study in metastatic colorectal cancer (mCRC).
Authors: Lee John J. , Palma John F. , Yao Lijing , Lovejoy Alexander F. , Yaung Stephanie , Zhang David , Wingate-Pearse Nasiema , Yau May , Williams Carolyn , Pimentel Monica , Munoz Abraham , Mayol Katrina , Mancao Christoph , Nicholas Alan , Sommer Nicolas , Hurwitz Herbert , Bendell Johanna C. , Rohr Ulrich Peter
Published: September 2018

e15118

Background: STEAM (NCT01765582) evaluated the efficacy and safety of concurrent (c) and sequential (s) FOLFOXIRI-bevacizumab (BEV) versus FOLFOX-BEV for first-line treatment of mCRC. Methods: The AVENIO ctDNA Expanded Kit (Research Use Only) was used to identify somatic mutations in 77 cancer-related genes by next-generation sequencing (NGS) in both pre- and post-induction plasma samples (n = 118 for both groups) from STEAM. Demographics for patient tested were similar to the overall cohort. The mutant allele fraction (mAF) represents the mutation frequency in ctDNA for single nucleotide variants (SNVs) and indels detected per patient. Results: Overall, patients with a pre-induction mAF below the median had longer PFS compared to patients with mAF above the median (13.4 vs 9.5 mo, HR 0.49, p = 0.002). A similar trend was seen for overall survival (OS). Within the below median mAF group, longer PFS was observed in patients treated with cFOLFOXIRI-BEV versus FOLFOX-BEV (25.2 vs 9.5 mo, HR 0.34, p = 0.020). In contrast, no differences in PFS were observed in the treatment arms in the above median mAF group. Patients with a post-induction mAF below the median had longer PFS compared to patients with mAF above the median (15.3 vs 8.1 mo, HR 0.51, p = 0.0064). Correlations of post-induction genomic changes with outcomes, according to treatment groups, will also be presented. Conclusions: The level of pre- and post-induction mAF appears to correlate with PFS in STEAM overall. Furthermore, a lower median pre-induction mAF suggests PFS benefit for cFOLFOXIRI-BEV versus FOLFOX-BEV. Thus, plasma analysis of mAF via the AVENIO ctDNA Expanded Kit may identify patients who benefit from specific treatment in mCRC. These results are hypothesis generating and require further clinical validation. Clinical trial information: NCT01765582.
Outcome disparities in elder patients with colorectal cancer receiving definitive surgery: A nationwide population-based study in Taiwan.
Authors: Liu Chia-Jen , Chen San-Chi , Yen Chueh-Chuan , Teng Hao Wei , Chen Ming-Huang , Liu Chun-Yu , Chao Ta-Chung , Chiou Tzeon-Jye , Chen Po-Min , Liu Jun-Huang , Teng Chung-Jen
Published: September 2018

e15119

Background: There are increasing numbers of elderly patients with colorectal cancer (CRC). With the advance of cancer treatment in recent years, more elderly CRC patients receive curative surgery and multidisciplinary cancer treatment. The purpose of this study is to identify the risk factors of mortality and to improve survival of these patients. Methods: We recruited newly diagnosed CRC patients between 2005 and 2012 from Taiwan's nationwide health insurance database. Patients without definitive surgery for CRC were excluded. CRC patients aged < 65 years (non-elderly) were served as a reference group. The study cohort was followed until the end of 2013. Univariate and multivariate Cox proportional hazards models were applied to find the predictors of death among our study cohort. Results: During the 9-year study period, 10,818 (30.6%) died among 35,298 elderly CRC patients receiving definitive surgery, with a median follow-up period of 3.0 years. The median overall survival (OS) of the elderly patients was improved 1.4% per year (95% confidence interval [CI] 0.5–2.4%). Multivariate analysis showed that adjusted hazard ratios (HRs) for OS were 1.00, 1.23, 1.56, 2.15 in the patients aged 65–70, 70–75, 75–80, and ≥ 80 compared to those aged < 65, respectively. The older patients had a higher probability of having ≥ 2 underlying comorbidities (71.4% vs. 31.4%) and without postoperative treatment (42.1% vs. 28.8%), which might be associated with the increase of mortality risk. Conclusions: This largest cohort study demonstrated an increasing risk of mortality in elderly CRC patients, especially those with ≥ 2 underlying comorbidities and those without postoperative treatment. [Table: see text]
Predictive value of circulating tumor DNA in locally advanced rectal cancer patients receiving neoadjuvant radiochemotherapy.
Authors: Li Min , Xiao WeiWei , Zhao Grace Q. , Guo Zhiwei , Yang Xuexi , Lin Shengrong , Ying Kang , Li Ming , Gao Yuan-Hong
Published: September 2018

e15125

Background: Neoadjuvant radiochemotherapy (RCT) is rapidly becoming the preferred treatment for patients diagnosed with late-stage locally advanced rectal cancer (LARC). Presently, tumor regression grades (TRG) is used to characterize treatment responsiveness; patients with low TRG scores have been shown to receive no benefit from surgery. To-date, however, there exists no reliable method for identifying low TRG-scoring patients without surgery. Here we propose the use of circulating tumor DNA (ctDNA) to identify low TRG-scoring patients to reduce overtreatment and improve quality of life. Methods: 30 LARC patients undergoing neoadjuvant RCT were prospectively enrolled in our study. Plasma was collected before treatment, immediately preceding cycle 3 chemotherapy, and 2 weeks following cycle 4 chemotherapy. Tumor tissue was also collected before treatment start. CtDNA and tumor DNA were sequenced using Accu-Act, a 61-gene NGS panel. Tumor response was classified as TRG1-5 according to Mandard classification system. Somatic mutation profiles were correlated with tumor response. The accuracy of ctDNA and tumor DNA in predicting TRG scores was calculated using the change of allele frequency. The predictive value of ctDNA was also compared to that of standard CEA and CA199 assays. Patients with CEA and CA199 scores below threshold were also considered for evaluation. Results: 18 of the 30 LARC patients enrolled had complete ctDNA profiling test among whom 13 had already undergone surgery. 17 somatic mutations were identified from the 10 patients with TRG scores of either 1, 2, or 3. Predictive accuracy of pretreatment ctDNA profiling was 70%, compared to that of CEA analysis (66%) and CA199 analysis (50%). TRG prediction using ctDNA successfully evaluated half of patients for whom CEA analysis failed to predict the change in tumor burden. Conclusions: Our findings suggest ctDNA mutation profiling may be a powerful tool for predicting TRG in LARC patients undergoing RCT. Further studies are needed to validate the utility of ctDNA in identifying patients who can be spared from unnecessary surgical treatment in LARC. Clinical trial information: NCT02031939.
Evaluation of meaningful change in bowel movement frequency for patients with carcinoid syndrome.
Authors: Hudgens Stacie , Gable Jonathon , Kulke Matthew H. , Bergsland Emily , Anthony Lowell Brian , Caplin Martyn E. , Oberg Kjell E. , Pavel Marianne , Banks Phillip , Yang Qi Melissa , Lapuerta Pablo
Published: September 2018

e15132

Background: Telotristat ethyl is a tryptophan hydroxylase inhibitor in development for the treatment of carcinoid syndrome (CS) in patients who receive somatostatin analog (SSA) therapy. In TELESTAR, a pivotal Phase 3 study, telotristat ethyl significantly reduced bowel movement (BM) frequency compared to placebo. The objective of this study was to psychometrically assess meaningful change in BM frequency using data collected within the TELESTAR study. Methods: An anchor-based approach consisted of mapping change from baseline in BM frequency to other patient reported assessments of change. These included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core Questionnaire (EORTC QLQ-C30) Diarrhea Symptom responders, the EORTC GI.NET21 GI Symptom responders, and patient reported adequate relief at Week 12 (responders had a ≥ 10-point decrease in scores from Day 1 to Week 12). Parameters included within group mean change from baseline to Week 12, t-tests of the change (Wilcoxon Rank Sum for adequate relief), effect size (ES: calculated as the difference between mean on-treatment and baseline BM frequency, divided by the standard deviation of the baseline), and related confidence intervals. Results: There were 135 patients with CS, with a mean age of 63.6 years and mean baseline BM frequency of 5.7 BM/day. Anchor-based analyses indicated significant differences in BM frequency between adequate relief groups at Week 12 (ES: −1.58 vs. −0.79; p = 0.014), responders and non-responders on the EORTC QLQ-C30 Diarrhea Symptoms domain (ES: −1.24 vs. −0.59; p < 0.0001), and responders and non-responders on the EORTC GI.NET21 GI Symptoms Domain (ES: −1.49 vs. −0.75; p = 0.0053). These corresponded to BM frequency reductions of 1.7–1.9 BM/day, or ≥ 30%. Conclusions: Results of this study indicated that patients with CS experienced clinically meaningful reductions in BM frequency of ≥ 30% over the course of 12 weeks. Clinical trial information: NCT01677910.
Similar T-cell repertoires of tumor infiltrating lymphocytes and Crohn’s-like lymphoid reaction in colorectal cancer.
Authors: Maoz Asaf , Greenson Joel K , Melas Marilena , Emerson Ryan O , Vignali Marissa , Robins Harlan , Qu Chenxu , Schmit Stephanie , Pinchev Mila , McDonnell Kevin J , Rennert Gad , Gruber Stephen B.
Published: September 2018

e15133

Background: Tumor infiltrating lymphocytes (TILs) and Crohn’s-like Lymphoid Reaction (CLR) are independently associated with improved survival in colorectal cancer (CRC). Whereas TILs are localized within tumors, CLR are extra-tumoral lymphocytic aggregates. The origins and relationships of the T-cell repertoire of TILs and the T cells within CLR of the colorectal cancer tumor microenvironment are unknown. Methods: Expert pathology review identified and circled areas of invasive adenocarcinoma and areas containing CLR from 13 CRC patients for macrodissection from formalin fixed paraffin embedded (FFPE) slides. DNA was extracted from matched tumor and CLR areas for multiplex PCR sequencing of the CDR3 region of the T-cell receptor beta chain (TCRβ), using the immunoSEQ platform. This approach permits 1) estimating the T-cell content of each sample, 2) measuring the clonality of the T-cell repertoire as a measure of diversity, and 3) quantifying the overlap and similarity of T-cell repertoires across samples. Results: The T-cell content (Spearman’s rs = 0.56, p = 0.046) and clonality (Spearman’s rs = 0.66, p = 0.014) were highly correlated among matched tumor and CLR samples. The ten most frequently identified TIL clones were found at similar frequencies in matched CLR enriched tissues. Comparisons of all the clones detected in tumor and matched CLR tissue demonstrated substantial similarity of these immune repertoires, with an average of 186 shared clones between samples. This degree of similarity was significantly greater than published reports of the similarity of the T-cell repertoire of colorectal tumors and adjacent normal tissue (p = 1.1e-5). Conclusions: The T-cell repertoire of CLR is highly similar to the tumor infiltrating T-cell repertoire, providing supporting evidence for the hypothesis that tumor-specific antigen presentation and lymphocyte maturation occur within CLR.
Comorbidity and cause of death after surgery for early stage colorectal cancer (CRC).
Authors: Justiniano Carla Francesca , Xu Zhaomin , Becerra Adan Z , Aquina Christopher Thomas , Boscoe Francis P. , Schymura Maria J. , Temple Larissa K. F. , Fleming Fergal J.
Published: September 2018

e15139

Background: Early stage (I/II) CRC is traditionally associated with relatively good prognosis at 90% relative survival. The probability of non-cancer death in CRC patients is associated with comorbidity burden; however, there is paucity of data evaluating this association in colon versus rectal cancer. This study examines the impact of comorbdity on 5-year mortality and cause of death after resection for early stage CRC. Methods: Linked patient-level data from the New York State Cancer Registry & Statewide Planning and Research Cooperative System was queried for 2004-2013 patients who underwent colectomy or proctectomy for Stage I-II CRC who survived beyond 30 days. Comorbidity burden was defined as the sum of Elixhauser Comorbidites plus steroid use, MI history, CVD (cardiovascular disease), and dementia to capture maximum number of unique comorbidities and characterized as low (0-1 comorbidity), moderate (2-3 comorbidities), and high (4+ comorbidities). Causes of death were evaluated according to comorbidity group and colon versus rectal cancer. Results: 24,643 (colon 21,384, rectal 3,250) met inclusion criteria, of which 5,464 (22%) died within 5 years. While both colon cancer (CC) and rectal cancer patients (RC) had identical overall mortality (22%), significant differences existed in the proportion of deaths due to the primary cancer with disease-specific mortality of 7% for CC and 11% for RC. Deaths due to CC decreased while CVD causes increased with escalating comorbidity burden. Deaths due to RC accounted for nearly 50% of all deaths even with increasing comorbidity burden (Table). Conclusions: CC is the predominant cause of 5-year mortality in early stage patients with low comorbidity burden while CVD drives mortality in high comorbidity burden patients. In contrast, RC drives early stage mortality regardless of the comorbidity burden; thus, emphasizing the importance of tailored survivorship programs to each cancer. [Table: see text]
KRAS mutational status in metastatic colorectal cancer and thrombotic risk.
Authors: Menapace Laurel Anne , Bena James , Morrison Shannon , Khorana Alok A.
Published: September 2018

e15140

Background: There is limited clinical evidence suggesting a possible association between KRAS mutational status and thrombotic risk in metastatic colorectal cancer (mCRC). We attempted to confirm previously published findings in a single institution study of mCRC patients initiating treatment at Cleveland Clinic. Methods: We evaluated the association of observed venous thromboembolic (VTE) events in relation to KRAS mutational status in a retrospective cohort of mCRC patients receiving treatment at Taussig Cancer Institute between 2009 and 2013.KRAS mutational status obtained from pathologic tissue specimens,specifically wild-type (WT) or mutant status, was recorded for each patient. Both inpatient and outpatient radiologic reports were reviewed for presence of pulmonary embolism (PE), deep venous thrombosis (DVT), and visceral vein thrombosis (VVT). All observed VTE events were analyzed, including asymptomatic or incidentally discovered VTE. Results: A total of 184 patients with newly diagnosed metastatic colorectal cancer were included in the analysis. There were a total of 47 combined VTE events observed in 42 patients. 5 subjects had more than one thrombotic event during the investigative period. 55.4% (n = 102) of mCRC patients were identified as WT whereas the remainder harbored a KRAS mutation (44.6%, n = 82). Both groups had similar rates of bevacizumab exposure. There were slightly more VTE events in the KRAS mutant cohort, with a total of 26 observed VTE events in 24 patients (29.3%) versus a total of 21 thrombotic events in 18 mCRC WT patients (17.6%). There were 16 DVTs, 6 PEs and 4 VVTs in the KRAS mutant group as compared to 10 DVTs, 9 PEs, and 2 VVTs in the WT cohort. There was no statistically significant difference in combined VTE (Odds Ratio 1.90 [0.96 - 3.91], p = 0.062), DVT (OR 0.82 [0.28 - 2.39], p = 0.06), PE (OR 2.23 [0.95 - 5.22], p = 0.71) and VVT (OR 2.60 [0.46 -14.4], p = 0.41) between groups. There was no difference in survival measured in days between KRAS mutant and WT mCRC patients. Conclusions: Based on these results, there is limited evidence that mCRC patients harboring KRAS mutations may be at greater risk for VTE. Further study of KRAS mutational status as a biomarker of thrombotic risk in cancer is indicated.
Phase Ib/II study of neoadjuvant chemoradiotherapy with CRLX101 and capecitabine for locally advanced rectal cancer.
Authors: Wang Andrew , McRee Autumn Jackson , Blackstock A. William , O'Neil Bert H. , Moore Dominic T. , Calvo Benjamin F. , Lee Michael Sangmin , Murphy Curran , Caliri Kim , Tynan Maureen T. , Senderowicz Adrian Mario , Tepper Joel E. , Sanoff Hanna Kelly ,   CRLX101
Published: September 2018

e15144

Background: There is strong interest in the development of novel agents to further improve the therapeutic ratio of neoadjuvant chemoradiotherapy for rectal cancer. CRLX101 is an investigational nanoparticle-drug conjugate with a camptothecin payload. The purpose of this Phase Ib/II study is to assess toxicity and to evaluate whether the addition of CRLX101 to chemoradiotherapy can improve pathologic complete response (pCR) for rectal cancer. Methods: This is a single-arm multicenter Phase Ib/II study examining the addition of CRLX101 to a standard capecitabine-based chemoradiotherapy regimen. Phase Ib employs a 3+3 dose escalation design with starting dose of 12 mg/m2 every other week (QOW). Dose level +1 was 15 mg/m2 (MTD for CRLX101 single agent QOW). Upon reaching MTD for QOW dosing, protocol was modified to evaluate QW CRLX101 dosing starting at 12 mg/m2 and 15 mg/m2as +1 level. Secondary endpoints included pCR and clinical outcome. Results: A total of 32 patients were enrolled on the trial. 26/32 had T3-4, 9/32 had N2 and 16/32 had N1 disease. For QOW dosing, 9 patients completed treatment without DLT and MTD was identified as 15 mg/m2 QOW. 14 patients were treated on the Phase II portion of the study at 15 mg/m2 QOW prior to the initiation of weekly dosing Phase Ib cohorts. For QW dosing, 0/3 patients experienced DLT at 12 mg/m2 and 1/6 patients experienced DLT at 15 mg/m2. The DLT was skin desquamation requiring treatment delay. QW MTD was identified as 15 mg/m2. Toxicities (all grade 3 except lymphopenia) that could possibly be attributed to CRLX101 are in Table 1. Full clinical and pathologic staging were available for 29/32 patients. Mean neoadjuvant rectal (NAR) score was 19 with standard deviation of 15. At the weekly MTD, 3/6 patients had pCR. Conclusions: CRLX101 weekly at 15 mg/m2+ standard capecitabine-based chemoradiotherapy appears to be well tolerated, with promising pCR rates that warrants further evaluation. A larger PhII trial should be considered with this regimen. Clinical trial information: NCT02010567. [Table: see text]
Role of adjuvant chemotherapy in patients with locally advanced rectal carcinoma after preoperative chemoradiotherapy: Single center experience.
Authors: Fedyanin Mikhail , Tryakin Alexey , Elsnukaeva Kheda , Gordeev Sergey , Sekhina Olga , Pokataev Ilya , Glebovskaya Valeriya , Kozlov Nikolay , Rasulov Arsen , Tjulandin Sergei
Published: September 2018

e15147

Background: Various national guidance provide different approaches in adjuvant chemotherapy for locally advanced rectal carcinoma initially treated with preoperative chemoradiotherapy. We evaluated the efficacy of adjuvant chemotherapy depending on the clinical stage of disease (prior to chemoradiotherapy) and yp stage (after surgery). Methods: Preoperative chemoradiotherapy was administered in 457 patients with locally advanced rectal carcinoma. Radiotherapy was performed in pts receiving capecitabine (64%), intravenous administration of 5-FU (16%) or combination fluoropyrimidines with oxaliplatin (20%). Adjuvant chemotherapy was administered in 98 patients (21%) (fluoropyrimidines alone (20%) or in combination with oxaliplatin (80% patients). Overall survival (OS) was the primary endpoint. Statistical analysis was performed in IBM SPSS statistics v.20 software package. Results: the mean age of patients was 56.6 years, male - 56%. Median of follow up was 42 months (2-141). Adjuvant chemotherapy did not result to better OS in any of clinical stage (p = 0.6 HR 1.1, 95% CI 0.6-2.1). However adjuvant chemotherapy tended to improve disease free survival (DFS) in stage ypT0-4N1-2M0 (р=0.1, HR=0.6, 95%CI 0.4-1.1). Subanalysis showed significant improvement of DFS in patients with ypT1-4N2M0: median of DFS in patients with adjuvant chemotherapy was 62 months, in patients from group of surveillance – 16 months (р<0.01, HR=0.3, 95%CI 0.14-0.7) and a tendency to improvement of OS (table). Conclusions: Our retrospective data confirmed the results of ADORE prospective trial, and showed that adjuvant chemotherapy for locally advanced rectal carcinoma after chemoradiotherapy should be administered only in patients with residual positive lymph nodes (yp stage III). [Table: see text]
Post neoadjuvant chemo-radiation positive anterior circumferential resection margin in carcinoma rectum: Extended resection of rectum versus total pelvic exenteration—Results from a single centre retrospective study.
Authors: Verma Kamlesh , Engineer Reena , Ostwal Vikas S. , Kumar Suman , Arya Supreeta , DeSouza Ashwin , Saklani Avanish
Published: September 2018

e15156

Background: Positive circumferential resection margin has been shown to be powerful predictor of poor prognosis in rectal CA. Radiologically positive anterior CRM (PACRM) after NACT+RT leads to either resection of involved organ alone ie.Extended resection of rectum (ERR) or Total pelvic exenteration (TPE). Purpose of this study is to compare recurrence rate and survival of patients undergoing ERR or TPE for PACRM after NACT+RT. Methods: Retrospective study of patients operated for rectal CA from January 2013 to December 2014. Results: Out of 237 patients with non-metastatic CA rectum, 51 patients (21.5%) had PACRM. After NACT+RT, 22 patients (43.1%) developed systemic metastases, 7 patients (13.8%) were downsized and underwent extra-mesorectal resection (AR/APR), remaining 22 patients (43.1%) had persistent PACRM. 13 patients with PACRM underwent ERR whereas 9 patients underwent TPE. Median duration of hospital stay in TPE group was 13 days (10 - 26) whereas it was 7 days (5 – 21) in ERR group. Negative pathological CRM was achieved in all TPE and 92.3% of ERR patients. After median follow-up of 31.6 months, 5 patients with TPE (55.6%) and 4 patients with ERR (30.7%) developed systemic recurrence. None of the TPE patient, whereas 3 patients with ERR (23.1%) developed local recurrence. Median D.F.S. was 12.3 months in TPE and 18.9 months in ERR whereas mean O.S. was 36.2 and 32.8 respectively. Conclusions: Due to lack of significant difference in O.S./ D.F.S. and low post-operative complication and duration of hospital stay, ERR can be considered acceptable alternative to TPE.
Long-term experience with oral fluoropyrimidines and oxaliplatin-based long-course chemoradiotherapy in locally advanced rectal cancer patients.
Authors: Diaz Beveridge Robert , Akhoundova Dilara , Bruixola Gema , Mendez Juan Antonio , Medina Maria Eugenia , Garcia Esther , Torres Alba , Navarro Edwin , Melian Marcos , Gimenez Alejandra , Segura Angel , Aparicio Jorge
Published: September 2018

e15159

Background: Neoadjuvant radiotherapy (RT) previous to surgery (S), both as short-course RT (SCRT) and as long-course RT with 5-FU-based chemotherapy (LCRCT), is used in locally advanced rectal cancer (LARC), with consistent benefits in the local relapse (LR) risk. However, survival benefits have been elusive to find, especially with the use of total mesorectal excision (TME). Concerns about over-treating patients (pts) and long-term side effects have also cast more doubts in a blanket approach of treating all pts with neoadjuvant RT, especially with LCRCT. Methods: Retrospective review of cT3-T4 and/or N+ rectal cancer pts (1999-2014) treated with LCRCT and oral 5-FU and oxaliplatin (65% of pts), followed by TME and 5-FU-based CT. Clinical, radiological and pathological prognostic factors for LR, distant metastases (DM), disease-free survival (DFS) and overall survival (OS) are shown. Results: 203 pts. 98.5% proceeded to S; TME done in 89.7%. Downstaging rate: 70.4% (mainly N staging); pathological complete responses: 14.9%. LR and DM rate was 8.3% and 27%. TNM pathological data (ypTN) were better prognostic factors than tumour regression grades. Prognostic factors (multivariate): circumferential margin (CRM) and perineural invasion. No benefit seen with the addition of oxaliplatin. Compliance to adjuvant CT was poor; < 50% received the full dose. 5- and 10-year DFS and OS: 71.4% and 54.9% and 75.4% and 62.4%. Elderly pts had a worse OS, due to higher unexpected toxicity and lower treatment compliance. Mucinous tumours showed a poor response to LCRCT. Prognostic factors (multivariate) for OS and DFS: older age, CRM invasion, an unsuccessful TME and a heavy lymph node burden. Conclusions: The identification of pts with a low risk of LR where RT could be avoided is based on the premise of an exquisite imaging staging and a surgical team specialized in TME. A free CRM and a successful TME are pivotal for success. Clinical lymph node staging is problematic. The role of adjuvant CT remains undefined, and compliance rates are poor. Neoadjuvant CT is an option, especially if there is a high risk of DM. Better tolerated options, such as SCRT, should be used in elderly or frail pts.
Clinical lymph node staging by imaging in colorectal cancer: A flip of the coin?
Authors: Brouwer Nelleke Pietronella Maria , Stijns Rutger Carel Hubert , Valery Lemmens , Nagtegaal Iris D. , Beets-Tan Regina GH , FÃ¼tterer Jurgen , Verhoeven Rob H.A. , de Wilt Johannes H.W.
Published: September 2018

e15160

Background: Clinical lymph node staging by MRI and CT is important in stratification for neoadjuvant therapy in colorectal cancer. Overstaging may result in unnecessary neoadjuvant therapy, but understaging may refrain patients from adequate preoperative treatment. This study aims to provide insight in current daily practice in clinical lymph node staging in CRC in the Netherlands. Methods: All patients with primary CRC, diagnosed between 2003-2014, who underwent lymph node dissection were selected from the nationwide population-based Netherlands Cancer Registry (n=100,211). Trends in patient- and tumor-characteristics, and lymph node staging were analyzed. For the years 2011-2014, sensitivity, specificity, positive (PPV) and negative predictive value (NPV) were calculated for clinical lymph node staging, with histology as the gold standard. Only patients without preoperative treatment were analyzed. Since prospective studies have shown that 5x5 Gy radiotherapy (RT) followed by total mesorectal excision within 10 days does not lead to nodal downstaging, an additional analysis was performed in this group. Results: The proportion clinically positive lymph nodes increased significantly between 2003-2014; from 7% to 22% for colon cancer and from 7% to 53% for rectal cancer. The proportion histological positive lymph nodes remained fairly stable over time (±35% colon, ±33% rectum). During 2011-2014, clinical lymph node staging was available in the registry in 86% of colon cancer patients, 92% of rectal cancer patients without neoadjuvant treatment and 95% of rectal cancer patients with 5x5 Gy RT. The parameters based on data from this period are presented in table 1. Conclusions: With a sensitivity and PPV of approximately 50%, clinical lymph node staging is about as accurate as flipping a coin. This leads to overtreatment in patients with rectal cancer with neoadjuvant RT. Acceptable specificity and NPV limit the risk of undertreatment. [Table: see text]
Colorectal cancer with mucinous component compared to clinicopathological and molecular features as mucinous adenocarcinoma.
Authors: Yang Liu , Cai Yue , Zhang Jianwei , Hu Huabin , Wenjing Wang , Wu Zehua , Deng Ru , Deng Yanhong
Published: September 2018

e15166

Background: CRC can be divided into 3 groups: regular adenocarcinoma (RA), mucinous adenocarcinoma (MA), and adenocarcinoma with mucinous component (MC, mucin formation <50 % ). MA is distinct from RA, however, little is known about MC. We aimed to compare the clinicopathological and genetic features of 3 groups. Methods: A retrospective chort of consecutive CRC patients with available gene status was enrolled. KRAS,NRAS,BRAF,PIK3CA gene, MSI(IHC method) status were analyzed. Results: A total of 1454 patients were enrolled, including 1179 RA, 106 MA and 169 MC. Similar to MA, MC patients were younger, tended in proximal colon, had more advanced T stage ,higher nodal and peritoneal metastasis compared to RA. MSI-H were more occurred in MA and MC than RA (18.9%, 15.1% vs.3.9%). MC and MA had identical mutation frequency.They had higher KRAS (62.1%,62.3% vs.41.4%), BRAF(10.1%,9.4% vs.1.9%) and PIK3CA(21.3%,21.7% vs.9.4%) mutation than RA. Among MA or MC patients, almost 80% had at least one mutation, 17% had double mutation,and the mutation rates between left and right colon was similar, which is distinguish from RA. Conclusions: MC has comparable patholgical and molecular features as MA, which is distinct from RA. We should consider mucinous histology and the genetic features into future clinical practice. [Table: see text]