bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of 16S rRNA sequencing in advanced colorectal cancer tissue samples.
Authors: An Hojung , Partha Mira A. , Lee Hojoon , Lau Billy , Shin Giwon , Almeda Alison Figueroa , Ji Hanlee P. 
Published: January 2022

163 Background: Changes in the colon’s microbiota composition are contributors to the pathogenesis of colorectal cancer (CRC). Features of this microbiome may have prognostic significance. For this study, we analyzed 16S rRNA sequencing data from tumor tissue samples of advanced CRC patients and determined if there were potential correlations between microbiome composition and clinical outcomes. Methods: One hundred and thirty three advanced CRC patients in St. Vincent’s Hospital in Korea were enrolled. DNA was extracted from collected tissue samples, the V3-V4 regions were amplified, and a 16S rRNA gene amplicon library was prepared using an Illumina protocol. DNA was sequenced on an Illumina MiSeq instrument. We used three different bioinformatic packages to process the sequence data and evaluate the microbiome composition of each tumor. Results: The classification performances of three different analytic pipelines (Kraken2, QIIME2, and DADA2) were compared in a microbiome control sample. Among these, DADA2 and QIIME2 were chosen for use in subsequent analysis, due to their lower Chi-square (χ2) test statistic values on the control data. After excluding samples that retained less than 5% of total reads after merging, 120 samples were analyzed. The median age of the cohort was 63 years, 63.3% were male, and all were Korean. The distribution over primary sites was 27.5% from the right-side colon, 30.8% from the left-side colon, and 41.7% from the rectum. All subjects received the first line of systemic treatment. The median progression-free survival time was 8.9 months. Twenty-nine patients (24.2%) survived more than 24 months. When examining the results from the two bioinformatic packages, pairwise comparisons showed positive correlations in the relative abundances of the top 20 genera. Fusobacterium, a microbe known to relate to pathogenesis and prognosis of CRC, was not detected by QIIME2. Stratifying by primary site, rectal cancers showed higher alpha diversity than left- or right-side colon cancers. Separately, a higher serum CEA level (≥8) at diagnosis, and the presence of lung metastasis were both found to be related to higher alpha-diversity, a global indicator of microbiome composition. When excluding minimally abundant (< 1% per patient) genera, beta-diversity was found to be differentiable by T stage, the presence of lung metastasis, and the presence of liver metastasis. Most notably, beta-diversity differed between patients who survived more than two years and patients who died within 2 years. Using the DADA2 results, we confirmed that the presence of Fusobacterium nucleatum in CRC tissue was found to be a strong predictor of poor overall survival (OS), along with old age and liver metastasis. Conclusions: This study suggests potential associations between microbiome composition and clinical parameters of advanced CRC. Microbial biomarkers may be a valuable prognostic tool in this population.
Use of ascites CEA as a predictive value for distant metastasis in high-risk stage II and III colorectal cancer.
Authors: Lee Chul Seung , Lee In Kyu 
Published: January 2022

164 Background: Adjuvant chemotherapy in patients with high-risk stage II and III colorectal cancer prevents recurrence by eliminating minimal residual disease. However, patients who are at high risk of recurrence after completing standard adjuvant therapy are currently unknown. Although ascites CEA level has been associated with long-term oncologic outcomes, the clinical significance of ascites CEA in high-risk stage II and stage III colorectal cancer (CRC) has not yet been described. The present study aimed to determine the long-term oncologic impacts of ascites CEA level after curative colorectal cancer. Methods: A total of 191 patients with stage II/III CRC were included in this study, between January 2015 and December 2018. CEA of peritoneal fluid sampled at the beginning of each operation was analyzed. long-term oncologic outcomes were analyzed with the known risk factors for recurrence in CRC. Results: Multivariate analysis of recurrence revealed that lymphatic invasion (HR 6.0, 95% CI 1.1–32.0, p = 0.04), vascular invasion (HR 2.9, 95%CI 1.0–8.0, p = 0.04), mucinous cancer (HR 5.5, 95% CI 1.6–18.4, p = 0.006), and peritoneal fluid CEA above 5 ng/dl (OR 4.2, 95% CI 1.2–15.0, p = 0.008) were significant risk factors (Table). Peritoneal fluid cytology, microsatellite instability, cancer obstruction did not significantly impact DFS in stage II/III CRC. There were 14 patients with liver metastasis, among them, 11 patients without peritoneal metastasis; they had high ascites CEA level. While 8 patients had lung metastasis, 7 of them confirmed high ascites CEA levels. Conclusions: Our results indicate that the ascites CEA may predict as an important biomarker to identify those at risk of distant metastasis in high-risk stage II and stage III CRC patients. We suggest ascites CEA analysis might be included in patient risk assessments and oncologic prediction tools.
Circulating nucleosomes for detection of colorectal cancer and high-risk advanced adenomas.
Authors: Chang Li-Chun , Herzog Marielle , Hardat Nathalie , Pamart Dorian , Chiu Han Mo 
Published: January 2022

169 Background: Detection and treatment of early colorectal cancer (CRC) or advanced adenomas (AA) is the key for superior outcomes and fecal immunochemical testing (FIT)-based screening has proven effective in reducing CRC death and the risk of advanced-stage CRC but the discrepancy in the effectiveness was observed between proximal and distal cancers. On the other hand, false-positive results of FIT with 60 % of negative colonoscopy is another concern, considering the burden to the screening participants and the healthcare providers. A blood-based test as an alternative or supplement to FIT has the potential to concurrently enhance the detection of high-risk neoplasms and identify individuals at risk who should then be referred to colonoscopy. We investigated the levels of circulating free nucleosomes containing different epigenetic modifications in patients referred for colonoscopy. Methods: 10mls whole blood was obtained from 520 asymptomatic patients prior to colonoscopy at National Taiwan University Hospital. Patients were classified into 5 groups based on their colonoscopy reports: (i) patient with CRC (n = 33), (ii) patients with AA (n = 123, including 18 with AA > 2cm); (iii) patients with non-AA (n = 168); (iv) patients with non-neoplastic polyps (n = 30); (vi) healthy controls with no endoscopic lesion (n = 166). Plasma samples were analyzed for nucleosome levels using 7 different quantitative immunoassays (Nu.Q assays; Belgian Volition SRL, Belgium) targeting H3.1-nucleosomes or different histone modifications (H3K27Me3-, H3K36Me3-, H3K9Me3-, H3K14Ac-, H3K27Ac- or H3R8Cit-nucleosomes). All study subjects were asked to collect a stool sample at home within 48-hours before the colonoscopy. The fecal samples were assayed with the Eiken OC-SENSOR FIT kit (Eiken Chemical Co., Ltd., Tokyo, Japan) for all study subjects. Results: At a cut-off of 20µg/g feces, the FIT test showed a sensitivity of 92,9% at 17.5% specificity for CRC +AA vs. Controls. All the CRC patients and 83.3% of the high-risk AA (> 2cm) patients were FIT positive. A combination of 2 Nu.Q biomarkers: H3K27Me3 and H3R8Cit with FIT in a logistic regression model showed improved sensitivity of 95% at 20.6% specificity allowing the detection of all CRC patients and 94.3% of AA patients including all the high-risk adenomas. The FIT test detected 46 out of 55 proximal adenomas whereas the combined model could detect 50 proximal adenomas including 3 proximal AA > 2cm not being detected by FIT (p < 0.05). The same combination would reduce unnecessary colonoscopies by 21.8% of the control and 23.3% of the non-neoplastic polyps subgroups compared to 17.5% and 6.7%, respectively with the FIT test alone. Conclusions: Our results indicate that H3K27Me3 and H3R8Cit-nucleosome levels in combination with FIT could improve the detection of proximal high-risk AA and could also provide a non-invasive method to reduce unnecessary colonoscopy.
The prevalence of common KRAS variants and associated outcomes in patients with metastatic colorectal cancer (mCRC).
Authors: Musselwhite Laura W. , Trufan Sally J. , Kadakia Kunal C. , Hwang Jimmy J. , Salem Mohamed E. 
Published: January 2022

173 Background: KRAS is the most common driver oncogene in mCRC. Comprehensive analysis of KRAS variants prevalence and the relationship between variants and outcomes are lacking. Herein, we aimed to examine the impact of KRAS variants on outcomes in patients (pts) with mCRC. Methods: A retrospective review of pts with mCRC with known KRAS mutation status was performed. Fisher’s exact test was used to analyze the association between KRAS variants. Cox Proportional Hazard modeling was used to study the relationship between KRAS variants and overall survival (OS). Kaplan-Meier method was used to assess OS. Results: A total of 423 pts diagnosed with mCRC from 2014-2020 with available extended KRAS status were evaluated. Median age at diagnosis was 59.8 yrs (22.3-92 range), 57% were male, 22% were Black, and 75% presented with de novo metastatic disease. A majority (56%) of tumors harbored KRAS mutations. The most frequent KRAS variants were G12D 47% (111), G12V 12% (28), G12C 13% (31), G13D 9% (21), and 20% (47) were other variants. In univariate analyses, the presence of a KRAS mutation, Black race, de novo metastatic disease, age, receipt of chemotherapy, and receipt of surgery were associated with OS. Tumor location was not associated with OS. In multivariable analyses, mutation type was a significant predictor of death and the presence of G12D was associated with an increased risk of death compared to G12V and KRAS wildtype. There was no increased risk of death in pairwise comparisons of G12D and G13D or other KRAS variants. Black race, de novo metastatic disease, and no receipt of surgery were additional independent predictors of death (Table). With a median follow-up of 25.7 months (mo.), median OS was 35.5 mo. (95% CI 10.5-50.9) with G12C, Not Reached (NR) (95% CI 21-NR) with G12V, 36.2 mo. (95%CI 14.9-58.5) with G13D, 26.2 mo. (95% CI 21.8-37) with G12D, 39.6 mo. (95% CI 22.4-47.9) for other KRAS mutations, and 59.6 mo. (95%CI 48.2-NA) for KRAS wildtype, respectively (p=0.0003). Conclusions: Our findings highlight differences in unadjusted overall survival when comparing G12D to some other KRAS variants. Codon and amino acid-specific mutations of KRAS should be considered when evaluating prognosis and further study on treatment effects and sequencing is warranted. [Table: see text]
Association of BRAF V600E mutation with survival in patients with metastatic mismatch repair-deficient colorectal cancer.
Authors: Tan Elaine , Whiting Junmin , Xie Hao , Imanirad Iman , Carballido Estrella M. , Felder Seth , Frakes Jessica M. , Mo Qianxing , Walko Christine Marie , Permuth Jennifer , Kim Richard D. , Anaya Daniel A. , Fleming Jason B. , Sahin Ibrahim Halil Halil 
Published: January 2022

174 Background: Colorectal cancer (CRC), while one of the most common cancer diagnoses, can behave heterogeneously based on molecular characteristics. A subset of patients (pts) with CRC are characterized with mismatch repair deficiency (MMR-d), these pts exhibit encouraging responses to immunotherapy. The predictive nature of various factors, such as BRAF status, age, and MMR-D protein loss type, have been investigated in pts with MMR-d CRC. However, the prognostic role of these factors has not been well established. The purpose of this study was to identify characteristics that influence survival in MMR-d mCRC. Methods: This study evaluated pts with MMR-d mCRC in the Flatiron database. Overall survival (OS) was determined from date of diagnosis of stage IV disease to date of death and stratified based on age greater than or less than 50 years, BRAF mutation status, RAS mutation status, and type of MMR gene loss. For statistical analysis, the Chi-Square test was implemented to determine the prognostic significance of clinical and molecular features. Univariate and multivariate analyses were determined through the Cox regression model. Results: There were 1,101 pts in the study. The majority of pts were older than 50 (79.7%), Caucasian (75%), and had ECOG 0-1 (83.4%). Among the 803 pts with known BRAF status, 44.3% (n=356) had BRAF V600E mutation and 55.7% (n=447) were BRAF wildtype. Pts with BRAF V600E mutation had OS of 18.9 months vs. 33.2 months for pts with wild type BRAF (HR 1.52, 95% CI: 1.25-1.86, p<0.001). Pts older than 50 had a lower median OS vs. those who were ≤50 at 21.4 months vs. 38.7 months (HR 1.66, 95% CI: 1.33-2.07, p<0.001). When comparing MSH2/MSH6 mutations to MLH1/PMS2, a trend towards improved OS was seen with median survival of 35.2 months vs. 22.7 months, respectively (HR 0.79, 95% CI: 0.61-1.02, p=0.067). On multivariate analysis, BRAF mutation and older age continued to be associated with differences in survival, while KRAS mutation and specific MMR gene loss did not. Conclusions: BRAF V600E mutation and age greater than 50 are associated with decreased survival for pts with MMR-D mCRC. KRAS mutations and specific MMR alterations are not associated with differences in survival.
ENDOV upregulation and outcomes in females with colorectal adenocarcinoma.
Authors: Bhan Chandur , Sun Chenyu , Bheesham Nimarta , Shakuntulla Fnu , Siddiqui Zain I. , Tuason John Pocholo W. , Paudel Arpana , Ahmed Marwan K. , Kim Na Hyun , Memon Burhan , Mohammed Abdul Humaed , Gerais Yasmin A. , Prasad Apurwa , Abid Qurrat-ul-ain 
Published: January 2022

175 Background: Colorectal adenocarcinoma (COAD) is a common cancer in gastrointestinal tract. Endonuclease V (ENDOV), an enzyme with specificity for deaminated adenosine (inosine) in nucleic acids, was found to be involved in the development of certain cancers. Thus, this study was performed to explore the effects of ENDOV on the prognosis of COAD. Methods: RNA-sequencing FPKM data and corresponding clinical information of 41 normal tissues and 480 tumor tissues of COAD were acquired from The Cancer Genome Atlas (TCGA). Then ENDOV expression differences between the normal and cancer tissues were compared with Wilcoxon rank-sum test via ‘limma’ package. Overall survival (OS) and disease specific survival (DSS) analyses were conducted by Kaplan–Meier (K–M) method via ‘survminer’ package. Subgroup analyses of different genders were also performed. Results: The expression of ENDOV was downregulated in tumors compared with normal tissues (p < 0.001). However, higher expression of ENDOV is associated with worse OS (HR: 1.83, 95%CI: 1.23-2.73, P = 0.003) and DSS (HR: 1.75, 95%CI 1.06-2.91, P = 0.03). Subgroup analysis found that higher expression of ENDOV was associated with worse OS (HR: 2.17, 95%CI 1.18-3.98, P = 0.012) in females, but not in males (HR: 1.48, 95%CI 0.86-2.53, P = 0.158). As for DSS, higher expression of ENDOV was also correlated with worse outcome (HR: 2.36, 95%CI 1.07-5.19, P = 0.033) in females, but not in males (HR: 1.45, 95%CI 0.73-2.86, P = 0.287). Conclusions: ENDOV is overall downregulated in COAD tumor samples. However, higher expression of ENDOV in certain COAD patients is associated worse OS and DSS in females but not in males. This indicates the potential role of ENDOV in predicating the prognosis of COAD in female patients.
Clinical usefulness of postoperative serum carcinoembryonic antigen in colorectal cancer patients with liver metastases.
Authors: Yoshino Koichiro , Osumi Hiroki , Shinozaki Eiji , Ito Hiromichi , Kamiimabeppu Daisaku , Ooki Akira , Wakatsuki Takeru , Shimozaki Keitaro , Nakayama Izuma , Ogura Mariko , Takahari Daisuke , Chin Keisho , Oba Atsushi , Ono Yoshihiro , Sato Takafumi , Inoue Yosuke , Takahashi Yu , Yamaguchi Kensei 
Published: January 2022

178 Background: Colorectal cancer with liver metastases (CLM) has high post operative recurrence rates, and optimizing the perioperative treatment is imperative. Post operative carcinoembryonic antigen (CEA) can help detecting minimal residual disease in colon cancer after curative resection. Methods: The aim of this study was to identify the potential role of serum CEA after liver resection in patients with CLM. This study was conducted at the Cancer Institute Hospital, Japanese Foundation for Cancer Research from 2004 to 2018. Patients with CLM who underwent complete resection of primary tumors and liver metastases were enrolled in this study. We studied the associations between the perioperative CEA levels and characteristics of recurrence. Results: Recurrence was detected during the median follow-up time of 50.9 months in 343 (54.1%) of the total 633 patients analyzed. Patients with postoperative CEA (>5) group had a significantly higher recurrence rate (75.7% vs 50.0%, p < 0.01), with a shorter time until recurrence (4.4 months vs 36.9 months, p < 0.01) than those with a postoperative CEA level (≤5) group. In multivariate analysis, a postoperative CEA level >5 ng/ ml was an independent predictor, with the highest hazard ratio for both recurrence free survival (RFS) and overall survival (OS) (RFS: 2.77, 95% confidence interval [CI] 2.14–3.60, p <0.01, OS: 3.18, 95% CI 2.41–4.19, p <0.01). In addition, there was a significantly shorter RFS in the postoperative CEA level (>5) group who did not have normalized CEA levels after adjuvant chemotherapy compared to normalized CEA group (3.3 months vs 18.5 months, p = 0.008). Conclusions: The postoperative CEA and postadjuvant chemotherapy CEA level in the CEA level (>5) group after surgery may be a predictor of RFS and OS.
Medullary carcinoma of the colon: A comprehensive analysis of a large cancer database.
Authors: Jabbal Iktej Singh , Nagarajan Arun , Rivera Carlos , Yaghi Marita , Liang Hong , Nahleh Zeina A. , Bejarano Pablo , Berho Mariana , Wexner Steven 
Published: January 2022

180 Background: Medullary carcinoma (MC) of the colon was described first in 1999 and is characterized by undifferentiated sheets of epithelial cells in a solid growth pattern with pushing borders and prominent lymphoplasmacytic infiltrates. It frequently shows microsatellite instability (MSI). However, the clinicopathological and survival outcomes between MC and the more common adenocarcinoma of the colon (AC) are not well defined in a large database. Therefore, we used a large national registry to explore the association of survival characteristics with sociodemographic, geographic, and disease variables in this cohort of patients. Methods: We sampled the National Cancer Database (NCDB) for colon cancer patients diagnosed with MC from 2004-2018. Multivariate cox regression models were used to compare hazard ratios for demographic, geographic, and disease characteristics. In addition, Kaplan-Meier survival plots were utilized to assess survival rate differences between MC and AC tumors located in the ascending, transverse, or descending colon. A p-value<0.05 was considered statistically significant. Results: Only 2,709 (0.29%) of the 922,667 patients with AC had MC. MC was seen in older patients than AC (76 vs. 69 years). MC was also more common in females than AC (72.5 vs. 49%). The most striking finding in our analysis was the predominance of poorly differentiated (63%) and undifferentiated (21.7%) pathologies in MC. This was in sharp contrast to AC, where 15.8% of patients were poorly differentiated, and only 2% were undifferentiated. Furthermore, undifferentiated and poorly differentiated MC tumors had a poor prognosis (HR 1.45, 95% CI 1.26-1.68, p<0.001 and HR 1.44, 95% CI 1.29-1.62, p<0.001 respectively) as compared to the other histological grades. Another notable finding in our analysis was the high prevalence of MSI in MC vs. AC (82.4% vs. 25.9%). Cecal MC (HR 1) had the worst prognosis of any colonic site. Left-sided MC tumors also had an inferior prognosis compared to AC (63.21 vs. 87.72 months), although not statistically significant (p=0.217). Conclusions: Colon cancer presenting as undifferentiated or poorly differentiated with associated MSI should raise the possibility of a medullary carcinoma diagnosis. However, given the rarity and difficulty in its pathological delineation, MC may remain underdiagnosed. In the modern treatment era, with the approval of immunotherapy for metastatic MSI colon cancer patients, survival and outcomes for metastatic MC may be improved.
A single-center comparative surveillance strategies of ctDNA (Signatera), imaging, and CEA in the surveillance of resected colorectal cancer.
Authors: Sandhu Jaideep Singh , Wang Chongkai , Chen Yi-Jen , Chevalier Dawnyel , Walia Sabrina , Kim Jae Y. , Melstrom Kurt , Kaiser Andreas M , Fakih Marwan 
Published: January 2022

200 Background: Signatera (S) assay is a CLIA certified minimal residual disease ctDNA assay that has become widely used for monitoring of disease relapse in patients (pts) with resected colorectal cancer. In a longitudinal study, S+ recurrence (SR) occurred at median > 10 months (mo) prior to radiographic disease recurrence (RDR) in a prospective clinical trial. However, the radiographic surveillance frequency in that study was inadequate by US standard practices. Methods: We retrospectively evaluated, in a single center, the sensitivity (ss), specificity (sp), positive predictive value (ppv) and negative predictive value (npv) of S, CT/MRI imaging (Im), and CEA in curatively resected stage II, III, IV pts against True Disease Recurrence (TDR). We considered TDR as any SR, RDR confirmed by pathology, RDR associated with CEA elevation, or RDR with sequential growth on imaging or regression with chemo. S and CEA were performed Q3 mo x 2 yrs and then Q6 mo x 3 yrs. Im was performed Q3 mo x 2 yrs and then Q6 mo x 3 yrs in resected stage IV, Q6 mo x 2 yrs and then Q yr x 3 in stage III/high-risk stage II, and Q yr x 5 yrs in low-risk stage II. Results: 48 pts underwent curative resection (31 stage II-III, 17 stage IV). 15 patients recurred during surveillance (6 stage II-III, 9 stage IV). The ss, sp, ppv, and npv of S, Im, CEA, and (Im and/or CEA) are tabulated below. S, Im, CEA, and Im or CEA were positive for recurrence at the diagnosis of TDR in 8, 9, 4, and 12, respectively. S sensitivity was poor for lung recurrence with 5/6 pts with lung-only mets (3 confirmed by path) being negative by S at the time of Im relapse. S was negative at the time of CNS recurrence and liver recurrence in 2 pts. 2 Pts with negative imaging at SR developed subsequent liver metastases. 2 Pts, counted as TDR, were SR and remain NED without any therapy, by CEA and Im > 1.5 years from S positivity. Conclusions: S does not appear to provide definitive advantages as a surveillance strategy over standard Im frequency- when performed as per NCCN guidelines. Sensitivity of S is particularly poor for low volume lung-only disease recurrence.[Table: see text]