bluuebunny/crossref_metadata_2025 huggingface dataset:
DNA methylation profiling from circulating tumor DNA for early-detection of colorectal cancer.
Authors: Zhang Wei , Sui Jinke , Wu Xianrui , Cao Fuao , Yu Guanyu , Wang Chenyang , Zhang Zhihong , Li Bingsi , Fang Shuai , Han-Zhang Han , Lou Zheng , Gong Haifeng , Liu Lianjie , Zheng Nanxin , Hao Liqiang , Lan Ping
Published: May 2019

e15076

Background: Colorectal cancer (CRC) develops as a result of neoplastic progression, which often takes decades, providing a window for early detection. Unfortunately, there has been little success in developing blood-based screening method due to the low amount of ctDNA present in the circulation, especially in patients with early stage disease. The role of aberrant DNA methylation, occurring very early in tumorigenesis, has been well elucidated. In this prospective study, we evaluated the potentiality of DNA methylation status obtained from ctDNA as an early detection method. Methods: Panel Design: Methylation data of tumor samples (12 types, n = 4,772), adjacent normal (8 types, n = 411), and normal white blood cells (n = 656) from TCGA and GSE were compared. Differentially methylated sites were extracted using modified wald-test with an adjusted p-value < 0.05 and fold-change > 2. Our panel covers 80,672 CpG sites, spanning 1.05Mb of human genome. We performed targeted bisulfite sequencing on plasma samples of 67 (stage I: 13, II:29, III: 23, IV: 2) Chinese CRC patients and 144 healthy individuals to construct a model for deriving markers that are differentially methylated and their associated weight. The model was validated in 2 independent cohorts. Results: We constructed a model using a support vector machine (SVM)-based machine learning classifier based on top 4,000 differentially methylated regions (DMRs) selected by random forest between tumor and normal plasma samples. Subsequently, 5-fold cross-validation with 100-time repeats were performed to gain a robust estimation of model performance, achieving a sensitivity of 91%, specificity of 98% and area under curve (AUC) of 98.6%. The model was subsequently validated in 2 independent cohorts: one consisted of 57 stage I-III CRC patients and 74 healthy individuals and another one with 47 stage IV patients and the same 74 healthy individuals. The model yielded a sensitivity of 83% and 95% for the early and late stage cohorts, respectively. A specificity of 95% was obtained for both cohorts. Conclusions: Our findings demonstrated the potential of profiling DNA methylation, which can effectively distinguish cancerous from healthy, for the purpose of screening. This method has potential to serve as a supplementary or alternative approach in early detection.
KLF4 p.A472D mutation: An acquired resistant mutation to cetuximab in colorectal cancer.
Authors: Yang Liu , Jiang Jiahong , Chang Lianpeng , Xu Yaping , Ni Chao , Huang Dongsheng
Published: May 2019

e15077

Background: With the increase of treatment course, acquired resistance of epidermal growth factor receptor (EGFR) blockade is inevitable in patients with metastatic colorectal cancer (mCRC). KRAS mutations have been considered to be primary drivers of this acquired resistance; however, the potential function of other genes has not been extensively investigated. Methods: This study included 17 mCRC patients with acquired cetuximab resistance, and mutations in circulating tumor DNA (ctDNA) from plasma samples were identified using target-capture deep sequencing. Analysis of mutational prevalence in ctDNA, three CRC tissue-based datasets and one ctDNA dataset was performed. Mutation predicted with significant effect on acquired resistance was selected and the functional analysis was validated in CRC cells. Results: The prevalence of mutations identified in ctDNA was consistent with CRC tissue-based and ctDNA datasets. Clonal analysis revealed that 41.2% of patients were positive for at least one subclonal. Multiply resistance mechanisms of cetuximab were co-existed in individual patient, with one of them even harbored nine distinct mutations. In particularly, function analysis of Krüppel-like factor 4 (KLF4) mutation p.A472D revealed increased cetuximab resistance in CRC cells, which was associated with the increased phosphorylation of downstream EGFR signaling proteins. Conclusions: The KLF4 mutation p.A472D contributes to acquired cetuximab resistance in patients with mCRC and it may serve as a new biomarker useful in clinical application. Monitoring somatic mutations related to acquired cetuximab resistance in mCRC patients through ctDNA is an appropriate means of providing real-time insights useful for clinical reference and treatment planning.
Evaluating cancer outcomes of outpatient colonoscopies in elderly patients older than 85 years of age.
Authors: Lee Joy A , Bi Xia , Huang Connie Y , Coyle Walter
Published: May 2019

e15079

Background: With increasing life expectancy, the incidence of colorectal cancer increases. Currently, there are few studies on cancer outcomes of outpatient colonoscopy in patients older than 85 years of age. Methods: The database at Scripps was queried for all outpatient colonoscopies performed under moderate sedation between April 1, 2012 to March 31, 2017 on patients aged 85 years and older. Patient demographics, indication for procedure, and endoscopic findings were obtained. Variables including location and stage of tumor, subsequent treatments, and overall mortality were analyzed. Results: 322 outpatient colonoscopies were reviewed. Median age was 86 years. 53% were females. Screening colonoscopies accounted for 2.1% of procedures. 40 (12.4%) colon cancers were detected. 38 (95%) were adenocarcinomas and 2 (5%) were neuroendocrine tumors. 26 (65%) were right sided colon cancers. Among those diagnosed with cancer, anemia was the most common indication followed by positive fecal occult blood test (FOBT). 20 (50%) of these patients had a FOBT within the past year. Of those FOBTs, 18 (90%) were positive. Median age of patients with colon cancer was 88 years. 70% were females. 12 (30%) patients had never had a colonoscopy. 19 (47.5%) were diagnosed at an advanced stage (stage III or IV). 32 (80%) pursued surgery, 10 (25%) received chemotherapy, and 5 (12.5%) received radiation. 3 (7.5%) patients received supportive care only. 1-year mortality was 22.5% and 3-year mortality was 40% from the time of diagnosis. Conclusions: To date, this is the first study in the United States that examines cancer outcomes in an elderly population undergoing an outpatient colonoscopy. Overall, patients over the age of 85 with colorectal cancer have good outcomes that are comparable to that of the general population and colonoscopies should be considered for appropriate candidates.
The prognostic value of KRAS mutation in locally advanced rectal cancer.
Authors: Bakalov Veli , Hasan Shaakir , Abel Stephen , Babar Laila , Shaikh Hira , Raj Moses S. , Finley Gene Grant , Monga Dulabh K. , Kirichenko Alexander V. , Wegner Rodney E
Published: May 2019

e15090

Background: The prognostic value and prognostic value of the KRAS proto-oncogene mutation in colorectal cancer has been debated. Herein, we analyzed the National Cancer Database (NCDB) to assess the role of KRAS mutation as a prognostic marker in patients with locally advanced rectal cancer (LARC). Methods: We identified LARC patients treated with neoadjuvant chemoradiation from 2004-2015 excluding those with stage I/IV disease and unknown KRAS status.Multivariable logistic regression identified variables associated with KRAS positivity. Propensity adjusted univariable and multivariable analyses identified predictors of survival. Results: Of the 784 eligible patients, 506 and 278 were KRAS negative (KRAS-) and KRAS positive (KRAS+). Median survival was 63.6 months and 76.3 months for KRAS+ and KRAS-patients, with propensity adjusted 3 and 5-year survival of (79.9% vs. 83.6%) and (56.7% vs 61.9%) respectively (HR 1.56, p 1.074-2.272). Male sex, no insurance, and KRAS+ disease was associated with poorer survival on unadjusted and propensity adjusted multivariable analyses (Table). Conclusions: Our analysis of KRAS+ LARC suggest that KRAS+ disease is associated with poorer overall survival. Given the inherent limitations of retrospective data, prospective validation is warranted. [Table: see text]
Effect of PTPRB on metastasis of colorectal carcinoma and induction of epithelial-mesenchymal transition.
Authors: Weng Xingyue , Zheng Shu
Published: May 2019

e15099

Background: Colorectal cancer (CRC) is one of the most common and lethal cancers worldwide. Metastasis and recurrence are believed to be responsible for limiting long-term survival of patients with CRC. Protein tyrosine phosphatase, receptor type B ( PTPRB) belongs to the protein tyrosine phosphatase family. Multiple studies have previously demonstrated that dysregulation of PTPRB function and expression has been shown to correlate with carcinogenesis and tumor progression in multiple cancer types. Methods: In this study, we used CRC cell lines to explore the expression of PTPRB and to analyze the biological function of PTPRB protein. Surgical tumor specimens were collected for immunohistochemical staining to evaluate PTPRB expression.Real-time polymerase chain reaction (PCR) and western blot analysis were used to confirm genes and proteins of interest, respectively. Results: PTPRB is expressed at significantly higher levels in CRC tissues compared to adjacent non-tumor tissues and in CRC cell lines with high metastasis potential. PTPRB knockdown decreased the number of invasive CRC cells in a vitro wound healing model, and also reduced tumor metastasis in vivo. Conversely, PTPRB overexpression decreased E-cadherin expression and promoted vimentin expression, while PTPRB knockdown had the opposite effect. Hypoxic conditions induced EMT and promoted metastasis in CRC cells, but these effects were eliminated by PTPRB knockdown. EMT blockade via TWIST1 knockdown inhibited the migration and invasiveness of CRC cells, and even increased PTPRB expression could not reverse this effect. Conclusions: PTPRB is upregulated in CRC and overexpression of PTPRB promotes the metastasis of CRC. Moreover, our study revealed the effect of PTPRB on promoting EMT, as reflected in increased vimentin and decreased E-cadherin expression. PTPRB is a novel therapeutic target for the treatment of CRC.
Prediction of trifluridine/tipiracil (TAS-102) effectiveness in patients with refractory metastatic colorectal cancer (mCRC): Real-life data from the Czech Republic.
Authors: Grell Peter , Dvorak Josef , Vocka Michal , John Stanislav , Tuskova Helena , Buchler Tomas , Borilova Simona , Selingerova Iveta , Vyzula Rostislav , Petruzelka Lubos B. , Kiss Igor , Obermannova Radka
Published: May 2019

e15102

Background: TAS-102 is effective in refractory mCRC and significantly improved survival versus placebo. Currently no predictive biomarkers are established and used in clinical practice. Methods: We analyzed data of 160 patients treated with TAS-102 in real clinical practice in Czech Republic. Different factors associated with progression-free survival (PFS) and overall survival (OS) were evaluated. Results: Baseline patients’ characteristics: median age 66 years (range 28-83), 106 patients were male (66.3 %), ECOG PS 0 had 38.1 %, RAS wt 45 %. Anti-VEGF treatment had 83.1 %, anti-EGFR 43.8 %. Median number of TAS-102 treatment line was 3 (range, 2 – 8), median TAS-102 cycles 3 (range 1 – 27). At the time of analysis 15 % continued in treatment, 73.7 % discontinued due to progression, 6.9 % due to toxicity, 3.8 % decided to discontinue in treatment. Median PFS was 3.3 months (95% CI, 3.0 – 3.5), and median OS 10.2 months (95% CI, 8.9 – 11.8). Factors significantly associated with PFS and/or OS were: PS, time from diagnosis of mCRC, initiation of TAS-102 treatment > 3 months from last fluoropyrimidine, baseline CRP, WBC, neutrophils count, monocytes count, NLR, neutropenia ≥ G2, diarrhea ≥ G1, thrombocytopenia ≥ G2, required TAS-102 dose reduction and cycle delay. We developed a scoring system TAScore from factors at the beginning of treatment (PS 0, initiation of TAS-102 > 3 months from fluoropyrimidine, time from diagnosis of mCRC, baseline CRP, WBC, monocytes count < 0.5 × 109/L). For each factor patient received 1 point, the overall score was the sum of these points and patients were divided into 3 groups: high risk group with 0 to 1 point, intermediate with 2 to 3, favorable with 4 or more points. OS according to risk group was: 5.7 months for high risk (11 patients), 8.7 for intermediate (63), 12.8 for favorable (59) (P < 0.0001). TAScore was also associated with PFS: 2.4 months for high risk, 2.9 intermediate and 3.9 for favorable risk group (P < 0.0001). Conclusions: TAS-102 is effective in patients with refractory mCRC. We propose simple scoring system TAScore to help with precise patient selection at the beginning of TAS-102 treatment.
Optimizing cut-offs for high neutrophil-to-lymphocyte ratio as poor survival prognostic factor in colorectal cancer.
Authors: Namuche Fernando , Leon Jorge , Montenegro Paola Catherine , Flores Claudio J.
Published: May 2019

e15111

Background: The incidence of colorectal cancer (CRC) in Peru has increased in the last decades. Needing to use all the possible tools for an accurate diagnosis and early treatment. Neutrophil-to-lymphocyte ratio (NLR) has been associated as poor prognostic factor in OS and PFS in CRC. There is no data that support this statement in Latin America. It is of a special utility in our country the detection of a simple and reproducible prognostic biomarker that guides the use of more advanced tests. Our objective was to explore the factors associated with OS in the local-locally advanced and metastatic settings. Methods: We retrospectively reviewed the electronic medical records of 609 patients with CRC from one specialized Peruvian cancer center between 2006 and 2016 Descriptive results for numeric variables were presented as means with standard deviation (SD) or medians with interquartile range (IQR), depending on their distributions; otherwise, we expressed the qualitative variables as numbers with percentages. We divided our population into two groups: Local-locally advanced (L-LA) (516 pts) and debut metastatic- recurrence (M-R) (108 pts). We performed a ROC curve analysis to determine an appropriate cut-off value for NLR in both groups (L-LA:NLR ≥3, M-R:NLR ≥5). A univariate survival analysis was performed with Kaplan Meier method, comparing the curves with Log Rank test. A multivariate analysis was performed using the Cox regression model with the statistically significant variables found in the univariate analysis. Results: Pts with high NLR had significantly shorter OS in L-LA [HR, 12.1; 95% CI,5.019-29.211; p < 0.001] M-R [HR, 5.382; 95% CI,2.835-10.217; p < 0.001] than pts with low NLR. In the multivariate model, NLR retained a significant association with OS in both groups. Cox regression demonstrated that in L-LA setting sex, histologic grade and lymph node involvement; and in M-R setting sidedness, histologic grade, LVI and metastasectomy performed were independently risk factors for a shorter OS. Conclusions: High NLR is associated with poor prognosis (with our cut-offs L-LA:NLR ≥3, M-R:NLR ≥5). There are other variables to be considered that affect the OS, as: sex, histologic grade and lymph node involvement, sidedness, histologic grade, LVI and metastasectomy performed.
The Idylla MSI Test (CE-IVD) multi-center concordance study: Microsatellite instability detection in colorectal cancer samples.
Authors: Pauwels Patrick , Steiniche Torben , Gazin Muriel , Van de Velde Jan , Bellon Ellen , Rondelez Evelien , Vandenbroeck Liesbeth , Zwaenepoel Karen , De Winne Koen , Meyer Tine , Mejer Julie , Stougaard Magnus , Decanniere Klaas , Devogelaere Benoit , Maertens Geert G. , De Craene Bram
Published: May 2019

e15112

Background: To validate the Idylla MSI Test to detect microsatellite instability (MSI) in colorectal cancer (CRC) samples in comparison with Promega MSI Analysis System v1.2 (Promega MSI) and in conditions similar to normal use. Methods: The study was performed on residual formalin-fixed and paraffin-embedded (FFPE) samples obtained from routine diagnostics by two centers, University Hospital Aarhus and University Hospital Antwerp. Samples originated from CRC patients (all stages). Both centers performed the Idylla MSI Test (with 7 novel homopolymer deletion markers) at their premises on 150 and 180 samples, respectively. The comparator method, Promega MSI, was performed for all 330 samples by University Hospital Antwerp. Results: Seven (n=7) of 330 samples were excluded from the concordance analysis due to invalid or error (failed) results for Idylla MSI Test and/or Promega MSI. For the 323 valid results, overall, positive and negative percentage agreement were 99.7% (98.3%-100%;), 98.7% (92.9%-99.8%) and 100% (98.5%-100%), respectively. A higher number of invalids was observed for Promega MSI (2.1%) compared to the Idylla MSI Test (0.6%) taking into account per protocol retesting (18 retests for Promega MSI (6%) and 3 for Idylla MSI Test (1%)). Conclusions: This study validated the Idylla MSI Test with high performance and low invalid rate to discriminate MSI-H from MSS status on a clinical routine set of CRC samples.
3D in vitro system for measuring treatment responses to immunotherapy in CRC patients.
Authors: Block Andreas , Stamm Hauke , Temovski Tamara Sutus , Konczalla Leonie , Brauneck Franziska , Stange Inke , Koellmann Sandra , Li Jun , Perez Daniel R. , Thastrup Jacob , Wellbrock Jasmin , Fiedler Walter M. , Kupper Juergen , Sturmheit Tabea
Published: May 2019

e15114

Background: Current clinical guidelines for the treatment of cancer patients mainly rely on intrinsic characteristics of a given tumor, such as its localization, its staging and in some instances also known genetic markers. The success of treatment administered according to this proceeding is, however, undermined by large inter-individual variability of tumors. Embedded in a unique meshwork of extracellular matrix, stromal cell and bioactive factors, malignant cells accumulate a distinctive pattern of genetic, epigenetic and metabolic alterations, resulting in unrestricted growth. Despite the potential availability of tailored drugs, matching cancer drug therapy to the unique characteristics of a patient’s tumor, is generally unfeasible in clinical practice. Methods: Addressing this need, 2cureX developed a functional test (IndiTreat) for measuring the responsiveness of micro-tumors (tumoroids) derived from colorectal cancer (CRC) and liver metastases to chemotherapeutic agents, targeted therapies and combinations thereof. To further broaden the applicability of the IndiTreat test, the present study aims to adapt the assay system to functional testing of immunotherapeutics. The success of immunotherapeutic treatment (I/O) regimens is currently limited to a small subset of CRC patients such as those with microsatellite instability (MSI) high tumors. However, new chemo-immunotherapies may prove beneficial for a greater percentage of patients. Results: To pre-therapeutically assess the potential efficacy of I/O interventions for individual patients, we co-culture tumoroids and autologous PBMCs and monitor immune-mediated killing of tumoroids in vitro. Subsequently, these culture systems will be tested regarding their susceptibility towards an array of single or combined I/O drugs. Tumoroids recapitulate the highly individual disease of cancer patients and, as demonstrated by our allogenic setting, constitute a valuable platform for testing different aspects of immune-mediated tumor cell recognition and killing. Conclusions: In light of an increasing number of cost-intensive I/O treatment options becoming available to CRC patients, pre-therapeutic testing of individual responses to immunotherapy will be of key relevance in assisting the oncologist to select the most potent treatment regime for every patient available.
Pattern of expression of CDX2 in colorectal cancer and its role in prognosis.
Authors: SINGH JAGDEEP
Published: May 2019

e15115

Background: CDX2 (Caudal Type Homeobox 2), a nuclear protein, is essential for the proliferation and development of intestinal epithelial cells and is frequently down-regulated during tumourogenesis. We have evaluated the pattern of expression of CDX2 in all stages of CRC (colorectal cancer) and its association with prognosis. Methods: We performed CDX2 staining by Immunohistochemistry (IHC) on the available biopsy block of patients of CRC registered with Medical Oncology, JIPMER, from January 2014-January 2018. CDX2 scoring was done by semi-quantitative method. Results: 286 patients were registered during study period, of which only 110 biopsy blocks were available for staining. Of 110 patients, 77 (70%) constituted colon cancer and 33 (30%) were rectal cancer. The median age was 54.2 years, 62 (56.4%) being male and 48 (43.6%) female with male to female ratio 1.3:1. In the study cohort, 33 (30%) patients had stage II disease, 30 (27.3%) stage III and 47(42.7%) were stage IV. 73 (66.4%) were positive for CDX2 and 37 (33.4%) were negative. Lack of CDX2 expression was significantly associated with advanced stage, rectal site, poor grade of differentiation, and presence of lympho-vascular invasion (LVSI). With median follow-up of 16 months, PFS (progression free survival) at 2 years was 30% for CDX2 negative patients compared to 67% CDX2 positive (P=0.009), while OS (overall survival) at 2 years was 46% for CDX2 negative versus 77% for positive patients (p=0.01). Conclusions: Lack of CDX2 is associated with significantly worse PFS and OS, serves as a poor prognostic factor in CRC. Lack of CDX2 expression is associated with advanced stage, higher tumor grade and presence of LVSI.
Turning on the lights in gastrointestinal oncology: How digital medicines reveal clinical insights on medication adherence and patient behaviors.
Authors: Morales Paul , Beiswenger Daniel , Lee Won Chan , Travis Ellen , Greeno Edward
Published: May 2019

e15118

Background: Oral therapies in colorectal cancer (CRC) introduce unique complexities in care. Understanding adherence in patients using capecitabine can be challenging. The Discover Program, a novel digital medicine program (DMP), was integrated into the treatment of CRC patients at Fairview Health Services and University of Minnesota Health, the first ever DMP in the field of oncology. The DMP consists of DigiMeds (medications with ingestible sensors), a small wearable patch, and a mobile app, which enable collection of objective adherence data, alongside biometrics (e.g., steps, rest, resting heart rate) giving patients, caregivers, and providers the ability to confirm treatment start dates, address missed doses and observe changes in physical function. Methods: From September 2018 to December 2018, patients with CRC were enrolled in the DMP. Clinical pharmacists (CPs) monitored adherence data and patient metrics through a secure web portal to enhance regular follow-up, address barriers to adherence, reveal unreported Adverse Events (AE), provide coaching and education, and target therapy adjustments when appropriate. Qualitative data regarding pharmacists’ experiences with the DMP and their evolving interactions with patients were collected. Results: Seven patients were enrolled in the DMP (mean age: 62.1 ± 8.45 years (mean ± SD); 85.7% female; patch wear: 92.4% ± 6.8%; average adherence: 89.7%± 7.8%; average days on DMP: 55.6± 39.2 days). CPs reported that objective medication adherence data eliminated the challenge of navigating patient recall about their medication taking and health overall. The DMP allowed prompt and tailored interventions for patients struggling with adherence to prescribed regimens and/or AEs. These interventions were more focused, personalized, and clinically meaningful with improved shared decision-making, increased patient engagement/adherence, and more efficient/effective AE management. Conclusions: DMP data yielded significant insights that are not available in the absence of this novel technology. Future pragmatic, large real-world studies are recommended to assess the impact of DMP on adherence, AE management, and clinical and economic outcomes.
RAS mutations in patients with metastatic colorectal cancer in Central America and the Caribbean.
Authors: Garcia-Aceituno Luis , Castro Noe , Alvarado Francisco , Castro Salguero Hugo Raul , Loo Yong Pain , Castro Jenny Lissette , Ramos Pier Angelo , Cabreja Angela Margarita , Rosales Finlander , Barillas Allan , Ramos-Esquivel Allan , Umanzor Jorge , Umanzor Funez Gerardo Antonio , Guardia Mario , Bacon Fonseca Ludwing Alexander
Published: May 2019

e15126

Background: Metastatic colorectal cancer (MCRC) survival has been improved in the last decade due to the identification of predictive and prognostic factors such as RAS gene status and also by the addition of targeted therapies to chemotherapy schemes. RAS mutation, a prognostic factor but must importantly a predictive factor for tumor response to monoclonal antibodies against the epidermal growth factor receptor in MCRC, has been reported between 16.3% and 43.6%. The aim of this study is to determine the frequency of RAS mutations in patients with MCRC in Central America and the Caribbean. Methods: This is a retrospective-descriptive analysis of RAS mutations performed in patients with MCRC in Central America and the Caribbean. An informed consent was required for the mutational analysis. The information obtained has been kept in an anonymized database. Results: 2,138 tissue samples were analyzed by real time PCR. RAS mutations were documented in 46.7% of the cases, of these 94.8% correspond to mutations in kRAS and 5.2% to mutations in nRAS. 67.5% of RAS mutations were found in codon 12, 21.3% in codon 13, 5.8% in codon 146 and 4% in codon 61. 51.5% of the mutations were in males and 48.5% in females. RAS mutations in central american population were identified in a 45.8% and in a 42.5% in the caribbean. Conclusions: This is the first report of RAS mutations in patients with MCRC in Central America and the Caribbean. Our findings are similar to the data reported in other regions of the world. A clinical and epidemiological analysis and correlation of these findings is underway.
Prognostic value of circulating cytokines in colorectal cancer: A prospective study in sixty colorectal cancer patients in Tunisia.
Authors: Ayari Jihene Braham , Guesmi Rania , Balti Mehdi , Ben Azaiz Mouna , Zribi Aref , Fendri Sana , Ben Nasr Sonia , Ghazouani Ezzedine , Agili Faida , Kullab Sharif Ahmed , Haddaoui Abderrazek
Published: May 2019

e15130

Background: Colorectal cancer is the third most common malignancy and fourth most common cause of cancer mortality worldwide. It is responsible for more than 600,000 deaths annually, and incidence rates are increasing in most of the developing countries. Pathophysiology implicates pro-inflammatory conditions that promote the tumor malignant progression, invasion, and metastasis. The aim of this study is to measure the level of circulating cytokines (IL1b, IL6, IL8, IL10, IL22, IL23 and TNFα) in sixty colorectal cancer patients in Tunisia and to evaluate their implication as prognostic factors. Methods: Serum samples were collected prospectively from a cohort of sixty colorectal cancer patients in Tunisia. Levels of circulating inflammatory cytokines, TNF-α, IL1b, IL6 and IL8 were measured using the technique of a solid-phase, two-site chemo-luminescent enzyme immune-metric assay (Immulite 1000, Simens, USA). Serum levels of IL10 were measured by enzyme-linked immunosorbent assays (ELISA) sandwich method. Results: The mean age of patients is 58 years (24–82 years), Thirty-sex among them were m and 24 women with sex ratio of 1.5. Twenty-five patients were at metastatic setting, and hepatic metastasis was found in 25% of cases. The mean level of cytokines Il6, IL10, TNFα, IL8 and IL1b were respectively 12.26 +/- 18.7 pg/ ml (min 2, max 117pg/ ml), 0.93 +/- 5.23 pg/ ml (min 0, max 39.35 pg/ml), 8.31 +/- 4.99 pg/ ml (min 4, max 27.20 pg/ ml), 61.9 +/- 159.71 pg/ml (min 5, max 1173 pg/ ml) and 1.13 +/- 3.34 pg/ ml (min 5, max 15.7pg/ml. We found a significant correlation between a high level of IL8 and metastatic disease (p=0.001), especially in mutant RAS cases (p=0.001). We found also a significant correlation between high level of IL1b and lymphovascular invasion (p=0.013) and young patients (p=0.01). On the other hand, there was significant correlation between IL8 and IL6 (r = 0.560, p = 0.00001); IL8 and TNFα (r = 0.404, p = 0.001); and IL10 with IL1b (r = 0.297, p = 0.021). Conclusions: Our results highlight the role of circulating IL8, TNFα, IL1b and IL10 as potential prognostic biomarkers in colorectal cancer patients. These cytokines could contribute to tumor growth and progression, namely for IL-8 level that was significantly correlated with poor prognosis and advanced stages. This correlation needs to be evaluated in large prospective trials and suggests a rational for the development and use of cytokine blockade in treatment of colorectal cancer patients.
Meat consumption and BRAF mutation status in colorectal cancer.
Authors: Frias Rosa L. , Lam Michael , Overman Michael J. , Morris Van K. , Fogelman David R. , Kee Bryan K. , Dasari Arvind , Raghav Kanwal Pratap Singh , Shureiqi Imad , Jiang Zhi-Qin , Jensen-Loewe Patricia A. , Wolff Robert A. , Eng Cathy , Menter David , Kopetz Scott , Davis Jennifer S.
Published: May 2019

e15135

Background: Consumption of red and processed meat has been associated with increased risk of developing colorectal cancers, but less is known about the association of meat consumption with tumor molecular features. In this study, we tested the association of total meat consumption with molecular features of colorectal cancer and overall survival in a local cohort of patients. Methods: Data on meat consumption were collected using self-directed environmental surveys from patients with stage IV/locally advanced, treatment refractory colorectal cancer who were enrolled on the Assessment of Targeted Therapies Against Colorectal Cancer clinical protocol. Data on tumor molecular features were collected through medical record review. Patients were categorized into low, medium or high meat consumption groups based on servings per day tertile. Associations between tumor molecular features and meat intake were evaluated by Chi-square and logistic regression. Potential effects of meat consumption on overall survival were assessed using Cox Proportional Hazards models. Analyses were conducted with IBM SPSS v25. Results: Patients consumed an average of 0.74, 1.57 and 3.32 servings of meat per day in the low, medium and high categories, respectively. Out of 593 patients with evaluable data, 27 were found to have a BRAF V600E mutation. Total meat consumption differed significantly by BRAF V600E mutation status (p value 0.02) and by sex (p value < .01), but did not differ by tumor location, microsatellite instability, or RAS mutation status. Using logistic regression, we found that compared to patients with the highest level of meat consumption, those in the medium consumption group may be less likely to have a BRAF V600E mutation (OR 0.24; p value 0.08). Although meat consumption may be associated with BRAF mutation status, it was not predictive of overall survival in our analyses. Conclusions: Among patients in our study, meat consumption may be associated with tumor BRAF V600E mutation status but is not directly associated with survival. Additional work is needed to test this association in cohorts including more BRAF mutant cases. If confirmed, this finding may add further insight into the etiology and biology of these tumors.
KRAS mutation and microsatellite instability in colorectal cancer: Screening pattern and mutational landscape across the US.
Authors: Uhlig Johannes , Stein Stacey , Lacy Jill , Kim Hyun S.
Published: May 2019

e15138

Background: To assess screening patterns for KRAS mutation and microsatellite instability (MSI), associated mutational prevalence in colorectal cancer (CRC), and whether mutational screening affects survival. Methods: Patients with adenocarcinoma of the colon, sigmoid, and rectum were included from the 2010-2015 National Cancer Database. Socioeconomic, geographic and cancer factors were correlated with screening patterns. Propensity score matching was used to account for confounding. Overall survival was assessed in the matched cohort via Cox proportional hazards models. Results: 371,669 patients were included, of which 113,197 (30.4%) were screened: n=63,967 for MSI, n=33,319 for KRAS, and n=15,911 for MSI + KRAS. Younger patients with private insurance, high income locally advanced and metastatic sigmoid CRC treated at academic centers in Middle Atlantic and New England states were more likely to be screened. MSI was more prevalent among older female Caucasians from East South Central and Middle Atlantic States. KRAS mutation showed no significant discrepancies according to patient age or US geography, but was more prevalent among female African Americans. KRAS mutation was associated with locally advanced and metastatic CRC. MSI was more common in localized, non-metastatic CRC. Distinct mutational patterns were evident among primary CRC sites, with highest mutation rates in cecum/appendix and ascending colon (table). In the propensity score matched cohort with balanced distribution of confounders (n=157,678), mutational screening was not associated with overall survival (HR=1.012, 95% CI: 0.99-1.03, p=0.15). MSI versus MSS did not significantly influence patients´ overall survival (matched cohort n=26,014, HR=1.00, 95% CI: 0.96-1.05, p=0.88). Kras mutation versus wildtype showed decreased overall survival after accounting for confounders (matched cohort n=28,084, HR=1.11, 95% CI: 1.07-1.15, p<0.001). Conclusions: Testing for MSI and Kras mutation in CRC shows distinct patterns across the US, but does not influence outcomes. Decreased overall survival is observed in those patients with Kras mutation versus wildtype. [Table: see text]
Colorectal cancer in young patients: An institutional experience.
Authors: Hanayneh Wissam , Wang Yu , George Thomas J. , Cameron Miles , Tan Sanda , Iqbal Atif , Read Thomas , Allegra Carmen Joseph , Parekh Hiral D.
Published: May 2019

e15140

Background: The incidence of colorectal cancer (CRC) in young patients (<50 years) is increasing but little is known about disease characteristics and treatment outcomes in this patient population. Methods: CRC patients diagnosed at < 50 years of age (UF registry 2000-2017) constituted the IRB approved study cohort. Statistical methods included descriptive statistics, uni-variable cox proportional hazard regression model, Pearson chi-square exact and Wilcoxon rank-sum test. Results: Young CRC patients (n= 286) comprised 16% of total CRC patients (n= 1806) treated at our institution. (See Table for demographics and tumor characteristics). The median age at diagnosis was 45 years (range 17-50) with 74% diagnosed between age 40-50. One third (35.7%) of patients had rectal primary. DNA mismatch repair gene deficiencies (dMMR) and/or microsatellite instability (MSI) was tested in 60.1%; 10.5% had MSI-H or dMMR tumors and 11 of those had confirmed Lynch syndrome. Next generation sequencing (n= 71) or mutational analysis (n= 79) was performed. Most common mutation was exon 12 of K- ras (40.7%, n = 61) followed by TP53 (7.33%; n = 11) and PIK3CA (5.33%; n = 8). BRAF V600E was seen in 5 patients. Patients who underwent curative resections had better hemoglobin (p=0.005), albumin levels (p <0.001) and lower CEA level (p<0.001). Factors associated with poor survival were low albumin ≤34 g/l, advanced primary tumor (T3/T4), nodal disease (N1/N2) and presence of diffuse metastases. For stage 4 disease, the cancer-specific survival (CSS) at 1 year was 77.2%, 3-year CSS was 46.1% and 5-year CSS was 29%; survival was better (HR=0.4; 95% CI 0.2-0.6, p<0.001) among patients who underwent metastatectomy. Conclusions: Our results reveal that the most young CRC were 40-50 years age group with a female preponderance. Young CRC patients were more likely to be managed in an aggressive manner with a higher proportion of early stage patients receiving perioperative therapy. A suggestion of an improved CSS was seen in advanced stage disease even with similar prognostic factors. Review of larger data sets are warranted. [Table: see text]
Metastatic pattern and tumor sidedness in colorectal cancer.
Authors: Muzaffar Mahvish , Naqash Abdul Rafeh , Liles Darla K. , Kachru Sumyra
Published: May 2019

e15147

Background: Tumor side has emerged as an important prognostic and predictive factor in metastatic colon cancer. We sought to study its impact on the metastatic pattern of colorectal cancer. Methods: The SEER database (version 8.3.5) was reviewed for patients with Stage IV colorectal cancer diagnosed between 2004-2015. We only included patients with labeled primary site, and excluded appendiceal, unlabeled and autopsy alone cases. Variables included in the analysis were: age, race, gender, grade, primary tumor side and sites of metastasis at diagnosis. Primary outcome analyzed was overall survival and disease specific survival.Cox proportional hazard regression model was employed to test the association between survival and side of cancer/ site of metastasis. Results: A total of 74,768 cases were identified who met the eligibility criteria. The mean age was 68.5 yrs. for right colon cancer (RCC),64.0 yrs. for left colon cancer (LCC). and 62.9 yrs. for rectal cancer. White race was predominant group for RCC, LCC and rectum. More females were vs men in RCC (52% vs 48%), LCC (44% vs 56%) and rectum (60% vs 40%). (The cox regression model suggested inferior outcome for black race HR 1.05(1.03-1.07) (<0.001), high grade HR 1.32(1.30-1.35) p<.0001, right side tumors HR 1.23(1.21-1.250, p <.0001 (table). Conclusions: Over last few years tumor sidedness has emerged as an important prognostic and predictive factor in colon cancer. Our study also highlights the impact of sidedness on survival irrespective of distant metastatic pattern. This analysis contributes to the ongoing discussion that right and left colon cancer are two distinct disease entities. Impact of primary tumor side and metastatic site on survival in colorectal cancer. [Table: see text]
IGF-1 and IL-6 as predictors of sarcopenia in non-metastatic colorectal cancer patients.
Authors: Khaddour Karam , Castellanos Karla , Fantuzzi Giamila , Mutlu Ece , Gomez-Perez Sandra L
Published: May 2019

e15150

Background: Insulin growth factor-1 (IGF1) and inflammatory biomarkers such as interleukin-6 (IL6) play a role in early carcinogenesis, predict prognosis and response to some therapies in colorectal cancer (CRC), and are altered in patients with sarcopenia. This study examines the association of IGF-1 and IL-6 with sarcopenia in patients with CRC. Methods: Fasting blood samples were collected at diagnosis of non-metastatic CRC (N = 59) and analyzed for serum IGF-1 and IL-6 by ELISA. Skeletal Muscle Index (SMI) was calculated from cross-sectional image at L3 from computed tomography. Sarcopenia was defined based on published cut points for adults with cancer stratified by body mass index (BMI) as: SMI < 43 cm2/m2 for men and < 41 cm2/m2 for women for normal and underweight; and SMI < 53 cm2/m2 for men and < 41 cm2/m2 for women for overweight and obese. Median and interquartile range (IQR) were reported for patients with sarcopenia versus those without sarcopenia. Spearman and logistic regression were used to examine associations between sarcopenia and serum biomarkers. Results: Median (IQR) age was 62 (49-85). Overall prevalence of sarcopenia was 44% (26/59). The prevalence of sarcopenia was 3% for males (2/59) and 5% for females (3/59) with a BMI < 25 and 27% for males (16/59) and 8% for females (5/59) with a BMI≥25. Median and (IQR) for serum biomarkers in patients with CRC and sarcopenia versus those without sarcopenia were: IGF-1 43 (16) vs. 58.7(27.9) ng/mL (p = 0.007). Correlation between IGF-1 and sarcopenia was (r = -0.4, p = 0.004), but was not statistically significant for IL-6 (r = 0.02, p = 0.88). Both IGF-1 (OR = 0.82, 95% CI 0.69-0.98, p = 0.03) and IL-6 (OR = 0.83, 95% CI 0.70-0.98, p = 0.002) were significant predictors of sarcopenia after adjusting for race and BMI. Conclusions: In this sample of patients with CRC, IGF-1 and IL-6 levels were both lower in patients with sarcopenia compared to those without sarcopenia and levels of both markers predicted the presence sarcopenia.
Clinicopathological description of a subset of schistosoma mansoni associated colorectal cancer patients in an endemic area in Brazil.
Authors: Almeida Gustavo Fernandes Godoy , Freitas Mauricio Assuero Lima de , Lira Mariana M M , Domingues Ana Lucia Coutinho , Neares Lais , Silva Lauro Vinicius Machado da , Moura Maxwell , Maior Marcelo , Mattos Luiz Alberto Reis ,   ASQO - Advanced Support for Quality-of-life in Oncology
Published: May 2019

e15154

Background: Schistosoma have been implicated in colorectal carcinogenesis. We aim to describe clinicopathological description of a subset of Schistosoma mansoni-associated colorectal cancer patients in an endemic area in Brazil. Methods: We have performed a survey at cancer registry and identified those colorectal cancer patients who underwent biopsy and/or surgery in our institution in the last 10 years. We performed a comparison between Schistosoma- and non-Schistosoma colorectal cancer patients. T-test were performed to compare clinico-pathological features. Results: 300 hundred patients were identified. From this population, 83 patients had encounters at gastroenterology unit, where schistosoma patients (among those with other diseases) are treated. Among them, 7 patients presented both conditions (colorectal cancer and schistosomiasis), corresponding to 8.4% of these selected population. We identified diferences among Schistosoma- and non-Schistosoma colorectal patients neither in age of cancer diagnosis nor in terms of laterality. We did not find diferences in terms of metastatic disease rate between both populations, however, we have observed a higher incidence of limph node metastasis among Schistosoma colorectal patients. Conclusions: Schistosoma colorectal patients present similarity in terms of age of cancer diagnosis and laterality when compared to non-Schistosoma colorectal patients, however, lymph node metastasis are increased in this population. Next publications from our group will provide information about survival curves and genetic profile.
Reirradiation and/or surgery for locoregionally recurrent rectal cancer: A systemic review and meta-analyses.
Authors: Rim Chai Hong , Lee Jeongshim
Published: May 2019

e15159

Background: Locoregional recurrence of rectal cancer (LRRC) might be occurred even after combination treatments including surgery and pelvic radiotherapy. Re-irradiation might provide the control of recurrence and/or symptomatic palliation, but possible complications are fearful hindrances. This study is to integrate information from various clinical studies, regarding re-irradiation and/or surgery of LRRC, and to provide practical information for clinical decision making. Methods: We searched four databases including pubmed, MEDLINE, Cochrane library, and Embase. The primary endpoint was overall survival (OS), and secondary endpoints were complications of grade ≥3, local control rate (LC), and symptomatic palliation rate. Results: A total of 17 studies, involving 18 cohorts and 744 patients with LRRC were included. Median OS among included studies ranged from 10 to 45 months (median: 24.5 months). Pooled 1-, 2-, and 3- year OS rates for all LRRC patients were 76.1% [95% confidence interval (CI): 61.7-86.3], 49.1% (38.5-59.7), and 38.3% (30.2-47.2), respectively. For patients who underwent re-irradiation and surgery (OP group), pooled 1-, 2-, and 3- year OS rates were 85.9% (95% CI: 74.0-92.9), 71.8% (54.6-84.4), and 51.7% (39.4-63.8). For patients who underwent re-irradiation but not surgery (non-OP group), pooled 1-, 2-, and 3-year OS rates were 63.5% (95% CI: 51.1-74.4), 34.2% (20.4-51.2), and 23.8% (15.4-34.8). The difference between two subgroups were significant for all 3 years analyses. Pooled 1-, 2-, and 3- year LC rates for OP group were 84.4% (95% CI: 75.5-90.4), 63.8% (55.2-71.5), and 46.9% (39.6-54.4), and for non-OP group were 72.0% (95% CI: 48.8-87.4), 54.8% (28.6-78.5), and 44.6% (16.6-76.5). The difference between subgroups were not statistically significant for all 3 years analyses. Pooled overall grade ≥3 acute complication rate was 11.7% (95% CI: 6.7-19.5), and for late complication was 25.5% (95% CI: 16.7-40.0). Patients who underwent surgery had a higher risk of grade ≥3 late complications (OR: 6.39, 95% CI: 3.2-12.7). Pooled symptomatic palliation rate was 75.2% (95% CI: 67.3-81.8). Conclusions: Re-irradiation and/or surgery might be an option with oncologic and palliative efficacies, where combined surgery provided more favorable survival outcome. However, late complication should be carefully considered especially when combined with surgery.
Prognostic impact of SOX9 in stage II colon cancer: Results from a large nationwide cohort.
Authors: Hansen Torben , Kjær-Frifeldt Sanne , Eriksen Ann Christina , Lindebjerg Jan , Jensen Lars Henrik , Jakobsen Anders Kristian Moeller , Sørensen Flemming Brandt
Published: May 2019

e15165

Background: Up-regulation of the transcription factor SOX9 has been described in colon cancer, and it has been argued that differences in the expression levels dictates cell proliferation. The aim of the present study was to analyze the prognostic impact of SOX9 in stage II colon cancer. Methods: Individual patient data and formalin fixed paraffin embedded tumor tissue were collected from a large unbiased, population-based cohort, representing all patients operated for stage II colon cancer in Denmark in 2002 and 2003. The SOX9 expression was evaluated by immunohistochemistry on whole tumor sections. Patients were classified into three groups dependent on the SOX9 expression gradient in the tumor: luminal, peripheral, and uniform for comparison with the clinical data. The endpoint was disease free survival (DFS). Results: A total of 1,153 patients were included. We detected an expression-dependent relationship between SOX9 and prognoses. Patients with tumors exhibiting a luminal expression pattern (N = 267, increasing SOX9 expression towards the luminal compartment of the tumor) were characterized by a significantly better DFS compared to the uniform (N = 846) and peripheral (N = 40) patterns, p = 0.0070. The five-year DFS rates were 74%, 67%, and 56%, respectively. Multiple Cox regression analysis, adjusted for all standard high risk factors, confirmed an independent prognostic advantage of the luminal SOX9 expression pattern, as compared to the uniform pattern, hazard ratio (HR) 0.7211 (95% confidence interval (CI) 0.5561-0.9351), p = 0.0137, whereas the possible disadvantage of the periphery pattern could not be verified, HR 1.4393 (95% CI 0.8869-2.3660), p = 0.1405. Conclusions: The present results support a prognostic impact of SOX9 in stage II colon cancer. The consequence of an altered SOX9 expression seems to differ between intra-tumoral compartments, and we propose that a gradient-dependent evaluation should be applied to provide the most clinically relevant information about this transcription factor.