bluuebunny/crossref_metadata_2025_split huggingface dataset:
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]